Antibioprophylaxie locale pour réduire les infections des voies respiratoires et la mortalité chez les adultes sous ventilation mécanique
Résumé scientifique
Contexte
Les patients traités par ventilation mécanique en unités de soins intensifs (USI) ont un risque élevé de développer des infections des voies respiratoires (IVR). On estime que les pneumopathies acquises sous ventilation mécanique (PAVM) touchent 5 à 40 % des patients traités par ventilation mécanique pendant au moins 48 heures. Le taux de mortalité attribuable aux PAVM a été estimé à environ 9 %. La décontamination digestive sélective (DDS), qui consiste en l'application locale d'agents antimicrobiens non absorbables dans l'oropharynx et au niveau gastro‐entérique pendant toute la période de ventilation mécanique, est souvent utilisée pour réduire le risque de PAVM. Un traitement connexe est la décontamination oropharyngée sélective (DOS), durant laquelle des antibiotiques locaux sont appliqués uniquement dans l'oropharynx. Ceci est une mise à jour d'une revue publiée pour la première fois en 1997 et actualisée en 2002, 2004 et 2009.
Objectifs
Évaluer l'effet des schémas antibiotiques locaux (DDS et DOS), administrés seuls ou en association avec des antibiotiques systémiques, pour prévenir la mortalité et les infections respiratoires chez les patients recevant une ventilation mécanique pendant au moins 48 heures en USI.
Stratégie de recherche documentaire
Le 5 février 2020, nous avons effectué des recherches dans le registre central des essais contrôlés de Cochrane (CENTRAL), qui contient le registre spécialisé du groupe Cochrane sur les Infections Respiratoires Aiguës (IRA), PubMed, et Embase. Le 5 février 2020, nous avons également consulté le système d'enregistrement international des essais cliniques (ICTRP) de l'Organisation mondiale de la santé (OMS) et le site ClinicalTrials.gov pour trouver des études en cours et non publiées. Toutes les recherches ont inclus des documents non rédigés en anglais. Nous avons effectué des recherches manuelles dans les références bibliographiques des revues systématiques liées au sujet et dans leurs listes d’études incluses.
Critères de sélection
Les essais contrôlés randomisés (ECR) et les essais contrôlés randomisés en grappes évaluant l'efficacité et la tolérance des traitements antibiotiques prophylactiques locaux chez les adultes recevant des soins intensifs et une ventilation mécanique. Les études incluses comparent les antibiotiques locaux en association avec les antibiotiques systémiques par rapport à un placebo ou à l'absence de traitement, les antibiotiques locaux par rapport à l'absence de traitement et les antibiotiques locaux en association avec les antibiotiques systémiques par rapport aux antibiotiques systémiques seuls.
Recueil et analyse des données
Nous avons suivi les procédures méthodologiques standard définies par Cochrane.
Résultats principaux
Nous avons inclus un total de 41 essais impliquant 11 004 participants (cinq nouvelles études ont été ajoutées dans cette mise à jour). La durée minimale de la ventilation mécanique variait de deux (19 études) à six jours (une étude). Treize études ont rapporté la durée moyenne du séjour en unité de soins intensifs, allant de 11 à 33 jours. Le pourcentage de patients immunodéprimés variait de 0 % (10 études) à 22 % (une étude).
La qualité des rapports de la majorité des études incluses était très mauvaise, de sorte que nous avons jugé que plus de 40 % des études présentaient un risque incertain de biais de sélection. Nous avons jugé que toutes les études présentaient un faible risque de biais de performance, bien que 47,6 % d'entre elles soient ouvertes, car les hôpitaux ont généralement des programmes standardisés de contrôle des infections, et il est peu probable que des décisions subjectives soient prises pour savoir qui doit être testé pour la présence ou l'absence d'IVR dans une unité de soins intensifs. En ce qui concerne le biais de détection, nous avons jugé que toutes les études incluses présentaient un faible risque sur le critère de jugement mortalité. Pour les résultats des IVR, nous avons jugé que toutes les études en double aveugle présentaient un faible risque de biais de détection. Nous avons jugé que cinq études ouvertes présentaient un risque élevé de biais de détection, car le diagnostic des IVR n'était pas basé sur des examens microbiologiques ; nous avons jugé que les autres études ouvertes présentaient un faible risque de biais de détection car un ensemble standardisé de critères de diagnostic, y compris les résultats des examens microbiologiques, était utilisé.
L’association antibioprophylaxie locale et systémique réduit la mortalité globale par rapport au placebo ou à l'absence de traitement (rapport de risque (RR) de 0,84, intervalle de confiance (IC) à 95 %, 0,73 à 0,96 ; 18 études ; 5 290 participants ; données probantes d’un niveau de confiance élevé). Sur la base d'un risque indicatif de 303 décès sur 1 000 personnes, cela équivaut à 48 (IC à 95 %, 15 à 79) décès en moins avec l’association antibioprophylaxie locale et systémique. L’association antibioprophylaxie locale et systémique réduit probablement les IVR (RR 0,43, IC à 95%, 0,35 à 0,53 ; 17 études ; 2 951 participants ; données probantes d’un niveau de confiance modéré). Sur la base d'un risque indicatif de 417 IVR chez 1 000 personnes, cela équivaut à 238 (IC à 95 %, 196 à 271) IVR de moins avec l’association antibioprophylaxie locale et systémique.
L'antibioprophylaxie locale réduit probablement la mortalité globale par rapport à l'absence d'antibioprophylaxie locale (RR 0,96, IC à 95 %, 0,87 à 1,05 ; 22 études, 4 213 participants ; données probantes d’un niveau de confiance modéré). Sur la base d'un risque indicatif de 290 décès sur 1 000 personnes, cela équivaut à 19 (IC à 95 %, 37 de moins à 15 de plus) décès en moins avec une antibioprophylaxie locale. L'antibioprophylaxie locale pourrait réduire les IVR (RR 0,57, IC à 95 %, 0,44 à 0,74 ; 19 études, 2 698 participants ; données probantes d’un niveau de confiance faible). Sur la base d'un risque indicatif de 318 IVR chez 1 000 personnes, cela équivaut à 137 (IC à 95 %, 83 à 178) IVR de moins avec une antibioprophylaxie locale.
Seize études ont rapporté des événements indésirables et des abandons dus à des événements indésirables, lesquels ont été mal rapportés, avec des données éparses. Le niveau de confiance des données probantes allait de faible à très faible.
