Effect of Early Adjunctive Vasopressin Initiation for Septic Shock Patients: A Target Trial Emulation

Effect of Early Adjunctive Vasopressin Initiation for Septic Shock Patients: A Target Trial Emulation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Early Adjunctive Vasopressin Initiation for Septic Shock Patients: A Target Trial Emulation Kyle C White, Rahul Costa-Pinto, Sebastiaan Blank, Stephen Whebell, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5988212/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 May, 2025 Read the published version in Critical Care → Version 1 posted 6 You are reading this latest preprint version Abstract Background In septic shock, the optimal timing of adjunctive vasopressin initiation shock is unknown. We aimed to assess the effect of its early initiation for patients with septic shock. Methods We conducted a multicenter target trial emulation to estimate the intensive care unit (ICU) mortality effect of early (≤ 6 hours) adjunctive vasopressin compared with usual care. Eligible patients had septic shock diagnosed within 6 hours of ICU admission. The primary outcome of this study was 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of early vasopressin start with peak norepinephrine-equivalent dose (NED) at 6 hours, APACHE score, peak lactate at 6 hours and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality and effect of NED at vasopressin start on 30-day ICU mortality. We used the parametric g-formula to emulate a target trial. Results Overall, 3,105 patients fulfilled the inclusion criteria. Mean age was 62 years and mean APACHE III score was 83. In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated. Estimated 30-day ICU mortality was 19.34% (95%CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95%CI, 16.26 to 20.63) in the early vasopressin group; relative risk 0.95 (95%CI, 0.93 to 0.98). The estimated 30-day ICU mortality effect of starting vasopressin was particularly strong at lower norepinephrine doses (< 0.25 µg.kg − 1 .min − 1 ) and significant at lower norepinephrine doses than recommended by the Surviving Sepsis Campaign Guidelines. Vasopressin administration progressively increased over the study period, from 35.2% (95%CI, 30.0 to 40.5) in 2015 to 45.1% (95%CI, 40.7 to 49.6) in 2021 (ß = +1.3% per year; 95%CI, + 0.46 to + 2.16, p = 0.011). Patients had progressively lower norepinephrine equivalent dose (ß = -0.05 µg.kg − 1 .min − 1 per year; 95%CI, -0.09 to -0.002, p = 0.038) and lower total SOFA score (ß = -0.1 point per year; 95%CI, -0.18 to -0.07, p < 0.001) at vasopressin start. Conclusions In this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock. vasopressin sepsis shock hypotension vasodilation critical care Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction There is increasing interest in catecholamine-sparing vasopressor strategies in the management of septic shock [ 1 , 2 ]. The Surviving Sepsis Campaign guidelines currently recommend norepinephrine as the first-line agent for this condition, with a weak recommendation for commencing adjunctive vasopressin when the dose of norepinephrine base is in the range of 0.25–0.5 µg.kg − 1 .min − 1 [ 3 ]. Thus, clinicians may regard vasopressin as a ‘rescue’ therapy rather than an essential component of a multimodal vasopressor strategy. Furthermore, current sepsis guidelines do not recommend a timing threshold for vasopressin initiation despite randomized and observational data suggesting that timing may be an important consideration [ 4 – 9 ]. An individual patient data meta-analysis of four randomized controlled trials of vasopressin in septic shock suggested potential benefit when vasopressin is commenced in less severe shock states (i.e., lower lactate levels, lower norepinephrine dose), and in the absence of established acute kidney injury [ 10 ]. Earlier initiation of adjunctive vasopressin in patients with less severe shock, therefore, warrants further investigation. Accordingly, we conducted a target trial emulation using a large, multicentre database to estimate the effect of early vasopressin initiation on mortality in septic shock patients. We aimed to test the primary hypothesis that early (≤ 6 hours) vasopressin initiation would be associated with lower hospital mortality compared with no vasopressin adjunction. Our secondary hypothesis was that late (> 6 hours) vasopressin therapy would be associated with worse outcomes. Methods Study design We conducted a target trial emulation (TTE) of early vasopressin in septic shock patients. We used routinely collected electronic medical record clinical data from twelve intensive care units (ICU) in Queensland, Australia. The study sites comprised five tertiary, three outer