Post on 11-Mar-2019
Pharmaceutical Services DivisionMinistry of Health Malaysia
Pharmaceutical Services DivisionMinistry of Health Malaysia
Lot 36, Jalan University,46350 Petaling Jaya,Selangor Darul Ehsan.
Tel : +603 7841 3200 Fax : +603 7968 2222Website : www.pharmacy.gov.my
Paediatric Pharmacy Services Guideline2
First Edition 2015Pharmaceutical Services DivisionMinistry of Health, Malaysia
©ALL RIGHTS RESERVED
This is a publication of the Pharmaceutical Services Division, Ministry of Health Malaysia. Enquiries are to be directed to the address below. Permission is hereby granted to reproduce information contained herein provided that such reproduction be given due acknowledgement and shall not modify the text.
Pharmaceutical Services DivisionMinistry of Health Malaysia
Lot 36, Jalan Universiti, 46350 Petaling Jaya, Selangor, Malaysia
Tel: 603 - 7841 3200 | Fax: 603 - 7968 2222Website: www.pharmacy.gov.my
Paediatric Pharmacy Services Guideline 3
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sage
MESSAGE
Paediatric pharmacists are in prime position to maximize the safe and effective use of medicines and influence the management of medicines for children and adolescents. Children are a special population which require detailed attention on the management and medications as their physiological function is still developing and yet to mature.
Paediatric pharmacy is a specialized clinical pharmacy service that is currently increasing in significance in Malaysia. We aim to have paediatric pharmacy service in all major hospitals and at least one paediatric pharmacist in secondary hospitals.
Therefore Clinical Pharmacy Working Committee ( Paediatric subspecialty ) Pharmaceutical Services Division, Ministry of Health has initiated to produce this guideline. I am optimistic that this guideline will assist paediatric pharmacist in their practices especially for those who will set up paediatric pharmacy services in their setting.
I would like to commend the Clinical Pharmacy Working Committee (Paediatric subspecialty) Pharmaceutical Services Division, Ministry of Health for their contribution and commitment to the development of this guideline.
Thank you.
Puan Abida Haq bt Syed M. HaqDirector of Pharmacy Practice and Development Division
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ADVISORS
Main Editorial Committees
Madam Abida Haq Syed M.HaqDirector of Pharmacy Practice & Development DivisionPharmaceutical Services Division, Ministry of Health, Malaysia
Madam Rosminah Mohd DinDeputy Director (Clinical Pharmacy & Technical)Pharmaceutical Services Division, Ministry of Health, Malaysia
Madam Noraini MohamadSenior Principal Assistant Director PharmacyPharmaceutical Services Division, Ministry of Health, Malaysia
Noor Haslina OthmanSenior Clinical PharmacistHospital Raja Perempuan Zainab II
Subasyini SivasupramaniamSenior Clinical PharmacistHospital Kuala Lumpur
Khoo Sze NiSenior Clinical PharmacistHospital Raja Permaisuri Bainun
Ng Boon YahSenior PharmacistHospital Pulau Pinang
Ng See YeeSenior Clinical PharmacistHospital Sultanah Bahiyah
Stella Chuo Sing HongSenior PharmacistHospital Sibu
Won Zi YunPharmacistHospital Putrajaya
Wong Pui MunSenior PharmacistHospital Serdang
Nurul Hidayah SallehPharmacistHospital Tengku Ampuan Afzan
Khairunnisa Mohamad PharmacistHospital Kemaman
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Wong Shien WoanPharmacistHospital Melaka
Sharini Sha’ariSenior PharmacistHospital Tuanku Ja’afar
Tea Ming HuiPharmacistHospital Sultanah Nora Ismail
Irwinder Kaur ChhabraPharmacistHospital Wanita dan Kanak - kanak Likas
Low Yong ChiaPharmacistHospital Wanita dan Kanak-kanak Likas
Tan Jing WenPharmacistHospital Kuala Lumpur
Angeline Tan Meng Wah Principal Assistant Director Pharmaceutical Services Division, MOH
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Table of Content
1.0 Introduction To The Guideline 8
2.0 Job Description Of A Paediatric Pharmacist 9
3.0 General Pediatrics 11
Respiratory Illness 12
Viral Bronchiolitis 12
Asthma 14
Neurology 24
Status Epilepticus 24
Epilepsy 28
Infantile Spasm 37
Nephrology 43
Acute Glomerulonephritis 43
Nephrotic Syndrome 45
Acute Renal Failure 49
Infectious diseases 52
Tuberculosis 52
Malaria 60
Meningitis 71
Urinary Tract Infection 77
Viral Croup 80
Pneumonia 84
Cardiovascular 92
Kawasaki Disease 92
Rheumatic Heart Disease 95
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4.0 Paediatric ICU 98
Fluid & Electrolyte Management 99
Nutrition In Critically Ill Patients 107
Shock Management 113
Neuromuscular Blockade 119
Stress Ulcer Prophylaxis 127
Sedation & Pain Management 131
5.0 Neonatal ICU 141
Neonatal Jaundice (NNJ) 142
Sedation & Pain Management 147
Total Parenteral Nutrition In Neonates 161
Fluid & Electrolyte Management 168
Necrotizing Enterocolitis 170
6.0 Dosing Considerations in Special Populations 181
7.0 Appendix 189
Corticosteroid Equipotency Chart 189
Nutrition Reference 190
Immediate-release Opioid Analgesics Comparison Chart 191
TDM Sampling Time 192
Growth Charts 193
Stability and Storage of Oral Medications 203
Drugs To Avoid In G6PD Deficiency 211
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1.0 Introduction To The Guideline
Neonates and paediatrics are vulnerable groups who require extra careful handling, and hence the role of paediatric pharmacists is crucial to ensure medication safety. With this insight, paediatric pharmacy service was introduced under the pharmacy program of Ministry of Health (MOH), Malaysia in 2006, and subsequently the first paediatric pharmacists working group committee was formed in 2009.
The role of paediatric pharmacists has gained recognition throughout the years. Despite the increasing demand for paediatric pharmacists, this remains as one of the most challenging clinical pharmacy field to venture in. The lack of evidence and standardized dosing in paediatrics and neonates can be a hurdle to practice evidence based medicine in this field. Also, the lack of standardized guidelines on the conduct of paediatric pharmacy services under facilities of MOH, Malaysia may lead to great differences in the expected roles and responsibilities as a paediatric pharmacist. The aim of this service guideline is to serve as a baseline reference and information for paediatric pharmacists who are new to this field on the conduct and practice of paediatric pharmacy. It can also be a basic reference for provisionally registered pharmacists (PRP) who will be doing paediatric clinical clerkship during clinical attachment. It is of great hope that with the introduction of this service guideline, paediatric pharmacy services under MOH, Malaysia can be further expanded and established.
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2.0 Job Description of a Paediatric Pharmacist
Paediatric pharmacy consists of general paediatric, paediatric intensive care and neonatal intensive care. The ultimate goal of paediatric pharmacy service is to assist in the best possible way to achieve safe and effective treatment. Hence, evidence-based practice should be the mainstay in the management of all patients at all time.
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2.0 Job Description Of A Paediatric Pharmacist Paediatric pharmacy consists of general paediatric, paediatric intensive care and neonatal intensive care. The ultimate goal of paediatric pharmacy service is to assist in the best possible way to achieve safe and effective treatment. Hence, evidence-based practice should be the mainstay in the management of all patients at all time.
Table 2.1: Job Description of Paediatric Pharmacist Job Scope Description
Admission clerking
• Medication history clerking, which includes non-prescription
drugs e.g. herbal remedies and over the counter drugs (OTC) • Compliance assessment (CP1 form) – if applicable • Medication reconciliation
Pharmacotherapy Rounds
• Active participation in ward rounds with doctors • Collaborate with other healthcare providers in developing
pharmaceutical care plans for the patients • Provide medication therapy evaluations and
recommendations to healthcare providers supported by evidence-based medicines
Monitor and review patients’ medication
• Case clerking and review (CP2 form) • Checking patient’s medication chart • Ensure medications are served • Ensure prescription is completely filled • Ensure safe and rational drug use • Ensure approppriate dilution and administration of injectable
drugs • Ascertain proper extemporaneous preparation • Therapeutic Drug Monitoring (TDM) / Total Parenteral
Nutrition (TPN) services
Identify Pharmaceutical Care Issues
• Dosing adjustment based on patient’s body weight, age
group, body surface area, renal and liver function. • Medication errors e.g. drug, dose, frequency, duration,
administration, etc • Drug- drug interactions • Drug incompatibilities and contraindications • Polypharmacy
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Adverse Drug Reaction Report
• Identifies and report any suspected adverse drug reaction (ADR) or drug allergy
• Provision of allergy card
Provision of Drug Information
• Drug availability • Safety and toxicology • Cost-effectiveness of medications • Maintains current drug references
Education
• Continuous Professional Development • Continuous Nursing Education • Provides drug therapy related to team members
Patient /caregiver counselling
• Bedside/Discharge counselling • Specialised drug delivery devices e.g. Insulin pen, inhalers,
spacers • Oral drug preparation (e.g. freshly prepared syrup, drug
reconstitution)
Research and Development
• Participate in research work/project pertaining to paediatric
pharmacy practice • Contributes to the pharmacy and medical literature for
examples case reports, pharmacokinetics and pharmacoeconomics reports
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3.0 General Paediatric
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Respiratory Illness
Viral Bronchiolitis
Introduction
Viral bronchiolitits is a common respiratory illness especially in infants aged 1 to 6 months old. Respiratory Syncytial Virus (RSV) remains the commonest cause of acute bronchiolitis in Malaysia. Although it is endemic throughout the year, cyclical periodicity with annual peaks occuring in the months of November December and January1. It is characterized by acute inflammation, edema and necrosis of epithelial cells lining small airways, increased mucus production, and bronchospasm2.
Clinical Features
Patients typically presents with a mild coryza, low grade fever and cough. Tachypnoea, chest wall recession, wheeze and respiratory distress subsequently develop. The chest may be hyperinflated and auscultation usually reveals fine crepitations and sometimes rhonchi. A majority of children with viral bronchiolitis has mild illness and about 1% of these children require hospital admission1.
Management
Pharmacotherapy
• 3% saline solution via nebulizer Shown to increase mucus clearance and significantly reduce hospital stay among non-severe acute bronchiolits. It improves clinical severity score in both outpatients and inpatients populations1.
• Inhaled ß2-agonists Pooled data have indicated a modest clinical improvement with the use of ß2 - agonist. A trial of nebulised ß2-agonist, given in oxygen, may be considered in infants with viral bronchiolitis. Vigilant and regular assessment of the child should be carried out1.Parameters to measure its effectiveness include improvements in wheezing, respiratory rate, respiratory effort, and oxygen saturation1.
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• Inhaled steroids Randomised controlled trials of the use of inhaled or oral steroids for treatment of viral bronchiolitis show no meaningful benefit1.
• Antibiotics Recommended for all infants with recurrent apnoea and circulatory impairment, possibility of septicaemia, acute clinical deterioration, high white cell count., progressive infiltrative changes on chest radiograph1.
Supportive Management
Arterial oxygenation by pulse oximetry (SPO2) should be performed at presentation and maintained above 93%. Administer supplemental humidified oxygen if necessary. Routine full blood count and bacteriological testing (of blood and urine) is not indicated in the assessment and management of infants with typical acute bronchiolitis1.
Special consideration
• Palivizumab Injection Clinicians may administer palivizumab prophylaxis to selected infants and children with chronic lung disease or a history of prematurity ( less than 35 weeks’ gestation ) or with congenital heart disease2. When given, prophylaxis should be given monthly for a total of 5 doses at a dose of 15mg/kg/dose administered intramuscularly2.
References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 31, Viral Bronchiolitis; p.161-2.
2. Lieberthal AS, Bauchner H, Hall CB, Johnson DW, Kotagal U,Light MJ, et al. Diagnosis and Management of bronchiolitis. American Academy of Pediatrics 2006;118:1774-1793.
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ASTHMA
Introduction
Asthma is defined as a chronic airway inflammation leading to increase airway responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or early morning. It is often associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. There is reversible and variable airflow limitation as evidenced by >15% improvement in PEFR (Peak Expiratory Flow Rate), in response to administration of a bronchodilator1.
Pre-school wheezing can be divided into two main categories, episodic (viral wheeze) and multiple trigger wheeze. Children who only wheeze with viral infections and are well between episodes can be classified as viral wheeze. Multiple trigger wheezers are children who have discrete exacerbations and symptoms in between these episodes. Triggers are smoke, allergens, crying, laughing and exercise1. The presence of atopy (eczema, allergic rhinitis and conjunctivitis) in the child or family supports the diagnosis of asthma. However, the absence of these conditions does not exclude the diagnosis1.
Management of Chronic Asthma
The management of chronic asthma can be based on either the severity of asthma or the degree of asthma control. Newly diagnosed patients will be categorized into different degrees of asthma severity by the physicians as in Table 11. Patients who are already on treatment should be assessed at every clinic visit on their control of asthma as in Table 22.
Respiratory Illness
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Asthma
Introduction
Asthma is defined as a chronic airway inflammation leading to increase airway responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or early morning. It is often associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. There is reversible and variable airflow limitation as evidenced by >15% improvement in PEFR (Peak Expiratory Flow Rate), in response to administration of a bronchodilator1.
Pre-school wheezing can be divided into two main categories, episodic (viral wheeze) and multiple trigger wheeze. Children who only wheeze with viral infections and are well between episodes can be classified as viral wheeze. Multiple trigger wheezers are children who have discrete exacerbations and symptoms in between these episodes. Triggers are smoke, allergens, crying, laughing and exercise1. The presence of atopy (eczema, allergic rhinitis and conjunctivitis) in the child or family supports the diagnosis of asthma. However, the absence of these conditions does not exclude the diagnosis1
.
Management of Chronic Asthma
The management of chronic asthma can be based on either the severity of asthma or the degree of asthma control. Newly diagnosed patients will be categorized into different degrees of asthma severity by the physicians as in Table 11. Patients who are already on treatment should be assessed at every clinic visit on their control of asthma as in Table 22.
Table 1: Evaluation of Newly Diagnosed Asthma
Clinical Parameters
Category
Intermittent Persistent
Mild Moderate Severe
Daytime symptoms Less than once a week More than once a week Daily Daily
Nocturnal symptoms Less than once a month More than twice a month More than once a week Daily
Exercise induced symptoms No Yes Yes Daily
Exacerbations Brief exacerbations not
affecting sleep and activity
> 1x/month affecting sleep, activity
> 2x/month affecting sleep, activity
Frequent >2x/month affecting sleep,activity
Lung function Normal PEFR / FEV1:> 80% PEFR / FEV1: 60 - 80%
PEFR / FEV1: < 60
• This division is arbitrary and the groupings may merge. An individual patient’s classification may change from time to time.
• There are a few patients who have very infrequent but severe or life threatening attacks with completely normal lung function and no symptoms between episodes. This type of patient remains very difficult to manage.
• PEFR = Peak Expiratory Flow Rate; FEV1 = Forced Expiratory Volume in One Second.
Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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Table 2: Evaluation of Asthma Control
Characteristics
Controlled
All of the following:
Partly Controlled
Any measure present in any week
Uncontrolled
Daytime Symptoms None >2 per week
≥ 3 features of
partly controlled
asthma present
in any week
Limitations of activities None Any
Nocturnal symptoms or awakenings None Any
Need for reliever None >2 per week
Lung function test Normal < 80% predicted or
personal best
Exacerbations None ≥ 1 per year One in any week
Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
Pharmacotherapy
The treatment of asthma consists of 2 components which consist of preventor therapy for reducing airway inflammation and reliever therapy for relieving the respiratory symptoms. Patients who have persistent asthma should be started on daily preventor medication. The initial medication and dosages depends on the severity and necessity to attain quick control of asthma2. A comprehensive treatment plan for asthma includes asthma education, avoidance of trigger factors and strategies to optimize pharmacotherapy. The management plan for each patient should be individualized because each patient has different trigger factors, asthma phenotypes and different responses to the medication2. Asthma management based on levels of control is a step up and step down approach as shown in Table 4. Before progressing to the next step, pharmacists can assist physicians in deciding the management of asthma by assessing the compliance and inhaler technique as well as any exposure to trigger factors and relaying the information to the physicians. It is important that the delivery system is appropriate to the child’s age2. Metered dose inhaler therapy via spacer with facemask is as efficacious as nebulizer therapy2.
Role of pharmacists:
• Provide medication education by providing information on the indication of the medications, dose, frequency and duration of the medications.
• Suggest the most suitable inhaler devices based on the patient's ability to understand the instructions and ability to use the inhalers correctly
• Counseling of proper inhaler techniques (metered dose inhalers [MDI], spacers with face mask, dry powder inhalers) and proper way of administrating medications (ie Montelukast Granules) to patients, parents or care givers
• Counsel patients on common side effects of each medications and how to prevent them (eg: Gargle after using inhaled corticosteroids to avoid oral thrush, sore throat and hoarse voice )
• Educate on the proper care of drug delivery devices for example spacers with face mask (refer to individual product care) as a properly functioning delivery device is essential to
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Pharmacotherapy
The treatment of asthma consists of 2 components which consist of preventor therapy for reducing airway inflammation and reliever therapy for relieving the respiratory symptoms. Patients who have persistent asthma should be started on daily preventor medication. The initial medication and dosages depends on the severity and necessity to attain quick control of asthma2. A comprehensive treatment plan for asthma includes asthma education, avoidance of trigger factors and strategies to optimize pharmacotherapy. The management plan for each patient should be individualized because each patient has different trigger factors, asthma phenotypes and different responses to the medication2. Asthma management based on levels of control is a step up and step down approach as shown in Table 4. Before progressing to the next step, pharmacists can assist physicians in deciding the management of asthma by assessing the compliance and inhaler technique as well as any exposure to trigger factors and relaying the information to the physicians. It is important that the delivery system is appropriate to the child’s age2. Metered dose inhaler therapy via spacer with facemask is as efficacious as nebulizer therapy2.
Role of pharmacists:
• Provide medication education by providing information on the indication of the medications, dose, frequency and duration of the medications.
• Suggest the most suitable inhaler devices based on the patient’s ability to understand the instructions and ability to use the inhalers correctly
• Counseling of proper inhaler techniques (metered dose inhalers [MDI], spacers with face mask, dry powder inhalers) and proper way of administrating medications ( ie Montelukast Granules ) to patients, parents or care givers
• Counsel patients on common side effects of each medications and how to prevent them (eg: Gargle after using inhaled corticosteroids to avoid oral thrush, sore throat and hoarse voice )
• Educate on the proper care of drug delivery devices for example spacers with face mask (refer to individual product care) as a properly functioning delivery device is essential to ensure optimum delivery of medication to patients.
• Encourage adherence to medications and find ways to overcome if any issues of nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)
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ensure optimum delivery of medication to patients. • Encourage adherence to medications and find ways to overcome if any issues of
nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)
Table 3: Inhaler Devices Recommended For Different Age
Children aged 0-6 years Metered dose inhaler + spacer with facemask
Children aged > 6 years
Metered dose inhaler + spacer with facemask Metered dose inhaler + spacer with mouthpiece Dry powder inhaler (may be suitable)
Source: Adapted from Clinical Practice Guidelines for the Management of Childhood Asthma 2014
Table 4: Management of Asthma
REDUCE ← → INCREASE
STEP 1 STEP 2 STEP 3 STEP 4 STEP 5
Intermittent Mild Persistent
Moderate Persistent
Severe Persistent
Severe Persistent
As needed rapid acting β2-agonist
Controller Options Select one Select one Add one / more Add one / more
Low dose inhaled
steroids
Low dose ICS + long acting β2-
agonist
Medium / High dose ICS
+ long acting β2-agonist
Oral Glucocorticoids
lowest dose
Leukotriene
receptor antagonist
Medium / High dose ICS
Leukotriene receptor antagonist
Anti-IgE
Low dose ICS +
Leukotriene receptor antagonist
SR Theophylline
Low dose ICS + SR Theophylline
ICS: Inhaled corticosteroid; SR: Sustained relase Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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ensure optimum delivery of medication to patients. • Encourage adherence to medications and find ways to overcome if any issues of
nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)
Table 3: Inhaler Devices Recommended For Different Age
Children aged 0-6 years Metered dose inhaler + spacer with facemask
Children aged > 6 years
Metered dose inhaler + spacer with facemask Metered dose inhaler + spacer with mouthpiece Dry powder inhaler (may be suitable)
Source: Adapted from Clinical Practice Guidelines for the Management of Childhood Asthma 2014
Table 4: Management of Asthma
REDUCE ← → INCREASE
STEP 1 STEP 2 STEP 3 STEP 4 STEP 5
Intermittent Mild Persistent
Moderate Persistent
Severe Persistent
Severe Persistent
As needed rapid acting β2-agonist
Controller Options Select one Select one Add one / more Add one / more
Low dose inhaled
steroids
Low dose ICS + long acting β2-
agonist
Medium / High dose ICS
+ long acting β2-agonist
Oral Glucocorticoids
lowest dose
Leukotriene
receptor antagonist
Medium / High dose ICS
Leukotriene receptor antagonist
Anti-IgE
Low dose ICS +
Leukotriene receptor antagonist
SR Theophylline
Low dose ICS + SR Theophylline
ICS: Inhaled corticosteroid; SR: Sustained relase Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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Table 5: Drug Doses Of Common Medications Used in Asthma
Drug Formulation Dose1.2.3.4.5.6 Additional information4,5,7
Salbutamol
Oral
0.15 mg/kg/dose 6-8H/ PRN
Metered dose inhaler
100-200 mcg/dose 4-6H/ PRN
Dry powder inhaler 100-200 mcg/dose 6H/ PRN
Intravenous
Bolus: 5-10 mcg/kg over 10 min
Infusion: Start 0.5-1 mcg/kg/min, increase by 1 mcg/kg/min every 15 min to a max of 20 mcg/kg/min
For continuous intravenous infusion,
dilute to a concentration of 200 micrograms/mL
with Glucose 5%, Sodium Chloride 0.9% ; if fluid-restricted,can be
given undiluted through central venous catheter
Nebuliser
0.15 mg/kg/dose (max 5 mg) or < 2 years old : 2.5 mg/dose > 2 years old : 5.0 mg/dose Continuous : 500 mcg/kg/hr
Terbutaline Subcutaneous 5-10mcg/kg (Maximum 0.5mg/dose)
Prednisolone Oral 0.5-1mg/kg/day x 3-5 days (Maximum: 60mg/day)
Hydrocortisone Intravenous 4 mg/kg/dose 6H (max 100mg/dose)
Methylprednisolone Intravenous
0.5-1 mg/kg 6H day 1, 12H day 2, then 1mg/kg daily, reducing to minimum effective dose
Beclomethasone Diproprionate /
Budesonide
Metered dose inhaler Dry powder inhaler
<400 mcg/day : low dose 400-800 mcg/day : Moderate 800- 1200 mcg/day: High
Fluticasone Propionate
Metered dose inhaler Dry powder inhaler
<200 mcg/day : Low 200-400 mcg/day : Moderate 400-600 mcg/day : High
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Ciclesonide
Metered dose inhaler
160 microgram daily 320 microgram daily
Licensed for children over 6 years old
Salmeterol + Fluticasone
Metered dose inhaler
Children 4 years and older:
2 inhalations of 25mcg/50mcg BD
12 years and older:
2 inhalations of 25mcg/50mcg BD or
2 inhalations of 25mcg/125mcg BD
There are no data available for use in children below 4 years old
Dry powder inhaler
12 years and older:
1 inhalation of 50mcg/250mcg BD or
1 inhalation of 50mcg/500mcg BD
Montelukast
Oral
1-5 years old: 4 mg granules ON
6-14 years old:
5mg/tablet chewable ON
>14 years old:
10mg/tablet ON
Theophylline
Oral Syrup Slow Release
5 mg/kg/dose TDS/QID 10 mg/kg/dose BD
Therapeutic drug monitoring: 10-20mg/L
Aminophylline Intravenous (IV)
6 mg/kg slow bolus (if not previously on theophylline) followed by infusion 0.5 -1mg/kg/hr
Ipratropium bromide
Nebuliser solution (250 mcg/ml)
< 5 years old : 250 mcg 4-6 hourly > 5 years old : 500 mcg 4-6 hourly
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Prevention
Identifying and avoiding the following common triggers may be useful1
• Environmental allergens These include house dust mites, animal dander, insects like cockroach, mould and pollen. Useful measures include damp dusting, frequent laundering of bedding with hot water, encasing pillow and mattresses with plastic / vinyl covers, removal of carpets from bedrooms, frequent vacuuming and removal of pets from the household
• Cigarette smoke
• Respiratory tract infections - commonest trigger in children
• Food allergy - uncommon trigger, occurring in 1-2% of children
• Exercise- Although it is a recognized trigger, activity should not be limited. Taking short acting 2-agonist prior to strenuous exercise ( 10-20 minutes before exercise )2 as well as optimizing treatment is usually helpful.
Asthma Action Plan
An asthma action plan is a written instruction by the physician for the patient, parents or care giver on the daily management of asthma and how to identify and manage asthma exacerbations. The asthma action plan may differ for different institutions. An example of asthma action plan is available in the Clinical Practice Guidelines for the Management of Childhood Asthma 2014, Malaysia.
Special Considerations :
Ciclesonide is the most recent inhaled corticosteroid available for use in children. It is a prodrug activated locally in the lung by pulmonary esterase to des-ciclesonide, which ensures high local concentration8.
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Management Of Acute Asthma
The management of acute asthma depends on the severity at presentation, the response to therapy, the availability of drugs and facilities at the particular clinic/ hospital and the experience of the attending doctor. Before children can receive appropriate treatment for the acute asthma in any setting, it is essential to assess accurately the severity of their attack2.
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Management Of Acute Asthma
The management of acute asthma depends on the severity at presentation, the response to therapy, the availability of drugs and facilities at the particular clinic/ hospital and the experience of the attending doctor. Before children can receive appropriate treatment for the acute asthma in any setting, it is essential to assess accurately the severity of their attack2.
Table 7: Assessment of Severity of Acute Asthma Exacerbation in Children
Parameters Mild Moderate Severe Life Threatening
Breathless When walking When talking Infant: When
feeding
At rest Infant: Stops
Feeding
Talks in Sentences Phrases Words Unable to speak
Alertness Maybe agitated Usually agitated
Usually agitated
Drowsy / confused/ coma
Respiratory Rate Normal to Mildly increased Increased Markedly
increased Poor Respiratory
Effort
Accessory Muscle Usage / retractions Absent Present –
Moderate Present –
Severe Paradoxical thoraco-abdominal movement
Wheeze Moderate, often
only end expiratory
Loud Usually loud Silent chest
SpO2 (on air) >95% 92-95% <92% Cyanosis & <92%
Pulse / min <100 100-120
>120 (>5 yrs)
>160 (infants)
Bradycardia
PEFR* >80% 60-80% <60% Unable to perform
*Peak Expiratory Flow Rate (PEFR) after initial bronchodilator, % predicted or of personal best
Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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Algorithm 1: Management of Acute Exacerbation of Bronchial Asthma in Children
Source: Adapted from Clinical Practice Guidelines for the Management of Childhood Asthma 2014
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References :
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 30, Asthma; p.149-60
2. Clinical Practice Guidelines for the Management of Childhood Asthma. A Consensus statement prepared for the Academy of Medicine of Malaysia, Malaysian Thoracic Society and Lung Foundation of Malaysia. 2014.
3. Shann F. Drug Doses.16th Edition. Australia:Royal Children’s Hospital Parkville, Victoria; 2014.
4. BMA, Royal Pharmaceutical Society, Royal College and Pediatric of Child Health. BNF for Children 2012-2013.
5. Seretide Evohaler [Package insert].Burgos, Spain: Glaxo Wellcome S.A; 2010
6. Seretide Accuhaler [Package insert].Ware,UK: Glaxo Wellcome Operations; 2010
7. Alvesco [Package insert].Leicester,England: Takeda GmbH; 2013
8. Rizzo MC, Solé D. Inhaled corticosteroids in the treatment of respiratory allergy: safety vs. efficacy. J Pediatr (Rio J). 2006;82(5 Suppl):S198-205.
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NEUROLOGY
Status Epilepticus
Introduction
Status epilepticus (SE) is defined as any seizure lasted > 30 minutes which can be continuous or intermittent with incomplete recovery of consciousness in between seizures. However, any seizure > 5 minutes warrants pharmacological intervention as it is unlikely to terminate rapidly or spontaneously by itself. Based on the electroclinical features, SE may be classified broadly as convulsive SE and non-convulsive SE1, 2.
Convulsive SE is defined as convulsions associated with rhythmic jerking of extremities and mental status impairment. It can be further classified as tonic-clonic SE, tonic SE, clonic SE and myoclonic SE. Generalised tonic-clonic SE is the most common form of SE1.
Non-Convulsive SE is defined as seizure activity seen on electroencephalogram (EEG) without physical convulsions. It is characterized by abnormal mental status, unresponsiveness, ocular motor abnormalities, persistent electrographic seizures and possible response to anticonvulsants1.
Seizure which is continuous or repetitive lasting longer than 60 minutes despite treatment with benzodiazepine and one standard anticonvulsant (usually phenytoin or phenobartbitone) in adequate loading dose is defined as refractory status epilepticus1.
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Management
Pharmacotherapy
Refer to Algorithm 1.
Algorithm 1: Management of Status Epilepticus
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Special Consideration
1. Benzodiazepine should be the agent of choice for emergent initial treatment of SE3.
2. If the patient is currently treated with antiepileptic drugs, a drug level (TDM) should be checked and history obtained regarding compliance3.
3. If < 2 years old, pyridoxine ( IV 100mg if available, oral dose up to 30mg / kg / day ) will be helpful especially for suspected pyridoxine dependent seizures2,4.
4. Avoid sodium valproate in metabolic encephalopathy ( patient with metabolic or mitochondrial disease)2.
5. Be aware of the severe complication associated with propofol- ‘propofol infusion syndrome’ especially on dose exceeds 5mg/kg/hr for more than 48 hours. It is a potentially fatal condition characterized by severe metabolic acidosis, hyperlipidemia, rhabdomyolysis and cardiovascular collapsed1.
6. Phenobarbitone has no anticonvulsant ceiling effect, titrate to achieve burst suppression pattern on EEG. High dose phenobarbitone up to 80mg/kg/ day, with serum level more than 1000 micromol/L (232 microgram/ml) has been shown to be effective in achieving seizure control children with refractory SE (eg. FIRES- Febrile Infection Related Epilepsy Syndrome). Major adverse effects of high dose phenobarbitone are sedation and respiratory depression which are usually subject to tolerance over a relatively short time1.
7. Therapeutic Drug Monitoring (TDM) sampling time and indication are important; always relate TDM results with clinical condition of patient2.
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References :
1. Cherian A, Thomas SV. Status Epilepticus. Annals of Indian Academy of Neurology 2009 Jul-Sep; 12(3): 140-53.
2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia;2013. Chapter 44, Status Epilepticus; p.207-12
3. Gretchen MB, Rodney B, Jan C, et al. Guideline for the Evaluation and Management of Status Epilepticus. Neurocritical Society 2012 April 24.
4. Gospe SM. Pyridoxine- dependent Epilepsy. NCBI Bookshelf; 2001.
5. Pediatric Dosage Handbook (Lexi-comp) 16th Edition
6. Product Insert Parental Dilantin Pfizer
7. Drug Doses Frank Shann 15th Edition 2010
8. Abend NS, Gutierrez-Colina AM, Monk HM, et al. Levetiracetam for Treatment of Neonatal Seizure. Child Neurol. 2011 April 26(4): 465-470.
9. University Collge London Hosputals NHS Fpundation Trust. Neonatal Unit Drug Monography - Phenobarbital; 2012 [cited 4 Nov 2014]. Available from www.uclhguide.com / fragr_image / media / phenobarbital
10.RPA Newborn Care Drug Database [cited 4 Nov 2014]. Available from www.sswahs.nsw.gov.au / rpa / neonatal / html / listview.asp ? DrugID=35
11.Taylor LM, Farzam F, Cook AM, Lewis DA, Baumann RJ, Kuhn RJ. Clinical Utility of a Continuous Intravenous Infusion of Valproic Acid in Pediatric Patients. Pharmacotherapy. 2007;27(4):519-25.
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Epilepsy
Introduction
Epilepsy is a neurological condition characterized by recurrent unprovoked epileptic seizures. According to The International League Against Epilepsy (ILAE) classification of seizure type revised in 2010, seizures are broadly classified as generalized, focal and unknown1.
19
Epilepsy Introduction
Epilepsy is a neurological condition characterized by recurrent unprovoked epileptic seizures. According to The International League Against Epilepsy (ILAE) classification of seizure type revised in 2010, seizures are broadly classified as generalized, focal and unknown1.
Chart 1: Category of Seizures
Tonic-clonic Absence Clonic Tonic Atonic Myoclonic - myoclonic - myclonic-atonic - myclonic-tonic
Typical
Absence with special features
- Myoclonic absence - Eyelid myoclonia
Atypical
Characterized according to one or more features:
Aura Motor
Autonomic Awareness/ responsiveness:
Altered (dyscognitive) or retained
Bilateral convulsive seizure (Old term: secondarily tonic clonic seizure)
May evolve to
- Epileptic spasms - Other
1. Generalised seizures (arising within and rapidly engaging bilaterally
distributed networks- involves whole brain)
2. Focal seizure Originating within networks limited
to one hemisphere
3. Unknown Insufficient evidence to characterize as focal, generalized or both)
NEUROLOGY
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Pharmacotherapy2
• Treatment recommended if ≥ 2 episodes ( recurrent risk up to 80% ).
• Monotherapy is preferred, choose most appropriate drug according to types of seizure and epileptic syndromes. Increase dose gradually until seizure controlled or maximum dose reached or side effects occur.
• Add on second AED if the first drug failed, then optimize 2nd AED and try to withdraw first AED ( alternative monotherapy ).
• Rational combination therapy (usually 2 or maximum 3 drugs) i.e. combines drugs with different mechanism of action, and consider their spectrum of efficacy, drug interactions and adverse effects
• TDM monitoring is not routinely required ( except for phenytoin ) unless non- compliance, toxicity or drug interaction suspected.
• When withdrawal of medication is planned ( generally after being seizure free for 2 years ), consideration should be given to epilepsy syndrome, likely prognosis and individual circumstances before attempting slow withdrawal of medicat ion over 3-6months ( maybe longer for clonazepam and phenobarbitone ). If seizures recur, the last dose reduction is reversed and medical advice sought.
20
Types of seizure Characteristic signs Tonic clonic (grand-mal)
Tonic stiffening (extension) followed by clonic flexion motions (muscle jerking). Seizure followed by postictal confusion May produce labored respirations, cyanosis, incontinence, involuntary tongue biting.
Absence (petit-mal) Staring, loss of expression, unresponsiveness, stopping from ongoing activity No convulsions or postictal symptoms Usually recovers immediately and resumes previous activity with no memory of the seizure.
Clonic Rapid, repetitive motor activity Tonic Sudden, brief stiffening of the muscles of whole body Atonic Sudden, brief loss of muscle tone of the body Myoclonic Brief but intense muscle jerks
Pharmacotherapy2
• Treatment recommended if ≥ 2 episodes (recurrent risk up to 80%).
• Monotherapy is preferred, choose most appropriate drug according to types of seizure and epileptic syndromes. Increase dose gradually until seizure controlled or maximum dose reached or side effects occur.
• Add on second AED if the first drug failed, then optimize 2nd AED and try to withdraw first
AED (alternative monotherapy).
• Rational combination therapy (usually 2 or maximum 3 drugs) i.e. combines drugs with different mechanism of action, and consider their spectrum of efficacy, drug interactions and adverse effects
• TDM monitoring is not routinely required (except for phenytoin) unless non-compliance, toxicity or drug interaction suspected.
• When withdrawal of medication is planned (generally after being seizure free for 2 years), consideration should be given to epilepsy syndrome, likely prognosis and individual circumstances before attempting slow withdrawal of medication over 3-6months ( maybe longer for clonazepam and phenobarbitone). If seizures recur, the last dose reduction is reversed and medical advice sought.
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21
Table 2: Choice of Antiepileptics
Selecting antiepileptic drugs according to seizure type Seizure type First line Second line
Focal Seizure
Carbamazepine Valproate
Lamotrigine, Topiramate, Lavetiracetam, Clobazam, Phenytoin, Phenobarbitone
Generalised Seizure Tonic-clonic/ clonic Valproate
Lamotrigine, Topiramate, Clonazepam, Carbamazepine1, Phenytoin1, Phenobarbitone
Absence Valproate Lamotrigine, Levetiracetam Atypical absences, Atonic, Tonic
Valproate Lamotrigine, Topiramate, Clonazepam, Phenytoin
Myoclonic Valproate Clonazepam
Topiramate, Levetiracetam, Clonazepam, Lamotrigine2, Phenobarbitone
Infantile Spasm Prednisolone4 ,Vigabatrin3, ACTH
Nitrazepam, Clonazepam, Valproate, Topiramate
Footnote: 1. May aggravate myoclonus/ absence seizure in Idiopathic Generalized Epilepsy. 2. May cause seizure aggravation in Dravet syndrome and Juvenile Myoclonic Epilepsy 3. Especially for patient with Tuberous Sclerosis (TS). 4. United Kingdom Infantile Spasms Study (UKISS) protocol
Antiepileptic Drugs That Aggravate Selected Seizure Type Phenobarbitone Absence seizure Clonazepam Causes Tonic Status in Lennox-Gastaut syndrome Lamotrigine Dravet syndrome
Myoclonic seizures in Juvenile Myoclonic Epilepsy Phenytoin Absence, Myoclonic seizure Vigabatrin Myclonic, Absence seizure Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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References :
1. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Boas WE, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Sheffer IE. Revised Terminology and Concepts for Organization of Seizures and Epilepsies: Reports of the ILAE Commision on Classification and Terminology, 2005-2009. Epilepsia 2010, 51 (4):676-685.
2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 44, Epilepsy; p.207-12
3. Kammerman S, Wasserman L. Seizure disorders: Part 1. Classification and Diagnosis. WJM 2001 August; 175.
4. Seizure SMART Classification of Seizures. Epilepsy Austria; March 2012. Available from: http://www.epilepsy.org.au/sites/default/files/Seizure%20 Smart%20-%20Classification%20of%20Seizures%20%28focal%29_0.pdf
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22
PH
AR
MA
CO
KIN
ETIC
S A
ND
SID
E EF
FEC
TS O
F C
OM
MO
N A
NTI
EPIL
EPTI
C D
RU
GS
DR
UG
PHA
RM
AC
OK
INET
IC
SU
BST
RA
TE
OF
CYP
IN
DU
CER
/ IN
HIB
IT C
YP
SI
DE
EFFE
CTS
CO
MM
ENTS
Car
bam
azep
ine1
t ½ 8
-14h
rs
Met
abol
ised
by
CY
P 3
A4
to
CB
Z-ep
oxid
e an
d ot
hers
Pro
tein
bin
ding
CB
Z 75
-90%
, ep
oxid
e 50
%
2C8
(min
or)
3A4
(maj
or)
Indu
ces
1A2
(stro
ng)
2B6
(stro
ng)
2C8
(stro
ng)
2C9
(stro
ng)
2C19
(stro
ng)
3A4
(stro
ng)
Pot
entia
lly fa
tal b
lood
cel
l ab
norm
aliti
es (a
plas
tic
anem
ia, a
gran
uloc
ytos
is),
seve
re d
erm
atol
ogic
re
actio
n: S
JS, t
oxic
ep
ider
mal
nec
rosi
s (h
ighe
r ris
k w
ith v
aria
nt H
LA-
B*1
502
alle
le),
elev
ated
liv
er e
nzym
e, ja
undi
ce.
AD
M: w
ith fo
od to
dec
reas
e G
I up
set.
Do
not c
rush
CR
tab.
A
dvic
e pt
to re
port
if de
velo
ps s
kin
rash
or a
ny s
ign/
sym
ptom
bon
e m
arro
w d
epre
ssio
n eg
. Fev
er, s
ore
thro
at, e
asy
brui
sing
, inf
ectio
ns.
Leve
l dec
reas
e ~3
wee
ks a
fter
initi
atio
n du
e to
sel
f -ind
uced
m
etab
olis
m.
Clo
baza
m4
t ½ 3
6-42
hrs
M
etab
olis
ed p
rimar
ily v
ia
3A4
to a
ctiv
e N
-de
smet
ylcl
obaz
am.
Exc
retio
n: re
nal 8
2% (9
4%
as m
etab
olite
) P
rote
in b
indi
ng 8
0-90
%
2C19
In
duce
3A
4 In
hibi
t 2D
6
Con
stip
atio
n (2
-10%
) D
rool
ing
(up
to 1
4%)
AD
M: w
ith o
r with
out f
ood
Tab
can
be c
rush
ed.
Clo
naze
pam
1 t ½
22-3
3hrs
M
etab
olis
ed in
live
r P
rote
in b
indi
ng 8
5%
3A4
-
Hyp
oten
sion
, res
pira
tory
de
pres
sion
, bro
nchi
al
hype
rsec
retio
n,
hype
ract
ivity
and
ag
gres
sion
.
AD
M: w
ith fo
od to
dec
reas
e G
I di
stre
ss
With
draw
gra
dual
ly w
hen
disc
ontin
uing
ther
apy.
Lam
otrig
ine1
With
enz
yme-
indu
cer
t ½
6-11
hrs
(age
10
mo-
5.3
yr) 7
-31h
rs
W
ith V
PA
: 30-
52hr
s (1
0 m
o-5.
3 yr
) 50
-74h
rs (5
-11y
o)
W
ith b
oth:
7-1
3 hr
s P
rote
in b
indi
ng 5
5%
- -
Ski
n ra
sh 1
0% (h
ighe
r in
cide
nce
in c
hild
ren
and
thos
e re
ceiv
ing
valp
roat
e,
high
initi
al d
ose
or w
ith
rapi
d do
se in
crem
ent).
S
ever
e sk
in ra
sh e
g.S
JS
0.8%
P
oten
tial f
atal
hy
pers
ensi
tivity
(wat
ch fo
r ea
rly s
igns
: ly
mph
aden
opat
hy, f
ever
)
AD
M: w
ithou
t reg
ard
to fo
od
Reg
ular
tab:
Do
not c
hew
, as
a bi
tter t
aste
may
resu
lt.
Dis
pers
ible
/ che
wab
le ta
b: O
nly
who
le ta
blet
s sh
ould
be
adm
inis
tere
d; m
ay s
wal
low
who
le,
chew
, or d
ispe
rse
in w
ater
or
dilu
ted
fruit
juic
e (~
5ml).
W
hen
disc
ontin
ue th
erap
y, ta
pper
do
se b
y 50
%/w
eek
over
at l
east
2
wee
ks u
nles
s sa
fety
con
cern
s.
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Dru
g Ph
arm
acok
inet
ic
Subs
trat
e of
C
YP
Indu
cer
/Inhi
bit
CYP
Si
de e
ffect
s C
omm
ents
Leve
tirac
etam
1
t ½ 5h
rs
enzy
mat
ic h
ydro
lysi
s, n
ot
cyto
chro
me
P45
0 de
pend
ent.
Exc
rete
d re
nally
as
unc
hang
ed d
rug
66%
and
in
activ
e m
etab
olite
s 27
%.
Cle
aran
ce d
ecre
ased
in
rena
l dys
func
tion.
P
rote
in b
indi
ng <
10%
- -
Neu
rops
ychi
atric
s/e
: be
havi
oura
l sym
ptom
s 38
%
(agi
tatio
n, a
ggre
ssio
n,
ange
r), s
omno
lenc
e 23
% ,
dizz
ines
s 7%
. hea
dach
e G
I: vo
miti
ng 1
5%, a
nore
xia
13%
, dia
rrhe
a 8%
H
emat
olog
ic: d
ecre
ased
in
RB
C, H
b, H
ct, W
BC
, and
ne
utro
phil.
AD
M: w
ithou
t reg
ard
to m
eals
. S
wal
low
who
le, d
o no
t bre
ak, c
rush
or
che
w if
pos
sibl
e.
Phe
noba
rbito
ne1
t ½ 20
-133
hrs
(inf
ant),
37-
73
hrs
(chi
ldre
n).
20-5
0% e
xcre
ted
unch
ange
d in
urin
e, c
lear
ance
can
be
incr
ease
d w
ith u
rine
alka
lizat
ion
or o
ral m
ultip
le-
dose
act
ivat
ed c
harc
oal.
Pro
tein
bin
ding
35-
50%
2C9
(min
or)
2E1
(min
or)
2C19
(maj
or)
Indu
ces
1A2
(stro
ng)
2A6
(stro
ng)
2B6
(stro
ng)
2C8
(stro
ng)
2C9
(stro
ng)
3A4
(stro
ng)
CV
S: h
ypot
ensi
on,
brad
ycar
dia
CN
S: d
row
sinw
ss,
CN
S
depr
essi
on, p
arad
oxic
al
exci
tem
ent,
hype
rkin
etic
ac
tivity
D
ER
M: s
kin
erup
tion,
rash
, ex
folia
tive
derm
atiti
s R
ES
PI:
depr
essi
on, a
pnea
H
epat
ic: h
epat
itis
AD
M: o
ral w
ith w
ater
, milk
or j
uice
R
apid
IV a
dmin
istra
tion
may
cau
se
resp
irato
ry d
istre
ss, a
pnea
, la
ryng
ospa
sm, o
r hyp
oten
sion
(do
not i
njec
t fas
ter t
han
1mg/
kg/m
in).
Phe
nyto
in1
t ½ 14
- 22h
rs
Maj
or m
etab
olite
(via
ox
idat
ion)
und
ergo
es
ente
rohe
patic
recy
clin
g an
d el
imin
ate
in u
rine
as
gluc
uron
ides
. P
rote
in b
indi
ng 9
0-95
%
2C9
(maj
or)
2C19
(maj
or)
3A4
(min
or)
Indu
ces
2B6
(stro
ng)
2C8
(stro
ng)
2C9
(stro
ng)
2C19
(stro
ng)
3A4
(stro
ng)
Ocu
lar:
nyst
agm
us,
dipl
opia
, blu
rred
vis
ion
CN
S: s
lurr
ed s
peec
h,
dizz
ines
s D
erm
: hirs
utis
m,
coar
seni
ng o
f fac
ial
feat
ures
, ras
h S
JS
GI:
ging
ival
hyp
erpl
asia
, gu
m te
nder
ness
, nau
sea,
vo
miti
ng
Oth
ers:
folic
aci
d de
plet
ion,
bl
ood
dysc
rasi
as
AD
M: M
ay a
dmin
iste
r with
food
or
milk
to re
duce
GI u
pset
. Hig
h fa
t m
eal r
educ
es b
ioav
aila
bilit
y of
ge
neric
pro
duct
s. S
witc
hing
bra
nd
may
affe
ct s
erum
con
cent
ratio
n.