Conclusions des auteurs
Les traitements basés sur la prophylaxie locale réduisent probablement les infections respiratoires, mais pas la mortalité, chez les patients adultes qui reçoivent une ventilation mécanique pendant au moins 48 heures, alors qu'une association d'antibiotiques prophylactiques locaux et systémiques réduit à la fois la mortalité globale et les IVR. Toutefois, on ne peut exclure que la composante systémique du traitement combiné apporte une contribution non négligeable à la réduction observée de la mortalité. Nous ne pouvons pas tirer de conclusion sur les événements indésirables car ils ont été mal rapportés, avec des données éparses.
PICO
Résumé simplifié
Les antibiotiques locaux pour aider à réduire les décès et les infections respiratoires chez les personnes en soins intensifs qui reçoivent une ventilation mécanique
Problématique de la revue
Nous avions pour objectif d'évaluer l'effet de deux schémas antibiotiques locaux (décontamination digestive sélective (DDS) et décontamination oropharyngée sélective (DOS)) sur la prévention des décès et des infections respiratoires chez les patients recevant une ventilation mécanique pendant au moins 48 heures, en unités de soins intensifs (USI). Dans le cadre de la DDS, des antibiotiques non absorbables sont appliqués dans l'oropharynx (tiers arrière de la langue, palais mou, parois latérales et arrière de la gorge et amygdales), l'œsophage, l'estomac et l'intestin. La DOS implique l'application d'antibiotiques non absorbables dans l'oropharynx uniquement. Ces régimes peuvent être administrés seuls ou en association avec des antibiotiques systémiques.
Contexte
Les infections acquises dans les unités de soins intensifs sont des complications importantes du traitement par ventilation (assistance respiratoire mécanique invasive) chez les patients atteints de maladies très graves qui nécessitent un tel traitement. Certaines de ces personnes vont mourir à cause de ces infections. Une méthode qui a été évaluée pour réduire ces complications est l'utilisation d'antibiotiques comme mesure préventive.
Date des recherches
Les données de cette revue Cochrane sont à jour jusqu’au 5 février 2020.
Caractéristiques des études :
Nous avons inclus 41 essais impliquant un total de 11 004 patients sous ventilation mécanique en USI pour savoir si l'administration d'antibiotiques locaux, seuls ou en association avec des antibiotiques systémiques, permet de prévenir les infections des voies respiratoires et de réduire la mortalité. Les antibiotiques étaient administrés soit par voie locale (par exemple, les antibiotiques étaient appliqués directement dans l'oropharynx ou l'estomac via une sonde nasogastrique), soit par voie systémique (par exemple, par voie intraveineuse (directement dans la veine du patient)).
Sources de financement des études
Vingt‐deux études (52,4 %) n'ont pas indiqué la source de financement, 6 études (14,3 %) ont été soutenues par des subventions institutionnelles publiques et 13 études (30,1 %) ont été totalement ou partiellement financées par des sociétés pharmaceutiques.
Principaux résultats
Chez les patients recevant l’association d'antibiotiques locaux et systémiques, il y a eu moins de décès (données issues de 18 études avec 5 290 patients) et probablement moins d'infections des voies respiratoires (données provenant de 17 études avec 2 951 patients) par rapport aux patients n’ayant pas reçu le traitement, ou ayant reçu un placebo, bien que nous ne puissions pas exclure la possibilité que la composante systémique des traitements ait contribué à la réduction des décès. En supposant un risque illustratif de 303 décès et de 417 cas d'infections des voies respiratoires chez 1 000 personnes sous ventilation mécanique, nous prévoyons 48 décès de moins chez les patients qui reçoivent une association d'antibiotiques locaux et systémiques et 238 cas de moins d'infections des voies respiratoires. Lorsque les patients qui ont reçu des antibiotiques locaux seuls ont été comparés à ceux qui n'ont pas reçu le traitement, ou lorsque les patients qui ont reçu des antibiotiques locaux en association avec des antibiotiques systémiques ont été comparés à ceux qui ont reçu des antibiotiques systémiques seuls, le nombre de décès était probablement similaire (données issues de 22 études avec 4 213 patients), bien qu'il puisse y avoir moins d'infections des voies respiratoires chez les patients qui ont reçu une prophylaxie locale (données issues de 19 études, 2 698 patients). Les événements indésirables ont été peu rapportés, avec des données limitées.
Niveau de confiance des données probantes
Nous avons jugé que le niveau de confiance des données probantes était élevé à modéré pour les décès et les infections des voies respiratoires, et faible à très faible pour les événements indésirables.
Authors' conclusions
Summary of findings
| Topical plus systemic prophylaxisversus placebo or no treatment in adults receiving mechanical ventilation for at least 48 hours | |||||
| Patient or population: adults receiving mechanical ventilation for at least 48 hours | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with no prophylaxis | Risk with topical plus systemic | ||||
| Overall mortality | Study population | RR 0.84 | 5290 | ⊕⊕⊕⊕ | |
| 303 per 1000 | 255 per 1000 | ||||
| Respiratory tract infections | Study population | RR 0.43 | 2951 | ⊕⊕⊕⊝ | |
| 417 per 1000 | 179 per 1000 | ||||
| Dropouts due to adverse events | Study population | RR 1.06 | 1287 | ⊕⊕⊝⊝ | |
| 6 per 1000 | 7 per 1000 | ||||
| Gastrointestinal adverse events | Study population | RR 1.08 | 2637 | ⊕⊕⊝⊝ | |
| 44 per 1000 | 48 per 1000 | ||||
| Allergic adverse events | Study population | RR 1.49 | 2981 | ⊕⊕⊝⊝ | |
| 0 per 1000 | 1 per 1000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| aDowngraded 1 level for suspected publication bias, as indicated by asymmetry in the funnel plot. | |||||
| Topical prophylaxis versus no topical prophylaxis in adults receiving mechanical ventilation for at least 48 hours | |||||
| Patient or population: adults receiving mechanical ventilation for at least 48 hours | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with control | Risk with topical | ||||
| Overall mortality | Study population | RR 0.96 | 4213 | ⊕⊕⊕⊝ | |
| 290 per 1000 | 279 per 1000 | ||||
| Overall mortality ‐ topical plus systemic prophylaxis versus systemic prophylaxis alone | Study population | RR 0.92 | 939 | ⊕⊕⊝⊝ | |
| 237 per 1000 | 218 per 1000 | ||||
| Overall mortality ‐ topical prophylaxis versus placebo or no treatment | Study population | RR 0.97 | 3274 | ⊕⊕⊕⊝ | |
| 305 per 1000 | 296 per 1000 | ||||
| Respiratory tract infections | Study population | RR 0.57 | 2698 | ⊕⊕⊝⊝ | |
| 318 per 1000 | 181 per 1000 | ||||
| Respiratory tract infections ‐ topical plus systemic prophylaxis versus systemic prophylaxis alone | Study population | RR 0.82 | 850 | ⊕⊕⊝⊝ | |
| 303 per 1000 | 248 per 1000 | ||||
| Respiratory tract infections ‐ topical prophylaxis versus no treatment or placebo | Study population | RR 0.50 | 1848 | ⊕⊕⊝⊝ | |
| 324 per 1000 | 162 per 1000 | ||||
| Dropouts due to adverse events | Study population | RR 2.20 | 1323 | ⊕⊝⊝⊝ | |
| 9 per 1000 | 20 per 1000 | ||||
| Gastrointestinal adverse events | Study population | RR 2.78 | 1859 | ⊕⊕⊝⊝ | |
| 22 per 1000 | 62 per 1000 | ||||
| Allergic adverse events | Study population | RR 2.64 | 2357 | ⊕⊝⊝⊝ | |
| 1 per 1000 | 2 per 1000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| a68% of studies at unclear risk and 1 study at high risk of selection bias. | |||||
Background
Description of the condition
Patients admitted to intensive care units (ICUs) are prone to acquire nosocomial infections, which may increase morbidity and mortality (Adrie 2017; Melsen 2013).
