Article Text
PDF
Abstract
Objective To demonstrate the therapeutic effect of vasopressin as an alternative treatment for cardiac arrest.
Design Systematic review and meta-analysis.
Methods PubMed, EMBASE, the Cochrane Library and Web of Science were searched for randomised controlled trials. The intervention included administration of vasopressin alone or vasopressin combined with epinephrine or vasopressin, steroids and epinephrine (VSE) versus epinephrine combined with placebo as control group. The primary outcome was the return of spontaneous circulation (ROSC). The secondary outcomes included mid-term survival and mid-term good neurological outcome. We conducted subgroup analyses of the primary outcome based on different settings, different study drug strategies and different types of initial rhythm.
Results Twelve studies (n=6718) were included, of which eight trials (n=5638) reported the data on patients with out-of-hospital cardiac arrest and four trials (n=1080) on patients with in-hospital cardiac arrest (IHCA). There were no significant differences between intravenous vasopressin and placebo in the outcomes of ROSC (relative risk (RR): 1.11; 95% CI: 0.99 to 1.26), mid-term survival (RR: 1.23; 95% CI: 0.90 to 1.66) and mid-term good neurological outcome (RR: 1.20; 95% CI: 0.77 to 1.87). However, in the subgroup analysis, intravenous vasopressin as part of VSE can significantly improve the rate of ROSC (RR: 1.32; 95% CI: 1.18 to 1.47) but not the rate of mid-term survival (RR: 2.15; 95% CI: 0.75 to 6.16) and mid-term good neurological outcome (RR: 1.80; 95% CI: 0.81 to 4.01) for patients with IHCA.
Conclusions Our study failed to demonstrate increased benefit from vasopressin with or without epinephrine compared with the standard of care. However, vasopressin as a part of VSE is associated with the improvement of ROSC in patients with IHCA, and the benefit on mid‐term survival or mid-term good neurological outcome is uncertain. Larger trials should be conducted in the future to address the effect of vasopressin only, vasopressin plus epinephrine or VSE on cardiac arrest.
PROSPERO registration number CRD42021293347.
- Adult intensive & critical care
- ACCIDENT & EMERGENCY MEDICINE
- CARDIOLOGY
Data availability statement
Data are available upon reasonable request. The data presented in this study are available on request from the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
STRENGTHS AND LIMITATIONS OF THIS STUDY
This study conducted comprehensive evaluation of the effect of vasopressin on cardiac arrest based on different settings, different intravenous vasopressin strategies and different patient types.
The detailed characteristics of the studies including vasopressin dose were summarised.
Mean arterial pressure and long-term outcomes could not be evaluated.
Due to the limited quality of studies and the heterogeneity of study populations, the findings of the study should be cautiously interpreted.
Background
Cardiac arrest is a major contributor to morbidity and mortality worldwide.1 For more than 100 years, epinephrine has been administered during cardiopulmonary resuscitation (CPR) for patients in cardiac arrest.2 However, previous reports suggested that endogenous vasopressin levels in successfully resuscitated patients were significantly higher than those in patients who died, and that intravenous vasopressin during CPR may give better results than epinephrine.3–6 Based on a randomised controlled trial (RCT)6 and some small case series,7 8 the American Heart Association Advanced Cardiac Life Support (ACLS) guidelines9 recommend vasopressin as an alternative to epinephrine for the treatment of cardiac arrest. However, the clinical benefit of vasopressin remains debated. A trial by Stiell et al10 showed no obvious benefit of vasopressin over epinephrine for in-hospital cardiac arrest (IHCA). However, a clinical trial11 demonstrated that a combination of vasopressin and epinephrine during CPR improves the outcome for patients with out-of-hospital cardiac arrest (OHCA). In addition, several studies12–14 have recently proposed that an emerging therapy using vasopressin, corticosteroid and epinephrine (VSE) during CPR may improve the outcomes for cardiac arrest. To evaluate the impact of vasopressors in patients who had cardiac arrest, a meta-analysis indicated that there was no benefit from vasopressin with or without epinephrine.15 However, these trials12–14 assessing the effect of VSE were not included in the meta-analysis. Currently, there is no systematic review or meta-analysis that has evaluated the overall therapeutic effect of vasopressin (vasopressin only, vasopressin plus epinephrine and VSE) and the effect based on the type of initial rhythm, witnessed and CPR by a bystander on cardiac arrest. Therefore, we performed a systematic review and meta-analysis to evaluate the therapeutic effect of vasopressin on cardiac arrest.
