Corticosteroids for pneumonia

  • Review
  • Intervention

Authors

  • Yuanjing Chen,

    1. West China Hospital, Sichuan University, Department of Anesthesiology, Chengdu, Sichuan, China
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  • Ka Li,

    1. West China Hospital, Sichuan University, Department of Surgery III, Chengdu, Sichuan, China
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  • Hongshan Pu,

    1. West China Hospital, Sichuan University, Chengdu, Sichuan, China
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  • Taixiang Wu

    Corresponding author
    1. West China Hospital, Sichuan University, Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training Centre, Chengdu, Sichuan, China
    • Taixiang Wu, Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training Centre, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. txwutx@hotmail.com.

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Abstract

Background

Pneumonia is an acute inflammation of the lungs and treatments differ depending on the type and severity. Corticosteroids can influence immune regulation, carbohydrate metabolism, protein catabolism, electrolyte balance and stress response. However, the benefits of corticosteroids for patients with pneumonia remains unclear.

Objectives

To assess the efficacy and safety of corticosteroids in the treatment of pneumonia.

Search methods

We searched Cochrane Central Register of Controlled Clinical Trials (CENTRAL) (The Cochrane Library 2010, Issue 11) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to December week 4, 2010), EMBASE (1974 to December 2010), the China National Knowledge Infrastructure (CNKI) (1978 to December 2010) and VIP (1986 to December 2010).

Selection criteria

Randomised controlled trials (RCTs) assessing the effectiveness of corticosteroids for pneumonia.

Data collection and analysis

Three review authors selected studies. We telephoned the trial authors to confirm the randomisation method used. We extracted and analysed the methodological details and data from the included studies.

Main results

We included six studies including 437 participants in the review. Two studies were of high methodological quality and three were of poor quality. All studies involved small numbers of participants. Two small studies provided weak evidence that corticosteroids did not significantly reduce mortality (Peto odds ratio (OR) 0.26; 95% CI 0.05 to 1.37), but accelerated the resolution of symptoms or time to clinical stability, and decreased the rate of relapse of the disease. Steroids can improve the oxygenation and reduce the need for mechanical ventilation in severe pneumonia. There was no significant difference between treatment groups with regards to the time to discharge from the intensive care unit (ICU). There were insufficient data to report the time to pneumonia resolution and admission to ICU. Typical adverse events associated with corticosteroid therapy were infrequent.

Authors' conclusions

In most patients with pneumonia, corticosteroids are generally beneficial for accelerating the time to resolution of symptoms. However, evidence from the included studies was not strong enough to make any recommendations.

Résumé scientifique

Corticostéroïdes dans le traitement de la pneumonie

Contexte

La pneumonie est une inflammation aiguë des poumons, et différents traitements sont utilisés selon type et la gravité de la maladie. Les corticostéroïdes peuvent avoir une influence sur la régulation immunitaire, le métabolisme des glucides, le catabolisme des protéines, l'équilibration électrolytique et la réponse au stress. Néanmoins, les effets bénéfiques des corticostéroïdes restent incertains chez les patients atteints de pneumonie.

Objectifs

Évaluer l'efficacité et l'innocuité des corticostéroïdes dans le traitement de la pneumonie.

Stratégie de recherche documentaire

Nous avons consulté le registre Cochrane des essais contrôlés (CENTRAL) (Bibliothèque Cochrane 2010, numéro 11), qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës, ainsi que MEDLINE (1966 à la 4ème semaine de décembre 2010), EMBASE (1974 à décembre 2010), la China National Knowledge Infrastructure (CNKI) (1978 à décembre 2010) et VIP (1986 à décembre 2010).

Critères de sélection

Les essais contrôlés randomisés (ECR) évaluant l'efficacité des corticostéroïdes dans la pneumonie.

Recueil et analyse des données

Trois auteurs de revue ont sélectionné les études. Nous avons contacté les auteurs des essais par téléphone afin de confirmer la méthode de randomisation utilisée. Nous avons extrait et analysé les détails et données méthodologiques des études incluses.

Résultats principaux

Six études portant sur 437 participants ont été incluses dans la revue. Deux études présentaient une qualité méthodologique élevée et trois étaient de mauvaise qualité. Toutes les études portaient sur des effectifs réduits. Deux petites études rapportaient des preuves non concluantes indiquant que les corticostéroïdes ne réduisaient pas significativement la mortalité (rapport des cotes de Peto de 0,26 ; IC à 95 %, entre 0,05 et 1,37), mais qu'ils accéléraient la résolution des symptômes ou le délai de stabilisation clinique et réduisaient le taux de rechute. Les stéroïdes peuvent améliorer l'oxygénation et réduire le recours à la ventilation mécanique dans la pneumonie sévère. Aucune différence significative n'était observée entre les groupes de traitement concernant la durée du séjour en unité de soins intensifs (USI). Les données étaient insuffisantes pour rapporter le délai de résolution de la pneumonie et les admissions en soins intensifs. Les événements indésirables généralement associés à la corticothérapie étaient peu fréquents.

Conclusions des auteurs

Chez la plupart des patients atteints de pneumonie, les corticostéroïdes sont généralement efficaces pour accélérer la résolution des symptômes. Néanmoins, les preuves provenant des études incluses n'étaient pas suffisamment solides pour émettre des recommandations.

Resumo

Corticoides para pneumonia

Introdução

Pneumonia é uma inflamação aguda dos pulmões e os tratamentos diferem de acordo o seu tipo e gravidade. Os corticoides podem influenciar a regulação imune, o metabolismo dos carboidratos, o catabolismo proteico, o balanço eletrolítico e, a resposta ao estresse. No entanto, os benefícios dos corticoides para os pacientes com pneumonia permanecem incertos.

Objetivos

Avaliar a eficácia e a segurança dos corticoides no tratamento da pneumonia.

Métodos de busca

Nós pesquisamos na the Cochrane Central Register of Controlled Clinical Trials (CENTRAL)(The Cochrane Library 2010, fascículo 11) que contém o the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 a Dezembro, semana 4, 2010), EMBASE (1974 a Dezembro de 2010), China National Knowledge Infrastructure (CNKI) (1978 a Dezembro de 2010) e VIP (1986 a Dezembro de 2010).

Critério de seleção

Ensaios clínicos randomizados (ECRs) que avaliando a efetividade dos corticoides no tratamento da pneumonia.

Coleta dos dados e análises

Três autores da revisão selecionaram os estudos. Nós realizamos contatos telefônicos com os autores dos ensaios clínicos para confirmar os métodos de randomização utilizados. Nós extraímos e analisamos os detalhes metodológicos e os dados dos estudos incluídos.

Principais resultados

Foram incluídos seis estudos, que incluíram 437 participantes na revisão. Dois estudos apresentaram alta qualidade metodológica e três apresentaram baixa qualidade. Todos os estudos envolveram pequeno número de participantes. Dois pequenos estudos forneceram evidências fracas de que os corticoides não reduziram a mortalidade significativamente (razão de chances de Peto (OR) 0,26; Intervalo de Confiança (IC) 95% 0,05 a 1,37), porém, aceleraram a resolução dos sintomas ou o tempo para a estabilidade clínica, e diminuíram as taxas de recidiva da doença. Os esteroides podem melhorar a oxigenação e reduzir a necessidade de ventilação mecânica em pneumonias graves. Não houve diferença significativa entre os grupos de tratamento com relação ao tempo para a alta da unidade de terapia intensiva (UTI). Não houve dados suficientes para relatar o tempo para resolução da pneumonia e para a admissão na UTI. Eventos adversos tipicamente associados à terapia com corticoides foram infrequentes.

Conclusão dos autores

Na maioria dos pacientes com pneumonia, os corticoides são geralmente benéficos em acelerar o tempo para a resolução dos sintomas. Entretanto, as evidências dos estudos incluídos não eram fortes o suficiente para permitir a realização de qualquer recomendação.

Notas de tradução

Traduzido por: Ricardo Augusto Monteiro de Barros Almeida, Unidade de Medicina Baseada em Evidências da Unesp, Brasil Contato: portuguese.ebm.unit@gmail.com

Plain language summary

Corticosteroids for pneumonia

Pneumonia is an acute respiratory disease that is usually caused by bacteria but it can also be caused by other infectious agents such as fungi, parasites and viruses. Corticosteroids can act as an anti-inflammatory agent for patients with pneumonia but they can adversely suppress the immune system, which prevents the body from fighting the causative pathogens and results in a serious infection. The purpose of this review was to assess whether corticosteroids for pneumonia are beneficial.

We identified six trials (437 participants) and found that although the effects of corticosteroids vary depending on the type and severity of pneumonia, the overall effect is beneficial for most patients. Corticosteroids did not significantly reduce mortality compared to the placebo group. Arrhythmia, upper gastrointestinal bleeding and malignant hypertension may be related to corticosteroids. The evidence from this review is weak due to limitations of the included studies. Large trials with more patients are needed to provide robust evidence.