Amongst respiratory tract infections (RTIs), ventilator‐associated pneumonia (VAP) has been estimated to affect 5% to 40% of patients treated with mechanical ventilation for at least 48 hours. However, this estimate is highly variable depending on the country, the type of ICU, and the criteria used to define the VAP (American Thoracic Society 2005; Reignier 2016; Seguin 2014).
Data from the US report estimates of incidence of VAP in the order of 1 to 2 cases per 1000 days of ventilation (Dudeck 2013), whilst the European study EU‐VAP/CAP has shown an incidence of 18.3 episodes of VAP per 1000 days of ventilation (Koulenti 2017). Higher incidences were also found in low‐ to middle‐income countries compared to high‐income countries (18.5 versus 9.0 per 1000 days of ventilation) (Bonell 2019). However, it should be noted that these differences are explained, at least partially, by the use of different definitions, and due to differences in microbiological sampling methods (Ego 2015). Incidence rates also vary according to the population studied, that is higher incidences have been reported in cancer patients, Stoclin 2020, and trauma patients (Cook 2010).
Based on aggregated results from 58 randomised studies on VAP prevention, the attributable mortality rate of VAP was reported as 9% (Melsen 2011). A competing risk survival analysis in a cohort of 4479 ICU patients in France reported that intensive care mortality attributable to VAP was approximately 1% on day 30 and 1.5% on day 60 (Bekaert 2011). Data from an individual patient meta‐analysis including 24 studies (6284 patients) showed that mortality was higher in surgical patients and in those with medium‐severity illness at ICU admission, when compared to traumatised and medical patients, or when compared to those with particularly high‐ or low‐severity illness at admission (Melsen 2013).
ICU‐acquired infections are also responsible for increased expenditure in an already costly healthcare setting. Interventions aimed at preventing these complications are therefore encouraged (Kollef 2012; Laupland 2006).
Description of the intervention
Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) are prophylactic antibiotic interventions used to eradicate colonisation of aerobic gram‐negative bacteria, Staphylococcus aureus, and yeasts, whilst leaving the anaerobic flora intact.
SDD consists of the topical application of non‐absorbable antimicrobial agents to the oropharynx and gastroenteric tract during the whole ICU stay, often in combination with a short initial course of intravenous antibiotics (usually intravenous second‐generation cephalosporin during the first four days of ICU stay).
SOD comprises oropharyngeal application of bactericidal non‐absorbable antibiotics.
Both interventions consist of enteral application of non‐absorbable antimicrobial agents, most often amphotericin B, tobramycin or gentamycin, and colistin, aiming to eradicate yeasts, S aureus, and aerobic gram‐negative bacteria.
Since the main goal of antibiotic prophylaxis is to prevent infections acquired in intensive care, the protocol was usually applied immediately after ICU admission and continued until ICU discharge or extubation (de Jonge 2003; de Smet 2009; Oostdijk 2014; Stoutenbeek 1984; Wittekamp 2018). The target population is patients admitted to ICU for at least 48 hours and undergoing invasive mechanical ventilation.
In early studies, antibiotic prophylaxis was assessed in the ICU setting to prevent VAP in trauma patients who received prolonged mechanical ventilation by using a four‐component “classic” SDD regimen (Hurley 2020). Recent studies have broadened the inclusion criteria beyond trauma patients receiving invasive mechanical ventilation, tested different regimens, and used endpoints other than VAP. Variable definitions for some endpoints, such as VAP and bacteraemia, as well as variable study designs including blind or non‐blind placebo‐controlled groups, receiving or not receiving parenteral antibiotic prophylaxis, or even without any control group, have further clouded the picture. Although no relationship between the administration of SDD and antimicrobial resistance was detected (Daneman 2013), the real impact of SDD on the onset of antibiotic resistance remains, to date, not fully defined. This was mainly due to the fact that most of the studies assessed the effects of SDD at the patient level rather than at the ICU level, and with limited follow‐up time (Sánchez‐Ramírez 2018). Distinguishing ICUs with low prevalence of antibiotic resistance from ICUs with moderate to high prevalence of resistance, three cluster‐randomised studies highlighted that in settings with low prevalence of antibiotic resistance, SDD has been consistently associated with improved patient outcome (de Jonge 2003; de Smet 2009; Oostdijk 2014). These benefits were not confirmed in a large international cluster‐randomised study in settings with moderate‐to‐high prevalence of antibiotic resistance, where clinical relevance of SDD on patient outcomes remains to be seen (Wittekamp 2018).
How the intervention might work
The hypothesis behind antibiotic prophylaxis with SDD/SOD is that intestinal flora may represent the origin of potential pathogenic micro‐organisms which, colonising the upper respiratory tract during hospitalisation, can induce an increased risk of VAP and infection‐related ventilator‐associated complication (IVAC) (Magill 2013).
SDD and SOD have been shown to reduce the incidence of RTIs, the colonisation with antibiotic‐resistant gram‐negative bacteria, and the incidence of nosocomial infections, and to improve patient survival (de Jonge 2018; de Smet 2009; Plantinga 2017; Vincent 2011). The prevention effect with antibiotic prophylaxis seems to exceed the VAP prevention effect of various non‐decontamination methods evaluated in the mechanically ventilated patient group (Landelle 2018).