Bio
avai
labi
lity
decr
ease
with
NG
tu
be a
nd a
ntac
id. H
old
feed
ings
/ an
taci
d fo
r 2 h
rs p
rior t
o an
d 2h
rs
afte
r phe
nyto
in a
dmin
istra
tion.
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DR
UG
PH
AR
MA
CO
KIN
ETIC
SU
BST
RA
TE
OF
CYP
IN
DU
CER
/IN
HIB
IT C
YP
SID
E EF
FEC
TS
CO
MM
ENTS
Ruf
inam
ide2
t ½
6-10
hrs
Ext
ensi
vely
via
ca
rbox
yles
tera
se-m
edia
ted
hydr
olys
is o
f the
ca
rbox
ylam
ide
grou
p P
rote
in b
indi
ng 3
4%
-
Inhi
bit
2E1
(wea
k)
In
duce
3A
4 (w
eak)
Som
nole
nce,
fatig
ue, g
ait
dist
urba
nces
, ata
xia,
sh
orte
ning
of Q
T in
terv
al,
mul
tiorg
an h
yper
sens
itivi
ty
reac
tions
(inc
ludi
ng s
ever
e he
patit
is).
AD
M: t
ake
with
food
(inc
reas
ed
abso
rptio
n)
Tabl
et m
ay b
e sw
allo
wed
who
le,
split
in h
alf,
or c
rush
ed.
Topi
ram
ate1
t ½ 7.
7-12
.8hr
s M
inor
am
ount
met
abol
ized
in
liver
. 70%
exc
rete
d un
chan
ged
in u
rine
Pro
tein
bin
ding
15-
41%
-
Inhi
bit 2
C19
(w
eak)
Indu
ce 3
A4
(wea
k)
Hyp
erch
lore
mic
met
abol
ic
acid
osis
may
occ
ur (i
nhib
its
carb
onic
anh
ydra
se,
incr
ease
s re
nal b
icar
bona
te
loss
cau
sing
dec
reas
ed
seru
m b
icar
bona
te).
Ocu
lar s
ympt
oms
(sec
onda
ry a
cute
ang
le
clos
ure
glau
com
a an
d ac
ute
myo
pia)
. O
ligoh
ydro
sis
(dec
reas
ed
swea
ting)
and
hyp
erth
erm
ia
Con
curr
ent u
se o
f val
proi
c ac
id m
ay re
sult
in
hype
ram
mon
emia
with
or
with
out e
ncep
halo
path
y S
omno
lenc
e, fa
tigue
al
opec
ia, r
ash,
pa
raes
thes
ia, t
rem
or e
tc.
Mon
itor s
ympt
oms
of m
etab
olic
ac
idos
is (h
yper
vent
ilatio
n, fa
tigue
, an
orex
ia, s
tupo
r, ca
rdia
c ar
rhyt
hmia
) and
pot
entia
l co
mpl
icat
ions
of c
hron
ic a
cido
sis
(nep
hrol
ithia
sis,
rick
ets,
redu
ced
grow
th ra
te).
Cou
nsel
pat
ient
s to
repo
rt an
y bl
urre
d vi
sion
and
/or e
ye p
ain.
C
ouns
el p
atie
nts
for p
reve
ntiv
e st
rate
gies
(hyd
ratio
n be
fore
and
du
ring
exer
cise
or e
xpos
ure
to h
ot
tem
pera
ture
). U
se w
ith c
autio
n in
pat
ient
s w
ith
inbo
rn m
etab
olic
err
ors
of
met
abol
ism
or d
ecre
ased
hep
atic
m
itoch
ondr
ial a
ctiv
ity.
AD
M: w
ithou
t reg
ards
to fo
od.
Tabl
et c
an b
e cr
ushe
d; b
roke
n ta
blet
s m
ay h
ave
bitte
r tas
te.
Spr
inkl
e ca
psul
e ca
n be
ope
ned
and
mix
the
cont
ent w
ith s
mal
l am
ount
of s
oft f
ood
(1 te
aspo
onfu
l of
oat
mea
l, pu
ddin
g, c
usta
rd,
appl
esau
ce, y
ogur
t or i
ce c
ream
), sw
allo
w w
hole
and
do
not c
hew
.
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25
DR
UG
PH
AR
MA
CO
KIN
ETIC
SU
BST
RA
TE
OF
CYP
IN
DU
CER
/IN
HIB
IT C
YP
SID
E EF
FEC
TS
CO
MM
ENTS
Val
proi
c ac
id 1,
2
t ½ 7-
12 h
rs, p
rolo
nged
with
liv
er d
isea
se
M
etab
olis
ed e
xten
sive
ly in
liv
er v
ia g
lucu
roni
de
conj
ugat
ion
30 -
50%
and
40
% v
ia m
itoch
ondr
ial b
eta-
oxid
atio
n.
Pro
tein
bin
ding
80-
90%
2A6
(min
or)
2B6
(min
or)
2C19
(min
or)
2C9
(min
or)
2E1
(min
or)
Inhi
bit
2C9
(wea
k)
2C19
(wea
k)
2D6
(wea
k)
3A4
(wea
k)
In
duce
2A
6 (w
eak/
m
oder
ate)
Sev
ere:
hep
atiti
s fa
ilure
, lif
e-th
reat
enin
g pa
ncre
atiti
s hy
pera
mm
onem
ic
ence
phal
opat
hy.
Ris
k of
thro
mbo
cyto
peni
a w
ith h
ighe
r dos
e.
Dro
wsi
ness
, irr
itabi
lity,
ra
sh, e
ryth
ema
mul
tifor
me,
tra
nsie
nt li
ver e
nzym
e el
evat
ion
etc.
Mon
itor p
atie
nt c
lose
ly fo
r ap
pear
ance
of m
alai
se, v
omiti
ng,
jaun
dice
, abd
omin
al p
ain,
un
expl
aine
d le
thar
gy, o
r cha
nged
in
men
tal s
tatu
s.
Cou
nsel
pat
ient
to re
port
if ea
sy
brui
sing
, yel
low
ski
n, lo
ss o
f ap
petit
e, n
ause
a, v
omiti
ng o
r un
expl
aine
d le
thar
gy o
ccur
s.
AD
M: m
ay ta
ke w
ith fo
od to
redu
ce
GI e
ffect
s. A
void
car
bohy
drat
e dr
ink
and
milk
. Do
not c
rush
or
chew
ent
eric
coa
ted
tabl
et.
Vig
abat
rin2
t ½ 5.
7-9.
5 hr
s, p
rolo
nged
w
ith re
nal i
mpa
irmen
t
Min
imal
met
abol
ism
80
% e
xcre
ted
unch
ange
d in
ur
ine
Do
not b
ind
to p
lasm
a pr
otei
n
- In
duce
2C
9 (w
eak/
m
oder
ate)
Per
man
ent b
ilate
ral
conc
entri
c vi
sual
fiel
d co
nstri
ctio
n (tu
nnel
vis
ion)
, bl
urre
d vi
sion
, dip
lopi
a,
nyst
agm
us.
Wei
ght g
ain,
som
nole
nce,
fa
tigue
, exc
itatio
n/ a
gita
tion,
na
usea
, abd
omin
al p
ain
etc.
Oph
thal
mol
ogic
exa
min
atio
n sh
ould
be
per
form
ed a
t bas
elin
e, 3
m
onth
ly (o
n th
erap
y) a
nd 3
-6m
onth
s af
ter d
isco
ntin
uatio
n.
Use
with
cau
tion
in p
atie
nts
with
re
nal i
mpa
irmen
t; do
sage
ad
just
men
t if
CrC
l <80
mL/
min
ute
AD
M:
with
out r
egar
d to
food
. Fi
lm c
oate
d ta
blet
: sw
allo
w w
hole
or
bre
ak in
to h
alf,
do n
ot c
rush
(m
anuf
actu
rer’s
reco
mm
enda
tion)
. If
tabl
et a
dmin
istra
tion
not f
easi
ble,
m
ay c
rush
tabl
et a
nd m
ix w
ith s
oft
food
eg.
yog
urt,
hone
y or
jam
, sw
allo
w w
hole
with
out c
hew
ing3 .
REF
EREN
CES
: 1.
P
edia
tric
Dos
age
Han
dboo
k (L
exi-c
omp)
16th
Edi
tion
2.
Onl
ine
Lexi
com
p 3.
M
edic
ines
for C
hild
ren
[Inte
rnet
]. In
form
atio
n fo
r car
eer a
nd p
aren
ts:v
igab
atrin
for p
reve
ntin
g se
izur
es; 2
014
[u
pdat
ed J
an, 2
014]
. Ava
ilabl
e fro
m w
ww
.med
icin
esfo
rchi
ldre
n.or
g.uk
4.
M
icro
med
ex v
1622
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References:
1. Pediatric Dosage Handbook (Lexi-comp) 16th Edition
2. Online Lexicomp
3. Medicines for Children [Internet]. Information for career and parents:vigabatrin for preventing seizures; 2014 [updated Jan, 2014]. Available from www. medicinesforchildren.org.uk
4. Micromedex v1622
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Infantile Spasm
Introduction
Infantile spasm (West syndrome) is a severe form of epilepsy of early infancy, onset during the first year of life with peak age between 3 and 7 month1. The 3 main features are a history of epileptic spasms, hypsarrhythmia (or modified hypsarrhythmia) on EEG and often development arrest or regression2.
Spasms maybe subtle, brief, and sudden, the most subtle being a head nod or tonic eye rolling, shown great variability in frequency which may be easily missed. Typically the spasms involve brief symmetrical contraction of musculature of neck, trunk and extremities lasting up to 5 seconds and occurring in clusters, occur before or on awaking or just before sleep. The number of spasms can vary from a few to more than hundreds per cluster with every cluster lasted from less than a minute to more than 10 minutes3. Early detection and prompt effective treatment is important to improve neurodevelopmental outcomes.
Management Pharmacotherapy 1. United Kingdom Infantile Spasm Study (UKISS) Protocol4
Hormone treatment: Prednisolone 10mg QID (not weight based) for 2 weeks, increasing to 20mg TDS after 1 week if spasm continued. After 2 weeks of treatment, tapper off Prednisolone slowly with reduction of 10mg every 5 days (over 2-3 weeks).
Ranitidine, omeprazole or esomeprazole should be considered to help prevent gastric ulcer that may be caused by high dose prednisolone3.
NEUROLOGY
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Special consideration5
• Prednisolone should be tapered off slowly to avoid acute adrenocortical insufficiency.
• Steroid may cause a level of immunosuppression, causing increased susceptibility of infection. Parents should be counseled to avoid contact with infectious person, in particular those with varicella infection.
• No live vaccines (e.g. MMR, MMR-V, varicella, BCG) should be given during therapy, and for 1 month after cessation of therapy.
• Similar efficacy between IM Tetracosactide (adrenocorticotrophic hormone ACTH) and oral prednisolone4. Oral prednisolone is easily available, cost effective, and having fewer side effects. It is recommended as an alternative to intramuscular ACTH in the treatment of non-TS infantile spasms8. 2. Vigabatrin
Vigabatrin is recommended as first line treatment for children with infantile spasm associated with tuberous sclerosis (TS) and also as second line treatment after 2-4 weeks of no response to corticosteroid in non-TS settings2.
Start with 50mg / kg / day in 2 divided doses, may titrate upwards by 25 to 50 mg / kg / day increments every 3 days based on response and tolerability ( max 150 mg / kg / day )6.
26
Infantile Spasm Introduction
Infantile spasm (West syndrome) is a severe form of epilepsy of early infancy, onset during the first year of life with peak age between 3 and 7 month1. The 3 main features are a history of epileptic spasms, hypsarrhythmia (or modified hypsarrhythmia) on EEG and often development arrest or regression2. Spasms maybe subtle, brief, and sudden, the most subtle being a head nod or tonic eye rolling, shown great variability in frequency which may be easily missed. Typically the spasms involve brief symmetrical contraction of musculature of neck, trunk and extremities lasting up to 5 seconds and occurring in clusters, occur before or on awaking or just before sleep. The number of spasms can vary from a few to more than hundreds per cluster with every cluster lasted from less than a minute to more than 10 minutes3. Early detection and prompt effective treatment is important to improve neurodevelopmental outcomes.
Management
Pharmacotherapy
1. United Kingdom Infantile Spasm Study (UKISS) Protocol4
Hormone treatment: Prednisolone 10mg QID (not weight based) for 2 weeks, increasing to 20mg TDS after 1 week if spasm continued. After 2 weeks of treatment, tapper off Prednisolone slowly with reduction of 10mg every 5 days (over 2-3 weeks). Ranitidine, omeprazole or esomeprazole should be considered to help prevent gastric ulcer that may be caused by high dose prednisolone3.
Tab Prednisolone 10mg QID Day 1- Day 7
D7 Spasm continued? Yes No
Day 8 - Day 14 Continue 10mg QID
Increase 20mg TDS
Tapper off Prednisolone with reduction of 10mg every 5 days
Over 2-3 weeks
With ranitidine, omeprazole or esomeprazole.
Monitor side effects:
§ Hypertension § Electrolytes
imbalance, particularly hypoK+
§ Immunosuppression § Irritability, restlessness § Increased appetite § Weight gain § Facial puffiness § Acne § Glucosuria § UTI
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Special considerations
• Side effects: hypotonia, somnolence or insomnia along with permanent vision field constriction (tunnel vision)7.
• Vigabatrin has also been associated with reversible signal changes at brain MRI localized at thalamus, basal ganglia, corpus callosum and mid brain7.
• Use with caution in patients with renal impairment; dosage modification may be necessary if CrCl <80 mL/minute6.
Non Pharmacotherapy
3. Ketogenic diet
Ketogenic diet is a strict diet which is high in fat, with adequate protein and low in carbohydrate used as a treatment in refractory seizure. It may be considered for children with infantile spasm who do not respond to hormone treatment and/or vigabatrin3. The exact mechanism still unknown, metabolic changes likely related to the its anticonvulsant properties include - but are not limited to - ketosis, reduced glucose, elevated fatty acid levels, and enhanced bioenergetic reserves9.
Pharmacist’s role in managing patient on ketogenic diet
Pharmacist plays important role in optimize patient’s treatment outcomes by restricting the use of concurrent medications with high carbohydrate content. A general rule of thumb is that carbohydrate content is the highest in suspensions and solutions, lower in chewable and disintegrating tablets, and lowest in tablets and capsules10.
General principles • No syrup medications, change to tablet or IV formulation. • Freshly prepared with water only.• No dextrose in IV drip, including diluents used for IV infusion.• Medications using saccharin as the sweetener are suitable.• Medications in suppository form are suitable for use on the ketogenic diet.• Medication labeled as ‘sugar free’ does not mean the product is carbohydrate free. Hidden carbohydrate source can be contributed by excipients.
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• Sugar ( dextrose, fructose, glucose, lactose, sucrose, sugar )
• Starches ( cornstarch, pregelatinized starch, sodium starch glycolate, sodium starch glycolate )
• Sorbitol
• Mannitol
• Xylitol
• Maltitol
• Isomalt
• Erythritol
• Alcohol
• Glycerin
• Hydrogenated Starch Hydrolysates (HSH)
• Ascorbic acid
• Su Cellulose
• Carboxymethylcellulose
• Hydroxymethylcellulose
• Microcrystalline cellulose
• Polyethylene glycol
• Magnesium stearate
• Aspartame
• Saccharine
• Asulfamine potassium (K)
Excipients which are source of carbohydrate11
Excipients which are not source of carbohydrate11
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Information on carbohydrate content in medications :
• www.matthewsfriends.org/Keto_Friendly_Medicine_List.doc
• Denis Lebel et al. (2001) The Carbohydrate and Caloric Content of Concomitant Medications for Children with Epilepsy on the Ketogenic Diet. Can. J. Neurol. Sci. 2001; 28: 322-340.
• Contact pharmaceutical companies for generic products
4. Other treatment options for infantile spasm
• Sodium valproate
• Topiramate etc.
References:
1. Hrachovy RA, Frost JD. Severe encephalopathic epilepsy in infants: infantile spasm (West syndrome). In Pediatric Epilepsy: Diagnosis and Therapy. Edited by Pellock JM, Bourgeois BF, Dodson WE, Nordli DR Jr,Sankar R. New York, NY: Demos Medical Publishing 2008:249–268.
2. Children’s Neuroscience Centre Management Guideline: Management of Infantile spasm (IS)/ West syndrome final 14-6-07
3. James WW, Patricia AG, Kari LR, Maria H, Christine OD, Vicky W, John MP. Infantile spasms (West syndrome): update and resource for pediatricians and providers to share with parents. BMC Pediatrics. 2012, 12:108.
4. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, Callaghan FJK, Verity CM, Osborne JP. The United Kingdom Infantile Spasm Study comparing vigabatrin with prednisolone or tetracosactide st 14 days: a multicentre, randomized controlled study. Lancet 2004 Nov 13: 364: 1773- 1778.
5. Guideline for Investigation and Management of Children with Infantile Spasms and West Syndrome. Nottingham University Hospital Trust; 2008 [cited 2014 Nov 4]. Available from: https://www.nuh.nhs.uk/handlers/downloads. ashx?id=52197
6. Lexicomp Online
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7. Piero P, Pasquale S, Raffaele F, Lorenzo P, Martino R. Infantile spasm syndrome, West syndrome and related phenotypes: what we know in 2013. Brain & Development. 2014, 739-751.
8. BH Ching, JW Tan, HS Heng, S Terumalay, TB Khoo, AR Mohamed. Paper presented at: Paediatric Neurology Update; 2013 Sept 28; Ipoh General Hospital, Perak, Malaysia.
9. Masino SA, Rho JM. Mechanisms of Ketogenic Diet Action. Jasper’s Basic Mechanisms of Epilepsies. 4th Edition. NCBI Bookshelf Online Book Version.
10. Runyon Am, So TY. Review Article The Useof Ketogenic Diet in Pediatric Patients with Epilepsy. International Scholarly Research Network ISRN Pediatrics volume 2012.
11. Minimising the carbohydrate content of medications on the ketogenic diet [cited 2014Nov 4]. Available from: http://www.gosh.nhs.uk/EasySiteWeb/ GatewayLink.aspx?alId=105274.
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NEPHROLOGY
Acute Glomerulonephritis
Introduction
Acute Glomerulonephritis (AGN) is an abrupt onset of one or more features of an Acute Nephritic Syndrome.Glomerular lesions are the results of glomerular deposition or insitu formation of immune complexes. Commonest cause of AGN in children (6-10 years old) is post-streptococcal infection of upper respiratory tract or skin1 due to group A Beta-Hemolytic Streptococcus2. Non-infectious causes of AGN are Henoch-Schoenlein purpura, IgA nephropathy, hereditary nephritis, systemic lupus erythematosus or systemic vasculitidis.
Clinical Features
The onset is usually abrupt and nephritis may follow 7–15 days after streptococcal tonsillitis and 4–6 weeks after impetigo2.
• Oedema (peripheral or periorbital). • Microscopic /macroscopic haematuria (urine: tea-coloured or smoky) • Decreased urine output (oliguria). • Hypertension.• Azotemia
Management
Fluid intake, urine output, daily weight and blood pressure (nephrotic chart) must be strictly monitor. Patient must be bed rested and put on salt-free diet. Fluid restriction if necessary until child diuresis and blood pressure (BP) is controlled.
Pharmacotherapy
• Penicillin V : Start oral Penicillin (7.5-15mg/kg 6 hourly) for 10 days to eliminate - haemolytic streptococcal infection (may use Erythromycin if allergic to Penicillin).
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Management of Severe Complications1
Hypertension
• For the management of hypertension use the following antihypertensives: oral Nifedipine 0.25 - 0.5 mg / kg up to 4 hourly if needed, Frusemide 1mg / kg / dose, Captopril 0.1-0.5mg / kg 8 hourly or Metoprolol 1-4mg / kg 12 hourly.
• Monitor closely for signs and symptoms of severe hypertension or hypertensive emergency / encephalopathy such as headache, vomiting, loss of vision, convulsions, papilloedema.
• Target of BP control is to reduce BP to <90th percentile of BP for age, gender and height percentile. Reduce BP by 25% of target BP over 3 - 12 hours and the next 75% reduction is achieved over 48 hours. Total BP to be reduced = Observed mean BP - Desired mean BP
Pulmonary Oedema
• IV Frusemide 2 mg/kg/dose stat; double this dose 4 hours later if poor response.
• Fluid restriction for 24 hours if possible.
• Consider dialysis if no response to diuretics.
Acute Kidney Injury
• Mild renal impairment is common.
References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 58, Post-Infectious Glomerulonephritis; p.275-78
2. Garabed E, Norbert L, Kai-Uwe E, et.al. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements 2012 June; 2(2):200-8.
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Nephrotic Syndrome
Introduction
Primary or idiopathic nephrotic syndrome (NS) is the commonest type of nephrotic syndrome in children. Secondary NS include post-streptococcal glomerulonephritis, systemic lupus nephritis1.
Definition2: • Relapses: Urine protein to creatinine ratio (uPCR) ≥2000mg/g (≥200mg/ mmol) or ≥ 3+ protein on urine dipstick for 3 consecutive days.
• Frequent relapses: ≥ 2 relapses within 6 months of initial response, or ≥ 4 relapses within any 12 month period.
• Steroid dependent: ≥ 2 consecutive relapses occurring during steroid taper or within 14 days of the cessation of steroids.
• Steroid resistant: failure to achieve response to an initial 4 weeks treatment with prednisolone at 60mg/m2/day.
Clinical Features
• Edema
• Hypoalbuminaemia of < 25g/l
• Proteinuria > 40 mg/m²/hour (> 1g/m²/day) or an early morning urine protein creatinine index of >200 mg/mmol (> 3.5 mg/mg)
• Hypercholesterolaemia
NEPHROLOGY
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Management
Pharmacotheraphy
• Oral Penicillin V For prevention of primary bacterial peritonitis, 125 mg Oral BD (1-5 years age), 250 mg BD (6-12 years), 500 mg BD (> 12 years)
• In patient with reduced urine output Human Albumin (20-25%) at 0.5 - 1.0 g / kg may be use with IV Frusemide at 1-2 mg/kg to produce a diuresis.
• Corticosteroid therapy, cyclophosphamide (refer algorithm).
Management of Complications1
• Hypovolaemia. Clinical features: abdominal pain, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. Treatment is to infuse Human Albumin at 0.5 to 1.0 g/kg/dose fast. If human albumin is not available, other volume expanders like human plasma can be used. Do not give Frusemide.
• Primary Peritonitis Clinical features: fever, abdominal pain and tenderness in children with newly diagnosed or relapse nephrotic syndrome. Peritonitis is treated with parenteral penicillin and a third generation cephalosporin
• Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed. Please consult a Paediatric Nephrologist.
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• Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed. Please consult a Paediatric Nephrologist.
Algorithm 1: Management of Nephrotic Syndrome
1. INITIAL EPISODE OF NEPHROTIC SYNDROME Prednisolone 60 mg/m²/day for 4 weeks
6. RELAPSES POST CYCLOPHOSPHAMIDE • As for (2) and (3) if not steroid toxic • If steroid toxic, refer paediatric nephrologist to consider therapy with cyclosporin or levamisole
2. RELAPSE • Prednisolone 60 mg/m²/day till remission • 40 mg/m²/alternate day for 4 weeks then stop
3. FREQUENT RELAPSES • Reinduce as (2), then taper and keep low dose alternate day Prednisolone 0.1 -‐ 0.5 mg/kg/dose for 6 months
4. RELAPSES WHILE ON PREDNISOLONE • Treat as for (3) if not steroid toxic • Consider cyclophosphamide if steroid toxic.
5. ORAL CYCLOPHOSPHAMIDE • 2-‐3 mg/kg/day for 8-‐12 weeks Cumulative dose 168 mg/kg
Prednisolone 40 mg/m²/alternate day for 4 weeks. then taper at 25% monthly over 4 months
Response No Response
RENAL BIOPSY
Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
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Special consideration
• If exposed to chickenpox and measles during corticosteroid therapy, it should be treated like any immunocompromised child who has come into contact with these diseases.
• Live vaccines should be deferred until prednisolone dose is <20mg/day or 2mg / kg on a l ternate days (<40mg on a l ternate days) and/or immunosuppressive agents have been stopped for at least 1-3 months2.
References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 59, Nephrotic Syndrome; p.279-84
2. Garabed E, Norbert L, Kai-Uwe E, et.al. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements 2012 June; 2(2):156-76
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Acute Renal Failure
Introduction
Acute renal failure (ARF) also known as acute kidney injury. It is an abrupt onset of rising in serum creatinine (SCr) level and decreased glomerular filtration rate (GFR) and inability of kidney to regulate electrolytes and fluid hemostasis. ARF is divided into pre-renal injury, intrinsic renal disease, or post-renal obstruction. ARF since childhood due to haemolytic-uremic syndrome, post-infectious acute glomerulonephritis or dehydration are reversible, but a small percentage may progress to chronic renal failure (CRF)1.
Clinical Features
• Oliguria (< 300 ml/m²/day in children; < 1 ml/kg/hour in neonates) or • Non-oliguria (Nephrotoxic injury, Interstitial Nephritis, or Neonatal Asphyxia)
Management
Pharmacotherapy
Fluid BalanceIn hypovolaemia, fluid resuscitation must be initiated regardless of oliguric / anuric state by crystalloids e.g. isotonic 0.9% saline / Ringer’s lactate 20 ml/kg fast (in < 20 minutes) after obtaining vascular access. Transfuse blood if haemorrhage is the cause of shock. If urine output increases, continue fluid replacemen homever if there is no urine output after 4 hours (confirm with urinary catheterization), monitor central venous pressure to assess fluid status3.
In hypervolaemia / fluid if necessary to give fluid, restrict to insensible loss (400 ml/m²/day or 30ml/kg in neonates depending on ambient conditions). Treat with IV Frusemide 2 mg/kg/dose (over 10-15 minutes), maximum of 5 mg/kg/dose or IV Frusemide infusion 0.5 mg/kg/hour. Dialysis if no response or if volume overload is life-threatening. Once normal volume status is achieved, give insensible loss plus obvious losses (urine / extrarenal) 3.
NEPHROLOGY
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Hypertension Usually related to fluid overload and/or alteration in vascular tone. Treatment with anti-hypertensive drugs depends on degree of BP elevation, presence of central nervous system symptoms of hypertension and cause of renal failure. A diuretic is usually needed.
Metabolic acidosis It is treated if pH < 7.2 or symptomatic or contributing to hyperkalaemia. Ensure that patient’s serum calcium is > 1.8 mmol/L to prevent hypocalcaemic seizures with Sodium bicarbonate therapy. Replace half the deficit with IV 8.4% Sodium bicarbonate (1:1 dilution) if indicated.
Bicarbonate deficit = 0.3 x body weight (kg) x base excess (BE)
Electrolytes abnormalities
• Hyperkalemia (K+> 6.0 mmol/l in neonates and > 5.5 mmol/l in children):
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Electrolytes abnormalities • Hyperkalemia (K⁺> 6.0 mmol/l in neonates and > 5.5 mmol/l in children):
Table 1: Treatment of Hyperkalemia in Acute Kidney Injury
TREATMENT OF HYPERKALEMIA IN AKI PATIENTS Do 12-‐lead ECG and look for hyperkalaemic changes If ECG is abnormal or plasma K+ > 7 mmol/l, connect patient to a cardiac monitor and give the following in sequence: 1 IV 10% Calcium gluconate 0.5 -‐ 1.0 ml/kg (1:1 dilution) over 5 -‐15 mins (Immediate onset of action) 2 IV Dextrose 0.5 g/kg (2 ml/kg of 25%) over 15 – 30 mins. 3 ± IV Insulin 0.1 unit/kg (onset of action 30 mins). 4 IV 8.4% sodium bicarbonate 1 ml/kg (1:1 dilution) over 10 -‐ 30 mins (Onset of action 15 -‐ 30 mins) 5 Nebulized 0.5% salbutamol 2.5 -‐ 5 mg (0.5 -‐ 1 ml : 3 ml 0.9% Saline) (Onset of action 30 mins)
6 Calcium polystyrene sulphonate 0.25g/kg oral or rectally 4 times/day (Max 10g/dose) (Calcium Resonium / Kalimate) [Give rectally (NOT orally) in neonates 0.125 – 0.25g/kg 4 times/day]
OR 6 Sodium polystyrene sulphonate 1g/kg oral or rectally 4 times/day (Max15g/dose) (Resonium) In patients with serum potassium between 5.5 -‐ 7 mmol/L without ECG changes, give calcium or sodium polystyrene sulphonate
If insulin is given after dextrose, monitor RBS / Dextrostix for hypoglycaemia. Dialyse if poor or no response to the above measures
Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
• Hyponatremia: fluid restriction if dilutional; if symptomatic or level Na+ <120 mmol/L give Sodium Chloride. [Sodium deficit: (desired sodium – actual sodium) x 0.6 x body weight] Give 50% of sodium deficit then reassess, avoid rapid correction.1
• Hyperphosphatemia: oral phosphate binder. • Hypocalcemia: Treat if symptomatic (usually serum Ca²⁺ < 1.8 mmol/L), and if Sodium
bicarbonate is required for hyperkalaemia, with IV 10% Calcium gluconate 0.5 ml/kg, given over 10 – 20 minutes, with ECG monitoring3.
Dialysis Indicated if there are severe complication. Special consideration
• Medications: dose adjustment, avoidance of nephrotoxic agents, dilutions of medications.3
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Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition
• Hyponatremia: fluid restriction if dilutional; if symptomatic or level Na+ <120 mmol/L give Sodium Chloride. [Sodium deficit: (desired sodium – actual sodium) x 0.6 x body weight] Give 50% of sodium deficit then reassess, avoid rapid correction.1
• Hyperphosphatemia: oral phosphate binder.
• Hypocalcemia: Treat if symptomatic (usually serum Ca² < 1.8 mmol/L), and if Sodium bicarbonate is required for hyperkalaemia, with IV 10% Calcium gluconate 0.5 ml/kg, given over 10 - 20 minutes, with ECG monitoring3.
Dialysis
Indicated if there are severe complication.
Special consideration
• Medications: dose adjustment, avoidance of nephrotoxic agents, dilutions of medications.3
References:
1. Chan, J.C.M, Williams, D.M., Roth, K.S. Pediarics in Review. Feb 2002; 23(2): 47-60.
2. Guideline on management and investigation of acute renal failure. Renal Unit Royal Hospital for Sick Children. November 2005. [cited on: 2014 Oct 20 ] Available from: http://www.clinicalguidelines.scot.nhs.uk
3. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 60, Acute Renal Failure; p.285-91
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INFECTIOUS DISEASES
Tuberculosis
Introduction
Tuberculosis (TB) is the most common cause of infection-related death worldwide1.
TB occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses2.
Disease may be pulmonary (PTB) or extrapulmonary (EPTB), (i.e. central nervous system (CNS), disseminated (miliary), lymph node, bone & joint) or both2.
Clinical features
Common clinical features suggestive of TB in children are prolonged fever, failure to thrive, unresolving pneumonia, loss of weight and persistent lymphadenopathy. TB should be suspected in a symptomatic child having history of contact with active TB2.
Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy should be evaluated for TB2.
Management
Pharmacotherapy
Corticosteroids3
• Indicated for children with TB meningitis
• May be considered for children with pleural and pericardial effusion (to hasten reabsorption of fluid), severe miliary disease (if hypoxic) and endobronchial disease
• Steroids should be given only when accompanied by appropriate antituberculous therapy
• Dosage: prednisolone 1-2mg/kg per day (max. 40 mg daily) for first 3-4 week, then taper over 3-4 weeks
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Table 1: Recommended Doses of AntiTB Drugs in Children2
DRUG
DAILY DOSE INTERMITTENT DOSE
SIDE EFFECTS4,5 DOSE (RANGE) IN MG/KG/DAY
MAXIMUM DOSE (MG) MG/KG/DAY MAXIMUM
DOSE (MG)
Isoniazid 10 (10-15) 300 10 900
Skin rash, jaundice, hepatitis,
anorexia, nausea, abdominal pain,
burning, numbness or
tingling sensation in the hands or
feet
Rifampicin 15 (10-20) 600 10 600
Skin rash, jaundice, hepatitis,
anorexia, nausea, abdominal pain, orange or red
urine, flu syndrome (fever, chills, malaise,
headache, bone pain)
Pyrazinamide 35 (30-40) 2000 - -
Skin rash, jaundice, hepatitis,
anorexia, nausea, abdominal pain &
joint pains Ethambutol 20 (15-25) 1000 30-50 2500 Visual impairment
Pyridoxine 5 - 10 mg daily needs to be added if isoniazid is prescribed
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Table 2: Suggested second line AntiTB Drugs in Children, Dosages and Side effects2
DRUG DAILY DOSE
SIDE EFFECTS4,5 DOSE (RANGE) IN MG/KG/DAY
MAXIMUM DOSE (MG) FREQUENCY
Kanamycin 15-30 1000 Daily Nephrotoxicity, peripheral neuropathy, rash, auditory damage Amikacin 15-22.5 1000 Daily
Capreomycin 15-30 1000 Daily
Nephrotoxicity, tubular dysfunction, azotaemia, proteinuria, urticaria or
maculopapular rash
Cyloserine* 10-20 1000 Daily/Twice daily
Neurological and psychiatric disturbances
Including headaches, irritability, sleep disturbances,
aggression and tremors, gum inflammation, pale
skin, depression, confusion, dizziness, restlessness, anxiety, nightmares, severe
headache, drowsiness
Ethionamide 15-20 1000 Twice daily
Severe gastrointestinal intolerance, psychotic
disturbances, neurotoxicity, gynecomastia
p-aminosalicylic acid (PAS)
200-300 12000 3-4 times equally divided dose
Gastrointestinal intolerance, careful use
in patients with glucose6-phosphate
dehydrogenase (G6PD) deficiency.
Clofazimine Safety and efficacy not estalished
Chthyosis,dry skin; pink to brownish-black
discolouration of skin, cornea, retina and urine; anorexia,
abdominal pain Ofloxacin
15-20 800 Twice daily
Gastrointestinal intolerance, headache,
malaise, insomnia, restlessness, dizziness,
allergic reactions, diarrhoea,
photosensitivity
Levofloxacin
7.5-10 750 Daily
Moxifloxacin 7.5-10 400 Daily
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* All patients receiving cycloserine should be given 50 mg pyridoxine for every 250 mg of cycloserine.
Monitoring of Drug Toxicity2
• Indications for baseline and routine monitoring of serum transaminases and bilirubin are recommended for: * Severe TB disease. * Clinical symptoms of hepatotoxicity. * Underlying hepatic disease. * Use of other hepatotoxic drugs (especially anticonvulsants). * HIV infection.
• Routine testing of serum transaminases in healthy children with none of the above risk factors is not necessary.
• Children on Ethambutol should be monitored for visual acuity and colour discrimination.
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Table 3: Recommended Treatment Regimens for Children in Different TB Diagnostic Categories2
TB cases
Regimen*
Remarks Intensive phase
Continuation phase
New smear positive PTB New smear negative PTB Less severe EPTB
2HRZ 4HR
Ethambutol can be added in the intensive phase of suspected isoniazid-resistance or extensive pulmonary disease cases
Severe concomitant HIV disease
2HRZE 4HR
Severe form of EPTB TB meningitis/ spine/bone
2HRZE 10HR
Previously treated smear positive PTB including relapse and treatment after interruption
3HRZE 5HRE
All attempt should be made to obtain culture and sensitivity result. In those highly suspicious of Multidrug resistant (MDR-TB), refer to paediatrician with experience in TB management.
Treatment failure TB
Refer to paediatrician with experience in TB management.
MDR-TB Individualised regimen
Refer to paediatrician with experience in TB management.
*Direct observation of drug ingestion is recommended especially during the initial phase of treatment and whenever possible during the continuation phase. Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2
Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants.
H=isoniazid, R=rifampicin, Z=pyrazinamide, E=ethambutol
Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2
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Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants.
Children younger than 5 years of age with LTBI have a 10 - 20% risk of developing TB disease
Management
Pharmacotherapy
Non-HIV infected children with latent tuberculosis infection should be treated with 6-month of isoniazid or 3-month of isoniazid plus rifampicin2.
There is no retrievable evidence of treatment for LTBI in HIV-infected children. However, WHO recommends 6-months isoniazid therapy2.
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Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2
Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants. Children younger than 5 years of age with LTBI have a 10 - 20% risk of developing TB disease Management Pharmacotherapy Table 4: Anti-TB Regimens for LTBI in Children
Drug Duration Interval Isoniazid 6 months Daily
Isoniazid + Rifampicin 3 months Daily Non-HIV infected children with latent tuberculosis infection should be treated with 6-month of isoniazid or 3-month of isoniazid plus rifampicin2. There is no retrievable evidence of treatment for LTBI in HIV-infected children. However, WHO recommends 6-months isoniazid therapy2. Congenital & Perinatal TB Congenital TB is defined as a direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery. Perinatal TB includes early postnatal transmission of the disease and is a more inclusive term2. After active TB is ruled out, babies at risk of infection from their mothers should be given six months of isoniazid preventive therapy, followed by BCG vaccination2. Alternatively, if three months of isoniazid is given, tuberculin skin test (TST) should be done on completion of treatment:- •If TST is negative (<5 mm), BCG vaccine should be administered and treatment stopped2
•If TST is positive (=5 mm), treatment should continue for six months, followed by the BCG at the end of treatment2.
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Congenital & Perinatal TB
Congenital TB is defined as a direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery. Perinatal TB includes early postnatal transmission of the disease and is a more inclusive term2.
After active TB is ruled out, babies at risk of infection from their mothers should be given six months of isoniazid preventive therapy, followed by BCG vaccination2.
Alternatively, if three months of isoniazid is given, tuberculin skin test (TST) should be done on completion of treatment:-
• If TST is negative (<5 mm), BCG vaccine should be administered and treatment stopped2
• If TST is positive (=5 mm), treatment should continue for six months, followed by the BCG at the end of treatment2
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Table 5: Prophylaxis for Infants with Maternal TB2
Active PTB diagnosed before delivery
Active PTB diagnosed after delivery
>2 months before
<2 months before
<2 months after
>2 months after
Smear negative just
before delivery
Smear positive
just before delivery
- - -
No prophylaxis for infant
Give prophylaxis: Isoniazid for six months OR isoniazid for three
months followed by TST
Give prophylaxis: Isoniazid for six months
OR isoniazid + rifampicin for three months
BCG at birth Defer BCG at birth, give after stopping isoniazid
Reimmunise with BCG after
stopping isoniazid
If BCG given at birth, no need to reimmunise
Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Special Consideration Breast-feeding and mother with PTB3
TB treatment in lactating mothers is safe as the amount of drug ingested by the baby is minimal. Hence if the mother is already on treatment and is non-infective, the baby can be breastfed. Women who are receiving isoniazid and are breastfeeding should receive pyridoxine. If the mother is diagnosed to have active PTB and is still infective:
• The newborn should be separated from the mother for at least 1 week while the mother is being treated.
• Mother should wear a surgical mask subsequently while breast feeding until she is
asymptomatic and her sputum is AFB-smear negative.
• Breast feeding is best avoided during this period but expressed breast milk can be given.
• The infant should be evaluated for congenital TB. If this is excluded, BCG is deferred and the baby should receive isoniazid for 3 months and then tuberculin tested. If tuberculin negative and mother has been adherent to treatment and non-infectious, isoniazid can be discontinued and BCG given. If tuberculin positive, the infant should be
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Special Consideration
Breast-feeding and mother with PTB3
TB treatment in lactating mothers is safe as the amount of drug ingested by the baby is minimal. Hence if the mother is already on treatment and is non-infective, the baby can be breastfed.
Women who are receiving isoniazid and are breastfeeding should receive pyridoxine.
If the mother is diagnosed to have active PTB and is still infective:
• The newborn should be separated from the mother for at least 1 week while the mother is being treated.
• Mother should wear a surgical mask subsequently while breast feeding until she is asymptomatic and her sputum is AFB-smear negative.
• Breast feeding is best avoided during this period but expressed breast milk can be given.
• The infant should be evaluated for congenital TB. If this is excluded, BCG is deferred and the baby should receive isoniazid for 3 months and then tuberculin tested. If tuberculin negative and mother has been adherent to treatment and non-infectious, isoniazid can be discontinued and BCG given. If tuberculin positive, the infant should be reassessed for TB disease and if disease is not present, isoniazid is continued for total of 6 months and BCG given at the end of treatment.
References
1. Pediatric Tuberculosis.Vandana Batra, MD; Chief Editor: Russell W Steele, MD http://emedicine.medscape.com/article/969401-overview#aw2aab6b4
2. Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH, 2012.
3. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 80, Tuberculosis; p.419-24.
4. World Health Organization. Treatment of tuberculosis Guidelines Fourth Edition. Geneva: WHO; 2010
5. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis 2011 Update. Geneva: WHO; 2011
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Malaria
Introduction
Malaria is a tropical infection caused by members of protozoan genus called Plasmodium that parasitize human red blood cells and liver. It is transmitted by anopheline mosquitoes and the most common Plasmodium species that caused malaria infection in human included P. falciparum, P.vivax, P.ovale, P. malariae and P.knowlesi1. According to WHO world report 2013, endemic area in Malaysia included Sabah, Sarawak and central Peninsular Malaysia, with majority infection caused by P.vivax (24%) and P. falciparum (18%). P.falciparum is associated with highest mortality and morbidity. Symptoms of malaria included fever, malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills, and / or cough2.
Management
Pharmacotherapy Disease management depends on the type of Plasmodium infection and the severity of infection3-5.
INFECTIOUS DISEASES
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Malaria
Introduction Malaria is a tropical infection caused by members of protozoan genus called Plasmodium that parasitize human red blood cells and liver. It is transmitted by anopheline mosquitoes and the most common Plasmodium species that caused malaria infection in human included P. falciparum, P.vivax, P.ovale, P. malariae and P.knowlesi1.
According to WHO world report 2013, endemic area in Malaysia included Sabah, Sarawak and central Peninsular Malaysia, with majority infection caused by P.vivax (24%) and P. falciparum (18%). P.falciparum is associated with highest mortality and morbidity. Symptoms of malaria included fever, malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills, and/or cough2.
Management Pharmacotherapy Disease management depends on the type of Plasmodium infection and the severity of infection3-5. (i) Uncomplicated P. falciparum infection3
Table 1: First line treatment for uncomplicated P. falciparum infection
First line : Artemisinin-based Combination Therapy (ACT)
Preferred treatment Alternative treatment Artesunate/Mefloquine (Artequine)* Dosage: 10-20kg: Artesunate 50mg OD x 3/7 Mefloquine 125mg OD x 3/7 Artequine 50/125mg (fixed dose pellets) OD x 3/7 20-40kg: Artesunate 100mg OD x 3/7 Mefloquine 250mg OD x 3/7 (Artequine 300/750) >40kg: Artesunate 200mg OD x 3/7 Mefloquine 500mg OD x 3/7 (Artequine 600/1500)
Artemether/Lumefantrine (Riamet) Dosage: 5-14kg: D1: 1 tab stat then 1 tab again after 8 hours, D2-D3: 1 tab BD 15-24kg: D1: 2 tabs stat then 2 tabs again after 8 hours D2-D3: 2 tabs BD 25-35kg: D1: 3 tabs stat then 3 tabs again after 8 hours D2-D3: 3 tabs BD >35kg: D1: 4 tabs stat then 4 tabs again after 8 hours D2-D3: 4 tabs BD
Riamet should NOT be used in young infant less than 5kg or less than 4 months. Treatment recommendation for these group of patients :
D1: IM Artesunate 1.2mg / kg or IM Arthemether 1.6mg / kg D2-D7: Oral Artesunate 2mg / kg / day OR
D1-7: Oral Quinine 10mg/kg TDS for 4 days, then 15-20mg/kg TDS for 4 days.
(Ref: Malaria in children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University)
(i) Uncomplicated P. falciparum infection3
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‘Add primaquine 0.75mg base/kg single dose OD if gametocyte is present at any time during treatment.
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Riamet should NOT be used in young infant less than 5kg or less than 4 months. Treatment recommendation for these group of patients : D1: IM Artesunate 1.2mg/kg or IM Arthemether 1.6mg/kg D2-D7: Oral Artesunate 2mg/kg/day
OR D1-7: Oral Quinine 10mg/kg TDS for 4 days, then 15-20mg/kg TDS for 4 days. (Ref: Malaria in children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University) (ii) Second line P. falciparum infection3
• An alternative ACT is used (if Riamet was used in the first regimen, use Artequine for
treatment failure and vice-versa). • Artesunate 4mg/kg OD plus Clindamycin 10mg/kg/dose bd for a total of 7 days. • Quinine 10mg salt/kg 8 hourly plus Clindamycin 10mg/kg/dose bd for a total of 7 days.
Add primaquine 0.75mg base/kg single dose OD if gametocyte is present at any time during treatment. (iii) Severe P. falciparum infection3
Table 2: Treatment for severe P. falciparum infection
Preferred Treatment Alternative treatment
IV Artesunate: 2.4mg/kg at 0,12 and 24 hours, then daily until patient is able to tolerate orally. The use of IV Artesunate should continue for minimum of 24 hours or as soon as patient can tolerate orally.
IV Quinine loading 7mg salt/kg over 1 hour followed by 10mg salt/kg over 4 hours then 10mg salt/kg every 8 hour OR IV Quinine loading 20mg salt/kg over 4 hours, then 10mg salt/kg every 8 hour, for 7 days. PLUS Children > 8 yrs old: Doxycycline 3.5mg/kg OD x 7 days OR Children < 8 yrs old: Clindamycin 10mg/kg BD x 7 days.
(iii) Severe P. falciparum infection3
(ii) Second line P. falciparum infection3
• An alternative ACT is used (if Riamet was used in the first regimen, use Artequine for treatment failure and vice-versa).
• Artesunate 4mg/kg OD plus Clindamycin 10mg/kg/dose bd for a total of 7 days.
• Quinine 10mg salt/kg 8 hourly plus Clindamycin 10mg/kg/dose bd for a total of 7 days.
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(iv) Treatment of P.vivax*, malariae or knowlesi3
Table 3: Treatment for P.vivax, malariae or knowlesi
Preferred Treatment
Chloroquine sensitive: Chloroquine (150mg base/tab) D1: 10mg base/kg stat then 5mg base/kg 6 hours later D2: 5mg base/kg OD D3: 5mg base/kg OD * Calculation of chloroquine dose should be based on the base, not salt form.
Primaquine (7.5mg base/tab)
§ Add on Primaquine 0.5mg base/kg
daily for 14 days to ensure radical cure of hypnozoites for P.vivax infection.
§ Check G6PD before giving Primaquine.
§ For mild to moderate G6PD deficiency, an intermittent Primaquine regimen of 0.75mg base/kg weekly for 8 weeks can be given under medical supervision.
§ In severe G6PD deficiency Primaquine is contraindicated.