metropolitan, and four regional ICUs and included most of Queensland’s state-wide ICU capacity. Population We included all adult ICU patients (≥ 18 years) admitted with a diagnosis of septic shock within the first six hours of admission. We excluded patients transferred from another ICU or were admitted solely for palliative care or organ donation. In addition, we excluded patients who commenced vasopressin within the first hour of ICU admission. We reasoned that such patients might have had vasopressin started before or within the first hour of ICU admission, introducing uncertainty about the real start time. Intervention Patients were assigned by TTE to treatment groups if they met eligibility criteria in the first six hours of ICU admission. In the primary analysis, patients in the treatment group commenced adjunctive vasopressin within six hours of septic shock. Patients in the control group did not commence adjunctive vasopressin at all. In secondary analyses, vasopressin was started either at a prespecified time or norepinephrine-equivalent dose (NED) threshold. Definitions The norepinephrine formulation used in all centres was norepinephrine tartrate [ 11 , 12 ]. Vasopressors other than vasopressin were converted to norepinephrine-equivalent doses according to previously published conversion tables [ 13 – 15 ]. Sepsis and septic shock were defined according to the Sepsis-3 consensus definition using previously published methodology [ 16 , 17 ]. Outcomes The primary outcome of this study was to assess the impact of early timing (≤ 6 hours since septic shock) of vasopressin initiation on 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of vasopressin start within 6 hours of ICU admission with peak NED at 6 hours, APACHE score, peak lactate at 6 hours and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality, effect of NED at vasopressin start on 30-day ICU mortality. Exploratory outcomes were changes in vasopressin administration over the study period (prevalence of prescription, NED at vasopressin start, total SOFA score at vasopressin start and time from ICU admission to vasopressin start). Statistical analysis Baseline characteristics are reported as absolute values with percentages for categorical variables or medians with the interquartile interval for quantitative variables. Annual proportion with a 95% confidence interval was calculated out of the yearly number of included ICU admissions. Changes in annual incidence were performed by testing its interaction with time via linear regression. To quantify the causal effect of early vasopressin start on 30-day ICU mortality, we used a target trial emulation protocol (electronic supplementary material, ESM, Table S1 ) and the parametric g-formula [ 18 – 21 ]. This method allows for the reliable estimation of the risk of outcomes under sustained interventions (analogous to a per-protocol analysis in a randomized controlled trial), adjusted for both pre-and post-baseline prognostic factors, which themselves might be influenced by preceding treatments ( ESM, Figure S1 -S3 ). This framework has demonstrated high stability and the ability to obtain precise adjustment in various situations [ 22 – 25 ]. Briefly, during g-modelling, parametric regression models are fitted to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history ( ESM, Table S2 ) and tested for fit with estimation of usual care ( Figure S3) . This joint distribution is then used in Monte Carlo simulations to estimate the risk of the outcome if all patients have had early vasopressin initiation and to compare such risk with the observed risk under an intervention that never allows for vasopressin initiation. In addition, nonparametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs). The results are reported as absolute risk, risk differences and risk ratios with 95% CIs. Statistical analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria) [ 26 ] with the packages ‘dplyr’[ 27 ], ‘ggplot2’[ 28 ], ‘ggpubr’ [ 29 ], ‘gtsummary’ [ 30 ], ‘mice’ [ 31 ] and ‘gfoRmula’ [ 32 ]. Sensitivity analyses, description of how missing data were handled, and details on missing data patterns are described in detail in the Online Data Supplement ( ESM, Table S3, Figure S4 ). Data access and storage We obtained hospital administrative data and intensive care data from the clinical information systems eCritical MetaVisionTM (iMDsoft, Boston, MA, USA) and the Australia and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE) Adult Patient Database (APD). The data were stored in a password-protected file in a non-identifiable format. Results Baseline characteristics Within the 7-year study period, there were 74,851 unique admissions to the twelve study ICUs. Within this