Why it is important to do this review
Antibiotic prophylaxis, especially SDD, has been discussed in intensive care literature for nearly 40 years (Stoutenbeek 1984). The diversity amongst the studies has fuelled controversy (Hurley 2020).
On the one hand, as early as 25 years ago, the summary evidence derived from more than 40 studies showed an apparent potent prevention effect against VAP, bacteraemia, and mortality (Hurley 1995). On the other hand, opinions regarding antibiotic prophylaxis have varied, even in the Netherlands, where many high‐quality studies have been conducted (Bonten 2001), and where SDD is the standard of care (SWAB 2018).
Although high‐quality evidence supports the use of SDD, its application is still a matter of debate, and it is not widely used in clinical practice (Reis 2015), due to the main concern that it may promote the emergence of antibiotic‐resistant strains (Brink 2013; Halaby 2013).
Given the uncertainty on the efficacy of antibiotic prophylaxis, and in light of the worldwide challenge of multidrug resistance, we considered it necessary to revisit this meta‐analysis, with the aim of redefining the role of the antibiotic prophylaxis in ICU patients requiring invasive mechanical ventilation.
Objectives
To assess the effect of topical antibiotic regimens (selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD)), given alone or in combination with systemic antibiotics, to prevent mortality and respiratory infections in patients receiving mechanical ventilation for at least 48 hours in intensive care units (ICUs).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and cluster‐RCTs on antibiotic prophylaxis for the prevention of respiratory tract infections (RTIs) and death in adults on mechanical ventilation in intensive care unit (ICU) patients. We included both blinded and unblinded studies.
Types of participants
Adult (≥ 18 years) patients admitted to an ICU for at least 48 hours. We excluded studies where the majority of patients (> 50%) did not undergo mechanical ventilation for at least 48 hours. We also excluded studies if they considered only patients with a higher‐than‐usual risk of infection (e.g. liver transplantation, neutropenic patients).
Types of interventions
Experimental intervention
Topical antibiotic prophylaxis applied to nasopharynx (selective oropharyngeal decontamination (SOD)) or to oropharynx and gastric tube (selective decontamination of the digestive tract (SDD)) for the whole period of mechanical ventilation, given alone or in combination with systemic antibiotic prophylaxis.
Control intervention
Placebo, no prophylaxis, or systemic antibiotic prophylaxis alone.
Types of outcome measures
Primary outcomes
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Overall mortality. We considered mortality at hospital discharge if this information was provided; otherwise we considered mortality in the ICU.
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Respiratory tract infections. We made no restriction on the type of RTI considered (pneumonia and tracheobronchitis, ventilator‐associated pneumonia (VAP), and infection‐related ventilator‐associated complication (IVAC)), nor on the RTI diagnostic criteria used. We considered both primary (diagnosed within 48 hours from admission) and acquired (diagnosed after 48 hours from admission) infections. In case both were reported, we considered data from the acquired group.
Secondary outcomes
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Dropouts due to adverse events.
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Participants with gastrointestinal adverse events.
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Participants with allergic adverse events.
Search methods for identification of studies
Electronic searches
For this update, we searched the following databases up to 5 February 2020. We imposed no language, publication year, or publication status restrictions. We identified published, unpublished, and ongoing studies by searching the following databases from their inception.
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Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, 2020 Issue 3 (searched 5 February 2020) (Appendix 1).
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MEDLINE PubMed (up to 5 February 2020) (Appendix 2).
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Embase Ovid (up to 5 February 2020) (Appendix 3).
We searched the following trials registries on 5 February 2020:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov); and
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).
Details of the previous search strategies are shown in Appendix 4.
Searching other resources
We searched the reference lists of retrieved included studies, systematic reviews, and meta‐analyses in order to identify other potentially eligible studies.
Data collection and analysis
Selection of studies
Two review authors (SP, SM) independently screened the titles and abstracts of all the references identified by the searches and retrieved and investigated all potentially relevant articles as full text to determine eligibility for inclusion in the review. Any disagreements were resolved by discussion or by involving a third review author (LB) if necessary.
Data extraction and management
Using a standardised data extraction form, three review authors (VP, SM and SP) collected the relevant study data, including study design, sample characteristics, description of the experimental and control interventions, outcomes, study funding, and conflicts of interest. Any disagreements were resolved by discussion. We contacted study authors for clarification when necessary.
Assessment of risk of bias in included studies
Two review authors (SM, VP) independently assessed the risk of bias using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The recommended approach for assessing risk of bias is a two‐part tool, addressing the specific domains of sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting (reporting bias). The first part of the tool involves describing what was reported to have occurred in the study, whilst in the second part a judgement is assigned relating to the risk of bias for each domain, that is low, high, or unclear risk. See Appendix 5 for details.
We assessed the risk of detection bias separately for mortality, RTIs, and adverse events.
Measures of treatment effect
We analysed dichotomous outcomes by calculating the risk ratio (RR) and its relative 95% confidence interval (CI).
Unit of analysis issues
In case of multi‐arm studies, we combined all the relevant experimental or control groups into a single group to avoid double‐counting of participants. In case of cluster‐RCTs, we adjusted the raw data for the 'design effect' by using the effective sample size approach, as recommended in the updated version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).
Dealing with missing data
Missing data are not a relevant issue in this setting and for our outcomes, as patients who meet the inclusion criteria are usually followed up until the end of the study, and outcome values are collected by the researchers.
Assessment of heterogeneity
We analysed heterogeneity using the I2 statistic and the Chi2 test. We considered heterogeneity as substantial if the I² was greater than 75%, or the P value was lower than 0.10 for the Chi2 test for heterogeneity (Higgins 2020).
Assessment of reporting biases
We used the visual inspection of funnel plots (plots of the effect estimate from each study against the effect standard error) to evaluate possible publication bias if there were at least 10 studies included in the meta‐analysis.
Data synthesis
We combined the outcomes from the individual trials through meta‐analysis where possible (comparability of intervention and outcomes between trials), using a random‐effects model, because we expected a certain degree of heterogeneity across trials. If the clinical or statistical heterogeneity was too high (i.e. 75% to 100%), we decided against pooling the data.
Subgroup analysis and investigation of heterogeneity
We did not perform subgroup analysis for type of drug because there were no data to assume a difference in effect amongst the considered prophylactic treatments. This obviously does not mean that all topical and systemic regimens are truly equivalent, but simply reflects our pragmatic working assumption.