Chloroquine resistant: § To use ACT in relapse or chloroquine
resistant P.vivax, OR § Quinine 10mg salt/kg three times a day for
7 days OR § Mefloquine 15mg/kg single dose
Severe and complicated P.vivax, malariae and knowlesi should be managed as severe falciparum malaria.
PLUS
S
(iv) Treatment of P.vivax*, malariae or knowlesi3
Severe and complicated P.vivax, malariae and knowlesi should be managed as severe falciparum malaria.
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(v) Chemoprophylaxis6-7
Table 4: Chemoprophylaxis for travelling to malaria endemic areas
Drug Duration of Prophylaxis Dosage
Atovaquone/Proguanil (Malarone) Pediatric tablet: (Atovaquone 62.5mg/Proguanil 25mg) Adult tablet: (Atovaquone 250mg/Proguanil 100mg)
Start 2 days before journey, continue daily during exposure and up to 7 days thereafter.
Pediatric tablet of 62.5mg Atovaquone and 25mg Proguanil: 5-8kg: ½ tablet daily >8-10kg: ¾ tablets daily >10-20kg: 1 tablet daily >20-30kg: 2 tablets daily >30-40kg: 3 tablets daily >40kg: 1 adult tablet daily
Mefloquine (250mg base, 275mg salt per tablet)
Start 2-3 weeks before, continue weekly during exposure and for 4 weeks thereafter
<15kg: 5mg salt/kg 15-19kg: ¼ tab/week 20-30kg: ½ tab/week 31-45kg: ¾ tab/week >45kg: 1 tab/week
Doxycycline Start 2 days before journey, continue daily during exposure and for 4 weeks thereafter. Maximum duration of prophylaxis: 4 months
2.2mg base/kg once daily (max 100mg) (ref: Lexi comp) <25kg or < 8 years old: Do not use 25-35kg or 8-10 yrs old: 50mg 36-50kg or 11-13 yrs old: 75mg >50kg or >14 yrs old: 100mg
Chloroquine phosphate 250mg (equivalent to Chloroquine base 155mg)
Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas.
5mg/kg base orally once/week, up to maximum of 300mg base
Primaquine (i) Prophylaxis for short- duration travel to areas with principally P.vivax (ii) Used for presumptive antirelapse therapy (terminal prophylaxis) to decrease the risk for relapses of P. vivax and P. ovale
(i) 0.5mg/kg base up to 30mg base (adult dose) orally, daily (ii) 0.5 mg/kg base up to adult dose orally, daily for 14 days after departure from the malarious area
(v) Chemoprophylaxis6-7
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f liq
uid
to e
nsur
e al
l rem
aini
ng
pelle
ts a
re s
wal
low
ed.
If pa
tient
vom
ited
with
in 1
hou
r of
adm
inis
tratio
n, o
ne re
plac
emen
t dos
e is
re
quire
d
-Not
to b
e us
ed in
chi
ldre
n <1
0kg.
- A
void
in c
hild
ren
with
epi
leps
y as
it
may
incr
ease
the
risk
of s
eizu
re (i
t may
lo
wer
the
plas
ma
conc
entra
tion
of
Val
proi
c ac
id, C
arba
maz
epin
e,
Phe
noba
rbita
l or P
heny
toin
). -N
o do
sage
adj
ustm
ent f
or li
ver a
nd
rena
l im
pairm
ent.
-Do
not a
dmin
iste
r Hal
ofan
trine
with
A
rtequ
ine
as it
may
cau
se p
oten
tially
fa
tal p
rolo
ngat
ion
of Q
T in
terv
al.
- Diz
zine
ss
- Dis
turb
ed s
ense
of b
alan
ce
- Neu
ro- p
sych
iatri
c re
actio
ns
-Abd
omin
al p
ain
-Nau
sea
- V
omiti
ng
- Dia
rrho
ea
-Ast
heni
a - A
nore
xia
-Hyp
okal
aem
ia
2 A
rtem
ethe
r/Lum
efan
trine
(R
iam
et)
Adm
inis
ter w
ith h
igh
fat d
iet.
In y
oung
chi
ldre
n, R
iam
et c
an b
e cr
ushe
d an
d m
ixed
with
liqu
ids.
-Do
not g
ive
Ria
met
for c
hild
ren
less
th
an 5
kg o
r les
s th
an 4
mon
ths
of li
fe
-No
dosa
ge a
djus
tmen
t for
live
r and
re
nal i
mpa
irmen
t.
-QT
inve
rval
pro
long
atio
n -F
atig
ue
-Diz
zine
ss
3 C
hlor
oqui
ne
sulp
hate
Adm
inis
ter w
ith m
eal t
o de
crea
se G
I up
set.
May
mix
with
cho
cola
te s
yrup
or
bana
na to
mas
k th
e bi
tter t
aste
. If
the
child
vom
its w
ithin
firs
t 30
min
utes
, fu
ll do
se to
be
repe
ated
, hal
f dos
e if
vom
ited
betw
een
30
min
utes
and
1 h
our)
-Ren
al a
djus
tmen
t dos
e ne
eded
. -U
se w
ith c
autio
n in
pat
ient
s w
ith li
ver
dise
ase,
G6P
D d
efic
ienc
y, s
eizu
re
diso
rder
, sev
ere
bloo
d di
sord
er a
nd
pre-
exis
ting
audi
tory
dam
age.
-U
se in
pre
gnan
cy s
houl
d be
avo
ided
un
less
ben
efit
outw
eigh
s th
e ris
k to
the
fetu
s.
-May
exa
cerb
ate
psor
iasi
s an
d po
rphy
ria.
-Irre
vers
ible
retin
al d
aman
ge
was
repo
rted
in p
atie
nts
with
lo
ng te
rm o
r hig
h do
se
ther
apy.
- A
gran
uloc
ytos
is, n
eutro
peni
a,
panc
ytop
enia
, th
rom
bocy
tope
nia
- Myo
path
y -A
lope
cia,
blu
e gr
ay s
kin
pigm
enta
tion
Paediatric Pharmacy Services Guideline66
3.0
G
ener
al P
edia
tric
s
Sp
ecia
l Con
sid
erat
ion6
-9
50
Ta
ble
6: S
peci
al c
onsi
dera
tions
in a
nti-m
alar
ials
No
A
ntim
alar
ial
A
dmin
istr
atio
n
Prec
autio
n/C
ontr
aind
icat
ions
Side
Effe
cts/
Rem
arks
1
Arte
suna
te/
Mef
loqu
ine
(Arte
quin
e)
Ped
iatri
c pe
llets
can
be
adm
inis
tere
d di
rect
ly o
n pa
tient
’s to
ngue
, or p
lace
d on
th
e sp
oon
and
mix
ed w
ith li
ttle
amou
nt o
f liq
uid.
The
n rin
se th
e m
outh
with
sm
all
amou
nt o
f liq
uid
to e
nsur
e al
l rem
aini
ng
pelle
ts a
re s
wal
low
ed.
If pa
tient
vom
ited
with
in 1
hou
r of
adm
inis
tratio
n, o
ne re
plac
emen
t dos
e is
re
quire
d
-Not
to b
e us
ed in
chi
ldre
n <1
0kg.
- A
void
in c
hild
ren
with
epi
leps
y as
it
may
incr
ease
the
risk
of s
eizu
re (i
t may
lo
wer
the
plas
ma
conc
entra
tion
of
Val
proi
c ac
id, C
arba
maz
epin
e,
Phe
noba
rbita
l or P
heny
toin
). -N
o do
sage
adj
ustm
ent f
or li
ver a
nd
rena
l im
pairm
ent.
-Do
not a
dmin
iste
r Hal
ofan
trine
with
A
rtequ
ine
as it
may
cau
se p
oten
tially
fa
tal p
rolo
ngat
ion
of Q
T in
terv
al.
- Diz
zine
ss
- Dis
turb
ed s
ense
of b
alan
ce
- Neu
ro- p
sych
iatri
c re
actio
ns
-Abd
omin
al p
ain
-Nau
sea
- V
omiti
ng
- Dia
rrho
ea
-Ast
heni
a - A
nore
xia
-Hyp
okal
aem
ia
2 A
rtem
ethe
r/Lum
efan
trine
(R
iam
et)
Adm
inis
ter w
ith h
igh
fat d
iet.
In y
oung
chi
ldre
n, R
iam
et c
an b
e cr
ushe
d an
d m
ixed
with
liqu
ids.
-Do
not g
ive
Ria
met
for c
hild
ren
less
th
an 5
kg o
r les
s th
an 4
mon
ths
of li
fe
-No
dosa
ge a
djus
tmen
t for
live
r and
re
nal i
mpa
irmen
t.
-QT
inve
rval
pro
long
atio
n -F
atig
ue
-Diz
zine
ss
3 C
hlor
oqui
ne
sulp
hate
Adm
inis
ter w
ith m
eal t
o de
crea
se G
I up
set.
May
mix
with
cho
cola
te s
yrup
or
bana
na to
mas
k th
e bi
tter t
aste
. If
the
child
vom
its w
ithin
firs
t 30
min
utes
, fu
ll do
se to
be
repe
ated
, hal
f dos
e if
vom
ited
betw
een
30
min
utes
and
1 h
our)
-Ren
al a
djus
tmen
t dos
e ne
eded
. -U
se w
ith c
autio
n in
pat
ient
s w
ith li
ver
dise
ase,
G6P
D d
efic
ienc
y, s
eizu
re
diso
rder
, sev
ere
bloo
d di
sord
er a
nd
pre-
exis
ting
audi
tory
dam
age.
-U
se in
pre
gnan
cy s
houl
d be
avo
ided
un
less
ben
efit
outw
eigh
s th
e ris
k to
the
fetu
s.
-May
exa
cerb
ate
psor
iasi
s an
d po
rphy
ria.
-Irre
vers
ible
retin
al d
aman
ge
was
repo
rted
in p
atie
nts
with
lo
ng te
rm o
r hig
h do
se
ther
apy.
- A
gran
uloc
ytos
is, n
eutro
peni
a,
panc
ytop
enia
, th
rom
bocy
tope
nia
- Myo
path
y -A
lope
cia,
blu
e gr
ay s
kin
pigm
enta
tion
51
4 P
rimaq
uine
A
dmin
iste
r with
mea
ls to
dec
reas
e G
I ef
fect
s; d
rug
has
a bi
tter t
aste
. E
xtem
pora
neou
s pr
epar
atio
ns fo
rmul
a av
aila
ble.
- Scr
een
for G
6PD
sta
tus
befo
re
initi
atin
g tre
atm
ent
- Can
not b
e us
ed b
y pr
egna
nt w
omen
- C
anno
t be
used
by
wom
en w
ho a
re
brea
stfe
edin
g un
less
the
infa
nt h
as a
lso
been
test
ed fo
r G6P
D d
efic
ienc
y
- Ane
mia
- M
ethe
mog
lobi
nem
ia (
in
NA
DH
-met
hem
oglo
bin
redu
ctas
e de
ficie
nt in
divi
dual
s)
- Leu
kope
nia
5 Q
uini
ne
Infu
sion
rate
sho
uld
be <
5 m
g sa
lt /k
g/hr
M
axim
um Q
uini
ne p
er d
ose
= 60
0mg
-May
pro
long
QT
inte
rval
or c
ause
ca
rdia
c ar
rhyt
hmia
s -r
educ
e do
se in
pat
ient
s w
ith im
paire
d liv
er fu
nctio
n.
-Con
train
dica
ted
in p
atie
nts
with
pre
-ex
istin
g Q
T pr
olon
gatio
n, m
yast
heni
a gr
avis
, opt
ic n
eurit
is, G
6PD
def
icie
ncy.
-U
se o
f Qui
nine
in p
regn
ancy
at
ther
apeu
tic d
ose
is g
ener
ally
co
nsid
ered
saf
e. (L
exi C
omp)
-May
cau
se s
igni
fican
t hy
pogl
ycae
mia
in p
regn
ancy
. -S
teve
ns J
ohns
on s
yndr
ome
and
toxi
c ep
ider
mal
nec
roly
sis
has
been
repo
rted.
- A
gran
uloc
ytos
is, a
plas
tic
anem
ia, I
TP, h
emol
ytic
ane
mia
- C
olou
r vis
ion
dist
urba
nce,
di
min
ishe
d vi
sual
fiel
ds, o
ptic
ne
uriti
s
6.
Arte
suna
te
-Inje
ct (1
ml)
5% N
aHC
O3 s
olut
ion
prov
ided
into
the
Arte
suna
te v
ial,
shak
e 2-
3 m
inut
es u
ntil
clea
r sol
utio
n is
ob
tain
ed.
-For
IV in
ject
ion,
add
5m
l of N
S o
r D5%
to
mak
e fin
al c
once
ntra
tion
of 1
0mg/
ml o
f A
rtesu
nate
. A
dmin
iste
r at t
he ra
te o
f 3-4
ml/m
in.
-For
IM in
ject
ion,
add
2m
l NS
or D
5% to
m
ake
final
con
cent
ratio
n of
20m
g/m
l (to
tal 3
ml)
-Inje
ct im
med
iate
ly a
fter r
econ
stitu
tion.
-Ani
mal
exp
erim
ents
hav
e sh
own
som
e em
bryo
toxi
c ef
fect
. Sho
uld
be u
sed
with
ext
rem
e ca
utio
n in
pre
gnan
cy
with
in fi
rst t
hree
mon
ths.
- N
o do
sage
adj
ustm
ent f
or li
ver a
nd
rena
l im
pairm
ent.
-Tra
nsie
nt re
ticul
ocyt
open
ia
may
occ
ur w
hen
>3.7
5mg/
kg is
us
ed.
Paediatric Pharmacy Services Guideline 67
3.0
G
ener
al P
edia
tric
s
Sp
ecia
l Con
sid
erat
ion6
-9
50
Ta
ble
6: S
peci
al c
onsi
dera
tions
in a
nti-m
alar
ials
No
A
ntim
alar
ial
A
dmin
istr
atio
n
Prec
autio
n/C
ontr
aind
icat
ions
Side
Effe
cts/
Rem
arks
1
Arte
suna
te/
Mef
loqu
ine
(Arte
quin
e)
Ped
iatri
c pe
llets
can
be
adm
inis
tere
d di
rect
ly o
n pa
tient
’s to
ngue
, or p
lace
d on
th
e sp
oon
and
mix
ed w
ith li
ttle
amou
nt o
f liq
uid.
The
n rin
se th
e m
outh
with
sm
all
amou
nt o
f liq
uid
to e
nsur
e al
l rem
aini
ng
pelle
ts a
re s
wal
low
ed.
If pa
tient
vom
ited
with
in 1
hou
r of
adm
inis
tratio
n, o
ne re
plac
emen
t dos
e is
re
quire
d
-Not
to b
e us
ed in
chi
ldre
n <1
0kg.
- A
void
in c
hild
ren
with
epi
leps
y as
it
may
incr
ease
the
risk
of s
eizu
re (i
t may
lo
wer
the
plas
ma
conc
entra
tion
of
Val
proi
c ac
id, C
arba
maz
epin
e,
Phe
noba
rbita
l or P
heny
toin
). -N
o do
sage
adj
ustm
ent f
or li
ver a
nd
rena
l im
pairm
ent.
-Do
not a
dmin
iste
r Hal
ofan
trine
with
A
rtequ
ine
as it
may
cau
se p
oten
tially
fa
tal p
rolo
ngat
ion
of Q
T in
terv
al.
- Diz
zine
ss
- Dis
turb
ed s
ense
of b
alan
ce
- Neu
ro- p
sych
iatri
c re
actio
ns
-Abd
omin
al p
ain
-Nau
sea
- V
omiti
ng
- Dia
rrho
ea
-Ast
heni
a - A
nore
xia
-Hyp
okal
aem
ia
2 A
rtem
ethe
r/Lum
efan
trine
(R
iam
et)
Adm
inis
ter w
ith h
igh
fat d
iet.
In y
oung
chi
ldre
n, R
iam
et c
an b
e cr
ushe
d an
d m
ixed
with
liqu
ids.
-Do
not g
ive
Ria
met
for c
hild
ren
less
th
an 5
kg o
r les
s th
an 4
mon
ths
of li
fe
-No
dosa
ge a
djus
tmen
t for
live
r and
re
nal i
mpa
irmen
t.
-QT
inve
rval
pro
long
atio
n -F
atig
ue
-Diz
zine
ss
3 C
hlor
oqui
ne
sulp
hate
Adm
inis
ter w
ith m
eal t
o de
crea
se G
I up
set.
May
mix
with
cho
cola
te s
yrup
or
bana
na to
mas
k th
e bi
tter t
aste
. If
the
child
vom
its w
ithin
firs
t 30
min
utes
, fu
ll do
se to
be
repe
ated
, hal
f dos
e if
vom
ited
betw
een
30
min
utes
and
1 h
our)
-Ren
al a
djus
tmen
t dos
e ne
eded
. -U
se w
ith c
autio
n in
pat
ient
s w
ith li
ver
dise
ase,
G6P
D d
efic
ienc
y, s
eizu
re
diso
rder
, sev
ere
bloo
d di
sord
er a
nd
pre-
exis
ting
audi
tory
dam
age.
-U
se in
pre
gnan
cy s
houl
d be
avo
ided
un
less
ben
efit
outw
eigh
s th
e ris
k to
the
fetu
s.
-May
exa
cerb
ate
psor
iasi
s an
d po
rphy
ria.
-Irre
vers
ible
retin
al d
aman
ge
was
repo
rted
in p
atie
nts
with
lo
ng te
rm o
r hig
h do
se
ther
apy.
- A
gran
uloc
ytos
is, n
eutro
peni
a,
panc
ytop
enia
, th
rom
bocy
tope
nia
- Myo
path
y -A
lope
cia,
blu
e gr
ay s
kin
pigm
enta
tion
52
7 A
tova
quon
e/P
rogu
anil
(Mal
aron
e)
Tabl
ets
are
not p
alat
able
due
to b
itter
ta
ste.
May
cru
sh th
e ta
blet
s an
d m
ix w
ith
cond
ense
d m
ilk in
chi
ldre
n w
ith d
iffic
ulty
sw
allo
win
g ta
blet
s.
Take
with
food
or a
milk
y dr
ink
(incr
ease
th
e ra
te a
nd e
xten
d of
abs
orpt
ion)
. Ta
ke d
aily
at t
he s
ame
time
each
day
w
hile
in th
e m
alar
ious
are
a an
d fo
r 7
days
afte
r lea
ving
suc
h ar
eas.
-Con
train
dica
ted
in p
eopl
e w
ith s
ever
e re
nal i
mpa
irmen
t (C
rCl <
30 m
l/min
) -N
ot re
com
men
ded
for c
hild
ren
wei
ghin
g <5
kg,
pre
gnan
t wom
en, a
nd
wom
en b
reas
tfeed
ing
infa
nts
wei
ghin
g <5
kg
-Abs
orpt
ion
of A
tova
quon
e m
ay b
e de
crea
sed
in p
atie
nts
who
hav
e di
arrh
oea
or v
omiti
ng.
- Tra
nsam
inas
e in
crea
ses
- Mus
cle
wea
knes
s - D
izzi
ness
and
hea
dach
e - A
bdom
inal
pai
n, a
nore
xia,
di
arrh
oea,
nau
sea,
vom
iting
. G
ood
for l
ast-m
inut
e tra
vele
rs
beca
use
the
drug
is s
tarte
d 1-
2 da
ys b
efor
e tra
velin
g to
an
area
whe
re m
alar
ia
trans
mis
sion
occ
urs
8 M
eflo
quin
e A
dmin
iste
r with
food
. B
itter
tast
e.
Tabl
ets
can
be c
rush
ed a
nd m
ixed
with
sm
all a
mou
nt o
f wat
er, m
ilk, a
pple
sauc
e,
choc
olat
e sy
rup,
jelly
or f
ood.
R
epea
t ful
l dos
e if
vom
iting
occ
urs
with
in
30 m
inut
es a
fter a
dmin
istra
tion.
R
epea
t add
ition
al h
alf d
ose
if vo
miti
ng
occu
rs w
ithin
30-
60 m
inut
es a
fter
adm
inis
tratio
n.
- Can
not b
e us
ed in
: •
area
s w
ith m
eflo
quin
e re
sist
ance
•
patie
nts
with
cer
tain
psy
chia
tric
cond
ition
s •
patie
nts
with
a s
eizu
re d
isor
der
• pa
tient
s w
ith c
ardi
ac c
ondu
ctio
n ab
norm
aliti
es
- Can
be
used
in p
regn
ancy
-A
void
con
curr
ent u
se o
f dru
gs k
now
n to
cau
se Q
T-in
terv
al p
rolo
ngat
ion
(eg.
ha
lofa
ntrin
e, q
uini
ne, q
uini
dine
) or
CY
P3A
4 in
hibi
tors
(eg.
ket
ocon
azol
e)
-Con
curr
ent u
se w
ith c
hlor
oqui
ne m
ay
incr
ease
risk
of s
eizu
re.
- Not
a g
ood
choi
ce fo
r las
t-min
ute
trave
lers
bec
ause
dru
g ne
eds
to b
e st
arte
d at
leas
t 2 w
eeks
prio
r to
trave
l
-Diz
zine
ss, v
ertig
o, ti
nnitu
s,
loss
of b
alan
ce
-Anx
iety
, dep
ress
ion,
re
stle
ssne
ss, c
onfu
sion
-A
gran
uloc
ytos
is, a
plas
tic
anem
ia
-Sin
us b
rady
card
ia, s
inus
ar
rhyt
hmia
, fis
t deg
ree
AV
bl
ock,
QT-
inte
rval
pr
olon
gatio
n, a
bnor
mal
T
wav
es
Due
to li
mite
d cl
inic
al
expe
rienc
e an
d do
sage
form
av
aila
bilit
y, W
HO
gui
delin
es
excl
ude
patie
nts
wei
ghin
g <5
kg fr
om a
ntim
alar
ial d
osag
e re
com
men
datio
ns b
ut C
DC
gu
idel
ines
do
not e
xclu
de
thes
e pa
tient
s.
9
Dox
ycyc
line
Adm
inis
ter w
ith li
quid
s, a
void
ant
acid
s,
infa
nt fo
rmul
a, m
ilk, d
airy
pro
duct
s, a
nd
iron
1 ho
ur b
efor
e or
2 h
ours
afte
r ad
min
istra
tion
of d
oxyc
yclin
e.
May
be
adm
inis
tere
d w
ith fo
od to
de
crea
se G
I ups
et.
May
mix
with
milk
, cho
cola
te p
uddi
ng,
appl
e ju
ice
to in
crea
se p
alat
abili
ty.
- Can
not b
e us
ed b
y pr
egna
nt w
omen
an
d ch
ildre
n <8
yea
rs o
ld.
- Use
with
cau
tion
in p
atie
nts
with
rena
l im
pairm
ent.
-Pho
tose
nsiti
vity
- V
agin
al th
rush
- P
seud
o-m
embr
anou
s co
litis
- N
eutro
peni
a - T
hrom
bocy
tope
nia
Paediatric Pharmacy Services Guideline68
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s
Sp
ecia
l Con
sid
erat
ion6
-9
50
Ta
ble
6: S
peci
al c
onsi
dera
tions
in a
nti-m
alar
ials
No
A
ntim
alar
ial
A
dmin
istr
atio
n
Prec
autio
n/C
ontr
aind
icat
ions
Side
Effe
cts/
Rem
arks
1
Arte
suna
te/
Mef
loqu
ine
(Arte
quin
e)
Ped
iatri
c pe
llets
can
be
adm
inis
tere
d di
rect
ly o
n pa
tient
’s to
ngue
, or p
lace
d on
th
e sp
oon
and
mix
ed w
ith li
ttle
amou
nt o
f liq
uid.
The
n rin
se th
e m
outh
with
sm
all
amou
nt o
f liq
uid
to e
nsur
e al
l rem
aini
ng
pelle
ts a
re s
wal
low
ed.
If pa
tient
vom
ited
with
in 1
hou
r of
adm
inis
tratio
n, o
ne re
plac
emen
t dos
e is
re
quire
d
-Not
to b
e us
ed in
chi
ldre
n <1
0kg.
- A
void
in c
hild
ren
with
epi
leps
y as
it
may
incr
ease
the
risk
of s
eizu
re (i
t may
lo
wer
the
plas
ma
conc
entra
tion
of
Val
proi
c ac
id, C
arba
maz
epin
e,
Phe
noba
rbita
l or P
heny
toin
). -N
o do
sage
adj
ustm
ent f
or li
ver a
nd
rena
l im
pairm
ent.
-Do
not a
dmin
iste
r Hal
ofan
trine
with
A
rtequ
ine
as it
may
cau
se p
oten
tially
fa
tal p
rolo
ngat
ion
of Q
T in
terv
al.
- Diz
zine
ss
- Dis
turb
ed s
ense
of b
alan
ce
- Neu
ro- p
sych
iatri
c re
actio
ns
-Abd
omin
al p
ain
-Nau
sea
- V
omiti
ng
- Dia
rrho
ea
-Ast
heni
a - A
nore
xia
-Hyp
okal
aem
ia
2 A
rtem
ethe
r/Lum
efan
trine
(R
iam
et)
Adm
inis
ter w
ith h
igh
fat d
iet.
In y
oung
chi
ldre
n, R
iam
et c
an b
e cr
ushe
d an
d m
ixed
with
liqu
ids.
-Do
not g
ive
Ria
met
for c
hild
ren
less
th
an 5
kg o
r les
s th
an 4
mon
ths
of li
fe
-No
dosa
ge a
djus
tmen
t for
live
r and
re
nal i
mpa
irmen
t.
-QT
inve
rval
pro
long
atio
n -F
atig
ue
-Diz
zine
ss
3 C
hlor
oqui
ne
sulp
hate
Adm
inis
ter w
ith m
eal t
o de
crea
se G
I up
set.
May
mix
with
cho
cola
te s
yrup
or
bana
na to
mas
k th
e bi
tter t
aste
. If
the
child
vom
its w
ithin
firs
t 30
min
utes
, fu
ll do
se to
be
repe
ated
, hal
f dos
e if
vom
ited
betw
een
30
min
utes
and
1 h
our)
-Ren
al a
djus
tmen
t dos
e ne
eded
. -U
se w
ith c
autio
n in
pat
ient
s w
ith li
ver
dise
ase,
G6P
D d
efic
ienc
y, s
eizu
re
diso
rder
, sev
ere
bloo
d di
sord
er a
nd
pre-
exis
ting
audi
tory
dam
age.
-U
se in
pre
gnan
cy s
houl
d be
avo
ided
un
less
ben
efit
outw
eigh
s th
e ris
k to
the
fetu
s.
-May
exa
cerb
ate
psor
iasi
s an
d po
rphy
ria.
-Irre
vers
ible
retin
al d
aman
ge
was
repo
rted
in p
atie
nts
with
lo
ng te
rm o
r hig
h do
se
ther
apy.
- A
gran
uloc
ytos
is, n
eutro
peni
a,
panc
ytop
enia
, th
rom
bocy
tope
nia
- Myo
path
y -A
lope
cia,
blu
e gr
ay s
kin
pigm
enta
tion
52
7 A
tova
quon
e/P
rogu
anil
(Mal
aron
e)
Tabl
ets
are
not p
alat
able
due
to b
itter
ta
ste.
May
cru
sh th
e ta
blet
s an
d m
ix w
ith
cond
ense
d m
ilk in
chi
ldre
n w
ith d
iffic
ulty
sw
allo
win
g ta
blet
s.
Take
with
food
or a
milk
y dr
ink
(incr
ease
th
e ra
te a
nd e
xten
d of
abs
orpt
ion)
. Ta
ke d
aily
at t
he s
ame
time
each
day
w
hile
in th
e m
alar
ious
are
a an
d fo
r 7
days
afte
r lea
ving
suc
h ar
eas.
-Con
train
dica
ted
in p
eopl
e w
ith s
ever
e re
nal i
mpa
irmen
t (C
rCl <
30 m
l/min
) -N
ot re
com
men
ded
for c
hild
ren
wei
ghin
g <5
kg,
pre
gnan
t wom
en, a
nd
wom
en b
reas
tfeed
ing
infa
nts
wei
ghin
g <5
kg
-Abs
orpt
ion
of A
tova
quon
e m
ay b
e de
crea
sed
in p
atie
nts
who
hav
e di
arrh
oea
or v
omiti
ng.
- Tra
nsam
inas
e in
crea
ses
- Mus
cle
wea
knes
s - D
izzi
ness
and
hea
dach
e - A
bdom
inal
pai
n, a
nore
xia,
di
arrh
oea,
nau
sea,
vom
iting
. G
ood
for l
ast-m
inut
e tra
vele
rs
beca
use
the
drug
is s
tarte
d 1-
2 da
ys b
efor
e tra
velin
g to
an
area
whe
re m
alar
ia
trans
mis
sion
occ
urs
8 M
eflo
quin
e A
dmin
iste
r with
food
. B
itter
tast
e.
Tabl
ets
can
be c
rush
ed a
nd m
ixed
with
sm
all a
mou
nt o
f wat
er, m
ilk, a
pple
sauc
e,
choc
olat
e sy
rup,
jelly
or f
ood.
R
epea
t ful
l dos
e if
vom
iting
occ
urs
with
in
30 m
inut
es a
fter a
dmin
istra
tion.
R
epea
t add
ition
al h
alf d
ose
if vo
miti
ng
occu
rs w
ithin
30-
60 m
inut
es a
fter
adm
inis
tratio
n.
- Can
not b
e us
ed in
: •
area
s w
ith m
eflo
quin
e re
sist
ance
•
patie
nts
with
cer
tain
psy
chia
tric
cond
ition
s •
patie
nts
with
a s
eizu
re d
isor
der
• pa
tient
s w
ith c
ardi
ac c
ondu
ctio
n ab
norm
aliti
es
- Can
be
used
in p
regn
ancy
-A
void
con
curr
ent u
se o
f dru
gs k
now
n to
cau
se Q
T-in
terv
al p
rolo
ngat
ion
(eg.
ha
lofa
ntrin
e, q
uini
ne, q
uini
dine
) or
CY
P3A
4 in
hibi
tors
(eg.
ket
ocon
azol
e)
-Con
curr
ent u
se w
ith c
hlor
oqui
ne m
ay
incr
ease
risk
of s
eizu
re.
- Not
a g
ood
choi
ce fo
r las
t-min
ute
trave
lers
bec
ause
dru
g ne
eds
to b
e st
arte
d at
leas
t 2 w
eeks
prio
r to
trave
l
-Diz
zine
ss, v
ertig
o, ti
nnitu
s,
loss
of b
alan
ce
-Anx
iety
, dep
ress
ion,
re
stle
ssne
ss, c
onfu
sion
-A
gran
uloc
ytos
is, a
plas
tic
anem
ia
-Sin
us b
rady
card
ia, s
inus
ar
rhyt
hmia
, fis
t deg
ree
AV
bl
ock,
QT-
inte
rval
pr
olon
gatio
n, a
bnor
mal
T
wav
es
Due
to li
mite
d cl
inic
al
expe
rienc
e an
d do
sage
form
av
aila
bilit
y, W
HO
gui
delin
es
excl
ude
patie
nts
wei
ghin
g <5
kg fr
om a
ntim
alar
ial d
osag
e re
com
men
datio
ns b
ut C
DC
gu
idel
ines
do
not e
xclu
de
thes
e pa
tient
s.
9
Dox
ycyc
line
Adm
inis
ter w
ith li
quid
s, a
void
ant
acid
s,
infa
nt fo
rmul
a, m
ilk, d
airy
pro
duct
s, a
nd
iron
1 ho
ur b
efor
e or
2 h
ours
afte
r ad
min
istra
tion
of d
oxyc
yclin
e.
May
be
adm
inis
tere
d w
ith fo
od to
de
crea
se G
I ups
et.
May
mix
with
milk
, cho
cola
te p
uddi
ng,
appl
e ju
ice
to in
crea
se p
alat
abili
ty.
- Can
not b
e us
ed b
y pr
egna
nt w
omen
an
d ch
ildre
n <8
yea
rs o
ld.
- Use
with
cau
tion
in p
atie
nts
with
rena
l im
pairm
ent.
-Pho
tose
nsiti
vity
- V
agin
al th
rush
- P
seud
o-m
embr
anou
s co
litis
- N
eutro
peni
a - T
hrom
bocy
tope
nia
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Non Pharmacotherapy
Malaria Protective Measures10-11
Mosquito avoidance methods:
• Minimize outdoors activities during its feeding time from dusk to dawn, and protect living quarters from mosquitoes to reduce exposure to the female Anopheles mosquito
• Avoid dark clothing, aftershaves, perfumes which can attract mosquitoes
• Covering exposed skin areas with long sleeve clothes and long pants
• Use mosquito repellents, eg. diethyltoluamide (DEET)-containing repellents (use DEET <35% in children) indoor and outdoor.
• Use mosquito nets, insecticidal (Deltamethrin, Permethrin, Alpha- cypermethrin) impregnated clothes and nets.
Mosquito repellents:
CDC recommends the use of products containing DEET, picaridin, IR3535, and some oil of lemon eucalyptus and para-menthane-diol products that provide longer-lasting protection. Most products can be used on children. The American Academy of Pediatrics recommended that insect repellents containing DEET should not be used on children under 2 months of age and ≤30% DEET should be used on children aged >2 months. Products containing oil of lemon eucalyptus should not to be used on children under the age of three years. (CDC, FDA)
References:
1. Centers for Disease Control and Prevention (CDC). CDC Health Information for International Travel. New York: Oxford University Press; 2014; Chapter 3. Available from http://wwwnc.cdc.gov/travel/page/yellowbook- home-2014. Accessed 26 Oct 2014.
2. World Health Organization. World Malaria Report 2013; 2013:147.ISBN: 9789241564694. Available from http://www.who.int/malaria/publications/ world_malaria_report_2013/en/. Accessed 26 Oct 2014.
3. Muhammad Ismail HI, Ng HP, Thomas T. Paediatric Protocols for Malaysian Hospitals. 3rd Ed. Ministry of Health;2013
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4. Stauffer W, Fischer PR. Diagnosis and treatment of malaria in children. Clinical Infectious Diseases. 2003;37:1340-1348.
5. Centers for Disease Control and Prevention (CDC). Treatment of Malaria (Guidelines For Clinicians). July 2013. Available from http://www.cdc.gov/ malaria/resources/pdf/clinicalguidance.pdf. Accessed 26 Oct 2014.
6. Centers for Disease Control and Prevention (CDC). Choosing a drug to prevent Malaria. Updated November 9, 2012. Available from http://www. cdc.gov/malaria/travelers/drugs.html. Accessed 26 Oct 2014.\
7. World Health Organization. Guidelines for the treatment of malaria, 2nd ed i t ion. March 2010. Ava i lab le f rom ht tp://whql ibdoc.who. in t / publications/2010/9789241547925_eng.pdf?ua=1. Accessed 16 Oct 2014. 8. Lexi-Comp Inc. Pediatric & Neonatal Lexi-Drugs. Lexi-Comp Inc.; Version 2.2.1 26 Oct 2014.
9. World Health Organization. Status report on artemisinin resistance. September 2014. Available from http://www.who.int/malaria/publications/ atoz/status-rep-artemisinin-resistance-sep2014.pdf?ua=1. Accessed 26 Oct 2014.
10. World Health Organization. WHO recommended long lasting insecticidal nets. February 2014. Available from http://www.who.int/whopes/Long_ lasting_insecticidal_nets_Jul_2012.pdf. Accessed 26 Oct 2014.
11. Centers for Disease Control and Prevention (CDC). Fight the bite for protection from malaria. Guidelines for DEET insect repellent use. Department of health and human services centers for disease control and prevention. Available from http://www.cdc.gov/malaria/toolkit/DEET. pdf. Accessed 26 Oct 2014.
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Meningitis
Introduction
Meningitis is still a major and sometimes fatal problem in Paediatrics1.
Bacterial meningitis, an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space that happens in response to bacteria and bacterial products, continues to be an important cause of mortality and morbidity in neonates and children2.
Morbidity is also high. A third of survivors have sequelae of their disease. However, these complications can be reduced if meningitis is treated early1.
Approach to a Child With Fever and Signs/symptoms of Miningitis
Fever & Symptoms/Signsof Bacterial Meningitis
• Do Blood, urline C&S• Start Anitibiotics + Dexamethasone
Lumbar Puncture (LP)Contra indicated
No Yes
Do LP
Abnormal CSF
Improvement No improvement
Change antibiotics
Positive Negetive
Continue antibiotics
Normal CSF, wait forCSF cuture and Latex agglutination
With Hold LP
-
Re-evaluate, Consider discontinue Antibiotics
Complate Treatment ( See Next Page )
Consider TB, Fungus or Encephalitis Complate course of antibiotics
Persistent Fever > 72 Hours andNeurological de�cit
(rule out various causes)
Consider Ultrasound / CT BrainRepeat LP if no evidence of
raised ICP
When NOT to do a Lumbar Puncture
• Glasgow coma Scale < 8
• Abnormal ‘dolls eye’ re�ex or unequal pupils
• Lateralized signs or abnormal posturing
• Immediately after a recent seizure
• Papilloedema
Management
INFECTIOUS DISEASES
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Table 1.0 Investigation of Cerebrospinal fluid (CSF) values in neurological disorders with fever1:
Cerebrospinal fluid (CSF) values in neurological disorders with fever
Condition Leukocytes
(mm³)
Protein (g/l) Glucose (mmol/l)
Comments
Acute Bacterial Meningitis
100 - >50,000 Usually 1- 5 <0.5 - 1.5 Gram stain may be positive
Partially-treated Bacterial Meningitis
1 - 10,000 Usually high
PMN, but may have lymphocytes
>1 low
CSF may be sterile in Pneumococcal, Meningococcal meningitis
Tuberculous (TB) Meningitis
10 - 500 Early PMN, later
high lymphocytes
1- 5 0 - 2.0
Smear for acid fast bacilli (AFB), TB Polymerase chain reaction (PCR) + in CSF; High Erythrocyte sedimentation rate (ESR)
Fungal Meningitis
50 – 500 Lymphocytes
0.5 - 2
Normal or low
CSF for Cryptococcal Ag
Encephalitis 10 - 1,000 Normal /
0.5-1
Normal CSF virology and HSV DNA PCR
Table 2.0: Gram Stain results of common bacteria causing community acquired bacteria meningitis3
ORGANISM CSF GRAM STAIN
Group B streptococcus Gram positive cocci resembling streptococci
Streptococcus pneumoniae Gram positive diplococci or GPC resembling streptococci
Neisseria meningitidis Gram negative diplococci or gram negative cocci
Haemophilus influenzae Gram negative cocco-bacilli
Enterobacteriaceae e.g. E coli Gram negative rods
Listeria monocytogenes Gram positive or Gram variable rods
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Pharmacotherapy
Table 3.0: Recommended antibiotic therapy according to likely pathogen1
Age Group Initial
Antibiotic
Likely Organism Duration
(if uncomplicated)
< 1 month
C Penicillin + Cefotaxime
Grp B Streptococcus E. coli
21 days
1 - 3 months C Penicillin + Cefotaxime
Group B Streptococcus
E. coli H. influenzae
Strep. pneumoniae
10 – 21 days
> 3 months
C Penicillin + Cefotaxime, OR
Ceftriaxone
H. influenzae Strep. pneumoniae
N. meningitides
7 – 10 days 10 – 14 days
7 days
Note: 1. Review antibiotic choice when infective organism has been identified. 2. Ceftriaxone gives more rapid CSF sterilisation as compared to Cefotaxime or Cefuroxime. 3. Ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone4. 4. If Streptococcal meningitis, request for MIC values of antibiotics MIC level Drug of choice: • MIC < 0.1 mg/L (sensitive strain) C Penicillin • MIC 0.1-< 2 mg/L (relatively resistant) Ceftriaxone or Cefotaxime • MIC > 2 mg/L (resistant strain) Vancomycin + Ceftriaxone or Cefotaxime 5.Extend duration of treatment if complications e.g. subdural empyema, brain abscess.
Table 4.0: Duration of therapy for uncomplicated cases of meningitis
Common organism Duration of therapy Group B streptococcus 21 days1
Gram negative rods 21 days3
Listeria monocytogenes 21 days3
Neisseria meningitidis 7 days3
Haemophilus influenzae type b 10 days3
Streptococcus pneumoniae 14 days3
‘Culture negative’ but significant CSF pleocytosis present, minimum of 7 days recommended3.
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Table 5.0 Estimates of CSF penetration of antibiotics used for the treatment of bacterial meningitis5-7
Antibiotics
CSF penetration
(Drug in CSF:plasma) in
uninflamed meninges
CSF penetration
(Drug in CSF:plasma) in inflamed meninges
Comments on use of antibiotic class for meningitis treatment
ß-lactams Benzylpenicillin Amoxicillin/ampicillin Cefotaxime Ceftriaxone Meropenem
0.02 0·01 0.1 0.007 0.1
0.1 0·05 0.2 0.1 0.3
Poor CSF penetration, but high systemic doses are well tolerated and attain CSF concentrations that greatly exceed the MIC of susceptible bacteria. 40% of cefotaxime vs 90% of ceftriaxone is protein bound. Avoid imipenem because it could lower the seizure threshold. Continuous infusions could enhance bacterial killing.
Aminoglycosides Gentamicin Amikacin
0.01 No data
0.1 0.1
Poor CSF penetration and toxicity limits increases in systemic doses. Consider intraventricular/intrathecal delivery if needed
Glycopeptides Vancomycin Teicoplanin
0.01 0.01
0.2 0.1
Poor CSF penetration and toxicity limits increases in systemic doses. Continuous infusions could enhance bacterial killing. Limited data for intraventricular/intrathecal delivery
Fluoroquinolones Ciprofloxacin Moxifloxacin Levofloxacin
0.3 0.5 0.7
0.4 0.8 0.8
Good CSF penetration. Moxifloxacin is an alternative agent for the treatment of penicillin-resistant pneumococcal meningitis
Others Chloramphenicol Rifampicin
0.6 0.2
0.7 0.3
Excellent CSF penetration, although toxicity concerns limit its use. 80% protein bound; CSF concentrations greatly exceed MIC of susceptible bacteria.
Newer agents Cefepime Linezolid Daptomycin Tigecycline
0.1 0.5 No data No data
0.2 0.7 0.05 0.5
Effective against penicillin-resistant pneumococcal meningitis Case report/series suggest eff ectiveness for pneumococcal, staphylococcal, and enterococcal meningitis, although high interindividual variability in CSF pharmacokinetics suggests therapeutic drug measurements could be needed Poor penetration, but CSF concentrations exceed MIC of susceptible bacteria; case reports/series suggest efficacy in staphylococcal and enterococcal meningitis Good CSF penetration, but concentrations achieved at current standard doses could be insufficient to ensure bacterial killing
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Corticosteroids in meningitis:
Corticosteroids are drugs that can reduce the inflammation caused by infection8.Dose: IV Dexamethasone 0.15 mg/kg 6 hly for 4 days or 0.4 mg/kg 12 hly for 2 days1
Do not use corticosteroids in children younger than 3 months with suspected or confirmed bacterial meningitis9.
If dexamethasone was not given before or with the first dose of antibiotics, but was indicated, try to administer the first dose within 4 hours of starting antibiotics, but do not start dexamethasone more than 12 hours after starting antibiotics9.
The corticosteroid dexamethasone leads to a reduction in hearing loss and other neurological sequelae in participants in high-income countries who have bacterial meningitis, but is not effective in low-income countries8.
An analysis for different bacteria causing meningitis showed that patients with meningitis due to Streptococcus pneumoniae treated with corticosteroids had a lower death rate, while no effect on mortality was seen in patients with Haemophilus influenzae and Neisseria meningitidis meningitis8.
Corticosteroids decreased the rate of hearing loss in children with meningitis due to H. influenzae, but not in children with meningitis due to other bacteria8.
Dexamethasone increased the rate of recurrent fever but was not associated with other adverse events8.
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References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 46, Meningitis; p.215-8.
2. Kim KS. Acute bacterial meningitis in infants and children. The Lancet infectious diseases. 2010;10(1):32-42.
3. NSW Health. Infants and Children: Acute Management of Bacterial Meningitis: Clinical Practice Guideline. 2014
4. Muller ML. Pediatric bacteria meningitis treatment and management. [Online]. 2014 Nov 03 [cited 2015 Aug 4]; Available from: http://emedicine.medscape. com/article/961497-treatment#d10
5. Van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. The Lancet. 2012;380(9854):1693-702.
6. Nau R, Sorgel F, Eiff ert H. Penetration of drugs through the blood- cerebrospinal fluid/blood–brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010; 23: 858–83.
7. Andes DR, Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in meningitis. Infect Dis Clin North Am 1999; 13: 595–618.
8. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2013;6.
9. NICE clinical guideline. Bacterial meningitis andmeningococcal septicaemia Management of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care. 2015
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Urinary Tract Infection
Introduction
UTI comprises 5% of febrile ilnesses in childhood. Around 2% of children will have had a UTI before the age of 2 years. UTI is an important risk factor for the development of hypertension, renal failure and end-stage renal disease1.
Management1
Pharmacotherapy
All infants with febrile UTI should be admitted and IV antibiotics started as for acute pyelonephritis. In patients with high risk of serious illness, it’s preferable to obtain a urine sample first; however treatment should be started if urine sample is unobtainable.
• Antibiotic Prophylaxis Antibiotic prophylaxis should not be routinely recommended in infants and children following first time UTI, as antimicrobial prophylaxis does not seem to reduce significantly the rates of recurrence of pyelonephritis, regardless of age or degree of reflux. However, antibiotic prophylaxis may be considered in the following:
- Infants and children with recurrent symptomatic UTI. - Infants and children with vesico-ureteric reflux grades of at least grade III.
INFECTIOUS DISEASES
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-
Antibiotic treatment for UTI Type of Infection Preferred Treatment Alternative Treatment
UTI (Acute cystitis) E. coli
PO Trimethoprim 4mg/kg/dose BD (max 300mg daily) for 1 week
PO Trimethoprim/ Sulphamethoxazole 4mg/kg/dose (TMP) BD for 1 week
Proteus spp.
• Cephalexin, cefuroxime can be ued especially in children who had prior antibiotics. • Single dose of antibiotic therapy is not recommended.
Upper Tract UTI (Acute pyelonephritis)
E. coli
IV Cefotaxime 100mg/kg/day q8h for 10-14 days
IV Cefuroxime 100mg/kg/day q8h OR IV Gentamicin 5-7mg/kg/day daily
Proteus spp.
• Repeat culture within 48 hours if poor response. • Antibiotics may need to be changed according to sensivity.
Suggest to continue IV antibiotic until a child is afebrile for 2-3 days and then switch to appropriate oral therapy after culture results. Eg. Cefuroxime for total 10-14 days.