population, 3,105 patients presented with septic shock within six hours of ICU admission and were eligible for the target trial ( Supplemental Figure S5 ). Their baseline characteristics are presented in Table 1 . The majority of patients were male (60%), with a mean age of 62 years and a mean APACHE III score of 83. Approximately half were admitted from the emergency department and one-third from the ward. Among patients admitted from the emergency department, the median length of stay before ICU admission was 5 hours (2.5–7.8). In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated, and 109 (3.5%) received renal replacement therapy. The maximum NED was 0.15 (0.06–0.28) µg.kg − 1 .min − 1 , and the mean peak lactate was 4.5 ± 3.2 mmol.L − 1 . Vasopressin was initiated in 1,209 (39%) patients and started at a mean time of 5.6 ± 7.1 hours from vasopressor start. Median NED at vasopressin initiation was 0.25 µg.kg − 1 .min − 1 (0.15–0.39). Table 1 Baseline characteristics and intervention of eligible cohort Variable N = 3,105 Demographic Age (years), Mean ± SD 62 ± 16 Sex female, n (%) 1,230 (40) Body mass index (kg.m − 2 ), Mean ± SD 30 ± 9 Admission ICU admission source, n (%) Emergency department 1,433 (46) Operating Theatre 505 (16) Other hospital 237 (7.6) Ward 877 (28) Comorbidities Chronic respiratory disease, n (%) 146 (4.7) Chronic cardiovascular disease, n (%) 98 (3.2) Chronic liver disease, n (%) 177 (5.7) Diabetes, n (%) 112 (3.6) Chronic immunosuppression, n (%) 543 (17) Hemopathy, n (%) 221 (7.1) Metastatic cancer, n (%) 100 (3.2) Prognosis scores APACHE III score, Mean ± SD 83 ± 29 APACHE III risk of death (%), Mean ± SD 40 ± 27 SOFA score, Mean ± SD 7.0 ± 3.1 Time of randomization (0h to 6h) Maximum noradrenaline equivalent dose (µg.kg-1.min-1) at 6h, Median (Q1 - Q3) 0.15 (0.06–0.28) Invasive ventilation at 6h, n (%) 1,864 (60) CRRT at 6h, n (%) 109 (3.5) Peak lactate at 6h, mmol.L − 1 , Mean ± SD 4.5 ± 3.2 Nadir pH at 6h, Mean ± SD 7.23 ± 0.14 Peak serum creatinine at 6h, µmol.L − 1 , Median (Q1 - Q3) 142 (94–222) Peak white cell count at 6h, 10 9 .L − 1 , Mean ± SD 17 ± 14 Day of vasopressor start (0h to 24h) Invasive ventilation at 24h, n (%) 1,920 (62) CRRT at 24h, n (%) 317 (10) Maximum noradrenaline dose (µg.kg − 1 .min − 1 ) at 24h, Median (Q1 - Q3) 0.17 (0.07–0.32) Peak lactate at 24h, mmol.L − 1 , Mean ± SD 5.0 ± 3.6 Nadir pH at 24h, Mean ± SD 7.23 ± 0.14 Peak serum creatinine at 24h, µmol.L − 1 , Mean ± SD 194 ± 156 Peak white cell count at 24h, 10 9 .L − 1 , Mean ± SD 19 ± 14 Hydrocortisone, n (%) 1,545 (50) Type of vasopressor Noradrenaline, n (%) 3,013 (97) Adrenaline, n (%) 676 (22) Vasopressin, n (%) 1,209 (39) Noradrenaline equivalent dose at vasopressin start (µg.kg − 1 .min − 1 ), Median (Q1 - Q3) 0.25 (0.15–0.39) Time from vasopressor start to vasopressin start (hrs), Mean ± SD 5.6 ± 7.1 Dopamine, n (%) 76 (2.4) Metaraminol, n (%) 767 (25) Dobutamine, n (%) 256 (8.2) Milrinone, n (%) 89 (2.9) Continuous values are presented as mean ± SD or median (Q1 - Q3), categorical variables are presented as n (%) Abbreviations: ICU, Intensive care unit; APACHE, Acute Physiology And Chronic Health Evaluation, SOFA, Sequential organ failure assessment; CRRT, Continuous renal replacement therapy Primary analysis – Vasopressin start within 6 hours of septic shock As shown in Fig. 1 , in 3,105 patients analysed in the target trial emulation, the estimated 30-day ICU mortality was 19.34% (95% CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95% CI, 16.26 to 20.63) in the early vasopressin start within 6 hours group; relative risk 0.95 (95% CI, 0.93 to 0.98). As shown in Fig. 2 , there was a time effect when comparing an approach that never allowed vasopressin use ( Supplemental Figure S6-S8 ) with vasopressin start within 6 hours showing the lowest relative risk for mortality. Subgroup and threshold analysis As shown in Fig. 3 , vasopressin start within 6 hours of septic shock diagnosis was associated with a decreased likelihood of 30-day ICU mortality in all sub-groups explored. As shown in in Fig. 4 and Figure S9-S10 , the estimated 30-day ICU mortality effect of starting vasopressin at lower doses of norepinephrine was stronger. Exploratory analyses As shown in Fig. 5 , vasopressin administration progressively increased over the study period, from 35.2 (95% CI, 30.0 to 40.5) in 2015 to 45.1 (95% CI, 40.7 to 49.6) in 2021 (ß = +1.3% per year; 95% CI, + 0.46 to + 2.16, p = 0.011). Patients had progressively lower NED (ß = -0.05 µg.kg − 1 .min − 1 per year; 95% CI, -0.09 to -0.002, p = 0.038) and lower total SOFA score (ß = -0.1 point per year; 95% CI, -0.18 to -0.07, p < 0.001) at vasopressin start. Discussion Key findings In this study, we emulated a hypothetical