Sensitivity analysis
To incorporate our assessment of risk of bias in the review process, we first plotted the intervention effect estimates stratified by risk of bias for allocation concealment (selection bias). We planned that if differences in the results were present amongst studies at different risks of selection bias, we would perform sensitivity analysis by excluding the studies at high risk of selection bias.
Summary of findings and assessment of the certainty of the evidence
We created two 'Summary of findings' tables (summary of findings Table 1; summary of findings Table 2) using the following outcomes: overall mortality, RTIs, dropouts due to adverse events, gastrointestinal adverse events and allergic adverse events. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We used the methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020), employing GRADEpro GDT software (GRADEpro GDT). We justified all decisions to down‐ or upgrade the quality of studies using footnotes, and made comments to aid the reader's understanding of the review where necessary.
The GRADE system uses the following criteria for assigning grades of evidence.
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High: We are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
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Very low: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Results
Description of studies
Results of the search
We included 36 trials involving 6914 people in the previous version of this review. In this 2020 update, we identified a total of 3201 records after de‐duplication, of which nine studies were considered as potentially relevant. We excluded seven studies and included two studies (Beshey 2014; Chaari 2014). We also decided to include two previously excluded studies (de la Cal 2005; de Smet 2009), and included one study that was missed in the previous version of the review (Koeman 2006). We identified two ongoing studies (IRCT20180110038298N1; NCT02389036). We included a total of 41 studies. See Figure 1.
Study flow diagram: 2020 update.
Included studies
We included 41 RCTs in this update. One study was a cluster‐RCT (de Smet 2009). All of the trials were published, 39 as full reports, and two in abstract form (Boland 1991; Finch 1991). See Characteristics of included studies table.
Characteristics of participants
Overall, the trials included 16,329 participants. In our analyses, we considered 11,004 participants as fulfilling the inclusion criteria of a minimum duration of mechanical ventilation of at least 48 hours. The minimum duration of mechanical ventilation was two days in 19 studies, three days in seven studies, four days in three studies, five days in eight studies, and six days in one study. In two studies the minimum duration of mechanical ventilation was not stated.
The number of participants included in the studies ranged from 39 to 4035. The reasons for admission were surgical for 4726 (29%) participants, medical for 5305 (32.5%) participants, and trauma for 2609 (16%) participants.
Length of stay in ICU was reported as median in 18 studies, ranging from 3.5 to 19.5 days, and as mean in 13 studies, ranging from 11.3 to 33 days. Ten studies did not report this information.
In eight studies (Blair 1991; Brun‐Buisson 1989; Cockerill 1992; de Jonge 2003; de la Cal 2005; de Smet 2009; Ulrich 1989; Winter 1992), not all participants were mechanically ventilated. Five studies did not report this information (Beshey 2014; Camus 2005; Cerra 1992; Finch 1991; Laggner 1994).
The percentage of immunocompromised participants ranged from 0% (10 studies) to 22% (1 study).
Characteristics of treatment regimens
Nineteen RCTs compared the combination of topical and systemic antibiotic prophylaxis versus no treatment or placebo (Abele‐Horn 1997; Aerdts 1991; Blair 1991; Boland 1991; Cockerill 1992; de Jonge 2003; de la Cal 2005; de Smet 2009; Finch 1991; Jacobs 1992; Kerver 1988; Krueger 2002; Palomar 1997; Rocha 1992; Sanchez‐Garcia 1998; Stoutenbeek 2007; Ulrich 1989; Verwaest 1997; Winter 1992); 16 RCTs compared topical prophylaxis alone to no treatment or placebo (Bergmans 2001; Beshey 2014; Brun‐Buisson 1989; Camus 2005; Cerra 1992; de Smet 2009; Gastinne 1992; Georges 1994; Koeman 2006; Korinek 1993; Pneumatikos 2002; Pugin 1991; Quinio 1995; Rodriguez‐Roldan 1990; Unertl 1987; Wiener 1995); and seven trials compared the combination of topical and systemic antibiotic prophylaxis versus systemic prophylaxis only (Chaari 2014; Ferrer 1994; Gaussorgues 1991; Hammond 1992; Laggner 1994; Lingnau 1997; Stoutenbeek 1996).
One study had three arms (de Smet 2009): one received the combination of topical and systemic antibiotic prophylaxis, one topical prophylaxis alone, and one arm received no prophylaxis.
Two studies were included in the 'topical SDD plus systemic antibiotic versus systemic antibiotic only' group (Gaussorgues 1991; Laggner 1994), though the use of systemic antibiotics was not explicitly stated in the description of interventions. However, all participants in both arms were treated with systemic antibiotics at admission.
Six studies had more than two arms and were analysed as follows. In two studies (Aerdts 1991; Verwaest 1997), the two control groups were pooled and compared to the treatment group. In Lingnau 1997, the participants in the two treatment arms were summarised and compared with the control arm. In two studies (Koeman 2006; Palomar 1997), one of the two control arms was excluded because the participants received only chlorhexidine and sucralfate, respectively. Another study was a four‐arm factorial design in which we considered only two arms comparing antibiotic prophylaxis versus placebo (Camus 2005). In Chaari 2014, we considered three arms as the experimental group.
Eight studies were conducted in the Netherlands, seven in France, six in Spain, four in Germany, four in the USA, three in the UK, and one each in Egypt, Ireland, Tunisia, South Africa, Austria, Greece, Switzerland, and Belgium. One study was multicentric and was conducted in Europe, Australia, and New Zealand.
Twenty‐two studies (52.4%) did not report the source of funding. Six studies (14.3%) were supported by public institutional grants. Thirteen studies (30.1%) were totally or partially funded by pharmaceutical companies.
Excluded studies
We excluded 33 trials (see Characteristics of excluded studies table). Grounds for exclusion were: only a subgroup of selected patients was included (12 studies); non‐randomised design (two studies); experimental intervention not in the inclusion criteria (two studies); both groups received topical prophylaxis (five studies); control intervention not in the inclusion criteria (four studies); objective of the study was not to assess efficacy and safety of topical prophylaxis on clinical outcomes (one study); unclear description of the interventions being compared (one study); paediatric population (four studies); unpublished study, unable to contact study authors for feedback (one study); and data available only from other published meta‐analyses so it was impossible to retrieve data from the original study (one study).
Risk of bias in included studies
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
We judged 25 studies (59.5%) as at low risk of bias. No information about the methods of sequence random generation was reported for the other 16 studies which were judged as at unclear risk of bias.