Résumé simplifié

Corticostéroïdes dans le traitement de la pneumonie

La pneumonie est une maladie respiratoire aiguë qui est généralement causée par des bactéries, mais qui peut également être provoquée par d'autres agents infectieux tels que des champignons, des parasites et des virus. Des corticostéroïdes peuvent être utilisés en tant qu'agent anti-inflammatoire chez les patients atteints de pneumonie, mais ils peuvent inhiber le système immunitaire, ce qui empêche l'organisme de lutter contre les agents pathogènes responsables de la maladie et entraîne une infection grave. L'objectif de cette revue était de déterminer si les corticostéroïdes pouvaient être bénéfiques dans la pneumonie.

Nous avons identifié six essais (437 participants) et observé que, bien que les effets des corticostéroïdes varient selon le type et la gravité de la pneumonie, ils sont globalement bénéfiques chez la plupart des patients. Les corticostéroïdes ne réduisaient pas significativement la mortalité par rapport au groupe du placebo. Une arythmie cardiaque, une hémorragie gastro-intestinale supérieure et une hypertension artérielle maligne pourraient être associées aux corticostéroïdes. Les preuves issues de cette revue ne sont pas concluantes en raison des limitations des études incluses. Des essais à grande échelle portant sur davantage de patients sont nécessaires afin d'obtenir des preuves solides.

Notes de traduction

Traduit par: French Cochrane Centre 1st December, 2012
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Resumo para leigos

Corticoides para pneumonia

A pneumonia é uma doença respiratória aguda que é geralmente causada por bactéria mas também pode ser causada por outros agentes infecciosos como os fungos, parasitas e vírus. Os corticoides podem atuar como um agente anti-inflamatório para pacientes com pneumonia, mas eles podem suprimir adversamente o sistema imune, o que impede o corpo de lutar contra os agentes patogênicos, resultando em uma infecção grave. O objetivo desta revisão foi avaliar se os corticoides são benéficos para a pneumonia.

Nós identificamos seis ensaios clínicos (437 participantes) e encontramos que, embora os efeitos dos corticoides modifiquem dependendo do tipo e da gravidade da pneumonia, o efeito geral é benéfico para a maioria dos pacientes. Os corticoides não reduziram a mortalidade significantemente quando comparados ao grupo placebo. Arritmia, sangramento do trato gastrointestinal alto e hipertensão maligna podem estar associados aos corticoides. As evidências desta revisão são fracas devido a limitações dos estudos incluídos. Ensaios clínicos amplos, com maior número de pacientes, são necessários para oferecer evidências robustas.

Notas de tradução

Traduzido por: Ricardo Augusto Monteiro de Barros Almeida, Unidade de Medicina Baseada em Evidências da Unesp, Brasil Contato: portuguese.ebm.unit@gmail.com

எளியமொழிச் சுருக்கம்

நிமோனியாவிற்கு கார்டிக்கோஸ்டீராய்ட்கள்

நிமோனியா என்பது, பொதுவாக பாக்டீரியாக்களினால் ஏற்படும் ஒரு கடுமையான சுவாச மண்டல நோயாகும், ஆனால், அது, பூஞ்சை, ஒட்டுண்ணிகள் மற்றும் வைரஸ் போன்ற பிற தொற்று காரணிகளாலும் ஏற்படக் கூடும். நிமோனியா கொண்ட நோயாளிகளுக்கு, கார்டிக்கோஸ்டீராய்ட்கள் ஒரு அழற்சி-நீக்கி முகமை மருந்தாக செயல்படும், ஆனால், அவை பாதகமான முறையில் நோய் எதிர்ப்பு மண்டலத்தை ஒடுக்குவதன் மூலம், நோய் காரணிகளை எதிர்த்து உடல் போரிடுவதை தடுத்து, மற்றும் ஒரு கடுமையான தொற்றிற்கு வழி வகுக்கும். நிமோனியாவிற்கு கார்டிக்கோஸ்டீராய்ட்கள் நன்மையளிக்குமா என்பதை மதிப்பிடுவதே இந்த திறனாய்வின் நோக்கமாகும்.

நாங்கள் ஆறு சோதனைகளை (437 பங்கேற்பாளர்கள்) அடையாளம் கண்டோம். மற்றும் கார்டிக்கோஸ்டீராய்ட்களின் விளைவுகள் நிமோனியாவின் வகை மற்றும் தீவிரத்தைப் பொருத்து வேறுப்பட்டாலும், பெரும்பாலான நோயாளிகளுக்கு, ஒட்டுமொத்த விளைவு நன்மையளிப்பதாக இருந்தது என்று நாங்கள் கண்டோம். போலி மருந்து குழுவை ஒப்பிடுகையில், கார்டிக்கோஸ்டீராய்ட்கள் இறப்பை குறிப்பிடத் தகுந்த வகையில் குறைக்கவில்லை. இதயத் துடிப்பு இலயமின்மை, மேல் குடலிய-இரைப்பை இரத்தக் கசிவு, மற்றும் வீரியம் மிக்க உயர் இரத்த அழுத்தம் ஆகியவை கார்டிக்கோஸ்டீராய்ட்களோடு தொடர்பு கொண்டவையாக இருக்கலாம். உள்ளடக்கப்பட்டுள்ள ஆய்வுகளின் வரம்புகள் காரணமாக இந்த திறனாய்விலிருந்த ஆதாரம் பலவீனமாக உள்ளது. திறம்பட்ட ஆதாரத்தை அளிப்பதற்கு அதிகமான நோயாளிகளைக் கொண்ட பெரியளவு சோதனைகள் தேவைப்படுகின்றன.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பாளர்கள்: சிந்தியா ஸ்வர்ணலதா ஸ்ரீகேசவன், தங்கமணி ராமலிங்கம், ப்ளசிங்டா விஜய், ஸ்ரீகேசவன் சபாபதி.

Background

Description of the condition

Pneumonia is an acute inflammation of the lungs caused by pathogens such as bacteria, viruses, mycoplasma, chlamydia, fungi and parasites. It is a common illness worldwide and is a major cause of death among all age groups. Symptoms include cough, sputum production, fever, chills, fatigue, shortness of breath, night sweats and pleuritic chest pain. Other symptoms may include loss of appetite, skin discolouration, nausea, vomiting, mood swings and joint pains or muscle aches (Hoare 2006). Chemotherapy or radiation therapy can also cause non-infective pneumonitis.

Pneumonia can be divided into community-acquired pneumonia (CAP), nosocomial (hospital-acquired) pneumonia (HAP) and aspiration pneumonia. CAP is the most common type of pneumonia and occurs when one is infected by pathogens without being recently hospitalized. People of all ages can contract CAP and the most common causative agents are Streptococcus pneumoniae (S. pneumoniae), Mycoplasma pneumoniae (M. pneumoniae), Haemophilus influenzae (H. influenzae), viruses and atypical bacteria. The annual incidence of CAP in Europe and North America is 34 to 40 cases per 1000 in children (Ostapchuk 2004), six per 1000 in the 18 to 59 year old population and 20 to 34 per 1000 in those aged 60 and older. It occurs three to four million times per year in the United States, accounting for about 500,000 hospitalizations annually (Plouffe 1996).

Nosocomial pneumonia, also called hospital-acquired pneumonia (HAP), is defined as pneumonia occurring in the first 48 hours after hospital admission (Leroy 2004). Approximately one-half of HAP cases occur in patients admitted to medical or surgical wards. The remaining episodes occur in patients admitted to intensive care units (ICUs) and are related to mechanical ventilation (Leroy 2004). Individuals with HAP usually have an underlying illness and have been exposed to bacteria, therefore it tends to be more serious than CAP (Gerald 2004).

Aspiration pneumonia (or aspiration pneumonitis) comprises a small percentage of community-acquired and hospital-acquired pneumonia. Aspiration pneumonitis occurs rapidly and some cases may be associated with inhalation of a large volume of sterile acidic gastric contents or aspirating other foreign objects.

Description of the intervention

Many patients with pneumonia do not require hospitalization and usually recover fully with oral antibiotics, fluids and rest. However, older people, people who have difficulty in breathing, or those who have severe medical conditions are at greater risk (d'Escrivan 2005) and may require corticosteroids (Garcia-Vidal 2007). The natural steroid cortisol is produced by the adrenal glands. Steroids, also known as corticosteroids, are a class of steroid hormones. Synthetic derivatives of the natural steroid include prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone and hydrocortisone. It is possible to administer corticosteroids by inhalation, orally or intravenously.

