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Every year some 8 million children in developing countries die before they reach their fifth birthday; many during the first year of life. Eight in ten of these deaths are due to neonatal conditions, acute respiratory infections (mostly pneumonia), diarrhoea (including dysentery), malaria, or severe malnutrition -or a combination of these conditions. The Pocket Book of Hospital Care for Children was first published in 2005, as a compilation of guidelines for the management of these common childhood illnesses at the first-referral level in low-resource settings with limited equipment and staff capacity. It is part of a series of documents and tools that support the Integrated Management of Childhood Illness (IMCI) guidelines for outpatient management of sick children. The Pocket Book guidelines focus on the inpatient management of the major causes of childhood mortality, such as pneumonia, diarrhoea, malaria, severe acute malnutrition (SAM), HIV/AIDS, and common or life-threatening causes of fever (i.e. meningitis, otitis media, and typhoid fever).
Since the first edition was published in 2005, new evidence has emerged resulting in updates of several WHO guidelines. These include: prevention and antiretroviral treatment in children with HIV; feeding of HIV-exposed children; treatment of tuberculosis (TB), malaria, and convulsions in children; management of chronic pain; and an update of the essential medicine list for children. These updates, and others, have meant that there was a need to update the relevant sections of the Pocket Book.
To ensure that most recommendations were up to date, the Pocket Book was reviewed by the Guidelines Steering Committee (GSC), which identified and prioritized chapters requiring updates (Annex 1). These constituted the basis of the collation and synthesis of the evidence for the recommendations on the management of common childhood conditions and illnesses. These recommendations specifically focussed on management of newborn conditions, treatment of cough and difficult in breathing, treatment of dysentery, management and treatment of common causes of fever, antibiotics in management of severe malnutrition, sublingual sugar for management of hypoglycaemia, detection of hypoxaemia and use of oxygen therapy, and choice of fluids in the management of shock.
This document provides the background, methods, and analysis of the evidence used in making all the recommendations put forth during the Guidelines Development Group (GDG) meeting convened in February 2011 at WHO headquarters in Geneva, Switzerland. These recommendations were made based on the best available evidence as of December 2010, and take into consideration their risks and benefits, as well as their acceptability, cost, and feasibility of implementation.

# Target audience
These recommendations are intended primarily for use by policy makers, child health programme managers, health-care providers, and professional bodies or technical partners involved in developing guidelines or advising ministries of health. They can also be used as a resource in medical training institutions in pre-service training.

# Objectives of the recommendations
These recommendations are part of a series that will be used to update several guidelines and tools for clinical management of common childhood illnesses at health facilities at all levels of care. The main objectives are:
n To provide evidence-based recommendations for the clinical management of common childhood illnesses. n To develop recommendations applicable in low-resource settings that maintain high standards of care. n To develop evidence based recommendations for the update of the Pocket Book of Hospital Care for Children guidelines and IMCI clinical guidelines for management of common illnesses with limited resources.

# Financial support
The main source of funding to support this work, including the systematic review of evidence, evidence compilation, convening the GDG panel meeting, editing, and printing of the recommendations, was provided by Better Medicines for Children Project funded by the Gates Foundation, with additional budget support and staff time from the WHO Department of Maternal, Newborn, Child and Adolescent Health. The WHO Collaborating Centre for International Child Health (CICH) in Melbourne, Australia, provided a full-time consultant to work with department for six months and participated in undertaking some of the systematic reviews.

# Management of conflict of interest
All participants completed and signed a declaration of interest form; decisions taken on verbal declarations by members of the GDG at the meeting were documented and kept as a record. Declaration forms were reviewed and discussed by the WHO GSC before the meeting, and outcomes were approved by the Director of Department of Maternal, Newborn, Child and Adolescent Health. Participants who declared receiving research funding from non-commercial organizations for projects related to the meeting participated in all aspects of the meeting. Those with academic conflicts of interest, i.e. having authored sections of the previous version of the Pocket Book, fully participated in the proceedings, but were not allowed to chair any of the sessions. Participants who had recent or current research funding or personal payments from commercial entities on topics related to the meeting were excluded from voting on final ratification the recommendations.
The following declarations of interest by members were assessed and found to be insufficient to exclude from full participation:
n Fizan Abdullah declared research grants from NIH for necrotizing enterocolitis; n Shinjini Bhatnagar declared research funding for projects related to the topic of the meeting; n Harry Campbell declared making public statements for international action against pneumonia; n Trevor Duke declared completing systematic reviews related to the subject of the meeting; n Michael English declared research grants from the Wellcome Trust, the Gates Foundation, the Royal College for Paediatrics and Child Health (RCPCH), and the Hillman Medical Education Fund (HMEF) on topics related to this meeting; n Andrew Gray declared receiving honorarium and travel support from Aspen pharmaceuticals and Fresenius Kabi South Africa as a guest speaker, in 2009; n Stuart Macleod declared being a director, which ceased in 2010, of an institution that received research grants with no direct involvement from several commercial and non-commercial entities.
The following members were excluded from final ratification of the recommendations:
n Haroon Saloojee received personal payments from the National Institute of Health (US$ 3000), was an advisory board member on rotavirus project of GlaxoSmith-Kline in 2008, as well as personal payment by Nestle Nutrition (US$ 2500); n Leonila Dans declared a current research grant not related to the topic of the meeting from Pfizer with personal payments of about US$ 2000/year in 2010.

# Guiding principles
The principles guiding the development of these recommendations were based on providing optimal public health guidance using the best available evidence in the management of common childhood conditions in settings with limited resources. The guiding principles are as follows:
n Prioritize and optimize the best options for treatment of common childhood illnesses to improve quality of care in hospitals in low-resource settings. n Promote best practices based on a high quality level of evidence supporting strong recommendations in order to deliver the highest standards of care despite limited resources. n Analyse and balance the benefits, risks, and feasibility of implementation of the recommendations in hospitals with limited resources. n Build consensus among experts on recommendations in situations where there is very low quality or no supporting evidence.

# Methodology and process 2.1 Defining the scope
The scope was defined by reviewing the 2005 edition of the Pocket Book of Hospital Care for Children and identifying the relevant recommendations that required updating. The department initiated a consultative process in 2009 to map out the status of WHO guidelines and recommendations that contributed to the development of the Pocket Book. In 2010, a Guidelines Steering Committee was set up consisting of members from key departments within WHO, including the Department of Maternal, Newborn, Child and Adolescent Health, Global Malaria Program (GMP), Essential Health Technologies (EHT), Mental Health and Substance Abuse (MSD), Essential Medicines and Pharmaceutical Policies (EMP), Stop TB (STB), and Nutrition for Health and Development (NHD). Consultations were undertaken with external experts implementing the Pocket Book or and with those who were previously involved in writing and/or editing the first edition in an effort to identify gaps, emerging evidence, or changes to clinical practice. Furthermore, feedback from the two field surveys conducted in 2008 and 2009 on the implementation and use of the Pocket Book were drawn upon to identify additional priority areas to be updated. The process identified two categories of updates for the Pocket Book:
n Revisions to align the Pocket Book recommendations with recently published Guideline Review Committee (GRC)-approved WHO guidelines. n Revisions of priority areas that required collation, analysis, and synthesis of the evidence to make recommendations in line with the current level of evidence.
In the first category, recommendations from existing GRC-approved WHO guidelines were identified for direct incorporation into the Pocket Book. The second category required systematic reviews to provide evidence to update or make new recommendations. The second category is the basis of this document wherein the group identified specific priority chapters, sections, and subsections of the Pocket Book requiring updates. As a result, a total of 34 PICO 1 questions were formulated for evidence collation and synthesis (Annex 2).
1 PICO: Population/Patient Group, Intervention, Comparator, and Outcome. A PICO question is one that is formulated using the PICO framework, wherein the health-care provider asks and answers a series of questions meant to elicit information about their patient and their condition, interventions that have been undertaken or should be taken, any comparisons between the current treatment and possible alternatives, and outcomes to be desired or achieved.
The priority areas that were identified included: management of selected neonatal conditions; management of cough or difficulty breathing; antibiotics for treatment of dysentery; management of conditions with fever; antibiotics for severe acute malnutrition; and supportive care (i.e. oxygen therapy, choice of intravenous fluids, and treatment of hypoglycaemia).

# Evidence retrieval and synthesis process
Throughout 2010, the Department of Maternal, Newborn, Child and Adolescent Health coordinated efforts to review and synthesize the evidence on the various, identified priority questions. This process included targeted, systematic reviews of relevant literature, preparation of GRADE profiles, and analysis of the risk-benefits, feasibility, and costs of implementation.
A literature search of the Cochrane Database and OVID-Medline was conducted in July 2010 to identify high quality, systematic reviews in the last two years that were relevant to the priority PICO questions. Where data were not available or up-todate from the two sources, systematic reviews were commissioned to various groups to collate the evidence. The systematic reviews, meta-analyses, and GRADE profiles followed the methodology recommended by the GRC and as described in Version 5.1.0 of the Cochrane Handbook for Systematic Reviews of Interventions. 1 Where data were lacking, systematic searches were conducted from various electronic databases, including Medline/PubMed, Embase, CENTRAL, NLM Gateway, and WHO regional databases.
For each question, data on critical and secondary outcomes were extracted and appraised by evaluating the quality, consistency, and external validity of the evidence. These were then graded from very low, low, medium, and high in tabular form using the GRADE methodology. Quality was defined as the extent to which one could be confident that an estimate of effect or association is correct and was based on the following criteria: n study design; n limitations of the studies, in terms of their conduct and analysis; n the consistency of the results across the available studies; n the precision of the results (wide or narrow confidence intervals); n the directness (or applicability or external validity) of the evidence with respect to the populations of interest, interventions, and low-resource settings where the proposed intervention will be applied.
Additional considerations included the magnitude of the effect, presence or absence of a dose response gradient, and direction of plausible biases. The quality of evidence was then categorized as: high, moderate, low, or very low as defined in GRADE tables from systematic reviews were cross-checked, and where relevant, risk-benefit analysis was produced by the GSC. Internal discussions were held to evaluate the quality of the evidence presented to the GDG and needed to produce draft recommendations, benefits, harms and risks, costs of implementation, and acceptability. Recommendations were then formulated and drafted in accordance with procedures outlined in the WHO Handbook for Guideline Development, 1 and guided by the quality of evidence using the GRADE methodology.
In drafting the recommendations, the WHO Secretariat used those summaries of evidence for the critical outcomes (i.e. morbidity, mortality, disease progression and sequelae, or adverse events for medicines); quality of evidence; risks and benefits of implementing the recommendations; acceptability; costs; and feasibility. The recommen dations were then were then ranked as strong or weak recommendation and research gaps or needs were identified.

# Consensus building and external peer review
Draft recommendations, along with the supportive evidence (including summary of the evidence of the systematic reviews with risk-benefit analysis and GRADE tables) were circulated to selected expert external reviewers and some Pocket Book users for feedback (Annex 4). This process was managed electronically through a (EZcollab site accessible to external reviewers. Results of the peer review process were used to modify the draft recommendations before presentation to the GDG panel.
To formulate the final recommendations, these evidence summaries, with riskbenefit analysis and GRADE tables, were presented and discussed at an expert panel meeting held at WHO headquarters in Geneva, Switzerland, in February 2011. The panel weighed the quality of evidence, risks, and benefits, including acceptability, and placed emphasis on the values and feasibility of implementation in low-resource settings while ensuring that the recommendations are in line with international standards of care. Although most decisions were based on the evidence from randomized clinical trials (RCTs), or large effect observational cohort data, where the panel determined that there was insufficient evidence, expert consensus was used.

# Assessment of strength of evidence

# LEVEL OF EVIDENCE RATIONALE
High Further research is very unlikely to change confidence in the estimate of effect.
Further research is likely to have an important impact on confidence in the effect.
Further research is very likely to have an estimate of effect and is likely to change the estimate.

# Very low
Any estimate of effect is very uncertain. The grading of the strength of the final recommendations, in addition to the quality of evidence, were influenced by the balance between risks and benefits, acceptability (values and preferences), and cost and feasibility implementation in low-resource settings.
All of the final recommendations were reached by consensus without the need for voting. The panel also provided advise on strategies to support implementation of the recommendations through the Pocket Book and other quality-of-care tools.
In deciding on the strength of the recommendations, the panel was guided by the agreed-on assessment criteria described in Table 2.2. The decisions were made by consensus or, where necessary, by vote.
The final, graded recommendations and remarks made by the panel were also circulated to external reviewers, including WHO regional and country child health staff, for comments; the results of these comments were posted on the SharePoint for discussion. Where the panel requested more information, the Secretariat provided the information to all panel members for agreement.
Review and update of the recommendations These recommendations will be regularly updated as more evidence is collated and analysed on a continuous basis with major reviews and updates at least every 3 to 5 years. However, reviews of evidence will be ongoing and where new data requires update of the recommendations, online interim updates will be produced. These recommendations will also form part of a technical series of the evidence behind several guidelines to be produced by the Department of Maternal, Newborn, Child and Adolescent Health over the coming years. The next major update will be done in 2014.

# METHODOLOGY AND PROCESS

# Assessment criteria for the strengths of recommendations

# STRENGTH OF RECOMMENDATION RATIONALE
The panel is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects.
The panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects. However: the recommendation is only applicable to a specific group, population or setting OR where the new evidence may result in changing the balance of risk to benefit OR where the benefits may not warrant the cost or resource requirements in all settings.
No recommendation Further research is required before any recommendation can be made.

# Implementation of the recommendations 3.1 Proposed subsidiary products
Although these recommendations were developed in the context of updating the Pocket Book of Hospital Care for Children used at the referral level, they will also be used to update the IMCI guidelines and other subsidiary child health implementation tools. Key tools to assist countries in the revision and update of national paediatric guidelines that are to be updated or developed include, but are not limited to:
n Pocket Book training CD-ROM n Hospital and self assessment tools n A manual for clinical use of oxygen n Integrated Management of Childhood Illiness clinical algorithms.
The recommendations will be disseminated through various tools for improving quality of care and capacity building. The Pocket Book training CD-ROM used for in-service and pre-service training will be updated and widely distributed. The recommendations and the Pocket Book will be made available electronically as part of the quality of care improvement CD-ROM resource package, which will include quality assessment tools, a framework for quality improvement, and self-assessment tools to support managers and clinicians with improving quality of hospital care.

# Implementation of the recommendations
In addition to publishing the recommendations as a stand alone reference document, they will be incorporated into various products mentioned above. They will mainly be circulated through the Pocket Book of Hospital Care for Children, which is the standard guideline used at first-referral level. The updated second edition of the Pocket Book will be translated into French, Spanish, and Russian in collaboration with regional offices for wider circulation and readership. The Pocket Book will be linked to the recommendations and the evidence used.
To increase its accessibility to the evidence used as the basis for the recommendations, it will also be made available for download from all of the WHO websites (headquarters, regional offices, and country offices) and select WHO Collaborating Centres websites in various electronic formats. While wider dissemination will continue through the Pocket Book sales in the WHO Bookshop, as well as through a distribution network to all medical libraries or individuals and through the nonprofit Teaching-Aids at Low Cost (TALC) website. 1 The Pocket Book will be introduced in medical and paramedical training institutions through national societies and in collaboration with the International Paediatric Association (IPA). WHO will also continue collaborating with various child health groups that have been instrumental in dissemination, implementation, and evaluation of the Pocket Book, including:
n International Child Health Review Collaboration (ICHRC), a database of the evidence-base for the Pocket Book recommendations (). n Centre for International Child health, a WHO Collaborating Centre in Melbourne, Australia (www.rch.org.au/cich). n National and regional networks whose missions are to improve the quality of care for children in hospitals, like the Kenya Medical Research Institute (KEMRI) (/). n Collaboration with various partners like the International Paediatric Association (IPA) who are collaborating with WHO on improving quality of care through their regional and national societies. n Collaboration with child health specialists at national, regional, and international levels to support national adaptation and implementation of the Pocket Book as part of the process of improving quality of care. n Collaboration with medical students through national, regional, and international societies.
Evaluation of the guidelines will continue to be undertaken through periodic quality of care assessments in hospitals and through country reviews undertaken by the department of Maternal, Newborn, Child and Adolescent Health using the quality of care framework and the hospital assessment tools mentioned above.

# National adaptation and implementation
These recommendations have been developed mainly to provide guidance in the updating and development of standard paediatric treatment guidelines at national level in resource-limited settings. It is expected that each country will adapt these recommendations to suit their context in consideration of the necessary resources required for implementation. This will be facilitated by updating the current Pocket Book of Hospital Care for Children, which countries may adapt in developing national standards of care.
Countries may already have various paediatric guidelines in the form of national treatment guidelines or hospital case management protocols. These guidelines would have to be reviewed and compared against the WHO Pocket Book for standards of care. It is recognized that implementation of some of the recommendations may be 1Teaching-Aids at Low Cost may be obtained at . Accessed on 29 August 2011. challenging as they require updating national essential medicine lists and building consensus at national level.
Establishing national standards for hospital care for children is critical in improving quality of care and is a major component of the quality improvement process. Countries will be encouraged to set up national technical working groups to support the national adaptation process with the involvement of all stakeholders. The standards will then be adapted and endorsed by stakeholders, locally translated as required, and disseminated to all hospitals in the country. In most cases, it may require orientation of the health workers on the new case management protocols as part of the quality of care improvement process.

# Recommendations for management of newborn conditions
Vitamin K prophylaxis in newborns a) All newborns should be given 1 mg of vitamin K intramuscularly (IM) after birth (i.e. after the first hour by which the infant should be in skin-to-skin contact with the mother and breastfeeding should be initiated).

# (Strong recommendation, moderate quality evidence)
b) Neonates requiring surgical procedures, those with birth trauma, preterm newborns, and those exposed in utero to maternal medication known to interfere with vitamin K are at especially high risk of bleeding and must be given vitamin K (1 mg IM).
(Strong recommendation, moderate quality evidence)

# Prophylactic antibiotics in newborns with risk factors for infection
A neonate with risk factors for infection (i.e. membranes ruptured > 18 hours before delivery, mother had fever > 38 C before delivery or during labour, or amniotic fluid was foul smelling or purulent) should be treated with the prophylactic antibiotics ampicillin (IM or intravenously, IV) and gentamicin for at least 2 days. After 2 days, the neonate should be reassessed and treatment continued only if there are signs of sepsis (or a positive blood culture).

# (Weak recommendation, very low quality evidence)

# Skin-to-skin contact in the first hour of life
Newborns without complications should be kept in skin-to-skin contact with their mothers during the first hour after birth to prevent hypothermia and promote breastfeeding.

# Prevention of hypothermia immediately after birth in LBW infants
LBW neonates weighing >1200g who do not have complications and are clinically stable should be put in skin-to-skin contact with the mother soon after birth and after drying them thoroughly to prevent neonatal hypothermia.

# (Weak recommendation, low quality evidence)
Recommendations for treatment of cough and difficulty in breathing 4.10 Treatment of non-severe pneumonia with wheeze Antibiotics are not routinely recommended for children aged 2-59 months with nonsevere pneumonia (i.e. fast breathing with no chest indrawing or danger sign) with a wheeze but no fever (< temperature 38 C), as the cause is most likely to be viral.

# (Strong recommendation, low quality evidence)
- 11 Antibiotic treatment for non-severe pneumonia with no wheeze a) Children with non-severe pneumonia (i.e. fast breathing with no chest indrawing or danger sign) should be treated with oral amoxicillin. The exception is in patients with HIV: -With low HIV prevalence, give amoxicillin at least 40mg/kg/dose twice daily for 3 days.
-With high HIV prevalance, give amoxicillin of at least 40mg/kg/dose twice daily for 5 days.