Methods
The methods and protocol of this meta-analysis were previously published in detail on the International Prospective Register of Systematic Reviews (registration number: CRD42021293347). Reporting of findings was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses.16
Eligibility criteria
Eligibility criteria were based on the Population, Intervention, Control, Outcomes and Study design framework as follows: (1) population—adult patients with cardiac arrest in any setting (IHCA or OHCA); (2) the intervention included administration of vasopressin alone or vasopressin combined with epinephrine or VSE versus epinephrine combined with placebo as control group; (3) the study reported at least one of the following outcomes: return of spontaneous circulation (ROSC), survival and good neurological outcome; and (4) study design: RCTs. The following criteria determined the ineligible studies: (1) use of vasopressin not during CPR; (2) inappropriate study designs, single-arm trials, observational studies or non-RCTs; (3) case reports or series and narrative and systematic reviews; (4) those with <20 patients; (5) those not reported in the English language; (6) studies with pregnant women or minors.
Search strategy
A systematic search of PubMed, EMBASE, the Cochrane Library and Web of Science was performed from database inception to 15 November 2022 with English language restrictions by two authors (WY and WD). In addition, we conducted a hand search of references obtained from identified studies and known meta-analyses. We combined the following search terms: cardiac arrest, heart arrest, cardiopulmonary resuscitation, advanced cardiovascular life support, ventricle fibrillation, asystole, pulseless electrical activity, ACLS, CPR and vasopressin. The actual search strategy was available in online supplemental file 1.
Supplemental material
Data collection and data items
Two authors (WY and XS) separately screened all retrieved citations by reviewing their titles and abstracts. Full-text articles were retrieved if either of the authors considered the abstract potentially suitable. Next, the same authors independently assessed each study’s eligibility based on the inclusion criteria. Disagreements were resolved by discussion or consensus with a third author (ZC). Two reviewers (WD and WZ) independently extracted individual study data using a predefined data extraction form. Any disagreements between review authors were resolved by consultation with a third author (ZC). Data extracted included the name of the first author, date, country, study design, location, sample size, age, sex, rhythm, therapeutic methods in the two groups and outcomes.
Risk of bias in individual studies
Two reviewers evaluated studies for risk of bias using a previously piloted standardised form and the Cochrane Risk of Bias 2 tool17 for RCTs. The following domains were assessed: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome and bias in the selection of the reported result. The overall risk of bias for each included study was categorised into low risk of bias, some concern of bias or high risk of bias. The risk of publication bias was assessed by visual interpretation of funnel plots if at least 10 studies could be identified reporting the outcome.
Outcomes and subgroups
These outcomes included ROSC, mid-term survival (at hospital discharge, 28 days, 30 days or 1 month) and mid-term good neurological outcome (at hospital discharge, 28 days, 30 days or 1 month). ROSC was defined as spontaneous circulation with no further need for chest compressions sustained for at least 15 min. The good neurological outcome was measured by the Cerebral Performance Category (CPC) or the modified Rankin Scale. The CPC score18 has five categories as follows: (1) good cerebral performance, (2) moderate cerebral disability, (3) severe cerebral disability, (4) coma or vegetative state, and (5) death. A CPC score of 1–2 is considered a good neurological outcome. The modified Rankin Scale19 is a 7-point scale, with higher scores indicating worse outcomes. A score of 0–3 was considered a good neurological outcome.