How the intervention might work

Corticosteroids influence immune regulation and also effect carbohydrate metabolism, protein catabolism, electrolyte balance and stress response. They are used for treating inflammatory diseases of the bowel (colitis), joints (arthritis), skin (dermatitis) and lungs (pneumonia or asthma). Corticosteroids act partly by inducing anti-inflammatory genes which repress inflammatory genes (Adcock 2000). A retrospective observational study suggests that systemic corticosteroids may reduce mortality in severe CAP cases (Garcia-Vidal 2007).

However, corticosteroids have side effects, most of which are related to the dose and duration of therapy (Seale 1986). The side effects only manifest after a long period of high-dose usage and the most common are disturbance of metabolism, immune depression, prolonged healing, growth retardation in children, hirsutism, diabetes, Cushing's Syndrome (also called hypercortisolism) and thinning of the bones (osteoporosis), particularly in women during and following menopause. In some cases they can cause emotional disturbances such as depression. Many of the adverse effects only occur over prolonged administration and most short-term adverse events are reversible when the drug is discontinued.

Why it is important to do this review

The benefits of corticosteroids for severe pneumonia remain unclear, although they are sometimes used in clinical practice. There is therefore a need to systematically review the effectiveness of corticosteroids for pneumonia.

Objectives

To assess the efficacy and safety of corticosteroids in the treatment of pneumonia. In particular, we aim to answer the following questions.

  1. Do corticosteroids reduce mortality and the incidence of pneumonia complications such as severe sepsis or acute respiratory distress syndrome (ARDS) in severe pneumonia?

  2. Do corticosteroids shorten symptoms in mild pneumonia?

  3. Is the occurrence of relative adrenal insufficiency a possible rationale for using corticosteroids in pneumonia?

  4. Are there any dose-effect relationships between corticosteroids and pneumonia?

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) assessing the effectiveness of corticosteroids for pneumonia.

Types of participants

Participants of any age or sex with pneumonia. The diagnosis of pneumonia is usually made from taking a medical history, physical examination and a chest X-ray. Occasionally sputum cultures assist diagnosis. Diagnosis can be difficult, especially in HAP and pneumonia of immunocompromised people. Computerised tomography (CT) scanning of the lungs is sometimes used to make the diagnosis (Wipf 1999).

We included people with pneumonia associated with chronic obstructive pulmonary disease (COPD) but excluded cases associated with immunosuppression, HIV, tuberculosis, acute schistosomiasis, fungal or parasitic infections, or chemotherapy and radiotherapy-associated lung changes.

Types of interventions

Trials comparing the following.

  1. Corticosteroids with antibiotics versus antibiotics alone.

  2. Corticosteroids with antibiotics versus corticosteroids of a different dose with antibiotics.

Types of outcome measures

Primary outcomes
  1. Mortality.

Secondary outcomes
  1. Time to resolution of symptoms or time to clinical stability. Symptoms include fever, cough, positive chest X-ray, elevation of white blood cell count, difficulty in breathing, etc.

  2. Relapse of pneumonia.

  3. Proportion of patients requiring either ventilatory or inotropic support, or both.

  4. Rate of admission to intensive care unit (ICU).

  5. Time to discharge from ICU.

Adverse events

Serious adverse events have been defined as any event that leads to death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, and any reported serious event that might jeopardise the patient or require an intervention to prevent it (ICHEWG 1997). All other adverse events are not considered to be serious.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) (The Cochrane Library 2010, Issue 11) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to December, 2010), EMBASE (1974 to December 2010), the China National Knowledge Infrastructure (CNKI) (1978 to December 2010) and VIP (1986 to December 2010).

We used the following search strategy to search MEDLINE and CENTRAL. We combined the search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2009). We adapted the search strategy for EMBASE (see Appendix 1), the China National Knowledge Infrastructure and VIP (Figure 1).

Figure 1.

Search strategy used in the Chinese databases

MEDLINE (Ovid)

1 exp Pneumonia/
2 pneumon*.tw.
3 CAP.tw.
4 HAP.tw.
5 Respiratory Distress Syndrome, Adult/
6 adult respiratory distress syndrome.tw.
7 acute respiratory distress syndrome.tw.
8 ARDS.tw.
9 or/1-8
10 exp Steroids/
11 steroid*.tw,nm.
12 exp Adrenal Cortex Hormones/
13 corticosteroid*.tw,nm.
14 prednisone.tw,nm.
15 prednisolone.tw,nm.
16 methylprednisolone.tw,nm.
17 betamethasone.tw,nm.
18 dexamethasone.tw,nm.
19 triamcinolone.tw,nm.
20 hydrocortisone.tw,nm.
21 or/10-20
22 9 and 21

Searching other resources

We did not impose any language or publication restrictions. We searched the Chinese Journals Full Text Database (1979 to February 2010), Chinese Journals Full Text Database Century Journals (1979 to February 2010), Chinese Doctoral Degree Thesis Full Text Database (1979 to February 2010), Chinese Outstanding Master Degree Thesis Full Text Database (1979 to February 2010) and WANFANG Database (1993 to February 2010).

We searched the WHO ICTRP Search Portal (http://www.who.int/ictrp/network/en/index.html) for ongoing trials.

Data collection and analysis

Selection of studies

Four review authors (YC, KL, HP, TW) undertook the selection of studies. Two review authors (YC, HP) independently scanned the titles and abstracts of all the articles identified by the literature search. The same review authors independently assessed whether the trials met the inclusion criteria. We resolved disagreements by discussion. We contacted trial authors of the original reports to obtain further information if the search results contained insufficient information to make a decision about eligibility. We excluded those trials which had not developed a research protocol, or in which coin tossing or card shuffling was used in the presence of the allocated participants, because there was high risk of selection bias. We recorded the trial ID, name and contact details of trialists, date of query to trialist, method of query (for example, telephone) and response of trialist for each trial, whether it was included or excluded. We recorded all of the information in an additional table.

Data extraction and management

Three review authors (YC, KL, HP) independently extracted the methodological details and data from publications. Data for extraction included study title; design; study population size; duration; number of drop-outs, withdrawals and loss to follow up and participants analysed in the different treatment groups; inclusion and exclusion criteria; intervention (route and dosage); and outcomes (Higgins 2009). There was no disagreement among the review authors.

Assessment of risk of bias in included studies

We assessed risk of bias using the following criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) and Wu 2007, and we graded the quality of evidence using GRADEprofiler.

Randomisation process

A - adequate sequence generation was reported using one of the following approaches: we considered a random numbers table or computer-generated random numbers; coin tossing; or shuffling used for generating the allocation sequence before the trial as having a low risk of selection bias.
B - does not specify one of the adequate methods outlined in (A) but only mentions 'random' - we considered this to have a moderate risk of selection bias.
C - we excluded other methods of allocation, for example quasi-randomisation, that appeared to have a high risk of bias.

Allocation concealment process

A - adequate measures to conceal allocation and the allocation sequences, such as central randomisation, and the use of sealed opaque envelopes - we considered this a low risk for selection bias.
B - unclear: concealed allocation where the author does not report the allocation concealment method used - we considered this a moderate risk for selection bias.
C - inadequately-concealed allocation, where an approach was reported that does not fall into one of the categories in (A).
D - does not conceal allocation.

C and D can be considered as high risks for selection bias.

Level of blinding

A - double-blinding: participants and results assessor were masked - we considered this a low risk for both performance and detection bias.
B - single-blinding of results assessor - we considered this a moderate risk for both performance and detection bias. If single-blinding was performed for participants but not the results assessor, we considered the study as having a high risk of detection bias.
C - we considered non-blinding as a high risk for both performance and detection bias.

Use of blinding for mortality was not required.

Incomplete outcome data

Low risk of bias - we considered number of drop-outs or loss to follow less than 10% as low risk of bias due to incomplete outcome data.
Moderate risk of bias - we considered this to be a rate of drop-out or loss to follow up between 10% and 15%.
High risk of bias - number of drop-outs or loss to follow higher than 15%.

Selective reporting bias

We expected to assess selective reporting bias by comparing the protocol and published trial reports. However, we were unable to locate the protocol and so were unable to identify whether reporting bias existed or not.

Other potential sources of bias

We expected to address potential sources of bias, for example, different doses of corticosteroids, length of follow up, and characteristics of participants (for example, age, stage of disease). However, we did not find any potential sources of bias in the included studies.

Measures of treatment effect

We expected both dichotomous and continuous data. We analysed different comparisons separately. We used the risk ratio (RR) with 95% confidence intervals (CI) and control events rates for reporting dichotomous data. We expressed continuous data as mean differences (MD) with 95% CI.

Dealing with missing data

We assessed incomplete outcome data for potential bias from exclusions and attrition.

  1. Low risk of bias: trials where few exclusions and attrition are noted and an intention-to-treat (ITT) analysis is possible.