target trial and found that, after adjustments, patients with septic shock who received early adjunctive vasopressin therapy (≤ 6 hours) had a lower risk ratio for 30-day ICU mortality than patients who never received vasopressin or who received late vasopressin therapy (> 6 hours). Moreover, this effect was progressively diminished as vasopressin start occurred after 12 hours, 18 hours and 24 hours. Similarly, the beneficial mortality effect was strongest when the NED was 0.1 µg.kg − 1 .min − 1 and diminished as the NED at the start of vasopressin moved to 0.125 and then 0.2 µg.kg − 1 .min − 1 and was absent at 0.25 µg.kg − 1 .min − 1 or above. The beneficial effect of vasopressin was pervasive and significant in all groups (high or low lactate, ventilated or not ventilated, APACHE score < 80 or ≥ 80). Relationship to previous studies There are limited data available on outcomes relating to early initiation of adjunctive vasopressin therapy in septic shock patients. The only multicentre randomised controlled trial to consider a timing threshold, the VANISH study, enrolled patients within six hours of shock onset [ 4 ]. Similar to our patient cohort, these patients had a ‘low dose’ vasopressor requirement with a median norepinephrine dose of 0.16 µg.kg − 1 .min − 1 . Furthermore, in the VANISH study, less than 60% of patients were mechanically ventilated and the median lactate was 2.3 mmol.L − 1 . This study did not identify any significant difference in mortality rates between the examined groups, in contrast with our results. However, the VANISH study included vasodilatory shock patients who are known to have different outcomes when compared to septic shock [ 33 ]. In addition, the study was underpowered, limiting the reliability of its conclusions. Notably, the study did not observe a beneficial effect of hydrocortisone treatment, a finding that contrasts with results from larger randomized controlled trials such as APPROACHS and ADRENAL, which have suggested its beneficial effects regarding ICU length of stay, duration of shock, and duration of mechanical ventilation [ 34 , 35 ]. A signal of benefit for early adjunctive vasopressin use compared with late initiation has been assessed in retrospective studies [ 5 , 9 ]. White et al. showed that, among septic shock patients, later time to vasopressin initiation was independently associated with hospital mortality [ 9 ]. This is consistent with our finding of higher mortality risk with late vasopressin initiation. However, in our study, we extended such findings by target trial emulation and found that compared to no vasopressin use, early vasopressin was associated with a decreased risk of death. Sacha et al’s study showed a linear association between hospital mortality and lactate concentration at time of vasopressin initiation [ 5 ]. Furthermore, the odds of death increased with increasing lactate concentration at vasopressin initiation when time from shock onset to vasopressin initiation increased. However, there was no independent association between hospital mortality and timing of vasopressin initiation. These results suggest a longer duration of hyperlactatemia without adjunctive treatment (and possibly ‘decatecholaminisation’ ) may be detrimental [ 1 ]. Similarly, in our study, the beneficial effect of early vasopressin was particularly strong when the lactate was > 4 mmol.L − 1 . Thus, a lactate > 4 mmol.L − 1 , despite a norepinephrine-equivalent infusion dose ≤ 0.25 µg.kg − 1 .min − 1 , may be an important clinical trigger to commence adjunctive vasopressin in the first six hours of septic shock management. Implications of study findings To our knowledge, this is the first target trial emulation of early adjunctive vasopressin use in septic shock patients. This is an important cohort of patients to consider given the time critical nature of septic shock treatment and current international guidelines, which do not advocate adjunctive vasopressor therapies below a norepinephrine base infusion dose threshold of 0.25 µg.kg − 1 .min − 1 . Our study provides important findings to help better inform patient selection and interventions for a prospective randomised-control trial for early adjunctive vasopressin use in septic shock. It implies that early vasopressin therapy may be desirable. Moreover, it implies that initiation at lower doses of norepinephrine administration (> 0.125 µg.kg − 1 .min − 1 but < 0.25 µg.kg − 1 .min − 1 of norepinephrine tartrate) than currently recommended by the Surviving Sepsis Campaign guidelines (between 0.25 and 0.50 µg.kg − 1 .min − 1 of norepinephrine base) may also be desirable. In addition, it suggests that patients with a lactate > 4 mmol.L − 1 and patients on mechanical ventilation