If the information was available, we planned to conduct subgroup analyses of the primary outcome based on: (1) different settings and different study drug strategies (patients with IHCA/OHCA receiving vasopressin only, vasopressin and epinephrine, and VSE); (2) different types of initial rhythm (ventricular fibrillation/tachycardia, asystole and pulseless electrical activity); (3) patients with witnessed arrest; (4) patients with CPR by a bystander; (5) different study qualities (study with low risk of bias, study with some concerns of bias and study with high risk of bias); (6) different study periods (before 2000 and after 2000) and (7) different study regions (North America, Europe and Asia).
Data synthesis
The meta-analysis was conducted using the Review Manager V.5.4 software (RevMan, The Cochrane Collaboration, 2020). Dichotomous data of ROSC, mid-term survival and mid-term good neurological outcome were represented as relative risk (RR) with 95% CIs. A random-effects model was used, and statistical significance was set at p<0.05 for all analyses. Heterogeneity was estimated visually in forest plots and statistically using I2 tests, as recommended by the Cochrane Collaboration. We considered heterogeneity low if I2 was <25%, moderate if 25%–50% and substantial if >50%. To examine heterogeneity, we performed subgroup analysis based on predefined moderator variables, including study region, study quality, age, IHCA versus OHCA and therapeutic methods. The primary outcome estimates for patients with shockable rhythms, with or without arrest witnessed and with or without CPR by a bystander, were also synthesised in the subgroup analysis.
Patient and public involvement
Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Results
Study selection and study characteristics
Our search strategy identified 12 randomised trials,6 10–14 20–25 including 6718 adult patients who met the eligibility criteria. The flow diagram for study inclusion was shown in figure 1. All included studies were prospective RCTs and included patients between the years 19946 and 2021.12 Seven trials6 11–14 21 23 were performed in Europe, three22 24 25 in Asia and two10 20 in North America. Eight trials (n=5638) included patients with OHCA6 11 20–25 (table 1) and four trials (n=1080) included patients with IHCA10 12–14 (table 2). One trial25 did not provide the mean age, and the mean age of patients included in the other 11 trials ranged from 5823 to 70 years.10 Four trials6 11 22 24 compared vasopressin with epinephrine in patients with OHCA; four trials20 21 23 25 compared epinephrine plus vasopressin with epinephrine and placebo in patients with OHCA (table 1). Three trials12–14 compared VSE with epinephrine plus placebo in patients with IHCA; and one trial10 compared vasopressin with epinephrine in patients with IHCA (table 2). The dosage and course of each trial were presented in tables 1 and 2. In the four trials of IHCA, patients of one trial10 by Stiell et al received one injection of 40 IU of vasopressin, followed by an additional treatment with epinephrine if necessary. Two trials13 14 by Mentzelopoulos et al in 2009 and 2013 administered hydrocortisone to resuscitated patients with circulatory shock in the intervention arm, whereas the trial12 by Andersen et al did not include any protocolised post-cardiac arrest interventions (table 2).
Literature search and study selection flow diagram.
Characteristics of the studies on out-of-hospital cardiac arrest (OHCA)
Characteristics of the studies on in-hospital cardiac arrest (IHCA)
Risk of bias in studies
The assessment of bias in the RCTs was listed in online supplemental figure 1. Two trials14 25 were considered to have a high risk of bias, seven6 10 11 20 22–24 were considered to have some concerns for risk of bias and the remaining three12 13 21 were considered to have a low risk of bias. The trial25 by Ghafourian et al did not report methods of randomisation and minimal baseline characteristics between groups; one22 by Mukoyama et al reported limited information on the process of randomisation; and two10 24 by Stiell et al and Ong et al reported some baseline imbalance between the groups.
Supplemental material
The plots for ROSC and mid-term survival were asymmetrical, which strongly imply publication bias (online supplemental figures 2 and 3). Owing to the small number of included studies, a funnel plot did not allow assessment of the publication bias in terms of mid-term good neurological outcome.
Primary outcome
The results of the primary and secondary outcomes are displayed in table 3. Eleven trials6 10–14 20–24 with 6607 patients reported the rate of ROSC. When all the trials were pooled, there was no significant difference in patients with ROSC outcome between intravenous vasopressin and placebo (RR: 1.11; 95% CI: 0.99 to 1.26; I2=62%; Figure 2). The statistical heterogeneity in this analysis was significant. Subgroup analyses were performed to examine the potential source of heterogeneity (table 3). The setting and different study drug strategies might be the source of heterogeneity.