  2. Moderate risk of bias: trials which report the rate of exclusion, attrition or both to be about 10%, whatever ITT analysis is used.

  3. High risk of bias: the rate of exclusion, attrition or both is higher than 15%, or wide differences in exclusions between groups, whatever ITT analysis is used.

Assessment of heterogeneity

We assessed clinical and methodological heterogeneity before pooling. If data were similar enough, we carried out an assessment for statistical heterogeneity using the Chi2 test with significance being set at P < 0.1. We used the I2 statistic to estimate the total variation across studies. An I2 < 40% is not considered important in terms of heterogeneity, 30% to 60% represents moderate heterogeneity, 50% to 90% substantial heterogeneity and 75% to 100% represents considerable heterogeneity (Higgins 2009).

Assessment of reporting biases

We did not investigate potential publication bias by funnel plot (Egger 1997) due to only a few studies being included, although we assessed reporting bias according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

  1. No - low risk of reporting bias: all of the outcomes were reported in detail.

  2. Probably yes - moderate risk of reporting bias: at least one of the outcomes were mentioned but not in detail.

  3. Yes - high risk of reporting bias: at least one of the outcomes were not reported.

Data synthesis

We carried out meta-analyses using the Review Manager 5 software program (RevMan 2008). We used a random-effects model for pooled data analysis. We did not combine results of trials with different comparator drugs.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses based on different types of corticosteroids and different comparators (Higgins 2009).

Sensitivity analysis

We did not perform sensitivity analyses to test the robustness of the evidence because of the small number of included studies. However, we did test the following:

  1. excluded studies with inadequate concealment of allocation;

  2. excluded studies in which the outcome evaluation was not blinded; and we

  3. compared the difference between pooling analysis results by using a fixed-effect model and a random-effects model because robust evidence should not be transposed by changing the effect model.

Results

Description of studies

We identified 50 controlled trials. Of these, we excluded 35 trials and 10 trials are awaiting for classification due to difficultly in retrieving the article or contacting the original trial authors. These data will be analysed when we update the review. The remaining six trials involving 437 participants met the inclusion criteria and were included in this review.

Results of the search

125 relevant studies appeared in our search.

Included studies

Participants in the included studies were of any age or sex with pneumonia. Two trials (Cao 2007; van Woensel 2003) mainly focused on children, while the other four (Confalonieri 2005; Marik 1993; McHardy 1972; Mikami 2007) focused on adults or the elderly.

One study was conducted in China (Cao 2007) with 120 children aged from three months to 14 years infected by M. pneumoniae. They were divided into four groups: 30 in the control group, 30 in the budesonide (Pulmicort) group, 30 in the clarityne (Loratadine tablets) group, and 30 in the thymosin or transfer factor (TF) injection group.

The Confalonieri 2005 study involved 48 participants: 24 in the hydrocortisone infusion group and 24 in the placebo group.

There were 30 patients in the Marik 1993 study: 14 in the hydrocortisone group and 16 in the placebo group.

One hundred and twenty six participants were included in McHardy 1972 and were divided to four groups: 43 in group 1, 20 in group 2, 43 in group 3 and 20 in group 4.

The Mikami 2007 study involved 31 patients: 15 received prednisolone intravenously for three days and 16 in the control group did not receive prednisolone.

There were 82 participants in the van Woensel 2003 study: 37 in the steroid group (including 18 participants with bronchiolitis and 17 with pneumonia) and 45 in the control group (including 21 participants with bronchiolitis and 22 with pneumonia).

In all trials, the interventions were antibiotics with corticosteroids versus antibiotics with placebo or antibiotics alone. The corticosteroids included hydrocortisone (Confalonieri 2005; Marik 1993), prednisolone (McHardy 1972; Mikami 2007), budesonide (Cao 2007) and dexamethasone (van Woensel 2003). In Confalonieri 2005, hydrocortisone was given as an intravenous 200 mg loading bolus followed by an infusion (hydrocortisone 240 mg in 500 cc 0.9% saline) at a rate of 10 mg/hour for seven days and protocol-guided antibiotic treatment.

In Marik 1993, the participants of the treatment group received 10 mg/kg of hydrocortisone intravenously 30 minutes prior to starting antibiotic therapy.

In McHardy 1972, group 1 and group 3 received 1 g ampicillin daily and 2 g ampicillin daily, respectively; group 2 received 1 g ampicillin plus 20 mg prednisolone and group 4 received 2 g ampicillin plus 20 mg prednisolone, respectively. In Mikami 2007, the corticosteroids group received 40 mg of prednisolone intravenously for three days plus intravenous antibiotics within eight hours of hospital admission. This was then modified, based on culture results.

In some of the studies, treatment of pneumonia with corticosteroids was just one part of the trial. In the study by Cao 2007 for example, the control group were given azithromycin or erythromycin for seven days, and in the budesonide (Pulmicort) group the participants also had budesonide (Pulmicort) inhalation 250 to 500 g/day for seven days in the control group. The study aimed to compare the effectiveness of budesonide and azithromycin and erythromycin for M. pneumonia in children. We only focused on the results of the effectiveness of budesonide.

The van Woensel 2003 study looked at the effectiveness of corticosteroids for pneumonia and bronchiolitis. The trial medication was intravenous dexamethasone (0.15 mg/kg six-hourly for 48 hours) or placebo and had to have been started within 24 hours of mechanical ventilation.

These trials mainly measured improvements in oxygenation (Confalonieri 2005), time to resolution of symptoms or time to clinical stability (Cao 2007; Confalonieri 2005; Mikami 2007) and the length of hospital stay or ICU stay (Marik 1993; Mikami 2007; van Woensel 2003). One study measured mortality (Marik 1993). The outcomes of each trial are noted in the Characteristics of included studies table.

Excluded studies

Most of the excluded studies were retrospective. Some did not use random allocation and were excluded because the trial author refused to give details of the study. The reasons for exclusion can be found in the Characteristics of excluded studies table.

Risk of bias in included studies

Two studies were of higher quality (Confalonieri 2005; van Woensel 2003) and four were of poorer quality (Cao 2007; Marik 1993; McHardy 1972; Mikami 2007). The summary of quality assessment can be found in Figure 2 and Figure 3.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All of the participants were randomly allocated. Randomisation methods for two studies (Confalonieri 2005; van Woensel 2003) involved generation in blocks of 10 for each participating site by a randomisation centre. The Cao 2007 study did not provide any information about the method of randomisation. We telephoned Dr. Cao who told us that the allocation sequence was generated by computer but we still judged the randomisation method as unclear and the allocation procedure was not concealed because the author mentioned that the participants "were selected by sampling from the in-patients". In Marik 1993, participants were randomized by a random number generator to receive either hydrocortisone or placebo. In McHardy 1972, the method of generating and concealing the allocation sequence was not mentioned. In Mikami 2007, the study did not reveal the details of the method of randomisation, it just mentioned that they divided the participants randomly but the allocation concealment in this trial was well done, because the investigators were not actively involved in the treatment of the participants and the physicians who took care of the participants were not informed of the outcome parameters. In fact, most of the included trials performed adequate allocation concealment, either by sealed envelopes (Cao 2007; Confalonieri 2005) or by keeping the concealed randomisation list in a separate location (van Woensel 2003). However, in the trial by Marik 1993, allocation concealment was not clearly stated.

Blinding

There was no blinding in McHardy 1972 and Mikami 2007 as they were open-label trials. In Cao 2007, blinding was not clearly stated in the article, so we contacted the trial author and discovered that it was a single-blinded trial, because the doctor knew the treatment assignment while the participants did not. The other trials are double-blinded, placebo-controlled studies.

Incomplete outcome data

Incomplete outcome data was clearly stated in the included studies if they had drop-outs or losses to follow up (Confalonieri 2005; van Woensel 2003). There was no risk of attrition bias for the other four studies.

Selective reporting

There was no evidence of selective reporting.

Other potential sources of bias

This was not clearly stated in the included studies.

Effects of interventions

We collected data on the basis of corticosteroid treatment plus antibiotic therapy or antibiotics only. The corticosteroid treatment included hydrocortisone, prednisolone, budesonide and dexamethasone. The baseline characteristics were clearly stated in the studies and the groups were comparable with regards to sex and age distribution and severity of the disease, except for Cao 2007 and van Woensel 2003. In Cao 2007, there were 32 more boys than girls. In van Woensel 2003 the proportion of males was higher and patients were significantly younger in the dexamethasone group than in the placebo group.

Mortality

In three studies participants receiving hydrocortisone or prednisolone displayed no statistically significant differences compared with placebo (Peto odds ratio (OR) 0.26; 95% CI 0.05 to 1.37; and Peto OR1.41, 95% CI 0.39 to 5.04, respectively). One participant died in the hydrocortisone group and five in the control group (Confalonieri 2005; Marik 1993) (Analysis 1.1), nine died in ampicillin alone groups and three in ampicillin plus prednisolone groups, respectively (McHardy 1972) (Analysis 2.1).