# (Weak recommendation, moderate quality evidence)
b) Children with non-severe pneumonia who fail on the first line treatment with amoxicillin should have the option of referral to a facility where there is appropriate second line treatment.
(Weak recommendation, expert opinion) 4.12 Antibiotics treatment for severe pneumonia a) Children aged 2-59 months with severe pneumonia (chest indrawing) should be treated with oral amoxicillin at least 40mg/kg/dose twice daily for 5 days.

# (Strong recommendation, moderate quality evidence)
b) In HIV/AIDS infected children, specific guidelines for treatment of severe pneumonia in the context of HIV should be followed.

# (Strong recommendation, low quality evidence)
- 13 Antibiotic treatment for very severe pneumonia a) Children aged 2-59 months with very 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 5 days -Gentamicin: 7.5 mg/kg IM/IV once a day for at least 5 days (Strong recommendation, moderate quality evidence) b) Ceftriaxone should be used as a second line treatment in children with severe pneumonia with failure on the first line treatment.

# (Strong recommendation, expert opinion)
- 14 Inhaled salbutamol for treatment of acute wheeze/asthma and bronchoconstriction a) Children with acute wheeze/asthma and bronchoconstriction should be treated with inhaled salbutamol using a metered dose inhaler (MDI) with spacer devices to relieve bronchoconstriction.

# (Strong recommendation, low quality evidence)
b) Oral salbutamol should not be used for treatment of acute or persistent wheeze except where inhaled salbutamol is not available. Oral salbutamol is not useful in testing response to bronchodilators.

# (Strong recommendation, low quality evidence)
Recommendations for treatment of dysentery 4.15 Antibiotics for treatment of dysentery a) Children with diarrhoea and blood in stool (i.e. dysentery) should be treated with ciprofloxacin as a first line treatment. Ceftriaxone should be given as a second line treatment in severely ill children where local antimicrobial sensitivity is not known.
-Ciprofloxacin: 15 mg/kg/dose twice daily for 3 days -Ceftriaxone: 50-80 mg/kg daily for 3 days

# (Strong recommendation, low quality evidence)
b) Where local antimicrobial sensitivity is known, local guidelines should be followed.

# (Strong recommendation, low quality evidence)
Recommendations for treatment of common causes of fever 4.16 Antibiotics for treatment of acute bacterial meningitis a) Children with acute bacterial meningitis should be treated empirically with 3rd generation cephalosporins.
-Ceftriaxone: 50mg/kg per dose IV every 12 hours or 100 mg/kg once daily, or -Cefotaxime: 50mg/kg per dose every 6 hours for 10-14 days.

# (Strong recommendation, moderate quality of evidence)
b) Where it is known that there is no significant resistance to chloramphenicol and beta lactam antibiotics among bacteria-causing meningitis follow national guidelines or choose any of the following two regimens: -Chloramphenicol: 25 mg/kg IM (or IV) every 6 hours plus ampicillin: 50 mg/ kg IM (or IV) every 6 hours OR -Chloramphenicol: 25 mg/kg IM (or IV) every 6 hours plus benzyl penicillin: 60 mg/kg (100 000 units/kg) every 6 hours IM (or IV).

# (Conditional recommendation, moderate quality evidence)
- 17 Antibiotics for treatment of acute otitis media a) Children with acute otitis media should be treated with oral amoxicillin at 40 mg/ kg twice per for 7-10 days.

# (Strong recommendation, low quality evidence)
b) Where pathogens causing acute otitis media are known to be sensitive to cotrimoxazole, this antibiotic could be used as an alternative given twice per day for 7-10 days.
(Strong recommendation, low quality evidence)

# Topical antibiotics for treatment of chronic suppurative otitis media (CSOM)
a) Children with chronic suppurative otitis media (CSOM) should, in addition to aural toilet by dry wicking, be treated with instillation of drops containing quinolones (such as ciprofloxacin, norfloxacin, ofloxacin) three times daily for two weeks.

# (Strong recommendation, low quality evidence)
b) Children who fail to respond to treatment should be referred for further evaluation for other causes of CSOM, especially tuberculosis.
(Strong recommendation, expert opinion)

# Topical antiseptics for treatment of chronic suppurative otitis media
Topical antiseptics and steroids should not be used for the treatment of CSOM in children.

# (Strong recommendation, low quality evidence)

# Topical steroids for treatment of chronic suppurative otitis media
Topical steroids should not be used in treating CSOM.

# (Weak recommendation, very low quality evidence)
- 21 Antibiotics for treatment of Typhoid Fever a) Children with typhoid fever should be treated with a fluoroquinolone (i.e. Ciprofloxacin, Gatifloxacin, Ofloxacin, and Perfloxacin) as a first line treatment for 7-10 days.
-Ciprofloxacin: orally 15 mg/kg/dose twice daily for 7-10 days.

# (Strong recommendation, moderate quality evidence)
b) If the response to treatment is poor, consider drug-resistant typhoid, and treat with a second line antibiotic like 3rd generation cephalosporins or azithromycin.
-Cetriaxone (IV): 80 mg/kg per day for 5-7 days, OR -Azithromycin: 20 mg/kg per day for 5-7 days.
(Strong recommendation, moderate quality evidence) c) Where drug resistance to antibiotics among salmonella isolates is known, follow the national guidelines according to local susceptibility data. -Benzyl penicillin: 50 000 U/kg IM/IV every 6 hours, or ampicillin: 50 mg/kg IM/IV every 6 hours for 2 days, then oral amoxicillin: 15 mg/kg/dose every 8 hours for 5 days. AND -Gentamicin: 7.5 mg/kg IM/IV once daily for 7 days.

# (Weak recommendation, low quality evidence)

# Recommendations on Use and Delivery of Oxygen Therapy

# Pulse oximetry for detection of hypoxaemia
Pulse oximetry is recommended to determine the presence of hypoxaemia and to guide administration of oxygen therapy in infants and children with hypoxaemia.

# Criteria for starting and stopping oxygen therapy
a) Children with hypoxaemia should be closely monitored using pulse oximetry.

# (Strong recommendation, very low quality evidence)
b) Oxygen therapy should be discontinued when oxygen saturation remains stable above recommended levels of 90% ( 2500M above sea level) or 87% (> 2500M above sea level) for at least 15 minutes on room air in a clinically stable child.

# (Strong recommendation, very low quality evidence)
Recommendations on treatment of hypoglycaemia

# Sublingual administration of sugar in the treatment of hypoglycaemia
Sublingual sugar may be used as an immediate first aid measure in managing hypoglycaemia in children in situations where intravenous administration of glucose may be impossible or delayed.

# (Strong recommendation, low quality evidence)
Recommendations on the choice of intravenous fluids 4.30 Choice of intravenous fluids for resuscitation and maintenance in children a) Resuscitation: Children severely dehydrated or with signs of shock should be resuscitated using isotonic intravenous (IV) solutions such as sodium chloride 0.9% or ringers lactate.

# (Strong recommendation, low quality evidence)
b) Intravenous maintenance fluid: For children who require IV fluids for maintenance, options include ringers lactate solution with 5% dextrose, sodium chloride 0.45% with glucose 5%, sodium chloride 0.45% with glucose 2.5%, or 0.9% sodium chloride with glucose 5%.

# (Strong recommendation, low quality evidence)
c) Low sodium-containing solutions, such as sodium chloride 0.18% with glucose 4%, or 5% glucose in water, should not be used as there is an increased risk of hyponatraemia leading to cerebral oedema.

# (Strong recommendation, low quality evidence)

# Evidence for recommendations on the newborn conditions

# Vitamin K prophylaxis in newborns
- All newborns should be given 1 mg of vitamin K intramuscularly (IM) after birth (i.e. after the first hour by which the infant should be in skin-to-skin contact with the mother and breastfeeding should be initiated).

# (Strong recommendation, moderate quality evidence)
- Neonates requiring surgical procedures, those with birth trauma, preterm babies, and those exposed in utero to maternal medication known to interfere with vitamin K are at especially high risk of bleeding and must be given vitamin K (1 mg IM).

# (Strong recommendation, moderate quality evidence)
The panel put large value on the expected benefits of vitamin K prophylaxis which clearly outweigh the harms. It also noted that implementation was feasible, and the cost affordable in most settings.

# Evidence and summary of findings
The incidence of classical vitamin K deficiency bleeding in the absence of vitamin K prophylaxis ranges from 10 to 1500 per 100 000 neonates, and that of late Vitamin K Dependant Bleeding (VKDB) ranges from 5 to 80 per 100 000. There is some evidence to indicate that the incidence of VKDB is at the higher end of the ranges given above in less-developed countries. We found moderate quality evidence to show that vitamin K prophylaxis reduces the risk of bleeding in newborns.
Only two RCTs conducted in the 1960s looked at the impact of vitamin K supplementation (0.1 to 5 mg IM) on bleeding in neonates [Vietti 1960, Sutherland 1967. These studies showed that vitamin K prophylaxis is effective in preventing post-circumcision (39% reduction, NNT 21, 95% CI 13 to 50) and non-circumcision bleeding (43% reduction, NNT 80, 95% CI 42 to 714). One of the above studies showed that vitamin K prophylaxis resulted in an 81% reduction in moderate or severe bleeding (NNT 75, 95% CI 48 to 177) and a 97% reduction in severe bleeding (NNT 140, 95% CI 90 to 500). There was no difference in groups given 0.1 mg or 5 mg of vitamin K. The quality of this evidence was graded as moderate to low (see GRADE table A7.1).
Vitamin K prophylaxis has been shown to reduce sub-clinical deficiency in the first week of life (measured as the presence of a protein induced by vitamin K deficiency, or PIVKA). There was no significant difference between oral or IM vitamin K on subclinical deficiency in the first week of life. Studies have also looked as prothrombin time (PT) but none of the studies that included infants had a PT outside the normal range in the intervention and control groups. Two studies, which examined the effect of vitamin K prophylaxis on prothrombin complex deficiency, reported that IM prophylaxis reduced deficiency by 72% and oral prophylaxis by 50%.
Data from two observational studies showed that vitamin K prophylaxis -single dose administered at birth by either IM or oral route -reduces the incidence of late VKDB substantially; prophylaxis by IM route was significantly better (about 97%) than that by the oral route (65-83%) in reducing the incidence of late VKDB. Although late VKDB is rare, about one third of infants with this condition die or have severe handicaps. The NNT estimated from two observational studies (incidence with no vitamin K prophylaxis, 6 per 100 000) is about 18 000. If the incidence were 30 per 100 000, the number needed to treat to prevent a case of late VKDB is about 3000. The quality of this evidence was graded as low or very low.

# Benefits and risks
Vitamin K prophylaxis significantly reduces the risk of bleeding in neonates. Twenty neonates undergoing circumcision need to be given prophylaxis to prevent one case of bleeding after circumcision. About 80 neonates need to be given prophylaxis to prevent one case of non-circumcision bleeding. Late VKDB can be prevented with vitamin K prophylaxis -one case prevented per about 3000 infants treated.
The first report of a potential association between vitamin K prophylaxis and childhood cancer appeared in 1990. Subsequent research has not substantiated this concern.

# Acceptability and feasibility
Vitamin K intervention is effective but the disease it prevents is relatively rare. Current practice in most developed countries is to give vitamin K prophylaxis to all newborn babies after birth. The cost of the medicine itself is US$ 0.195 per 1 mg injection. Costs of the syringe and needle and the supply of vitamin K, etc. would be additional. The costs for routine vitamin K administration may not be justifiable in low-resource settings.

# Prophylactic antibiotics in newborns at risk of infection
A neonate with risk factors for infection (i.e. membranes ruptured > 18 hours before delivery, mother had fever > 38 C before delivery or during labour, or amniotic fluid was foul smelling or purulent) should be treated with prophylactic antibiotics ampicillin (IM or IV) and gentamicin for at least 2 days. After 2 days, the neonate should be reassessed and treatment continued only if there are signs of sepsis (or a positive blood culture).

# (Strong recommendation, Very low quality evidence)
The panel made this recommendation based on expert consensus as there was very low quality evidence that the intervention may prevent neonatal sepsis. There was no evidence available to evaluate harms and the risk of increasing antibiotic resistance, injection safety, and keeping a baby in hospital up to or for 5 days.

# Evidence and summary of findings
The Cochrane review included only two studies. There were no deaths reported in the intervention or control groups in either of the studies. Similarly, one of the studies found no cases of sepsis in either of the groups. The quality of evidence from these two single studies is very low (see GRADE table A7.
None of the infants who participated in the trials died in the neonatal period. One of the studies (Wolf, 1976) reported four cases of neonatal sepsis, all of which occurred in the control (selective treatment) group. This difference was statistically non-significant (49 participants, RR = 0.12, 95% CI 0.01 to 2.04).
Data are insufficient to provide evidence of a beneficial effect of immediate prophylactic antibiotic compared to selective use of antibiotics on either neonatal mortality or on incidence of neonatal sepsis. The two trials were small and underpowered to detect any effect on the two outcomes of interest. The overall quality of evidence is very low.

# Benefits and risks
The intervention is likely to prevent neonatal sepsis.
No evidence is available to evaluate harms.

# Acceptability and feasibility
IM antibiotic administration should be possible in small hospitals. Median price of ampicillin (250 mg) is US$ 0.18/vial and gentamicin (10mg/ml) is US$ 0.07/ml making the cost of implementation affordable in most low-resource settings.

# Skin-to-skin contact in the first hour of life
Newborns without complications should be kept in skin to skin contact (SSC) with their mothers during the first hour after birth to prevent hypothermia and promote breastfeeding.

# (Standard recommendation, low quality evidence)
The panel made the recommendation based largely on expert consensus and put large value on the expected benefits of skin-to-skin contact benefits on breastfeeding rates at 1-4 months age and on exclusive breastfeeding at 4-6 months after birth. It also noted that although there is low quality evidence, the cost of its implementation is low and is most likely to be feasible to implement in low-resource settings.

# Evidence and summary of findings
There was very low quality evidence from one Cochrane review published in 2007, although the studied population and intervention evaluated was generally in line with the intervention of interest. The exception was skin-to-skin contact was started after the first hour of birth in some of the studies included in the recommendation. Hence, the results should be interpreted with caution. Notably, there were important variations in the implementation of the intervention of interest. In many studies, the intervention was not initiated immediately after birth and its duration ranged from a few minutes to several hours in different trials. This is a common practice and being implemented currently according to WHO guidelines. Since there was no notable harm in implementing this recommendation, the expected benefits outweighed the risks.
There was very low quality evidence (see GRADE table A7.3) in making this recommendation. None of the studies included in the review examined the impact of early SSC on neonatal mortality. Ten studies involving 552 participants have showed significant positive effects of early SSC on breastfeeding at 1-4 months post birth (OR=1.8, 95% CI 1.08 to 3.07). Only one available trial with 92 participants assessed the effect of SSC on exclusive breastfeeding at 4-6 months post birth. Results were positive and statistically significant (OR=5.67, 95% CI 2.27 to 14.16). The pooled effect on mean duration of breastfeeding from seven trials (324 participants) was not statistically significant (weighted mean difference  = 42.55 days, 95% CI -1.69 to 86.79).
Three studies, with 168 participants, measured the effect of SSC on body temperature in the second hour of life. Two of them measured the temperature after 90 minutes of SSC and the third after 2 hours of SSC. All three studies started the intervention immediately after birth. The first two studies observed a positive, statistically significant effect while the third failed to demonstrate a significant difference in temperature between groups. Meta-analysis of these three studies showed a pooled WMD of 0.25 degrees centigrade, 95% CI -0.15 to 0.65.
Although there were a few studies from developing country settings, the majority were conducted in hospitals from high-income countries. No adverse effects were shown.

# Benefits and risks
Benefits SSC has a positive effect on breastfeeding 1-4 months post birth and on exclusivity of breastfeeding at 4-6 months after birth (low quality evidence for both). As exclusive breastfeeding is associated with improved survival, SSC may be expected to reduce neonatal mortality.
There is no evidence of harm with this intervention.

# Acceptability and feasibility
The intervention has a low cost and should be feasible to implement. However, it requires acceptance by the mother, family, and community in general. Cultural barriers might need to be overcome in order to implement this intervention.
Management of neonatal jaundice 3. Phototherapy should be stopped once serum bilirubin is 50 mmol/l (3 mg/dl) or below the phototherapy threshold.

# (Standard recommendation, expert opinion)
These suggested levels represent a consensus by the expert panel members based on very limited evidence, and the levels shown are approximations consistent with other international guidelines. The emphasis should be on preventive actions and risk evaluation where lower cut-offs for exchange transfusion may prevent some additional cases of kernicterus. This recommendation should be accompanied by a brief description on how to give phototherapy in clinical guidelines.

# Evidence and summary of findings

# Association between serum bilirubin levels and adverse neurodevelopmental outcomes:
The systematic review by the National Institute of Health and Clinical Excellence (NICE), UK, and four additional studies were identified. Three observational studies evaluated the association of high serum bilirubin levels (> 340 micro mol/litre) with adverse sequelae: two studies were in term babies and one in babies with birth weight less than 1000 g. One study in term babies found no statistically significant association between hyperbilirubinaemia and IQ, abnormal neurological examination, or sensorineural hearing loss. Another study reported severe jaundice requiring exchange transfusion and early onset of jaundice as statistically significant risk factors for hearing loss. The third study found a weak association between high serum bilirubin levels and neurodevelopmental impairment, hearing impairment, and psychomotor impairment in babies with birth weight less than 1000 g. The NICE Guidelines Development Group (NICE GDG) concluded that term neonates with serum bilirubin > 340 micro mol/litre are at an increased risk of kernicterus.
Age-specific bilirubin cut-offs for instituting phototherapy or exchange transfusion: Two randomized trials relevant for this question were identified. One high quality study addressed this question in extremely low birth weight neonatal population (birth weight < 1000 gm; constituting < 1% of total newborn population) showing no role of aggressive phototherapy. The other trial found that there was little advantage in starting phototherapy early in babies with birth weight greater than 2500g. This evidence indicates that the currently used conventional cut-offs do not need to be further reduced. However, the "conventional" cut-offs are somewhat different than those in the current version of the Pocket Book. No direct evidence is available for the cut-off for exchange transfusion. The consensus cut-offs developed by the NICE GDG for exchange transfusions are somewhat lower than those in the current version of the Pocket Book.

# Benefits and risks
Lower cut-offs for phototherapy may avoid the need for exchange transfusion in the majority of infants with jaundice. Lower cut-offs for exchange transfusion may prevent some additional cases of kernicterus; but there is no evidence for the best cutoff which has to be agreed by consensus.
Aggressive phototherapy may not be beneficial and may be associated with adverse effects in non-specialized settings.

# Acceptability and feasibility
Exchange transfusion is only possible in tertiary care settings.

# EVIDENCE FOR RECOMMENDATIONS ON THE NEWBORN CONDITIONS
Empirical antibiotics for suspected neonatal sepsis a) Neonates with signs of sepsis should be treated with ampicillin (or penicillin) and gentamicin as the first line antibiotic treatment for at least 10 days.

# (Strong recommendation, low quality of evidence)
b) If a neonate with sepsis is at greater risk of staphylococcus infection (e.g. extensive skin pustules, abscess, or omphalitis in addition to signs of sepsis), should be given cloxacillin and gentamicin instead of penicillin and gentamicin.
(Strong recommendation, expert opinion) c) Where possible, blood cultures should be obtained before starting antibiotics. If an infant does not improve in 2-3 days, antibiotic treatment should be changed, or the infant should be referred to a neonatologist for further management.

