Steroids and Survival in Critically Ill Adult Patients: A Meta-analysis of 135 Randomized Trials

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Steroids and survival in critically-ill adult patients: a meta-analysis of 135 randomized trials Enrico A. MARTINO, Martina BAIARDO REDAELLI, Salvatore SARDO, Rosalba LEMBO, Vito F. GIORDANO, Dario WINTERTON, Laura RUGGERI, Ludhmilla A. HAJJAR, Alberto ZANGRILLO, Giovanni LANDONI

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S1053-0770(18)30244-1 https://doi.org/10.1053/j.jvca.2018.04.017 YJCAN4657

To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Enrico A. MARTINO, Martina BAIARDO REDAELLI, Salvatore SARDO, Rosalba LEMBO, Vito F. GIORDANO, Dario WINTERTON, Laura RUGGERI, Ludhmilla A. HAJJAR, Alberto ZANGRILLO and Giovanni LANDONI, Steroids and survival in critically-ill adult patients: a meta-analysis of 135 randomized trials, Journal of Cardiothoracic and Vascular Anesthesia,doi:10.1053/j.jvca.2018.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title page Steroids and survival in critically-ill adult patients: a meta-analysis of 135 randomized trials Authors Enrico A. MARTINO1; Martina BAIARDO REDAELLI1; Salvatore SARDO2; Rosalba LEMBO1; Vito F. GIORDANO1; Dario WINTERTON1; Laura RUGGERI1; Ludhmilla A. HAJJAR3; Alberto ZANGRILLO1, 4; Giovanni LANDONI1, 4 1. Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy 2. Department of Medical Sciences “M. Aresu”, University of Cagliari, Cagliari, Italy 3. Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil 4. Vita-Salute San Raffaele University, Milan, Italy

Short title: Steroids in critically-ill adults Corresponding Author Rosalba Lembo, MsC Department of Anesthesia and Intensive Care San Raffaele Hospital Via Olgettina 60 Milan, 20132 Italy Phone: +390226436154 Fax +390226436152 Email: [email protected] Conflicts of interest: No conflicts of interest to declare.

Abstract Objective: Corticosteroids have important effects on intermediate outcomes in critically ill patients but their effect on survival is unknown. The objective of this meta-analysis was to analyze the effect on mortality of corticosteroids in critical and perioperative settings. Design: A meta-analysis of randomized trials. Setting: PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trialswere searched up to February 1st 2018 for randomized trials comparing corticosteroids with placebo or standard care. Participants: Critically ill or surgical adult patients. Interventions: Corticosteroids compared with placebo or standard care Measurements and Main Results: A total of 44,553 patients from 135 studies were included. Overall, mortality in the corticosteroid group and in the control group were similar (16% vs 16%; p =0.9). Sub-analyses identified a beneficial effect of corticosteroids on survival in patients with respiratory system diseases (9% vs 13%; p<0.001), and bacterial meningitis (28% vs 32%; p=0.04), and a detrimental effect on survival in patients with traumatic brain injury (22% VS 19%; p <0.001). No differences in mortality were found in patients with cardiac diseases (7% vs 6%; p=0.7), in patients undergoing cardiac surgery (2.8% vs 3.2% p=0.14) and when treatment duration or patients age were considered. Conclusions: This meta-analysis documents the safety of corticosteroids in the overall critically ill population with the notable exception of brain injury patients, a setting where we confirmed their detrimental effect on survival. A possible beneficial effect of corticosteroids on survival was found among patients with respiratory diseases and in patients with bacterial meningitis.

Keywords: steroids; corticosteroids; mortality; meta-analysis; critically ill; surgery;