Improvement in oxygenation

There are several ways to measure oxygenation, including as partial pressure of oxygen in arterial blood (PaO2), inspired oxygen concentration (FIO2) and saturation of blood oxygen (SpO2). In Confalonieri 2005, participants receiving hydrocortisone displayed significantly greater improvement in PaO2: FIO2 compared with placebo (mean difference (MD) 95.00; 95% CI 45.17 to 144.83) (Analysis 1.3) and significantly more participants had PaO2: FIO2 improvement ≥100 from study entry (RR 2.50, 95% CI 1.40 to 4.47) (Analysis 1.2). In Mikami 2007, the trialists detected the days to normalisation of SpO2. However, participants receiving prednisolone did not display significantly faster normalisation of SpO2 (MD -2.10; 95% CI -4.43 to 0.23) (Analysis 2.4).

Time to pneumonia resolution

There were no reports of time to pneumonia resolution.

Time to resolution of symptoms or time to clinical stability

Resolution of symptoms and clinical stability can be calculated as improvement in chest radiograph and normalisation of body temperature, respiratory rate, white blood cell (WBC) and C reactive protein. In Confalonieri 2005, participants receiving prednisolone displayed significantly lower chest radiograph scores (MD -1.50; 95% CI -2.10 to -0.90) and significantly higher improvement in chest radiograph scores from day 1 to day 8 (RR 4.20; 95% CI 1.91 to 9.21) (Analysis 1.4, Analysis 1.5).

In McHardy 1972 the duration of treatment, change of treatment, resolution of temperature, clearance of pathogens from sputum or laryngeal swabs and maximum radiological clearance were reported. None of the outcomes identified important differences between ampicillin groups and ampicillin plus prednisolone groups (Analysis 2.2 and Analysis 2.3).

In Mikami 2007, participants receiving prednisolone showed faster normalisation of body temperature (MD -3.60; 95% CI -6.28 to -0.92) (Analysis 2.7), respiratory rate (MD -3.40; 95% CI -5.52 to -1.28) (Analysis 2.8) and normalisation of C reactive protein (MD -4.10; 95% CI -7.15 to -1.05) (Analysis 2.9) compared to the placebo group. There was no significant difference between prednisolone and placebo in terms of WBC (MD 2.00; 95% CI -0.61 to 4.61) (Analysis 2.10). The Cao 2007 study showed clinical symptoms disappearing faster in the budesonide treatment group than in the control group (MD -8.00; 95% CI -9.25 to -6.75) (Analysis 3.1).

Relapse of the disease

In Cao 2007, participants receiving budesonide showed a lower rate of relapse (MD -2.43; 95% CI -2.79 to -2.07) compared with the comparison group (Analysis 3.2).

Proportion of patients requiring either ventilatory or inotropic support, or both

Participants receiving hydrocortisone in two trials (Confalonieri 2005; Marik 1993) displayed less need for mechanical ventilation (RR 0.43; 95% CI 0.22 to 0.85) than participants receiving placebo (Analysis 1.6). In van Woensel 2003 the dexamethasone group had significantly longer mechanical ventilation (MD 0.80; 95% CI 0.15 to 1.45) and duration of supplemental oxygen (MD 1.70; 95% CI 0.75 to 2.65) compared to the placebo group (Analysis 4.1 and Analysis 4.2).

Rate of admission to intensive care unit (ICU)

There were no reports of admissions to ICU.

Time to discharge from ICU

In Marik 1993, participants receiving hydrocortisone displayed no difference in length of stay in the ICU (MD -0.30; 95% CI -3.81 to 3.21) compared to the placebo group (Analysis 1.7). In van Woensel 2003 there was no difference between the dexamethasone group and the placebo group in terms of length of stay in the pediatric ICU (MD 0.20; 95% CI -0.50 to 0.90) (Analysis 4.3).

Adverse events

Arrhythmia (one case) and upper gastrointestinal bleeding (one case) were reported in Confalonieri 2005. One participant developed malignant hypertension three days after medication (van Woensel 2003). No other severe adverse events were reported.

Discussion

Summary of main results

In statistical terms, corticosteroids did not significantly reduce mortality in participants with pneumonia. However, there was obvious clinical value: in two small studies (Confalonieri 2005; Marik 1993) one participant the corticosteroid group died compared to five deaths in the placebo group. Corticosteroids can accelerate the resolution of symptoms and clinical stability and reduce relapse rates of the disease. Improvement in oxygenation, need for ventilatory or inotropic support and time to discharge from the intensive care unit (ICU) differed between the studies, therefore subgroup analyses were necessary. There were no data, or insufficient data, to examine the time to pneumonia resolution and rate of admission to ICU. Typical adverse events associated with corticosteroid therapy were infrequent.

The use of corticosteroids showed significantly better oxygenation in terms of PaO2:FIO2 and PaO2, FIO2 improved in the Confalonieri 2005 trial but it did not coincide with an improvement of SpO2 in the Mikami 2007 study. These differences can be attributed to the participants in these two studies: the Mikami 2007 study excluded severe and septic cases, while Confalonieri 2005 study participants had severe community-acquired pneumonia (CAP). In mild pneumonia the decrease in oxygenation is not obvious, thus improvement associated with corticosteroid use can be subtle in these cases. As a result, with respect to oxygenation, corticosteroids are only beneficial for severe pneumonia. We should note that although the PaO2 and FIO2 appeared to be statistically significantly better compared to receiving hydrocortisone with placebo (mean difference (MD) 95.00; 95% CI 45.17 to 144.83) its clinical importance is still doubtful.

In Confalonieri 2005 and Marik 1993, the application of hydrocortisone also reduced the need for mechanical ventilation and length of stay in the ICU, while in van Woensel 2003 the need for mechanical ventilation and supplemental oxygen increased, as did the length of stay in ICU after using dexamethasone. Although the three studies focused on participants with severe pneumonia, the difference was that participants in the van Woensel 2003 study were respiratory syncytial virus (RSV) infected children, including both the bronchiolitis and pneumonia subgroups. RSV is a common cause of lower respiratory tract infection in infants and children. The results of the van Woensel 2003 trial showed that corticosteroids benefited the bronchiolitis subgroup only. In other participants with severe pneumonia, the reduced need for mechanical ventilation was related to oxygenation improvement and inflammation relief from corticosteroids (Confalonieri 2005; Marik 1993).

In Cao 2007, the main focus was M. pneumoniae in children; it detected the duration of clinical symptoms and the rate of relapse. The results of this study showed that the a corticosteroid (budesonide) can decrease the duration of clinical symptoms and the rate of relapse. Mycoplasma pneumoniae (M. pneumoniae) infection is a common cause of pneumonia, especially in children, accounting for 10% to 40% of all pneumonia in children and it is characterized by a long clinical course and repeated infection (Esposito 2001). M. pneumoniae is a superantigen which can activate the macrophages and induce secretion of cytokine, so the inflammation response is intense. Corticosteroids can act as an anti-inflammatory agent for children with M. pneumoniae.

We would have liked to have answered three important questions:

  1. whether the incidence of complications of pneumonia (such as severe sepsis or acute respiratory distress syndrome (ARDS)) could be reduced by corticosteroids;

  2. whether the occurrence of relative adrenal insufficiency is a possible rationale for using corticosteroids in pneumonia; and

  3. whether there are any dose-effect relationships between corticosteroids and pneumonia?

Overall completeness and applicability of evidence

On the whole, corticosteroids can improve clinical symptoms and reduce the rate of relapse of mild pneumonia. In severe pneumonia corticosteroids can improve oxygenation and clinical symptoms and reduce mechanical ventilation and length of stay in ICU. Further trials would help clarify the validity of the findings of this review and could determine more clearly the role of corticosteroids in patients with pneumonia in comparison with other therapies.

Quality of the evidence

In general, the quality of the evidence is still weak (Figure 4; Figure 5; Figure 6; Figure 7; Figure 8; Figure 9) due to the fact that the results were taken from small, single studies. We collected the information by telephoning trial authors rather than relying on published articles. In addition, the blinding procedures were not adequate (Cao 2007). The Mikami 2007 study was an open-label study and the detailed method of randomisation was not clearly stated. Allocation concealment was not clear in Marik 1993 so there is also a risk of selection bias. The two other higher quality studies included only small numbers of participants (Confalonieri 2005; van Woensel 2003).

Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.

Potential biases in the review process

Some of the trials that we encountered claimed to be randomized controlled trials. We contacted the trial authors and found out that many of the studies were either retrospective or incorrect in their method of randomisation. We allocated studies where we could not contact the trial author or we could not find the full text to Studies awaiting classification.