Allocation concealment
We judged 22 studies (52.4%) as at low risk of bias. One study was judged at high risk of bias (Brun‐Buisson 1989). The remaining 18 studies did not report methods of allocation concealment and were therefore judged as at unclear risk of bias.
Blinding
Performance bias
We judged all of the included studies to be at low risk of bias. Twenty (47.6%) studies were open‐label; however, hospitals usually have standardised infection control programmes. Possible subjective decisions on who should be tested for the presence or absence of RTIs are unlikely in an ICU setting because routine care includes daily laboratory tests and scheduled radiologic and microbiologic studies. Moreover, all ventilated patients are at high risk for infections independently of antibiotic prophylaxis, so knowledge of it does not change diagnostic workup.
Detection bias
Mortality: We judged all studies to be at low risk of bias.
RTIs: We judged all the double‐blind studies as at low risk of bias. Twenty studies (47.6%) were open‐label. We judged five open‐label studies as at high risk of bias because the diagnosis of RTI was not based on microbiological exams (Blair 1991; Cockerill 1992; Stoutenbeek 2007; Ulrich 1989; Unertl 1987). We judged all the other open‐label studies as at low risk of bias because a standardised set of diagnostic criteria, including results of microbiological exams, was used.
Adverse events (AEs): We judged all studies as at unclear risk of bias because methods for AEs collection were poorly reported, and AEs were heterogeneous.
Incomplete outcome data
We judged four studies as at high risk of bias because they excluded patients from the analyses for reasons that were not stated in the study exclusion criteria.
We judged the remaining 37 studies as at low risk of bias, as there were no dropouts. In 27 of these studies, the number of participants analysed was lower than that of those randomised; the authors of these studies decided to exclude from the analysis those participants who either died too soon after ICU admission, or who were extubated early. We did not judge these studies as at high risk of bias, as antibiotic prophylaxis is usually started on admission, whilst meeting the minimum stay in the ICU inclusion criterion can only be verified after at least 48 hours postrandomisation.
In 14 studies, the number of participants who were randomised and analysed was the same. In these cases, if not otherwise specified, we assumed that either no participants were excluded after randomisation, or that the study authors decided to consider as randomised and analysed only those participants who fulfilled the inclusion criteria after randomisation.
Selective reporting
The protocol was available only for one study (de Smet 2009), which was judged as at low risk of bias as the results for all the outcomes described in the protocol were reported in the final publication. We judged the remaining studies as at unclear risk of bias.
Effects of interventions
See: Summary of findings 1 Topical plus systemic prophylaxis versus placebo or no treatment in adults receiving mechanical ventilation for at least 48 hours; Summary of findings 2 Topical prophylaxis versus no topical prophylaxis in adults receiving mechanical ventilation for at least 48 hours
We grouped studies in the following comparisons:
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topical plus systemic prophylaxis versus no treatment (19 studies); and
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topical prophylaxis versus no topical prophylaxis (23 studies).
We further stratified the studies included in the comparison 'topical prophylaxis versus no topical prophylaxis' into two groups:
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topical plus systemic prophylaxis versus systemic prophylaxis (7 studies); and
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topical prophylaxis versus no treatment (16 studies).
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Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment
See: summary of findings Table 1
Primary outcomes
1. Overall mortality
We found a significant reduction in overall mortality amongst participants who received topical plus systemic prophylaxis compared to placebo or no treatment (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.73 to 0.96; 18 studies; 5290 participants; high‐certainty evidence; Analysis 1.1).
2. Respiratory tract infections
We found a significant reduction in the incidence of respiratory tract infections amongst participants who received topical plus systemic prophylaxis compared to placebo or no treatment (RR 0.43, 95% CI 0.35 to 0.53; 17 studies; 2951 participants; moderate‐certainty evidence; Analysis 1.2).
Secondary outcomes
1. Dropouts due to adverse events
We did not find a significant difference in dropouts due to adverse events in participants who received topical plus systemic prophylaxis compared to placebo or no treatment (RR 1.06, 95% CI 0.30 to 3.76; 4 studies; 1287 participants; low‐certainty evidence; Analysis 1.3).
2. Participants with gastrointestinal or allergic AEs
Gastrointestinal AEs
We did not find a significant difference in participants who received topical plus systemic prophylaxis compared to no treatment (RR 1.08, 95% CI 0.57 to 2.04; 6 studies; 2637 participants; low‐certainty evidence; Analysis 1.4).
Allergic AEs
We did not find significant differences between groups (RR 1.49, 95% CI 0.09 to 25.33; 6 studies; 2981 participants; low‐certainty evidence; Analysis 1.5).
Comparison 2: Topical prophylaxis versus no topical prophylaxis
See: summary of findings Table 2
Primary outcomes
1. Overall mortality
We did not find a significant difference in overall mortality between participants who received and those who did not receive topical prophylaxis (RR 0.96, 95% CI 0.87 to 1.05; 22 studies, 4213 participants; moderate‐certainty evidence; Analysis 2.1).
Topical plus systemic prophylaxis versus systemic prophylaxis alone
We did not find a significant difference between groups (RR 0.92, 95% CI 0.72 to 1.18; 7 studies; 939 participants; low‐certainty evidence; Analysis 2.1).
Topical prophylaxis alone versus no treatment
We did not find a significant difference between groups (RR 0.97, 95% CI 0.87 to 1.07; 15 studies; 3274 participants; moderate‐certainty evidence; Analysis 2.1).
2. Respiratory tract infections
We found a significant reduction in the incidence of respiratory tract infections in participants who received topical prophylaxis compared to those who did not receive topical prophylaxis (RR 0.57, 95% CI 0.44 to 0.74; 19 studies; 2698 participants; low‐certainty evidence; Analysis 2.2).
Topical plus systemic prophylaxis versus systemic prophylaxis alone
We found no significant difference between groups (RR 0.82, 95% CI 0.58 to 1.16; 6 studies; 850 participants; low‐certainty evidence; Analysis 2.2).
Topical prophylaxis alone versus no treatment
We found a significant reduction in the incidence of respiratory tract infections in favour of topical prophylaxis alone (RR 0.50, 95% CI 0.36 to 0.69; 13 studies; 1848 participants; low‐certainty evidence; (Analysis 2.2).
Secondary outcomes
1. Dropouts due to adverse events
We did not find a significant difference in dropouts due to adverse events in participants who received topical prophylaxis compared to those who did not receive topical prophylaxis (RR 2.20, 95% CI 0.57 to 8.54; 7 studies; 1323 participants; very low‐certainty evidence; Analysis 2.3).