Introduction Corticosteroids represent a valid therapeutic option in several settings, including the critically ill and surgical patient, due to their numerous mechanisms of action. They have antiinflammatory and immunosuppressive properties determining a palliative effect (such as pain control, appetite improvement, nausea suppression, and relief from fatigue), but they are neither specific nor curative, and are therefore used in addition to specific therapies. Furthermore, due to their potent effects, corticosteroids are involved in many physiological processes such as the stress response, the anabolism and catabolism of carbohydrates and proteins, the regulation of electrolyte concentrations and many others. Corticosteroids are physiologically secreted by the cells of the adrenal cortex, and they are tightly regulated by complex central systems involving the release of corticotrophin from the pituitary gland and important negative feedback mechanisms. Hypercortisolemia has been observed in critically ill patients, secondary to the down-regulation of the cortisol-metabolizing enzimes, but the clinical implications for the patients are still unknown.1 For this reason, glucocorticoids are among the most widely used drugs, but, with the exception of replacement therapy in various steroid deficiencies, their use is still largely empirical. Even if chronic use of corticosteroids is mainly associated with the suppression of hypothalamic-pituitary-adrenal function, iatrogenic diabetes and Cushing’s syndrome, acute use of corticosteroids in critically-ill patients is considered beneficial, virtually without harmful effects, with notable exceptions.2

Hypertension and improved cardiovascular function are observed in patients treated with glucocorticoids, and with an increased glucocorticoids endogenous secretion. The most notable effect of corticosteroids on the cardiovascular system results from the Na+ renal retention induced by the mineralcorticoid effect, which act on the kidney enhancing Na+ reabsorption and K+ and H+ excretion. This effect account for the positive Na+ balance with increase in the extracellular fluid volume, leading to replacement of effective blood volume. The mineralcorticoid receptor activation also plays direct activity on the heart and vessels walls, with evidence in animal models of aldosterone induced hypertension and interstitial cardiac fibrosis.3 Furthermore, corticosteroids enhance vascular reactivity to other vasoactive substances, probably due to the expression of adrenergic receptors in the vascular wall, thus increasing systemic vascular resistance. On the one hand corticosteroids have immediate dramatic beneficial effects in several categories of critically ill patients. The desirable effects of corticosteroids include hemodynamic improvement and the reduction of inflammatory response under several critical conditions such as systemic inflammatory response syndrome (SIRS) and septic shock3, exacerbation of chronic obstructive pulmonary disease (COPD), acute asthma and severe community acquired pneumonia (CAP).5 Corticosteroids have also been extensively studied in the perioperative setting. Most of these studies investigated the role of corticosteroids in cardiac surgery, where their anti-inflammatory effects may play a central role in modulating inflammatory response to cardiopulmonary bypass and surgical trauma.6,7 On the other hand, short-term and mid-term effects on mortality are unknown, even if the literature suggests that corticosteroids can be deleterious in specific settings such as traumatic brain injury (TBI), as an important trial about on this topic showed that patients receiving corticosteroids have a higher risk of death from all causes.8

In the setting of these contrasting evidences, we sought to assess the role of corticosteroids in critically ill and surgical patients by performing a meta-analysis of all randomized controlled trials (RCTs) published on corticosteroid use in these patients.

Methods Search strategy and study selection PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched for all the pertinent RCTs with no time limit (last update February 1st 2018), by two investigators (EAM, MBR). The full search strategy developed for PubMed is available as Supplemental Material. Additionally, backward snowballing was employed to identify further RCTs of interest. Articles were first screened by title/abstract, and if considered pertinent, retrieved as complete manuscript. Assessment of the eligibility of the identified studies was independently performed by two authors (EAM, MBR). Different opinions were discussed between the authors until consensus was reached.

Studies were considered eligible if they met all of the inclusion criteria: 1) publication in a peer reviewed journal, 2) randomized controlled trial design, 3) dealt with the administration of corticosteroids compared to placebo or standard therapy, 4) critically ill patient or surgical setting. Articles were excluded if they met at least one of the following exclusion criteria: 1) used a quasi-randomized or non-randomized methodology, 2) included less than ten patients 3) dealt only with paediatric population (less than 14 years), 4) did not report mortality data, 5) corticosteroids used topically (eg skin creams or eye drops).