Agreements and disagreements with other studies or reviews

We were unable to find other reviews or meta-analyses of corticosteroids for pneumonia, but a review of corticosteroid therapy for sepsis and related syndromes (Annane 2009) found that prolonged low-dose corticosteroid therapy could have a beneficial effect on short-term mortality.

Authors' conclusions

Implications for practice

In patients with pneumonia, corticosteroids may relieve symptoms but the evidence is weak. In severe pneumonia, corticosteroids can also be used to improve oxygenation and reduce the use of mechanical ventilation. However, there is insufficient evidence to confirm whether they can reduce mortality and resolve pneumonia. We do not recommend the use of steroids for respiratory syncytial virus-infected children with pneumonia because there is no significant benefit for the patient. However, we do recommend corticosteroids for M. pneumoniae infected children because corticosteroids can significantly relieve clinical symptoms and prevent relapse of the disease. Our included studies did not compare the effects of different doses of corticosteroids and so we are unable to make any recommendations with regards to the dosage of corticosteroids in clinical practice. Due to the limitations of the included studies and the review process, the quality of evidence is low.

Implications for research

More large clinical trials of corticosteroids for pneumonia are needed to enhance the body of evidence. These trials need to be designed for patients with severe pneumonia and patients with mild pneumonia, and children and adults, covering the different causes of pneumonia. We encourage trialists to measure changes in pneumonia resolution, symptom relief, oxygenation, length of stay in ICU and rate of admission to ICU. In the meantime, more data concerning adverse events need to be reported to guide our application of corticosteroids. Future studies should explore whether the occurrence of relative adrenal insufficiency is a possible rationale for using corticosteroids in pneumonia or not, and whether prolonged low-dose corticosteroid therapy can benefit mortality or not.

Acknowledgements

The review authors wish to thank Elizabeth Dooley (Managing Editor), Clare Dooley (Assistant Managing Editor) and Sarah Thorning (Trials Search Co-ordinator) of the Cochrane ARI Group. We would also like to thank the following people for commenting on the draft protocol: Anne Lyddiatt, Chanpen Choprapawon, Marco Confalonieri, Sree Nair and Allen Cheng; and Amanda Young, Marco Confalonieri, Robert Ware and Allen Cheng for commenting on the draft review.

Data and analyses

Download statistical data

Comparison 1. Hydrocortisone versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality276Peto Odds Ratio (Peto, Fixed, 95% CI)0.26 [0.05, 1.37]
2 PaO2:FIO2improvement ≥100 from study entry146Risk Ratio (M-H, Fixed, 95% CI)2.5 [1.40, 4.47]
3 PaO2:FIO2146Mean Difference (IV, Fixed, 95% CI)95.00 [45.17, 144.83]
4 Chest radiograph score146Mean Difference (IV, Fixed, 95% CI)-1.5 [-2.10, -0.90]
5 Improvement in chest radiograph score from day 1 to day 8146Risk Ratio (M-H, Fixed, 95% CI)4.2 [1.91, 9.21]
6 On mechanical ventilation276Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.22, 0.85]
7 Length of stay in the ICU130Mean Difference (IV, Fixed, 95% CI)-0.30 [-3.81, 3.21]
Analysis 1.1.

Comparison 1 Hydrocortisone versus placebo, Outcome 1 Mortality.

Analysis 1.2.

Comparison 1 Hydrocortisone versus placebo, Outcome 2 PaO2:FIO2improvement ≥100 from study entry.

Analysis 1.3.

Comparison 1 Hydrocortisone versus placebo, Outcome 3 PaO2:FIO2.

Analysis 1.4.

Comparison 1 Hydrocortisone versus placebo, Outcome 4 Chest radiograph score.

Analysis 1.5.

Comparison 1 Hydrocortisone versus placebo, Outcome 5 Improvement in chest radiograph score from day 1 to day 8.

Analysis 1.6.

Comparison 1 Hydrocortisone versus placebo, Outcome 6 On mechanical ventilation.

Analysis 1.7.

Comparison 1 Hydrocortisone versus placebo, Outcome 7 Length of stay in the ICU.

Comparison 2. Prednisolone plus antibiotics versus antibiotics alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1126Peto Odds Ratio (Peto, Fixed, 95% CI)1.41 [0.39, 5.04]
1.1 Ampicillin (1g daily) vs ampicillin (1g daily) with prednisolone (20mg daily)163Peto Odds Ratio (Peto, Fixed, 95% CI)2.72 [0.56, 13.22]
1.2 Ampicillin (2g daily) vs ampicillin (2g daily) with prednisolone (20mg daily)163Peto Odds Ratio (Peto, Fixed, 95% CI)0.41 [0.05, 3.57]
2 Participants require to change the treatment1126Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.33, 2.14]
2.1 Ampicillin (1g daily) vs ampicillin (1g daily) plus prednisolone163Odds Ratio (M-H, Fixed, 95% CI)1.46 [0.27, 7.96]
2.2 Ampicillin (2g daily) vs ampicillin (2g daily) plus prednisolone163Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.20, 2.01]
3 Duration of treatment (number of participants to be treated more than two weeks)1126Odds Ratio (M-H, Fixed, 95% CI)2.0 [0.53, 7.53]
3.1 Ampicillin (1g) vs ampicillin (1g) plus prednisolone (20mg)163Odds Ratio (M-H, Fixed, 95% CI)3.08 [0.35, 27.48]
3.2 Ampicillin (2g) vs ampicillin (2g) plus prednisolone (20mg)163Odds Ratio (M-H, Fixed, 95% CI)1.46 [0.27, 7.96]
4 Time to normalisation of spO2 (days)131Mean Difference (IV, Fixed, 95% CI)-2.10 [-4.43, 0.23]
5 Length of hospital stay (days)131Mean Difference (IV, Fixed, 95% CI)-4.20 [-10.14, 1.74]
6 Duration of IV antibiotics (days)131Mean Difference (IV, Fixed, 95% CI)-3.80 [-6.94, -0.66]
7 Time to normalisation of body temperature (days)131Mean Difference (IV, Fixed, 95% CI)-3.6 [-6.28, -0.92]
8 Time to normalisation of respiratory rate (days)131Mean Difference (IV, Fixed, 95% CI)-3.40 [-5.52, -1.28]
9 Time to normalisation of C reactive protein (days)131Mean Difference (IV, Fixed, 95% CI)-4.1 [-7.15, -1.05]
10 Time to normalisation of WBC (days)131Mean Difference (IV, Fixed, 95% CI)2.00 [-0.61, 4.61]
Analysis 2.1.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 1 Death.

Analysis 2.2.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 2 Participants require to change the treatment.

Analysis 2.3.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 3 Duration of treatment (number of participants to be treated more than two weeks).

Analysis 2.4.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 4 Time to normalisation of spO2 (days).

Analysis 2.5.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 5 Length of hospital stay (days).

Analysis 2.6.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 6 Duration of IV antibiotics (days).

Analysis 2.7.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 7 Time to normalisation of body temperature (days).

Analysis 2.8.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 8 Time to normalisation of respiratory rate (days).

Analysis 2.9.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 9 Time to normalisation of C reactive protein (days).

Analysis 2.10.

Comparison 2 Prednisolone plus antibiotics versus antibiotics alone, Outcome 10 Time to normalisation of WBC (days).

Comparison 3. Budesonide (Pulmicort) plus antibiotics versus antibiotics only
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to clinical symptoms disappearing160Mean Difference (IV, Fixed, 95% CI)-8.0 [-9.25, -6.75]
2 Rate of relapse160Mean Difference (IV, Fixed, 95% CI)-2.43 [-2.79, -2.07]
Analysis 3.1.

Comparison 3 Budesonide (Pulmicort) plus antibiotics versus antibiotics only, Outcome 1 Time to clinical symptoms disappearing.

Analysis 3.2.

Comparison 3 Budesonide (Pulmicort) plus antibiotics versus antibiotics only, Outcome 2 Rate of relapse.

Comparison 4. Intravenous dexamethasone versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Duration of mechanical ventilation141Mean Difference (IV, Fixed, 95% CI)0.80 [0.15, 1.45]
2 Duration of supplemental oxygen141Mean Difference (IV, Fixed, 95% CI)1.70 [0.75, 2.65]
3 Length of stay in the paediatric intensive care unit141Mean Difference (IV, Fixed, 95% CI)0.20 [-0.50, 0.90]
4 Length of stay in the hospital141Mean Difference (IV, Fixed, 95% CI)2.60 [1.43, 3.77]
Analysis 4.1.

Comparison 4 Intravenous dexamethasone versus placebo, Outcome 1 Duration of mechanical ventilation.

Analysis 4.2.

Comparison 4 Intravenous dexamethasone versus placebo, Outcome 2 Duration of supplemental oxygen.