Data analysis of primary and secondary outcomes
Forest plot of return of spontaneous circulation. IHCA, in-hospital cardiac arrest; OHCA, out-of-hospital cardiac arrest; VSE, vasopressin, steroids and epinephrine.
When analysing the subgroups, including three trials, intravenous VSE in patients with IHCA was associated with significant increase in the rate of ROSC (RR: 1.32; 95% CI: 1.18 to 1.47; I2=0%; figure 2). There was no significant heterogeneity in the results. There were no significant differences in the rate of ROSC in patients with OHCA receiving vasopressin only (RR: 1.03; 95% CI: 0.87 to 1.23; I2=38%; figure 2) and in patients with OHCA receiving vasopressin plus epinephrine (RR: 0.97; 95% CI: 0.87 to 1.08; I2=0%; figure 2). In addition, in the subgroup analyses, there was no significant difference in the rate of ROSC for patients with ventricular fibrillation (RR: 1.02; 95% CI: 0.84 to 1.25; I2=30%), asystole (RR: 1.01; 95% CI: 0.90 to 1.14; I2=0%), pulseless electrical activity (RR: 1.00; 95% CI: 0.82 to 1.21; I2=0%), witnessed arrest (RR: 1.04; 95% CI: 0.82 to 1.33; I2=66%) and CPR by a bystander (RR: 1.22; 95% CI: 0.89 to 1.67; I2=38%).
Secondary outcomes
Mid-term survival
Twelve trials with 6680 patients reported the rate of mid-term survival. Eleven trials6 10 11 13 14 20–25 reported the survival rate at hospital discharge, and one trial12 reported the rate of survival at 30 days. When all the trials were pooled, there was no significant difference in patients with mid-term survival outcome between intravenous vasopressin and placebo (RR: 1.23; 95% CI: 0.90 to 1.66; I2=39%; figure 3). In subgroup analyses, including three trials, there was no important difference in the rate of mid-term survival for patients with IHCA who received VSE (RR: 2.15; 95% CI: 0.75 to 6.16; I2=76%; figure 3). The test for heterogeneity was significant. After excluding one trial,12 the heterogeneity decreased significantly (I2 value from 76% to 0%). Notably, no significant heterogeneity was observed between the two trials,13 14 the study protocols were the same and both were reported by the same study group. In addition, there was no significant difference in the rate of mid-term survival for patients with OHCA receiving vasopressin only (RR: 1.14; 95% CI: 0.84 to 1.53; I2=0%; figure 3) and in patients with OHCA receiving vasopressin plus epinephrine (RR: 0.86; 95% CI: 0.56 to 1.33; I2=0%; figure 3).
Forest plot of mid-term survival. IHCA, in-hospital cardiac arrest; OHCA, out-of-hospital cardiac arrest; VSE, vasopressin, steroids and epinephrine.
Mid-term good neurological outcome
Six trials10–14 22 with 2548 patients provided data to evaluate the effect of vasopressin on good neurological outcome. One trial12 reported good neurological outcome at 30 days, and the remaining reported good neurological outcome at hospital discharge. There was no significant difference in patients with mid-term good neurological outcome between intravenous vasopressin and placebo (RR: 1.20; 95% CI: 0.77 to 1.87; I2=47%; figure 4). For patients with IHCA, patients of three trials12–14 receiving VSE did not improve good neurological outcome (RR: 1.80; 95% CI: 0.81 to 4.01; I2=56%; figure 4). Statistical heterogeneity in the subgroup was significant. After excluding the 2021 trial,12 the heterogeneity decreased significantly (I2 value from 76% to 0%).
Forest plot of mid-term good neurological outcome. IHCA, in-hospital cardiac arrest; OHCA, out-of-hospital cardiac arrest; VSE, vasopressin, steroids and epinephrine.