Patients were considered to be critically ill if they had at least one organ dysfunction and/or were receiving intensive care or emergency treatments (regardless of patient location), at the time of randomization. This study is registered with PROSPERO, number CRD42016046386. Data extraction For each study we extracted details on the paper (title, year of publication, authors, journal, disease investigated), on the RCT methodology (type, doses and administration regimen of corticosteroid and its comparator, days of therapy, setting, blinding, sample size, number of centres where the study was performed), on mortality, and on the study population (mean age of enrolled patients). In case of RCTs reporting mortality at more than one landmark time we chose the latest, following recent literature suggesting that different mortality time points do not influence pooled points estimates of the effects at study level.9 Three trained investigators (EAM, SS, VFG) independently extracted data, and conflicts were discussed and resolved with a fourth author (GL). Outcomes The primary outcome was mortality from any cause. As secondary endpoints we assessed mortality sorted by different organ affected, the type of steroid molecule used, and duration of the treatment. Therefore, we performed sub-analyses on respiratory, liver, heart, central nervous system (CNS), systemic or infectious diseases. Furthermore, we assessed mortality outcome differences comparing surgical and non-surgical patients. The primary outcome was all-cause mortality at the longest follow up available.

Statistical analysis

Analysis was performed with RevMan (Review Manager version 5.3, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, 2014) and Stata (version 14.1, Stata Corp., College Station, Texas). Pooled odd ratios (ORs) were calculated using a fixed-effects model. Hypothesis of statistical heterogeneity was tested by means of Cochran Q statistic and I2 values.10 The I2 statistic was used to estimate the percentage of total variation across studies due to heterogeneity rather than chance, with values exceeding 50% indicative of considerable heterogeneity and analyzed with the random effect model. Statistical significance was set at p-value < 0.05 (two-sided). Publication bias and small study effect was visually assessed for primary endpoints using funnel plots comparing mean difference estimates with standard error. Egger’s linear regression method and Begg’s test for interdependence of variance were used to detect funnel plot asymmetry.11,12 When baseline data was available only as median and interquartile range we assumed median as mean while standard deviation was calculated by median and interquartile range.13 Sensitivity analyses were computed by performing subgroup analyses according to the type of drug used, age, treatment duration, year of publication, multicentre or not multicentre trial, blinded or unblinded trial, surgery or not surgical intervention, and infectious or not infectious diseases. All analyses were performed according to the intention-to-treat (ITT) principle. Some articles did not report ITT data and in these cases we used the data as presented in the paper. Search strategy, study selection, data extraction, and data analysis were performed in accordance with The Cochrane Collaboration and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.14-16

Results Study Characteristics Our search strategy yielded 1,991 articles. Excluding 1,767 non-pertinent titles or abstracts, we retrieved and assessed for eligibility 224 papers. Eighty-nine studies were then excluded, mostly because they lacked mortality data. Ultimately, we identified 135 articles

7,8,17–100,100–148

including 44,553 patients for the

analyses: 22,160 were treated with corticosteroids and 22,160 were in the control group. Of the 135 RCTs, 127 (94%) were conducted with a blind trial design. The study selection process is illustrated is Figure 1. Main characteristics of the included studies are summarized in Supplemental Table 1. The studies analysed 8 different steroid molecules, with methylprednisolone being the most frequently studied agent (48/135 RCTs, 35.5%), followed by hydrocortisone (29/135 RCTs, 21.5%) and dexamethasone (28/135 RCTs, 20.7%). (Supplementary table 2) Thirty-eight (28%) trials included patients with cardiac disease (32 trials before, during or after elective cardiac surgery, 3 trials after cardiac arrest, 2 trials to treat tuberculous pericarditis and 1 trial in patients with unstable angina). In 27 trials (21%), corticosteroids were used to treat respiratory diseases (12 trials on pneumonia, 6 trials on Adult Respiratory Distress Syndrome (ARDS) and 9 articles on COPD). In 23 trials (17%), corticosteroids were used to treat sepsis patients, either septic shock (n=14) or sepsis (n=9). Sixteen trials (12%) investigated the use of corticosteroids in liver diseases, 15 trials (11%) CNS diseases, and the remaining 15 trials (11%) dealt with ventilator weaning, fat embolism syndrome, leptospirosis, haemolysis elevated liver enzyme levels and low platelets (HELLP) syndrome, pulmonary tromboendarterectomy, hip fracture, pancreaticoduodenectomy, postoperative SIRS, patients who needed endotracheal intubation, multiple trauma, burn, oesophageal