# (Strong recommendation, expert opinion)
In making this recommendation, the panel considered the high antimicrobial sensitivity to third generation cephalosporins, and the lack of enough evidence to choose between beta-lactams plus gentamicin and 3rd generation cephalosporins.
In developing countries, streptococci continue to be highly sensitive to betalactams, although sensitivity to gentamicin of staphylococcus aureus (40-95%) and gram negative enteric bacteria (32-100%) is variable. In order to guide empirical prescribing, it is crucial to monitor changes in the pattern of causative organisms and their antimicrobial susceptibility profiles since the effects may depend on antibiotic susceptibility patterns.

# Evidence and summary of findings
The evidence for these recommendations are from two existing Cochrane reviews that have concluded there is not enough evidence to choose between different antibiotic combinations for first line treatment of early or late neonatal sepsis. Sepsis in neonates is classified as early (presenting within 72 hours after birth) and late (presenting after 72 hours after birth) because this predicts aetiology. In early sepsis the most common organisms are Group B streptococcus and gram negative enteric bacteria (esp. E. coli). Late onset community acquired infections are predominantly caused by Strep. Pneumoniae, Staphylococcus aureus, E. coli and other gram negatives. The evidence is from four RCTs of 3rd generation cephalosporin monotherapy versus penicillin and aminoglycoside combination that were identified. One of these was conducted in South Africa and all others were conducted in Europe. Two trials used cefotaxime and the other two used ceftazidime monotherapy as the intervention. Three trials used ampicillin or benzyl penicillin with gentamicin as the control treatment, while one trial used penicillin with netilmicin as the control treatment. The overall quality of evidence was graded as low (see GRADE table A7.4).
Mortality and cure rates were similar between intervention and control groups in three of the four studies. However, there was a significantly higher cure rate in the South African study. Overall, there was no difference in mortality or cure rates between the intervention and control groups. One study reported that a combination of ceftazidime plus ampicillin had higher cure rates than the ampicillin-gentamicin combination.

# Benefits and risks
Available evidence indicates no difference in cure rates and mortality between 3rd generation cephalosporin monotherapy and penicillin-aminoglycoside combination therapy. However, effects may vary in different settings depending on antibiotic susceptibility patterns. Other benefits of 3rd generation cephalosporins are good cerebrospinal fluid penetration and convenient once/twice daily administration.
The risks of ceftriaxone include displacement of bilirubin from albumin leading to higher free bilirubin and risk of kernicterus and promotion of beta-lactamase resistance.

# Acceptability and feasibility
Neonates with suspected sepsis will require admission irrespective of the antibiotic chosen. Therefore differences in the convenience of administration are less important. Median price of ampicillin (250 mg) is US$ 0.18/vial, gentamicin (10mg/ ml) is US$ 0.07/ml, and ceftriaxone (250 mg) is US$ 0.44/vial. Cefotaxime is more expensive than ceftriaxone.

# Head or whole body cooling in management of hypoxic ischaemic encephalopathy
Head or whole body cooling should not be done outside well-resourced, tertiary neonatal intensive care units, because there is potential for harm from this therapy in low-resource settings.

# (Strong recommendation, moderate quality evidence)
The panel made this recommendation on the basis of potential harm from body cooling if applied outside a neonatal intensive care unit where mechanical ventilation, sedation and other supportive care cannot safely be provided. It noted that in low resource settings there was no evidence supporting this therapy and that it was expensive. However, in well resourced tertiary neonatal intensive care units, treatment with whole body cooling as part of high quality intensive care support improves survival and reduces disability for term neonates with asphyxia and hypoxic ischaemic encephalopy.

# Evidence and summary of findings
There is moderate quality evidence that induced hypothermia (cooling) of newborn babies who may have suffered from a lack of oxygen at birth reduces death or disability, without increasing disability in survivors. The damage caused by the lack of oxygen continues for some time afterwards. One way to try and stop this damage is to induce hypothermia by cooling the baby or just the baby's head for hours to reduce the amount of damage to brain cells. The evidence from trials show that induced hypothermia helps to improve survival and development at 18 months for term newborn babies at risk of brain damage. However, all the studies were done in highly resourced, neonatal intensive care units with adequate support with no data from settings in developing countries. Eight RCTs were included in this review, comprising 638 term infants with moderate or severe encephalopathy and evidence of intrapartum asphyxia. Six were performed as pilot studies, three in single centres in New Zealand, Turkey and China; and the others at multiple centres in Australia and North America. All 8 trials included term newborn infants with moderate or severe encephalopathy and evidence of intrapartum hypoxia-ischaemia without obvious congenital abnormalities. Infants in all studies were randomised with initiation of the intervention by six hours of age.
Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.76, 95% CI 0.65, 0.89; typical RD -0.15, 95% CI -0.24, -0.07; NNT 7,95% CI 4,14). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.74, 95% CI 0.58, 0.94; typical RD -0.09, 95% CI -0.16, -0.02; NNT 11, 95% CI 6, 50) and in neurodevelopmental disability in survivors (typical RR 0.68, 95% CI 0.51, 0.92; typical RD -0.13, 95% CI -0.23, -0.03). Some adverse effects of hypothermia included an increase in the need for inotrope support of borderline significance and a significant increase in thrombocytopaenia.
This result is both statistically significant and clinically important, with a relative risk reduction of 24%, absolute risk reduction of 15%, and NNT of 7.

# Benefits and risks
There clear benefits of cooling on survival and neurodevelopment which outweigh the short-term adverse effects associated with therapeutic hypothermia.
There is possible increased risk of thrombocytopaenia and hypotension from the therapeutic hypothermia.

# Acceptability and feasibility
Parents may be willing to allow their child to undergo this procedure as they would reasonably expect that cooling would decrease their baby's chance of dying and may lessen the occurrence of a major disability, if their child survived.

# Antibiotics for treatment of necrotizing enterocolitis
Young neonates with suspected necrotizing enterocolitis (NEC) should be treated with IV or IM ampicillin (or penicillin) and gentamicin as a first line antibiotic treatment for 10 days.

# (Standard recommendation, low quality evidence)
The panel noted that it has been common practice to add metronidazole to the treatment of NEC. Although there is no evidence to judge its benefits, metronidazole covers gastrointestinal tract anaerobic bacteria (such as Bacteroides fragilus). It also noted that while a combination of vancomycin and ceftriaxone is a suitable alternative, the only evidence is from tertiary western intensive care units. Vancomycin and 3rd generation cephalosporins are expensive, and would not be feasible to use as a first line antibiotic treatment for NEC in low-resource settings.

# Evidence and summary of findings
NEC is a serious disease characterized by varying degrees of mucosal necrosis, seen predominantly in premature infants. The underlying pathogenesis remains unclear and pathogenic organisms are not isolated in many cases. Clustering of cases and outbreaks in nurseries suggest an infective component to its aetiology. Four studies were found directly comparing antibiotic regimens in NEC. One non-concurrent cohort study from Belgium was excluded as the effect of the addition of metronidazole to an existing antibiotic regimen could not be separated from other simultaneous modifications to an existing management protocol (e.g. earlier and different surgical approaches, changes in anaesthesia, and modification of intensive care management routines).
One study included 46 cases of NEC in 1982-3 treated with ampicillin and gentamicin, and 44 cases in 1984-5 treated with vancomycin and ceftriaxone. There were no statistical differences in any measured outcomes for infants of birth weight > 2200g and complications were infrequent in both groups. For infants < 2200g, those treated with Vancomycin demonstrated statistically lower rates of death (p = 0.048), need for surgery (p = 0.04), culture positive peritonitis (p = 0.01), and major complications (p = 0.004): these included peritonitis, strictures, feed intolerance, and recurrent NEC and thrombocytopenia. The quality of evidence was graded as very low.
One RCT allocated 42 premature infants with radiographically confirmed NEC to receive IV ampicillin and gentamicin or to receive ampicillin, gentamicin, and clindamycin. This study found an increased rate of complicating strictures in the clindamycin group (NNT harm 3, 95% CI 2 to 13) with a consequently longer time needed to restart feeds (8.4 days versus 22.3). There were no significant differences in rates of death or in incidence of gangrene/perforation. The study was terminated early due to significantly higher rates of strictures in the clindamycin group. The quality of evidence was graded as low (see GRADE table A7.5).
One RCT allocated 20 infants with NEC to receive ampicillin and gentamicin versus IV ampicillin and gentamicin with oral gentamicin for 4 days. In this study, enrolled infants were more mature (ampicillin and gentamicin 34.71.3 weeks gestation and ampicillin and gentamicin with oral gentamicin 35.61.1 weeks) and higher birth weight (ampicillin and gentamicin 2220295g and ampicillin and gentamicin with oral gentamicin 2180198g) than many studies reporting NEC. This study found no significant differences in outcomes (p > 0.05), including days with peritonitis, days with pneumatosis, major complications including perforation, stricture and ileus, and death. This study was underpowered to detect most differences, with blinding and allocation concealment not well defined. The quality of this evidence was graded as low.

# Benefits and risks
Vancomycin and ceftriaxone may be better than ampicillin and gentamicin for treatment of NEC but the confidence in this statement is low, because factors other than antibiotics may have resulted in or contributed to the beneficial effect as the study was a non-concurrent study. There is no evidence to judge the benefits of metronidazole.
Clindamycin was administered in one study to cover gram negative organisms and resulted in a significantly higher rate of stricture formation. There is no evidence to judge the risks of metronidazole.

# Acceptability and feasibility
A combination of vancomycin and ceftriaxone may not be feasible and may be expensive to use as a first line antibiotic treatment in infants with NEC.

# Kangaroo Mother Care
Low birth weight (LBW) neonates weighing < 2000 g who are clinically stable should be provided Kangaroo Mother Care (KMC) early in the first week of life.

# (Strong recommendation, moderate quality evidence)
The panel noted that although there is no evidence for KMC in babies > 2000 g, KMC may be beneficial in neonates who have temperature instability. However, implementation will require a description on how to provide KMC.

# Evidence and summary of recommendations
We identified one recent systematic review  which aimed to assess the effect on neonatal mortality and morbidity from complications of preterm birth of KMC compared to no care at all or compared to conventional care. A preterm death was defined as a neonatal death in a baby with a birth weight < 2000 g. KMC was defined as the combination of continuous skin-to-skin contact, support for exclusive breastfeeding or other appropriate feeding and early recognition, and response to complications. Studies where KMC was only commenced after the first week of life were excluded. Measured outcomes were neonatal mortality due to complications of preterm birth, or morbidity related to prematurity. The review included 15 studies: nine randomized controlled trials (RCT), and six observational studies. All studies were from low or middle-income countries. Of the RCTs, six reported mortality data, but only three were included in the analysis. Two studies were excluded because median time of initiation of KMC was greater than 1 week after birth, and the third study -a community trial from Bangladesh -was thought to have important methodological limitations and was not conducted in health facilities. Analysis of the three remaining trials -from India, Colombia and Ethiopia -showed a major mortality reduction with KMC for babies < 2000 g (RR 0.49, 95% CI 0.29 to 0.82; 988 infants (High quality evidence, see GRADE table A7.6).
These mortality results are supported by results from three observational studies (8257 infants) which also showed a mortality reduction (RR 0.68, 95% CI 0.58-0.79), though this was heavily influenced by a large South African study that contributed 96% to the weight of the pooled estimate.
Five RCTs reported data on serious morbidity, defined as severe pneumonia, sepsis, jaundice, and other severe illness. There were variations in study definitions and heterogeneity in the results (I 2 = 70%, P < 0.01). However, KMC was associated with a reduction in serious neonatal morbidity (RR 0.34; 95% CI 0.17 to 0.65; 1520 babies. (Moderate quality evidence, see GRADE table A7.6).

# Benefits and risks
There is high quality evidence that KMC leads to a significant reduction in neonatal mortality, and moderate quality evidence that it reduces serious morbidity, when compared to conventional care for babies < 2000 grams in low-to middle-income countries. Other benefits were seen with breastfeeding and bonding.
Possible risks include apnoea and bradycardia in some babies. It should be noted that KMC should be started once the LBW infants are clinically stable.

# Acceptability and feasibility
The benefits would be highly valued by families, health providers and programme managers/policy makers. Additional costs for training health workers and counseling mothers and families in KMC would be offset by the cost for conventional care (i.e. use of incubators).

# Prevention of hypothermia immediately after birth in low birth weight infants
Low birth weight (LBW) neonates weighing > 1200 g who do not have complications and are clinically stable should be put in skin-to-skin contact with the mother soon after birth and after drying them thoroughly to prevent neonatal hypothermia.

# (Strong recommendation, low quality evidence)
In making the recommendation, the panel noted that although the plastic wraps for LBW infants are beneficial in reducing hypothermia, the possible risks of using plastic wraps in settings in developing country were not known. There is very little experience with this intervention in developing countries and further research into the type of plastic to be used, as well as the practicality and appropriateness of using the plastic-wrap technique in low-resource settings, is required.

# Evidence and summary of findings
We identified one recent systematic review through Cochrane  that sought to assess the effect on interventions to prevent hypothermia in preterm and/or LBW infants. The review included three interventions of interest: (1) plastic wraps;
(2) plastic caps; and (3) skin-to-skin contact. Studies were included that evaluated these interventions started within 10 minutes of birth. Hypothermia was defined as core body temperature < 36.5 C on admission to neonatal intensive care unit (NICU) or up to 2 hours after birth. There was low to moderate quality evidence that caps or plasticwraps reduced hypothermia, and moderate quality evidence that skin to skin contact significantly reduced hypothermia in LBW newborns (GRADE table A7.7) Plastic wraps or bags were effective in reducing heat loss in infants < 28 weeks' gestation (four studies; n = 223; WMD 0.68 C; 95% CI 0.45, 0.91), but not in infants between 28 to 31 weeks gestation (1 study, n = 41). Two of the studies in infants of gestational age < 29 weeks showed that plastic wrap significantly reduces the risk of hypothermia on admission to the NICU (two studies, n = 152; RR 0.66, 95% CI 0.51, 0.84; RD -0.27; 95% CI -0.41, -0.13. Four infants would need to be wrapped in plastic in order to prevent one infant from becoming hypothermic (NNT 4, 95% CI 2 to 8).
Plastic caps were effective in reducing heat losses in infants < 29 weeks' gestation (one study; n = 64; MD 0.80C; 95% CI 0.41, 1.19). This study also reported that plastic caps significantly reduce the risk of hypothermia on admission to the NICU (RR 0.48, 95% CI 0.32, 0.73; RD -0.47; 95% CI -0.67, -0.27). Two infants would need to wear a plastic cap in order to prevent one infant from becoming hypothermic (NNT 2, 95% CI 2 to 4).
For infants with a birth weight between 1200 and 2199g, evidence suggests that skin-to-skin contact significantly reduces the risk of hypothermia (as defined by the study) within 6 hours of birth when compared to conventional incubator care (one study; n = 31; RR 0.09, 95% CI 0.01, 0.64; RD -0.56, 95% CI -0.84, -0.27). Two infants would need to receive skin-to-skin contact in order to prevent one infant from becoming hypothermic (NNT 2, 95% CI 1 to 4).

# Benefits and risks
Plastic wrap or plastic cap used immediately after birth prevents hypothermia in infants of gestation < 29 weeks. For LBW infants above 1200 g, skin-to-skin contact immediately after birth effectively prevents hypothermia.
No evidence of reported harms was available.

# Acceptability and feasibility
Plastic wraps are relatively of low cost, may be easy to use and acceptable to parents of LBW newborns.

# Evidence for recommendations
for treatment of pneumonia

# Antibiotic treatment for non-severe pneumonia with wheeze
Antibiotics are not routinely recommended for children with non-severe pneumonia (i.e. fast breathing with no chest indrawing or danger sign) with a wheeze but with no fever (< temperature 38 C), as the cause is most likely to be viral.

# (Strong recommendation, low quality evidence)
This recommendation is applicable only in situations where the health workers are able to assess "wheeze". The panel observed that there is evidence that WHO criteria for diagnosing pneumonia performs poorly in children with wheeze; that the addition of fever to WHO criteria improves diagnostic accuracy in this group of children; and that children with wheeze and no fever are very unlikely to have bacterial pneumonia.

# Evidence and summary of findings
No systematic reviews addressing the effectiveness of antibiotics in children with non-severe pneumonia were identified. However, two recent RCTs provide direct evidence. The evidence for the effectiveness of antibiotics is mixed, in part due to the significant (but as yet undetermined) proportion of children fulfilling the criteria for non-severe pneumonia, who have either a viral illness or non-infectious aetiology. In Asia, up to 60% of children with non-severe pneumonia are reported to also have an audible wheeze by auscultation.
Observational data provides evidence that: the addition of fever to the WHO criteria for pneumonia improves its specificity for children with wheeze, and children with non-severe pneumonia and wheeze, with no fever or history of fever, have a low risk of bacterial pneumonia and most recover without antibiotics. There is also new evidence from one trial in Pakistan showing that antibiotics are no better than placebo for children with WHO-defined non-severe pneumonia (see GRADE table A7.8).

# Antibiotics in all children presenting with non-severe pneumonia in Pakistan
Hazir et al (2010) conducted a double-blinded, randomized, placebo-controlled trial of oral amoxicillin versus placebo for non-severe pneumonia in four centres in Pakistan. Children were enrolled if they fulfilled WHO criteria for non-severe pneumonia: cough or difficulty breathing and fast breathing (using age-dependant WHO cut-offs). The study recruited 900 children, and randomized 450 children to each group. At baseline, 73-80% of children had a history of fever, and 30-50% recorded a temperature >37.8 C. While 50-60% of children had wheeze on examination, only 5-6% reported history of wheeze.
Using intention-to-treat (ITT) analysis, by day 3, 50 children in the amoxicillin group (11.1%) and 45 children in the placebo group (10%) failed treatment. The difference was not statistically significant: odds ratio (95% CI) 1.13 (0.72 to 1.76). Cumulative treatment failure by day 5 was also similar between the two groups (OR 0.87, 95% CI 0.61 to 1.24). Per-protocol, 7.2% (31/431) of children in the amoxicillin group and 8.3% (37/442) in the placebo group failed treatment on day 3 (OR 0.85, 95% CI 0.50 to 1.43). There was no difference in relapse by day 14 (OR 0.58, 95% 0.11 to 2.81).
There were no differences between groups in the number of children requiring change (or initiation) of antibiotics, the number of children who developed danger signs, or the number of children requiring hospitalization. There were no deaths.
On logistic regression analysis, treatment failure was associated with a history of difficulty breathing (OR 2.86, 95% CI 1.13 to 7.23), and temperature > 37.8 C (OR 1.99, 95% CI 1.37 to 2.90) at enrolment.