2. Participants with gastrointestinal or allergic AEs
Gastrointestinal AEs
We did not find a significant difference in participants who received topical prophylaxis compared to those who did not receive topical prophylaxis (RR 2.78, 95% CI 0.26, to 29.50; 3 studies; 1859 participants; low‐certainty evidence; Analysis 2.4).
Allergic AEs
We did not find a significant difference between groups (RR 2.64, 95% CI 0.34 to 20.69; 5 studies; 2357 participants; very low‐certainty evidence; Analysis 2.5).
Discussion
Since the introduction of selective digestive decontamination (SDD) as a preventive measure against the development of infections in critically ill patients (Stoutenbeek 1984), its use as an antibiotic prophylaxis has been controversial.
Initial studies aimed at quantifying the effectiveness of SDD in preventing ventilator‐associated pneumonia (VAP) in intensive care units (ICUs) highlighted the difficulty in drawing solid conclusions regarding the effectiveness of the treatment, given the lack of a standardised protocol and the limited numbers of patients included in individual clinical trials (de Jonge 2018; de Smet 2009; Plantinga 2017; Vincent 2011). Concerns were even raised regarding the possible role of the SDD in inducing antimicrobial resistance, as well as the costs associated with its implementation. Furthermore, pneumonia, often considered the target outcome for evaluating efficacy of SDD, can be measured using different clinical, microbiological, and radiological criteria that are often difficult to apply in the ICU setting (Chahoud 2015; Waters 2015). Finally, ICU mortality depends on a number of factors only partially related to VAP.
As those enrolled in SDD trials gradually changed from trauma patients to other patient categories (surgical and medical, with complex medical histories and comorbidity, with prior antibiotic use in the presence of bacteria non‐susceptible to cephalosporin), SDD regimens have varied over time. Endpoints have also changed in some clinical trials from VAP to bacteraemia or ICU mortality (Hurley 2020).
Compared to other published meta‐analyses (Heyland 1994; Hurley 1995; Kollef 1994; Nathens 1999; SDD Group 1993; Vanderbrouk‐Grauls 1991), we decided in our previously published review, D'Amico 2009, to separately analyse trials testing a combination of systemic and topical antibiotics, and those testing topical antibiotics alone. Though there is no consensus on the best way to classify antibiotic prophylaxis regimens, it seemed more appropriate to consider the two groups of trials as distinct approaches to antibiotic prophylaxis. We made this decision a priori, independent of knowing the results.
Summary of main results
We included 41 RCTs with a total of 11,004 participants who were mechanically ventilated for at least 48 hours. Nineteen RCTs compared the combination of topical and systemic antibiotic prophylaxis versus no treatment or placebo; 16 studies compared topical prophylaxis alone to no treatment or placebo; and seven trials compared the combination of topical and systemic antibiotic prophylaxis versus systemic antibiotic only.
Compared to no treatment or placebo, there was a significant reduction in overall mortality (high‐certainty evidence) and a significant reduction of RTIs (moderate‐certainty evidence) in participants receiving topical plus systemic prophylaxis. We also found low‐certainty evidence that participants receiving topical antibiotic prophylaxis achieved a significant reduction of RTI, but moderate‐certainty evidence that mortality did not change, when compared with placebo, no treatment, or systemic prophylaxis alone.
We found low‐certainty evidence of no relevant differences in mortality and RTIs in the subgroup of studies comparing topical plus systemic prophylaxis versus systemic prophylaxis alone. In the subgroup of studies comparing topical prophylaxis alone versus placebo or no treatment, RTIs were significantly reduced (low‐certainty evidence), whilst there was no difference in mortality rate (moderate‐certainty evidence). Although these results could suggest that the systemic component of prophylaxis plays a key role in mortality reduction, caution is advised in interpreting such results on the basis of indirect comparisons. Moreover, as the certainty of the evidence was low, the contribution of adding topical to systemic prophylaxis remains uncertain.
The incidence of adverse events was reported in few studies with inconsistent and uninformative results (low‐ to very low‐certainty evidence).
Overall completeness and applicability of evidence
Overall, the characteristics of participants and ICUs considered in the included studies represent well the actual ICU setting in high‐income countries, although many of the studies were conducted more than 20 years ago. Despite the fact that modalities to prevent the development of infections have changed over time, as well as the characteristics of patients admitted to ICUs, RTIs are still an important cause of mortality.
One limitation of this meta‐analysis is that the patient population, the antibiotic regimens, and the outcome definitions varied across studies. Nevertheless, we believe that it provides the best global picture of the effectiveness of the intervention, despite some recent criticisms on the quality of primary studies and their combination (van Nieuwenhoven 2001), which we feel we have convincingly addressed (Liberati 2001).
Quality of the evidence
Seventy‐three per cent of the included studies were published before the 2001, the year in which the revised CONSORT statement was published and endorsed by many journals. This is the likely explanation for why the reporting of the majority of the studies was poor, which limited our ability to assess risk of bias. We judged more than 40% of the included studies as at unclear risk of selection bias, which led to the downgrading of the certainty of the evidence for the comparison 'topical antibiotic prophylaxis versus no prophylaxis'. In contrast, although about 48% of the studies were open‐label, we judged all studies to be at low risk of performance bias, as hospitals usually have standardised infection control programmes, making subjective decisions on who should be tested for the presence or absence of RTIs unlikely. We judged only five studies as at high risk of detection bias, as they were open‐label and did not use microbiological exams to diagnose RTIs. We judged all studies as at low risk of detection bias for the outcome mortality. We did not find any relevant inconsistency amongst trials. We found asymmetry in the funnel plot indicating possible publication bias for the outcome respiratory tract infection. Finally, we judged evidence for adverse events low or very low due to sparse data
Potential biases in the review process
We performed a comprehensive search without language or publication restrictions. The inspection of funnel plots did not show asymmetry suggestive of possible publication bias. See Figure 4 and Figure 5.
Funnel plot of comparison: 1 Topical plus systemic prophylaxis versus placebo or no treatment, outcome: 1.1 Overall mortality.
Funnel plot of comparison: 2 Topical prophylaxis versus no topical prophylaxis, outcome: 2.1 Overall mortality.