Asymptomatic bacteriuria No treatment recommended
Antibiotic prophylaxis for UTI UTI prophylaxis
PO Trimethoprim 1-2mg/kg ON
PO Nitrofurantoin 1-2mg/kg ON OR PO Cephalexin 5mg/kg ON
• Antibiotic prophylaxus is not to be routinely recommended in children with UTI. • Prophylactic antibiotics should be given for 3 days with MCUG done on second day. • A child who develops an infection while on prophylactic medication, treatment should be
with a different antibiotic and not a higher dose of the same prophylactic antibiotic.
Normal Renal Tracts
• Prophylactic antibiotic not required.
• Urine culture during any febrile illness or if the child is unwell.
No vesicoureteric reflux but renal scarring present
• Repeat urine culture only if symptomatic.
• Assessment includes height, weight, blood pressure and routine tests for proteinuria.
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Vesicoureteric Reflux
Management
• Antibiotic prophylaxis
• Surgical management or endoscopic treatment is considered if the child has recurrent breakthrough febrile UTI.
Non Pharmacotherapy1
Measures to reduce risk of infections
• Dysfunctional elimination syndrome (DES) or dysfunctional voiding is defined a an abnormal pattern of voiding of unknown etiology characterised by fecal and/or urinary incontinence and witholding of both urine and feces.
• Treatment of DES includes high fibre diet, use of laxatives, timed frequent voiding, and regular bowel movement.
• If condition persists, referral to a pediatric urologist/nephrologist is needed.
Summary
• All children less than 2 years of age with unexplained fever should have urine tested for UTI.
• Antibiotic prophylaxis should not be routinely recommended following first time UTI.
Reference:
1. Hussain Imam MI, Ng HP, Thomas T. Urinary Tract Infection. Paediatric Protocols For Malaysian Hospitals 3rd Edition. 63:305-312.
• Children with a minor, unilateral scarring do not need long-term follow up unless recurrent UTI/family history/lifestyle risk factors for hypertension.
• Children with bilateral abnormalities, impaired renal function, raised blood pressure and/or proteinuria should be managed by a nephrologist.
• Close follow up during pregnancy.
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Viral Croup
Introduction
Viral Croup is a clinical syndrome that is characterized by barking cough, inspiratory stridor, hoarse voice and respiratory distress of varying severity. It is also known as laryngotracheobronchitis, as it involved the inflammation of larynx, trachea and bronchi. Virus that commonly caused croup included Parainfluenza 1 and 2 and Respiratory Syncytial Virus (RSV), Adenovirus, Enterovirus, Influenza virus type A & B, and it mostly affects children between 6 and 36 months of age, although may occur on older children. Croup may cause various degrees of airway obstruction. However, several structural and infective conditions may also cause airway obstruction (eg. laryngomalacia, foreign body, epiglottitis, subglottic hemangioma). Hence, other causes need to be ruled out as the management may differ.
MANAGEMENT
Management of croup depends on the severity upon presentation. Mild croup can be managed as outpatient but moderate and severe croup will warrant hospital admission for further management (treatment algorithm as below-paeds protocol).
Assessment of severity Clinical Assessment of Croup (Wagener) • Mild : Stridor with excitement or at rest, with no respiratory distress. • Moderate : Stridor at rest with intercostal, subcostal or sternal recession. • Severe : Stridor at rest with marked recession, decreased air entry and altered level of consciousness.
INFECTIOUS DISEASES
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Viral Croup Introduction1
Viral Croup is a clinical syndrome that is characterized by barking cough, inspiratory stridor, hoarse voice and respiratory distress of varying severity. It is also known as laryngotracheobronchitis, as it involved the inflammation of larynx, trachea and bronchi. Virus that commonly caused croup included Parainfluenza 1 and 2 and Respiratory Syncytial Virus (RSV), Adenovirus, Enterovirus, Influenza virus type A & B, and it mostly affects children between 6 and 36 months of age, although may occur on older children. Croup may cause various degrees of airway obstruction. However, several structural and infective conditions may also cause airway obstruction (eg. laryngomalacia, foreign body, epiglottitis, subglottic hemangioma). Hence, other causes need to be ruled out as the management may differ. MANAGEMENT Management of croup depends on the severity upon presentation. Mild croup can be managed as outpatient but moderate and severe croup will warrant hospital admission for further management (treatment algorithm as below-paeds protocol). Assessment of severity Clinical Assessment of Croup (Wagener)
• Mild: Stridor with excitement or at rest, with no respiratory distress. • Moderate: Stridor at rest with intercostal, subcostal or sternal recession. • Severe: Stridor at rest with marked recession, decreased air entry and
altered level of consciousness.
Pharmacological treatment
• Corticosteroid2-6
The mechanism of action of systemic corticosteroid is believed to be due to its rapid anti-inflammatory effects or rapid vasoconstriction actions on the upper airways. The use of systemic steroids is associated with significant reduction of the number of adrenaline nebulization needed and reduced the average length of stay in Emergency Department9,10.
Dexamethasone and prednisolone has been shown to have equivalent initial clinical response7 but there is a higher representation rate with prednisolone8 is no superiority in the choice of route of administration for the steroids (IV, IM or oral), however oral route maybe preferable if the child can tolerate orally as it is the least expensive and least traumatic way for the child (Feyzullah 2004).The anti-inflammatory effect of Dexamethasone can last for 2-4 days.
The use of inhaled corticosteroid (eg. inhaled Budesonide) is also effective in treating moderate croup. The onset of action is within 30 minutes5, which is comparable to the systemic steroid, which the onset of action is 1 hour1,2,6.
• Nebulised Adrenaline
Nebulised Adrenaline should be used if the patient present with severe croup, or no improvement or stridor worsened after the use of corticosteroid. It has been suggested that inhaled adrenaline reduce bronchial and tracheal epithelial vascular permeability to help decrease airway edema, which results in increase in airway radius and improved airflow1,2. The onset of action is clinically rapid (30 minutes), and the duration of effect is 2 hours3,4. However, in severe croup, the dose maybe repeated every 15-20 minutes. if the child required repeated doses of Adrenaline nebulization, it may indicate that the child required intubation4.
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Non pharmacological treatment4
• Oxygen
Oxygen is considered as the standard treatment for any patient with severe croup, SpO2 <93% or with any significant respiratory distress. It can be given concurrently with other pharmacological treatment such as corticosteroid and adrenaline nebulization.
• Steam
Cold mist, steam and humidified air was once the mainstay of treatment in croup during the 19th and 20th century, but there is no evidence that this strategy can speed recovery, yet it may be associated with burns and scalds, hence the use is not recommended in most of the treatment guidelines.
• Heliox
Heliox is a mixture of Helium and Oxygen (with not less than 20% oxygen). Despite the conflicting findings from several clinical trials on the efficacy of Heliox compared to other conventional modalities, there is still insufficient evidence to establish the beneficial effect of the role of Heliox in the management of croup
Special Consideration
The use of adrenaline should be cautioned in patients with ventricular outflow obstruction such as TOF.
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References:
1. Klassen TP. Croup: A Current Perspective in Emergency Medicine. Pediatric Clinic of North America. 1999;46(6):1167-1178
2. Fitzgerald DA, Mellis CM, Johnson M, Copper PC, Allen HA, Van Asperren PP, Nebulised Budesonide as Effective as Nebulised Adrenaline in moderately severe croup. Pediatrics. 1996;97:722-725.
3. Waissman Y, Klein BL, Boenning DA et al. Prospective randomised double blind study comparing L-epinephrine and racemic epinephrine aerosols in the treatment of laryngotracheitis (croup). Pediatrics.1992;89:302-306.
4. Fitzgerald DA, Mellis CM. Management of acute upper airways obstruction in children. Mod. Med Aust. 1995; 38:80-88
5. Husby S, Agertoft L, Mortensen S, Pedersen S. Treatment of croup with nebulised steroid (Budesonide): a double blind, placebo controlled study. Arch Dis Child.1993;68:352-355.
6. Geelhoed GC, MacDonald WB. Oral and inhaled steroid in croup: A randomized, placebo-controlled trial. Pediatr Pulmonol.1995; 20:362-368.
7. Fifoot and Ting. EMA 2007;19:51-58.
8. Sparrow and Geelhoed GC. Arch Dis Child 2006:91;580-583.
9. Cruz MN, Stewart G, Rosenberg N. Use of Dexamethasone in the outpatient management of acute laryngotracheitis. Pediatrics. 1995; 96:220-223
10. Jaffe D. The treatment of croup with glucocorticoids. N Eng J Med. 1998; 339:498-503.
11. Super DM, Cartelli NA, Brooks LJ et al. A prospective randomised double blind study to evaluate the effect of dexamethasone in acute laryngotracheitis. J Pediatr .1989;115:323-329.
12. Cetinkaya F, Tufekci BS, Kutluk G. A comparison of nebulised budesonide, and intramuscular, and oral dexamethasone for treatment of croup. International Journal of Pediatric Otorhinolaryngology. 2004 April; 68(4): 453-456.
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Pneumonia
Introduction
There are two clinical definitions of pneumonia:
• Bronchopneumonia: a febrile illness with cough, respiratory distress with evidence of localised or generalised patchy infiltrates1.
• Lobar pneumonia: similar to bronchopneumonia except that the physical findings and radiographs indicate lobar consolidation1.
Clinical features
Criteria for Respiratory Distress in Children With Pneumonia2
Signs of Respiratory Distress
1. Tachypnea, respiratory rate, breaths/min
Age 0–2 months: > 60/min
Age 2–12 months: >50/min
Age 1–5 Years: >40/min
Age >5 Years: >20/min
2. Dyspnea
3. Retractions (suprasternal, intercostals, or subcostal)
4. Grunting
5. Nasal flaring
6. Apnea
7. Altered mental status
8. Pulse oximetry measurement ,90% on room air
INFECTIOUS DISEASES
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Criteria for hospitalization1
• Community acquired pneumonia can be treated at home
• Identify indicators of severity in children who need admission, as pneumonia can be fatal. The following indicators can be used as a guide for admission:
• Children aged 3 months and below, whatever the severity of pneumonia.
• Fever ( more than 38.5 °C ), refusal to feed and vomiting
• Fast breathing with or without cyanosis
• Associated systemic manifestation
• Failure of previous antibiotic therapy
• Recurrent pneumonia
• Severe underlying disorder, e.g. Immunodeficiency
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Pneumonia
Introduction There are two clinical definitions of pneumonia: • Bronchopneumonia: a febrile illness with cough, respiratory distress with evidence of localised or generalised patchy infiltrates1. • Lobar pneumonia: similar to bronchopneumonia except that the physical findings and radiographs indicate lobar consolidation1. Clinical features Criteria for Respiratory Distress in Children With Pneumonia2
Signs of Respiratory Distress 1. Tachypnea, respiratory rate, breaths/min
Age 0–2 months: > 60/min Age 2–12 months: >50/min Age 1–5 Years: >40/min Age >5 Years: >20/min
2. Dyspnea 3. Retractions (suprasternal, intercostals, or subcostal) 4. Grunting 5. Nasal flaring 6. Apnea 7. Altered mental status 8. Pulse oximetry measurement ,90% on room air
Table 1.0 Severity assessment3
Mild to moderate Severe Infants Temperature <38.5˚C
Respiratory rate <50 breaths/min Mild recession Taking full feeds
Temperature >38.5˚C Respiratory rate >70 breaths/min Moderate to severe recession Nasal flaring Cyanosis Intermittent apnoea Grunting respiration Not feeding Tachycardia Capillary refill time >2 s
Older children
Temperature <38.5˚C Respiratory rate <50 breaths/min Mild breathlessness No vomiting
Temperature >38.5˚C Respiratory rate >50 breaths/min Severe difficulty in breathing Nasal flaring Cyanosis Grunting respiration Signs of dehydration Tachycardia Capillary refill time >2 s
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Management
Pharmacotherapy
Specific aetiological agents are not identified in 40% to 60% of cases1. It is often difficult to distinguish viral from bacterial disease. The majority of lower respiratory tract infections are viral in origin, e.g. Respiratory syncytial virus, Influenza A or B, Adenovirus, Parainfluenza virus.
A helpful indicator in predicting aetiological agents is the age group.
Table 2.0 Predominant bacterial pathogens of pneumonia according to age group
When treating pneumonia, consider clinical, laboratory, radiographic findings, as well as age of the child, and the local epidemiology of respiratory pathogens and resistance/sensitivity patterns to microbial agents1.
Majority of infections are caused by viruses and do not require antibiotics1.
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Criteria for hospitalization1
• Community acquired pneumonia can be treated at home • Identify indicators of severity in children who need admission, as pneumonia
can be fatal. The following indicators can be used as a guide for admission: • Children aged 3 months and below, whatever the severity of pneumonia. • Fever ( more than 38.5 °C ), refusal to feed and vomiting • Fast breathing with or without cyanosis • Associated systemic manifestation • Failure of previous antibiotic therapy • Recurrent pneumonia • Severe underlying disorder, e.g. Immunodeficiency
Key features that suggest a child requires transfer to intensive care3
• failure to maintain oxygen saturation >92% in fractional inspired oxygen of >0.6; • shock; • rising respiratory and pulse rate with clinical evidence of severe respiratory distress
and exhaustion, with or without a raised arterial carbon dioxide tension; • recurrent apnoea or slow irregular breathing
Management
Pharmacotherapy
Specific aetiological agents are not identified in 40% to 60% of cases1. It is often difficult to distinguish viral from bacterial disease. The majority of lower respiratory tract infections are viral in origin, e.g. Respiratory syncytial virus, Influenza A or B, Adenovirus, Parainfluenza virus. A helpful indicator in predicting aetiological agents is the age group. Table 2.0 Predominant bacterial pathogens of pneumonia according to age group Pathogens for Pneumonia Age Bacterial Pathogens Newborns Group B streptococcus, Escherichia coli,
Klebsiella species, Enterobacteriaceae Infants 1- 3 months Chlamydia trachomatis Preschool age Streptococcus pneumoniae, Haemophilus
influenzae type b, Staphylococcal aureus Less common: Group A Streptococcus, Moraxella catarrhalis, Pseudomonas aeruginosa
School age Mycoplasma pneumoniae, Chlamydia pneumoniae
When treating pneumonia, consider clinical, laboratory, radiographic findings, as well as age of the child, and the local epidemiology of respiratory pathogens and resistance/sensitivity patterns to microbial agents1. Majority of infections are caused by viruses and do not require antibiotics1.
Key features that suggest a child requires transfer to intensive care3
• failure to maintain oxygen saturation >92% in fractional inspired oxygen of >0.6;
• shock;
• rising respiratory and pulse rate with clinical evidence of severe respiratory distress and exhaustion, with or without a raised arterial carbon dioxide tension;
• recurrent apnoea or slow irregular breathing
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Table 3.0 Bacterial pathogens and Recommended antimicrobial agents1
Pathogens Antimicrobial Agents Beta-lactam susceptible Streptococcus pneumonia Penicillin, cephalosporins Haemophilus influenzae type b Ampicillin, chloramphenicol, cephalosporins Staphylococcus aureus Cloxacillin Group A Streptococcus Penicillin, cephalosporin Mycoplasma pneumoniae Macrolides, e.g. erythromycin, azithromycin Chlamydia pneumoniae Macrolides, e.g. erythromycin, azithromycin Bordetella pertussis Macrolides, e.g. erythromycin, azithromycin Table 4.0 Bacterial pathogens and recommended antimicrobial agents2. Pathogen Parenteral therapy Oral therapy (step-down therapy
or mild infection) Streptococcus pneumoniae with MICs for penicillin ≤ 2.0 mcg/mL
Preferred: ampicillin (150–200 mg/kg/day every 6 hours) or penicillin (200 000–250 000 U/kg/day every 4–6 h); Alternatives: ceftriaxone (50–100 mg/kg/day every 12–24 hours) (preferred for parenteral outpatient therapy) or cefotaxime (150 mg/kg/day every 8 hours); may also be effective: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)
Preferred: amoxicillin (90 mg/kg/day in 2 doses or 45 mg/kg/day in 3 doses); Alternatives: second- or third-generation cephalosporin (cefpodoxime, cefuroxime, cefprozil); oral levofloxacin, if susceptible (16–20 mg/kg/day in 2 doses for children 6 months to 5 years old and 8–10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg) or oral linezolid (30 mg/kg/day in 3 doses for children <12 years old and 20 mg/kg/day in 2 doses for children ≥12 years old)
S. pneumoniae resistant to penicillin, with MICs ≥4.0 mcg/mL
Preferred: ceftriaxone (100mg/kg/day every 12–24 hours); Alternatives: ampicillin (300–400 mg/kg/day every 6 hours), levofloxacin (16–20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8–10 mg/kg/day once daily for children 5–16 years old; maximum daily dose, 750 mg), or linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children >12 years old); may also be effective: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)
Preferred: oral levofloxacin (16–20 mg/kg/day in 2 doses for children 6 months to 5 years and 8–10 mg/kg/day once daily for children 5–16 years, maximum daily dose, 750 mg), if susceptible, or oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years); Alternative: oral clindamycin (30–40 mg/kg/day in 3 doses)
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Group A Streptococcus
Preferred: intravenous penicillin (100 000–250 000 U/kg/day every 4–6 hours) or ampicillin (200 mg/kg/day every 6 hours); Alternatives: ceftriaxone (50–100 mg/kg/day every 12–24 hours) or cefotaxime (150 mg/kg/day every 8 hours); may also be effective: clindamycin, if susceptible (40 mg/kg/day every 6–8 hours) or Vancomycin (40–60 mg/kg/day every 6–8 hours)
Preferred: amoxicillin (50–75 mg/kg/day in 2 doses), or penicillin V (50–75 mg/kg/day in 3 or 4 doses); Alternative: oral clindamycin (40 mg/kg/day in 3 doses)
Stapyhylococcus aureus, methicillin susceptible (combination therapy not well studied)
Preferred: cefazolin (150 mg/kg/day every 8 hours) or semisynthetic penicillin, eg oxacillin (150–200 mg/kg/day every 6–8 hours); Alternatives: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)
Preferred: oral cephalexin (75–100 mg/kg/day in 3 or 4 doses); Alternative: oral clindamycin (30–40 mg/kg/day in 3 or 4 doses)
S. aureus, methicillin resistant, susceptible to clindamycin (combination therapy not well-studied)
Preferred: vancomycin (40–60 mg/kg/day every 6–8 hours or dosing to achieve an AUC/MIC ratio of >400) or clindamycin (40m g/kg/day every 6–8 hours); Alternatives: linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children ≥12 years old)
Preferred: oral clindamycin (30–40 mg/kg/day in 3 or 4 doses); Alternatives: oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years)
S. aureus, methicillin resistant,resistant to clindamycin (combination therapy not well studied)
Preferred: vancomycin (40–60 mg/kg/day every 6-8 hours or dosing to achieve an AUC/MIC ratio of >400); Alternatives: linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children ≥12 years old)
Preferred: oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years old); Alternatives: none; entire treatment course with parenteral therapy may be required
Haemophilus influenza, typeable (A-F) or nontypeable
Preferred: intravenous ampicillin (150-200 mg/kg/day every 6 hours) if b-lactamase negative, ceftriaxone (50–100 mg/kg/day every 12-24 hours) if b-lactamase producing, or cefotaxime (150 mg/kg/day every 8 hours);
Preferred: amoxicillin (75-100 mg/kg/day in 3 doses) if b-lactamase negative) or amoxicillin clavulanate (amoxicillin component, 45 mg/kg/day in 3 doses or 90 mg/kg/day in 2 doses) if b-lactamase producing;
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Alternatives: intravenous ciprofloxacin (30 mg/kg/day every 12 hours) or intravenous levofloxacin (16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg)
Alternatives: cefdinir, cefixime, cefpodoxime, or ceftibuten
Mycoplasma pneumoniae
Preferred: intravenous azithromycin (10 mg/kg on days 1 and 2 of therapy; transition to oral therapy if possible); Alternatives: intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours) or levofloxacin (16-20 mg/kg/day every 12 hours; maximum daily dose, 750 mg)
Preferred: azithromycin (10 mg/kg on day 1,followed by 5 mg/kg/day once daily on days 2–5); Alternatives: clarithromycin (15 mg/kg/day in 2 doses) or oral erythromycin (40 mg/kg/day in 4 doses); for children >7 years old, doxycycline (2–4 mg/kg/day in 2 doses; for adolescents with skeletal maturity, levofloxacin (500 mg once daily) or oxifloxacin (400 mg once daily)
Chlamydia trachomatis or Chlamydophila pneumoniae
Preferred: intravenous azithromycin (10 mg/kg on days 1 and 2 of therapy; transition to oral therapy if possible); Alternatives: intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours) or levofloxacin (16-20 mg/kg/day in 2 doses for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg)
Preferred: azithromycin (10 mg/kg on day 1,followed by 5 mg/kg/day once daily days 2–5); Alternatives: clarithromycin (15 mg/kg/day in 2 doses) or oral erythromycin (40 mg/kg/day in 4 doses); for children >7 years old, doxycycline (2-4 mg/kg/day in 2 doses); for adolescents with skeletal maturity, levofloxacin (500 mg once daily) or oxifloxacin (400 mg once daily)
Doses for oral therapy should not exceed adult doses. Supportive treatment1
i. Fluids
• Withhold oral intake when a child is in severe respiratory distress. • In severe pneumonia, secretion of anti-diuretic hormone is increased as such
dehydration is uncommon. Avoid overhydrating the child. ii. Oxygen
• Oxygen reduces mortality associated with severe pneumonia. • It should be given especially to children who are restless, and tachypnoeic with
severe chest indrawing, cyanosis, or is not tolerating feeds. • Maintain the SpO2 > 95%.
Supportive treatment1
i. Fluids
• Withhold oral intake when a child is in severe respiratory distress.
• In severe pneumonia, secretion of anti-diuretic hormone is increased as such dehydration is uncommon. Avoid overhydrating the child.
ii. Oxygen
• Oxygen reduces mortality associated with severe pneumonia.
• It should be given especially to children who are restless, and tachypnoeic with severe chest indrawing, cyanosis, or is not tolerating feeds.
• Maintain the SpO2 > 95%.
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iii. Cough medication
• Not recommended as it causes suppression of cough and may interfere with airway clearance. Adverse effects and overdosage have been reported.
iv. Temperature control
• Reduces discomfort from symptoms, as paracetamol will not abolish fever
v. Chest physiotherapy
• This assists in the removal of tracheobronchial secretions: removes airway obstruction, increase gas exchange and reduce the work of breathing.
• No evidence that chest physiotherapy should be routinely done.
Scientific basis of WHO recommendations for treatment of pneumonia4
• Children with fast breathing pneumonia with no chest indrawing or general danger sign should be treated with oral amoxicillin: at least 40mg/kg/dose twice daily (80mg/kg/day) for five days. In areas with low HIV prevalence, give amoxicillin for three days.
• Children with fast-breathing pneumonia who fail on first-line treatment with amoxicillin should have the option of referral to a facility where there is appropriate second-line treatment.
• Children age 2–59 months with chest indrawing pneumonia should be treated with oral amoxicillin: at least 40mg/kg/dose twice daily for five days.
• Children aged 2–59 months with severe pneumonia should be treated with parenteral ampicillin (or penicillin) and gentamicin as a first-line treatment. - Ampicillin: 50 mg/kg, or benzyl penicillin: 50 000 units per kg IM/IV every 6 hours for at least five days - Gentamicin: 7.5 mg/kg IM/IV once a day for at least five days
• Ceftriaxone should be used as a second-line treatment in children with severe pneumonia having failed on the first-line treatment.
• Ampicillin (or penicillin when ampicillin is not available) plus gentamicin or ceftriaxone are recommended as a first-line antibiotic regimen for HIV-infected and -exposed infants and for children under 5 years of age with chest indrawing pneumonia or severe pneumonia.
• For HIV-infected and -exposed infants and for children with chest indrawing pneumonia or severe pneumonia, who do not respond to treatment with ampicillin or penicillin plus gentamicin, ceftriaxone alone is recommended for use as second-line treatment.
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• Empiric cotrimoxazole treatment for suspected Pneumocystis jirovecii (previously Pneumocystis carinii) pneumonia (PCP) is recommended as an additional treatment for HIV-infected and -exposed infants aged from 2 months up to 1 year with chest indrawing or severe pneumonia.
• Empirical cotrimoxazole treatment for Pneumocystis jirovecii pneumonia (PCP) is not recommended for HIV-infected and - exposed children over 1 year of age with chest indrawing or severe pneumonia.
References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 33, Pneumonia; p.165-8.
2. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clinical Infectious Diseases. 2011;53(7):e25-e76.
3. Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011;66(Suppl 2):ii1-ii23.
4. Organization WH. Revised WHO classification and treatment of pneumonia in children at health facilities: evidence summaries. 2014.
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CARDIOVASCULAR
Kawasaki Disease
Introduction
Kawasaki disease (KD) is an acute, self-limited febrile illness mainly affecting small- to medium-sized vessels and occurs in early childhood. The etiology is currently unknown, however it likely results from an immunologic response triggered by microbial agents, with documented genetic susceptibility. KD typically presents in children younger than 5 years as a febrile illness with mucocutaneous changes. If untreated, KD can result in coronary aneurisms in 25% patients1,2.
In 1990 the American Heart Association(AHA) committee on rheumatic fever, endocarditis, and Kawasaki disease gave the case definition that has been generally accepted—ie, a febrile illness of at least five days with at least four of the five following signs and no other reasonable cause for the findings1:
a) Bilateral conjunctival injection – (there is no corneal ulceration but there may be a concomitant anterior uveitis on slit lamp examination)
b) Oral changes (erythema of lips or oropharynx, strawberry tongue due to prominent papillae, or fissuring of the lips)
c) Peripheral extremity changes (oedema, erythema, or generalised or periungal desquamation); erythema is seen in the first week whereas desquamation begins about 14–21 days after the onset of the illness
d) Rash – this starts in the first few days; it is often diffuse and polymorphic and lasts a week before fading. Vesicles are rarely seen; however, the rash can appear macular, maculopapular, urticarial, scarlettina or even morbilliform
e) Cervical lymphadenopathy is found in about 50% of cases; most often there is a painful solitary enlarged lymph gland, >1.5 cm in diameter
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Fever is an essential feature; it is most often sudden in onset and swinging, going above 40°C. It must last at least for five days but can persist for up to a month. If coronary arterial aneurysms (CAA) are present, one of the most important complications of Kawasaki disease, then only three of the clinical features are required to clinch the diagnosis.
There are ‘incomplete cases’ when not all of the four (three with CAA) diagnostic clinical features are present; some of these cases may evolve into complete cases. Some incomplete cases are diagnosed by CAA on echocardiography or at necropsy and the benefit of hindsight of the preceding clinical features.
For most children there is a subacute phase that lasts up to 30 days and a full recovery by day 50 following the onset of the illness.
Management2
Pharmacotherapy
74
Management2
Pharmacotherapy
Table 1. Treatment dose for Kawasaki Disease Drug Dose Suggested
monitoring Additional information
Primary treatment
IV Immunoglobulins 2 Gm/kg infusion over 10 - 12 hours
WBC (4500-11000 cell/µL)
If white blood cell increases from the normal range 4500-11000 cell/µL
then infusion rate has to be slowed down until it falls
within the range
Oral Aspirin
30 mg/kg/day for 2 wks or until patient is afebrile for 2-3
days
Bleeding Creatinine :
0.2 to 1.0 mg/dL PT:10-13.5 Sec APTT:26-42 Sec
INR:<1.5
Lower the dose if aspirin levels: >300 mcg/ml (toxic)
Maintainence
Aspirin
3-5 mg/kg daily for 6 - 8 weeks
or until ESR and platelet count
normalise.
Bleeding Creatinine :
0.2 to 1.0 mg/dL PT:10-13.5 Sec APTT:26-42 Sec
INR:<1.5
If coronary aneurysm present, then continue aspirin until resolves
Dipyridamole (Alternative for
Aspirin) 3- 5 mg/kg daily. Blood Pressure
Heart Rate
Additional treatment (Not responding to primary treatment. Persistent or recrudescent fever ≥ 36hrs after
completion of initial dose of IV Immunoglobulins) IV Immunoglobulins 2 Gm/kg infusion over 10 - 12 hours
Special Consideration regarding vaccinations : The use of Immunoglobulins may impair efficacy of live-attenuated virus vaccines. Delay these vaccinations for at least 11 months.
REFERENCES
1. Best Practice - Kawasaki Disease, Ian K Maconochie, Arch Dis Child Educ Pract Ed 2004;89:ep3–ep8. doi: 10.1136/adc.2004.053728
2. Paediatric Protocol for Malaysian Hospitals, 3rd Edition
3. Risk factors for refractory Kawasaki disease, Maria Cristina Maggio*, Eugenia Prinzi, Giovanni Corsello, 21st European Pediatric Rheumatology (PReS) Congress, Belgrade, Serbia Pediatric Rheumatology 2014, 12(Suppl 1):P359 http://www.ped-rheum.com/content/12/S1/P359
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Special Consideration regarding vaccinations : The use of Immunoglobulins may impair efficacy of live-attenuated virus vaccines. Delay these vaccinations for at least 11 months.
References :
1. Best Practice - Kawasaki Disease, Ian K Maconochie, Arch Dis Child Educ Pract Ed 2004;89:ep3–ep8. doi: 10.1136/adc.2004.053728
2. Paediatric Protocol for Malaysian Hospitals, 3rd Edition
3. Risk factors for refractory Kawasaki disease, Maria Cristina Maggio*, Eugenia Prinzi, Giovanni Corsello, 21st European Pediatric Rheumatology (PReS) Congress, Belgrade, Serbia Pediatric Rheumatology 2014, 12(Suppl 1):P359 http://www.ped-rheum.com/content/12/S1/P359
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Rheumatic Heart Disease
Introduction
Acute Rheumatic Fever
• Acute Rheumatic Fever (ARF) is an illness caused by a reaction to a bacterial infection with group A streptococcus (Streptococcus pyogenes)1.
• It causes an acute, generalised inflammatory response and an illness that targets specific parts of the body, including the heart, joints, brain and skin2.
• Individuals with ARF are often unwell, have significant joint pain and require hospitalisation. Despite the dramatic nature of the acute episode, ARF typically leaves no lasting damage to the brain, joints or skin, but can cause persisting heart damage, termed ‘rheumatic heart disease’ (RHD)2.
Rheumatic Heart Disease
• Rheumatic Heart Disease(RHD) is damage to the heart that remains after the acute ARF episode has resolved. It is caused by an episode or recurrent episodes of ARF, where the heart has become inflamed; the heart valves remain stretched and/or scarred, and normal blood flow is interrupted.
• Recurrences of ARF may cause further valve damage, leading to worsening of RHD.
• Preventing recurrences of ARF by using prophylactic treatment with penicillin is therefore of great importance in controlling RHD.
• Peak incidence 5 to 15 years old; more common in females1.
CARDIOVASCULAR
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Management1
Aim to suppress inflammatory response so as to minimize cardiac damage, provide symptomatic relief and eradicate pharyngeal streptococcal damage, provide symptomatic relief and eradicate pharyngeal streptococcal infection.
• Bed rest. Restrict activity until acute phase reactants return to normal.
• Anti-streptococcal therapy: IV C.Penicilline 50 000iu/kg/dose 6H or Oral Penicillin V 250mg 6H (<30kg), 500mg 6H (>30kg) x 10/7. Oral Erythromycin x 10/7 if allergic to penicillin.
• Anti-inflammatory therapy: Mild/no carditis: Oral aspirin 80-100mg/kg/day in 4 doses fr 2-4 weeks, tapering over 4 weeks.
Pericarditis, or moderate to severe carditis :
Oral Prednisolone 2mg/kg/day in 2 divided doses for 2-4 weeks, taper with addition of aspirin as above.
• Anti-failure medications: Diuretics, ACE inhibitors, digoxin (to be used with caution).
Secondary Prophylaxis of Rheumatic Fever1
• IM Benzathine Penicillin 6 MU (<30 kg) or 1.2 MU (>30kg) every 3 to 4 weeks.
OR
• Oral Penicillin V 250mg BD
OR
• Oral Erythromycin 250mg BD if allergic to penicillin.
Duration of Prophylaxis1
• Until age 21 years or 5 years after last attack of ARF whichever was longer.
• Lifelong for patients with carditis and valvular involvement.
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References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 38, Acute Rheumatic Failure; p.185-6.
2. RHDAustralia. Management of Rheumatic Heart Disease. Ch.5. 2nd Ed.
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FLUID & ELECTROLYTE MANAGEMENT
Fluid Management
Introduction
Fluid can be administered through parenteral or enteral (oral) route; however, enteral route should be used wherever possible. Fluids are given through parenteral route for resuscitation, maintenance of daily requirement, and replacement of fluid deficit or abnormal losses such as severe dehydration due to excessive vomiting.
Resuscitation
Fluid boluses of 10-20ml/kg should be used during resuscitation to restore circulation. Repeated fluid boluses may be necessary to correct the hypovolemia after re-assessment. Crystalloids (normal saline, Ringer’s Lactate, Hartmann’s solution) and colloids (albumin, gelatin, and blood) can be used during fluid resuscitation. The volume and choice of fluid should be appropriate to patient’s cause of circulatory collapse. If patient’s blood glucose is low, 2ml/kg of 10% dextrose solution can be given1.
Maintenance
Maintenance fluid is the volume of fluid required daily to replace the ongoing losses, including both sensible (urine and stool) and insensible losses (evaporative and respiratory). Children experience greater fluid loss because children have larger body surface area and higher metabolic and respiratory rate compared to adult; thus requiring higher maintenance fluid2. Clinical conditions and illnesses (eg. meningitis, pneumonia. fever, burn or diarrhea) may affect the fluid loss; therefore the requirement should be individualized. Holliday-Segar method is very commonly used for calculating maintenance fluid requirement and estimating the infusion rate (ml/hour) in children. It is however, only applicable to children above 2 weeks old3.
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Ideal body weight should be used for calculating maintenance fluid requirement for obese or overweight patients.
Deficit
Deficit fluid is the volume of fluid that is loss before medical intervention, for instance the fluid loss in patient with diarrhea, vomiting and significant blood loss. Deficit fluid is usually administered over a period of time depending on clinical condition; however, generally the total volume is administered over the first 24 hours of hospitalization. Isotonic solution (eg. 0.9% normal saline) should be given in replacement of deficit.
Total deficit volume to be replaced (ml) = Weight (kg) x degree of dehydration (%) x 10
Infusion rate/hour = Total deficit volume to be replaced / hour of infusion
Monitor daily electrolytes, fluid input and output and weight (if feasible) for all children on IV fluids.
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FLUID & ELECTROLYTE MANAGEMENT Fluid Management
Introduction
Fluid can be administered through parenteral or enteral (oral) route; however, enteral route should be used wherever possible. Fluids are given through parenteral route for resuscitation, maintenance of daily requirement, and replacement of fluid deficit or abnormal losses such as severe dehydration due to excessive vomiting.
Resuscitation
Fluid boluses of 10-20ml/kg should be used during resuscitation to restore circulation. Repeated fluid boluses may be necessary to correct the hypovolemia after re-assessment. Crystalloids (normal saline, Ringer’s Lactate, Hartmann’s solution) and colloids (albumin, gelatin, and blood) can be used during fluid resuscitation. The volume and choice of fluid should be appropriate to patient’s cause of circulatory collapse. If patient’s blood glucose is low, 2ml/kg of 10% dextrose solution can be given1.
Maintenance
Maintenance fluid is the volume of fluid required daily to replace the ongoing losses, including both sensible (urine and stool) and insensible losses (evaporative and respiratory). Children experience greater fluid loss because children have larger body surface area and higher metabolic and respiratory rate compared to adult; thus requiring higher maintenance fluid2. Clinical conditions and illnesses (eg. meningitis, pneumonia. fever, burn or diarrhea) may affect the fluid loss; therefore the requirement should be individualized.
Holliday-Segar method is very commonly used for calculating maintenance fluid requirement and estimating the infusion rate (ml/hour) in children. It is however, only applicable to children above 2 weeks old3.
Table 1: Calculation of maintenance fluid requirement and infusion rate, Holliday-Segar method3.
Weight Total fluids requirement Infusion rate First 10kg 100 ml/kg 4 ml/kg/hour Subsequent 10kg 50 ml/kg 2 ml/kg/hour All additional kg 20 ml/kg 1 ml/kg/hour
Ideal body weight should be used for calculating maintenance fluid requirement for obese or overweight patients.
Deficit
Deficit fluid is the volume of fluid that is loss before medical intervention, for instance the fluid loss in patient with diarrhea, vomiting and significant blood loss. Deficit fluid is usually administered over a period of time depending on clinical condition; however, generally the
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total volume is administered over the first 24 hours of hospitalization. Isotonic solution (eg. 0.9% normal saline) should be given in replacement of deficit.
Total deficit volume to be replaced (ml) = Weight (kg) x degree of dehydration (%) x 10
Infusion rate/hour = Total deficit volume to be replaced / hour of infusion
Monitor daily electrolytes, fluid input and output and weight (if feasible) for all children on IV fluids.
Table 2: Commonly used intravenous fluids4,5
Fluid Na+ (mmol/l)
Cl- (mmol/l) kcal/l Osmolality
(mOsm/l)
Tonicity (with
reference to cell
membrane)
Uses
Dextrose 5% - - 200 278 Hypotonic Maintenance
Dextrose 10% - - 400 555 Hypotonic Hypoglycemia correction
Hartmann’s solution 131 111 0 278 Isotonic
Initial resuscitation
and used intra- and
post-operatively
0.45% NaCl 77 77 0 154 Hypotonic Maintenance
0.9% NaCl 150 150 0 308 Isotonic
Initial resuscitation
and maintenance
3% NaCl 513 513 0 1026 Hypertonic Sodium replacement
0.18% NaCl with 4.23% Glucose
31 31 170 296 Hypotonic Maintenance
0.18% NaCl with 10% Glucose
30 30 400 615 Hypotonic Maintenance
0.45% NaCl with 5% Glucose
77 77 200 432 Hypotonic Maintenance
0.9% NaCl with 5% Glucose
150 150 200 585 Isotonic Maintenance
Electrolyte Management
Table 3: Normal range and daily requirement of electrolytes6.
Electrolytes Normal range Daily requirement Sodium 135-145 mmol/l 2-5 mmol/kg/day
Potassium 3.5-5.0 mmol/ l 2-4 mmol/kg/day Calcium 2.1-2.6 mmol/l 0.25-2 mmol/kg/day
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Management of Common Electrolyte Abnormalities
• Hyponatremia
Hyponatremia is defined as serum sodium < 135mmol/l, which can be due to severe dehydration or dilutional from fluid overload. Signs and symptoms of hyponatremia include headache, nausea/vomiting, lethargy, and neurological involvement such as altered consciousness and seizure. Encephalopathy is a very serious complication of hyponatremia, which can cause poor neurological outcome and even death if not detected early and treated promptly and adequately. A bolus of 4 ml/kg of 3% sodium chloride administered over 15-30 minutes will raise the serum sodium by 3 mmol/l and usually could cease the hyponatremic seizure. Subsequent 3% saline boluses may be required if there are ongoing seizures or persistent hyponatremia7. Thereafter, sodium should be corrected gradually at a rate of not more than 8 mmol/l over 24 hours because rapid correction may cause irreversible cerebral demyelination8.
Sodium required for correction in acute hyponatremia (mmol)9
= (Desired serum Na – present Na level) x 0.6 x weight(kg)
Depending on the hydration status of the child, 0.9% sodium chloride and 3% sodium chloride solutions can be used for sodium correction. Hyponatremia without symptom can be treated with enteral fluids or 0.9% sodium chloride. Frequent serum sodium should be checked (every 1-2 hours) until patient is stable, subsequently every 4-6 hours until serum sodium normalize.
Electrolyte Management
Table 3: Normal range and daily requirement of electrolytes6.
Electrolytes Normal range Daily requirement
Sodium 135-145 mmol/l 2-5 mmol/kg/day
Potassium 3.5-5.0 mmol/ l 2-4 mmol/kg/day
Calcium 2.1-2.6 mmol/l 0.25-2 mmol/kg/day
Magnesium 0.75-1.1 mmol/l 0.15-0.25 mmol/kg/day
Phosphate 1.3-2.3 mmol/l 0.5-2 mmol/kg/day
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• Hypernatremia
Hypernatremia is defined as serum sodium > 145 mmol/l, which can be due to water loss in excess of sodium, water deficit or excess sodium gain. Symptoms usually occur when there is severe hypernatremia, that is when the serum Na+ > 160 mmol/l. Signs and symptoms include nausea/vomiting, irritability, restlessness, lethargy, anorexia, tremor, and may also lead to subarachnoid hemorrhage and coma. Management will depend on severity and the cause of hypernatremia. Lowering sodium slowly at a rate not more than 0.5 mmol/l/hr because rapid correction can cause cerebral edema, convulsion, and death. However, for patient in shock, resuscitation with 20ml/kg of 0.9% sodium chloride boluses is required7. In contrast, if the hypernatremia is caused by water deficit due to central diabetes insipidus, vasopressin can be used. Monitor the serum sodium every 6 hours until patient stabilize.
• Hypokalemia
Hypokalemia is defined as serum potassium < 3.5mmol/l. Signs and symptoms of hypokalemia include generalized muscle weakness, paralytic ileus, cardiac arrhythmias, ECG changes, confusion, and impaired respiratory function. The common causes of hypokalemia are excess loss from renal or gastrointestinal tract; other causes include diabetic ketoacidosis, sepsis, and iatrogenic. Identify and treat the underlying cause, and correct hypokalemia in patient with serum potassium < 3.0mmol/l or clinically symptomatic patient with potassium < 3.4 mmol/l, either using potassium chloride (oral or IV infusion) or IV potassium dihydrogen phosphate
Table 4: Potassium chloride administration10,11
Preferred Maximum
Concentration ofinfusion
40mmol/l 60-80 mmol/l (peripheral)*200mmol/l (central)*
Rate of infusion< 0.2 mmol/kg/hr
(peripheral)< 0.4 mmol/kg/hr (central)
1 mmol/kg/hr*
Footnote - * Infusion at concentration and rate higher than the preferred range should be used only after discussion with specialist / senior medical staff and in intensive care setting
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• Hyperkalemia
Hyperkalemia is defined as serum potassium > 5.5mmol/l. Hyperkalemia may be presented with muscles weakness, ileus, paresthesia or palpitation. Causes are dehydration, acute renal failure, diabetic ketoacidosis, hypoaldosteronism, tumour lysis syndrome and atrogenic. Underlying cause need to be identified and treated accordingly.
Table 5: Drugs used in treatment of hyperkalemia1,7,12
Drugs Dosage Onset Duration
Nebulizedsalbutamol
≤ 2.5 yrs : 2.5mg;2.5-7.5 yrs: 5mg;>7.5 yrs: 10mg
30 mins 2-3 hrs
IV calciumgluconate
0.5-1.0 ml/kg (max 20 ml)(1:1 dilution) over 5-15 mins <3 mins ~30 mins
IV 8.4% sodiumbicarbonate
1ml/kg (1:1 dilution) over10-30 mins 30-60 mins 2-3 hrs
PO/PR calciumpolystyrenesulphonate
0.25g/kg (max 10g/dose) 4times /day
4-6 hrs (PO),1hr (PR)
variable
IV dextrose 0.5g/kg (2mls/kg of 25%)over 15-30 mins
IV insulin shortaction
0.1 unit/kg
15 minspeak 60 mins,
2-3 hrs
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Algorithm 1: Hyperkalemia treatment1
Hyperkalemia (K+.5.5 mmol/l)
Stop all K+ Supplementation
Stop medications causing hyperkalemia
Exclude pseudo hyperkalemia
Recheck with venous sample
Child unstableor symptomatic
Discuss for dialysis
IV Calcium (0.1 mmol/kg)
IV Bicarbonate (1-2mmol/kg)
Neb Salbutamol( <2.5 yrs; 2.5-7.5 yrs:5mg; >7.5yrs: 10mg)
+ IV Bicarbonate if acidosis
+ PR/PO Resonium
IV Insulin with glucose + Neb Salbutamol
Discuss for dialysis Discuss for dialysis
Abnormal
K+> 7 mmol/l K+> 6, < 7 mmol/l
Normal ECG Normal ECG
Child stable asymptomatic
Child stable asymptomatic
Cardiac monitoring
K+> 5.5, < 6 mmol/l
+ PR/PO Resonium
+ IV Bicarbonate if acidosis
References:
1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 3, Paediatric Fluid and Electrolyte Guidelines; p.19-26.
2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 60, Acute Kidney Injury; p.285-291.
3. Meyers R. Pediatric fluid and electrolyte therapy. The Journal of Pediatric Pharmacology and Therapeutics 2009 Oct-Dec; 14(4):204-211
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4. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823-832
5. Terris M, Crean P. Fluid and electrolyte balance in children. Anaesthesia and intensive care medicine. Elsevier. 2011; 13(1): 15-19
6. Product labels:
a) INFUSOL® D5. Ain Medicare Sdn. Bhd.
b) INFUSOL® D10. Ain Medicare Sdn. Bhd
c) INFUSOL® HM. Ain Medicare Sdn. Bhd.
d) INFUSOL® HS. Ain Medicare Sdn. Bhd.
e) INFUSOL® NS. Ain Medicare Sdn. Bhd.
f) INFUSOL® S3. Ain Medicare Sdn. Bhd.
g) INFUSOL® QSD10. Ain Medicare Sdn. Bhd.
h) INFUSOL® QSD10. Ain Medicare Sdn. Bhd.
i) 0.45% Sodium Chloride And 5% Glucose Intravenous Infusion
B.P. B. Braun Medical Industries S/B.
j) INFUSOL® NSD5. Ain Medicare Sdn. Bhd.
7. The ASPEN Nutrition Support Manual, 2nd Edition, American Society for Parenteral and Enteral Nutrition; 2005.
8. Clinical practice guidelines: Intravenous fluids. The Royal Children’s Hospital Melbourne, Australia.
9. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Seminars in Nephrology. 2009; 29:282–299
10. Farrell C, Del Rio M. Hyponatremia. Pediatrics in Review. 2007; 28:426-428.
11. Micromedex Healthcare Series. DRUGDEX System. Truven Health Analytics Inc. Vol. 163
12. Paediatric Formulary Committee. British National Formulary for Children 2011-2012. London and Chicago: BMJ Pub. Group, RPS Pub., RCPCH Pub.; 2011.
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Introduction
Critically ill children have a high risk of malnutrition because of stress-induced changes in intermediary metabolism; these changes are characterized by an increased basal metabolic rate and intensive protein catabolism. In general, the development or perpetuation of malnutrition during hospitalization in the paediatric intensive care unit (PICU) is due to illness, unknown nutrition condition, and an inadequate supply of nutrients. In these patients, malnutrition is associated with physiological instability. As a result, more intensive clinical care is required, and the mortality rate is high4.