# Antibiotics in children presenting with non-severe pneumonia and wheeze in India
Awasthi et al ( 2008) was a double-blinded, randomized controlled multi-centre trial in India using amoxicillin (31-54 mg/kg/day) versus placebo for children 2-59 months with WHO non-severe pneumonia and wheeze (audible or auscultatory). The study was powered to detect non-inferiority of placebo. Children were enrolled if they presented with WHO-defined non-severe pneumonia, did not respond to up to three doses of inhaled salbutamol, and had a normal chest X-ray. Recruited children were treated as outpatients with oral salbutamol and either amoxicillin or placebo. Outcomes were treatment failure at day 4, defined as development of WHO-defined severe or very severe pneumonia, hypoxaemia (SpO2<90%), or persistence of nonsevere pneumonia, wheeze or fever. Clinical relapse was defined as cases which were clinically cured by day 4, but showed signs of WHO-defined pneumonia by day 11-14.
The study recruited 1671: 836 in the placebo group and 835 in the amoxicillin group. Loss to follow-up was <5% by day 14. Baseline characteristics of both groups were similar: adherence to placebo and amoxicillin was higher than 95%, and there were no differences between groups in adherence to oral salbutamol. Respiratory syncytial virus (RSV) was detected in nasopharyngeal aspirates of 48 of 778 children in the placebo group (6.2%) and 40 of 780 children in the amoxicillin group (5.1%). About 15% of children had audible wheeze; for the rest, wheeze was only heard on auscultation.
On ITT analysis, placebo was inferior to amoxicillin: 24% of children in the placebo and 19.9% in the amoxicillin groups failed treatment (difference 4.2%, 95% CI 0.2 to 8.2). There was no difference in the rates of relapse. Clinical failure due to the development of severe or very severe pneumonia or hypoxaemia was similar between groups.
Evidence from observational studies and indirect evidence Hazir et al (2004) showed that 62% of 1004 children presenting with non-severe pneumonia and wheeze responded to bronchodilators. Among responders, only 15% showed clinical deterioration at follow-up. Predictors of deterioration were: fever > 38 C (OR 6.61, 95% CI 2.73 to 16.11); history of fever (OR 2.11, 95% CI 1.44 to 3.03); or age 1-11 months (OR 1.83, 95% CI 1.26 to 2.66).
A prospective observational study of children presenting with fast breathing or lower chest indrawing and wheeze  followed-up with children fulfilling the WHO criteria for non-severe pneumonia and wheeze responsive to bronchodilator. Of 263 children with non-severe pneumonia and wheeze, 85% responded to bronchodilators and were discharged on oral salbutamol but no antibiotics. On follow-up, symptoms had resolved in 96% of children by day 3, and in 97% by days 5-7. The only independent predictor of clinical deterioration was age 1-11 months. On a separate analysis, the following factors predicted non-response to bronchodilators in children presenting with WHO-defined non-severe or severe pneumonia and wheeze: age 12-59 months; history of fever; no family history of wheeze; fever > 38.0 C; and presence of lower chest indrawing. Kabir et al (2009) conducted a non-blinded, randomized multi-centre trial of antibiotics for bronchiolitis in Bangladesh. Children aged <24 months with runny nose, cough, breathing difficulty, chest indrawing, and rhonchi on auscultation were enrolled and allocated to one of three groups: ampicillin (7 days); oral erythromycin (7 days); or no antibiotics. All children received nebulized salbutamol, oxygen (if SpO 2 < 90%), IV fluids, nasogastric feeding, and oropharyngeal suction. The study recruited 327 children; 10% dropped out. Baseline characteristics were similar across groups. There were no significant differences in clinical improvement between groups. Children in the no-antibiotic group had a significantly shorter duration of hospital stay than the antibiotic groups (p<0.001). For all children, most breathing or chest symptoms (i.e. cough, breathing difficulty, wheeze, chest indrawing, tachypnoea, tachycardia, rhonchi, and crepitations) gradually improved after day 4. Cardoso et al (2010) studied the ability of WHO criteria to identify pneumonia among children presenting with wheeze. Children 2-59 months presenting to the paediatric emergency department of five hospitals in Brazil with acute lower respiratory tract infections (LRTI) were prospectively recruited. Diagnoses were further subclassified as pneumonia, acute bronchitis, acute bronchiolitis, wheezing, and recurrent wheezing. All diagnoses where made by three physicians, blinded to each others' diagnoses: the admitting paediatrician; a chest physician; and a radiologist. Chest X-rays were taken for all cases of suspected pneumonia and bronchiolitis. Where a chest X-ray was done, the final diagnosis required the agreement of at least two of the three physicians.
Data for 390 children were analyzed. Chest X-rays were performed for 153 of these children. Diagnoses were acute bronchitis in 28 (7%) children, acute bronchiolitis in 7 (2%), wheezing in 117 (30%), recurrent wheezing in 168 (43%) and pneumonia in 70 (18%; 15 of whom also had recurrent wheezing). Agreement between the paediatricians' and the paediatric chest physicians' diagnoses was high (=0.86, 95% CI 0.82 to 0.90).
Overall, WHO criteria had a sensitivity of 84% and a specificity of 19% in predicting pneumonia. Adding fever to the WHO criteria slightly reduced the sensitivity to 81%, but improved specificity to 46%. In children with wheeze, WHO criteria had a sensitivity of 90% and a specificity of 12% for predicting pneumonia. The addition of fever reduced the sensitivity to 85%, but improved specificity to 42%. The ability of WHO criteria to predict pneumonia was much better in children without wheeze (sensitivity 76% and specificity 62%). The addition of fever to the criteria had no effect on the sensitivity and improved the specificity to 70%.
conducted a prospective cohort study in a paediatric emergency department in the USA to determine the clinical predictors of pneumonia among children with wheeze. Children (<18 years) with wheeze on examination, and who underwent a chest X-ray for evaluation of pneumonia were enrolled. Pneumonia was defined radiographically, and required the consensus of two blinded radiologists.
The study included 526 patients; 75% were less than 5 years old. A total of 26 patients had pneumonia. Eighty-one percent of patients with pneumonia had a history of fever at home, compared with 58% of patients with no pneumonia (positive LR: 1.39, 95% CI: 1.13-1.70); p < 0.02). Fifty percent of patients with pneumonia had a triage temperature of < 38.0 C, compared with only 25% of patients without pneumonia (positive LR: 2.03, 95% CI: 1.34-3.07; p < 0.01). Seventy-three percent of patients with pneumonia had a temperature of < 38.0C in the emergency department, compared with 38% of patients who did not have pneumonia (positive LR: 1.92, 95% CI: 1.48-2.49; p < 0.001). Among afebrile children (temperature of < 38 C) with wheezing, pneumonia was very uncommon (2.2%, 95% CI: 1.0-4.7).

# Benefits and risks
Rationalizing antibiotic therapy avoids the risk of side effects for the patient, and reduces the risk of antimicrobial resistance.
Withholding antibiotics from children with bacterial pneumonia.

# Acceptability and feasibility
Withholding antibiotics may be less acceptable to caregivers. Implementation of this recommendation will require training health workers to educate and council caregivers, and the need for close follow-up. Health workers will require training in auscultation.
Antibiotic treatment for non-severe pneumonia with no wheeze a) Children with non-severe pneumonia (i.e. fast breathing with no chest indrawing or danger sign) should be treated with oral amoxicillin. The exception is in patients with HIV.
-With low HIV prevalence, give amoxicillin of at least 40mg/kg/dose twice daily for 3 days. -With high HIV prevalence, give amoxicillin of at least 40mg/kg/dose twice daily for 5 days.

# (Weak recommendation, moderate quality evidence)
b) Children with non-severe pneumonia who fail on the first line treatment with amoxicillin should have the option of referral where there is no appropriate second line treatment.

# (Weak recommendation, expert opinion)
This recommendation was made based on mostly RCTs that were conducted in Asia, and more likely in low HIV prevalence settings. Amoxicillin was recommended based on values and preferences since dispersible amoxicillin is becoming more available and the cost is decreasing. The panel also clarified that the moderate quality evidence relates to comparisons of the duration of the two antibiotic regimens of amoxicillin for 3 versus 5 days which showed that they were no different in terms of cure and clinical failure rates.

# Evidence and summary of findings
Randomized trials have not shown significant differences in the effectiveness of different oral antibiotics for the treatment of non-severe pneumonia in children (see GRADE table A7.9). Amoxicillin and co-trimoxazole are the most widely available antibiotics. Amoxicillin has been shown to be more effective than co-trimoxazole for treating severe pneumonia in one trial. There is no significant difference between short duration (3 day) and long duration (5 day) antibiotic therapy for non-severe pneumonia in low HIV prevalence settings.
A systematic review  identified trials comparing different oral antibiotics and short-course (3 days) versus long-course (5 days) oral antibiotics.

# Choice of antibiotic
Three studies compared oral co-trimoxazole with oral amoxicillin. The studies involved 3952 children (2067 in the co-trimoxazole group and 1885 in the amoxicillin group) between 2 months and 59 months of age with WHO-defined non-severe pneumonia. One study  also included a subset of children with severe pneumonia. Two studies were double blinded RCTs, with adequate allocation concealment. The third study was an open-label and cluster-randomized. Primary outcomes were clinical cure and failure. Comparing amoxicillin to co-trimoxazole, pooled analysis shows no difference in clinical failure (RR 1.09, 95% CI 0.93 to 1.27; 3 studies) nor cure rate (RR 0.99, 95% CI 0.96 to 1.01; 2 studies).
One open-label RCT compared oral levofloxacin with oral co-amoxiclavulanic acid. The study involved 708 children (including 270 children < 5 years), with infiltrates on chest X-ray and at least two clinical indicators of pneumonia. There was no difference in cure rate at 10-17 days after completing treatment for children < 5 years between the two groups (RR 1.02, 95% CI 0.93 to 1.11).
Two RCTs involving 393 children compared azithromycin with co-amoxiclavulanic acid in children with chest X-ray and clinical findings of pneumonia. Treatment failure at 2 weeks was not significantly different between groups (RR 1.20, 95% CI 0.45 to 3.21).
One study from Chile of 47 children between 1 month and 14 years with X-ray and clinical signs suggestive of classical bacterial pneumonia compared oral azithromycin and oral amoxicillin. Children receiving azithromycin normalised their chest X-ray on day 7 significantly more often than those treated with amoxicillin (p<0.009). However, clinical response on days 3, 7, and 14 were not significantly different.
One open-label RCT involving 100 children aged 2 months to 12 years with nonsevere pneumonia in Nigeria compared amoxicillin with co-amoxyclavulanic acid. Cure rates were better with co-amoxiclavulanic acid (OR 10.44, 95% CI 2.85 to 38.21); however, allocation concealment was inadequate.
An open randomized multi-centre study involving 68 children aged 2-16 years with radiologically proven pneumonia compared oral azithromycin with oral erythromycin. There was no significant difference in clinical success or adverse outcomes.
Aetiology and antibiotic susceptibility  Aetiological data comes from studies of inpatients with severe pneumonia. The common bacterial pathogens are Streptococcus pneumoniae (17-37%), Haemophilus influenzae (0-31%) and Staphylococcus aureus (1-33%). Approximately 25% of community acquired pneumonia has a positive viral diagnostic test.
Given that there are limited data on the aetiology of non-severe pneumonia, antibiotics have been targeted at the pathogens known to cause severe pneumonia. There are limited data on the effect of antibiotic resistance in pneumonia. There are data showing in-vitro resistance to co-trimoxazole correlating with poor clinical outcome in acute otitis media. Although the trial by Strauss et al showed higher failure rate for children with severe pneumonia receiving co-trimoxazole as compared to amoxicillin, it is not clear whether this was due to resistance.

# Treatment duration
Four studies involving 6513 participants were identified that compared the same antibiotic for different durations (3 days versus 5 days). Two studies compared amoxicillin three times daily (30-50 mg/kg/day), and two studies compared cotrimoxazole. All were randomized, double-blinded, placebo-controlled trials. Pooled analysis found no difference in cure rates (RR 0.99, 95% CI 0.98 to 1.01, n=5892), failure rates (RR 1.07, 95% CI 0.92 to 1.25, n=5892), and relapse rate (RR 1.06, 95% CI 0.82 to 1.37, n=2753) between long-versus short-duration treatment.

# Benefits and risks
Amoxicillin and co-trimoxazole are the most widely available oral antibiotics for non-severe pneumonia. The study by Strauss et al suggests higher treatment failure in severe pneumonia with co-trimoxazole as compared to amoxicillin.
Studies of the duration of amoxicillin therapy are briefly summarized here, and have been assessed and summarized in a WHO 2003 consultative meeting report. Trials in low-HIV prevalence settings have shown equal effectiveness between short-(3 days) and long-(5 day) duration therapy. The benefits of shortterm therapy are increased compliance, lower cost, and lower exposure to potential antibiotic side effects. However, shortened courses have not been as well-studied in areas of high-HIV prevalence, where a substantially greater burden of severe bacterial pneumonia exists among persons infected with HIV. Prudence indicates that shortening treatment to a 3-day course should be studied before being implemented in such settings.

# Acceptability and feasibility
Amoxicillin and co-trimoxazole are widely available. Oral amoxicillin was preferred as first line treatment over co-trimoxazole, because it is effective against both nonsevere and severe pneumonia in low HIV settings. In high HIV settings, amoxicillin is also preferred because oral co-trimoxazole is recommended for PCP prophylaxis. Oral amoxicillin will also be recommended as first line treatment for children with severe pneumonia tolerating feeds, and this should simplify uptake.
Amoxicillin is slightly more expensive than co-trimoxazole. Cost of amoxicillin 250 mg is US $0.018 per capsule and US$ 0.022 per dispensable tablet. Cost of standard combination co-trimoxazole is US$ 0.013.
Antibiotics treatment for severe pneumonia a) Children aged 2-59 months with severe pneumonia (chest indrawing) should be treated with oral amoxicillin of at least 40mg/kg/dose twice a day for 5 days.

# (Strong recommendation, moderate quality evidence)
Although this recommendation may be applicable to case management at the community or outpatient level, its implementation should be guided by the clinical context and setting. It is not applicable in children infected with HIV/AIDS for whom clinicians should follow the current HIV specific guidelines.
b) In children infected with HIV/AIDS, specific guidelines for treatment of severe pneumonia in the context of HIV should be followed.
(Strong recommendation, low quality evidence)

# Evidence and summary of findings
A recent systematic review included five studies that compared oral with injectable antibiotics for WHO-defined severe pneumonia. Overall, there is moderate quality evidence that oral therapy with amoxicillin is an effective and safe alternative to parenteral antibiotics in low HIV settings (see GRADE tables A7.10 & A7.11). Oral amoxicillin is an effective and safe alternative to parenteral antibiotics in low HIV settings in children with severe pneumonia (chest indrawing) who do not have any other serious signs or symptoms. Campbell et al (1988) compared oral co-trimoxazole versus IM procaine penicillin followed by oral ampicillin in 134 children with non-severe or severe pneumonia. At day 7 of follow up, treatment failure occurred in 6 out of 66 patients (9.1%) in the oral co-trimoxazole group and 7 out of 68 patients (10.2%) in the combined-treatment group. The risk difference was not significant: -0.01% (95% CI -0.11 to 0.09). The study reported one death during the follow-up period in the injectable therapy group.
Straus et al (1998) included 302 children with severe pneumonia and compared oral cotrimoxazole (n=203) with oral amoxicillin (n=99). Treatment failure rates were higher in the cotrimoxazole group (33%) compared to oral amoxicillin (18%) (RR 1.79; 95% CI 1.13 to 2.84). There was no significant association between antimicrobial minimum inhibitory concentration and outcome among bacteraemic children treated with co-trimoxazole and amoxicillin.
Addo-yobo et al ( 2004) evaluated 1702 children with severe pneumonia, comparing oral amoxicillin (n = 857) versus IV penicillin (n = 845) for two days followed by oral amoxicillin. After 48 hours, treatment failure occurred in 161 out of 845 patients (19%) in the amoxicillin group and 167 out of 857 patients (19%) in the parenteral penicillin group. The risk difference was not significant: -0.4% (95% CI -4.2 to 3.3). At the end of follow up (14 days), the cumulative proportion of deaths in each group was 0.2% in oral versus 1% in parenteral, but this did not reach statistical significance (RD -0.6%, 95% CI -0.1 to 1.3). The authors reported similar recovery in both groups at 5 and 14 days.
Atkinson et al ( 2007) conducted a study in eight paediatric centres in England (general district and tertiary hospitals) and enrolled all but the most severe cases of pneumonia. Children were randomly assigned to a 7-day treatment of either oral amoxicillin (n = 100) or IV benzyl penicillin (n = 103). The primary outcome examined was time for temperature to be < 38 C for 24 continuous hours. The study found equivalence between the two treatments, with a median time of 1.3 days for the primary outcome to be achieved in both groups.
Hazir et al 2008 compared hospitalization and parenteral ampicillin four times a day for 2 days followed by 3 days oral amoxicillin with ambulatory home-treatment (n = 1025) versus oral amoxicillin twice daily for 5 days (n = 1012). The primary outcome was treatment failure measured by clinical deterioration. There were 87 (8.6%) treatment failures in the hospitalization group and 77 (7.5%) treatment failures in the ambulatory group by day 6: a non-statistically significant risk difference of 1.1%, 95% CI -1.3 to 3.5. Five (0.2%) children died within 14 days of enrolment, one in the ambulatory group and four in the hospitalized group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation.
Another RCT that compared day care versus hospital care management of pneumonia but did not compare an oral antibiotic arm with injectable antibiotics. Children 2 to 59 months of age with severe pneumonia received either day care, with injectable ceftriaxone once daily for 5 days, feeding, and supportive care (n = 180) or hospital care (n = 180) with similar 24-hour treatment. The mean  SD durations of day care and hospital care were 7.1  2.3 and 6.5 2.8 days, respectively. Primary outcome was treatment success based on SpO 2 > 95% in-room air. In the day care group, 24 (13.3%) children failed therapy, while in the hospital care group 7 (3.9%) children failed therapy (RR 3.4, 95% CI 1.5 to 7.8) with the difference in failure rate being predominantly due to hypoxaemia defined as SpO 2  95%. During the follow-up period, 22 (14.1%) children in the day care group and 11 (6.4%) children in the hospital care group required readmission to hospitals (RR 2.0, 95% CI 0.99 to 4.0). Two children died in the hospital group during the 3-month follow-up period. The estimated cost per child treated successfully at the clinic and the hospital were US$ 114 and US$ 178, respectively.

# Benefits and risks
Oral antibiotic therapy will be favorable to the health system as it will be less expensive and will lead to reduced burden on the health system. Despite concerns about reported in vitro (laboratory) resistance of pneumococcus to penicillin, there are no reports of clinical failure. Oral amoxicillin is more effective than oral cotrimoxazole for the treatment of severe pneumonia (chest indrawing).
Amoxicillin is a very safe drug. Mild adverse events like skin rash and diarrhoea may occur in a small number of children. In rare cases, penicillin-related anaphylactic reaction may.

# Acceptability and feasibility
Home treatment with a 5-day course of amoxicillin is preferable, because of the associated reduction in referral, admission, risk of nosocomial infections, and treatment costs as well as the reduced invasiveness of oral treatment when compared with parenteral treatment. Day care treatment with injectable ceftriaxone would be much more expensive than oral antibiotic treatment at home. Cost of amoxicillin 250 mg is US$ 0.018 per capsule and US$ 0.022 per dispersible tablet. Cost of injectable benzyl penicillin 1 million i.u (600 mg) is US$ 0.354 and of injectable ceftriaxone 1G is US$ 1.056, which is higher than oral amoxicillin.
It is feasible to distribute oral amoxicillin in resource-limited settings as it is available in all countries.
Antibiotics treatment for very severe pneumonia 1. Children aged 2-59 months with very 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 5 days -Gentamicin: 7.5 mg/kg IM/IV once a day for at least 5 days

# (Strong recommendation, moderate quality evidence)
- Ceftriaxone should be used as second line treatment in children with severe pneumonia with failure of the first line treatment.

# (Strong recommendation, expert opinion)
In making this recommendation, the panel noted that there is good evidence for the superiority of ampicillin and gentamicin over chloramphenicol, as well as major concerns about future supplies. However, there is poor evidence in favour of ampicillin and gentamicin as compared to other antibiotics. Although there was no data on the use of ceftriaxone, the panel recognized the need to include ceftriaxone as a second line treatment for children with very severe pneumonia, especially for hospital care.