Agreements and disagreements with other studies or reviews
Prior to the publication of the previous version of this systematic review, several non‐Cochrane Reviews and meta‐analyses were published on the effect of SDD on RTIs and mortality (D'Amico 1998; Heyland 1994; Hurley 1995, Kollef 1994; Nathens 1999; Redman 2001; Silvestri 2007; SDD Group 1993; Vanderbrouk‐Grauls 1991). Two systematic reviews were recently published (Price 2014; Righy 2017). All reviews assessing the incidence of RTIs supported the hypothesis that antibiotic prophylaxis is effective, though the magnitude of the treatment effect varied across reviews. The same results were observed in the majority of systematic reviews regarding mortality.
Study flow diagram: 2020 update.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 1 Topical plus systemic prophylaxis versus placebo or no treatment, outcome: 1.1 Overall mortality.
Funnel plot of comparison: 2 Topical prophylaxis versus no topical prophylaxis, outcome: 2.1 Overall mortality.
Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment, Outcome 1: Overall mortality
Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment, Outcome 2: Respiratory tract infections
Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment, Outcome 3: Dropouts due to adverse events
Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment, Outcome 4: Gastrointestinal adverse events
Comparison 1: Topical plus systemic prophylaxis versus placebo or no treatment, Outcome 5: Allergic adverse events
Comparison 2: Topical prophylaxis versus no topical prophylaxis, Outcome 1: Overall mortality
Comparison 2: Topical prophylaxis versus no topical prophylaxis, Outcome 2: Respiratory tract infections
Comparison 2: Topical prophylaxis versus no topical prophylaxis, Outcome 3: Dropouts due to adverse events
Comparison 2: Topical prophylaxis versus no topical prophylaxis, Outcome 4: Gastrointestinal adverse events
Comparison 2: Topical prophylaxis versus no topical prophylaxis, Outcome 5: Allergic adverse events
| Topical plus systemic prophylaxisversus placebo or no treatment in adults receiving mechanical ventilation for at least 48 hours | |||||
| Patient or population: adults receiving mechanical ventilation for at least 48 hours | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with no prophylaxis | Risk with topical plus systemic | ||||
| Overall mortality | Study population | RR 0.84 | 5290 | ⊕⊕⊕⊕ | |
| 303 per 1000 | 255 per 1000 | ||||
| Respiratory tract infections | Study population | RR 0.43 | 2951 | ⊕⊕⊕⊝ | |
| 417 per 1000 | 179 per 1000 | ||||
| Dropouts due to adverse events | Study population | RR 1.06 | 1287 | ⊕⊕⊝⊝ | |
| 6 per 1000 | 7 per 1000 | ||||
| Gastrointestinal adverse events | Study population | RR 1.08 | 2637 | ⊕⊕⊝⊝ | |
| 44 per 1000 | 48 per 1000 | ||||
| Allergic adverse events | Study population | RR 1.49 | 2981 | ⊕⊕⊝⊝ | |
| 0 per 1000 | 1 per 1000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| aDowngraded 1 level for suspected publication bias, as indicated by asymmetry in the funnel plot. | |||||
| Topical prophylaxis versus no topical prophylaxis in adults receiving mechanical ventilation for at least 48 hours | |||||
| Patient or population: adults receiving mechanical ventilation for at least 48 hours | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with control | Risk with topical | ||||
| Overall mortality | Study population | RR 0.96 | 4213 | ⊕⊕⊕⊝ | |
| 290 per 1000 | 279 per 1000 | ||||
| Overall mortality ‐ topical plus systemic prophylaxis versus systemic prophylaxis alone | Study population | RR 0.92 | 939 | ⊕⊕⊝⊝ | |
| 237 per 1000 | 218 per 1000 | ||||
| Overall mortality ‐ topical prophylaxis versus placebo or no treatment | Study population | RR 0.97 | 3274 | ⊕⊕⊕⊝ | |
| 305 per 1000 | 296 per 1000 | ||||
| Respiratory tract infections | Study population | RR 0.57 | 2698 | ⊕⊕⊝⊝ | |
| 318 per 1000 | 181 per 1000 | ||||
| Respiratory tract infections ‐ topical plus systemic prophylaxis versus systemic prophylaxis alone | Study population | RR 0.82 | 850 | ⊕⊕⊝⊝ | |
| 303 per 1000 | 248 per 1000 | ||||
| Respiratory tract infections ‐ topical prophylaxis versus no treatment or placebo | Study population | RR 0.50 | 1848 | ⊕⊕⊝⊝ | |
| 324 per 1000 | 162 per 1000 | ||||
| Dropouts due to adverse events | Study population | RR 2.20 | 1323 | ⊕⊝⊝⊝ | |
| 9 per 1000 | 20 per 1000 | ||||
| Gastrointestinal adverse events | Study population | RR 2.78 | 1859 | ⊕⊕⊝⊝ | |
| 22 per 1000 | 62 per 1000 | ||||
| Allergic adverse events | Study population | RR 2.64 | 2357 | ⊕⊝⊝⊝ | |
| 1 per 1000 | 2 per 1000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| a68% of studies at unclear risk and 1 study at high risk of selection bias. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Overall mortality Show forest plot | 18 | 5290 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.73, 0.96] |
| 1.2 Respiratory tract infections Show forest plot | 17 | 2951 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.35, 0.53] |
| 1.3 Dropouts due to adverse events Show forest plot | 4 | 1287 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.30, 3.76] |
| 1.4 Gastrointestinal adverse events Show forest plot | 6 | 2637 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.57, 2.04] |
| 1.5 Allergic adverse events Show forest plot | 6 | 2981 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [0.09, 25.33] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Overall mortality Show forest plot | 22 | 4213 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.87, 1.05] |
| 2.1.1 Topical plus systemic prophylaxis versus systemic prophylaxis alone | 7 | 939 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.72, 1.18] |
| 2.1.2 Topical prophylaxis alone versus no treatment | 15 | 3274 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.87, 1.07] |
| 2.2 Respiratory tract infections Show forest plot | 19 | 2698 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.44, 0.74] |
| 2.2.1 Topical plus systemic prophylaxis versus systemic prophylaxis alone | 6 | 850 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.58, 1.16] |
| 2.2.2 Topical prophylaxis alone versus no treatment | 13 | 1848 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.36, 0.69] |
| 2.3 Dropouts due to adverse events Show forest plot | 7 | 1323 | Risk Ratio (M‐H, Random, 95% CI) | 2.20 [0.57, 8.54] |
| 2.4 Gastrointestinal adverse events Show forest plot | 3 | 1859 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [0.26, 29.50] |
| 2.5 Allergic adverse events Show forest plot | 5 | 2357 | Risk Ratio (M‐H, Random, 95% CI) | 2.64 [0.34, 20.69] |