Nutrition therapy is indicated when a patient is unable to receive calories and nutrients orally for a long period of time. Enteral nutrition (EN) is preferred because it is more physiologic, promotes intestinal trophism, stimulates the immune system, and reduces the incidence of bacterial translocation and sepsis. However, when it is impossible to use the digestive tract, parenteral nutrition (PN) is the only alternative for ensuring an adequate supply of nutrients during hospitalization. The combination of EN and PN may be useful for the first 72 hours of intensive clinical car or when EN alone is not sufficient to meet the nutrition demands of the patient4.
Recommendation from ASPEN for nutrition support of the critically ill child is list in Table 1. While Table 2 – 9 are the total daily requirement for paediatric.
Complications of PN
Complications may be considered in 3 groups: central venous catheter (CVC) related stability of the PN solutions and interactions with added drugs, metabolic or nutritional and other organ systems.
CVC related complications include infection, occlusion, central venous thrombosis, pulmonary embolism and accidental removal or damage1. Metabolic or nutritional complications include deficiency or excess of individual PN components including electrolytes, mineral, glucose, essential fatty acids, vitamin, trace element and the presence of contaminants1.
NUTRITION IN CRITICALLY ILL PATIENTS
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Other organ systems may be affected by the PN solutions, the underlying disease process or both. Complications include hepatobiliary disease, metabolic bone disease and growth impairment, some of which may be life threatening and raise the need for other therapeutic interventions such as non-transplant surgery or small bowel and liver transplantation1.
Monitoring of PNSevere investigations are required such as full blood count, renal profile, dextrostix, liver function test and lipid profile to monitor the complications of PN.
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Table 1: ASPEN guidelines: Nutrition Support of the Critically Ill Child 20092.
Aspect Guideline recommendations Grade
Nutrition assessment
Children admitted with critical illness should undergo nutrition screening to identify those with existing malnutrition and those who are nutritionally-at-risk
D
A formal nutrition assessment with the development of a nutrition care plan should be required, especially in those children with premorbid malnutrition
E
Energy requirement
Energy expenditure should be assessed throughout the course of illness to determine the energy needs of critically ill children. Estimates of energy expenditure using available standard equations are often unreliable.
D
IN a subgroup of patients with suspected metabolic alterations or malnutrition, accurate measurement of energy expenditure using indirect calorimetry (IC) is desirable. If IC is not feasible or not available, initial energy provision may be based on published formulas or namograms. Attention to imbalance between energy intake and expenditure will help to prevent overfeeding and underfeeding in this population.
E
Macronutrient intake during critical illness
There are insufficient data o make evidence-based recommendations for macronutrient intake in critically ill children. After determination of energy needs for critically ill child, the rational partitioning of the major substrates should be based upon understanding of protein metabolism and carbohydrate- and lipid- handling during critical illness
E
Route of nutrient intake (enteral
nutrition)
In critically ill children with a functioning gastrointestinal tract, enteral nutrition (EN) should be the preferred mode of nutrient provision, if tolerated.
C
A variety of barriers to EN exist in the paediatric intensive care unit (PICU), clinicians must identify and prevent avoidable interruptions to EN in critically ill children.
D
There are insufficient data to recommend the appropriate site (gastric vs post-pyloric/transpyloric) for enteral feeding in critically ill children. Post-pyloric or transpyloric feeding may improve caloric intake when compared to gastric feeds. Post-pyloric feeding may be considered in children at high risk of aspiration or those who have failed a trail of gastric feeding.
C
Immunonutrition in the PICU
Based on the available paediatric data, the routine use of immunonutrition or immune-enhancing diets/nutrients in critically ill children is not recommended.
D
Nutrition support team and feeding
protocols
A specialized nutrition support team in the PICU and aggressive feeding protocols may enhance the overall delivery of nutrition, with shorter time to goal nutrition, increased delivery of EN, and decreased use of parenteral nutrition. The effect of these strategies on patient outcomes has not been demonstrated.
E
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Table 2: Total Daily Fluid Requirement1,3.
Weight Total daily fluid required (ml/kg/day) ASPEN ESPEN
< 1.5kg 130 – 150 100 1.5-2kg 110 – 130
2-10kg 100 Subsequent 10kgs 50 50 All subsequent additional kgs 20 20
Table 3: Total Daily Energy Requirement1,3.
Age Total daily energy required (kcal/kg/day) ASPEN ESPEN
<6 months old 85 - 105 90 - 100 6-12 months old 80 - 100 1-7 years old 75 – 90 75 - 90 7-12 years old 50 – 75 60 - 75 > 12-18 years old 30 – 50 30 - 60
Table 4: Total Daily Protein Requirement1,3.
Age Total daily protein required (g/kg/day) ASPEN ESPEN
Infants 2 – 3 1 - 2.5 Child 1-3 years old 1 – 2 Child 3-10 years old 1 - 2 Adolescent 11-17 years old 0.8 - 1.5
Table 5: Total Daily Lipid Requirement1.
Age Total daily lipid required
(g/kg/day) ESPEN
Infants 3 Child 1-10 years old 2 – 3 Child >10 years old 1 - 2.5
Table 6: Total Daily Carbohydrate Requirement1.
Age Total daily carbohydrate
required (mg/kg/min) ESPEN
Infants 10 – 12 Child 1-10 years old 8 – 10 Child >10 years old 5 – 6
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Table 7: Total Daily Electrolyte and Mineral Requirement1,3.
Electrolyte ASPEN (mmol/kg/day) ESPEN (mmol/kg/day)
Infants/children Adolescent / child >50kg Infants Child >1
years old Sodium 2 - 5 1 – 2 2 – 3 1 - 3
Potassium 2 - 4 1 – 2 1 – 3 1 - 3
Calcium 0.25 - 2 5 - 10 0-6
months old: 0.8
7-12 months old: 0.5
0.2
Phosphorus 0.5 - 2 10 - 40 0.5 0.2 Magnesium 0.15 - 0.25 5 - 15 0.2 0.1
Acetate As needed to maintain acid-base balance
As needed to maintain acid-base balance
Chloride As needed to maintain acid-base balance
As needed to maintain acid-base balance
Table 8: Total Daily Trace Elemental Requirement1,3.
Trace elemental
ASPEN ESPEN
Infants (mcg/kg/day)
Children (mcg/kg/day)
Adolescent or child >40kg
(per day)
Infants (mcg/kg/day)
Children (mcg/kg/day)
Zinc 50 - 250 50 - 125 2 - 5mg
<3 months
old: 250
>3 months
old: 100
50 (maximum 5mg/day)
Copper 20 5 - 20 200 - 500mcg 20 20
Manganese 1 1 40 - 100mcg 1
1 (maximum
50mcg/day)
Chromium 0.2 0.14 - 0.2 5 - 15mcg 0.2 0.2
(Maximum 5mcg/kg/day)
Selenium 2 1 - 2 40 - 60mcg 2 – 3 2 - 3
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Table 9: Total Daily Vitamin Requirement1,3.
Vitamin
ASPEN ESPEN
1-3 kg (dose/day)
> 3kg (dose/day)
Infants (dose/body weight/day)
Children (dose/day)
Vitamin A (mcg)*
450 690 150 – 300 150
Vitamin D (IU) 260 (6.5mcg) 400 (10mcg) 32 (0.8mcg) 400 (10mcg)
Vitamin E (mg)
4.1 (4.5IU) 6.3 (7IU) 2.8 - 3.5 (3.1-3.9IU)
7 (7.7IU)
Vitamin K (mcg)
130 200 10 200
Ascorbic acid (mg)
52 80 15 – 25 80
Thiamine (mg)
0.78 1.2 0.35 - 0.5 1.2
Riboflavin (mg)
0.91 1.4 0.15 - 0.2 1.4
Niacin (mg) 11.05 17 4 - 6.8 17 Pantothenic acid (mg)
3.25 5 1 – 2 5
Pyridoxine (mg)
0.65 1 0.15 – 2 1
B12 mcg) 0.65 1 0.3 1
Biotin (mcg) 13 20 5 – 8 20
Folic acid (mcg)
91 140 56 140
*1 mcg RE (retinol equivalent) = 1 mcg all-trans retinol =3.33 IU Vitamin A
REFERENCES:
1) Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guideline on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41(2):S1-S87
2) Mehta NM, Compher C, A.S.P.E.N Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child. Journal of Parenteral and Enteral Nutrition. 2009;33(3):260-276.
3) Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, Seres D, Guenter P. Safe Practices for Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70.
4) Zamberlan P, Delgado AF, Leone C, Feferbaum R, Okay TS. Nutrition Therapy in a Pedaitric Intensive Care Unit: Indications, Monitoring and Complications. Journal of Parenteral and Enteral Nutrition. 2011;35(4):523-529
References :
1) Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guideline on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41(2):S1-S87
2) Mehta NM, Compher C, A.S.P.E.N Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child. Journal of Parenteral and Enteral Nutrition. 2009;33(3):260-276.
3) Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, Seres D, Guenter P. Safe Practices for Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70.
4) Zamberlan P, Delgado AF, Leone C, Feferbaum R, Okay TS. Nutrition Therapy in a Pedaitric Intensive Care Unit: Indications, Monitoring and Complications. Journal of Parenteral and Enteral Nutrition. 2011;35(4):523-529
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Introduction
Shock is a physiologic state characterized by a significant, systemic reduction in tissue perfusion; resulting in decreased tissue oxygen delivery and diminished removal of harmful by-products of metabolism (eg, lactate). Children with compromised circulation must be identified promptly. Successful management requires rapid initiation of treatment (often before the cause of shock is apparent) and careful assessment of the response to each intervention. Specific therapy must be initiated as soon as the evaluation suggests a cause of shock. Most children will improve with fluid resuscitation. Those who do not must quickly receive more aggressive treatment. According to Paediatric Advanced Life Support (PALS) course, shock is further classified into the following stages: • Compensated shock – During compensated shock, the body’s homeostatic mechanisms rapidly compensate for diminished perfusion and systolic blood pressure is maintained within the normal range. Heart rate is initially increased. Signs of peripheral vasoconstriction (such as cool skin, decreased peripheral pulses, and oliguria) can be noted as perfusion becomes further compromised5. • Decompensated shock – During this stage, compensatory mechanisms are overwhelmed. Heart rate is markedly elevated and hypotension develops. Signs and symptoms of organ dysfunction (such as altered mental status as the result of poor brain perfusion) appear. Systolic blood pressure falls, although children who have lost as much as 30 to 35 percent of circulating blood volume can typically maintain normal systolic blood pressures. Once hypotension develops, the child’s condition usually deteriorates rapidly to cardiovascular collapse and cardiac arrest5. • Irreversible shock – During this stage, progressive end-organ dysfunction leads to irreversible organ damage and death. Tachycardia may be replaced by bradycardia and blood pressure becomes very low. The process is often irreversible, despite resuscitative efforts5. In addition to these stages of shock, three broad mechanisms of shock are recognized: hypovolemic, distributive, and cardiogenic. Each type is characterized
Shock Management
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Disease management
Initial management should focus on fluid resuscitation with isotonic crystalloid solution and specific pharmacologic therapies as indicated once the aetiology of shock is identified. The following algorithm for initiating and re-evaluating therapy once shock is recognized has been adapted from consensus recommendations for the management of septic shock in children which were based primarily upon evidence extrapolated from adult studies5.
by one primary physiologic derangement in table 1.
However, a patient may have more than one type of shock (such as an infant with cardiogenic shock from supraventricular tachycardia who is also hypovolemic because he has been unable to drink or a child with underlying cardiomyopathy who is septic)5.
90
Table 1: Hemodynamic profiles of the types of shock5. Physiologic
variable Preload Pump function Afterload Tissue
perfusion
Examples Clinical measurement
Pulmonary capillary wedge
pressure
Cardiac Output
Systemic vascular
resistance
Mixed venous oxygen
saturation
Hypovolemic ↓ ↓ ↑ ↓
haemorrhage, gastrointestinal losses, insensible losses (e.g., burns), or third spacing
Cardiogenic ↑ ↓ ↑ ↓ sepsis, anaphylaxis, or acute injury to the spinal cord or brain
Distributive ↓ or ↔ ↑ ↓ ↑
primary myocardial injury, arrhythmias, congenital heart disease, or acquired obstructive conditions (eg, pneumothorax, cardiac tamponade, or pulmonary embolism)
Disease management
Initial management should focus on fluid resuscitation with isotonic crystalloid solution and specific pharmacologic therapies as indicated once the aetiology of shock is identified. The following algorithm for initiating and re-evaluating therapy once shock is recognized has been adapted from consensus recommendations for the management of septic shock in children which were based primarily upon evidence extrapolated from adult studies5.
Vasoactive agents may be useful for children with shock (other than hypovolemic shock) who have not improved with initial fluid resuscitation. These agents have effects on myocardial contractility, heart rate, and vasculature that can improve cardiac output. Initiation of vasoactive agents prior to or in place of adequately fluid resuscitating the patient, regardless of the etiology of shock, may lead to end-organ ischemia. Furthermore, these agents should be avoided in children with hypovolemic shock5.
Drugs that are typically used during the initial management of children with shock include dopamine , epinephrine , norepinephrine, dobutamine , and phosphodiesterase enzyme inhibitors. The choice of agent depends on the pathophysiologic parameters that must be manipulated5.
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Vasoactive agents may be useful for children with shock (other than hypovolemic shock) who have not improved with initial fluid resuscitation. These agents have effects on myocardial contractility, heart rate, and vasculature that can improve cardiac output. Initiation of vasoactive agents prior to or in place of adequately fluid resuscitating the patient, regardless of the etiology of shock, may lead to end-organ ischemia. Furthermore, these agents should be avoided in children with hypovolemic shock5.
Drugs that are typically used during the initial management of children with shock include dopamine , epinephrine , norepinephrine, dobutamine , and phosphodiesterase enzyme inhibitors. The choice of agent depends on the pathophysiologic parameters that must be manipulated5.
FIGURE 1: Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Proceed to next step if shock persists. 1) First hour goals—Restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the first hour/emergency department. Support oxygenation and ventilation as appropriate. 2) Subsequent intensive care unit goals—If shock is not reversed, intervene to restore and maintain normal perfusion pressure (mean arterial pressure [MAP]-central venous pressure [CVP]) for age, central venous O2 saturation >70%, and CI >3.3, <6.0 L/min/m2 in pediatric intensive care unit (PICU). Hgb, hemoglobin; PICCO, pulse contour cardiac output; FATD, femoral arterial thermodilution; ECMO, extracorporeal membrane oxygenation; CI, cardiac index; CRRT, continuous renal replacement therapy; IV, intravenous; IO, interosseous; IM, intramuscular1.
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Tabl
e 2:
Inot
rope
s &
Vas
opre
ssor
s3,5
Inot
rope
s D
ose
MO
A
Hea
rt ra
te
Syst
olic
fu
nctio
n D
iast
olic
fu
nctio
n M
yoca
rdia
l O
2 de
man
d SV
R
PVR
Dop
amin
e 1-
5mcg
/kg/
min
D
opam
inge
rgic
ag
onis
t In
crea
se
Min
imal
ef
fect
N
o ef
fect
M
inim
al
incr
ease
M
inim
al
incr
ease
N
o ef
fect
6-10
mcg
/kg/
min
β1
ago
nist
In
crea
se
Incr
ease
N
o ef
fect
In
crea
se
Incr
ease
M
inim
al
incr
ease
11
-20m
cg/k
g/m
in
α ag
onis
t In
crea
se
Incr
ease
N
o ef
fect
In
crea
se
Sig
nific
ant
incr
ease
M
inim
al
incr
ease
N
otes
: The
effe
ct o
f dop
amin
e is
dos
e-de
pend
ent.
At l
ow d
oses
, it s
timul
ates
the
hear
t and
impr
oves
rena
l blo
od fl
ow.
At h
ighe
r dos
es, i
t
c
ause
s va
soco
nstri
ctio
n an
d in
crea
ses
syst
emic
vas
cula
r res
ista
nce
(SV
R).
In m
ost s
ituat
ions
, dop
amin
e sh
ould
be
used
firs
t whe
n va
soac
tive
infu
sion
s ar
e re
quire
d to
trea
t sho
ck th
at h
as n
ot re
spon
ded
to fl
uid
adm
inis
tratio
n.
Dob
utam
ine
1-10
mcg
/kg/
min
β1
ago
nist
, α
anti-
agon
ist
Incr
ease
In
crea
se
No
effe
ct
Incr
ease
D
ecre
ase
Min
imal
de
crea
se
Not
es: D
obut
amin
e in
crea
ses
myo
card
ial c
ontra
ctili
ty a
nd h
eart
rate
. It a
lso
decr
ease
s sy
stem
ic v
ascu
lar r
esis
tanc
e, w
hich
can
cau
se
hypo
tens
ion.
It is
use
ful f
or p
atie
nts
with
dec
reas
ed m
yoca
rdia
l fun
ctio
n w
ho a
re n
orm
oten
sive
. E
pine
phrin
e 0.
01-1
mcg
/kg/
min
β1
ago
nist
> α
ag
onis
t In
crea
se
Sig
nific
ant
incr
ease
N
o ef
fect
S
igni
fican
t in
crea
se
Incr
ease
M
inim
al
incr
ease
N
otes
: E
pine
phrin
e st
imul
ates
the
hear
t and
is a
pot
ent v
asoc
onst
ricto
r. It
also
rela
xes
bron
chia
l sm
ooth
mus
cle.
It is
typi
cally
use
d fo
r
p
atie
nts
with
ana
phyl
axis
or t
hose
who
do
not r
espo
nd to
dop
amin
e, p
artic
ular
ly th
ose
with
sep
tic s
hock
and
incr
ease
d S
VR
(col
d
sho
ck).
Nor
epin
ephr
ine
0.01
-1m
cg/k
g/m
in
β1 a
goni
st <
α
agon
ist
Incr
ease
S
ome
incr
ease
N
o ef
fect
In
crea
se
Sig
nific
ant
incr
ease
M
inim
al
incr
ease
N
otes
: Lik
e ep
inep
hrin
e, n
orep
inep
hrin
e st
imul
ates
the
hear
t and
cau
ses
vaso
cons
trict
ion.
Vas
ocon
stric
tive
effe
cts
are
usua
lly g
reat
er
th
an th
e ef
fect
s on
con
tract
ility
and
hea
rt ra
te. I
t can
be
used
for c
hild
ren
who
do
not r
espo
nd to
dop
amin
e an
d is
pre
ferr
ed o
ver
epin
ephr
ine
by s
ome
expe
rts fo
r tho
se p
atie
nts
with
sep
sis
and
decr
ease
d S
VR
(war
m s
hock
).
Milr
inon
e 0.
1-1m
cg/k
g/m
in
Pho
spho
dies
tera
se
inhi
bito
r N
o ch
ange
In
crea
se
Impr
oves
M
inic
al In
crea
se
Dec
reas
e D
ecre
ase
Not
es: P
hosp
hodi
este
rase
enz
yme
inhi
bito
rs (i
e, m
ilrin
one
) im
prov
e ca
rdia
c co
ntra
ctili
ty a
nd re
duce
afte
rload
. The
y m
ay b
e us
ed to
trea
t
card
ioge
nic
shoc
k.
Vaso
pres
sors
N
eosy
neph
rine
0.1-
2 m
cg/k
g/m
in
Pur
e α
agon
ist
No
effe
ct
No
effe
ct
No
effe
ct
No
effe
ct
Sig
nific
ant
incr
ease
N
o ef
fect
Vas
opre
ssin
0.
0003
-0.0
08
mcg
/kg/
min
V
rece
ptor
ago
nist
N
o ef
fect
N
o ef
fect
N
o ef
fect
N
o ef
fect
S
igni
fican
t in
crea
se
Effe
ct
unkn
own
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Special consideration
Children can effectively compensate for circulatory dysfunction (primarily by increasing heart rate, systemic vascular resistance, and venous tone), maintaining normal blood pressures despite significantly compromised tissue perfusion. Consequently, hypotension is a very late and ominous finding. The challenge for the clinician is to recognize children in shock early (before they develop hypotension), when they are more likely to respond favorably to treatment5.
Paediatric inotropic therapy has been furnished with some new understanding of older agents, and new ways of using them. Some agents are gaining an evidence base, whilst even newer agents need such a base. Guidelines are emerging to facilitate their use2.
Table 3: Shock & Inotropes3
Shock Infusions to consider Comments
Septic
Early or warm • Dopamine • Norepinephrine
• Decreased SVR • Increase CO
Late or cold • Dopamine • Epinephrine • Vasopressin
• Increased SVR • Decrease CO • ? Decrease in
vasopressin levels Cardiogenic
Normotensive • Milrinone • Dobutamine
• Increased SVR • Decerase CO
Hypotensive • Epinehrine • Slow addition of Milrinone
once BPs improved
• Increased SVR • Decrease CO
Hypovolemic • Dopamine • Epinephrine
• Increased SVR • Decreased CO
Obstructive • Dopamine • Epinephrine • Milrinone
• Increased SVR • Decreased CO
Distributive • Neosynephrine • Decreased SVR • Normal CO
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References:
1. Brierley J, Carcillo J.A., Choong K, Cornell T, DeCaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med, 2009: Vol. 37, No. 2: 666-688.
2. Clifford M. Inotropes in Children. Australasian Anaesthesia. 2005;pg 129-134
3. Kache S. Sanford PICU Rotation Guide. [Internet]. Stanford School of Medicine.
Available from: http://peds.stanford.edu/Rotations/picu/pdfs/15_inotropes_ tables.pdf accessed 08/09/2014
4. Waltzman M. Initial management of shock in children. Up to date, 2013 [updated 2013 Apr 4]. Available from http://www.uptodate.com/contents/ initial-management-of-shock-in-children
5. Waltzman M. Initial evaluation of shock in children. Up to date, 2013 [updated: 2013 Jan 7]. Available from http://www.uptodate.com/contents/initial- evaluation-of--shock-in-children.`
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Introduction
Neuromuscular blocking agents (NMBAs) are used in critically ill children for a variety of reasons. The main indications for the use of NMBAs are based on the optimization of immobility of the patient for procedures like:
• Short term (less than 6 hours)
1. Tracheal intubation
2. High-risk invasive procedures
• Long term (more than 6 hours)
1. Synchrony with mechanical ventilation (dyssynchrony, excessive hyperventilation or hypoventilation, nonconventional ventilation)
2. Reduction of metabolic demand or work of breathing
3. Treatment of intense agitation unresponsive to higher doses of analgesia and sedation
4. Therapeutic hypothermia (decreased shivering)
5. Protection of surgical repairs
It is important to remember that in all these indications, the use of NMBAs should be considered in patients that deep sedation & analgesia have failed to reach the desired effect1,2,5. The choice of the best NMBA becomes very difficult and dependent on the degree and necessity of the muscular relaxation desired. Neuromuscular blocking agents
Neuromuscular Blockade
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1) Depolarizing NMBAs
a. Succinylcholine
Succinylcholine is the only depolarizing NMBA in clinical use. It produces the most rapid onset and ultra-short duration of neuromuscular block. Succinylcholine can cause tachycardia, bradycardia, increase in intraocular pressure, hyperkalaemia, myoglobinaemia, malignant hyperthermia, and even fatal hyperkalaemia cardiac arrests. Therefore, succinylcholine is restricted to emergency endotracheal intubation and instances where immediate securing of the airway such as laryngospasm, difficult airway and full stomach1,2,4,5.
2) Non-depolarizing NMBAs
a. Benzylquinolium e.g. atracurium & cisatracurium
• Atracurium
Atracurium is a bisquaternary benzylquinolinium diester with an intermediate duration of clinical action. The adverse effect associated with atracurium relate mainly to histamine release such as macular rash, erythema, hypotension, tachycardia or bronchospasm. Another adverse effect of atracurium is dose-related cardiovascular changes. Long term infusions have been associated with the development of tolerance, necessitating dose increment1,2,5.
• Cisatracurium
Cisatracurium is an isomer of atracurium. Like atracurium, it is an intermediate duration NMBAs. The potency of cisatracurium is about 3 times that of atracurium. Increase potency is associated with slower onset of action which necessitates a relative high dose to achieve reliable intubating conditions at 2 minutes. Cisatracurium has less propensity for histamine release and provides greater cardiovascular stability compared to atracurium2.
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b. Aminosteroidal compounds e.g. pancuronium, vecuronium & rocuronium
• Pancuronium
Pancuronium is a potent, long-acting, bisquaternary aminosteroid NMBAs which has vagolytic effect (increase in heart rate of 30-40% and systolic blood pressure of 10-15%). This vagolytic effect may be an advantage in infants, in whom bradycardia is highly undesirable, or patients undergoing anaesthesia with high-dose opiods, which tend to decrease heart rate and blood pressure. Patients with renal and liver impairment will have prolonged neuromuscular blockade due to accumulation of pancuronium and its active metabolite5.
• Vecuronium
Vecuronium is a monoquaternary derivative of pancuronium with greater selectivity of pharmacological profile, a shorter duration of action, less vagolytic effect and less cumulative properties compared to pancuronium. Same as pancuronium, vecuronium will prolong the neuromuscular blockade in patients with renal or liver impairment. Vecuronium is clearly a long-acting NMBA in newborns and infants, in agreement with its increased residence time in younger patients1,2.
• Rocuronium
Rocuronium is a desacetoxy analogue of vecuronium with a more rapid onset of action. Rapid onset is the result of reduced potency, which necessitates an increase in dose. Rocuronium has minimal cardiovascular effect (tachycardia at high dose). Like vecuronium, rocuronium is longer acting in infants than in children; however, rocuronium still retains the characteristics of an intermediate-acting NMBA in infants. Same as vecuronium, rocuronium will prolong the neuromuscular blockade in patients with renal or liver impairment Rocuronium would be an acceptable alternative to succinylcholine for rapid sequence induction2.
The pharmacological properties and drug-drug interaction of the NMBAs are listed in Table 1 and Table 2.
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Tabl
e 1:
Sum
mar
y of
Pha
rmac
olog
ical
pro
pert
ies
of N
MB
As1,
2,5,
6,7 .
NM
BA
Su
ccin
ylch
olin
e A
trac
uriu
m
Cis
atra
curiu
m
Panc
uron
ium
Ve
curo
nium
R
ocur
oniu
m
Dos
e
Infa
nts
IM: 3
-4m
g/kg
/dos
e IV
: 2m
g/kg
/dos
e th
en m
aint
ain
by
0.3-
0.6m
g/kg
/dos
e ev
ery
5-10
min
as
need
ed
Chi
ldre
n >
1 ye
ar
old
& a
dole
scen
ts
IM: 3
-4m
g/kg
/dos
e IV
: 1m
g/kg
/dos
e th
en m
aint
ain
by
0.3-
0.6m
g/kg
/dos
e ev
ery
5-10
min
as
need
ed
Infa
nts
& c
hild
< 2
ye
ars
old
IV: 0
.3-0
.4
mg/
kg/d
ose
then
m
aint
ain
by 0
.3-
0.4m
g/kg
/dos
e;
repe
at d
oses
as
need
ed
Con
tinuo
us
infu
sion
: 10-
20m
cg/k
g/m
in
Chi
ld >
2 y
ears
old
&
ado
lesc
ents
IV
: 0.4
-0.
5mg/
kg/d
ose
then
0.0
8-0.
1 m
g/kg
/dos
e 20
-45
min
afte
r ini
tial
dose
; rep
eat a
s
need
ed a
t 15-
25
min
ute
inte
rval
s C
ontin
uous
in
fusi
on: I
nitia
l 9-
10m
cg/k
g/m
in th
en
mai
ntai
n by
5-
9mcg
/kg/
min
Infa
nts
& c
hild
<
2 ye
ars
old
IV:
0.15
mg/
kg/d
ose
C
ontin
uous
in
fusi
on: 1
-4m
cg/k
g/m
in
Chi
ld >
2 y
ears
ol
d &
ad
oles
cent
s IV
: 0.1
-0.
5mg/
kg/d
ose
Con
tinuo
us
infu
sion
: 1-
4mcg
/kg/
min
Infa
nts
IV: 0
.1m
g/kg
/dos
e ev
ery
30-6
0 m
in a
s ne
eded
C
ontin
uous
infu
sion
: 0.
4-0.
6mcg
/kg/
min
C
hild
ren
IV: 0
.15m
g/kg
/dos
e ev
ery
30-6
0 m
in a
s ne
eded
C
ontin
uous
infu
sion
: 0.
5-1.
7mcg
/kg/
min
A
dole
scen
ts &
adu
lts
IV: 0
.15m
g/kg
/dos
e ev
ery
30-6
0 m
in
Con
tinuo
us in
fusi
on:
0.4-
0.6m
cg/k
g/m
in
Infa
nts
IV:
0.1m
g/kg
/dos
e;
repe
at e
very
ho
ur a
s ne
eded
C
ontin
uous
in
fusi
on: 1
-1.
5mcg
/kg/
min
C
hild
> 1
yea
r ol
d &
ad
oles
cent
s IV
: 0.
1mg/
kg/d
ose;
re
peat
eve
ry
hour
as
need
ed
Con
tinuo
us
infu
sion
: 1.5
-2.
5mcg
/kg/
min
Rap
id
sequ
ence
in
tuba
tion
Chi
ldre
n &
ad
oles
cent
s 0.
6-1.
2mg/
kg/d
ose
Trac
heal
in
tuba
tion,
su
rgic
al
Infa
nts,
chi
ld,
adol
esce
nts
IV: 0
.45-
0.6m
g/kg
/dos
e in
itial
ly th
en
mai
ntai
n by
0.
075-
0.15
mg/
kg/d
ose;
re
peat
as
need
ed
Con
tinuo
us
infu
sion
: 7-
12m
cg/k
g/m
in,
use
the
low
er
end
of d
osin
g ra
nge
for i
nfan
ts
and
uppe
r end
fo
r chi
ldre
n >2
ye
ars
old.
O
nset
30
-60
sec
1-3
min
2-
3 m
in
2-4
min
1-
3 m
in
30-6
0 se
c
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NM
BA
Su
ccin
ylch
olin
e A
trac
uriu
m
Cis
atra
curiu
m
Panc
uron
ium
Ve
curo
nium
R
ocur
oniu
m
Dur
atio
n 4-
6 m
in
25-3
5 m
in
35-4
5 m
in
90-1
00 m
in
35-4
5 m
in
25-4
0 m
in
Met
abol
ism
Rap
idly
hyd
roly
sed
by p
lasm
a ch
olin
este
rase
Hof
man
n el
imin
atio
n (p
H &
te
mpe
ratu
re) i
nto
laud
anos
ine
&
acry
late
Hof
man
n el
imin
atio
n (p
H &
te
mpe
ratu
re) i
nto
laud
anos
ine
&
acry
late
30-4
0% m
etab
oliz
ed
by li
ver i
nto
activ
e m
etab
olite
3-
hydr
oxyp
ancu
roni
um
40-5
0%
met
abol
ized
by
liver
into
3
activ
e m
etab
olite
s
50-6
0%
met
abol
ized
by
liver
Elim
inat
ion
10%
exc
rete
d as
un
chan
ged
drug
in
urin
e
<10%
exc
rete
d as
un
chan
ged
drug
in
urin
e
<10%
exc
rete
d as
unc
hang
ed
drug
in u
rine
40%
exc
rete
d as
un
chan
ged
drug
in
urin
e &
11%
exc
rete
d in
bile
50%
exc
rete
d in
bile
& 2
5%
excr
eted
as
unch
ange
d dr
ug in
urin
e
70%
exc
rete
d in
bi
le &
up
to 3
0%
excr
eted
as
unch
ange
d dr
ug
in u
rine
His
tam
ine
rele
ase
No
Yes
M
inim
um
No
No
No
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Table 2: Drug Interactions affecting NMBAs.3,5,7.
Drug potentiating the action of NMBAs Drug antagonising the action of NMBAs
Aminoglycosides Calcium channel blocker
Clindamycin Colistimethate sodium Corticosteroid (prolonged coadministration)N
CyclophosphamideS
Cyclosporine Frusemide (0.1-10mcg/kg)B
Lignocaine Lithium carbonate Magnesium MetoclopramideS
Polymyxin B Procainamide Quinidine Quinine SpironolactoneN Tetracycline Vancomycin
Frusemide (1-4mg/kg)B
CarbamazepineN
CorticosteroidN PhenytoinN TheophyllineA
S Succinylcholine only N Non-depolarizing NMBAs only A Aminosteroid NMBAs only (eg rocuronium, pancuronium & vecuronium) B Succinylcholine & aminosteroid NMBAs only
Monitoring of NMBAs
Many factors can influence the depth of neuromuscular blockade such as acid-base derangement, electrolytes imbalance and drug-drug interaction. Therefore, all patients receiving NMBAs should be monitored both clinically and by train-of-four (TOF) monitoring to assess the degree of neuromuscular blockade.
The use of TOF monitoring in attempts to optimise the degree of neuromuscular blockade has been shown to reduce the total dose requirements of patients for NMBAs and allow faster recovery of neuromuscular function and spontaneous ventilation and allow cost savings5.
Complications of NMBAs
The major described complication is the prolonged muscle weakness after its discontinuation. This complication is well documented in children, generally with the use longer than 48 hours. This effect could last for up to 6 months. There are 2 patterns of neuromuscular dysfunction: the persistent block of the NM junction (PBNMJ) and the acute myopathy.
PBNMJ is probably due to accumulation of drugs or its active metabolites mainly in patients with renal or hepatic failure. Co-administration of aminosteroid NMBA and corticosteroid is significantly associated with PBNMJ. This drug-drug interaction is very important since one of the major indications of NMBAs in paediatric is the child with status asthmaticus with
S Succinylcholine onlyN Non-depolarizing NMBAs onlyA Aminosteroid NMBAs only (eg rocuronium, pancuronium & vecuronium)B Succinylcholine & aminosteroid NMBAs only
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Monitoring of NMBAs
Many factors can influence the depth of neuromuscular blockade such as acid-base derangement, electrolytes imbalance and drug-drug interaction. Therefore, all patients receiving NMBAs should be monitored both clinically and by train-of-four (TOF) monitoring to assess the degree of neuromuscular blockade.
The use of TOF monitoring in attempts to optimise the degree of neuromuscular blockade has been shown to reduce the total dose requirements of patients for NMBAs and allow faster recovery of neuromuscular function and spontaneous ventilation and allow cost savings5.
Complications of NMBAs The major described complication is the prolonged muscle weakness after its discontinuation. This complication is well documented in children, generally with the use longer than 48 hours. This effect could last for up to 6 months. There are 2 patterns of neuromuscular dysfunction: the persistent block of the NM junction (PBNMJ) and the acute myopathy.
PBNMJ is probably due to accumulation of drugs or its active metabolites mainly in patients with renal or hepatic failure. Co-administration of aminosteroid NMBA and corticosteroid is significantly associated with PBNMJ. This drug-drug interaction is very important since one of the major indications of NMBAs in paediatric is the child with status asthmaticus with dyssynchrony with mechanical ventilation (and who uses short or long term corticosteroids). The acute myopathy also leads to prolonged paralysis, but is not caused by delayed recuperation of the neuromuscular junction1.
Muscular atrophy, joint contractures, thrombotic or embolic events, ulcers of the skin, atelectasis, pneumonia and corneal drying are other possible complications. Special attention should be given to the neurological assessment of patient with status epilepticus and receiving NMBAs as NMBAs can completely obscure many of the clinical manifestations of seizure activity1,5.
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Antagonism of NMBAs
Any residual neuromuscular block due to non-depolarizing NMBAs should be antagonised by an anticholinesterase. This is especially important in neonates and small infants because of their reduced respiratory reserve. The most commonly used anticholinesterases are neostigmine and edrophonium5. Sugammadex, a cyclodextrine which can reverse neuromuscular blockade that induced by aminosteroid NMBAs and its mechanism of action is differently than cholinesterase inhibitors4.
References :
1) Almeida JFL de, Filho WJK, Troster EJ. Neuromuscular Blockade in Children. Rev. Hosp. Clin. Fac. Med. S. Paulo.2000;55(3):105-110
2) Meakin GH. Neuromuscular blocking drugs in infants andchildren. Continuing Education in Anaesthesia. Critical Care & Pain. 2007;7(5):143-147
3) Micromedex® Healthcare Series. [Internet database]. Available from: Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc ; 2011. [cited 20/11/2014]
4) Owczarek M, Bultowicz R, Kazmirczuk R, Owczarek KS, Paciorek P, Jakubczyk M, Kupczyk K, Kusza K. Is suxamethonium still useful for paediatric anaesthesia? Anestezjol Intents Ter. 2011;44(3):181-185.
5) Playfor S. Nueromuscular Blocking Agents in Critically Ill Children. Paediatric and Perinatal Drug Therapy.2002; 5(1):35-46.
6) Shann F. Drug Doses, 16th Edition, Royal Children’s Hospital, Australia. 2014
7) Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010
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Introduction
Stress-related mucosal damage (SRMD) is the board term used to describe the spectrum of pathology attributed to the acute, erosive, inflammatory insult to the upper gastrointestinal tract associated with critical illness. SRMD represents a continuum from asymptomatic superficial lesions found incidentally during endoscopy, occult gastrointestinal bleeding causing anemia, overt gastrointestinal bleeding and clinically significant gastrointestinal bleeding.
Risk factors including:1,5
1) Coagulopathy2) Shock3) Surgery lasting for longer than 3 hours4) Trauma5) Pneumonia6) Peadiatric Risk of Mortality Score ≥ 107) Thermal injury
Prophylaxis agent for SRMD
Prophylaxis is recommended for SRMD, but there is insufficient evidence to recommend prophylaxis based on current trials on critically ill child1,5.
1) Sucralfate
Sucralfate acts by adhering to epithelial cells forming a physical cytoprotective barrier at the ulcer site, thereby protecting the gastric mucosa from the effects of acid and pepsin4.
Stress Ulcer Prophylaxis
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2) Histamine-2 receptor blockers (H2RBs)
H2RBs competitively inhibit histamine binding to its G-protein coupled receptor on the basolateral membrane of gastric parietal cells, which results in a reduction in acid production and an overall decrease in gastric secretions4.
3) Proton Pump Inhibitors (PPIs)
PPIs inactivate the H+/K+ ATPase enzyme at the secretory surface of the parietal cell, inhibiting the secretion of H+ ions and thereby increasing the pH of the gastric contents4.
The pharmacological properties and drug-drug interaction of the prophylaxis agents for SRMD are listed in Table 1.
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Tabl
e 1:
Sum
mar
y of
Pha
rmac
olog
ical
pro
pert
ies
of p
roph
ylax
is a
gent
s fo
r SR
MD
6,7 .
Age
nt
Sucr
alfa
te
His
tam
ine-
2 R
ecep
tor B
lock
ers
Prot
on P
ump
Inhi
bito
rs (P
PIs)
Ran
itidi
ne
Esom
epra
zole
La
nsop
razo
le
Om
epra
zole
Pa
ntop
razo
le
Dos
e
PO
: 0-
2 ye
ars
old:
25
0mg
q6h
3-12
yea
rs o
ld:
500m
g q6
h >1
2 ye
ars
old:
1g
q6h
PO
: 2-5
mg/
kg/d
ose
q8-1
2h
IV: 1
mg/
kg/d
ose
q6-8
h C
ontin
uous
infu
sion
: 2m
cg/k
g/m
in
PO
: 0.4
-0.
8mg/
kg/d
ose
daily
IV
: 0.4
-0.
8mg/
kg/d
ose
q24h
PO
: 1
year
s ol
d –
30kg
: 15m
g da
ily
>30k
g: 3
0mg
daily
PO
: 0.4
-0.
8mg/
kg/d
ose
q12-
24h
PO
: 1m
g/kg
q12
-24
h IV
: 1m
g/kg
q12
-24
h
Ons
et
1-2
hr
1 hr
-
- P
O: 1
hr
PO
: 2.5
hr
IV: 1
5-30
min
Dur
atio
n U
p to
6 h
r P
O: 4
-12
hr
- P
O: ≥
24
hr
PO
: 72
hr
PO
: 24
hr
IV: 2
4 hr
Met
abol
ism
Not
met
abol
ized
M
etab
oliz
ed b
y liv
er
Ext
ensi
vely
by
CY
P2C
19,
CY
P3A
3 &
C
YP
3A4
Ext
ensi
vely
by
CY
P2C
19 a
nd
CY
P3A
4
Ext
ensi
vely
by
CY
P2C
19 a
nd
CY
P3A
4
Ext
ensi
vely
by
CY
P2C
19 a
nd
CY
P3A
4
Elim
inat
ion
90%
exc
rete
d in
st
ool
Exc
rete
d 30
% (P
O) &
70
% (I
V) a
s un
chan
ged
drug
in
urin
e; fe
ces
as
met
abol
ite
80%
exc
rete
d as
in
activ
e m
etab
olite
in
urin
e; 2
0%
excr
eted
in fe
ces
67%
exc
rete
d in
fe
ces;
33%
ex
cret
ed in
urin
e
77%
exc
rete
d as
m
etab
olite
in u
rine
71%
exc
rete
d as
m
etab
olite
in u
rine;
18
% e
xcre
ted
in
fece
s
Dru
g In
tera
ctio
n
Dig
oxin
, fru
sem
ide,
ph
osph
ate
supp
lem
ent,
quin
idin
e,
quin
olon
e,
vita
min
D
anal
ogs,
vita
min
K
ant
agon
ists
,
Cef
urox
ime
Itrac
onaz
ole
Ket
ocon
azol
e P
rote
ase
inhi
bito
r
Fluc
onaz
ole
Itrac
onaz
ole
Ket
ocon
azol
e M
etho
trexa
te
Pro
teas
e In
hibi
tor
Vor
icon
azol
e
Fluc
onaz
ole
Itrac
onaz
ole
Ket
ocon
azol
e M
etho
trexa
te
Pro
teas
e In
hibi
tor
Vor
icon
azol
e
Fluc
onaz
ole
Itrac
onaz
ole
Ket
ocon
azol
e M
etho
trexa
te
Pro
teas
e In
hibi
tor
Vor
icon
azol
e
Fluc
onaz
ole
Itrac
onaz
ole
Ket
ocon
azol
e M
etho
trexa
te
Pro
teas
e In
hibi
tor
Vor
icon
azol
e
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Long-term and Serious Safety Concern with PPIs Use
Long-term inhibition of gastric acid secretion secretion leads to prolonged hypergastrinemia and concerns for enterochromaffin-like cell hyperplasia, carcinoid formation, vitamin B12 deficiency, hypomagnesemia, necrotizing enterocolitis, osteoporosis, atrophic gastritis, and increased infections. These concerns have been raised in adults, but paediatric studies are limited8.
Suppression of gastric acid secretion may predispose patients to certain infections (Clostridium difficile infections, other enteric infections and respiratory infections, including community-acquired pneumonias). The mechanism for this may be that acid suppression eliminates a defense against pathogens2.
References:
1. ASHP Board of Directors. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. America: Am J Health-Syst Pharm; 1999. 33 p.
2. Chen LL, Gao WY, Johnson AP, Niak A, Troiani J, Korvick J, Snow N, Estes K, Taylor A, Griebel D. Proton Pump Inhibitors Use in Infants: FDA Reviewer Experience. JPGN. 2012;54(1):8-14
3. Micromedex® Heal thcare Ser ies. [ In ternet database] . Ava i lab le from:Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc ; 2011. [cited 25/3/2015]
4. Pummer MP, Blaser AR, Deane AM. Stress Ulceration: Prevalence, Pathology and Association with Adverse Outcomes. Critical Care. 2014;18:213
5. Reveiz L, Lozano RG, Camacho A, Yara L, Mosquera PA. Stress Ulcer, Gastritis, and Gastrointestinal Bleeding Prophylaxis in Criticlly Ill Pediatric: A Systematic Review. Pediatr Crit Care Med. 2010;11(1):124-132
6. Shann F. Drug Doses, 16th Edition, Royal Children’s Hospital, Australia. 2014
7. Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010
8. Ward RM, Kearns GL. Proton Pump Inhibitors in Pediatrics. Pediatr Drugs. 2013;15:119-131
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Introduction
The indications for sedation in the paediatric intensive care unit (PICU) patient are varied ranging from short term use for various procedures to prolonged administration to provide comfort during mechanical ventilation11.
Due to diversity among patients and the varied indications for sedative and analgesic drugs, it is not possible to provide a ‘cookbook’ of definite guidelines for sedation and analgesia. Sedative and analgesia agents should not be administered strictly on a per kilogram basis like other medications such as antibiotics. Dosage recommendations are meant as guidelines for starting doses. The actual amount administered should be titrated up or down to achieve the desired level of sedation or analgesia11.
Undersedation and oversedation are both harmful. Agitation and inadequate sedation have been correlated with adverse short- and longer-term outcomes. Recent data have highlighted the intensive care and surgery are associated with long-term dysregulation of nociceptive mechanisms, which may change behaviour and responses to future sensory and pain stimuli. By contrast, oversedation delays recovery promotes tolerance to the drugs and leads to distressing symptoms on withdrawal (agitation, seizures, hallucinations, psychosis, fever and tachycardia)12.
Opioids, in particular, are associated with dose-dependent immunosuppression of both humoral and cell-mediated immunity, which acts on promote infection and sepsis during a longer PICU stay12. Sedative Agents
• Benzodiazepine
Mechanism of action of benzodiazepine is through the facilitations in the CNS of the activity of the inhibitory neurotransmitter, Y-aminobutyric acid (GABA).Midazolam are the most commonly used benzodiazepine in PICUs8. Midazolam is a water-based acidic preparation; at plasma pH, it converts into an un-ionised form that crosses the blood-brain barrier rapidly. It has the shortest elimination half-life of the benzodiazepine group8.
SEDATION & PAIN MANAGEMENT
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Generally, midazolam is a safe and effective sedative agent if given as short- term infusion and it tends to accumulate if given as continuous infusion due to its high volume distribution and high lipophilicity4. Dose reduction is necessitating in patients with hepatic and/or renal dysfunction8,11.
The main adverse events associated with midazolam are tolerance, dependence and withdrawal following discontinuation7.
• Dexmedetomidine
Dexmedetomidine is a selective 2-adrenergic agonist and is structurally related to clonidine, but has a much greater affinity for æ2-receptors over æ2-receptors. It is extensively metabolized through the cytochrome P450 enzyme system, therefore dose reduction is recommended for patient with hepatic dysfunction2.
The most significant adverse reasons are hypotension and bradycardia, resulting from its sympatholytic activity. Both are rarely clinically significant or required intervention to correct. Transient hypertension has been reported with the administration of the loading dose due to initial vasoconstriction caused by stimulation of peripheral postsynaptic 2-adrenergic receptors. Management consists of slowing the infusion rate, but rarely is discontinuation of treatment necessary. Dexmedetomidine is recommended to be used with caution in patients with history of atrioventricular nodal block or severe ventricular dysfunction, as well as in hypovolemic patients or those with chronic hypertension2.
Although not well studied, abrupt cessation of dexmedetomidine may produce withdrawal symptoms. Slowly taper off the dose of dexmedetomidine may be useful to minimize the risk for withdrawal2.
• Ketamine
Ketamine is a dissociative anaesthetic agent, structurally similar to phencyclidine, which produces a cataleptic trance-like state by apparently producing an electrophysiological dissociation between the limbic and thalamoneocortical systems7.