# Evidence and summary of findings
Evidence from one systematic review that included two large, RCTs comparing betalactam and gentamicin versus chloramphenicol for very severe pneumonia shows high quality evidence that ampicillin/penicillin and gentamicin reduce clinical failure rates compared to chloramphenicol. There is moderate quality evidence for a trend towards reduced death rates for treatment with ampicillin/penicillin and gentamicin compared to chloramphenicol (see GRADE table A7.12).
The first RCT  conducted in the highlands of Papua New Guinea (1600-1800 m above sea level) included 1116 children aged 1-59 months with WHOdefined very severe pneumonia (modified to include heart failure as a danger sign). Enrolled children had a median oxygen saturation of 71%. Five hundred and fiftynine (559) children were treated with 100 mg/kg/day chloramphenicol; 557 children were treated with penicillin (200 mg/kg/day) plus gentamicin (7.5 mg/kg/day). Duration of treatment was 14 days. Measured outcomes were: death, treatment failure by day 5, and readmission. More children in the penicillin/gentamicin group required a change of antibiotic (60 versus 49), while 147 (26%) children treated with chloramphenicol and 123 (22%) treated with penicillin and gentamicin had adverse outcomes (p = 0.11, not significant). Thirty-six children treated with chloramphenicol and 29 treated with penicillin and gentamicin died (difference not significant). More children treated with chloramphenicol than penicillin and gentamicin represented with severe pneumonia within 1 month of hospital discharge (p = 0.03).
The second RCT  was a multi-country study, with 80% of children residing at sea level. Children aged 2-59 months were enrolled: 479 randomized to receive chloramphenicol (75 mg/kg/day), and 479 randomized to receive amoxicillin (200 mg/kg/day) and gentamicin (7.5 mg/kg/day). Median oxygen saturation on admission was higher than for the PNG study (88%). Duration of treatment was 10 days. More children in the chloramphenicol group required a change in antibiotic (45 versus 26). Measured outcomes were death or treatment failure by days 5, 10, and 21. More children failed treatment with chloramphenicol at day 5 (16% versus 11%; relative risk 1.43, 95% CI 1.03 to 1.97) and also by days 10 and 21. There was a trend towards reduced death rates in children treated with amoxicillin plus gentamicin, but this was not significant.

# Benefits and risks
Combination beta-lactam plus gentamicin reduces failure rates and may reduce pneumonia mortality.
Side effects/toxicity of recommended antibiotics as outlined in section 6.2 in the WHO Model Formulary for Children.

# Acceptability and feasibility
Value was placed on reduction in failure rates and likely reduction in mortality with beta-lactam and gentamicin combination. All drugs are in the Essential Medicines for Children List. Ampicillin, gentamicin and chloramphenicol are the currently recommended options for management of very severe pneumonia.
Ampicillin and gentamicin are more expensive per dose than chloramphenicol. Median price :
-Ampicillin 250 mg: US$ 0.1786/vial -Gentamicin 10mg/ml: US$ 0.0665/ml -Chloramphenicol 1 g: US$ 0.3600/vial 6.5 Salbutamol for treatment of acute wheeze/asthma and bronchoconstriction a) Children with acute wheeze/asthma and bronchoconstriction should be treated with inhaled salbutamol using a metered dose inhaler (MDI) with spacer devices to relieve bronchoconstriction.

# (Strong recommendation, low quality evidence)
b) Oral salbutamol should not be used for treatment of acute or persistent wheeze except where inhaled salbutamol is not available but has no utility in testing response to a bronchodilator.
(Strong recommendation, low quality evidence)

# Evidence and summary of findings
The panel identified a review undertaken for the Expert Committee on the Selection and Use of Essential Medicines 2008, focusing on whether oral salbutamol should remain on the WHO Paediatric Model List. The review identified five studies comparing lung function tests of asthmatics treated with oral, inhaled, or combination oral and inhaled salbutamol. Most studies showed that inhaled salbutamol was superior in improving lung function, was effective at lower doses, and therefore caused fewer side effects than oral salbutamol. However, oral salbutamol was still an effective bronchodilator and, in one study, the bronchodilatory effect of oral salbutamol lasted longer than inhaled salbutamol.
One study randomized 780 children with WHO-defined non-severe or severe pneumonia and wheeze to standard dosages of either oral (390 children) or inhaled (390 children) salbutamol. Children were sent home on antibiotics and a bronchodilator. Sixty-six children in the oral group and 62 children in the inhaled group failed treatment by day 5, but this difference did not reach statistical significance (RR 0.94, 95% CI 0.68 to 1.29) (see GRADE table A7.13).

# Benefits and risks
Oral salbutamol is inexpensive (taking into account the cost of metered-dose inhalers for inhaled salbutamol), easy to store, easy to deliver, and therefore more likely to promote compliance.
With delayed onset of action, a higher dose is required, and there is a greater likelihood of side effects. Oral salbutamol cannot be used as a 'trial of bronchodilator' (for which inhaled salbutamol should be used) as recommended by IMCI for children with wheeze and fast-breathing.

# Acceptability and feasibility
Oral salbutamol is inexpensive, much easier to prescribe and deliver than inhaled salbutamol, and is likely to be more acceptable to parents and children. However, it is an inferior mode of delivery. The emphasis should therefore be on making inhaled salbutamol and metered-dose inhalers more available globally.

# Evidence for recommendations
for treatment of dysentery b) Where local antimicrobial sensitivity is known, local guidelines should be followed.

# (Strong recommendation, low quality evidence)
The panel noted that the evidence of impact of antibiotics comes from epidemics in the 1970s where different antibiotics were used with widely varying case fatality rates, and only one randomized control trail. It was also noted that although the evidence from RCTs is specifically for management of Shigella dysentery, the guidelines refer to bloody diarrhoea as in most cases there will be no prior testing before treatment. The increasingly widespread antibiotic resistance to ampicillin, co-trimoxazole, chloramphenicol, nalidixic acid, tetracycline, gentamicin, and 1st and 2nd generation cephalosporin make them less effective for treatment. There is also reported resistance to ciprofloxacin, and hence the need for continued drug resistance surveillance.

# Evidence and summary of findings
There was low quality evidence from two systematic reviews, a recently updated Cochrane review (see GRADE table A7.14) and a WHO Children Health Epidemiology Reference Group (CHERG) review that most of the antibiotics used were effective depending on antimicrobial sensitivity patterns. The reviews confirm the current WHO recommendations and current practice as it is not possible to recommend a specific antibiotic or antibiotic group that would be universally effective due to wide variation in antimicrobial sensitivity.
The Cochrane review included all RCTs comparing the efficacy of one antibiotic to placebo, or comparing the efficacy of various antibiotics, in children as well as in adults. Many of the RCTs included in this systematic review were conducted prior to the 1990s and involved antibiotics that are no longer used because of highly resistant Shigella (i.e., cotrimoxazole, ampicillin, nalidixic acid). The review focused on outcome variables of limited interest: duration of diarrhoea and continuation of dysentery. It also includes studies conducted in developing as well as developed countries, without taking into account the type of Shigella strains responsible for the dysentery, therefore limiting the generalizability of the findings.
The CHERG review only included studies published after 1990, evaluating the efficacy of antibiotics presently recommended by WHO (i.e. ciprofloxacin, ceftriaxone, pivmecillinam, and azithromycin) and to which resistance is so far not a problem in children aged < 16 years, and conducted in middle-and low-income countries. The review was, therefore, more generalizable to the paediatric population and low-resource settings. The review also focused on three outcome variables that have a direct impact on survival:
n Clinical failure: Absence of marked improvement in, or worsening of, illness with the presence of bloody mucoid stools, more than a trace of blood in stool, abdominal pain, tenesmus and/or fever;
n Cacteriological failure: Failure to clear an enteropathogen isolated from an individual on admission to the study, by the end of the treatment period; and
n Bacteriological relapse: Reappearance of an enteropathogen in stool after the enteropathogen was cleared by treatment.
The Cochrane systematic review identified two RCTs comparing antibiotics and placebo or no drug, and 14 RCTs comparing the effectiveness of different antibiotics regimens for treatment of Shigella dysentery. The trials included a total of 1748 participants and were randomized based on clinical symptoms of dysentery, prior to bacteriological confirmation. The GRADE tables show low-to moderate quality evidence that antibiotic therapy significantly reduces the number of children with dysentery on follow-up compared to no antibiotic. The review had two primary efficacy outcomes. The first primary outcome, diarrhoea on follow-up, was reported by all but three trials ; the duration of follow-up was five days in 10 out of 13 trials. The second primary outcome, relapse, was reported by four trials [Haltalin 1973;Salam, 2010;Shanks 1999;Leibovitz 2000); the duration of follow-up for this outcome ranged from 10 to 20 days.
Limited data from one three-armed trial of people with moderately severe illness suggest that antibiotics reduce the episodes of diarrhoea at follow-up (furazolidone versus no drug RR 0.21, 95% CI 0.09 to 0.48, 73 participants; cotrimoxazole versus no drug RR 0.30, 95% CI 0.15 to 0.59, 76 participants).
The review did not find robust evidence to suggest that antibiotics of a particular class were better than those belonging to a different class. However, there were limited data from a subgroup of studies to suggest that fluoroquinolone (ciprofloxacin) was more effective than beta-lactam (ampicillin) in reducing diarrhoea among adults and that beta-lactams were more effective than fluoroquinolones in reducing diarrhoea among children with proven Shigella dysentery.
Drug resistance patterns from several trails show that at various periods of time different antibiotics have been effective against Shigella dysentery isolates in different parts of the world (Table A6.1). The antibiotics used included ampicillin, cotrimoxazole, nalidixic acid, and fluoroquinolones like ciprofloxacin, pivmecillinam, ceftriaxone, and azithromycin. Oral gentamicin was relatively ineffective, due to poor absorption when given orally, compared to nalidixic acid and therefore is not recommended. However, there is evidence of high rates of resistance of Shigella dysentery in some parts of the world to ampicillin, co-trimoxazole, chloramphenicol, and nalidixic acid.
The CHERG systematic review identifies eight studies, with some studies contributing data for multiple antibiotics or more than one outcome measure. Eight studies reported on clinical failure (12 unique data points), most of them 3 days after treatment was initiated (range 3-6 days). Four studies reported on bacteriological failure (6 unique data points) and five reported on bacteriological relapse (seven unique data points).
Results of the CHERG systematic review were as follows:
n Clinical failure: Antibiotics (ciprofloxacin, pivmecillinam, ceftriaxone, and azithromycin) reduce clinical signs of dysentery in 99.9% (95% CI 99.5-100) of cases. n Bacteriological failure: Antibiotics successfully clear dysentery pathogens from 100% (95% CI 99.9-100) of cases. n Bacteriological relapse: Antibiotics successfully prevent bacteriological relapse in 100% (95% CI 99-100) of cases.

# Benefits and risks:
Reductions in clinical and bacteriological failure, likely reduction in time to cessation of diarrhoea or bloody stools.
None of the antibiotics studied in the trials were associated with major adverse events that were drug related.

# Acceptability and feasibility:
Shigellosis can lead to life-threatening complications, including sepsis, intestinal perforation, toxic megacolon, and, in predisposed individuals, haemolytic uraemic syndrome and Reiter's syndrome. As a result, value was placed on recommending an effective antibiotic treatment. The benefits of effective antibiotic therapy outweigh the risk of side effects, and short duration of treatment (3 to 5 days) poses minimal burden to patients. Oral ciprofloxacin and ceftriaxone are the currently recommended treatment for dysentery and already on the Essential Medicines List for Children. It is therefore feasible to implement as it will not require policy change in most countries.

# Evidence for recommendations on treatment of fever conditions 8.1
Antibiotics for treatment of acute bacterial meningitis a) Children with acute bacterial meningitis should be treated empirically with 3rd generation cephalosporins.
-Ceftriaxone: 50mg/kg per dose IV every 12 hours, or 100 mg/kg once daily, or -Cefotaxime: 50mg/kg per dose 6 hourly for 10-14 days.

# (Strong recommendation, moderate quality of evidence)
b) Where it is known that there is no significant resistance to chloramphenicol and beta lactam antibiotics among bacteria-causing meningitis, follow national guidelines or choose any of the following two regimens: -Chloramphenicol: 25 mg/kg IM (or IV) every 6 hours plus ampicillin: 50 mg/ kg IM (or IV) every 6 hours. OR -Chloramphenicol: 25 mg/kg IM (or IV) every 6 hours plus benzyl penicillin: 60 mg/kg (100 000 units/kg) every 6 hours IM (or IV).

# (Conditional recommendation, moderate quality evidence)
The panel noted that, based on data from developed countries, most international guide lines recommended treatment for at least 10 days for bacterial meningitis patients with no adverse or poor prognostic factors. However, data from recent multicentre study conducted in five developing countries showed that in children beyond the neonatal age with purulent meningitis caused by Staphylococcus pneumoniae, Haemophilus influenzae, Type b, or Nesiria meningitidis who are stable by day 5 of ceftriaxone treatment, could safely discontinue antibiotics. However, the panel choose to adopt the more conservative approach pending further evidence of the safety of shortened duration treatment. The panel also raised concern about the possibility of overuse of ceftriaxone if there is a loose definition of "suspected meningitis", hence the need for promoting use of a lumbar puncture in suspected meningitis before commencing treatment.
It was also noted that the use of steroids is not effective in developing countries most likely due to late presentation.

# Evidence and summary of findings
The panel identified one Cochrane review comparing 3rd generation cephalosporin with standard chloramphenicol-based regimes for bacterial meningitis in children. The review involved 19 RCTs with 1496 patients comparing 3rd generation cephalosporins (ceftriaxone or cefotaxime) with conventional antibiotics (penicillin/ampicillin-chloramphenicol combination, or chloramphenicol alone) as empirical therapy for treating acute bacterial meningitis. The primary outcomes evaluated were death, severe sensorineural deafness, and other disabling sequelae.
The evidence used for making this recommendation was of moderate quality showing no differences in efficacy and safety between conventional antibiotics and cephalosporins in the initial treatment of acute bacterial meningitis (see GRADE table A7.15). However, there was increasing evidence from several sensitivity studies that bacteria which cause meningitis are more likely to be resistant to conventional antibiotics leading to increased mortality and morbidity. Early appropriate treatment with 3rd generation cephalosporins may improve patient outcomes since the choice of antibiotic is often made without knowledge of drug resistance.
The systematic review of 3rd generation cephalosporins versus chloramphenicolbased regimens show that there is moderate quality evidence of no difference between chloramphenicol-based regimens and 3rd generation cephalosporins in terms of mortality or rates of treatment failure. There is low quality evidence of a decreased risk of culture positivity for treatment with ceftriaxone compared to chloramphenicol-based regimens.
Overall, there were no statistically significant differences in the risk of death 52 (6.9%) of 750 in the cephalosporin group versus 50 (6.7%) of 746 in the conventional group (RD -0%; 95% CI -3% to +2%), risk of sensorineural deafness 21 (8.5%] of 247 in the cephalosporin group versus 30 (11.8%) of 254 in the conventional group (RD -4%; 95% CI -9% to +1%), and risk of treatment failure 63 (8.4%) of 750 in the cephalosporin group versus 65 (8.7%) of 746 in the conventional group (RD -1%; 95% CI -4% to +2%). There was a statistically significant difference in cerebrospinal fluid culture positivity 10-48 hours after the start of treatment favouring cephalosporins -14 (6.1%) of 228 in the cephalosporin group versus 25 (11.7%) of 214 in the conventional group (RD -6%; 95% CI, -11% to -0%). (See GRADE table 15).
Subgroup analysis of 10 of the 19 trials included from developing country settings showed no statistical difference in the primary outcomes: risk of death 37 (9.0%) of 409 in the cephalosporin group versus 36 (9.4%) of 382 in the conventional group (RD -1%; 95% CI -5% to +3%), risk of sensorineural deafness two (3.6%) of 55 in the cephalosporin group versus three (4.5%) of 66 in the conventional group (RD -1%; 95% CI -9% to +8%), and risk of treatment failure 39 (9.5%) of 409 in the cephalosporin group versus 39 (10.2%) of 382 in the conventional group (RD -1%; 95% CI -5% to +3%).

# Treatment duration
A review of five RCTs involved children (3 weeks to 16 years) of short-(4-7 days) versus long-course (7-14) duration of ceftriaxone for meningitis OR 1.24, 95% CI 0.73 to 2.11); longterm neurological complications (five RCTs, 367 patients, FEM, OR 0.60, 95% CI 0.29 to 1.27); long-term hearing impairment (four RCTs, 241 patients, FEM, OR 0.59, 95% CI 0.28 to 1.23); total adverse events (two RCTs, 122 patients, FEM, OR 1.29, 95% CI 0.57 to 2.91); or secondary nosocomial infections (two RCTs, 139 patients, random effects model, OR 0.45, 95% CI 0.05 to 3.71). In two RCTs where hospital stay was not determined by protocol, the duration of hospitalisation was significantly shorter in the short-course treatment arms, (137 patients, FEM, WMD 22.17 days, 95% CI 23.85 to 20.50).
There is low quality evidence that for patients with no adverse prognostic factors (i.e. delayed presentation, severe illness, persistent CSF culture), short course (4-7 days) is equivalent to long course (7-14 days) ceftriaxone for rates of clinical success and neurological sequelae, and reduces duration of hospital stay (see GRADE table A7.16).

# Antimicrobial resistance
There is a reported, increasing trend in the proportion of H. influenzae, S. pneumoniae and N. meningitidis showing resistance to penicillin and chloramphenicol. Thus, use of conventional antibiotics may be associated with higher mortality and morbidity. Penicillin-resistant pneumococcal meningitis has been shown to have poor response to treatment with chloramphenicol. The list below shows reported chloramphenicol resistance:
n Pneumococcal resistance to chloramphenicol :
-6.4% USA -4.8% Latin America -10% Europe -15.8% Asia Pacific n Chloramphenicol resistance in children with meningitis:
-11-14% in Nigeria  -13% in Ethiopia  -17% in Malawi  -5.6% of all meningitis, and 20% of haemophilus meningitis in PNG

# Benefits and risks
Although there is no difference between cephalosporins and conventional antibiotics in the clinical outcomes, cephalosporins provide an advantage because of the reduced culture positivity after 10 to 48 hours, currently low levels of resistance, and only once daily required dosing. Single daily dosing of ceftriaxone is a significant advantage over the 6-hourly injections of the standard chloramphenicol/beta-lactam combination. Use of cephalosporins as initial therapy would be of benefit in situations where antimicrobial resistance is not known in the context of increasing resistance to avoid high mortality.
There is substantial evidence to suggest that an increasing proportion of H. influenzae and S. pneumoniae isolated from meningitis cases are resistant to ampicillin and chloramphenicol. Since these are the common causes of acute bacterial meningitis, their use as an empirical treatment may lead to poor clinical outcomes.
Cephalosporins were associated with short-term diarrhoea.

# Acceptability and feasibility
Single daily dosing of ceftriaxone has significant advantage over the multiple, daily injections that require more staff time and inconvenience children and care givers. Single daily dosing recommendation is much simpler than the current recommendation and may be preferred by clinicians and nurses.
The reduced frequency of administration of ceftriaxone, along with the reduced time burden on staff, offsets its cost. The cost of cephalosporins will decrease with the increasing availability of generics. Median prices :
n Chloramphenicol 1 g: US$ 0.4372/vial n Ampicillin 250 mg: US$ 0.1786/vial n Benzyl penicillin 600 mg: US$ 0.0864/vial n Ceftriaxone 250 mg: US$ 0.4395/vial
Antibiotic treatment for Acute Otitis Media (AOM) a) Children with acute otitis media (AOM) should be treated with oral amoxicillin 40 mg/kg twice per day for 7-10 days. OR b) Where pathogens causing acute otitis media are known to be sensitive to cotrimoxazole, this antibiotic could be used as an alternative given twice per day for 7-10 days.

# (Strong recommendation, low quality evidence)
The panel noted that there was a lack of RCTs addressing the treatment of AOM from developing countries as most studies had been conducted in developed countries.
In addition, it was noted that poor performance of diagnostic criteria makes interpretation of AOM studies difficult as has been reported in a recent systematic review. The choice of amoxicillin was not entirely based on the evidence from the data reviewed in the RCTs, but also on the consideration of aetiological causes of AOM and data on antibiotic resistance. It was also found much more feasible and easy to implement by keeping the same first line antibiotic recommendation for treatment of AOM and non-severe pneumonia.