Discussion
Our meta-analysis failed to demonstrate benefit from vasopressin with or without epinephrine compared with the standard of care. However, we found that intravenous vasopressin, as part of the VSE during CPR in patients with IHCA, significantly increased the rate of ROSC, but not mid-term survival and mid-term good neurological outcome.
When all the trials were pooled, intravenous vasopressin did not have benefit in patients in cardiac arrest. In a previous trial,6 Lindner et al found that intravenous vasopressin during CPR significantly increased the benefit for patients with OHCA with ventricular fibrillation. Moreover, one subgroup analysis of an RCT10 by Stiell et al showed that vasopressin was superior to epinephrine in patients with OHCA with asystole, and that the use of vasopressin followed by epinephrine may be more effective than the use of epinephrine alone. However, we found no subgroup differences in patients with ventricular fibrillation, asystole, pulseless electrical activity, witnessed and CPR by a bystander. Our meta-analysis differed from previous trials by Lindner et al and Stiell et al, which the following possible reasons may explain. First, 5638 patients with OHCA were included, which contributed to 84% of the study population. For patients with OHCA, an early risk identification, high-quality CPR and emergency medical services (EMS) improved the outcomes among patients in cardiac arrest.26 As shown in table 1, a small number of patients received a bystander CPR in patients with OHCA. All these factors led to the high mortality rate. High mortality may limit the certainty of the evidence for these comparisons. Second, our study included patients from different countries, and the results could have been affected by the ethnic differences, different resuscitation guidelines and EMS, leading to bias. In our planned subgroup analysis, the outcomes have no significant difference with respect to Europe, Asia and North America. However, the results of a previous meta-analysis27 showed that the combination of vasopressin and epinephrine could improve the ROSC of OHCA in Asia, but patients from other regions did not achieve this result. The main reason for this inconsistency was that we did not include any RCT published in languages other than English. Finally, there was some heterogeneity in dosage and course of vasopressin. Vasopressin is a dose–response drug.11 In our analysis, eight trials of OHCA included four trials of only one dose of vasopressin (40 IU), two trials had a maximum of two doses, one trial had a maximum of three doses and one trial had a maximum of four doses (table 1). We could not obtain sufficient data to evaluate the effect of different doses. Inadequate dosing may have contributed to this negative result.
However, using vasopressin is not entirely without benefit. The most significant finding was that vasopressin, as a part of VSE, did improve the rate of ROSC for patients with IHCA but did not improve mid-term survival and mid-term good neurological outcome. The finding was inconsistent with the results of a previous meta-analysis28 that suggested that VSE are associated with improved outcomes in cardiac arrest, including good neurological outcome, survival to hospital discharge and ROSC. A recent study by Granfeldt et al29 performed a systematic review and individual participant data meta-analysis of VSE for the treatment of cardiac arrest. A Bayesian framework was used to estimate posterior treatment assuming various prior beliefs. Results favoured vasopressin and glucocorticoids for ROSC but were more uncertain for survival at hospital discharge and favourable neurological outcomes. The conclusion coincides with the results from our study. Moreover, a meta-analysis by Saghafi et al30 suggested that VSE combination therapy during and after IHCA may have beneficial effects in terms of the ROSC, renal and circulatory failure free days, and mean arterial pressure. In our study, three trials12–14 receiving VSE were included, and three trials used the same VSE protocol during CPR, as shown in table 2.