may be easily identifiable candidates in whom early administration of vasopressin may be particularly beneficial. Finally, our results highlight the limited magnitude of effect that investigators should expect when designing such trials. Strengths and limitations This study had several strengths. In particular, this target trial emulation cohort was sampled from a large, comprehensive ICU patient database covering nearly all ICU admissions in a large state of Australia. This population is generalisable to the wider Australian population and likely to other high-income countries. Moreover, our highly granular study data was electronically extracted from a mature clinical information system in daily clinical use at all twelve study sites. There were minimal missing data points. In addition, the methods to emulate a hypothetical target trial, selection and adjustment for confounding variables and strict eligibility criteria minimise immortal time bias and confounding by indication and prespecified sensitivity analyses were performed with results consistent with our primary analysis. Finally, our study design encompassed all patients with the condition of interest, avoiding the selection bias frequently found in randomized controlled trials. We acknowledge some limitations. First, the groups differed significantly at baseline, with the treatment group having a higher severity of illness. This raises the possibility of residual confounding. However, the adjustments performed with target trial emulation methodology are likely to have addressed such differences. Second, we do not have data to explain why clinicians commenced vasopressin early or late in this patient cohort. Therefore, despite being reduced by the study design, there may still be confounding factors due to vasopressin being given to patients whom clinicians judge most likely to survive. However, early initiation of vasopressin may also easily indicate greater illness severity and such indication bias may have actually decreased the true magnitude of the benefits associated with vasopressin. Third, although there is a significant effect across all subgroups, the severity of patients may impact outcomes. Fourth, we only admitted patients diagnosed with septic shock during the first six hours of their ICU stay, which limits the applicability of these results to other groups. Fifth, a time-related effect might have affected our results as we covered a six-year period. Finally, despite the imputation method we performed, missing values may have biased our results. Conclusion In this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration even when the NED was low, the peak serum lactate was > 4 mmol.L − 1 , or mechanical ventilation was being applied. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock. Declarations Ethics approval and consent to participate The study was approved by the Metro South Hospital and Health Service Human Research Ethics Committee (HREC/2022/QMS/82024) with an individual waiver of consent granted. Consent for publication Not applicable. Availability of data and materials Data cannot be shared publicly due to institutional ethics, privacy, and confidentiality regulations. Data released for the purposes of research under section 280 of the Public Health Act 2005 requires an application to the Director-General of Queensland Health ( [email protected] ) Competing interests The authors have no competing interests to declare. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions The study conception and design (all authors); data acquisition (KW); analysis (AC, KW); interpretation of data (all authors); article drafting (RCP, AC, RB, KW), article revision for important intellectual content (all authors); final approval of the version submitted for publication (all authors); agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Acknowledgements The authors thank the ANZICS CORE management committee and the clinicians, data collectors and researchers at the following contributing sites: Caboolture Hospital, Cairns Hospital, Gold Coast University Hospital, Logan Hospital, Mackay Base Hospital, Princess Alexandra Hospital, Redcliffe Hospital, Rockhampton Hospital, Royal Brisbane and Women’s Hospital, Sunshine Coast University Hospital, The Prince Charles Hospital, and The Townsville Hospital. Collaborators - Queensland Critical Care Research Network Group: Mahesh Ramanan, Prashanti Marella, Patrick Young, Phillipa McIlroy, Ben Nash, James McCullough, Kerina J Denny, Mandy Tallott, Andrea Marshall, David Moore, Hayden White, Sunil Sane, Aashish Kumar, Lynette Morrison, Pam Dipplesman, Jennifer Taylor, Stephen Luke, Anni Paasilahti, Ray Asimus, Jennifer Taylor, Kyle White, Jason Meyer, Rod Hurford, Meg Harward, James Walsham, Neeraj Bhadange, Wayne Stevens, Kevin Plumpton, Sainath Raman, Andrew Barlow, Alexis Tabah, Hamish Pollock, Stuart Baker, Kylie Jacobs, Antony G. Attokaran, David Austin, Jacobus Poggenpoel, Josephine Reoch, Kevin B. Laupland, Felicity Edwards, Tess Evans, Jayesh Dhanani, Marianne Kirrane, Pierre Clement, Nermin Karamujic, Paula Lister, Vikram Masurkar, Lauren Murray, Jane Brailsford, Todd Erbacher, Kiran Shekar, Jayshree Lavana, George Cornmell, Siva Senthuran, Stephen Whebell, Michelle Gatton, Sam Keogh References Wieruszewski PM, Khanna AK. 