# Evidence and summary of findings
There were no placebo-controlled trials from developing countries.
A Cochrane review (updated 2010) assessed 10 placebo controlled trials of oral antibiotics conducted in developed countries with a total of 2928 children ranging in age from infancy to 15 years. Enrolment in the trials was based on clinical diagnosis, and primary outcomes included reported pain and health professional-determined clinical cure. The antibiotics used were mostly beta-lactams, although macrolides and sulphonamides were also studied (see GRADE table A7.17).
There is low-moderate quality evidence from the review for the equivalence of a range of antibiotics, although the studies that were included were small, and the outcomeused, clinical response is likely to overestimate the effect of ineffective antibiotics because of a high rate of spontaneous recovery (see GRADE table A7.18).
Combined results of the trials showed that pain was not reduced at 24 hours from the start of treatment but it was reduced at 2 to 7 days, (RR 0.72; 95% CI 0.62 to 0.83). Compared with delayed treatment, immediate antibiotic treatment was associated with decreased ear pain at day four (RR 0.77; 95% CI 0.50 to 1.17). In the four trials that measured tympanometry, there was no clinically or statistically significant difference in tympanometry results at 1 or 3 months after the acute episode, suggesting no effects on hearing. The review also found that antibiotics appeared to reduce the development of contralateral otitis, although the difference was not statistically significant. Individual patient data meta-analysis of a subset of the included trials found antibiotics to be most beneficial in children aged less than 2 years or those with bilateral AOM and otorrhoea.
There are too few complications to be able to compare these across groups (eg. one child out of 2928 children had mastoiditis). In applying these results to developing countries with a higher frequent risk of more serious complications like mastoiditis, antibiotic treatment would be strongly advised.
A meta-analysis of 1643 children from six trials aged 6 months to 12 years looked at the effect of antibiotics on an extended episode of AOM lasting 3-7 days. Randomized placebo-controlled trials were included. Three of the six trials were included in the Cochrane review. The relative risk of an extended course of AOM at 3-7 days with antibiotics was 0.83 (95% CI 0.78-0.89), for fever was 0.95 (95% CI 0.92-98), and for pain was 0.86 (95% CI 0.81-0.91). A significant reduction in pain, fever, or both was noted in the treatment arm for those less than 2 years of age with bilateral disease (55% versus 30%; RD -25; 95% CI -36,-15) with a NNT of 4 and those with otorrhoea (60% versus 24%; RD -36; 95% CI -53,-19; NNT 3).
In another systematic review, short-term clinical success was higher for immediate use of ampicillin or amoxicillin versus placebo respectively (73% versus 60%; pooled rate difference, 12%; 95% CI 5%-18%; pooled rate difference, 12%; 95% CI 5%-18%]; NNT, 9, 95% CI, 6-20).
Resistance profiles of pathogens causing AOM are variable across studies, but show a high level of co-trimoxazole resistance (28-45%), although data are only from two countries (Israel and Costa Rica) (see table A6.2). Resistance to penicillins is lower (2-29%). Amoxicillin is preferred over co-trimoxazole because of its lower rates of in-vitro resistance, and because it is the first line outpatient antibiotic for non-severe pneumonia, and may therefore be more accessible.

# Short versus long course treatment
Thirty-five trials primarily conducted in developed countries (11 in Europe, 10 each in North America and Asia, and four were multi-centre from different continents) were evaluated. The duration of antibiotic use in the long course arm was 10 days in 33 analytic components, 7-14 days in two analytic components, seven days in two analytic components, and five days in one analytic component. Of the 35 trials, three used short-acting oral antibiotics, 21 used azithromycin, and 11 used parenteral ceftriaxone in the short course arm.
There was no evidence of an increased risk of treatment failure with a shorter course of antibiotics ( 3 days). The overall relative risk for treatment failure with a short course of antibiotics in comparison to a longer course was 1.06 (95% CI 0.95 to 1.17, P=0.298; test for heterogeneity: Cochran Q=37.02, I2=0.1%, P=0.468). Use of a short acting oral antibiotic in the short course arm was associated with a significantly increased risk of treatment failure (2.27, 95% CI 1.04 to 4.99). The slightly increased risk of treatment failure with parenteral ceftriaxone (1.13, 95% CI 0.99 to 1.30) was not statistically significant; however, the lower limit of confidence interval was close to 1. There is very low quality evidence for the equivalence of short-course ( 3 days) versus-long course (> 3 days) antibiotics  (see Grade table A7.19).
Limited data did not suggest that a short course of antibiotics resulted in an increased risk of: (i) treatment failure in culture positive cases or in high-risk groups (children below two years of age, perforated eardrum, recurrent otitis media, and specific bacterial pathogens), (ii) bacteriologic failure, (iii) relapse, (iv) recurrence, or (v) persistent middle ear effusion.

# Benefits and risks
There is no evidence for the safety of not giving antibiotics for AOM in settings where the prevalence of AOM and its complications are high. The benefits of antibiotic treatment for AOM are: n reduced pain in acute ear infection; n reduced risk of acute, serious complications; n possible reduced risk of long-term sequelae, including chronic suppurative otitis media (CSOM) and mastoiditis.
In developing countries where there could be a high rate of serious acute complications, such as mastoiditis, and where short-term and long-term complications of untreated AOM can lead to death or severe disability, antibiotic use is beneficial.
In a Cochrane review, use of antibiotics resulted in a 37% (95% CI 0.05 to 0.67) relative increase in risk of adverse events: 16% (110 out of 690) of children treated with antibiotics versus 11% (83 out of 711) of children treated with placebo experienced vomiting, diarrhoea, or rash. Others have reported antibiotics to cause adverse effects in 4% to 10% of children.

# Acceptability and feasibility
Until there is more direct evidence specifically addressing the effectiveness of antibiotics in children with AOM in developing countries, and the safety of withholding them, it would not be safe to withhold antibiotics. There is a high incidence of possible complications; the 'watch and wait' approach of not giving antibiotics and observation is limited in developing countries by poor systems for follow-up, poor access to health facilities, and resource limitations. Implementation of this recommendation exists based on the fact that it is feasible to distribute oral amoxicillin in resource-limited settings as it is available in tablet and suspension form in all countries. Oral amoxicillin is the recommended treatment for non-severe pneumonia, and should therefore be widely accessible.
Antibiotic treatment for Chronic Suppurative Otitis Media (CSOM)
a) Children with chronic suppurative otitis media (CSOM) should, in addition to aural toilet by dry wicking, be treated with instillation of drops containing quinolones (such as ciprofloxacin, norfloxacin, ofloxacin) three times daily for two weeks.

# (Strong recommendation, low quality evidence)
b) Children who fail to respond to treatment should be referred for further evaluation for other causes of CSOM, especially tuberculosis.

# (Strong recommendation, expert opinion)
The duration of treatment was not clear from studies and depended on clinical circumstances, therefore the panel could not make a definitive recommendation on the duration of treatment. It was noted that the price of ciprofloxacin varies widely across different countries, and in some settings it may not be the cheapest fluoroquinolone and therefore necessitates the recommendation of any of the other available alternative fluoroquinolones.

# Evidence and summary of findings
Two systematic reviews of antibiotic therapy for CSOM in children were identified: one compared topical versus systemic antibiotics and the other compared the effec-tiveness of various topical antibiotics. There is low-moderate quality evidence that topical quinolones are better than topical non-quinolones at reducing discharge at 2-3 weeks, but there was no significant difference in discharge at 1 week (see GRADE A7.20).
There was moderate quality evidence that improvement in hearing thresholds is better with topical quinolone when compared to topical antiseptics or no treatment. The review of topical antibiotics included 14 trials (1724 ears). Study quality was lowmoderate and definitions of CSOM varied, with some studies including children with otitis externa and mastoid cavity infections. There is moderate quality evidence that topical quinolone antibiotics were better than no treatment in preventing the persistence of discharge at 1 week (RR 0.83, 95% CI 0.76 to 0.89) (see GRADE table A7.21). One study in Malawi  compared hearing thresholds for children treated with ciprofloxacin versus boric acid and showed a difference in mean 59 improvement of 2.17db (95% CI 0.09 to 4.24) at 2 weeks, and 3.43 (95% CI 1.34 to 5.52) at 4 weeks in favour of ciprofloxacin.
The review of systemic versus topical antibiotics included 8 trials (474 participants). The definition of CSOM varied between studies. Study quality ranged from very low to moderate, with most studies having inadequate allocation concealment and no blinding. There was moderate quality evidence for higher rates of treatment failure with systemic antibiotics compared to topical quinolone antibiotics. There was no significant difference in treatment failure between systemic non-quinolone and topical non-quinolones antibiotics (very low quality evidence), or systemic antibiotics and topical antiseptics (moderate quality evidence) (see GRADE table 22).

# Benefits and risks
Topical quinolone antibiotics reduce persistent discharge, hearing thresholds improve.
Local discomfort, opportunistic fungal infection..

# Acceptability and feasibility

# Topical antiseptics for treatment of Chronic Suppurative Otitis Media (CSOM)
Topical antiseptics and steroids should not be used for the treatment of chronic suppurative otitis media (CSOM) in children.

# (Strong recommendation, low quality evidence)

# EVIDENCE FOR RECOMMENDATIONS ON TREATMENT OF FEVER CONDITIONS
There was no evidence to support the use of topical antiseptics and steroids in the treatment of CSOM in children.

# Evidence and summary of findings
One systematic review identified two RCTs that included arms which compared the effectiveness of topical antiseptics versus no treatment or placebo.
There was low quality evidence that there is no statistically significant difference in the rates of treatment failure between topical antiseptic and placebo or no treatment (see GRADE table A7.23). However, both studies were underpowered and had some methodological flaws.
In the first RCT, 60 children with otorrhoea in a hospital clinic in South Africa compared aluminium acetate solutions of varying concentrations (13.00%, 3.25%, and 1.30%). The most dilute solution was considered to be inactive. The RCT found no significant difference in dry ears after 2 weeks (21 out of 26 patients (81% of ears) with 13.00% aluminium acetate versus 15 out of 20 patients (75%) with 3.25% aluminium acetate versus 5 out of 10 patients (50%) with 1.30% aluminium acetate; p = 0.18). However, this study may have lacked power to detect a clinically significant difference.
The second RCT included 134 children (180 ears) and compared five interventions: ear cleansing alone, ear cleansing plus topical antiseptic, ear cleansing plus topical antiseptic plus topical antibiotics plus corticosteroid, ear cleansing plus topical antiseptic plus topical antibiotics plus corticosteroid plus oral antibiotic (clindamycin), and no treatment. It found no significant difference between ear cleansing plus topical antiseptic (boric acid 2%) 4 times daily and ear cleansing alone in the proportion of children with no change in otoscopic appearance after 6 weeks (43 children, 58 ears: 12 out of 32  with topical antiseptic versus 13 out of 26  with ear cleansing alone; OR 0.61, 95% CI 0.22 to 1.71).

# Benefits and risks
The studies show that there is no added value in using topical antiseptics as they do not reduce ear discharge compared to placebo. Therefore, they do not have a benefit in treating CSOM.
The two RCTs gave no information on adverse effects where topical antiseptics were used compared to placebo. However, in one systematic review of topical antiseptics versus topical antibiotics, there was increased adverse events (e.g. ear pain, irritation, and bleeding on ear mopping combined; 30 out of 206  with boric acid versus 17 out of 210  with ciprofloxacin; Absolute Risk 6.5%, 95% CI 0.3% to 12.7%). One study also reported cochlear and vestibular otototoxity at high doses.
There is also a risk of delaying effective treatment, especially in children infected with HIV, who may have tuberculosis as the cause of CSOM.

# Acceptability and feasibility
Although this has been previously recommended, the use of topical antiseptics has not been widespread due to limited availability. The current evidence does not justify the cost or the potential discomfort associated with the use of topical antiseptics; as a result, they will be less accepted by clinicians. Antibiotics would be much preferred to the use of topical antiseptics.
Topical antiseptics are not currently part of the WHO Essential Medicines List for Children (WHO, 2010).

# Topical steroids for treatment of Chronic Suppurative Otitis Media (CSOM)
Topical steroids should not be used in treating chronic suppurative otitis media (CSOM).

# (Weak recommendation, very low quality evidence)

# Evidence and summary of findings
A PubMed search was conducted using the terms 'chronic suppurative otitis media' and 'steroids'. Forty-five results were retrieved; there was only one relevant study from Malaysia. The most recent review the panel could find was from 2006 and this concluded that there had been no formal evaluations of the role of topical steroids up to that point. The 2004 WHO report on Chronic Suppurative Otitis Media  was also consulted to cross-check results and identify indirect evidence.
Overall, the only study identified that directly evaluated the role of steroids in CSOM shows no difference in outcomes between two groups treated with antibiotics with steroids and antibiotics without steroids. Indirect evidence suggests that steroids may have a role in improving the efficacy of topical quinolones and reducing the toxicity of amingoglycosides. However, there is currently insufficient evidence to support their use in the treatment of children with CSOM. Indudharan (2005) conducted a non-blinded, quasi-randomized trial in Malaysia to assess the role of topical steroids in the management of CSOM with perforation. Subjects with specialist-diagnosed CSOM with perforation (no diagnostic criteria provided), but no complications, were enrolled. The external ear of these patients were cleaned with antiseptic and dried. The middle ear was then cleaned by suction.
Consecutive subjects were alternately divided into two groups to receive either 0.3% gentamicin or 0.3% gentamicin with 0.1% betamethasone combination drops. Treatment was continued for 3 weeks, with follow-up at the end of week 4. Middle ear swabs and pure-tone audiogram were performed pre-and post-treatment. Outcomes were clinical and bacteriological improvement. Clinical improvement was defined as a dry ear on follow-up. Bacteriological improvement was defined as failure to isolate organisms on post-treatment middle-ear swab.
A total of 135 patients (152 ears) aged 2-84 years were enrolled: 77 ears were treated with gentamicin and 75 with gentamicin-betamethasone. Only 70% of patients in both groups were followed-up, but attrition was similar in both groups. Bacteria were isolated from 83% of pre-treatment middle-ear swabs. The most common organisms were Pseudomonas aeruginosa (34%) and Staphylococcal aureus (17%).
Comparing the gentamicin and the gentamicin-betamethasone groups, there was no statistical difference in clinical improvement (87.7% versus 86.5%, p > 0.05) nor bacteriological improvement (82.5% versus 75%, p > 0.05). Bone and air conduction were not statistically different between groups, and no complications attributable to the treatment regimens.
Effect of topical steroid in acute otitis media with otorrhoea through a tympanostomy tube Roland (2003) was a multicentre trial that compared the effectiveness of ciprofloxacin 0.3%/dexamethasone 0.1% with ciprofloxacin 0.3% in resolving acute tympanostomy tube otorrhoea. Children aged 6 months to 2 years with acute otitis media (AOM) with tympanostomy tubes (AOMT) of less than or equal to 3 weeks' duration and visible otorrhoea were randomized to either group. Clinical signs and symptoms of AOMT were evaluated on days 1 (baseline), 3, 8 (end-of-therapy), and 14 (test-ofcure), and twice-daily assessments of otorrhoea were recorded in patient diaries.
One hundred and sixty-seven (167) children had a positive culture. For these children, the mean time to cessation of otorrhoea were significantly shorter (4.22 versus 5.31 days; p =.004). The clinical responses on days 3 and 8 were significantly better (p <.0001 and p =.0499, respectively) with topical ciprofloxacin/dexamethasone than with ciprofloxacin alone. There were no significant differences between the two treatment groups in either the clinical response or the microbial eradication rate by day 14.

# Indirect evidence
A number of in-vitro studies have suggested a protective role of topical steroids on reducing the toxicity of topical antibiotics. Park (2004) demonstrated in-vitro that the toxicity of gentamicin to rodent-isolated outer cochlear cells was reduced with the addition of dexamethasone. Himeno (2002) showed that intra-cochlear administration of dexamethasone attenuated aminoglycoside toxicity in the guinea pig.

# Benefits and risks
No data on benefits or risks of using topical steroids are available. The addition of steroids to other topical medications did not seem to provide any additional benefit. There is a possible risk of exaggerating fungal overgrowth that is reported when using topical antibiotics.

# Acceptability and feasibility
This has no additional value and use will increase the cost of treatment.
Antibiotic treatment for Typhoid Fever a) Children with typhoid fever should be treated with a fluoroquinolone (i.e. ciprofloxacin, gatifloxacin, ofloxacin, and perfloxacin) as a first line treatment for 7-10 days.
-Ciprofloxacin: orally 15 mg/kg per dose twice daily for 7-10 days.
(Strong recommendation; moderate quality evidence)
b) If the response to treatment is poor, consider drug-resistant typhoid and treat with a second line antibiotic like 3rd generation cephalosporins or azithromycin.
-Cetriaxone IV: 80 mg/kg per day for 5-7 days OR -Azithromycin: 20 mg/kg per day for 5-7 days (Strong recommendation, moderate quality evidence) c) Where drug resistance to antibiotics among salmonella isolates is known, follow the national guidelines according to local susceptibility data.

# (Strong recommendation, moderate quality evidence)
The panel noted that patterns of antimicrobial resistance to salmonella isolates are constantly changing, making continuous surveillance of resistance levels critical for clinicians to keep abreast of treatment options. Currently, nalidixic acid resistance is very common and widespread across many countries and there is increasing resistance to ciprofloxacin. This trend in antibiotic resistance to fluoroquinolones may have implications on the effectiveness of ciprofloxacin in some countries, which may require use of alternative fluoroquinolone determined by local susceptibility data.
It was also noted that the duration of treatment varied from 7 to15 days in the RCTs studies that were reviewed making it difficult to draw a conclusive decision about duration. However, it was clear that treatment required at least  7 days of first line antibiotics.

# Evidence and summary of findings
First line antibiotics, including beta-lactams and chloramphenicol, have gradually become less useful with increasing drug resistance. Studies of antibiotic resistance since 1989 in the Indian subcontinent and China have shown that 50-80% of all Salmonella typhi isolates were multidrug resistant (MDR). The choice of antibiotics for enteric fever has been based on studies of the prevalence of MDR Salmonella typhi and paratyphi.
A Cochrane review evaluated fluoroquinolone antibiotics for treating enteric fever in children and adults compared with other antibiotics, different fluoroquinolones, and different durations of fluoroquinolone treatment. The review included 38 trials; 22 had unclear allocation concealment and 34 did not use blinding. Only four trials exclusively included children, seven had both adults and children, and three studied outpatients. There are no conclusive data to make firm recommendations regarding the superiority of fluoroquinolones over first line antibiotics (i.e. chloramphenicol, ampicillin, amoxicillin) or cephalosporins (i.e. cefixime, ceftriaxone) in children. However, there is a general trend in favour of using fluoroquinolones as first line treatment, and either 3rd generation cephalosporins or azithromycin as second line antibiotics for enteric fever due to the rising level of resistance in many parts of the world.
In children, there was a high proportion of nalidixic acid-resistant strains; older fluoroquinolones increased clinical failures compared with azithromycin (OR 2.67, 95% CI 1.16 to 6.11; 125 participants, one trial), with no differences using newer fluoroquinolones (285 participants, one trial). Fluoroquinolones and cefixime were not statistically significantly different (82 participants, one trial).Trials comparing different durations of fluoroquinolone treatment also were not statistically significantly different (889 participants, nine trials). Norfloxacin had more clinical failures than other fluoroquinolones (417 participants, five trials).
Indirect evidence from the adults showed that there is: There was a wide range of different durations of therapy compared in several trials, and the trials for each comparison were small -mostly with small sample sizes and lacking considerably in statistical power. The review found only two trials that compared a short-course regimen (7 days or less) with a long-course regimen (more than 7 days). Clinical failure, microbiological failure, and relapse rates were low in both arms, but the data were not sufficient to make any conclusion.