Therefore, vasopressin may improve the rate of ROSC in patients with IHCA. However, we cannot exclude the effects of corticosteroids for mid-term survival and mid-term good neurological outcome. First, the two trials by Mentzelopoulos et al13 14 that received VSE, using glucocorticoids as an add-on treatment during the post-resuscitation period, showed that VSE could improve mid-term survival and good neurological outcome. However, the Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial12 did not accept glucocorticoids during the post-resuscitation period and did not achieve better outcomes of mid-term survival and good neurological outcome. The use of glucocorticoids after ROSC could directly improve the outcomes. In addition, in our analysis, the two trials reported survival at hospital discharge and good neurological outcome at hospital discharge as mid-term outcomes. However, the VAM-IHCA trial reported survival at 30 days and good neurological outcome at 30 days as mid-term outcomes. The two outcome measures may have an effect on the results of mid-term survival and good neurological outcome. It is worth noting that the average dose of vasopressin used in the VAM-IHCA Study was 47 IU, while the average dose was 70.3–73.3 IU in the studies by Mentzelopoulos et al in 2013 and 2009. Therefore, the VAM-IHCA Study provided an insufficient dose of vasopressin in the intervention group.31
A difference between our study and those two recent studies29 30 by Granfeldt et al and Saghafi et al is that we evaluated the overall impact of vasopressin in cardiac arrest. There is no single optimal method suitable for all patients. Each regimen is worthy of further exploration. However, the effect of vasopressin only or vasopressin combined with epinephrine is still not conclusive due to limited high-quality data. Current international guidelines9 32 do not recommend the use of vasopressin as a resuscitation drug for cardiac arrest. We would like to point out that the effect of vasopressin on patients in cardiac arrest cannot be denied. First, the previous trial11 demonstrated that a combination of vasopressin and epinephrine during CPR improves the outcome for patients with OHCA. In vitro studies have indicated that adjuvant therapy with exogenous vasopressin during CPR is more effective than optimal doses of epinephrine in improving blood flow to critical organs.33 Second, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the ROSC in IHCA. However, a meta-analysis showed that there was no difference demonstrated in patients with IHCA receiving corticosteroids only or in patients with OHCA receiving corticosteroids only.28 Thus, we did evaluate the effect of three vasopressin regimens, and we did summarise the characteristics of each RCT in tables 1 and 2 . We hope that our study can shed some light for future studies. Moreover, patients with OHCA, constituting a significant proportion of the cases treated in the emergency department, were not included in the VSE therapy studies. Therefore, better-designed trials on a large group of patients should be conducted in the future to address the therapeutic effect of vasopressin only, vasopressin combined with epinephrine or VSE on cardiac arrest.
Our systematic review has several limitations. First, there are limited high-quality data to analyse the effect of vasopressin. Nine RCTs contained a high or unclear risk of bias in each domain. Second, data of the included patients were heterogeneous, based on baseline characteristics. The proportion of patients with ventricular fibrillation in each trial was different. Although we performed subgroup analysis of ventricular fibrillation, some trials did not provide data on outcomes of ventricular fibrillation. Third, despite finding vasopressin as part of VSE that may increase the ROSC, we cannot draw a firm conclusion whether VSE improves mid-term survival or good neurological outcome in patients with IHCA because we cannot exclude the effects of receiving hydrocortisone in resuscitated patients with circulatory shock. Finally, whether the results of this meta-analysis can be generalised to all patients in cardiac arrest remains uncertain. Patients with OHCA, constituting a significant proportion of the study, may influence the generalisability of our results. There are distinct differences in the treatment of patients who experience cardiac arrest in a hospital setting where disease processes, aetiologies and illness severity differ and medical response time is often shorter.26
Conclusions
Our study failed to demonstrate increased benefit from vasopressin with or without epinephrine compared with the standard of care. However, vasopressin, as a part of VSE, is associated with the improvement of ROSC in patients with IHCA, and the benefit on mid‐term survival or mid-term good neurological outcome is uncertain. Better-designed trials on a large group of patients should be conducted in the future to address the therapeutic effect of vasopressin only, vasopressin plus epinephrine or VSE on cardiac arrest.
Data availability statement
Data are available upon reasonable request. The data presented in this study are available on request from the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
This article does not contain any studies with human participants or animals performed by any of the authors because it relies on primary studies.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors WY and XS wrote the draft. WY and XS searched the database. WD and WZ assessed each study eligibility. WY, WZ and WD completed statistical analyses. ZC resolved discordant assessments and conflicting results. ZC conceived the idea and reviewed articles. ZC was guarantor.
Funding This work was supported by the National Natural Science Foundation of China (grant number 82160020).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.