Analysis 4.3.

Comparison 4 Intravenous dexamethasone versus placebo, Outcome 3 Length of stay in the paediatric intensive care unit.

Analysis 4.4.

Comparison 4 Intravenous dexamethasone versus placebo, Outcome 4 Length of stay in the hospital.

Appendices

Appendix 1. Embase.com search strategy

#16. #12 AND #15
#15. #13 OR #14
#14. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross-over':ab,ti OR 'cross over':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#13. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#12. #6 AND #11
#11. #7 OR #8 OR #9 OR #10
#10. prednisone*:ab,ti OR prednisolone*:ab,ti OR methylprednisolone*:ab,ti OR betamethasone*:ab,ti OR dexamethasone*:ab,ti OR triamcinolone:ab,ti OR hydrocortisone*:ab,ti
#9. steroid*:ab,ti OR corticosteroid*:ab,ti
#8. 'corticosteroid'/exp
#7. 'steroid'/exp
#6. #1 OR #2 OR #3 OR #4 OR #5
#5. 'adult respiratory distress syndrome':ab,ti OR 'acute respiratory distress syndrome':ab,ti OR ards:ab,ti
#4. 'adult respiratory distress syndrome'/de
#3. cap:ab,ti OR hap:ab,ti
#2. pneumon*:ab,ti
#1. 'pneumonia'/exp

What's new

Last assessed as up-to-date: 31 December 2010.

DateEventDescription
5 July 2012AmendedCorrection to Analysis 1.5 graph label made

Contributions of authors

All four review authors, Yuanjing Chen (YC), Ka Li (KL), Hongshan Pu (HP) and Taixiang Wu (TW) were responsible for developing and writing the protocol and review.

Declarations of interest

None known.

Sources of support

Internal sources

  • West China Hospital, Sichuan University, China.

External sources

  • Cochrane Acute Respiratory Infections Group, Australia.

Differences between protocol and review

We were unable to conduct sensitivity analyses and funnel plots for analysing publication bias due to the small number of included studies.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cao 2007

Methods

Design: randomized controlled trial

Method of randomisation: adequate. Randomisation numbers were generated by computer

Concealment of allocation: adequate. The randomisation numbers were sealed in envelopes

Outcome assessor blinding: unclear

Withdrawals/drop-outs: all participants accounted for

Participants

Country: China

Eligible: not clearly stated in the article

Randomised: 120 (30 in control group, 30 in budesonide (Pulmicort) group, 30 in clarityne (loratadine tablets) group, 30 in thymosin or Transfer Factor injection)

Completed: 120

Age: from 3 months to 14 years old. The detail of the age proportion in each group was not stated in the article

Sex: 76 males and 44 females in the study, but the detail of the sex proportion in each group was not stated in the article

Diagnosis: not clearly stated in the article

Interventions

Control group: azithromycin or erythromycin

Budesonide (Pulmicort): azithromycin or erythromycin as control group plus budesonide (Pulmicort) inhalation 250 to 500 g/d for 7 days

Clarityne group: azithromycin or erythromycin as control group plus oral clarityne (loratadine tablets) for 1 month

Thymosin or Transfer Factor injection: thymosin 5 mg or Transfer Factor 1 U per time, twice a week for 1 month

Outcomes

The period until clinical symptoms resolved

The frequency of recurrent respiratory tract infections

The level of serum eosinophil cationic protein (ECP), eosinophils (EOS), interleukin-4 (IL- 4) and total immunoglobulin E (T- IgE)

NotesIn the article there was no description about the randomisation method. We telephoned the author and were told that the allocation sequence was generated by computer and the randomized numbers were sealed in envelopes. The assignment of the treatment for each participant was done by opening the envelopes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method was not mentioned in the article
Allocation concealment (selection bias)High riskNot mentioned in the article
Blinding (performance bias and detection bias)
All outcomes
High riskNot stated clearly in the text. We contacted the author who told us it was single-blinded because the doctor knew the assignment of the treatment
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data in the study
Selective reporting (reporting bias)Unclear riskNot described
Other biasHigh riskNot clearly stated in the article

Confalonieri 2005

Methods

Design: randomized, double-blind, placebo-controlled trial

Method of randomisation: adequate. Randomisation schemes were generated in blocks of 10 for each participating site by a central randomisation centre

Concealment of allocation: adequate. The randomisation assignment was given to the recruiting centre in sealed envelopes

Outcome assessor blinding: yes

Withdrawals/drop-outs: all participants accounted for, apart from 2 participants who met the exclusion criteria after randomisation

Participants

Eligible: assessed 121 for eligibility, 52 met eligibility criteria and 48 participants consented to the study

Randomised: 48 (24 in hydrocortisone infusion group, 24 in placebo group)

Completed: 46 (23 in hydrocortisone infusion group, 23 in placebo group)

Age: hydrocortisone infusion group: 60.4 (± 17.3), placebo group: 66.6 (± 14.7)

Sex (male): hydrocortisone infusion group: 15, placebo group: 17

Diagnosis: clinical and radiographic evidence of pneumonia

Interventions

Hydrocortisone infusion group: hydrocortisone was given as an intravenous 200 mg loading bolus followed by an infusion (hydrocortisone 240 mg in 500 cc 0.9% saline) at a rate of 10 mg/hour for 7 days and protocol-guided antibiotic treatment

Placebo group: protocol-guided antibiotic treatment plus placebo

Outcomes

Improvement in PaO2:FiO2 (PaO2:FiO2 300 or 100 increase from study entry)

Multiple organ dysfunction syndrome (MODS) score by study day 8

Development of delayed septic shock

Duration of mechanical ventilation

Length of ICU and hospital stay

Survival until hospital discharge and to 60 days after discharge

NotesRandomisation schemes were generated in blocks of 10 for each participating site by a central randomisation centre. The randomisation assignment was given to the recruiting centre in sealed envelopes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation schemes were generated in blocks of 10 for each participating site by a central randomisation centre
Allocation concealment (selection bias)Low riskThe randomisation assignment was provided to the recruiting centre in sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskThe participants did not know whether they were given hydrocortisone or placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for, except 2 participants who met the exclusion criteria after randomisation
Selective reporting (reporting bias)Unclear riskNot described
Other biasUnclear riskNot clearly stated in article

Marik 1993

Methods

Design: prospective, randomized, placebo-controlled trial

Method of randomisation: adequate; participants were randomized by a random number generator to receive either hydrocortisone or placebo

Concealment of allocation: unclear

Outcome assessor blinding: yes

Withdrawals/drop-outs: all participants accounted for

Participants

Eligible: not stated

Randomised: 30 (14 in hydrocortisone group, 16 in placebo group)

Completed: 30 (14 in hydrocortisone group, 16 in placebo group)

Age: hydrocortisone group: 40.6 ± 14.7, placebo group: 31.7 ± 12.8

Sex: not stated in the article

Diagnosis: the diagnosis of pneumonia was based on clinical signs and symptoms of lower respiratory tract infection

Interventions

The participants received 10 mg/kg of hydrocortisone or placebo intravenously 30 minutes prior to starting antibiotic therapy

All participants were treated with cefotaxime 1 g intravenously every 6 hours

Outcomes

The level of Tumour Necrosis Factor-α in both groups

The length of stay in the ICU

APACHE score

Mortality

NotesParticipants were randomized by a random number generator to receive either hydrocortisone or placebo
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomized by a random number generator to receive either hydrocortisone or placebo
Allocation concealment (selection bias)High riskIt was not clearly stated in the text
Blinding (performance bias and detection bias)
All outcomes
Low riskThe participants did not know the drug they were given
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data in the trial
Selective reporting (reporting bias)Unclear riskNot reported
Other biasUnclear riskNot described

McHardy 1972

MethodsThe study was carried out in the respiratory wards of the City Hospital, Edinburgh, New South Wales, Australia. Parallel design
Participants

126 participants were included and no children under 12 years of age. The criteria for inclusion were radiological evidence of pneumonia or clinical evidence of pneumonia if no pre-treatment chest radiograph was available. Participants with pneumonia were excluded if they were either classed as "desperately ill" and judged to be at risk of dying within 24 hours, if they were known to be hypersensitive to penicillin or ampicillin. Patients with diabetes mellitus or symptoms of recent peptic ulceration were included in the ampicillin dosage trial but excluded from the random allocation of prednisolone

The participants were divided into four groups, 43 in group 1, 20 in group 2, 43 in group 3 and 20 in group 4