# Benefits and risks
Although there was no difference in the clinical failure in patients without MDR when fluoroquinolones are compared with first line antibiotics, there was a clear benefit in favour of fluoroquinolones in fever clearance, microbiological failure, and relapse. There is also a clear benefit of using fluoroquinolones over chloramphenicol; reduced relapse rate and convalescent faecal carriage (298 patients in three studies with RR 0.17, 95% CI 0.04 to 0.70); and reduced risk of treatment failure given increasing frequency of participants with MDR.
There is now growing concern about increasing frequency of MDR strains of S. Typhi and S. Paratyphi with reduced susceptibility to first line antibiotics and old fluoroquinolones. Resistance to nalidixic acid has been used to identify these strains. There is, therefore, a risk of treatment failure, if the current first line antibiotics are used for treatment. The review identified only three instances of adverse events: severe leucopenia in the chloramphenicol group; anaphylaxis in the ceftriaxone group, and a rash in the ciprofloxacin group. Side effects/toxicity of recommended antibiotics as outlined in section 6.2, WHO Model Formulary for Children.

# Acceptability and feasibility:
Value was placed on the benefits of recommended antibiotics in hastening recovery, improving symptoms, and preventing complications of poorly treated disease. Although the current first line antibiotics may be cheap, the cost of a shorter course of ciprofloxacin may be comparable to a 14-day chloramphenicol regimen. In addition, the increasing numbers of clinical failures with the current first line treatment suggest there is a cost advantage of using more efficacious medicines in the rising levels of resistance.
Although fluoroquinolones are effective and safe, there are still unfounded concerns of ciprofloxacin safety in children that may still affect its uptake by physicians. -Benzyl penicillin: 50 000 U/kg IM/IV every 6 hours, or ampicillin 50 mg/kg IM/IV every 6 hours for 2 days, then oral amoxicillin: 15 mg/kg/dose every 8 hours for 5 days) AND -Gentamicin: 7.5 mg/kg IM/IV once daily for 7 days.

# (Weak recommendation, low quality evidence)
The recommendation was based on the current WHO definition of complicated Severe Acute Malnutrition (SAM). The panel emphasized that where a child with SAM has complications of very severe pneumonia or meningitis, treatment should be based on the specific guidelines for these conditions.
The panel had concern that the recommendation to give antibiotic to all children with SAM, even those with no complications, would apply to a substantial number of children in the Indian subcontinent. It was observed that there should be a distinction between the acute form of SAM, which is common in Africa and chronic SAM, which is common in Asia. The panel made a decision not to make a recommendation to give antibiotics in SAM with no complications, but to follow community case management recommendations for consistency.

# Evidence and summary of findings
A systematic review  identified three studies of antibiotic effectiveness in treating children with SAM. The use of broad-spectrum antibiotics in children hospitalized with SAM is supported by strong epidemiological data and low quality clinical studies. However, there is insufficient data from RCTs to determine the most effective antibiotic regimen. The role of antibiotics in home treatment of 'uncomplicated' malnutrition is not clear, and there is very low quality evidence that antibiotics may not be of benefit in this group (see GRADE table A7.27). Wilkinson et al. (1996), used a pre-post design to compare mortality rates of 300 children admitted with SAM in South Africa over two time periods: a 6-month period before introduction of a specific antibiotic protocol compared with the following 6-month period, when standardized guidelines for antibiotics and management of hypoglycemia were introduced. The recommended antibiotics were ampicillin (7 days) and gentamicin (5 days). In the pre-protocol period, there were 32 deaths in 162 admissions (case rate fatality  20%). In the post-protocol period, there were 8 deaths in 138 admissions (CFR 6%). This translates to a risk ratio of 0.25 (95% CI 0.14 to 0.62), or a 75% (95% CI 38-86%) reduction in the risk of mortality.
In a cohort of children with uncomplicated SAM treated at home, Amthor et al ( 2009) retrospectively analyzed the recovery at 12 weeks (Weight for Height > 2 Standared Deviation and no oedema) between a group treated with oral amoxicillin for 7 days (n = 514) with a group not receiving antibiotics (n = 1850). The chance of recovery was 29% (95% CI 7-46%) higher in the group not receiving antibiotics. However, the two studied populations differed, in that children in the antibiotic group were more likely to be wasted and less likely to have oedema.
In an open, randomized, controlled trial in a therapeutic feeding centre in Sudan, Dubray et al ( 2008) compared ceftriaxone (75 mg/kg/day once daily for 2 days) with oral amoxicillin (80 mg/kg/day, twice daily for 5 days) for uncomplicated malnutrition. Two hundred and thirty (230) children were randomized to the amoxillin group, and 228 to the ceftriaxone group. Randomization was adequate, with intention-to-treat analysis. There was no significant difference between the two groups in weight gain (RR 0.96, 95% CI 0.81 to 1.31), recovery rate (RR 0.94, 95% CI 0.84 to 1.05), mortality (RR 1.27, 95% CI 0.48 to 3.36) or antibiotic-related adverse events (RR 3.9, 95% CI 0.85 to 18.5). The cost of treatment with amoxicillin was significantly lower than ceftriaxone (US$ 1.60 versus US$ 0.20 for a 10 kg child).

# Indirect evidence

# Uncomplicated SAM
There are no data on the prevalence or aetiology of bacteraemia in children with 'uncomplicated malnutrition', and the role of antibiotics for 'treatment' of an occult infection is therefore not clear. SAM in children is a cause of immunosuppression. Cotrimoxazole prophylaxis reduces mortality and morbidity in children with HIV/AIDS and is currently recommended. Cotrimoxazole prophylaxis may have similar benefits in children with malnutrition given the associated immunosuppression.

# Complicated SAM
There is a high incidence of bacterial infections in children with SAM, with bacteraemia reported in 9-29% of children (seven studies), UTI in 17-31% (three studies) and pneumonia in 28%. In 162 severely malnourished children in Tanzania, 92% had at least one bacterial infection, and 49% acquired an infection during hospitalization.
Frequently isolated pathogens include pneumococcus, staph. aureus, Klebsiella, Salmonella typhi/enteritidis, E.coli and other enteric bacilli (see table A6.3). Recent studies of antibiotic resistance/sensitivity patterns show high levels of resistance to co-trimoxazole (75% and 93%, two studies) and some resistance to ampicillin and sensitivity to ciprofloxacin and ceftriaxone. Pharmacokinetic studies do not provide evidence for the need for dose or frequency adjustment for beta lactams antibiotics, gentamicin or ceftriaxone in severe malnutrition. The majority of studies of chloramphenicol suggest greater drug accumulation, and erratic oral absorption in malnourished children.

# Benefits and risks
There is significant reduction in mortality for children with complicated malnutrition. Antibiotics may be of benefit in uncomplicated malnutrition in preventing opportunistic infections or treating occult infections.
Side effects/toxicity of recommended antibiotics as outlined in section 6.2, WHO Model Formulary for Children.

# Acceptability and feasibility
Value was placed on the significant reduction in mortality with antibiotic therapy for children with complicated malnutrition. Given the increased risk of mortality associated with malnutrition, value was also placed on the likely benefits of antibiotics in uncomplicated malnutrition. All drugs are in the Essential Medicines List for Children.

# Evidence for recommendations on the oxygen use and delivery 10.1 Pulse oximetry for detection of hypoxaemia
- Pulse oximetry is recommended to determine the presence of hypoxaemia and to guide administration of oxygen therapy in all infants and children with hypoxaemia.

# (Strong recommendation, low quality evidence)
The panel noted that although there are no studies comparing arterial blood gases versus pulse oximetry in children, the meta-analysis in adults shows a very high correlation. Pulse oximetry is non-invasive, feasible to implement, and does not require any special skills. It is, therefore, more suitable for use more widely.

# Evidence and summary of findings
A systematic review of the accuracy of pulse oximetry in children was not found. A meta-analysis of 74 studies of adult subjects, published between 1976-1994, reported the correlation between pulse oximetry measurements and arterial blood gas (ABG) analysis, and investigated how a number of factors affected this relationship  (see GRADE table A7.28). The available low quality evidence shows that pulse oximetry is the best non-invasive method of detecting hypoxaemia, and should be made globally available. Subjects included in the studies were healthy adult volunteers (25.7%), respiratory patients (20.3%), cardiac and thoracic surgical patients (18.9%), critically ill patients (16.2%), and athletes (5.4%). Of 39 studies that reported sufficient data on the number of subjects and data points to calculate the correlation coefficient (r) between pulse oximetry and ABG, the weighted mean r was 0.895 (+/-0.014). This estimate did not significantly change when only higher quality studies were considered (r = 0.883). The highest correlation was in healthy volunteers (r = 0.957), and the lowest in critically ill patients (r = 0.760).
The accuracy of oximeters differed depending on the oximeter make, particularly at saturations below 70%. Finger probes were found to have a significantly higher correlation with SaO 2 than ear probes (p < 0.0001). The correlation coefficient in five studies of hypoxic subjects (SaO 2 67.6 -87.8%) was high (r = 0.938). Factors that reduced accuracy included dyshemoglobinemia, hypothermia, and skin pigmentation.

# Benefits and risks
As compared to clinical signs, pulse oximetry is: n much more accurate at detecting hypoxaemia n requires less training than detection of clinical signs As compared to blood gas analysis, pulse oximetry is: n non-invasive n faster n less expensive n requires minimal infrastructure and no laboratory facilities n less prone to erroneous measurements n allows continuous monitoring
Unlike blood gas analysis, pulse oximetry does not give an indication of ventilation (pCO 2 or pH.

# Acceptability and feasibility
Given the large global burden of hypoxaemia, the mortality benefit in detecting and treating with oxygen, and the inaccuracy and unreliability of the detection and interpretation of clinical signs, the cost of pulse oximetry is justified. Blood gas analysis is expensive for most low-resource settings, given the high level of laboratory infrastructure required, as well as the cost and difficulty in obtaining and analysing an arterial sample in a timely manner.
Oximeters are becoming more affordable. Depending on the type and make, prices can range from US$ 35-400 (digit oximeters), US$ 60-1200 (hand-held oximeters) to US$ 800-4500 (oximeters with monitor displays, which can also be used in ICU and theatre).
Several studies have shown the feasibility of implementing and sustaining oxygen systems, including pulse oximetry, in low-resource district and provincial hospitals in developing countries, including Malawi and Papua New Guinea.

# Clinical signs in detection of hypoxaemia in children
a) Use pulse oximetry wherever possible is recommended for the detection of hypoxaemia in children with severe lower respiratory infections. If oximetry is not available then the following clinical signs could be used to guide the need for oxygen therapy: -central cyanosis -nasal flaring -inability to drink or feed (where this is due to respiratory distress) -grunting with every breath -depressed mental state (drowsy, lethargic)

# (Strong recommendation, low quality evidence)
b) In some situations and depending on the overall clinical condition, children with the following less-specific signs may also need oxygen:
-severe lower chest wall indrawing -respiratory rate of 70/min or above -head nodding

# (Strong recommendation, very low quality evidence)
In view of the unreliability of the clinical signs in detecting hypoxaemia, the panel strongly recommended that clinical signs should not be relied upon to detect hypoxaemia. Pulse oximetry is a non-invasive procedure and relatively inexpensive.
It should be made globally available to ensure that it is part of the assessment of hypoxaemia in seriously ill children.

# Evidence and summary of findings
A systematic review of the clinical signs of hypoxaemia in children aged 2-59 months with pneumonia  identified 11 diagnostic studies (see table A6.5).
Included studies differed in inclusion criteria (radiological pneumonia, WHOdefined pneumonia, or physician diagnosis), altitude (six studies at altitude > 1500 m above sea level), and the definition of hypoxaemia (ranging from < 93% at sea level to < 85% at high altitudes). Three studies included neonates, while five did not stratify results by age. Most studies clearly described the clinical signs investigated, and all used pulse oximetry as the gold standard. The clinical signs investigated were, in order of those most studied: tachypnoea, cyanosis, grunting, crepitations, chest indrawing, difficulty feeding, nasal flaring, and altered mental status. Overall, all clinical signs tested had poor accuracy for predicting hypoxaemia. Most of the respiratory signs and symptoms have better specificity than sensitivity. However, signs with high specificity (i.e. cyanosis, grunting, difficulty feeding, altered mental status), also had poor sensitivity, and vice versa. Cyanosis, nasal flaring, grunting, mental status, or difficulty in feeding are moderately specific signs. Nasal flaring, chest indrawing, and crepitations were most sensitive.

# Benefits and risks
There were no data to assess benefits and risks.

# Acceptability and feasibility
More data on how accurately health workers can detect these signs in daily clinical practice are needed. Pulse oximetry is a much more accurate method of detecting hypoxaemia.

# Oxygen therapy in treatment of hypoxaemia
a) Children with hypoxaemia should receive appropriate oxygen therapy.

# (Strong recommendation, low quality evidence)
b) Effective oxygen delivery systems should be a universal standard of care, and should be made more widely available.

# (Strong recommendation, expert opinion)
The panel noted that although there are no RCTs on the effectiveness of oxygen use, new studies cannot be conducted as it will be unethical. The recommendation was made based on historical and ecological data of very low quality, and pre-post observational data of low quality but with large sample size.

# Evidence and summary of findings
A systematic review  found no trials comparing outcomes of children receiving oxygen versus those not receiving it. A WHO review of oxygen therapy, published in 1993, compared mortality rates for pneumonia in the pre-antibiotic era for patients who were treated prior to oxygen being standard treatment, and therefore did not receive it, and patients who did receive oxygen. Overall, there was a trend towards mortality reduction with oxygen (RR 0.79, 95% CI 0.53 to 1.18). When only patients with saturation < 80% at admission are considered, there is a significant reduction in mortality (RR 0.50, 95% CI 0.38 to 0.66).
There is low quality evidence from two pre-post observational studies in PNG comparing pneumonia mortality rates before and after the introduction of pulse oximetry and improved oxygen supplies (table A6.4). These showed a 38% reduction in pneumonia mortality (RR 0.72, 95% CI 0.60 to 0.86) (see GRADE table A7.29).

# Benefits and risks
Significant reduction in mortality for hypoxaemic patients.
No significant risk in the post-neonatal period.

# Acceptability and feasibility:
Oxygen is currently available in most hospitals, though supplies are unreliable. In hospitals with no or poor access to oxygen, studies from Malawi, the Gambia, and PNG have shown the feasibility of implementing systems for addressing this. Oxygen concentrators, machines that distil room air to produce > 95% oxygen, are becoming less expensive and cost US$ 800-1500; these can supply 2-4 patients at one time.
Thresholds for administering oxygen therapy a) Administering oxygen therapy should be guided by pulse oximetry where available and thresholds for giving oxygen vary depending on the altitude.

# (Strong recommendation, very low quality evidence)
b) Children living at  2500 m above sea level should receive oxygen therapy if their oxygen saturation is  90%, as measured by pulse oximetry.

# (Strong recommendation, very low quality evidence)
c) In children living at high altitude (> 2500 m above sea level), the normal oxygen saturation is lower than those living at sea level. At these altitudes, a lower level of saturation, such as SpO 2  87%, could be used as a threshold for giving oxygen.

# (Recommendation, very low quality evidence)
The panel strongly recommended that children with oxygen saturation < 90% should be administered oxygen therapy. At high altitudes, a lower level of SpO 2 was recommended because of resource implications by consensus. However, this recommendation excludes oxygen therapy in preterm neonates, where care needs to be taken to avoid hyperoxia-related complications.

# Evidence and summary of findings
A systematic review  could not identify any studies that have compared outcomes of children receiving oxygen at different thresholds. The evidence base for the cut-off of SpO 2 indicating the need for oxygen is weak. The normal saturation drops with increasing altitude. A threshold of 90-94% at sea level and 85-87% at high altitudes has been used in clinical studies, and is reported to be safe.
One observational study at high altitude shows increasing risk of death with lower saturations at admission, and mortality benefit using SpO 2 < 85% as threshold for giving oxygen. At sea level, there is a physiological argument to maintain oxygen saturation above 90%, because the sigmoidal shape of the oxygen dissociation curve means that for saturations below this a small drop in SaO 2 corresponds to a large drop of PaO 2. Studies of normal saturation in healthy children at sea level show that normal SpO 2 ranges from 97-100% in this population. However, using any SpO 2 below this range to indicate the need for oxygen would result in over-treatment of healthy children. Anecdotally, thresholds between 90-94% have been used in clinical practice and studies for decades.
Normal oxygen saturation drops with altitude. Figure 1 shows at an altitude of 2500 m above sea level, SpO 2 of 90% is within the normal range. Therefore, at high altitude, a lower level of SpO 2 defines hypoxaemia than at sea level, and using a universal threshold would therefore result in over-treatment of children residing in these settings. The potential drawbacks of over-treating non-hypoxaemic children with oxygen are increased rates of hospitalization, increase lengths of stay in hospital, and parental anxiety. Previous studies at high altitude have used definitions ranging from SpO 2 85-87% to account for the effect of altitude, and have not reported any adverse outcomes as a result of this.
The definition has resource implications. One observational study from PNG reports on the prevalence of hypoxaemia when it is defined at varying levels of SpO 2. Thirteen percent of children were hypoxaemic using a definition of SpO 2 < 85%; 26% using SpO 2 < 90% and 44% using SpO 2 < 93%.

# Benefits and risks
Oxygen reduces pneumonia mortality in children with hypoxaemia. Pulse oximetry is the most reliable method of detecting hypoxaemia. Having clear and simple guidelines that health workers can follow is necessary for the timely detection and treatment of hypoxaemia.
Recommending a cut-off SpO 2 of 90% and a lower level (85-87%) at high altitudes to indicate the need for oxygen: n prevents over-hospitalization n conserves oxygen in settings where it is a limited resource
Oxygen being combustible, fire hazard and tank explosion is always there. Catheters and masks used to administer oxygen may cause injury to the nose and mouth while dry and non-humidified gas can cause dryness and crusting. Hypoventilation can lead to hypercapnia and CO 2 narcosis although the risk is small with low flow oxygen therapy.

# Acceptability and feasibility
Value was placed on having clear and simple guidelines for oxygen therapy to address the large global burden of hypoxaemia. Pulse oximetry is the best method of detecting the presence or absence of hypoxaemia. The technology is affordable (oximeters range from US$ 35 for handheld devices to US$ 4500 for more sophisticated models). Studies from Malawi  and PNG  have shown that it is feasible to train health workers in criteria for initiating oxygen therapy using recommended cut-offs of SpO 2.
Oxygen therapy delivery methods a) Nasal prongs are the preferred method for delivering oxygen in infants and children under five years of age with hypoxaemia who require oxygen therapy.

# (Strong recommendation, moderate quality evidence)
b) Where nasal prongs are not available, nasal or nasopharyngeal catheters could be used as alternative delivery methods. Face masks or head-boxes are not recommended.

# (Strong recommendation, moderate quality evidence)
The panel noted that the use of face masks or head-boxes is not recommended as the preferred method because it requires higher flow rates leading to oxygen wastage.
Patients using a nasopharyngeal catheter should be closely monitored, as they are likely to develop serious complications (e.g. catheter entering the oesophagus).