surgery, vascular surgery, non-cardiac surgery, typhoid fever and post-extubation laryngeal oedema (Supplemental Table 1). Quantitative data synthesis The overall analysis showed that there was no significant mortality difference in patients receiving corticosteroids when compared with control ((3570/22393 (16%) in the group treated with corticosteroids vs 3448/22160 (16%) in the control group; OR=1; p=0.9; I2 =40%) (Supplemental Figure 1). Sub-analyses in specific clinical settings and divided by organ are shown in Figure 2. A reduction in mortality was identified when analysing respiratory diseases (Supplemental Figure 2), especially pneumonia (mortality 6% in steroid group vs 9.3% in control group; OR=0.56; p=0.001; I2=44%) and ARDS (mortality 27% in steroid group vs 37% in control group; OR=0.48 ; p=0.03; I2=55%) (Supplemental Figure 3). Furthermore, corticosteroids increased survival in patients with bacterial meningitis (28% in steroid group vs 32% in placebo group; OR=0.8; p=0.04; I2=50%). Conversely, the use of corticosteroids significantly increased mortality in TBI (22% in steroid group vs 19% in control group; OR=1.19; p=0.0002; I2=0%), (Figure 2). When overall mortality was reassessed excluding studies on TBI, the analysis showed that mortality was lower in patients receiving steroids compared with controls (OR=0.93; p=0.03; I2=33%) (Supplemental Figure 4). No differences in mortality were found in patients with alcoholic hepatitis (Supplemental Figure 5), infectious diseases (Supplemental Figure 6), sepsis, and septic shock and heart disease (Supplemental Figure 7). No effect on patients’ age or treatment duration or surgical/non surgical setting on survival were noted (Supplemental Figures 8, 9 and 10), (Figure 2).

STEROIDS MOLECULES When considering the different steroid molecules included in the meta-analysis, dexamethasone was associated with a statistically significant improvement in survival (OR=0.8; p=0.005; I2=39%), while methylprednisolone was associated with a statistically significant increase in mortality (OR=1.11; p=0.01; I2=42%) when compared to controls without steroid treatment (Supplemental Figure 11). METHODOLOGICAL VARIABLES Patients receiving corticosteroids had a lower mortality when compared to control patients if single center studies only were considered (OR = 0.85; p =0.002; I2 = 33%), and when only studies with small sample size (<100 patients) were included in the analyses (17.9% in corticosteroids group vs 19.5% in control group; OR 0.68; p < 0.001; I2= 31%). Small study publication bias was present (Supplemental Figures 12-16, Supplemental Table 3). No differences emerged according to publication period. (Supplemental Figure 15) CORTICOSTEROIDS IN CARDIOVASCULAR PATIENTS. When focusing on the use of steroids in heart disease, no beneficial effect was found. In 16,983 analyzed patients mortality was 6.9% in steroid group vs 6.1% in the control group (OR =0.97; I2=2%; p=0.66).(Supplemental Figure 7) The majority of these studies (55%) were performed in cardiac surgery patients (mortality was 2.8% in steroid group vs 3.2% in control group; OR=0.87, I2=0%; p=0.14), with 32 trials and 15,270 patients analyzed. (Supplemental Figure 7)

Discussion Key Findings Our meta-analysis of 135 randomized controlled trials is the first to comprehensively investigate the effect of corticosteroids on overall mortality in critically ill and perioperative

patients. It is also the first to pool studies according to the different target organs. We found that in critically ill patients the administration of corticosteroids is safe and does not result in overall increased mortality. Our findings are of interest especially because the short term effects of corticosteroids on intermediate outcomes (eg increase in blood pressure in shock patients or reduced inflammatory status in many conditions) are impressively documented and widespread. This observation is in accordance with the highest quality trial published so far147 which documented no difference in mortality in septic shock patients but at the same time showed improvement in several intermediate outcomes (es median time to resolution of shock and ICU stay). Our findings also confirm the hypothesis that corticosteroids can improve short-term survival in selected groups of patients: a mortality reduction was in fact observed in respiratory diseases (pneumonia and ARDS in particular) and bacterial meningitis. The positive findings of our meta-analysis in selected subgroups and in the nonTBI patients (32,733 patients, representing 73% of the overall study population) are to be interpreted with caution in view of the possible biases (eg. small study bias and single center study bias). Dexamethasone was associated with survival benefit. Although the difference in mortality was statistically significant, the improvement in survival was small. Conversely, methylprednisolone was associated with increased mortality in the treatment group, but the result may be driven by the large study from Roberts, et al. on TBI.8 Furthermore, length of corticosteroids administration was not associated with mortality difference. Thus, no recommendations on which steroid regimen is the best choice in critically ill patients can be formulated.