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Ketamine produces a dose-related acceleration of heart rate and blood pressure thought to be caused by the release of endogenous catecholamines through its stimulatory effect on the sympathetic nervous system. The indirect sympathomometic effect of ketamine is assumed to dominate over its direct negative inotropic properties, therefore resulting in reduced risk of hypotension. In addition, respiratory function is well maintained with ketamine. Functional residual capacity, minute ventilation and tidal volume are unchanged, pulmonary compliance is improved and bronchospasms are relieved due to release of catecholamines6.
Although ketamine generally preserves airway patency, rare cases of pulmonary aspiration, apnea, arterial hypoxemia and laryngospasm have been reported. Ketamine is a potent sialagogue. It increases salivary and bronchial mucous gland secretions through stimulation of cholinergic receptors. Ketamine also increases intracranial pressure (ICP) and pulmonary vascular resistance. Therefore, is contraindicated for patients with pulmonary hypertension or at risk for elevated intracranial pressure6.
Emergency phenomena are a hallmark event for ketamine and have been described as vivid dream, hallucinations, floating sensations, delirium, recovery agitation and dysphoria. Benzodiazepines have been co- administrated with ketamine to reduce the frequency of emergency phenomena, however, it is controversial3,6.
• Propofol
Propofol is a unique sedative-hypnotic agent with a rapid onset and offset of action. Propofol also acts on the GABA receptor like benzodiazepine although the side of action on this receptor is different4. It offers the advantages of a quick onset of action, quick recovery once discontinued and lacks of active metabolites11.
In addition to its sedative and amnesia effects, propofol also decreases cerebral oxygen consumption and reduces intracranial pressure. It also shows excellent antiepileptic activities with proven efficacy in treating patients with refractory seizures11.
Propofol is a highly lipophilic compound and is essentially insoluble in water or other aqueous medium. Therefore, it is formulated as an intravenous emulsion with 10% lipid11. Propofol-related infusion syndrome is a rare but frequently fatal complication characterised by acidosis, bradyarrhythmia and rhabdomyolysis. It has been demonstrated that transient elevations in malonylcarnitine and C5-acylcarnitine occur during propofol-related infusion syndrome, suggesting that propofol impairs fatty acid oxidation and mitochondrial activity at the subcellular level8.
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Tabl
e 1:
Sum
mar
y of
pha
rmac
olog
ical
pro
pert
ies
of s
edat
ive
agen
ts5,
9,10
.
Age
nt
Mid
azol
am
Dex
med
etom
idin
e K
etam
ine
Prop
ofol
Dos
e
Sed
atio
n:
IV b
olus
/ IM
: 0.1
-0.
2mg/
kg/d
ose
(max
imum
dos
e: 0
.5m
g/kg
) In
fusi
on: 1
-4m
cg/k
g/m
in
ICU
: In
fusi
on: 0
.4m
cg/k
g/hr
P
roce
dure
: In
fusi
on: 0
.5-1
mcg
/kg/
min
ov
er 1
0-20
min
, the
n 0.
6 m
cg/k
g/hr
Ana
esth
esia
: IV
: 1-2
mg/
kg/d
ose
IM: 5
-10m
g/kg
/dos
e In
fusi
on: 1
0-40
mcg
/kg/
min
A
nalg
esia
: IV
: 1-1
.5m
g/kg
IM
: 3-4
mg/
kg
Infu
sion
: 2-6
mcg
/kg/
min
Ana
esth
esia
: IV
: 2.5
-3.5
mg/
kg s
tat,
then
7.
5-15
mg/
kg/h
r S
edat
ion:
IV
: 1-3
mg/
kg/h
r
Ons
et
IV: 1
-5 m
in
IM: <
5 m
in
IV: 3
0 m
in
Ana
esth
esia
: IV
: <30
sec
IM
: 3-4
min
A
nalg
esia
: IM
: 10-
15 m
in
IV: 1
0-50
sec
Max
imum
ef
fect
IV
: 5-7
min
IM
: 15-
30 m
in
- IM
: 15-
30 m
in
-
Dur
atio
n IV
: 20-
30 m
in
IM: 2
-6 h
r IV
: 4 h
r IM
: 2.5
hr
Ana
esth
esia
: IV
: 5-1
0 m
in
IM: 1
2-25
min
A
nalg
esia
: IM
: 15-
30 m
in
IV: 3
-10
min
Full
reco
very
M
ay ta
ke >
24 h
ours
-
IV: 1
-2 h
r IM
: 3-4
hr
-
Met
abol
ism
Ext
ensi
ve m
etab
oliz
e in
live
r vi
a C
YP
3A4.
P
rimar
y m
etab
olite
(á-
hydr
oxy-
mid
azol
am) i
s ac
tive
and
equi
pote
nt to
mid
azol
am
Met
abol
ize
in li
ver v
ia
CY
P2A
6 in
to in
activ
e m
etab
olite
s
Met
abol
ize
in li
ver v
ia
CY
P2B
6, C
YP
2C9
& C
YP
3A4
into
nor
keta
min
e (a
ctiv
e m
etab
olite
) and
its
pote
ncy
is
one
third
of t
he p
aren
t co
mpo
und.
Ext
ensi
ve in
live
r via
CY
P2B
6 in
to in
activ
e m
etab
olite
s
Elim
inat
ion
Urin
e:
63-8
0% e
xcre
ted
as á
-hy
drox
y-m
idaz
olam
; <1
% e
xcre
ted
as u
ncha
nged
dr
ug
Fece
s:
2-10
% a
s un
chan
ged
drug
Urin
e:
95%
Fe
ces:
4%
Urin
e:
Maj
ority
exc
rete
d as
inac
tive
met
abol
ite; 4
% e
xcre
ted
as
unch
ange
d dr
ug o
r no
rket
amin
e Fe
ces:
<5
%
Urin
e:
88%
exc
rete
d as
met
abol
ites;
<3
% e
xcre
d as
unc
hang
ed
drug
Fe
ces:
<2
%
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Age
nt
Mid
azol
am
Dex
med
etom
idin
e K
etam
ine
Prop
ofol
A
mne
sia
Yes
Y
es
Yes
Y
es
Ana
lges
ia
No
Yes
Y
es
No
Dru
g in
tera
ctio
n
Con
train
dica
ted:
E
favi
renz
; Pro
teas
e in
hibi
tors
; In
crea
sed
effe
ct /
toxi
city
M
idaz
olam
may
incr
ease
the
leve
ls/e
ffect
s of
: C
loza
pine
, CN
S d
epre
ssan
t; m
etho
trim
epra
zine
; ph
enyt
oin;
pro
pofo
l Th
e le
vels
/effe
cts
of
mid
azol
am in
crea
sed
by:
Ant
ifung
al a
gent
s (A
zole
de
rivat
ives
, sys
tem
ic);
Apr
epita
nt; a
torv
asta
tin;
CC
B (n
on-d
ihyd
ropy
ridin
e);
cim
etid
ine;
con
trace
ptiv
es
(est
roge
ns &
pro
gest
ins)
; C
YP
3A4
inhi
bito
rs;
Efa
vire
nz; I
soni
azid
; M
acro
lide
antib
iotic
s;
Pro
pofo
l; P
rote
ase
inhi
bito
rs;
PP
I; S
SR
I D
ecre
ased
effe
ct
The
leve
ls/e
ffect
s of
m
idaz
olam
may
be
decr
ease
d by
: C
arba
maz
epin
e; C
YP
3A4
indu
cers
; def
eras
irox,
rif
ampi
cin
deriv
ativ
es;
theo
phyl
line
deriv
ativ
es
Incr
ease
d ef
fect
/ to
xici
ty
Mid
azol
am m
ay in
crea
se th
e le
vels
/effe
cts
of:
Hyp
oten
sive
age
nts
The
leve
ls/e
ffect
s of
m
idaz
olam
incr
ease
d by
: B
eta-
bloc
keer
s; C
YP
2A6
inhi
bito
rs; M
AO
inhi
bito
rs
Dec
reas
ed e
ffect
Th
e le
vels
/effe
cts
of
mid
azol
am m
ay b
e de
crea
sed
by:
Ant
idep
ress
ants
(α2-
anta
goni
st);
SS
RI;
tricy
clic
an
tidep
ress
ants
Incr
ease
d ef
fect
/ to
xici
ty
The
leve
ls/e
ffect
s of
ket
amin
e in
crea
sed
by:
CY
P2B
6 in
hibi
tors
; CY
P2C
9 in
hibi
tors
; CY
P3A
4 in
hibi
tors
; de
satin
ib; q
uaze
pam
D
ecre
ased
effe
ct
The
leve
ls/e
ffect
s of
ket
amin
e m
ay b
e de
crea
sed
by:
CY
P2C
9 in
duce
rs;
Peg
inte
rfero
n α-
2b
Incr
ease
d ef
fect
/ to
xici
ty
Pro
pofo
l may
incr
ease
the
leve
ls/e
ffect
s of
: M
idaz
olam
; rop
ivac
aine
Th
e le
vels
/effe
cts
of p
ropo
fol
incr
ease
d by
: A
lfent
anil;
CY
P2B
6 in
hibi
tors
; m
idaz
olam
; qua
zepa
m
Dec
reas
ed e
ffect
Th
e le
vels
/effe
cts
of p
ropo
fol
may
be
decr
ease
d by
: P
egin
terfe
ron α
-2b
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Analgesic Agents
Opioids produce analgesia via a variety of central and peripheral opioids receptors, particularly μ- and k-receptors. To varying degrees the opioids tend to produce hypotension and respiratory depression7.
• Morphine
Morphine has the lowest lipid solubility of all the opioids, which accounts for its delayed onset of clinical effect. Dose reduction of morphine is necessity for patients with hepatic and/or renal dysfunction. Morphine stimulates the release of significant amounts of histamine and inhibits compensatory sympathetic responses; the resultant vasodilatation may result in hypotension. Discontinuation of morphine is associated with withdrawal syndrome7.
• Fentanyl
Fentanyl is a potent synthetic opioid with a rapid onset of action, which is associated with less histamine release than morphine, and therefore, produces less hypotension; although it may reduce cardiac output by decreasing the heart rate. Fentanyl is 100 times more potent compared to morphine. When given intravenously there is rapid redistribution to peripheral compartments, giving fentanyl a relatively short half-life of 30-60 minutes7. An infrequenct adverse effect is chest wall rigidity, which is related to the dose used, rate of infusion and age < 6 months1. Prolonged administration of fentanyl is associated with tolerance7.
• Remifentanil
Remifentanil is a synthetic opioid with cardio-respiratiory effects similar to other opioids and which is equipotent to fentanyl. Remifentanil has a half-life of 3 minutes in all age groups because it is metabolised by plasma and tissue esterases. No dosage adjustment is needed for patients with liver and/or renal dysfunction. Prolonged administration of remifentanil is associated with tolerance7.
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Tabl
e 2:
Sum
mar
y of
pha
rmac
olog
ical
pro
pert
ies
of a
nalg
esic
age
nts.
5,9,
10
Age
nt
Mor
phin
e Fe
ntan
yl
Rem
ifent
anil
Dos
e
Ven
tilat
ed p
atie
nt:
IV: 0
.1-0
.2m
g/kg
/dos
e In
fusi
on: 2
0-80
1mcg
/kg/
hr
Ven
tilat
ed p
atie
nt:
IV: 5
-10m
cg/k
g/do
se
Infu
sion
: 5-1
0mcg
/kg/
hr
Ven
tilat
ed p
atie
nt:
Infu
sion
: 0.5
-1m
cg/k
g/m
in
Ons
et
IV: 5
min
IM
: 10-
30 m
in
IV: A
lmos
t im
med
iate
IM
: 7-1
5 m
in
IV: 1
-3 m
in
Max
imum
ef
fect
IV: 2
0 m
in
IM: 3
0-60
min
-
IV: 3
-5 m
in
Dur
atio
n
IV/IM
: 3-5
hr
IV: 3
0-60
min
IM
: 1-2
hr
IV: 3
-10
min
Met
abol
ism
Met
abol
ize
in li
ver v
ia g
lucu
roni
de
conj
ugat
ion
to m
orph
ine-
6-gl
ucur
onid
e (a
ctiv
e) &
mor
phin
e-3-
gluc
uron
ide
(inac
tive)
Met
abol
ize
in li
ver v
ia C
YP
3A4
into
in
activ
e m
etab
olite
s
Met
abol
ized
rapi
dly
by b
lood
and
tis
sue
este
rase
s in
to in
activ
e m
etab
olite
s
Elim
inat
ion
Urin
e:
90%
exc
rete
d in
urin
e; 2
-12%
exc
rete
d as
unc
hang
ed d
rug
Fece
s:
7-10
%
Urin
e:
75%
exc
rete
d as
met
abol
ites;
7-
10%
exc
rete
d as
unc
hang
ed d
rug
Fece
s:
1-9%
as
met
abol
ites
Urin
e:
90%
exc
rete
d as
inac
tive
met
abol
ites
His
tam
ine
rele
ase
Yes
N
o N
o
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Age
nt
Mor
phin
e Fe
ntan
yl
Rem
ifent
anil
Dru
g in
tera
ctio
n
Incr
ease
d ef
fect
/ to
xici
ty
Mor
phin
e m
ay in
crea
se th
e le
vels
/effe
cts
of:
CN
S d
epre
ssan
t; de
smop
ress
in;
SS
RI;
thia
zide
diu
retic
s Th
e le
vels
/effe
cts
of m
orph
ine
may
be
incr
ease
d by
: A
mph
etam
ines
; ant
ipsy
chot
ic a
gent
s;
succ
inyl
chol
ine
Dec
reas
ed e
ffect
Th
e le
vels
/effe
cts
of m
orph
ine
may
be
decr
ease
d by
: A
mm
oniu
m c
hlor
ide;
mix
ed a
goin
ist /
an
tago
nist
opi
oids
; peg
inte
rfero
n α
-2b
; rifa
mpi
cin
deriv
ativ
es
Con
train
dica
ted:
P
rote
ase
inhi
bito
rs, M
AO
inhi
bito
rs
Incr
ease
d ef
fect
/ to
xici
ty
Fent
anyl
may
incr
ease
the
leve
ls/e
ffect
s of
: B
eta-
bloc
kers
; CC
B (n
on-
dihy
drop
yrid
ine)
; CN
S d
epre
ssan
t; de
smop
ress
in; M
AO
inhi
bito
rs; S
SR
I; th
iazi
de d
uire
tics
Th
e le
vels
/effe
cts
of fe
ntan
yl m
ay b
e in
crea
sed
by:
Am
phet
amin
e, a
ntip
sych
otic
age
nts;
C
YP
3A4
inhi
bito
rs; M
AO
inhi
bito
rs;
succ
inyl
chol
ine
Dec
reas
ed e
ffect
Th
e le
vels
/effe
cts
of fe
ntan
yl m
ay b
e de
crea
sed
by:
Am
mon
ium
chl
orid
e; m
ixed
ago
inis
t /
anta
goni
st o
pioi
ds; r
ifam
pici
n de
rivat
ives
Con
train
dica
ted:
M
AO
inhi
bito
rs
Incr
ease
d ef
fect
/ to
xici
ty
Rem
ifent
anil
may
incr
ease
the
leve
ls/e
ffect
s of
: B
eta-
bloc
kers
; CC
B (n
on-
dihy
drop
yrid
ine)
; CN
S d
epre
ssan
t; de
smop
ress
in; M
AO
inhi
bito
rs; S
SR
I; th
iazi
de d
uire
tics
Th
e le
vels
/effe
cts
of re
mife
ntan
il m
ay
be in
crea
sed
by:
Am
phet
amin
es; a
ntip
sych
otic
age
nts;
su
ccin
ylch
olin
e D
ecre
ased
effe
ct
The
leve
ls/e
ffect
s of
rem
ifent
anil
may
be
dec
reas
ed b
y:
Am
mon
ium
chl
orid
e; m
ixed
ago
inis
t /
anta
goni
st o
pioi
ds
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Withdrawal syndrome
Withdrawal syndrome may occur following the discontinuation of sedative agents, particularly benzodiazepines and opioids, and is thought to be related to the total drug doses received. The withdrawal syndrome occurs in 50% of the cases with a cumulative fentanyl dose greater than 1.5mg/kg or administration longer than 5 days, rising to 100% when the cumulative dose is greater than 2.5mg/kg or with an administration longer than 9 days. The incidence of this syndrome increases significantly with an cumulative midazolam dose greater than 60mg/kg1.
Different methods are used to prevent the development of the withdrawal syndrome, such as gradual reduction in doses, enteral sedative agents and subcutaneous use of fentanyl and midazolam and avoidance of continuous intravenous sedation1. References:
1) Bartolomé SM, Cid JLH, Freddi N. Analgesia and Sedation in Children: Practical Approach for the Most Frequent Situations. Jornal de Pediatria. 2007;83(2):S71-S82.
2) Buck ML. Dexmedetomidine Use in Pediatric Intensive Care and Procedural Sedation. J Pediatr Pharmacol Ther. 2010;15(1):17-29
3) Dolansky G, Shah A, Mosdossy G, Rieder MJ. What is the Evidence for the Safety and Efficacy of Using Ketamine in Children? Paediatr Child Health. 2008;13(4):307-308
4) Gommers D, Bakker J. Medications for Analgesia and Sedation in the Intensive Care Unit: An Overview. Critical Care. 2008;12(3):S1-S5.
5) Micromedex® Healthcare Series. [Internet database]. Available from: Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc; 2011. [cited 20/11/2014]
6) Mistry RB, Nahata MC. Ketamine for Conscious Sedation in Pediatric Emergency Care. Pharmacotherapy. 2005;25(8):1104-1111
7) Playfor SD. Analgesia and Sedation in Critically Ill Children. Arch. Dis. Child Ed. Pract. 2008;93:87-92.
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8) Playfor S, Jenkins I, Boyles C, Choonara I, Davies G, Haywood T et al. Consensus Guidelines on Sedation and Analgesia in Critically Ill Children. Intensive Care Med. 2006;32:1125-1136
9) Shann F. Drug Doses. 16th ed. Victoria. Royal Children’s Hospital; 2014
10) Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010
11) Tobias JD. Sedation and Analgesia in Paediatric Intensive Care Units Paediatr Drugs. 1999;1(2):109-126
12) Wolf AR. Analgesia and Sedation in Pediatric Intensive Care. South Afr J Anaesth Analg. 2012;18(5):258-261
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5.0 Neonatal ICU
Paediatric Pharmacy Services Guideline142
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Introduction
Neonatal Jaundice (NNJ) is one of the most common medical conditions in newborns. All newborn babies have a transient rise in serum bilirubin but only about 75% are visibly jaundiced. There are other risk factors that may be associated with significant hyperbilirubinemia including prematurity, G6PD deficiency and ABO incompatibility.
Jaundice or hyperbilirubinaemia is either unconjugated or conjugated. Without treatment, high levels of unconjugated bilirubin may lead to acute and chronic bilirubin encephalopathy. This causes neurodevelopmental problems including athetoid cerebral palsy, hearing loss and, visual and dental problems.
Risk factors for severe NNJ: • Prematurity • Low birth weight
• Jaundice in the • Mother with Blood first 24 hours of life Group O or Rhesus Negative
• G6PD deficiency • Sepsis
• Rapid rise of total serum bilirubin • Exclusive breastfeeding
• Excessive weight loss • High predischarge bilirubin level
• Cephalhaematoma or bruises • Family history of severe NNJ in• Baby of diabetic mothers siblings
Pharmacotherapy
There is limited good evidence on pharmacotherapy in NNJ and no conclusive evidence to support the use of IVIG, human albumin and phenobarbitone in the management of NNJ.
Non-Pharmacotherapy
• Phototherapy
Phototherapy is the mainstay of treatment in NNJ. There are many types of devices that can be used to provide phototherapy such as fluorescent tubes, Light Emitting Diode (LED), fibreoptic and halogen bulbs
NEONATAL JAUNDICE (NNJ)
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• Exchange Transfusion
-> Exchange transfusion (ET) should be considered when total serum bilirubin reaches the threshold levels in neonatal jaundice (NNJ).
-> ET procedure should follow a standardized protocol and supervised by experienced personnel. Babies undergoing ET should be closely monitored.
-> Reconstituted blood products may be used if citrated fresh whole blood is not available for ET in NNJ.
-> Blood product used most commonly for ET is citrated fresh whole blood.However, some centres use reconstituted blood products when it is not available.Both citrated fresh whole blood and reconstituted blood products are comparable in terms of efficacy and safety
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4.0 NEONATAL ICU
Neonatal Jaundice (NNJ) Introduction
Neonatal Jaundice (NNJ) is one of the most common medical conditions in newborns. All newborn babies have a transient rise in serum bilirubin but only about 75% are visibly jaundiced. There are other risk factors that may be associated with significant hyperbilirubinemia including prematurity, G6PD deficiency and ABO incompatibility.
Jaundice or hyperbilirubinaemia is either unconjugated or conjugated. Without treatment, high levels of unconjugated bilirubin may lead to acute and chronic bilirubin encephalopathy. This causes neurodevelopmental problems including athetoid cerebral palsy, hearing loss and, visual and dental problems.
Risk factors for severe NNJ:
• Prematurity • Low birth weight • Jaundice in the first 24 hours of life • Mother with Blood Group O or
Rhesus Negative • G6PD deficiency • Rapid rise of total serum bilirubin • Sepsis
• Excessive weight loss • Exclusive breastfeeding • High predischarge bilirubin level • Cephalhaematoma or bruises • Baby of diabetic mothers • Family history of severe NNJ in
siblings
Pharmacotherapy
There is limited good evidence on pharmacotherapy in NNJ and no conclusive evidence to support the use of IVIG, human albumin and phenobarbitone in the management of NNJ.
Non-Pharmacotherapy
• Phototherapy
Phototherapy is the mainstay of treatment in NNJ. There are many types of devices that can be used to provide phototherapy such as fluorescent tubes, Light Emitting Diode (LED), fibreoptic and halogen bulbs.
Care of babies during phototherapy
• Babies should be regularly monitored for vital signs including temperature and hydration status.
• Babies should be adequately exposed. • Babies’ eyes should be covered to prevent retinal damage. • Breastfeeding should be continued.
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• Exchange Transfusion • Exchange transfusion (ET) should be considered when total serum bilirubin
reaches the threshold levels in neonatal jaundice (NNJ). • ET procedure should follow a standardized protocol and supervised by
experienced personnel. Babies undergoing ET should be closely monitored. • Reconstituted blood products may be used if citrated fresh whole blood is not
available for ET in NNJ. • Blood product used most commonly for ET is citrated fresh whole blood.
However, some centres use reconstituted blood products when it is not available. Both citrated fresh whole blood and reconstituted blood products are comparable in terms of efficacy and safety.
TABLE 1: TSB levels for phototherapy & ET in babies ≥35 weeks gestation
Age LOW RISK >38 weeks & well
MEDIUM RISK >38 weeks with risk factors or 35 - 37 weeks + 6 days & well
HIGH RISK 35 - 37 weeks + 6 days with risk factors
Hours of life
Conventional Phototherapy - TSB in mg/dL (µmol/L)
ET - TSB in mg/dL (µmol/L)
Conventional Phototherapy - TSB in mg/dL (µmol/L)
ET - TSB in mg/dL (µmol/L)
Conventional Phototherapy - TSB in mg/dL (µmol/L)
ET - TSB in mg/dL (µmol/L)
<24* 24 9 (154) 19 (325) 7 (120) 17 (291) 5 (86) 15 (257) 48 12 (205) 22 (376) 10 (171) 19 (325) 8 (137) 17 (291) 72 15 (257) 24 (410) 12 (205) 21 (359) 10 (171) 18.5
(316) 96 17 (291) 25 (428) 14 (239) 22.5 (385) 11 (188) 19 (325) >96 18 (308) 25 (428) 15 (257) 22.5 (385) 12 (205) 19 (325)
a. Start intensive phototherapy at TSB 3 mg/dL (51 µmol/L) above the level for conventional phototherapy or when TSB increasing at >0.5 mg/dL (8.5 µmol/L) per hour
b. Risk factors are isoimmune haemolytic disease, G6PD deficiency, neonatal encephalopathy & sepsis.
*Jaundice appearing within 24 hours of life is abnormal & needs further evaluation.
• Complementary/Alternative Medicine/Practices
There is no good quality evidence to support the use of complementary/alternative medicine/practices in the management of babies with NNJ.
Impact of Breastfeeding
• Breastfeeding, because of its benefits, should be continued in the jaundiced babies. • Adequate lactation/breastfeeding support should be provided to all mothers, particularly
those with preterm babies. In breastfed babies with jaundice associated with inadequate intake, excessive weight loss or dehydration, supplementation with expressed breast milk or formula may be considered
*Jaundice appearing within 24 hours of life is abnormal & needs further evaluation.
• Complementary/Alternative Medicine/Practices
There is no good quality evidence to support the use of complementary/ alternative medicine/practices in the management of babies with NNJ.
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Impact of Breastfeeding
• Breastfeeding, because of its benefits, should be continued in the jaundiced babies.
• Adequate lactation/breastfeeding support should be provided to all mothers, particularly those with preterm babies. In breastfed babies with jaundice associated with inadequate intake, excessive weight loss or dehydration, supplementation with expressed breast milk or formula may be considered
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References:
1. Clinical Practice Guidelines Management of Neonatal Jaundice 2nd Edition December 2014 Ministro of Health Malaysia
2. Huang MS, Lin MC, Chen HH, et al. Risk factor analysis for late-onset neonatal hyperbilirubinemia in Taiwanese infants. Pediatr Neonatol 2009 Dec;50(6):261-265.
3. Jangaard KA, Fell DB, Dodds L, et al. Outcomes in a population of healthy term and near-term infants with serum bilirubin levels of >or=325 micromol/L (>or=19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics. 2008 Jul;122(1):119-124.
4. Kuzniewicz MW, Escobar GJ, Wi S, et al. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr. 2008 Aug;153(2):234-240.
5. National Collaborating Centre for Women’s and Children’s Health. Neonatal jaundice. London: NCC-WCH; 2010.
6. Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant > or =35 weeks’ gestation: an update with clarifications. Pediatrics. 2009 Oct;124(4 ):1193-1198.
7. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316.
8. Boo NY, Gan CY, Gian YW, et al. Malaysian mothers’ knowledge & practices on care of neonatal jaundice. Med J Malaysia. 2011 Aug;66(3):239-243.
9. Salas AA, Mazzi E. Exchange transfusion in infants with extreme hyperbilirubinemia: an experience from a developing country. Acta Paediatr. 2008 Jun;97(6):754-758.
10.Weng YH, Chiu YW. Comparison of efficacy and safety of exchange transfusion through different catheterizations: Femoral vein versus umbilical vein versus umbilical artery/vein. Pediatr Crit Care Med. 2011 Jan;12(1):6 64.
11. Chen HN, Lee ML, Tsao LY. Exchange transfusion using peripheral vessels is safe and effective in newborn infants. Pediatrics. 2008 Oct;122(4):e905-910.
12. Gharehbaghi MM, Hosseinpour SS. Exchange transfusion in neonatal hyperbilirubinaemia: a comparison between citrated whole blood and reconstituted blood. Singapore Med J. 2010 Aug;51(8):641-644.
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13. amidi M, Zamanzad B, Mesripour A. Comparing the effect of clofibrate and phenobarbital on the newborns with hyperbilirubinemia. EXCLI Journal. 2013;12:75-78.
14. Xiong T, Chen D, Duan Z, et al. Clofibrate for unconjugated hyperbilirubinemia in neonates: a systematic review. Indian Pediatr. 2012 Jan;49(1):35-41.
15. Ashkan MM, Narges P. The effect of low and moderate doses of clofibrate on serum bilirubin level in jaundiced term neonates. Paediatric and Perinatal Drug Therapy. 2007;8(2):51-54.
16. Louis D, More K, Oberoi S, et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta- analysis. Arch Dis Child Fetal Neonatal Ed. 2014 Jul;99(4):F325-331.
17. Ismael AS, Alrabaty AA. Role of Intravenous Human Albumin in Management of Neonatal Hyperbilirubinemia. JSMC. 2013;3(1).
18. Shahian M, Moslehi MA. Effect of albumin administration prior to exchange transfusion in term neonates with hyperbilirubinemia-a randomized controlled trial. Indian Pediatr. 2010 Mar;47(3):241-244. 19. Suresh G, Martin CL, Soll R. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database of Systematic Reviews. 2003;Issue 1. Art. No.: CD004207.
20. Chawla D, Parmar V. Phenobarbitone for prevention and treatment of unconjugated hyperbilirubinemia in preterm neonates: a systematic review and meta-analysis. Indian Pediatr. 2010 May;47(5):401-407.
21. Hussain Imam MI, Ng HP, Thomas T, et al. Malaysian Paediatric Protocol for Malaysian Hospitals 3rd Edition. Putrajaya: MoH; c2012.
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Sedation & Pain Management
Table 1: Responses of Neonates to Pain
Physiological changes
Behavioral changes
Hormonal changes
Autonomic changes
Body movements
Increase in: Heart rate Blood pressure Respiratory rate Oxygen consumption Mean airway pressure Muscle tone Intracranial pressure
Grimacing Pain Definition An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage 8 Responses of Neonates to Pain Prolonged or severe pain may cause short- or long term physiological, behavioral, hormonal and metabolic changes. These changes may result in higher morbidity and mortality as well as alter subsequent responses to pain 4 Screwing up eyes Nasal flaring Curving of the tongue Quivering of the chin
Increased release of: Cortisol Catecholamine Glucagon Growth hormone Renin Aldosterone Antidiuretic hormone Decreased secretion of: Insulin
Mydriasis Sweating Flushing Pallor
Finger clenching Trashing of limbs Writhing Arching of back Head hanging
SEDATION & PAIN MANAGEMENT
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Pain Assessment Pain assessment in neonatal patients is mainly via self-reporting by staffs and indirect measurement including behavioral, physiological and hormonal changes 10.
Sedation
Definition
Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety2.
Level of Sedation / Depth of Sedation
Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.
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Pain Assessment Pain assessment in neonatal patients is mainly via self-reporting by staffs and indirect measurement including behavioral, physiological and hormonal changes 10.
Table 2: Commonly used Pain Assessment Tools in Neonatal Patients
Assessment Tools
Premature Infant Pain
Profile (PIPP)
Neonatal Facial Coding Scale
(NFCS)
Neonatal Infant Pain
Scale (NIPS) CRIES Score
Variables assessed
Gestational age Behavioural state Heart Rate Oxygen saturation Brow bulge Eye squeeze Nasolabial furrow
Brow bulge Eye squeeze Nasolabial furrow Open lips Stretch mouth Lip purse Taut tongue Chin quiver Tongue protrusion
Facial expression Cry Breathing patterns Arms Legs State of arousal
Crying Requires increase Oxygen administration Increased vital signs Expression Sleeplessness
Sedation Definition Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety 2. Level of Sedation / Depth of Sedation Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.
Table 3: Continuum of Depth of Sedation adopted by American Society of Anaesthesiologists
Level of Sedation
Minimal sedation / Anxiolysis
Moderate sedation/
Conscious sedation
Deep sedation General anaesthesia
Responsiveness
Normal response to
verbal stimulation
Purposeful response to verbal
or tactile stimulation
Purposeful response following repeated or painful
stimulation
Unarousable even with painful
stimulus
Airway Unaffected No intervention required
Intervention may be required
Intervention often required
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Pain Assessment Pain assessment in neonatal patients is mainly via self-reporting by staffs and indirect measurement including behavioral, physiological and hormonal changes 10.
Table 2: Commonly used Pain Assessment Tools in Neonatal Patients
Assessment Tools
Premature Infant Pain
Profile (PIPP)
Neonatal Facial Coding Scale
(NFCS)
Neonatal Infant Pain
Scale (NIPS) CRIES Score
Variables assessed
Gestational age Behavioural state Heart Rate Oxygen saturation Brow bulge Eye squeeze Nasolabial furrow
Brow bulge Eye squeeze Nasolabial furrow Open lips Stretch mouth Lip purse Taut tongue Chin quiver Tongue protrusion
Facial expression Cry Breathing patterns Arms Legs State of arousal
Crying Requires increase Oxygen administration Increased vital signs Expression Sleeplessness
Sedation Definition Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety 2. Level of Sedation / Depth of Sedation Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.
Table 3: Continuum of Depth of Sedation adopted by American Society of Anaesthesiologists
Level of Sedation
Minimal sedation / Anxiolysis
Moderate sedation/
Conscious sedation
Deep sedation General anaesthesia
Responsiveness
Normal response to
verbal stimulation
Purposeful response to verbal
or tactile stimulation
Purposeful response following repeated or painful
stimulation
Unarousable even with painful
stimulus
Airway Unaffected No intervention required
Intervention may be required
Intervention often required
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Spontaneous ventilation Unaffected Adequate May be inadequate Frequently
inadequate Cardiovascular
function Unaffected Usually maintained Usually maintained Maybe impaired
General Principles of Pain Management & Sedation
• In both preterm and term neonates, neuroanatomical components and neuroendocrine systems are developed sufficiently to allow transmission of painful stimuli 10.
• Newborns may be more sensitive to pain and may be more susceptible to long term effects of pain. However, pain in newborns are often not recognized and undertreated10
• Sedation does not provide pain relief and may mask the patient’s response to pain • Approach to pain prevention and management: 10
- Avoiding and limiting noxious stimuli - Minimizing painful procedure
Eg: placement of peripheral lines to reduce repeated IV punctures - Applying non-invasive measurement
Eg: oximeter - Assessment of neonatal pain - Behavioral methods / non-pharmacological therapy
Eg: sucrose, swaddling, non-nutritive sucking, skin to skin contact - Pharmacological therapy as pre-emptive analgesic - Pharmacological therapy for on-going pain
Pain & Sedation Management in Ventilated Patient 4,9.
• Analgesia/sedation should be used in neonates receiving continued ventilation. • Morphine
Continuous morphine infusion may improve neurological outcome and reduce adverse responses during endotracheal suctioning. Titrate up the morphine infusion according to response. If a patient is ventilated for ≥ 1 week and on full enteral feed without needing the intravenous access, switching to oral morphine can be considered.
• Midazolam Intermittent during intubation and continuous infusion of midazolam can be used as sedation
Pain & Sedation Management in Procedures 6,11
• Behavioral methods / Non-pharmacological therapy - Hypnosis & distraction - Music - Non-nutritive sucking - Breast-feeding during procedure - Sucrose
Sucrose can be used for short term pain prior to minor procedures eg: venipuncture, cannulation, heel prick, IM/SC injection, dressing change and eye examination. It is not for continuing pain.
General Principles of Pain Management & Sedation
• In both preterm and term neonates, neuroanatomical components and neuroendocrine systems are developed sufficiently to allow transmission of painful stimuli10.
• Newborns may be more sensitive to pain and may be more susceptible to long term effects of pain. However, pain in newborns are often not recognized and undertreated10
• Sedation does not provide pain relief and may mask the patient’s response to pain
• Approach to pain prevention and management: 10
- Avoiding and limiting noxious stimuli
- Minimizing painful procedure Eg: placement of peripheral lines to reduce repeated IV punctures
- Applying non-invasive measurement Eg: oximeter
- Assessment of neonatal pain
- Behavioral methods / non-pharmacological therapy Eg: sucrose, swaddling, non-nutritive sucking, skin to skin contact
- Pharmacological therapy as pre-emptive analgesic
- Pharmacological therapy for on-going pain
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Pain & Sedation Management in Ventilated Patient4,9.
• Analgesia/sedation should be used in neonates receiving continued ventilation.
• Morphine
Continuous morphine infusion may improve neurological outcome and reduce adverse responses during endotracheal suctioning. Titrate up the morphine infusion according to response. If a patient is ventilated for ≥ 1 week and on full enteral feed without needing the intravenous access, switching to oral morphine can be considered.
• Midazolam
Intermittent during intubation and continuous infusion of midazolam can be used as sedation
Pain & Sedation Management in Procedures 6,11
• Behavioral methods / Non-pharmacological therapy
- Hypnosis & distraction - Music - Non-nutritive sucking - Breast-feeding during procedure
- Sucrose
Sucrose can be used for short term pain prior to minor procedures eg: venipuncture, cannulation, heel prick, IM/SC injection, dressing change and eye examination. It is not for continuing pain.
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Table 4: Mechanism of action, Dosing, Age group, Administration, Adverse Effects, Cautions and Contraindications of Sucrose
Mechanism of action Elusive, maybe behavioral effect 13 Age group 1st month – 18months of life 11 Dosing 11 Maximum volume sucrose
24-33% solution per procedure
Maximum volume sucrose 24-33% solution within 24hours
Gestational Age / Birthweight Nil orally 0.2ml 1ml < 1500gm 0.5ml 2.5mls < 1 month of age 1ml 5mls 1-18months of age 2mls 5mls Administration method 11,13
I) Prepare the total amount of sucrose to be given for a procedure using a syringe Ii) Give a quarter of the total amount of sucrose 2minutes prior to procedure Iii) Administer on to the anterior of the tongue / by dip of pacifier (0.2ml per dip) Iv) Give the rest of the sucrose incrementally throughout the procedure
Adverse effects5 Safe for one-off use Repeated and frequent use in preterm neonate may cause possible adverse neurobiological effect
Caution13 Coughing, choking and desaturation with oral administration Contraindications4 Necrotizing enterocolitis, paralysed, absent of gag reflex
Pharmacological Therapy Topical anesthesia Methods that provide topical anesthesia including:
• Local Anesthesia Lubricant Gel 7,13
Examples of local anesthesia lubricant gel include Lidocaine 1% and 2%( not available in MOH formulary). They can be used prior to urinary catheterization, nasogastric tube insertion and circumcision.
• Vapo-coolant Sprays 7,13
Examples of vapo-coolant sprays include Ethyl Chloride Spray which is available in MOH formulary. Vapo-coolant sprays cause evaporative cooling thus provide transient numbness. It is suitable for procedures lasting ≤ 60 seconds eg: venipuncture and immunisations. Ethyl Chloride Spray should be sprayed at a distance of about 30cm until a fine white film is produced.
Pharmacological Therapy
Topical anesthesiaMethods that provide topical anesthesia including:
• Local Anesthesia Lubricant Gel 7,13
Examples of local anesthesia lubricant gel include Lidocaine 1% and 2%( not available in MOH formulary). They can be used prior to urinary catheterization, nasogastric tube insertion and circumcision.
• Vapo-coolant Sprays 7,13
Examples of vapo-coolant sprays include Ethyl Chloride Spray which is available in MOH formulary. Vapo-coolant sprays cause evaporative cooling thus provide transient numbness. It is suitable for procedures lasting ≤ 60 seconds eg: venipuncture and immunisations. Ethyl Chloride Spray should be sprayed at a distance of about 30cm until a fine white film is produced.
• Topical Local Anesthesia Cream
Topical anesthesia is obtained by passive diffusion of cream through skin surface to inhibit sensory neurons transmission in the dermis and epidermis. Examples of topical anesthesia cream include EMLA Cream and Ametop Gel (Tetracaine 4% Gel). Ametop Cream is not available in MOH formulary as well as not in Malaysia market.
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• Topical Local Anesthesia Cream Topical anesthesia is obtained by passive diffusion of cream through skin surface to inhibit sensory neurons transmission in the dermis and epidermis. Examples of topical anesthesia cream include EMLA Cream and Ametop Gel (Tetracaine 4% Gel). Ametop Cream is not available in MOH formulary as well as not in Malaysia market.
Table 5: Mechanism of action, Age Limit, Dosing, Adverse Effects, Cautions and
Contraindications of EMLA cream
Active ingredients Lignocaine 2.5% and Prilocaine 2.5%
Mechanism of action 9
Decrease the neuronal membrane’s permeability to sodium ions, resulting in inhibition of depolarization, blocking the initiation and conduction of nerve impulses, thus cause local anesthesia action
Onset of action for dermal analgesia 9
60minutes
Duration of action after removal 9
1-2hours
Age limit 3 Not licensed for < 1 year old
Adverse effects 9
Hypotension, angioedema Shock Burning, erythema, itching, rash Bronchospasm
Caution 9
G6PD deficiency (EMLA cream will predispose the patient to methaemoglobinemia) Anemia Methaemoglobinemia
Contraindications 9
Open wound Mucous membrane Atopic dermatitis
Dosing 9
Age and weight Max total dose Max application area Max application time
GA < 37weeks 0.5g No data 1 hour GA ≥ 37weeks 1g 10cm2 1 hour 1 to <3mo or <5kg 1g 10cm2 1 hour 3 to <12mo and >5kg 2g 20cm2 4hour 1-6yo and >10kg 10g 100cm2 4hour
Non-opioid Analgesics
Non-opioid analgesics do not cause respiratory depression, do not impair gastrointestinal motility and do not cause dependence. Insufficient analgesic potency for procedural analgesia, thus mainly used for the relief of post-operative pain3,13
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Non
-opi
oid
Ana
lges
ics
Non
-opi
oid
anal
gesi
cs d
o no
t ca
use
resp
irato
ry d
epre
ssio
n, d
o no
t im
pair
gas
troin
test
inal
mot
ility
and
do
not
caus
e de
pend
ence
. In
suffi
cien
t ana
lges
ic p
oten
cy fo
r pro
cedu
ral a
nalg
esia
, thu
s m
ainl
y us
ed fo
r the
relie
f of p
ost-o
pera
tive
pain
3 &
13
Tabl
e 6:
Mec
hani
sm o
f ac
tion,
indi
catio
ns,
rout
es a
vaila
ble,
tim
e of
ons
et,
dura
tion,
dos
age,
adv
erse
effe
cts
and
cont
rain
dica
tion
of n
on-
opio
id a
nalg
esic
s 3,
9, 1
2 &
13
Non
-opi
oid
Ana
lges
ics
Para
ceta
mol
N
on-s
tero
idal
Ant
i-inf
lam
mat
ory
Dru
gs
Dic
lofe
nac
Ibup
rofe
n
Mec
hani
sm o
f ac
tion
Inhi
bit t
he s
ynth
esis
of p
rost
agla
ndin
in
CN
S a
nd p
erip
hera
lly b
lock
pai
n im
puls
e ge
nera
tion
Inhi
bit p
rost
agla
ndin
syn
thes
is b
y de
crea
sing
the
activ
ity o
f cy
cloo
xyge
nase
Inhi
bit p
rost
agla
ndin
syn
thes
is b
y de
crea
sing
th
e ac
tivity
of c
yclo
oxyg
enas
e
Indi
catio
n ap
prov
ed in
M
OH
fo
rmul
ary
1) M
ild-M
oder
ate
Pai
n
2) P
ost-O
pera
tive
Pai
n 3)
Pai
n
1) P
ain
And
Infla
mm
atio
n In
Rhe
umat
ic
Dis
ease
& J
uven
ile A
rthrit
is
1) P
ain
And
Infla
mm
atio
n In
Rhe
umat
ic
Dis
ease
FDA
-app
rove
d in
dica
tion
1) M
ild-M
oder
ate
Pai
n
2) M
oder
ate-
Sev
ere
Pai
n (A
djun
ct)
3) F
ever
1) M
ild-M
oder
ate
Pai
n
1) P
ain
2)
Rhe
umat
oid
Arth
ritis
3)
Fev
er
Rou
te o
f ad
min
istra
tion
PO
, IV
, PR
P
O ,
IV, P
R
PO
Tim
e of
ons
et
PO
: < 1
hour
IV
: 5-1
0min
utes
P
R: a
bsor
ptio
n is
var
iabl
e &
pro
long
ed
PO
: 1 h
our
PR
: ≤ 1
hour
30
- 60m
inut
es
Ana
lges
ic
dura
tion
PO
; IV
: 4-6
hour
s
No
data
4-
6 ho
ur
Dos
age
Dos
age
for P
O &
PR
12 :
RO
A
LD
MD
Fr
eq.
PO
20
-25
mg/
kg
12-1
5 m
g/kg
Te
rm:
QID
PR
30
m
g/kg
12
-18
mg/
kg
Pre
m P
MA
≥
32w
eek:
TD
S
Pre
m P
MA
<
32w
eek:
BD
D
osag
e fo
r IV
: N
eona
te: L
imite
d da
ta
Infa
nt/C
hild
ren
< 2y
o:
7.5-
15m
g/kg
QID
(Max
: 60m
g/kg
/day
9)
Dos
age
for m
ild-m
oder
ate
pain
, for
≥6
mo,
PO
or P
R:
0.
3-1m
g/kg
(Max
: 50m
g) T
DS
3 D
osag
e fo
r pos
t-op
pain
for ≥
6yo,
PR
: 1-
2mg/
kg/d
ay in
BD
-TD
S (M
ax:
150m
g/da
y, 4
days
) 3 D
osag
e fo
r pos
t-op
pain
for ≥
2yo,
IM:
0.3-
1mg/
kg O
D-B
D, (
Max
: 2da
ys) 3
Dos
age
for i
nfan
ts:
4-10
mg/
kg/d
ose
TDS
-QID
M
ax: 4
0mg/
kg/d
ay 9
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132
Non
-opi
oid
Ana
lges
ics
Para
ceta
mol
N
on-s
tero
idal
Ant
i-inf
lam
mat
ory
Dru
gs
Dic
lofe
nac
Ibup
rofe
n
Adv
erse
ef
fect
s
Live
r to
xici
ty
(exc
essi
ve
dose
or
pr
olon
ged
use/
>
48ho
urs
of
ther
apeu
tic d
ose)
R
ash
Feve
r Th
rom
bocy
open
ia,
leuk
open
ia,
neut
rope
nia
12
Nau
sea
(7%
) D
iarr
hea
(6%
) LF
T ra
ised
(15%
) C
onst
ipat
ion
(8%
) U
RTI
(8%
) A
cute
rena
l fai
lure
G
IT h
aem
orrh
age
GIT
per
fora
tion
Ras
h (3
-9%
)
Nau
sea
(3-9
%)
Vom
iting
(1-3
%)
G
IT h
aem
orrh
age
(<1%
) G
IT p
erfo
ratio
n (<
1%)
H
epat
itis
(<1%
) A
cute
rena
l fai
lure
(rar
e)
Con
train
di-
catio
n
Hyp
erse
nsiti
vity
S
ever
e he
patic
impa
irmen
t H
yper
sens
itivi
ty
Ast
hma
H
isto
ry o
f alle
rgic
-rea
ctio
n to
asp
irin
Hyp
erse
nsiti
vity
A
sthm
a
His
tory
of a
llerg
ic-r
eact
ion
to a
spiri
n
Pro
duct
s av
aila
ble
in
MO
H
form
ular
y
1.P
arac
etam
ol s
yrup
125
mg/
5ml
2.P
arac
etam
ol
supp
osito
ry
125m
g;
250m
g
1.D
iclo
fena
c ta
blet
50m
g
2.D
iclo
fena
c su
ppos
itory
12.