InterventionsPariticipants in group 1 were administered ampicillin 1 g daily; ampicillin 1 g plus prednisolone 20 mg daily in group 2; ampicillin 2 g daily in group 3 and ampicillin 2 g plus prednisolone 20 mg daily in group 4
Outcomes1. Death
2. Duration of treatment
3. Change of treatment
4. Resolution of temperature
5. Clearance of pathogens from sputum or laryngeal swabs
6. Maximum radiological clearance
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of generating the allocation sequence was not described in detail
Allocation concealment (selection bias)High riskAllocation concealment was not mentioned
Blinding (performance bias and detection bias)
All outcomes
High riskNot mentioned
Incomplete outcome data (attrition bias)
All outcomes
Low risk 

Mikami 2007

Methods

Design: prospective, randomized, open-label, controlled trial

Method of randomisation: unclear

Concealment of allocation: adequate

Outcome assessor blinding: yes

Withdrawals/drop-outs: all participants were accounted for

Participants

Eligible: 110 hospitalized participants with adult CAP; 60 met eligibility criteria and 31 patients consented to the study

Randomised: 31

Completed: 31 (15 in steroid group, 16 in control group)

Age: steroid group: 75.9 (± 16.0), control group: 68.4 (± 22.8)

Sex (male): steroid group: 73.3%, control group: 75.0%

Diagnosis: the diagnosis of CAP was based on clinical signs and symptoms of lower respiratory tract infections. Radiographic abnormalities consistent with infection were neither pre-existing nor caused by any other previous conditions

Interventions

Steroid group: 40 mg of prednisolone intravenously for 3 days plus intravenous antibiotics within 8 hours of hospital arrival and modified based on culture results

Control group: intravenous antibiotics within 8 hours of hospital arrival and modified based on culture results

Outcomes

Length of hospital stay

Duration of IV antibiotic treatment and time required to stabilise vital signs

Notes

The investigators were not actively involved in the treatment of the participants and the physicians who took care of the participants were not informed of the outcome parameters. Decisions on the time to discharge or the time to finish intravenous antibiotic therapy were made with objective data and were dependent on the condition of the participant

Sources of the drugs not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMentioned randomisation in the article, but did not describe the method
Allocation concealment (selection bias)High riskDid not mention this in the article
Blinding (performance bias and detection bias)
All outcomes
High riskAn open-label study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing data
Selective reporting (reporting bias)Unclear riskNot reported
Other biasUnclear riskNot described

van Woensel 2003

  1. a

    APACHE score = Acute Physiology and Chronic Health Evaluation Score
    CAP = community-acquired pneumonia
    FIO2 = inspired oxygen concentration
    ICU = intensive care unit
    IV = intravenous
    PaO2 = partial pressure of oxygen in arterial blood
    PICU = Paediatric Intensive Care Unit
    RSV = respiratory syncytial virus
    SpO2 = saturation of blood oxygen

Methods

Design: prospective, multicentre, randomized, double-blind, placebo-controlled trial

Method of randomisation: adequate

Concealment of allocation: adequate

Outcome assessor blinding: yes

Withdrawals/drop-outs: 3 participants dropout

Participants

Eligible: 155 eligible patients. Not randomized (n = 70) including not approached for participation (n = 29), more than 24 hours mechanical ventilation (n = 12), corticosteroids before randomisation (n = 11), and no permission from parents (n = 18)

Randomised: 85 (39 in steroid group, 46 in control group)

Completed: 82 (37 in steroid group including 18 bronchiolitis and 17 pneumonia, 45 in control group including 21 bronchiolitis and 22 pneumonia)

Age: steroid group: 5.9 (0.9), control group: 9.8 (1.6)

Sex: steroid group male: 30, control group: 27

Diagnosis: the diagnosis was based on clinical signs and symptoms of lower respiratory tract infection. The presence of RSV infection was confirmed by direct immunofluorescence assay (Imagen, Dako, Denmark) of a nasopharyngeal aspirate during the first 24 hours after hospital admission

InterventionsThe trial medication was intravenous dexamethasone (0.15 mg/kg 6-hourly for 48 hours) or placebo and had to be started within 24 hours after the start of mechanical ventilation
Outcomes

Duration of mechanical ventilation

Length of stay in the PICU and in the hospital

Duration of supplemental oxygen

NotesParticipants were allocated to dexamethasone or placebo by computerized block randomisation in groups of 10, centrally performed by an independent pharmacist. Each participating centre received a randomisation list and the trial medication preparation protocol. The trial medication was prepared in advance in the pharmacy centre where the concealed randomisation list was kept until the study was completed. Each enrolled participant received the trial medication with the next number in sequence
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were allocated to dexamethasone or placebo by computerized block randomisation in groups of 10, centrally performed by an independent pharmacist. Each participating centre received a randomisation list and the trial medication preparation protocol
Allocation concealment (selection bias)Low riskThe trial medication was prepared in advance in the pharmacy centre where the concealed randomisation list was kept until the study was completed
Blinding (performance bias and detection bias)
All outcomes
Low riskEach enrolled participant received the trial medication with the next number in sequence
Incomplete outcome data (attrition bias)
All outcomes
Low riskAfter enrolment 3 participants were withdrawn: 1 (dexamethasone group) because she died 4 days after admission due to severe cerebral oedema in combination with refractory seizures already existing before inclusion, and 2 because their medication vials (1 containing dexamethasone and the other placebo) were accidentally interchanged
Selective reporting (reporting bias)Unclear riskNo report
Other biasUnclear riskNot described

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bai 2003The author refused to explain the details of the study
Cai 2007We contacted the trial author who told us it was a retrospective study
Chen 2006We contacted the trial author who told us it was a retrospective study
Chen 2006bWe contacted the trial author who told us it was a retrospective study
Chen 2007The study mainly worked on the effect of ambroxol. We contacted the trial author who told us it was a retrospective study
Chu 2009We contacted the trial author who told us that there was no blinding in the study and the participants were allocated by the date of administration
Dai 2009We contacted the trial author who told us it was a retrospective study
Fang 2003We contacted the trial author who told us it was a retrospective study
Feng 2001We contacted the trial author who told us it was a retrospective study
Finch 2002The treatment drug did not include corticosteroids
Guan 2004We contacted the author but she refused to give details of the study
Han 2003We contacted the trial author who told us it was a retrospective study
Han 2007We contacted the trial author who told us it was a retrospective study
He 2008A prospective study. The participants were allocated casually by the doctor and there was no blinding in the study
Hong 2005We contacted the trial author who told us it was a retrospective study
Huang 2008We contacted the author who told us the study was retrospective and prospective. In the prospective part, the participants were allocated by the doctor according to the date of administration
Li 2006We contacted the trial author who told us it was a retrospective study
Marks 1972Hydrocarbon pneumonia is one of the most significant complications after ingestion of hydrocarbon distillates. Study did not meet our inclusion criteria
Mer 1998An uncontrolled, retrospective, prospective study
Song 2005We contacted the trial author who told us it was a retrospective study
Song 2008Mainly compared the effect of Mucosolvan in the study
Sun 2006We contacted the trial author who told us it was a retrospective study
Tao 2008We contacted the trial author who told us it was a retrospective study
Wang 2007We contacted the trial author who told us it was a retrospective study
Wong 2006In the study the investigator compared the effect of corticosteroids plus Mucosolvan; this did not meet our intervention inclusion criteria
Wu 2007We contacted the trial author who told us it was a retrospective study
Wu 2009We could not contact the author as he had changed workplace, so we could not determine whether the study was a randomized controlled trial
Xie 2005We contacted the trial author who told us it was a retrospective study
Zhang 2004We contacted the trial author who told us it was a retrospective study
Zhao 2008We contacted the author who told us it was a retrospective study. In addition, there were some other interventions in the corticosteroid group
Zheng 2008We contacted the trial author who told us it was a retrospective study

Characteristics of studies awaiting assessment [ordered by study ID]

Braun 1986

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Chen 2003

MethodsWe could not find the author as she had changed workplace
Participants 
Interventions 
Outcomes 
Notes 

Confalnonier 2006

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Dambrava 2006

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Hatakeyama 1995

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Lee 1980

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Li 2005

MethodsWe are trying to contact the author to identify the randomisation method used
Participants 
Interventions 
Outcomes 
Notes 

Li 2007

MethodsThe author was abroad, so we could not contact her
Participants 
Interventions 
Outcomes 
Notes 

Liu 2008

MethodsWe are trying to contact the author to identify the randomisation method used
Participants 
Interventions 
Outcomes 
Notes 

Lv 1991

MethodsWe are trying to contact the author to identify the randomisation method used
Participants 
Interventions 
Outcomes 
Notes 

Ma 2006

MethodsThe author was abroad, so we could not contact her
Participants 
Interventions 
Outcomes 
Notes 

Soboleva 2000

MethodsWe are trying to retrieve the article
Participants 
Interventions 
Outcomes 
Notes 

Wang 2008

MethodsWe are trying to contact the author to identify the randomisation method used
Participants 
Interventions 
Outcomes 
Notes 

Ancillary