Relationship to previous studies Corticosteroids are the most potent anti-inflammatory drugs and their beneficial modulation of the immune response has been reported since 1956.147 When excluding TBI patients the

findings of our meta-analysis confirm the trend in literature towards a beneficial effect on steroids use136,149,150, although identifying specific populations of patients in whom steroid use is detrimental. More specifically, our results are in accordance with other studies showing an increase in survival in patients with pneumonia151-153, and ARDS154,155, Considering steroid use in patients with TBI, our findings differ from those of Alderson et al156, as we have identified a worse outcome when corticosteroids are used. This is likely due to the inclusion of more recent studies, and is in line with the most important trial on the topic.8,157 No differences in mortality in infectious disease neither in septic shock emerged from our meta-analysis. This findings are consistent with the recent multicenter double blind trial in septic shock by the ANZIC Trial Group.147 Two recent large multicenter randomized trials6,7 evaluated the effects of corticosteroids in cardiac surgery, failing to demonstrate survival benefit, as now confirmed by our metaanalysis. Even if a blend of benefit on secondary outcomes can be extrapolated from these two studies, possible harm was not excluded. In the study by Dielman and colleagues6 the use of dexamethasone was associated with a significantly reduced incidence of respiratory failure, postoperative infections, postoperative mechanical ventilation, intensive care unit and hospital stay although this findings on respiratory failure, infections and length of hospital stay were not confirmed by Whitlock et al.7 Notably, Dielman’s study, which showed improved clinical outcomes was performed using dexamethasone, while Whitlock’s used methylprednisolone, confirming the effect of different corticosteroids highlighted by our meta-analysis. Notably, a trend toward an increase in myocardial infarction and in mortality elderly patients (>80 years) were reported by Withlock and Dielman respectively.6,7

Significance of study findings and what this study adds to our knowledge To the best of our knowledge, this is the first meta-analysis to investigate the effect of corticosteroids on survival in critically ill patients, considering all acute care and surgical settings and separating trials both by disease and by affected organs. Our results support the use of steroids in non TBI critically ill patients, summarize the contexts in which they are most beneficial, and confirm safety in cardiac diseases, regardless of treatment duration.

Strengths of the study The strength of our results is supported by various aspects. Firstly, all analysed trials had a randomized design and were published in peer-reviewed journals. Secondly, the comparator was always either placebo or standard care. Thirdly, this is the largest meta-analysis performed on the topic, and the high number of trials included renders the results robust. Finally, we performed various sub-analyses according to both organ and disease, so to explore differences in the study population and identify areas where corticosteroids are more beneficial or are detrimental.

Limitations of the study The major limitation of our study is a common limitation of large meta-analyses, which is the heterogeneity of trials, as inclusion/exclusion criteria, severity of patients and drug use vary widely. We also identified small study bias and single center design bias. Moreover, the wide difference in years of publication might be a concern, as the standards of care have changed consistently in time. Finally, some included studies were unblinded, possibly introducing systematic biases. Another limitation is the exclusion of 88 potentially pertinent trials for the lack of data on mortality. These trials could potentially affect the overall study results, but the absence of mortality data makes it impossible to include them. We also acknowledge that we

did not perform sub analyses based on drug dosage (high vs low) since we failed to effectively dichotomize the dose due to heterogeneity.

Future studies and prospects Further studies are required in the areas identified as neutral in our meta-analysis. Further research should also investigate the effects of dexamethasone compared to other steroid drugs. Since no or small differences in mortality emerged, future studies should probably focus on different clinical outcome.

Conclusions This large and comprehensive meta-analysis of RCTs confirms the overall safety of corticosteroids in critically ill patients regardless of treatment duration and patients age. Survival benefit in non TBI patients is suggested with the use of corticosteroids, especially in some specific settings, such as respiratory disease even if several methodological biases exist. Further studies should probably focus on other clinical outcomes, different from mortality.

Acknowledgements Fundings: none. Conflict of interest: none.

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Figure Legends Figure 1. Diagram of the study selection process Figure 2. Subanalyses on the effect of steroids on survival in critically ill patients