5mg;
25m
g &
50m
g
3.D
iclo
fena
c in
ject
ion
75m
g
1.Ib
upro
fen
tabl
et 2
00m
g
Opi
oids
Ana
lges
ics
Opi
oid
anal
gesi
cs h
ad b
een
used
for a
nalg
esia
and
sed
atio
n. E
g: M
orph
ine,
tram
adol
, fen
tany
l. Tr
amad
ol is
not
lice
nsed
for t
he u
se in
chi
ldre
n <
12yo
.
Ta
ble
7: M
echa
nism
of a
ctio
n, ro
utes
ava
ilabl
e, ti
me
of o
nset
, dur
atio
n, d
osag
e an
d ad
vers
e ef
fect
s of
opi
oid
anal
gesi
cs3,
9, 2
&13
Opi
oid
Ana
lges
ics
Mor
phin
e Fe
ntan
yl
Mec
hani
sm o
f ac
tion
Ana
lges
ic:
Bin
d to
opi
oid
rece
ptor
s in
CN
S c
ausi
ng in
hibi
tion
of
desc
endi
ng p
ain
path
way
S
edat
ion:
B
ind
to o
pioi
d re
cept
ors
in C
NS
, cau
sing
gen
eral
ized
C
NS
dep
ress
ion
Act
on
opio
id m
u re
cept
or in
CN
S
Pro
perti
es
1) a
nalg
esic
2)
sed
ativ
e 1)
ana
lges
ic
2) s
edat
ive
3)
ane
sthe
sia
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Opioids Analgesics
Opioid analgesics had been used for analgesia and sedation. Eg: Morphine, tramadol, fentanyl. Tramadol is not licensed for the use in children < 12yo.
Table 7: Mechanism of action, routes available, time of onset, duration,dosage and adverse effects of opioid analgesics3,9, 2 &13
Opioid Analgesics Morphine Fentanyl
Mechanism of action Analgesic:
Bind to opioid receptors in CNS causing inhibition of descending pain pathway
Sedation:
Bind to opioid receptors in CNS, causing generalized CNS depression
Act on opioid mu receptor in CNS
Properties 1) analgesic 2) sedative
1) analgesic 2) sedative 3) anesthesia
Uses 1) Pain 2) Post-Op Pain
1) Pain2) Intra-Op Pain3) Immediate Post-Op Pain 4) Adjunct In Maintenance Of General/Regional Anesthesia
Route of administration PO IV; IM; SC (IV is preferred)
IVIM (for> 1yo)
Time of onset IV: 5-10minsPO: 30mins
IV: almost immediate IM: 8mins
Duration of action 4 hours IV: 0.5-1 hour IM: 1-2 hours
Dosage PO: 0.08mg/kg Q4-6hr
IV over 5mins, IM, SC: 0.05-0.2mg/kg/dose, repeat PRN (Q4hr)
IVI: LD 0.1-0.15mg/kg then MD 10-30mcg/kg/hour (Max: 30mcg/kg/hour) 9 & 12
Sedation/analgesia (IV slow push): 0.5-4mcg/kg, repeat PRN (Q2-4hr)
Sedation/analgesia (IVI):1-5mcg/kg/hour
Anesthesia (IV): 5-50mcg/k/dose 12
Adverse effects 1) Respiratory depression 2) Sedation 3) Nausea & vomiting 4) Reduced GIT motility: constipation, ileus 5) Urinary retention 6) Tolerance 7) Withdrawal symptoms 8) Hypotension, bradycardia
Sedation/analgesia (IV slow push): 0.5-4mcg/kg, repeat PRN (Q2-4hr)
Sedation/analgesia (IVI):1-5mcg/kg/hour
Anesthesia (IV): 5-50mcg/k/dose 12
Notes • reliable & predictable effects •easily reversed by naloxone
• synthetic opioid analgesic • 50-100times more potent than morphine • < hypotensive effect & safer in hyperactive airway disease• easily reversed by naloxone
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Benzodiazepine
• Benzodiazepine have anxiolytic, amnestic and skeletal muscle relaxant properties, but not analgesic effects. (Eg: Midazolam, diazepam, lorazepam.)
• Lorazepam has long duration of action, not used for procedural sedation. Midazolam is commonly used due to its short half-life and fast onset. Diazepam is used too but it has long half-life, active metabolites and erratic absorption.
Table 8: Mechanism of action, routes available, time of onset, duration,dosage and adverse effects of benzodiazepines3,9, 2 &13
Benzodiazepine Midazolam Diazepam
Mechanism of action Bind receptor at several sites within CNS, increase inhibitory effect of GABA
Modulate postsynaptic effect of GABA-A transmission, resulting in increase in presynaptic effect Act on limbic system as well as thalamus & hypothalamus, inducing a calming effect
Uses 1) procedural sedation2) sedation
1) sedation/muscle relaxant (for children)
Route of administration PO; IV; IM Intranasal (use 5mg/ml injection) Sublingual (5mg/ml injection, mixed with syrup)Buccal (for ≥ 6mo)PR (for ≥ 6mo)
POIV/IM
Time of onset IV: 3-5mins IM: ≤ 5mins
IV: 2-3mins
Duration IV: 20-30mins IM: 2-6hoursFull recovery maybe ≥ 24hours
IV: 30-90mins
Dosage PO0.25mg/kg/dose
Intranasal0.2mg/kg/dose
Sublingual0.2mg/kg/dose
IV (over 5mins); IM 0.05-0.15mg/kg, repeat PRN, Q2-4hr
IVI 1-4mcg/kg/min 12
For procedures: PO: 0.2-0.3mg/kg (Max: 10mg) pre-procedureIV over 5mins:0.05-0.1mg/kg, titrate slowly (Max: 0.25mg/kg total dose)
For sedation/muscle relaxant: PO:0.12-0.8mg/kg/day in TDS-QID IV/IM: 0.04-0.3mg/kg/dose Q2-4hour (Max: 0.6mg/kg/within 8hour) 9
Adverse effects Decreased respiratory effect (23%) Apnea (15%) Drowsiness (1-5%) Nausea-vomiting (3%) Cough (1%) SomnolenceHeadache Hiccoughs Respiratory arrest Hypotension
Common (frequency unknown): Hypotension Respiratory depression Fatigue Muscle weakness Urinary retention
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Barbiturates
Barbiturates act on GABA receptors and hyperpolarize the nerve cell membrane via chlor ide channels. Barbiturates have sedation andamnesia properties but not analgesic effect. Barbiturates have neuro-protective effect as they can lower intracranial pressure and they haveanticonvulsant effect.
Eg: Pentobarbital & ThiopentalPentobarbital is not available in MOH formulary.
135
Apnea (15%) Drowsiness (1-5%) Nausea-vomiting (3%) Cough (1%) Somnolence Headache Hiccoughs Respiratory arrest Hypotension
Hypotension Respiratory depression Fatigue Muscle weakness Urinary retention
Barbiturates Barbiturates act on GABA receptors and hyperpolarize the nerve cell membrane via chloride channels. Barbiturates have sedation and amnesia properties but not analgesic effect. Barbiturates have neuro-protective effect as they can lower intracranial pressure and they have anticonvulsant effect. Eg: Pentobarbital & Thiopental Pentobarbital is not available in MOH formulary. Table 9: Mechanism of action, routes available, time of onset, duration, dosage and adverse effects of thiopental
Uses Induction of anesthesia (non-FDA approved for pediatric use)
Route of administration IV
Dosage 2-6mg/kg IV slow push
Adverse effects Respiratory depression
Tolerance, dependence, cardiovascular depression
(prolonged use)
Products available in
MoH formulary
Thiopental sodium injection 500mg
Table 9: Mechanism of action, routes available, time of onset, duration, dosage and adverse effects of thiopental
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Age
nt
Ket
amin
e
Prop
ofol
D
exm
edet
omid
ine
N
itrou
s ox
ide
Mec
hani
sm o
f ac
tion
Non
com
petit
ive
NM
DA
re
cept
or a
ntag
onis
t A
ct o
n G
AB
A-A
rece
ptor
an
d bl
ock
NM
DA
rece
ptor
S
elec
tive
alph
a-2
adre
nerg
ic
agon
ist w
ith s
edat
ive
effe
cts
-
Pro
perti
es
1) S
edat
ive
2)
Ana
lges
ic
3) A
mne
stic
1)
Sed
ativ
e
1) S
edat
ive
1) A
nxio
lytic
s 2)
Am
nest
ic
3) m
ild-m
oder
ate
anal
gesi
c
Use
s in
pe
diat
ric
patie
nts
1) s
edat
ion
pre-
proc
edur
e (
1m
o)
2) In
duct
ion
& m
aint
enan
ce
of a
nest
hesi
a
1) s
edat
ion
( 1
mo)
2)
Indu
ctio
n &
m
aint
enan
ce o
f ane
sthe
sia
( 1
mo)
Saf
ety
and
effic
acy
is n
ot
esta
blis
hed
in p
edia
tric
patie
nts
1) m
aint
enan
ce o
f ane
sthe
sia
with
oth
er a
nest
hest
ic a
gent
2)
ana
lges
ia
Rou
te o
f ad
min
istra
tion
IV
IM
IV
IV
Inha
latio
n
Dos
age
3
Indu
ctio
n &
mai
nten
ance
of
anes
thes
ia (s
hort
proc
edur
e)
IV o
ver
1m
in:
1-2m
g/kg
IM
4m
g/kg
In
duct
ion
& m
aint
enan
ce o
f an
esth
esia
(lon
g pr
oced
ure)
8-
30m
g/kg
/min
- -
Mai
nten
ance
of a
nest
hesi
a:
50-6
% in
oxy
gen
A
nalg
esia
U
p to
50%
in o
xyge
n
Adv
erse
effe
cts
1) H
yper
tens
ion,
tach
ycar
dia
2)
Psc
ychi
atric
sig
n &
sy
mpt
oms
-
- 1)
hyp
oxia
2)
meg
alob
last
ic a
nem
ia
3) n
euro
logi
cal t
oxic
effe
ct
Pro
duct
s av
aila
ble
in
MoH
form
ular
y
Ket
amin
e In
ject
ion
10m
g/m
l; 50
mg/
ml
Pro
pofo
l Inj
ectio
n 10
mg/
ml;
20m
g/m
l D
exm
edet
omid
ine
Inje
ctio
n 10
0mcg
/ml
-
Mis
ce
llan
eo
us
ag
en
tsE
g:
Ke
tam
ine
, p
rop
ofo
l, d
exm
ed
eto
mid
ine
, n
itro
us
oxi
de
Tab
le 1
0:
Me
ch
an
ism
of
ac
tio
n,
rou
tes
ava
ilab
le,
tim
e o
f o
nse
t, d
ura
tio
n,
do
sag
e a
nd
ad
vers
e e
ffe
cts
of
mis
ce
llan
eo
us
ag
en
t.3
,9,1
2,1
3
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References:
1. American Society of Anesthesiologists Home of Delegates. Continuum of Depth of Sedation: Definition of General Anesthesia and Levels of Sedation / Analgesia, 2009 October
2. Bhatt M, Kennedy RM, Osmond MH, McAllister JD, Ansermino JM, Evered LM, Roback MG. Consensus-Based Recommendations for Standardizing Terminology and Reporting Adverse Events for Emergency Department Procedural Sedation and Analgesia in Children. 2009 Apr; 53(4): 426-435.
3. BMA, Royal Pharmaceutical Society, Royal College and Pediatric of Child Health. BNF for Children 2011-2012.
4. Brighton and Sussex University Hospital, NHS. Pain Management Guideline, July 2010
5. Holsti L, Grunau RE. Considerations for Using Sucrose to Reduce Procedural Pain in Preterm Infants. Pediatrics. 2010 April; 125(5): 1042-1047.
6. Lefrak L, Burch K, Caraventes R, Knoerlein Kim, DeNolf N, Duncan J, Hampton F, Johnston C, Lockey D, Martin-Walters C, McLendon D, Porter M, Richardson C , Robinson C, Toczylowski K. Sucrose Analgesia: Identifying Potentially Better Practices. Pediatrics. 2006 Nov; 118 (S2): S197-S202.
7. My Pharmacist House. My Blue Book version 2.3.1
8. Pain Terms: A Current List with Definitions and Notes on Usage. International Association for the Study of Pain Taxonomy Working Group; 2011. [cited 06 October 2014]. Available from: http://iasp.files.cms-plus.com/Content/ ContentFolders/Publications2/ClassificationofChronicPain/Part_III- PainTerms.pdf
9. Pediatric & Neonatal Lexi Drugs, Lexicomp version 2.7.2
10. The Royal Australasian College of Physicians, Pediatrics & Child Health Divisions. Guideline Statement: Management of Procedure- related Pain in Neonates, 2005
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11. The Royal Children’s Hospital Melbourne. Sucrose (Oral) for Procedural Pain Management in Infants, 14 Dec 2012.
12. Thomson Reuters. Neofax 24th edition 2011.
13. Wilson-Smith, EM. Procedural Pain Management in Neonates, Infants and Children. Reviews in Pain. 2011 Sept; 5(3): 4-12.
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Indications for Total Perenteral Nutrition (TPN)
• Birth weight < 1000 gm
• Birth weight 1000-1500 gm and anticipated to be not on significant feeds for 3 or more days.
• Birth weight > 1500 gm and anticipated to be not on significant feeds for 5 or more days.
• Surgical conditions in neonates: necrotizing enterocolitis, gastroschisis, omphalocoele, tracheo-esophageal fistula, intestinal atresia, malrotation, short bowel syndrome, meconium ileus and diaphragmatic hernia.
Components Of Parenteral Nutrition
1. Macronutrients
• Proteins
• Carbohydrates • Lipid
2. Micronutrients
• Electrolytes
• Trace elements
• Vitamins
3. Fluids
• Water for injection
138
Total Parenteral Nutrition In Neonates Indications for Total Perenteral Nutrition (TPN)
• Birth weight < 1000 gm • Birth weight 1000-1500 gm and anticipated to be not on significant feeds for 3 or more
days. • Birth weight > 1500 gm and anticipated to be not on significant feeds for 5 or more days. • Surgical conditions in neonates: necrotizing enterocolitis, gastroschisis, omphalocoele,
tracheo-esophageal fistula, intestinal atresia, malrotation, short bowel syndrome, meconium ileus and diaphragmatic hernia.
Energy Requirement
Table 1 : Parenteral Energy Requirement
Age (Year) Energy Requirements (Kcal/kg/day) Pre-term 110 - 120
0-1 90 - 100 1-7 75 - 90
7-12 60 - 75 12-18 30 - 60
Components Of Parenteral Nutrition
1. Macronutrients
• Proteins
• Carbohydrates
• Lipid
2. Micronutrients
• Electrolytes
• Trace elements
• Vitamins
3. Fluids
• Water for injection
TOTAL PARENTERAL NUTRITION IN NEONATES
Energy Requirement
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1.Macronutrients
Proteins
• Mult iple studies have demonstrated that earl ier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake
• It decreases frequency and severity of neonatal hyperglycaemia by stimulating endogenous insulin secretion and stimulates growth by enhancing the secretion of insulin and insulin-like growth factors.
• Reduction in dosage may be needed in critically ill, significant hypoxaemia, suspected or proven infection and high dose steroids.
• Adverse effects of excess protein include a rise in urea and ammonia and high levels of potentially toxic amino acids such as phenylalanine.
1g amino acids provide 4kcal energy
The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53%
Lipids
• Lipids prevent essential fatty acid deficiency, provide energy substrates and improve delivery of fat soluble vitamins.
• LBW infants may have immature mechanisms for fat metabolism. Some conditions inhibit lipid clearance e.g. infection, stress, malnutrition.
• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy.
139
1. Macronutrients
Proteins
• Multiple studies have demonstrated that earlier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake
• It decreases frequency and severity of neonatal hyperglycaemia by stimulating endogenous insulin secretion and stimulates growth by enhancing the secretion of insulin and insulin-like growth factors.
• Reduction in dosage may be needed in critically ill, significant hypoxaemia, suspected or proven infection and high dose steroids.
• Adverse effects of excess protein include a rise in urea and ammonia and high levels of potentially toxic amino acids such as phenylalanine.
Proteins requirement
Table 2 : Parenteral amino acid supply Age (Year) Protein Requirement (g/kg/day)
Preterm Infants 1.5 - 4.0 Term Neonates 1.5 - 3.0
2nd Month to 3rd Year 1.0 - 2.5 3rd to 18th Year 1.0 - 2.0
(Critically ill patients may require upto 3.0) 1g amino acids provide 4kcal energy The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53% Lipids
• Lipids prevent essential fatty acid deficiency, provide energy substrates and improve delivery of fat soluble vitamins.
• LBW infants may have immature mechanisms for fat metabolism. Some conditions inhibit lipid clearance e.g. infection, stress, malnutrition.
• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy. Lipids requirement
Table 3 : Lipid Requirement
Age Initiate, g/kg/day Increase by, g/kg/day Maximum, g/kg/day Preterm Neonates 0.5 - 1.0 0.5 - 1.0 3.0 - 4.0
Term Neonates 1.0 0.5 - 1.0 3.0 - 4.0 • Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided
with as little as 0.5-1g/kg/day of fat emulsion. • 1g of lipid provide 9 kcal of energy. • Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an
advantage over LCT lipid emulsions.
139
1. Macronutrients
Proteins
• Multiple studies have demonstrated that earlier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake
• It decreases frequency and severity of neonatal hyperglycaemia by stimulating endogenous insulin secretion and stimulates growth by enhancing the secretion of insulin and insulin-like growth factors.
• Reduction in dosage may be needed in critically ill, significant hypoxaemia, suspected or proven infection and high dose steroids.
• Adverse effects of excess protein include a rise in urea and ammonia and high levels of potentially toxic amino acids such as phenylalanine.
Proteins requirement
Table 2 : Parenteral amino acid supply Age (Year) Protein Requirement (g/kg/day)
Preterm Infants 1.5 - 4.0 Term Neonates 1.5 - 3.0
2nd Month to 3rd Year 1.0 - 2.5 3rd to 18th Year 1.0 - 2.0
(Critically ill patients may require upto 3.0) 1g amino acids provide 4kcal energy The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53% Lipids
• Lipids prevent essential fatty acid deficiency, provide energy substrates and improve delivery of fat soluble vitamins.
• LBW infants may have immature mechanisms for fat metabolism. Some conditions inhibit lipid clearance e.g. infection, stress, malnutrition.
• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy. Lipids requirement
Table 3 : Lipid Requirement
Age Initiate, g/kg/day Increase by, g/kg/day Maximum, g/kg/day Preterm Neonates 0.5 - 1.0 0.5 - 1.0 3.0 - 4.0
Term Neonates 1.0 0.5 - 1.0 3.0 - 4.0 • Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided
with as little as 0.5-1g/kg/day of fat emulsion. • 1g of lipid provide 9 kcal of energy. • Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an
advantage over LCT lipid emulsions.
Lipids Requirement
Proteins Requirement
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• Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided with as little as 0.5-1g/kg/day of fat emulsion.
• 1g of lipid provide 9 kcal of energy.
• Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an advantage over LCT lipid emulsions.
Carbohydrate
• For ELBW neonates, continuous glucose infusion is needed to cater relatively high energy requirement in maintaining cerebral function.
• Maximum rate: 12 - 13 mg/kg/min (lower if lipid also administered) but in practice often limited by hyperglycaemia.
• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secret ion and insul in resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.
Carbohydrate requirement
• Source of carbohydrate is Dextrose 50%
• 1g of carbohydrate provides 4kcal energy.
*The use of early insulin therapy to prevent hyperglycemia is not recommended. The glucose infusion rate should be reduced by 1-2 mg/kg/min and insulin should be administered (0.05 IU/kg/h) when hyperglycemia is uncontrollable with glucose infusion rate being 4 mg/kg/min .
Fluids
• Fluids usually started at 60-80 ml/kg/day (if newborn), or at whatever stable fluid intake the baby is already receiving. • Postnatal weight loss of 5 - 15 % per day in the ELBW is acceptable. • Volumes are increased over the first 7 days in line with the aim to deliver 120- 150ml/kg/day by day 7.
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Carbohydrate
• For ELBW neonates, continuous glucose infusion is needed to cater relatively high energy requirement in maintaining cerebral function.
• Maximum rate: 12 - 13 mg/kg/min (lower if lipid also administered) but in practice often limited by hyperglycaemia.
• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secretion and insulin resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.
Carbohydrate requirement
Table 4 : Rate of administration of dextrose in pediatric patients on PN
Age Initiate, mg/kg/day
Increase by, mg/kg/day
Maximum rate, mg/kg/day
Preterm Neonates 4 - 6 1 - 2 12 - 13 Term Neonates 6 - 8 2 - 4 -
Infant 6 - 8 2 - 4 13 - 14 Children 6 - 8 2 - 4 6 - 9
• Source of carbohydrate is Dextrose 50%
• 1g of carbohydrate provides 4kcal energy.
*The use of early insulin therapy to prevent hyperglycemia is not recommended. The glucose infusion rate should be reduced by 1-2 mg/kg/min and insulin should be administered (0.05 IU/kg/h) when hyperglycemia is uncontrollable with glucose infusion rate being 4 mg/kg/min .
Fluids
• Fluids usually started at 60-80 ml/kg/day (if newborn), or at whatever stable fluid intake the baby is already receiving.
• Postnatal weight loss of 5 - 15 % per day in the ELBW is acceptable. • Volumes are increased over the first 7 days in line with the aim to deliver 120-150
ml/kg/day by day 7.
Fluids requirements
Table 5 : Parenteral fluid intake during first postnatal week
Days After Birth
Recommended fluid intake (ml/kg/day)
1st Day 2nd Day 3rd Day 4th Day 5th Day 6th Day Term
Neonate 60 -‐ 120 80 -‐ 120 100 -‐ 130 120 -‐ 150 140 -‐ 160 140 -‐ 180
Preterm Neonate 60 -‐ 80 80 -‐ 100 100 -‐120 120 -‐150 140 -‐ 160 140 -‐ 160
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>1500g Preterm Neonate <1500g
80 -‐ 90 100 -‐ 110 120 -‐130 130 -‐150 140 -‐ 160 160 -‐ 180
Factors affecting fluids requirement
2. Micronutrients
Electrolytes
• Sodium supplementation should be started after initial diuresis (usually after the 48 hours), when serum sodium starts to drop or at least at 5-6% weight loss.
• Failure to provide sufficient sodium may be associated with poor weight gain.
• Potassium needs are 2-3 mEq/kg/day in both term and preterm infants. Start when urine output improves after the first 2-3 days of life.
• In extrauterine conditions, intrauterine calcium accretion rates is difficult to attain. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.
• Monitoring for osteopaenia of prematurity is important especially if prolonged PN.
• A normal magnesium level is a prerequisite for a normal calcaemia. In well balanced formulations, however, magnesium level does not give rise to major problems.
2. Micronutrients
Electrolytes
• Sodium supplementation should be started after initial diuresis (usually after the 48 hours), when serum sodium starts to drop or at least at 5-6% weight loss.
• Failure to provide sufficient sodium may be associated with poor weight gain.
• Potassium needs are 2-3 mEq/kg/day in both term and preterm infants. Start when urine output improves after the first 2-3 days of life.
• In extrauterine conditions, intrauterine calcium accretion rates is difficult to attain. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.
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Carbohydrate
• For ELBW neonates, continuous glucose infusion is needed to cater relatively high energy requirement in maintaining cerebral function.
• Maximum rate: 12 - 13 mg/kg/min (lower if lipid also administered) but in practice often limited by hyperglycaemia.
• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secretion and insulin resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.
Carbohydrate requirement
Table 4 : Rate of administration of dextrose in pediatric patients on PN
Age Initiate, mg/kg/day
Increase by, mg/kg/day
Maximum rate, mg/kg/day
Preterm Neonates 4 - 6 1 - 2 12 - 13 Term Neonates 6 - 8 2 - 4 -
Infant 6 - 8 2 - 4 13 - 14 Children 6 - 8 2 - 4 6 - 9
• Source of carbohydrate is Dextrose 50%
• 1g of carbohydrate provides 4kcal energy.
*The use of early insulin therapy to prevent hyperglycemia is not recommended. The glucose infusion rate should be reduced by 1-2 mg/kg/min and insulin should be administered (0.05 IU/kg/h) when hyperglycemia is uncontrollable with glucose infusion rate being 4 mg/kg/min .
Table 5 : Parenteral fluid intake during first postnatal week
Days After Birth
Recommended fluid intake (ml/kg/day)
1st Day 2nd Day 3rd Day 4th Day 5th Day 6th Day Term
Neonate 60 -‐ 120 80 -‐ 120 100 -‐ 130 120 -‐ 150 140 -‐ 160 140 -‐ 180
Preterm Neonate >1500g
60 -‐ 80 80 -‐ 100 100 -‐120 120 -‐150 140 -‐ 160 140 -‐ 160
Preterm Neonate <1500g
80 -‐ 90 100 -‐ 110 120 -‐130 130 -‐150 140 -‐ 160 160 -‐ 180
Factors affecting fluids requirement Factors affect ing f luids requirement
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Electrolytes requirement
Table 6 : Daily electrolyte requirements for pediatric patients
Electrolytes Preterm Neonates Infants/Children Sodium 2 - 5 mEq/kg 2 - 5 mEq/kg
Potassium 2 - 4 mEq/kg 2 - 4 mEq/kg Calcium 2 - 4 mEq/kg 0.5 - 4 mEq/kg
Phosphorus 1 - 2 mmol/kg 0.5 - 2 mmol/kg Magnesium 0.3 - 0.5 mEq/kg 0.3 - 0.5 mEq/kg
Acetate As needed to mantain acid base balance
As needed to mantain acid base balance
Table 7 : Recommendations on the daily intake of Ca, P, Mg and vitamin D for preterm VLBW infants issued by different bodies & authors
Intake Reccomenda
tion
ESPGAN 1987
ESPGHAN 2010
LSRO 2002
Atkinson & Tsang 2005
RIGO 2007
AAP 2013
Current authors
Proposal 2013
Ca, mg/kg/day 70 -140 120-140 150-220 120-200 100-160 150-220 120-200
P, mg/kg/day 50-90 60-90 100-130 70-120 60-90 75-140 60-140 Mg,
mg/kg/day 4.85-9.7 8-15 6.8-17mg/ 100kCal 7.2-9.6 Not
provided Not
provided 8-15
Vitamin D, IU/day 800-1600 800-1000 90-225 200-1000 800-
1000 200-400 400-1000
• Monitoring for osteopaenia of prematurity is important especially if prolonged PN.
• A normal magnesium level is a prerequisite for a normal calcaemia. In well balanced formulations, however, magnesium level does not give rise to major problems.
Electrolytes Requirement
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Tab
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: A
ccep
tab
le r
ange
of v
itam
in in
take
s fo
r V
LBW
& E
LBW
infa
nts
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Table 8 : Acceptable range of vitamin intakes for VLBW & ELBW infants
Trace elements requirement
Trace Elements
Product Dosage Peditrace
Neonates < 15kg : 1ml/kg/day Infants & Children >15kg : 15ml/day Max : 15mL / day
Water soluble vitamins requirement
Water Soluble Vitamin
Product Dosage Soluvit N
Neonates < 10kg : 1ml/kg/day Infants & Children >10kg : 10ml/day Max : 10mL / day
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Table 8 : Acceptable range of vitamin intakes for VLBW & ELBW infants
Trace elements requirement
Trace Elements
Product Dosage Peditrace
Neonates < 15kg : 1ml/kg/day Infants & Children >15kg : 15ml/day Max : 15mL / day
Water soluble vitamins requirement
Water Soluble Vitamin
Product Dosage Soluvit N
Neonates < 10kg : 1ml/kg/day Infants & Children >10kg : 10ml/day Max : 10mL / day
References :
1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Societyof Paediatric Research (ESPR) 2005; Berthold Koletzko, Olivier Goulet, oanne Hunt, Kathrin Krohn, and Raanan Shamir
2. Paediatric Protocols For Malaysian Hospitals 3rd Edition ; Hussain Imam Hj Muhammad Ismail; Ng Hoong Phak; Terrence Thomas
3. Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 49–63 ( DOI: 10.1159/000358458
Trace elements requirement
Water soluble vitamins requirement
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Fluid, electrolyte, and nutrition management is important because most infants in a neonatal intensive care unit (NICU) require intravenous fluids (IVFs) and have shifts of fluids between intracellular, extracellular, and vascular compartments. Therefore, careful attention to fluid and electrolyte balance is essential. If inappropriate fluids are administered, serious morbidity may result from fluid and electrolyte imbalances. Inadequate attention to nutrition in the neonatal period leads to growth failure, osteopenia of prematurity, and other complications.
Total fluid requirements
Total fluid requirement includes the maintenance requirement to replace measure losses (urine, stool) and insensible water loss (IWL) and the fluid requirement for growth.
• Total fluids = Maintenance + Growth
• Maintenance = SWL (sensible water lost) + IWL (Insensible water lost)
• Start with D10W (10% dextrose in water) Sodium and Potassium added on the second/third day
• Slower rates of increment for preterm infants, i.e. of 20 mls/kg/day.
• More increments may be needed if evidence of dehydration, i.e. excessive weight loss and hypernatraemia >145 mmol/l.
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Fluid & Electrolyte Management Fluid, electrolyte, and nutrition management is important because most infants in a neonatal intensive care unit (NICU) require intravenous fluids (IVFs) and have shifts of fluids between intracellular, extracellular, and vascular compartments. Therefore, careful attention to fluid and electrolyte balance is essential. If inappropriate fluids are administered, serious morbidity may result from fluid and electrolyte imbalances. Inadequate attention to nutrition in the neonatal period leads to growth failure, osteopenia of prematurity, and other complications.
Fluid and Electrolyte Management
Total fluid requirements
Total Fluid requirement includes the maintenance requirement to replace measure losses (urine, stool) and insensible water loss (IWL) and the fluid requirement for growth.
• Total fluids = Maintenance + Growth • Maintenance = SWL (sensible water lost) + IWL (Insensible water lost) • Start with D10W (10% dextrose in water) Sodium and Potassium added on the
second/third day • Slower rates of increment for preterm infants, i.e. of 20 mls/kg/day. • More increments may be needed if evidence of dehydration,
i.e. excessive weight loss and hypernatraemia >145 mmol/l.
Table 1: Empiric Fluid Therapy for newborns
0-24 hours 60 ml/kg/day 24-48 hours 90 ml/kg/day 48-72 hours 120 ml/kg/day > 72 hours 150 ml/kg/day
Fluid Issues Associated With Common Neonatal Conditions:
Issues requiring fluid restriction:
� RDS: Excessive fluid can lead to fluid overload and increased risk of BPD � BPD: Excessive fluid can worsen therefore treated with diuretics to reduce
pulmonary edema � PDA: Volume overload can open ductus and worsen respiratory status � HIE: Associated with ATN and/or SIADH and can lead to subsequent volume
overload
Electrolyte Requirements
Table 1 : Empiric Fluid Therapy for Newborns
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Fluid Issues Associated With Common Neonatal Conditions:
Issues requiring fluid restriction:
• RDS: Excessive fluid can lead to fluid overload and increased risk of BPD • BPD: Excessive fluid can worsen therefore treated with diuretics to reduce pulmonary edema • PDA: Volume overload can open ductus and worsen respiratory status • HIE: Associated with ATN and/or SIADH and can lead to subsequent volume overload
Electrolyte Requirements
First 24h of life: No electrolytes (except Ca)
• Ca especially important for preterm infants After 24h of life: • Na : 2-3 mmol/kg/day • K : 1-2 mmmol/kg/day
Supplemetation of elctrolytes will need to be fine-tuned according to measurement of electrolytes and urine output and disease status.
* Extremely pre-term infants with metabolic acidosis (loss of bicarb in urine) may benefit from sodium acetate
After the first week of life, during active groth the requirement of sodium and potassium increases;
• Na: 3-5 mmol/kg/day• K: 2-3 mmmol/kg/day
Many preterm may require 6-8mmol/kg/day of sodium and up to 12mmol/kg/day. This is partly due to inability to retain sodium and secondary use of diuretics
References:
1. Hussain Imam Hj Muhammad Ismail, Ng Hoong Phak, Terrence Thomas. Paediatric Protocols for Malaysian Hospitals, 3rd ed. : Kementerian Kesihatan Malaysia; 2012
2. O’Brien, F., Walker, I. A. (2014), Fluid homeostasis in the neonate. Pediatric Anesthesia, 24: 49–59. doi: 10.1111/pan.12326
3. B. Koletzko, C. Agostoni, P. Ball et al. ESPGHAN Guidelines on paediatric parenteral nutrition.Journal of Pediatric Gastroenterology and Nutrition 2005;41:S1-S87
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Introduction
As mentioned by Morgan JA et al, necrotising enterocolitis (NEC) is the commonest neonatal gastrointestinal emergency.7 NEC is an inflammatory disease of the intestine which is often associated with sepsis and frequently complicated by perforation, peritonitis and death12
Spontaneous intestinal perforation (SIP) among preterm infants had been categorized as necrotizing enterocolits. However it has different disease entity and different pathogenesis. SIP usually occurs in the 1st several days after birth and is not associated with enteral feeding. SIP is associated with minimal intestinal inflammation and necrosis with low level of serum inflammatory markers8
Risk Factors7,9 (1) Prematurity (<28weeks)
(2) Enteral feeding
(3) Growth restricted neonate
(4) Maternal hypertensive disease of pregnancy
(5) Placental abruption
(6) Absent or reversed end diastolic flow velocity
(7) Use of umbilical catheters
(8) Low Apgar scores
(9) Packed cell transfusions Pathogenesis6,8,9,12
The pathogenesis of NEC is not completely understood, it is considered to be multifactorial. It is a combination of the following causes:
(1) Immature epithelial barrier
(2) Abnormal microbial colonization in the intestine
(3) Hypoxia-ischemia
(4) Genetic predisposition
NECROTIZING ENTEROCOLITIS
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• Immature epithelial barrier 12
The intestinal mucosa presents a persistent equilibrium state between injury and repair. Intestinal mucosa injury can be due to various factors including hypoxia, infection, and starvation. In physiological conditions, healing of epithelium starts with migration of matured enterocytes from health to the injured area. Subsequently, new enterocytes will mature and migrate to the surface epithelium. In NEC, there is a marked inhibition in both the enterocyte migration and proliferation, resulting more intestinal mucosa injury.
Toll-like receptors (TLRs) are innate immunity components located on the epithelial surface which play a major role in tissue repair. TLR type 4 (TLR4) are crucial in NEC development. The activation of TLR4 inhibits the enterocyte migration and maturation thus.
• Abnormal microbial colonization in the intestine9,12
Mechanism by which infection contribute to NEC remain unknown. The suggested mechanism is the decreased microbial diversity and alteration in the microbial species that may happen in prolonged antibiotic therapy, which may reduce the colonization resistance. The usual rich diversity of intestinal microflora which protect the host against hospital-acquired pathogens is lacking. Studies suggest that NEC is not due to a single species but is more likely from an undefined dysbiosis, that may cause TLR4 activation and pathogens translocation across the epithelium.
• Hypoxia-ischemia8
Hypoxia and ischemia modulate the balance in microvascular tone related to the production of vascular regulator eg nitric oxide and endothelin which may cause NEC
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Complications6,9
(1) higher incidence of nosocomial infection(2) lower level of nutrient intake(3) slower growth development(4) longer duration of intensive care and hospital stay(5) higher incidence of bronchopulmonary dysplasia(6) higher incidence of retinopathy of prematurity(7) growth restriction in long term(8) neurodisability(9) adverse neurodevelopment in long term
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Studies suggest that NEC is not due to a single species but is more likely from an undefined dysbiosis, that may cause TLR4 activation and pathogens translocation across the epithelium.
• Hypoxia-ischemia 8
Hypoxia and ischemia modulate the balance in microvascular tone related to the production of vascular regulator eg nitric oxide and endothelin which may cause NEC
Fig 1: Pathogenesis of NEC (Adapted from Terrin G) 12
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Table 1: Clinical presentation of NEC (Modified Bell Classification) (Adapted from Patel BK)9
Complications6,9 (1) higher incidence of nosocomial infection (2) lower level of nutrient intake (3) slower growth development (4) longer duration of intensive care and hospital stay (5) higher incidence of bronchopulmonary dysplasia (6) higher incidence of retinopathy of prematurity (7) growth restriction in long term (8) neurodisability (9) adverse neurodevelopment in long term Management
Table 2: Management of NEC based on Modified Bell Classification (Adopted from Neu J)8
Modified Bell Classification
Management
“Suspected” NEC
(1) Clinical observation of increased abdominal distension and feeding intolerance (2) Brief discontinuation of feeding eg: 24hr-NBM (3) Abdominal radiograph (if have yet done) (4) Monitor FBC (5) Blood C&S (6) Short course of IV antibiotics
“Defined” NEC
(1) Enteral feeding discontinuation for 7-10days (2) Monitor FBC (3) Blood C&S (4) IV antibiotics 7-10days (5) Refer surgical team
“Advanced” NEC (1) Exploratory laparotomy with resection if necessary
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Table 1: Clinical presentation of NEC (Modified Bell Classification) (Adapted from Patel BK)9
Complications6,9 (1) higher incidence of nosocomial infection (2) lower level of nutrient intake (3) slower growth development (4) longer duration of intensive care and hospital stay (5) higher incidence of bronchopulmonary dysplasia (6) higher incidence of retinopathy of prematurity (7) growth restriction in long term (8) neurodisability (9) adverse neurodevelopment in long term Management
Table 2: Management of NEC based on Modified Bell Classification (Adopted from Neu J)8
Modified Bell Classification
Management
“Suspected” NEC
(1) Clinical observation of increased abdominal distension and feeding intolerance (2) Brief discontinuation of feeding eg: 24hr-NBM (3) Abdominal radiograph (if have yet done) (4) Monitor FBC (5) Blood C&S (6) Short course of IV antibiotics
“Defined” NEC
(1) Enteral feeding discontinuation for 7-10days (2) Monitor FBC (3) Blood C&S (4) IV antibiotics 7-10days (5) Refer surgical team
“Advanced” NEC (1) Exploratory laparotomy with resection if necessary
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(2) Primary peritoneal drainage without laparotomy
Indications for surgery9 (1) clinical deterioration despite maximal medical intervention (2) presence of pneumoperitoneum (3) abdominal mass with intestinal obstruction (4) development of intestinal stricture Prevention Numerous approaches have been proposed to prevent NEC:
Table 3: Strategies to Prevent NEC (Adapted from Neu J & Walker WA)8
Evidence of Efficacy & Safety
Evidence of Efficacy but Questionable
Safety
Evidence of Efficacy in Animal Models but Not in Human
Proposed Efficacy but Lack of Evidence
Breast-milk feeding Probiotics Growth factors Prebiotics Non-aggressive enteral feeding
Arginine Anticytokines TLR4 modulation
Enteral antibiotics Glutamine Glucocorticoids n-3 fatty acids
• Arginine
Nitric oxide (NO) plays an important role in mediating intestinal vasomotor tone. It is an inhibitory neurotransmitter in the gastrointestinal system inducing gut smooth muscle relaxation, regulate mucosal blood flow, maintain mucosal integrity and intestinal barrier function. Arginine is involved in NO production. A relative deficiency of arginine results in inadequate NO, causing vasoconstriction, ischemic reperfusion injury and development of NEC. A systemic review included 2 studies ie. Amin et al 2002 and Polycarpou et al 2013 had been carried out.
Table 4: A study of Arginine Supplementation in Prevention of NEC in Preterm Infants
Study Population Study design
Results Conclusion
Mitchell K et al. (2014)6
2 RCT Systematic review
59% NEC reduction in L-arginine group
L-arginine can prevent NEC in preterm infants. However large RCTs are needed.
• Epidermal Growth Factor (EGF)
EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9
• Feeding Strategies - Cautious Advancement of Feeds
Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6
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(2) Primary peritoneal drainage without laparotomy
Indications for surgery9 (1) clinical deterioration despite maximal medical intervention (2) presence of pneumoperitoneum (3) abdominal mass with intestinal obstruction (4) development of intestinal stricture Prevention Numerous approaches have been proposed to prevent NEC:
Table 3: Strategies to Prevent NEC (Adapted from Neu J & Walker WA)8
Evidence of Efficacy & Safety
Evidence of Efficacy but Questionable
Safety
Evidence of Efficacy in Animal Models but Not in Human
Proposed Efficacy but Lack of Evidence
Breast-milk feeding Probiotics Growth factors Prebiotics Non-aggressive enteral feeding
Arginine Anticytokines TLR4 modulation
Enteral antibiotics Glutamine Glucocorticoids n-3 fatty acids
• Arginine
Nitric oxide (NO) plays an important role in mediating intestinal vasomotor tone. It is an inhibitory neurotransmitter in the gastrointestinal system inducing gut smooth muscle relaxation, regulate mucosal blood flow, maintain mucosal integrity and intestinal barrier function. Arginine is involved in NO production. A relative deficiency of arginine results in inadequate NO, causing vasoconstriction, ischemic reperfusion injury and development of NEC. A systemic review included 2 studies ie. Amin et al 2002 and Polycarpou et al 2013 had been carried out.
Table 4: A study of Arginine Supplementation in Prevention of NEC in Preterm Infants
Study Population Study design
Results Conclusion
Mitchell K et al. (2014)6
2 RCT Systematic review
59% NEC reduction in L-arginine group
L-arginine can prevent NEC in preterm infants. However large RCTs are needed.
• Epidermal Growth Factor (EGF)
EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9
• Feeding Strategies - Cautious Advancement of Feeds
Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6
Indications for surgery9
(1) clinical deterioration despite maximal medical intervention(2) presence of pneumoperitoneum(3) abdominal mass with intestinal obstruction(4) development of intestinal stricture
PreventionNumerous approaches have been proposed to prevent NEC:
• Arginine
Nitric oxide (NO) plays an important role in mediating intestinal vasomotor tone. It is an inhibitory neurotransmitter in the gastrointestinal system inducing gut smooth muscle relaxation, regulate mucosal blood flow, maintain mucosal integrity and intestinal barrier function. Arginine is involved in NO production. A relative deficiency of arginine results in inadequate NO, causing vasoconstriction, ischemic reperfusion injury and development of NEC. A systemic review included 2 studies ie. Amin et al 2002 and Polycarpou et al 2013 had been carried out.
Management
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(2) Primary peritoneal drainage without laparotomy
Indications for surgery9 (1) clinical deterioration despite maximal medical intervention (2) presence of pneumoperitoneum (3) abdominal mass with intestinal obstruction (4) development of intestinal stricture Prevention Numerous approaches have been proposed to prevent NEC:
Table 3: Strategies to Prevent NEC (Adapted from Neu J & Walker WA)8
Evidence of Efficacy & Safety
Evidence of Efficacy but Questionable
Safety
Evidence of Efficacy in Animal Models but Not in Human
Proposed Efficacy but Lack of Evidence
Breast-milk feeding Probiotics Growth factors Prebiotics Non-aggressive enteral feeding
Arginine Anticytokines TLR4 modulation
Enteral antibiotics Glutamine Glucocorticoids n-3 fatty acids
• Arginine
Nitric oxide (NO) plays an important role in mediating intestinal vasomotor tone. It is an inhibitory neurotransmitter in the gastrointestinal system inducing gut smooth muscle relaxation, regulate mucosal blood flow, maintain mucosal integrity and intestinal barrier function. Arginine is involved in NO production. A relative deficiency of arginine results in inadequate NO, causing vasoconstriction, ischemic reperfusion injury and development of NEC. A systemic review included 2 studies ie. Amin et al 2002 and Polycarpou et al 2013 had been carried out.
Table 4: A study of Arginine Supplementation in Prevention of NEC in Preterm Infants
Study Population Study design
Results Conclusion
Mitchell K et al. (2014)6
2 RCT Systematic review
59% NEC reduction in L-arginine group
L-arginine can prevent NEC in preterm infants. However large RCTs are needed.
• Epidermal Growth Factor (EGF)
EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9
• Feeding Strategies - Cautious Advancement of Feeds
Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6
• Epidermal Growth Factor (EGF)
- EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9
• Feeding Strategies - Cautious Advancement of Feeds Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6
- Trophic Feeding
As quoted by Patel BK & Shah JS, Cochrane review of 8 studies concluded that trophic feeding has no significant effect on NEC9
• Gastric Acid Suppression - As quoted by Morgan JA et al., Guillet R & colleagues showed that the use of H2-blocker which suppress gastric acidity in preterm infants is associated with higher risk of NEC. Gastic acid may play crucial role in preventing the infection and inflammation that will cause NEC development. As quoted by Morgan JA et al., Anderson P & Guillet R recommended that use of H2- blocker should be restricted until further evidence that benefits outweigh the harm is available7
• Glutamine - Experimental studies have shown that glutamine serve as fuel for enterocytes, stimulate the mucosal cell proliferation and differentiation and maintain the integrity of tight junctions thus reduce mucosal damage and lower the risk of invasive infection7,9 However, as quoted by Morgan JA etal., a Cochrane review of good quality randomized controlled trial, by Tubman TR published in 2008 indicated that glutamine supplementation does not confer benefits for preterm infants7
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Table 6: Studies on Prolonged Empirical Antibiotics Increase the Incidence of NEC or Death
Study Population Study design Results Cotton MC et al. (2009) 1
(1) N= 5693 (2) ≤ 1.0kg
Retrospective cohort study
NEC or death is higher in the group of prolonged empirical antibiotics (≥5days) (61%, p<.001)
Kuppala V et al. (2011) 3
(1) N= 365 (2) ≤ 32weeks gestational age & ≤1.5kg
Retrospective cohort study
Late-onset-sepsis, NEC or death is significantly higher in the group of prolonged empirical antibiotics (≥5 days) (41% vs 18%, p<.0001)
Based on the findings of these studies, Morgan JA et al reinforce that empirical antibiotics for preterm infants should be started early when sepsis is suspected and to be discontinued early once sepsis is excluded7
• Lactoferrin Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram-negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7,9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4
Table 7: RCT of Lactoferrin Supplementation in Prevention NEC in VLBW Infants
Study Population Study design Results Manzoni P et al. (2009)4
472 VLBW infants Multicenter, double blind, RCT
Nil NEC in Lactoferrin + probiotic group; 6% NEC in control group (p=.002)
• Modulation of TLR4 Signal
Only animal model has been tested, more human clinical trials are needed
• Oral Immunoglobulins (Ig) Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9
• Prebiotics Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance
• Human milk
- It is suggested that human milk may reduce the risk of NEC by reducing pathogenic bacterial colonization, promote the growth of non-pathogenic microflora, enhance the maturation of gastrointestinal tract and regulate the pro-inflammatory response in preterm neonates. The positive effects of human milk may be due to several factors eg: macrophages, lymphocytes, lysozyme, lactoferrin, oligosaccharides, nucleotides, cytokines, growth factors and enzymes. Studies have demonstrated positive effect of human milk in lowering incidence of NEC8,9,12
• Judicious Restriction of Prolonged Empirical Antibiotics
Studies have shown that prolonged empirical antibiotics lead to higher NEC risk in premature infants.