# Evidence and summary of findings
A systematic review  identified four relevant studies. Overall, there is moderate quality evidence that nasal prongs and catheters are equivalent in terms of treatment failure and flow rates. There is high quality evidence for a lower risk of nasal obstruction/severe mucous production with nasal prongs compared to catheters (relative risk 0.18, 95% CI 0.08 to 0.43) (see GRADE table A7.30). There is very low quality evidence that the use of a head-box or face mask is associated with lower rates of treatment failure (RR 0.4, 95% CI 0.34 to 0.5) (see GRADE table A7.31).
However, these methods required four times higher flow rate (4 l/min) than catheters or nasal prongs.
Treatment failure was measured as the number of hypoxaemic episodes during therapy, or the time or flow required to achieve adequate SpO 2. Complications assessed were mucous production, nasal ulceration, intolerance, nasal obstruction, and abdominal distension (secondary to dislodgement).
Three studies (399 children) compared nasal prongs with nasal or nasopharyngeal catheters. There was no difference in treatment failure (RR 0.96, 95% CI 0.51 to 1.78) or mean flow rates required (standard mean difference 0.08, 95% CI -0.14 to 0.29). In one study treatment failure for nasal catheters was not significantly different to that of nasal prongs (p = 0.64). There was a significantly lower risk of nasal obstruction when prongs were used (RR 0.18, 95% CI 0.08 to 0.43), but no significant difference in nasal ulceration or discomfort.
Only one study assessed face-masks and head-box. These methods required a much higher flow (4 l/min, compared to 1 l/min for prongs and catheters). The risk of treatment failure (PaO 2  60) was significantly lower with either a head box or a facemask as compared to catheters or nasal prongs. However, this study had important limitations. It was a cross-over design, where 80 children were treated with different delivery methods sequentially, but no information was provided as to how or when children were allocated to each group.

# Benefits and risks
As compared to a face-mask or head-box, prongs and catheters are less expensive, easier to use, more available, require lower flow rates, and conserve oxygen supplies.
As compared to catheters, nasal prongs have a lower risk of nasal obstruction or excessive mucous production, are easier to apply, and do not require humidified oxygen.
Oesophageal placement of nasopharyngeal catheters, nasal ulceration, and obstruction.

# Acceptability and feasibility
Value was placed on nasal prongs being easier to apply than catheters. Both prongs and catheters are less expensive and require lower flow rates of oxygen than face-masks and head-boxes. They are, therefore, more appropriate in low-resource settings. Nasal prongs are more expensive than catheters, but can be washed and reused.

# Criteria for starting and stopping oxygen therapy
a) Children with hypoxaemia should be closely monitored using pulse oximetry.

# (Strong recommendation, very low quality evidence)
b) Oxygen therapy should be discontinued when oxygen saturation remains stable above recommended levels of 90% (2500M above sea level) or 87% (> 2500M above sea level) for at least 15 minutes on room air in a clinically stable child.

# (Strong recommendation, very low quality evidence)

# Evidence and summary of findings
A systematic review  could not identify any studies comparing outcomes for different criteria of starting and stopping oxygen therapy. There is expert opinion that where pulse oximetry is available, a safe way to ensure that a child is no longer hypoxaemic is a trial off oxygen once they are stable. Maintaining saturations above 90% on room air for 15 minutes has been used in clinical trials that employed hypoxaemia as an outcome. Studies that have implemented these criteria, combined with improvements in the detection and treatment of hypoxaemia, have demonstrated a 35-50% reduction in pneumonia mortality (Duke, 2008;Enarson 2009). Where pulse oximetry is not available, then the only indication of recovery from hypoxaemia is the absence of clinical signs of hypoxaemia.

# Benefits and risks
Clear guidelines for when to start and stop oxygen therapy are important for improving the detection and treatment of hypoxaemia.

# Acceptability and feasibility
Pulse oximetry is a non-invasive method and the best method of detecting the presence or absence of hypoxaemia which is easily acceptable by patients. The technology is affordable (oximetres range from US$ 35 for handheld devices to US$ 4500 for more sophisticated models), and numerous studies have shown it to be adaptable and sustainable in low-resource settings.

# Evidence for Recommendations for Treatment of Hypoglycaemia

# Sublingual administration of sugar in treatment of hypoglycaemia
Sublingual sugar may be used as an immediate first aid measure in managing hypoglycaemia in children in situations where intravenous administration of glucose may be impossible or delayed.

# (Strong recommendation, low quality evidence)
This recommendation places value on ease of use, low cost, and high availability in the absence of any serious risk, although the evidence is of low quality.

# Evidence and summary of findings
The panel identified two randomized controlled trials (RCTs) from Burkina Faso and Mali, cited in a recent review of the management of hypoglycaemia. Barennes et al (2005) conducted an open-label, quazi-randomized trial of intravenous glucose, sublingual sugar, and oral sugar in Burkina Faso. Children aged 6 months to 15 years presenting to the outpatient department were eligible if: 1) they had symptoms and signs of either acute respiratory infection (excluding pneumonia) or malaria; 2) the caregiver agreed to attend an appointment the next morning; and 3) they had a blood glucose level between 3.3 to 5 mmol/l.
The study screened 156 children; 87 were excluded, including 19 children initially assigned to the sublingual group, who swallowed the sugar within the first 10 minutes. Sixty-nine were randomized to one of five groups: 1) half a tablespoon of water (n = 11); 2) IV glucose (8 mL of 30% dextrose administered in a single bolus); 3) oral glucose (2.5 g sugar); 4) single dose sublingual group (2.5 g of wet sugar under the tongue); or 5) double dose sublingual group. The main outcome was treatment failure: the proportion of children who did not reach blood glucose >5.6 during the study period.
Baseline characteristics were similar across groups. There were no treatment failures in the sublingual or intravenous groups, compared with 8 (53%) and 9 (81.8%) in the oral and water groups respectively (p  5.6 was 28.5 (10.6) minutes and 25.7 (9.5) for the sublingual and intravenous groups, respectively. Graz et al (2008) was an open-RCT of intravenous versus sublingual sugar in children with severe malaria and hypoglycaemia in Mali. Children were eligible if they had: 1) WHO-defined severe malaria; 2) seizures, or an altered/impaired state of consciousness; and 3) hypoglycaemia (blood gluocose < 3.3 mmol/L).
Twenty-six children were randomly allocated to receive sublingual sugar (a teaspoon  of moistened sugar; n = 14) or intravenous sugar (5 ml/kg 10% glucose; n = 12). Sublingual administration was repeated every 20 minutes for 2 hours. Primary outcome was treatment response rate: reaching a blood glucose > 3.3 mmol/L during the first 40 minutes. Secondary outcomes included relapse rate and treatment delay.
The only difference in baseline characteristics was a trend towards more children with coma in the intravenous group (p = 0.06). There was no significant difference in the treatment response rate (71% in sublingual and 67% in intravenous, p = 0.81). However, there was a trend towards more relapses in the sublingual group (30% versus 17%, p=0.55). Treatment delay was longer for the intravenous group (18.9 minutes versus 5 minutes), and due to this, the increase in blood glucose from time of diagnosis of hypoglycaemia was faster in the sublingual group.
Complications: two children in the sublingual group swallowed the sugar, and failed to reach normo-glycaemia by 40 minutes. According to study protocol, they were switched to intravenous delivery. In the intravenous group, the infusion was blocked in one child.

# Benefits and risks
Sublingual sugar appears to be well-tolerated, safe, and efficacious. It is easy to administer, rapidly increases blood glucose levels, and is better than no treatment in situations where IV glucose infusion may be delayed or not available. It can be administered by unskilled health-care workers or parents as a first-aid measure in many rural health centres.
Possibility of treatment failures because of clenched teeth and swallowing of the sugar. It has 30% hypoglycaemia relapse and could give false confidence in situations where blood glucose levels may not be monitored.

# Acceptability and feasibility
Sublingual sugar is child-friendly, easy to administer, and does not require skilled health workers. Children will not be distressed due to inserting an IV line and would be a more acceptable treatment than IV infusions. Active participation by parents in the care of their children may also increase. As sugar is readily available in most places, it may be immediately administered in most circumstances and does not require a prescription or other additional materials for use. It is easy to implement widely in all settings, including peripheral health centres and in the communities where intravenous glucose is not available.

# Evidence for recommendations on the choice of intravenous fluids
- 1 Choice of intravenous fluids for resuscitation and maintenance in children a) Resuscitation: Children severely dehydrated or with signs of shock should be resuscitated using isotonic intravenous (IV) solutions such as sodium chloride 0.9% or ringers lactate.

# (Strong recommendation, low quality evidence)
b) Intravenous maintenance fluid: For children who require intravenous (IV) fluids for maintenance, options include ringers lactate solution with 5% dextrose, sodium chloride 0.45% with glucose 5%, sodium chloride 0.45% with glucose 2.5%, or 0.9% sodium chloride with glucose 5%.

# (Strong recommendation, low quality evidence)
c) Low sodium-containing IV solutions such as sodium chloride 0.18% with glucose 4%, or 5% glucose in water, should not be used as there is an increased risk of hyponatraemia.

# (Strong recommendation, low quality evidence)
There is evidence that there is a greater level of risk of hyponatraemia associated with the use of very low sodium-containing solutions in paediatric patients in comparison to fluids where the sodium content is 75-150mmol/L. The panel also emphasized that IV maintenance fluids should contain glucose to avoid hypoglycaemia and starvation ketosis. Enteral feeding should be used in sick children, as it provides nutrition and avoids complications associated with IV fluids. If oral nutrition is not tolerated, nasogastric tube feeding should be considered.

# Evidence and summary of findings
There is evidence of a greater level of risk of hyponatraemia associated with the use of hypotonic solutions: the odds of developing hyponatraemia following hypotonic solutions are 17.2 times greater than with isotonic fluids. Within the range of hypotonic solutions available, the use of sodium chloride 0.18% with glucose 4% presents an even greater risk.
The panel identified a systematic review published in 2006 that sought to compare outcomes for children receiving hypotonic versus isotonic fluid therapy. The review included six studies: two controlled trials of children (1-12 years, n = 60) and adolescent females (12-18 years, n = 12) undergoing elective procedures; one trial of children with gastroenteritis and dehydration (6 months-14 years, n = 104); one case-control study of children treated for iatrogenic hyponatraemia (mean age 7 years, n = 148); one cohort study of children undergoing scoliosis repair (6-16 years, n = 24); and one retrospective chart review of children undergoing craniofacial surgery (2 months-15 years, n = 56). Hypotonic solutions used in the studies ranged from 0.16-0.45% sodium chloride.
Only three studies reported on morbidity and mortality. Wilkinson et al reported seizures in 2 out of 26 patients receiving hypotonic fluids (OR 6.22; 95% CI 0.29 to 135.8). Hoorn et al  reported nausea and vomiting more commonly in patients with hospital acquired hyponatraemia (p = 0.008) but numbers were too small to evaluate these outcomes with sufficient power.
Meta-analysis of the effect on serum sodium showed that hypotonic maintenance solutions significantly increased the risk of developing hyponatraemia (OR 17.22; 95% CI 8.67 to 34.2). Mean plasma sodium in patients following hypotonic solutions was significantly lower (OR -3.39 mmol/l; 95% CI -5.35 to -1.43), than those who received isotonic solutions. In children receiving hypotonic solutions, the mean plasma sodium decreased significantly more after fluid administration (OR -5.37 mmol/l; 95% CI -8.79 to -1.94). Three studies reported a decrease in plasma sodium despite the infusion of isotonic or near-isotonic maintenance fluids, but none reported on the risk of hypernatraemia with these fluids.

# Benefits and risks
In two institutions in the UK where there were incidents of hyponatraemia due to use of hypotonic fluids, no further cases of iatrogenic hyponatraemia have been reported since the solution was removed from the ward stock. There is growing awareness of the dangers associated with use of hypotonic solutions and there have been various statements and changes in the national guidelines discouraging their use in children. In 2003, the Royal College of Anaesthetists issued a statement advising against the use of hypotonic fluids. In 2007, the UK National Patient Safety Agency (NPSA) issued an alert advice to health-care organizations of how to minimize the risks associated with administering intravenous infusions to children.
All sick children are potentially at risk of hyponatraemia, especially those with pulmonary and central nervous system infections, and post operative surgical cases. The use of hypotonic fluids may be harmful and cause water overload with possible severe hyponatraemia and other complications. Among children who develop symptomatic hyponatraemia, the incidence of permanent brain damage in adulthood is significantly increased.

# Outline of the research gaps 13.1 Vitamin K prophylaxis in newborns
- Research to understand why vitamin K usage is low in developing countries 2. Need for more information on incidence of Vitamin K Dependent Bleeding in developing countries 3. Evaluation of intervention delivery issues and into How to best deliver the intervention in remote settings 4. Testing the possibility of combining with the birth dose of Hepatitis B vaccine 5. Research to improve injection safety

# Prophylactic antibiotics to neonates with risk factors for infection
- RCT for determining efficacy of prophylactic antibiotics to the neonate when the mother has risk factors for neonatal infection 2. What should be the duration of treatment? 3. What is the efficacy of a combination of oral antibiotic (e.g. amoxicillin) and IM gentamicin 4. Bacteriology data on neonatal sepsis

# Skin-to-skin contact in the first hour of life
- New studies to have high quality evidence of efficacy of this intervention. Also, to ascertain: -effect on preterm and SGA infants? -effect and feasibility after caesarean section? 2. The studies should be designed for the outcomes to include breastfeeding, hypothermia, engorgement, and bonding. Control group should receive immediate drying and wrapping, and counselling for early breastfeeding. 3. Health care providers and mothers views on acceptability of early skin-to-skin contact of neonates with mothers after birth

# Management of neonatal jaundice
- Non-invasive serum bilirubin measurement at point of care 2. RCTs evaluating different cut-offs for phototherapy in babies with hyperbilirubinaemia 3. Perceptions, care seeking and causes of prolonged jaundice 13.5 Kangaroo Mother Care 1. Implementation, scaling up issues 2. Ongoing KMC at home post-discharge, feasibility, how long to continue 3. Effectiveness, feasibility of early community initiation of KMC

# Prevention of hypothermia immediately after birth in VLBW infants
- The group recommended an RCT of plastic wraps for VLBW babies in district and provincial hospitals in developing country settings

# Management of children with non-severe pneumonia and wheeze
- Studies on withholding antibiotics in young children with wheeze, no fever and non-severe pneumonia need to be replicated in other settings, including health workers ability to identify these children at very low risk of bacterial infection, and the acceptability of withholding antibiotics 2. Studies testing accuracy of different diagnostic algorithms for pneumonia and definitions of treatment failure 13.8 Antibiotics for severe pneumonia 1. More data is needed to assess appropriate antibiotic therapy of severe pneumonia in high HIV settings 2. More research is needed on ambulatory care for severe pneumonia/requisites for safely treating such children at home or in day clinic settings 3. Research in moderately malnourished children with pneumonia 4. Repeat the clinical trials for treatment outcomes in countries with high Hib and pneumococcal vaccine coverage.

# Antibiotics for very severe pneumonia
- Data on shifts in bacterial patterns due to coverage of H. influenzae type b and S. pneumococcus vaccines and implications for treatment of pneumonia and antimicrobial resistance 2. Comparison of the recommended treatment (injectable ampicillin (or penicillin) and gentamicin) versus injectable ceftriaxone 3. What should be second line therapy for children failing on first line therapy? 4. Impact of improved comprehensive care packages on outcomes for children with very severe pneumonia.

# Treatment of non-severe pneumonia
- Studies to determine the duration of therapy in settings other than Asia 2. Repeat the clinical trials for treatment outcomes in countries with high Hib and pneumococcal vaccine coverage 3. Research on treatment failure definition, and choice of second line treatment 4. Research on increasing specificity of pneumonia diagnosis and aetiology of pneumonia

# Antibiotics for Meningitis
- There is need for comparative studies on dose and frequency of ceftriaxone, 2. Improved surveillance for antibiotic resistance among pathogens causing meningitis 3. The role and accuracy of rapid point of care diagnostic tests, that can be used in district hospitals that do not have culture facilities 4. Studies of the aetiology on meningoencephalitis in settings with high coverage of SP/Hib vaccine coverage 13.12 Antibiotics for Acute Otitis Media 1. RCTs in developing countries with pragmatic definition of otitis 2. Follow up studies in developing countries to quantify complication rates, especially in high prevalence HIV settings 3. Systematic review of treatment of otorrhoea (as may merit separate guidelines) 4. RCT of different durations of antibiotic treatment (including BD versus TID)

# Antibiotics for Typhoid Fever

# Oxygen systems and delivery methods
- Large-scale effectiveness trials of improved oxygen systems on outcomes from pneumonia 2. Studies of alternative power supplies to run oxygen concentrators and pulse oximeters in remote settings where power supplies are unreliable 3. The role of inexpensive forms of CPAP in the management of severe pneumonia 4. Are there safe methods for cleaning and reuse of oxygen delivery equipment in high HIV prevalence settings?

# Job aids and charts 
Represents sections where no or editorial changes are expected to be made in the pocket book.
Represents sections where changes will be made to align with new recommendations/ guidelines already approved through GRC Represents sections where evidence was reviewed and recommendations made by the expert panel meeting in February 2011 are provided in this publication.

# ANNEX 2

# List of PICO questions
CHAPTER SUB-CHAPTER QUESTION

# Problems of the neonate and young infant
- 1 Routine care of the newborn at delivery Among healthy newborn infants in low-and middleincome countries (P), does early skin-to-skin contact of the baby with the mother in the first hour of life (I) compared with drying and wrapping (C) have an impact on neonatal mortality, hypothermia or initiation/ exclusivity/ duration of breastfeeding (O)?

# Routine care for all newborn babies after delivery
For all neonates (P), should vitamin K prophylaxis (I) be given for the prevention of vitamin K deficiency bleeding (O)?
- 5 Management of the child with perinatal asphyxia
For neonates requiring prolonged resuscitation and at risk of HIE (P), should head or body cooling (I) be initiated to prevent death and sequelae (O)?

# Serious bacterial infections
For young infants (0-2 months) with suspected sepsis managed in health facilities (P), should third generation cephalosporin monotherapy (I) replace currently recommended ampicillin-gentamicin combination (C) as first line empiric treatment for preventing death and sequelae (O)?

# Babies with low birth weight
In low-birth-weight/pre-term neonates in health facilities (P), are plastic wraps or caps used immediately after birth (I) more effective than conventional care (C) in preventing hypothermia (O)?
In low-birth-weight/pre-term neonates in health facilities (P), is skin to skin contact immediately after birth (I) more effective than conventional care (C) in preventing hypothermia (O)?
In low-birth-weight/pre-term neonates in health facilities (P), is Kangaroo Mother Care (I) more effective than conventional care (C) in reducing mortality and/or morbidity (O)?           ; Hansen ; Faix ; Scheifele  QUALITY ASSESSMENT                 None of the studies were analyzed as 'intention to treat', as culture negative subjects were excluded. However, this applied to both intervention and comparison, and it is unlikely that this would have biased the results in a given direction. Therefore no points were deducted.

# Necrotising enterocolitis
b OR (Odds Ratio) reported in the review converted to RR (Relative Risk).  None of the studies were analyzed as 'intention to treat', as culture negative subjects were excluded. However, this applied to both intervention and comparison, and it is unlikely that this would have biased the results in a given direction. Therefore no points were deducted.   None of the studies were analyzed as 'intention to treat', as culture negative subjects were excluded. However, this applied to both intervention and comparison, and it is unlikely that this would have biased the results in a given direction. Therefore no points were deducted.  There is unexplained variability (underestimation or overestimation of the test versus gold standard). In addition to methodological sources of variability such as study quality, year of publication or oximetre models, the systematic review explores different subgroups. The association of more than one of these factors could have better explained the variability.

# Effectiveness of oxygen therapy
Question: What is the effectiveness of administering oxygen to children with hypoxaemia? Population: Children with hypoxaemia Intervention: oxygen therapy for hypoxaemia.

# Setting: PNG