Based on the findings of these studies, Morgan JA et al reinforce that empirical antibiotics for preterm infants should be started early when sepsis is suspected and to be discontinued early once sepsis is excluded7
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- Trophic Feeding As quoted by Patel BK & Shah JS, Cochrane review of 8 studies concluded that trophic feeding has no significant effect on NEC9
• Gastric Acid Suppression As quoted by Morgan JA et al., Guillet R & colleagues showed that the use of H2-blocker which suppress gastric acidity in preterm infants is associated with higher risk of NEC. Gastic acid may play crucial role in preventing the infection and inflammation that will cause NEC development. As quoted by Morgan JA et al., Anderson P & Guillet R recommended that use of H2-blocker should be restricted until further evidence that benefits outweigh the harm is available7
• Glutamine Experimental studies have shown that glutamine serve as fuel for enterocytes, stimulate the mucosal cell proliferation and differentiation and maintain the integrity of tight junctions thus reduce mucosal damage and lower the risk of invasive infection7,9 However, as quoted by Morgan JA et al., a Cochrane review of good quality randomized controlled trial, by Tubman TR published in 2008 indicated that glutamine supplementation does not confer benefits for preterm infants7
• Human milk It is suggested that human milk may reduce the risk of NEC by reducing pathogenic bacterial colonization, promote the growth of non-pathogenic microflora, enhance the maturation of gastrointestinal tract and regulate the pro-inflammatory response in preterm neonates. The positive effects of human milk may be due to several factors eg: macrophages, lymphocytes, lysozyme, lactoferrin, oligosaccharides, nucleotides, cytokines, growth factors and enzymes. Studies have demonstrated positive effect of human milk in lowering incidence of NEC8,9 & 12
Table 5: Studies on Effect of Human Milk on NEC Development
Study Population/Subjects Study
Design Results
McGuire &
Anthony,
20035
4 clinical trials Meta-analysis Infants on human milk were 4
times less likely to have confirmed
NEC
Sullivan et
al, 201010
207 preterm infants Randomized
Controlled
Trial
Exclusive human milk result in
lower incidence of NEC
• Judicious Restriction of Prolonged Empirical Antibiotics
Studies have shown that prolonged empirical antibiotics lead to higher NEC risk in premature infants.
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Table 6: Studies on Prolonged Empirical Antibiotics Increase the Incidence of NEC or Death
Study Population Study design Results Cotton MC et al. (2009) 1
(1) N= 5693 (2) ≤ 1.0kg
Retrospective cohort study
NEC or death is higher in the group of prolonged empirical antibiotics (≥5days) (61%, p<.001)
Kuppala V et al. (2011) 3
(1) N= 365 (2) ≤ 32weeks gestational age & ≤1.5kg
Retrospective cohort study
Late-onset-sepsis, NEC or death is significantly higher in the group of prolonged empirical antibiotics (≥5 days) (41% vs 18%, p<.0001)
Based on the findings of these studies, Morgan JA et al reinforce that empirical antibiotics for preterm infants should be started early when sepsis is suspected and to be discontinued early once sepsis is excluded7
• Lactoferrin Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram-negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7,9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4
Table 7: RCT of Lactoferrin Supplementation in Prevention NEC in VLBW Infants
Study Population Study design Results Manzoni P et al. (2009)4
472 VLBW infants Multicenter, double blind, RCT
Nil NEC in Lactoferrin + probiotic group; 6% NEC in control group (p=.002)
• Modulation of TLR4 Signal
Only animal model has been tested, more human clinical trials are needed
• Oral Immunoglobulins (Ig) Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9
• Prebiotics Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance
• Lactoferrin
- Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram- negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7.9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4
• Modulation of TLR4 Signal
- Only animal model has been tested, more human clinical trials are needed
• Oral Immunoglobulins (Ig)
- Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9
• Prebiotics
- Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance the proliferation of bifidobacteria and lactobacilli in the colon9. However, up to date, the evidence regarding the effectiveness of prebiotics use in preterm infants is still limited.
• Probiotics
- Probiotics are live microorganisms such as lactobacilli and bifidobacteria which when administered in adequate amount confer a health benefit on the host. Potential benefits of probiotics including:
(1) inhibition of pathogenic colonization and produce anti-inflammatory effects
(2) secretion of lactic acid that lower local pH thus inhibit the growth of pathogenic bacteria
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Table 6: Studies on Prolonged Empirical Antibiotics Increase the Incidence of NEC or Death
Study Population Study design Results Cotton MC et al. (2009) 1
(1) N= 5693 (2) ≤ 1.0kg
Retrospective cohort study
NEC or death is higher in the group of prolonged empirical antibiotics (≥5days) (61%, p<.001)
Kuppala V et al. (2011) 3
(1) N= 365 (2) ≤ 32weeks gestational age & ≤1.5kg
Retrospective cohort study
Late-onset-sepsis, NEC or death is significantly higher in the group of prolonged empirical antibiotics (≥5 days) (41% vs 18%, p<.0001)
Based on the findings of these studies, Morgan JA et al reinforce that empirical antibiotics for preterm infants should be started early when sepsis is suspected and to be discontinued early once sepsis is excluded7
• Lactoferrin Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram-negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7,9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4
Table 7: RCT of Lactoferrin Supplementation in Prevention NEC in VLBW Infants
Study Population Study design Results Manzoni P et al. (2009)4
472 VLBW infants Multicenter, double blind, RCT
Nil NEC in Lactoferrin + probiotic group; 6% NEC in control group (p=.002)
• Modulation of TLR4 Signal
Only animal model has been tested, more human clinical trials are needed
• Oral Immunoglobulins (Ig) Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9
• Prebiotics Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance
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the proliferation of bifidobacteria and lactobacilli in the colon9. However, up to date, the evidence regarding the effectiveness of prebiotics use in preterm infants is still limited.
• Probiotics Probiotics are live microorganisms such as lactobacilli and bifidobacteria which when administered in adequate amount confer a health benefit on the host. Potential benefits of probiotics including: (1) inhibition of pathogenic colonization and produce anti-inflammatory effects (2) secretion of lactic acid that lower local pH thus inhibit the growth of pathogenic bacteria (3) communicate directly with pathogenic bacteria thus modulating their gene expression, reducing the binding to the host epithelial cells (4) stimulation of production of secretory immunoglobulins and cause positive effect to immunity response Some clinical trials have demonstrated that supplementing the diet of preterm infants with probiotics is beneficial.
Table 8: Clinical Trials of Probiotics Supplementation Decrease the Incidence of Neonatal NEC
Study Population / Subjects Study
Design Results
Lin et al. (quoted by Patel BK)9
Multicenter, 434 infants Masked randomized controlled trial
1.8% probiotics group developed NEC; 6.5% non-probiotics group developed NEC
Deshpande et al.2
15 randomized controlled trial
Meta analysis 30% reduction in NEC (p<.00001)
Wang et al.13
20 randomized controlled trial
Meta analysis 3% probiotics group developed NEC; 7.4% placebo-group developed NEC (p<.00001)
A recent commentary by Tarnow-Modi WO and colleagues also suggest the routine use of probiotics11 However, a systematic review by Milhatsch et al, published in 2012 concluded that there is still no conclusive evidence to recommend routine use of probiotics in preterm infants. In settings with high incidence of NEC, clinicians may consider off-label use of specific probiotics. There are still limitations of routine probiotics use14: (1) unknown optimal strain and dosing (2) no evidence showing whether single or multiple strain are more effective (3) safety and efficacy of each probiotic strain has to be studied (4) non convincing data that probiotics prevent sepsis (5) possibility of infections caused by probiotics (6) long term effects on fecal flora and immune system
(3) communicate directly with pathogenic bacteria thus modulating their gene expression, reducing the binding to the host epithelial cells
(4) stimulation of production of secretory immunoglobulins and cause positive effect to immunity response some clinical trials have demonstrated that supplementing the diet of preterm infants with probiotics is beneficial.
A recent commentary by Tarnow-Modi WO and colleagues also suggest the routine use of probiotics11
However, a systematic review by Milhatsch et al, published in 2012 concluded that there is still no conclusive evidence to recommend routine use of probiotics in preterm infants.
In settings with high incidence of NEC, clinicians may consider off-label use of specific probiotics.
There are still limitations of routine probiotics use14:
(1) unknown optimal strain and dosing (2) no evidence showing whether single or multiple strain are more effective (3) safety and efficacy of each probiotic strain has to be studied (4) non convincing data that probiotics prevent sepsis (5) possibility of infections caused by probiotics (6) long term effects on fecal flora and immune system
• Prophylatic Enteral Antibiotics
- As quoted by Patel BK & Shah JS and also Neu J & Walker WA, several small studies suggest that oral antibiotics can reduce incidence of NEC8,9
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• Prophylatic Enteral Antibiotics As quoted by Patel BK & Shah JS and also Neu J & Walker WA, several small studies suggest that oral antibiotics can reduce incidence of NEC8,9
Table 9: Studies of Enteral Antibiotics Reduce the Incidence of NEC
Study Enteral antibiotics
Quoted by Patel BK & Shah JS 9 Egan et al. (1977) Kanamycin Siu YK et al. (1998) Vancomycin Bury RG (2000) Systemic review Quoted by Neu J & Walker WA Grylack LJ et al (1978) Gentamicin
Nonetheless, as being quoted by Patel BK, Cochrane review by Bury RG showed concern on resistant bacteria thus routine use of prophylactic enteral antibiotics is not recommended9
• Polyunsaturated Fatty Acids (PUFA) PUFA have been proposed to modulate inflammation and immunity. As quoted by Patel BK & Shah JS, Carlson et al (1998) demonstrated lower incidence of NEC9
• Synbiotics Synbiotic is a product contain both probiotics and prebiotics. As quoted by Patel BK & Shah JS, RCT done by Underwood MA & friends in 2009 demonstrated positive result in synbiotics-group9
• Zinc Zinc participates in many metabolic pathway. As quoted by Patel BK & Shah JS, Terrin R et al. demonstrated that zinc plays important role in maintenance of epithelial barrier function and induction of adequate immune response. Terrin R & colleagues (2013) showed that high dose zinc is also effective in reducing NEC in preterm infants9
Nonetheless, as being quoted by Patel BK, Cochrane review by Bury RG showed concern on resistant bacteria thus routine use of prophylactic enteral antibiotics is not recommended9
• Polyunsaturated Fatty Acids (PUFA)
- PUFA have been proposed to modulate inflammation and immunity. As quoted by Patel BK & Shah JS, Carlson et al (1998) demonstrated lower incidence of NEC9
• Synbiotics
- Synbiotic is a product contain both probiotics and prebiotics. As quoted by Patel BK & Shah JS, RCT done by Underwood MA & friends in 2009 demonstrated positive result in synbiotics-group9
• Zinc
- Zinc participates in many metabolic pathway. As quoted by Patel BK & Shah JS, Terrin R et al. demonstrated that zinc plays important role in maintenance of epithelial barrier function and induction of adequate immune response. Terrin R & colleagues (2013) showed that high dose zinc is also effective in reducing NEC in preterm infants9
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References:
1. Cotten MC, Taylor S, Stoll B, Goldberg R, Hansen NI, Sanchez PJ, Ambalavanan N, Benjamin DK. Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated with Increased Rates of Necrotising Enterocol i t is and Death for Extremely Low Birth Weight Infants. Pediatrics. 2009; 123(1): 58-66.
2. Deshpande G, Rao S, Patole S, Bulsara M. Updated Meta-analysis of Probiotics for Preventing Necrotising Enterocolitis in Preterm Neonates. Pediatrics. 2010;125: 921-30.
3. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibbler KR. Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants. Journal of Pediatric. 2011: 159(5): 720-25.
4. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MC, Messner H, Stolfi I, Decembrino L, Laforgia N, Vagnarelli F, Memo L, Bordignon L, Saia OS,Maule M, Gallo E, Mostert M, Magnani C, Quercia M, Bollani L, Pedicino R, Renzullo L, Betta P, Mosca P, Ferrari F, Magaldi R, Stronati M, Farina D. Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomised Trial.JAMA. 2009; 302(13): 1421-28.
5. McGuire W, Anthony AY. Donor Human Milk versus Formula for Preventing Necrotising Enterocolitis in Preterm Infants: Systemic Review. Arch Dis Child Fetal Neonatal, 2003; 88: F11-14.
6. Mitchell K, Lyttle A, Amin H, Shaireen H, Robertson HL, Lodha A. Arginine Supplementat ion in the Prevention of Necrot ising Enterocol i t is in the Premature Infant: An Updated Systemic Review. BMC Pediatrics. 2014; 14 (226): 1-10.
7. Morgan JA, Young L, McGuire W. Pathogenesis and Prevention of Necrotising Enterocolitis. Current Opinion in Infectious Diseases. 2011; 24: 183-189. doi: 10.1097
8. Neu J, Walker WA. Necrotising Enterocolitis. The New England Journal of Medicine. 2011 Jan 20; 36(43): 255-263.
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9. Patel BK, Shah JS. Necrotizing Enterocolitis in Very Low Birth Weight Infants: A Systemic Review. International Scholarly Research Network, 2012 June 19: 1-7. doi: 10.5402
10. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kohlendorfer UK, Chan GM, Blanco CL, Abrams S, Cotton M, Laroia N, Ehrenkranz R, Dudell G, Cristofalo E, Meier P, Lee ML, Retchman DJ, Lucas A. An Exclusively Human-milk Based Diet is Associated with a Lower rate of Necrotising Enterocolitis than A Diet of Human Milk and Bovine Milk-Based Products. The Journal of Pediatrics. 2010; 156: 562-67.
11. Tarnow-Modi WO, Wilkinson D, Trivedi A, Brok J. Probiotics Reduce All- Cause Mortality and Necrotising Enterocolitis: It Is Time to Change Practice. Pediatrics. 2009; 125: 1068-70.
12. Terrin G, Scipione A, Curtis MD. Update in the Pathogenesis and Prospective in Treatment of Necrotisong Enterocolitis. BioMed Research International. 2014 July 17: 1-9. doi: 10.1155
13. Wang Q, Dong J, Zhu Y. Probiotic Supplement Reduces Risk of Necrotizing Enterocolitis and Mortality in Preterm Very Low-Birth Weight Infants: An Updated Meta-Analysis of 20 Randomized, Controlled Trials. Journal of Pediatric Surgery. 2012; 47: 241-48.
14. Mihatsch WA, Braegger CP, Decsi T, Kolacek S, Lanzinger H, Mayer B, Moreno LA, Pohlandt F, Puntis J, Shamir R, Stadtmuller U, Szajewska H, Turck D, Gondoever JB. Crit ical Systemic Review of the Level of Evidence for Routine Use of Probiotics For Reduction of Mortality and Prevention of Necrotising Enterocolitis and Sepsis in Preterm Infants. Clinical Nutrition. 2012; 31: 6-15
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Dosing considerations in underweight, overweight & obese children
When initiating drug therapy for children, the patient’s total body weight or body surface area is used to calculate the dose required. However, special consideration must be given to patients whose weight does not fall within the accepted healthy weight range. Definition of Healthy Weight: Children > 2 years or older : BMI-for-age is above the 5th percentile and below the 85th percentile compared with children of the same age and sex which reflects the desirable body weight for a particular age and height that is optimal for nutrition status.
Dosing in Underweight Patients :
Definition of Underweight: Children > 2 years or older : BMI-for-age is below the 5th percentile compared with children of the same age and sex.
Dosing utilizes the actual total body weight while taking into consideration general nutritional status and precautions regarding possible altered drug clearance e.g. renal and hepatic function.
Dosing in overweight & obese children :
Definition of Overweight:
Children < 2 years of age: Normal BMI not available, hence weight-for-height values above the 95th percentile in this age group can be categorized as overweight.
Children >2 years or older : BMI-for-age at or above the 85th and below the 95th percentile compared with children of the same age and sex
6.0 DOSING CONSIDERATIONS INSPECIAL POPULATIONS
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Definition of Obese:
Children 2 years to adolescence: BMI-for-age at or above the 95th percentile on the BMI for age charts compared with children of the same age and sex.
Adolescents: Obesity may be defined as BMI at or greater than the 95th percentile OR 30kg/m2, whichever is lower.
There is limited data on the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs. Obese patients have significantly higher total body water, body volume, lean mass, fat mass and bone mineral content. They also have an increased hydration of lean mass, which is attributed to increased extracellular water. The increases in fat mass are substantially more than that of lean mass.1
Fat mass in the body will alter a drug’s volume of distribution whereby obese patients will generally have a higher volume of distribution for lipophilic medications due to its distribution into adipose tissue. Hydrophilic drugs will also have an altered volume of distribution due to increased lean body mass, blood volume & a decreased percentage of total body water. This may affect the loading dose, dosing intervals, plasma half-life and the time to reach the steady-state concentration. Obesity may also alter the metabolism and elimination of drugs.1-3
Loading doses are based on the volume of distribution (VD), body composition, blood flow and plasma protein binding.
• Hydrophilic drugs are generally loaded based on ideal body weight (IBW)
• Partially lipophilic drugs are loaded based on an adjusted body metric with consideration of the variability in distribution.
• Lipophilic drugs distribute freely into fat tissue resulting in greater distribution. A larger dose may be needed for adequate response. Some recommend dosing lipophilic medications on TBW. (However this should be assessed on a case by case basis where the risks of toxicity are considered. For example, propofol and thiopentone are lipophilic and are recommended for IBW dosing).
Maintenance doses depend on the clearance rate for drugs, which is determined by renal and hepatic function. The effect of obesity on metabolic activities in children is not known and measures of renal function in children are not validated in obesity.
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Utilizing an obese patient’s body weight or body surface area to calculate the dose may result in doses exceeding the recommended adult doses, which are used as a threshold for maximum doses in paediatric patients. Conversely, using the maximum dose recommended may result in a sub therapeutic dose as compared to the recommended weight-based dose if the drug is lipophilic.2
There is little evidence supporting the use of adjusted body weight to calculate safe and efficacious doses in obese children as it assumes that the body composition and functions are similar in obese and non obese children. Using adjusted body weights may lead to subtherapeutic doses in obese children.1,2
Weight -based dosing should be utilized in patient’s <18 years of age who are < 40kg.
For children who are >40kg, weight based dosing should be used, unless the patient’s dose or dose per day exceeds the recommended adult dose. If available, pharmacokinetics analysis for adjusting medications can be used to ensure safe and effective regimen.
Consideration of other patient factors such as renal and hepatic function, drug interactions and co-morbid states should also be considered when applying the recommendations.1
References:
1. Johnson PN, Miller JL, Boucher EA, et al; PPAG Advocacy Committee. Medication dosing in overweight and obese children. http://www.ppag.org/ obesedose/ Accessed April 30th, 2015.
2. Jessica C. Stovel. How Should Medicat ions Be Dosed in Obese Children? Medscape, Updates Sep 03, 2013. http://www.medscape.com/ viewarticle/81037/ Accessed May 2nd, 2015.
3. Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Prac Ed. 2010;95:112-117
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Children with renal impairment
Renal excretion of drugs depend on glomerular filtration, renal tubular secretion/absorption mechanism, molecular size of the drug involved and the extent of protein binding of the drug. When renal function is impaired, glomerular filtration becomes impaired and elimination of drugs will be decreased, resulting in a prolonged plasma half-life of drugs.1
The rate of drug elimination excreted by the kidneys is proportional to the glomerular filtration rate. The Schwartz equation, Traub Equation or a nomogram based on serum creatinine clearance and height are the generally accepted methods of estimating Glomerular Filtration Rate(GFR) in children <18 years of age.1
The gold standard for calculating endogenous creatinine clearance is still a timed collection of urine.
The Traditional Schwartz Equation:1,2
CrCl = Creatinine clearance, mL/min/1.73m2Scr = Serum Creatinine expressed as mg/dL (1 µmol/L = 0.0113mg/dL).K = Constant proportionality that is age specific
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3. Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Prac Ed. 2010;95:112-117
Children with renal impairment
Renal excretion of drugs depend on glomerular filtration, renal tubular secretion/absorption mechanism, molecular size of the drug involved and the extent of protein binding of the drug. When renal function is impaired, glomerular filtration becomes impaired and elimination of drugs will be decreased, resulting in a prolonged plasma half-life of drugs.1
The rate of drug elimination excreted by the kidneys is proportional to the glomerular filtration rate. The Schwartz equation, Traub Equation or a nomogram based on serum creatinine clearance and height are the generally accepted methods of estimating Glomerular Filtration Rate(GFR) in children <18 years of age.1
The gold standard for calculating endogenous creatinine clearance is still a timed collection of urine.
The Traditional Schwartz Equation:1,2
CrCl = Creatinine clearance, mL/min/1.73m2
Scr = Serum Creatinine expressed as mg/dL (1 µmol/L = 0.0113mg/dL).
K = Constant proportionality that is age specific
Age K Low birth weight 0.33
Full term ≤ 1 year old 0.45 1-12 years 0.55
13-21 years (Female) 0.55 13-21 years (Male) 0.70
However, this formula should not be used with SCr measurements calibrated to reference measurements by IDMS(Isotope dilution mass spectroscopy). Using IDMS creatinine values in the traditional Schwartz equation will result in an overestimation of GFR by 18%–39%, depending on the patient’s age. The overestimation is highest in children younger than 3 years.
In 2009, the equation was updated to account for more modern creatinine calculations done by laboratories. The modified Schwartz no longer uses a variable K value and instead uses a set K of 0.413.
The modified Schwartz equation :1,2
CrCl (mL/min/1.73m2) = 0.413 x L(cm) / SCr(mg/dL)*
*1 µmol/L = 0.0113mg/dL.
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However, this formula should not be used with SCr measurements calibrated to reference measurements by IDMS(Isotope dilution mass spectroscopy). Using IDMS creatinine values in the traditional Schwartz equation will result in an overestimation of GFR by 18%–39%, depending on the patient’s age. The overestimation is highest in children younger than 3 years.
In 2009, the equation was updated to account for more modern creatinine calculations done by laboratories. The modified Schwartz no longer uses a variable K value and instead uses a set K of 0.413.
The modified Schwartz equation :1,2
CrCl (mL/min/1.73m2) = 0.413 x L(cm) / SCr(mg/dL)*
*1 µmol/L = 0.0113mg/dL.
However, the Schwartz equation has its limitations. It can potentially overestimate GFR, especially in moderate to severe renal insufficiency as serum creatinine is a crude marker of GFR . Alternative methods based on additional factors such as cystatin C or blood urea nitrogen have been proposed to estimate GFR in children with renal insufficiency such as chronic kidney disease.2
The Paediatric Protocol for Malaysian Hospitals (3rd Edition) recommends the following equation for estimating the GFR once the serum creatinine level remains constant for at least 2 days :3
Creatinine Clearance (ml/min/1.73m2) =
References:
1. Michael E. Brier, PhD and George R. Aronoff, MD. Drug Prescribing in Renal Failure, 5th Edition: American College of Physicians; 2007
2. Sandra Benavides, Milap C. Nahata,Michael Chicella, Michelle Condren, et al. Paediatric Pharmacotherapy, 1st Edition. Kansas: American College of Clinical Pharmacy; 2013. p. 23-25.
3. Hussain Imam B. Hj. Muhammad Ismail, Ng Hoong Phak, Terrence Thomas, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia;p.290-1.
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Tpn In Special Populations
Total energy needs of a healthy individual are the sum of the basal metabolic rate (BMR), diet induced thermogenesis (DIT), physical activity (PA) and growth. Nutritional status, underlying diseases, energy intake, energy losses, age and gender may affect the energy needs. Goran et al (1991) found that fat free mass, gender and fat mass are important determinants of total energy expenditure (TEE) in prepubertal children. On the other hand, gender, body composition and season affects energy expenditure during puberty and adolescence.
Since body composition is an important factor in determining total energy expenditure, patients who are obese or malnourished may have different energy requirements. Prediction of energy needs should be based on fat free mass, to account for differences in body composition.
Energy needs can be either measured or calculated based on acceptable equations. The best way to assess energy needs in children is to measure total energy expenditure or alternatively REE.1
TPN In Obese Paediatric Patients2
The American Academy of Pediatrics (AAP) defines obesity as children aged between 2–20 years with a body mass index ≥ 95th percentile. Body mass index is the preferred practical method to screen children for obesity.
(Grade D Evidence)
Pediatric obese inpatients may be at increased nutrition risk. Potential laboratory abnormalities should be tested for safety reasons. Examples include fasting blood sample, including lipid profile, glucose, phosphorus, and complete blood count. This may aid in the development of a formal nutrition care plan as obese paediatric patients are at risk for anemia, low concentrations of fat-soluble vitamin levels, low vitamin B status, hyperlipidemia, insulin resistance and hyperglycemia.
(Grade E Evidence)
Whenever possible, energy requirements of obese hospitalized children should be assessed using indirect calorimetry rather than predictive equations as the Resting Energy Expenditure (REE) varies with obesity status. Using the excess weight to estimate the ideal body weight using predictive equations leads to imprecise estimations. This is because for every kilogram of weight above the ideal weight, the percentage of lean body mass varies, which will result in varying REE.
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Indirect calorimetry is considered the gold standard for determining energy expenditure, enabling feeding to be adapted to the measured energy expenditure.
(Grade D Evidence)
Evidence is lacking regarding the clinical outcomes of the use of hypocaloric or hypercaloric feeding during hospitalization in obese children. Therefore, until more evidence is available, the goals for the provision of energy to pediatric obese inpatients should be similar to the goals for their non obese counterparts.
(Grade E Evidence)
TPN in Malnourished Children1
During the first 2 years of life and later on during adolescence, changes in organ maturation and higher growth velocity requires extra caloric needs as compared to adults. The energy needed to maintain accelerated growth represents 30–35% of the energy requirements in term neonates and is greater in preterm infants.
Children recovering from malnutrition need extra calories to correct their growth deficits (weight, height). Thus, energy needs may be calculated based on the 50th percentile of weight and height for the actual age, rather than the present weight. This difference will provide extra calories (above daily needs) to achieve catch-up growth.
Alternatively, calculation may be based on the actual weight multiplied by 1.2–1.5, or even by 1.5 to 2 times in severe cases of failure to thrive, to provide the extra calories needed for catch up growth. Further caloric needs should be adjusted according to weight and height gain.
ESPGHAN 2005 Guidelines for Paediatric Parenteral Nutrition quotes the Schofield -WH equation to be the best predicting equation for calculating estimated daily energy needs in cases of failure to thrive.
Schofield (WH) Equations for calculating REE and BMR (kcal/day) in children from 0-3 years
Male BMR = 0.167 x Wt(kg) + 1517.4 x Ht(m) - 617.6 Female BMR = 16.25 x Wt(kg) + 1023.2 x Ht(m) - 413.5
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N
eona
tal I
cu
Schofield-(WH) Equations for calculating REE and BMR (kcal/day) in children from 3–10 years
Male BMR = 19.6 x Wt(kg) + 130.3 x Ht(m) + 414.9 Female BMR = 16.97 x Wt(kg) + 161.8 x Ht(m) + 371.2
Schofield (WH) Equations for calculating REE and BMR (kcal/day) in children from 10-18 years
Male BMR = 16.25 x Wt(kg) + 137.2 x Ht(m) + 515.5 Female BMR = 8.365 x Wt(kg) + 465 x Ht(m) + 200
A caveat to refeeding the malnourished child is the risk of refeeding syndrome, due to the sudden disruption to the adaptative state of semi-starvation. These rapid changes in metabolic status can create life-threatening complications, so the nutritional regimen must be chosen wisely and monitored closely. Kindly refer to the ESPGHAN 2005 Guidelines on Paediatric Parenteral Nutrition for strategies to reduce the risk of developing complications of refeeding syndrome.
References:
1. Berthold Koletzko, Olivier Goulet, Joanne Hunt, Kathrin Krohn,Raanan Shamir . Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). Journal of Pediatric Gastroenterology and Nutrition 2005; Volume 41(Sup 2): p. S5- 8, S79.
2. Cheryl Jesuit, Cristin Dillon, Charlene Compher, Carine M. Lenders. A.S.P.E.N. Clinical Guidelines: Nutrition Support of Hospitalized Pediatric Patients With Obesity. Journal of Parenteral and Enteral Nutrition 2010; 34(1): p.13-20.
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Corticosteroid Equipotency Chart
163
Appendix
Corticosteroid Equipotency Chart
Corticosteroid
Potency relative to Hydrocortisone Half-Life
Equivalent Glucocorticoid
Dose (mg)
Anti-Inflammatory Mineralocorticoid Plasma
(minutes) Biological
(hours)
Short Acting
Hydrocortisone 20 1 1 90 8-12
Cortisone Acetate 25 0.8 0.8 30 8-12
Intermediate Acting
Prednisone 5 4 0.8 60 12-36
Prednisolone 5 4 0.8 200 12-36
Triamcinolone 4 5 0 300 12-36
Methylprednisolone 4 5 0.5 180 12-36
Long Acting
Dexamethasone 0.75 30 0 200 36-54
Betamethasone 0.6 30 0 300 36-54
Mineralocorticoid
Fludrocortisone 0 15 150 240 24-36
Aldosterone 0 0 400+ 20 -
REFERENCE:
1) Steven K. H. Adrenal cortical steroids. In: Drug facts and comparisons. 5th ed. St. Louis: Facts and Comparisons, Inc.; 122–128 (1997).
References:
1) Steven K. H. Adrenal cortical steroids. In: Drug facts and comparisons. 5th ed. St. Louis: Facts and Comparisons, Inc.; 122–128 (1997).
7.0 APPENDIX
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Nutrition Reference
165
Nutrition Reference Supplement Nutrient Content Calories Indications And Contraindications
Carbohydrate Polycose Infant rice cereal
Glucose polymers from hydrolyzed cornstarch Rice
3.8kcal/g powder; 2kcal/mL liquid 15 cal/tbsp
Calorie supplemetation (lactose and gluten free) Contains Na, K, Ca, Cl and P (Limiting formula intake while increasing calories may compromise protein, vitamin, and mineral intake, which may also lead to hyperglycemia and diarrhea) Thickens feedings
Fat Medium-chain triglyceride Vegetable oil Microlipid
Lipid fraction of coconut oil Soy, corn oil Safflower oil, Soy lecithin, ascorbic acid, linoleic acid
8.3 kcal/g, 7.7 cal/mL 9.0 cal/g (120 cal/tbsp) 4.5 cal/mL, 5.9 g/tbsp
Limit to 50% calories from fat to prevent ketosis; may cause diarrhea; do not use in bronchopulmonary dysplasia (BPD) because risk of aspiration pneumonia To increase calories if fat absorption is normal To increase caloric density, fluid restriction
Protein Beneprotein
Whey protein isolate/soy lecithin
4.1 cal/g (6 g of protein/packet) Calcium = 30mg/scoop Sodium = 15mg/scoop Potassium = 35mg/scoop Phosphorus = 15mg/scoop Calories = 25/scoop
Useful for protein and calorie supplementation
Adapted from: Gomella TL, Cunningham MD, Eyal FG, et al, editor. Neonatology management, procedures, on-call problems, diseases and drugs. 6th ed. New York: Mc Graw Hil
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Immediate-Release Opioid Analgesics Comparison Chart
166
IMMEDIATE-RELEASE OPIOID ANALGESICS COMPARISON CHART
Drug
Equianalgesic doses
Usual starting IV doses and Intervals Parenteral
/ oral ratio
Usual starting oral doses and intervals
Parenteral Oral Child <50kg Child > 50kg
Child <50kg
Child > 50kg
Codeine 120mg 200mg - - 1:2 0.5-1 mg/kg q 3-4 hr
30-60 mg q 3-4 hr
Morphine 10mg 30mg (long term)
Bolus: 0.1 mg/kg q 2-4 hr Infusion: 0.02-0.03 mg/kg/hr
Bolus: 5-8 mg q 2-4 hr Infusion: 1.5mg/kg/hr
1:3
Immediate release: 0.3mg/kg q 3-4 hr
Immediate release: 15-20mg q 3-4 hr Sustained release: 30-45 mg q 8-12 hr
Oxycodone - 15-20 mg - - -
0.1-0.2 mg/kg q 3-4 hr
5-10 mg q 3-4 hr
Methadone 10mg 10-20mg 0.1mg/kg 5-8 mg q 4-
8 hr 1:2 0.1mg/kg q 8-12 hr
2.5-10 mg q 8-12 hr
Fentanyl 100mcg (0.1mg) -
Bolus: 0.5-1 mcg/kg q 1-2 hr Infusion: 0.5-2mcg/kg/hr
Bolus: 25-50 mcg q 1-2 hr Infusion: 25-100 mcg/hr
- - -
Hydromorphone 1.5-2 mg 6-8 mg
Bolus: 0.02 mg q 2-4 hr Infusion: 0.006mg/kg/hr
Bolus: 1 mg q 2-4 hr Infusion: 0.3 mg/hr
1:4 0.04-0.08 mg/kg q 3-4 hr
2-4 mg q 3-4 hr
Meperdine (Pethidine) 75-100 mg 300
mg
Bolus: 0.8-1 mg/kg q 2-3 hr
Bolus: 50-75mg q 2-3 hr
1:4 2-3 mg/kg q 3-4 hr
100-150 mg q 3-4 hr
REFERENCE:
1) Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Eng J Med. 2002;347:1094-1103
References:
1) Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Eng J Med. 2002;347:1094-1103
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TDM Sampling Time
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Growth Charts
168
GROWTH CHARTS
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Stability And Storage Of Oral Medications
The following information was adapted from Hospital Kuala Lumpur’s Pharmacy Department Guidelines of Compilation of Medication Management (2013) :
DEFINITION
Stability The extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., shelf-life/BUD/etc), the same properties and characteristics that it possessed at the time of its manufacture/compounding/repackaging. There are five (5) types of stability which are generally recognized i.e. Chemical, Physical, Microbiological, Therapeutic and Toxicological stability.
Stability studies conducted by the manufacturer are used determine shelf life and thus the expiry date of a product.
Expiration Date
Expiration date is the identified time up to which the product is expected to meet the requirements of the Pharmacopeial monograph, provided it is kept under the prescribed storage conditions. Expiration date limits the time during which the product may be dispensed or used. It is determined using stability studies and is not the same as Beyond-Use Date (BUD)/ DiscardAfter Date.
In the event where stability studies are unavailable as in the case of extemporaneous products, BUD will be assigned to the product.
Beyond-Use Date (BUD)/ Discard-After Date/ Shelf Life
Beyond-Use Date (BUD)/Discard-After Date/Shelf Life are equivalent and it is the time/date after which a product (usually compounded/repackaged) must not be used. It is assigned, using the criteria stated in the relevant sections below. In the absence of appropriate stability studies to support expiration dates used and the assigned BUD must be less than the expiration date of any of the initial product/raw material/s.
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Extemporaneous/Compounded Preparation
A medicinal product (internal and external) where its use (prescribing, dispensing and/or administration), involves some element of recipe or formula preparation. This recipe or formulation must be present in at least one step in prescribing, dispensing and/or administration but does not have to be present in all steps.
Repackaging/Pre-packing
An act of removing a preparation/drug from its original primary container and placing it into another primary container (may be called secondary if Unit-Dose packaging), usually of smaller size.
Storage
Procedures to maintain a proper storage environment for pharmaceutical products, and to ensure product integrity, including its appearance, until it reaches the user. Children >2 years or older : BMI-for-age at or above the 85th and below the 95th percentile compared with children of the same age and sex
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178
Sto
rage
Pro
cedu
res
to m
aint
ain
a pr
oper
sto
rage
env
ironm
ent f
or p
harm
aceu
tical
pro
duct
s, a
nd to
en
sure
pro
duct
inte
grity
, inc
ludi
ng it
s ap
pear
ance
, unt
il it
reac
hes
the
user
.
Equ
ival
ent C
onta
iner
-Clo
sure
Sys
tem
Ref
ers
to a
con
tain
er-c
losu
re s
yste
m th
at y
ield
s th
e sa
me,
or b
ette
r, m
oist
ure
vapo
ur
trans
mis
sion
rate
(MV
TR),
oxyg
en a
nd li
ght t
rans
mis
sion
as
the
orig
inal
mar
ket c
onta
iner
.
Mul
tidos
e P
acka
ging
Mul
tidos
e pa
ckag
ing
is th
e pa
ckag
ing
of m
ore
than
one
sin
gle-
dosa
ge u
nit i
n a
reus
able
co
ntai
ner.
Uni
t-Dos
e P
acka
ging
Uni
t-dos
e pa
ckag
ing
is th
e pa
ckag
ing
of a
sin
gle
dose
in a
non
-reu
sabl
e co
ntai
ner.
Med
icat
ions
in
uni
t-dos
e pa
ckag
ing
are
easi
ly id
entif
iabl
e an
d ca
n be
retu
rned
to th
e ph
arm
acy
if th
e m
edic
atio
n is
dis
cont
inue
d/w
ithho
ld.
Stor
age
& S
tabi
lity
For E
xtem
pora
neou
s / N
on-S
teril
e C
ompo
unde
d Pr
epar
atio
ns
The
assi
gnm
ent o
f sta
bilit
y, o
f an
exte
mpo
rane
ous/
non-
ster
ile c
ompo
unde
d pr
epar
atio
n sh
ould
be
don
e w
ith p
rude
nt p
harm
aceu
tical
judg
men
t by
atte
ndin
g ph
arm
acis
t bas
ed o
n lit
erat
ures
/ pu
blic
atio
ns/ r
efer
ence
s on
form
ulas
with
sta
bilit
y da
ta.
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Equivalent Container-Closure System
Refers to a container-closure system that yields the same, or better, moisture vapour transmission rate (MVTR), oxygen and light transmission as the original market container.
Multidose Packaging
Multidose packaging is the packaging of more than one single-dosage unit in a reusable container.
Unit-Dose Packaging
Unit-dose packaging is the packaging of a single dose in a non-reusable container. Medications in unit-dose packaging are easily identifiable and can be returned to the pharmacy if the medication is discontinued/withhold.
Storage & Stability For Extemporaneous / Non-Sterile Compounded Preparations
The assignment of stability, of an extemporaneous/non-sterile compounded preparation should be done with prudent pharmaceutical judgment by attending pharmacist based on literatures/ publications/ references on formulas with stability data.
In the absence of stability information or if only anecdotal data is available; the following maximum BUD are recommended for extemporaneous/non-sterile compounded preparations, that are packed in tight, light resistant (if applicable) containers and stored at Controlled-Room Temperature (CRT), unless otherwise indicated:-
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179
In th
e ab
senc
e of
sta
bilit
y in
form
atio
n or
if o
nly
anec
dota
l dat
a is
ava
ilabl
e; th
e fo
llow
ing
max
imum
BU
D a
re re
com
men
ded
for e
xtem
pora
neou
s/no
n-st
erile
com
poun
ded
prep
arat
ions
, th
at a
re p
acke
d in
tigh
t, lig
ht re
sist
ant (
if ap
plic
able
) con
tain
ers
and
stor
ed a
t Con
trolle
d-R
oom
Te
mpe
ratu
re (C
RT)
, unl
ess
othe
rwis
e in
dica
ted:
-
Inte
rnal
a)
All
exte
mpo
rane
ous/
com
poun
ded
prep
arat
ion
mus
t util
ize
form
ulas
with
refe
renc
es w
hene
ver
poss
ible
. Pre
para
tions
with
out s
uch
form
ulas
or w
ith a
necd
otal
refe
renc
e on
ly, s
houl
d be
use
d w
ith p
rude
nt p
harm
aceu
tical
judg
men
t by
the
atte
ndin
g ph
arm
acis
t. b)
Sta
bilit
y of
pre
para
tion
shou
ld b
e la
bele
d ap
prop
riate
ly w
here
by, t
he te
rm ‘E
xpiry
Dat
e’
shou
ld b
e us
ed fo
r for
mul
as w
ith s
tabi
lity
stud
ies
and
‘BU
D’ s
houl
d be
use
d fo
r for
mul
as w
ithou
t re
fere
nces
on
stab
ility
stu
dies
or f
or fo
rmul
as w
ith o
nly
anec
dota
l ref
eren
ces.
c)
If a
form
ula
is n
ot a
vaila
ble,
‘fre
shly
pre
pare
d’ (‘
just
prio
r to
adm
inis
tratio
n’) o
r tab
let
disp
ersi
on m
etho
d (s
tabl
e fo
r 24
hour
s) is
reco
mm
ende
d.
d) A
ll pr
epar
atio
ns s
houl
d be
refri
gera
ted
(Col
d te
mpe
ratu
res
[2°C
to 8
°C])
unle
ss s
tate
d ot
herw
ise.
Syr
ups,
Sus
pens
ions
, Sol
utio
ns m
ade
from
Pow
der;
are
to b
e st
ored
at C
ontro
lled-
Roo
m T
empe
ratu
re u
nles
s ot
herw
ise
indi
cate
d.
e) H
owev
er, A
ntib
iotic
sus
pens
ion/
solu
tion
(pre
pare
d fro
m in
gred
ient
s in
sol
id fo
rm) i
s st
able
for
14 d
ays
if st
ored
in C
old
Tem
pera
ture
, unl
ess
stat
ed o
ther
wis
e on
pac
kage
. f)
All
othe
r for
mul
atio
ns: o
nce
used
, mus
t be
disc
arde
d up
on c
ompl
etio
n of
ther
apy
OR
not
mor
e th
an 3
0 da
ys, w
hich
ever
is e
arlie
r.
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Internal
a) All extemporaneous/compounded preparation must utilize formulas with references whenever possible. Preparations without such formulas or with anecdotal reference only, should be used with prudent pharmaceutical judgment by the attending pharmacist.
b) Stability of preparation should be labeled appropriately whereby, the term ‘Expiry Date’ should be used for formulas with stability studies and ‘BUD’ should be used for formulas without references on stability studies or for formulas with only anecdotal references.
c) If a formula is not available, ‘freshly prepared’ (‘just prior to administration’) or tablet dispersion method (stable for 24 hours) is recommended.
d) All preparations should be refrigerated (Cold temperatures [2°C to 8°C]) unless stated otherwise. Syrups, Suspensions, Solutions made from Powder; are to be stored at Controlled-Room Temperature unless otherwise indicated.
e) However, Antibiotic suspension/solution (prepared from ingredients in solid form) is stable for 14 days if stored in Cold Temperature, unless stated otherwise on package.
f) All other formulations: once used, must be discarded upon completion of therapy OR not more than 30 days, whichever is earlier.
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External
a) Refer Internal a) – b).
b) Material Safety Data Sheet (MSDS) should be readily available, for easy retrieval and interpretation, in particular the safety hazard information; to all staff preparing drug substances or bulk chemical on the compounding premise.
c) Stability of preparation should be assigned using the recommended expiry date or BUD (refer above).
Repackaging/Prepacking Storage & Stability
Repackaging/prepacking operations should be conducted under conditions that meet requirements; including specific storage temperature, i.e. maintenance of CRT. Written procedures must be maintained for traceability of end product. Repackaged/prepacked containers must be labeled with: 1. Generic name 2. Manufacturer name 3. Manufacturers batch number4. Expiry date (new)/BUD
Package inserts (PI) or other appropriate literature of the item being repackaged/prepacked should be readily available, for easy reference, in order to properly select an equivalent container-closure system.
Manufacturer’s original expiration date may be used without additional stability testing if the drug product is repackaged/prepacked into an equivalent container-closure system.
If an equivalent container-closure system is not available, a stability data for the new containerclosure system must be generated to justify the expiry date assigned. In the absence of stability information or only anecdotal data is available; the following maximum BUD are recommended for repackaged/prepacked products in an equivalent container-closure system and stored at Controlled-Room Temperature (CRT) (if applicable), unless otherwise indicated:-
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182
Drugs To Avoid In G6PD Deficiency
Definite Risk Of Hemolysis Pharmacological Class Drugs
Anthelmintics • ß-Naphthol • Niridazole • Stibophen
Antibiotics
• Nitrofurans - Nitrofurantoin - Nitrofurazone
• Quinolones - Ciprofloxacin - Moxifloxacin - Nalidixic acid - Norfloxacin - Ofloxacin
• Chloramphenicol • Sulfonamides
- Co-trimoxazole (Sulfamethoxazole + Trimethoprim)
- Sulfacetamide - Sulfadiazine - Sulfadimidine - Sulfamethoxazole - Sulfanilamide - Sulfapyridine - Sulfasalazine
(Salazosulfapyridine) - Sulfisoxazole
(Sulfafurazole)
Antimalarials
• Mepacrine • Pamaquine • Pentaquine • Primaquine
Antimethemoglobinaemic Agents • Methylene blue
Antimycobacterials
• Dapsone • Para-aminosalicylic
acid • Sulfones - Aldesulfone sodium
(Sulfoxone) - Glucosulfone - Thiazosulfone
Antineoplastic Adjuncts • Doxorubicin • Rasburicase
Genitourinary Analgesics • Phenazopyridine (Pyridium)
Others • Acetylphenylhydrazine • Phenylhydrazine
Source : Adapted from MIIMS 2006 For further information, Kindly refer : www.g6pd.org
Possible Risk Of Hemolysis Pharmacological Class Drugs
Analgesics
• Acetylsalicylic acid (Aspirin)
• Acetanilide • Paracetamol
(Acetaminophen) • Aminophenazone
(Aminopyrine) • Dipyrone (Metamizole) • Phenacetin • Phenazone (Antipyrine) • Phenylbutazone • Tiaprofenic acid
Antibiotics
• Furazolidone • Streptomycin • Sulfonamides • Sulfacytine • Sulfaguanidine • Sulfamerazine • Sulfamethoxypyridazole
Anticonvulsants • Phenytoin Antidiabetics • Glibenclamide Antidotes • Dimercaprol (BAL)
Antihistamines • Antazoline (Antistine) • Diphenhydramine • Tripelennamine
Antihypertensives • Hydralazine • Methyldopa
Antimalarials
• Chloroquine & derivatives
• Proguanil • Pyrimethamine • Quinidine • Quinine
Antimycobacterials • Isoniazid
Antiparkinsonism • Trihexyphenidyl (Benzhexol)
Cardiovascular Drugs • Dopamine (L-dopa) • Procainamide • Quinidine
Diagnostic Agent for Cancer Detection • Toluidine blue
Gout Preparations • Colchicine • Probenecid
Hormonal Contraceptives • Mestranol
Nitrates • Isobutyl nitrite
Vitamin K Substances
• Menadiol Na sulfate • Menadione • Menadione Na bisulfite • Phytomenadione
Vitamins • Ascorbic acid (Vit C) (rare)
Others
• Arsine • Berberine (in Coptis
chinensis) • Fava beans • Naphthalene (in
mothballs) • Para-aminobenzoic acid
For further information, Kindly refer : www.g6pd.org
Drugs To Avoid In G6PD Deficiency
Lot 36, Jalan University,46350 Petaling Jaya,Selangor Darul Ehsan.
Tel : +603 7841 3200 Fax : +603 7968 2222Website : www.pharmacy.gov.my