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Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot J-P, Siami S, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378:809–18. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378:797–808. Additional Declarations No competing interests reported. Supplementary Files 20250202vasopressinttesupplementalmaterial.docx Cite Share Download PDF Status: Published Journal Publication published 12 May, 2025 Read the published version in Critical Care → Version 1 posted Editorial decision: Revision requested 27 Mar, 2025 Reviews received at journal 25 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 22 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5988212","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":433721378,"identity":"c053be8f-dbaa-4873-a64e-d817f3020605","order_by":0,"name":"Kyle C White","email":"data:image/png;base64,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","orcid":"","institution":"Princess Alexandra Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kyle","middleName":"C","lastName":"White","suffix":""},{"id":433721380,"identity":"5841a921-274e-4fee-9f70-60fb67f33a03","order_by":1,"name":"Rahul Costa-Pinto","email":"","orcid":"","institution":"Austin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rahul","middleName":"","lastName":"Costa-Pinto","suffix":""},{"id":433721381,"identity":"31eae0a1-36d3-40c7-8f0a-b275f3ac86a2","order_by":2,"name":"Sebastiaan Blank","email":"","orcid":"","institution":"Cairns Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sebastiaan","middleName":"","lastName":"Blank","suffix":""},{"id":433721382,"identity":"7a7501d3-556e-4b7c-8edf-3a7f2150f83a","order_by":3,"name":"Stephen Whebell","email":"","orcid":"","institution":"Townsville Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Whebell","suffix":""},{"id":433721383,"identity":"2b64706b-fb6e-40e7-822a-0a6ccf7ac2ac","order_by":4,"name":"Lachlan Quick","email":"","orcid":"","institution":"Princess Alexandra Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lachlan","middleName":"","lastName":"Quick","suffix":""},{"id":433721384,"identity":"0b4f1d2e-af52-4529-acea-acb71004c0a8","order_by":5,"name":"Stephen Luke","email":"","orcid":"","institution":"James Cook University","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Luke","suffix":""},{"id":433721385,"identity":"fcc5a4c6-fa0e-4ea4-82a9-0019d2650621","order_by":6,"name":"Antony G Attokaran","email":"","orcid":"","institution":"University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Antony","middleName":"G","lastName":"Attokaran","suffix":""},{"id":433721387,"identity":"07fcdd16-7a48-4ae2-bd84-d7999300ca95","order_by":7,"name":"Peter Garrett","email":"","orcid":"","institution":"Griffith University","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Garrett","suffix":""},{"id":433721388,"identity":"ea701fce-bbec-415a-b658-ca57db5e83b9","order_by":8,"name":"Mahesh Ramanan","email":"","orcid":"","institution":"University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Mahesh","middleName":"","lastName":"Ramanan","suffix":""},{"id":433721389,"identity":"7770907b-0483-4132-9886-392718a9e48f","order_by":9,"name":"Alexis Tabah","email":"","orcid":"","institution":"University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"","lastName":"Tabah","suffix":""},{"id":433721391,"identity":"e1297c4f-8ea9-4470-9698-1f0e19445499","order_by":10,"name":"Kiran Shekar","email":"","orcid":"","institution":"University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Kiran","middleName":"","lastName":"Shekar","suffix":""},{"id":433721392,"identity":"c2ec4661-faf8-419e-9a57-6a1f400adbd6","order_by":11,"name":"Kevin B Laupland","email":"","orcid":"","institution":"Queensland University of Technology (QUT)","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"B","lastName":"Laupland","suffix":""},{"id":433721393,"identity":"fc5a2bc2-be3b-43a8-aa1c-c6dd4c6fe12e","order_by":12,"name":"Aashish Kumar","email":"","orcid":"","institution":"Logan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aashish","middleName":"","lastName":"Kumar","suffix":""},{"id":433721394,"identity":"e0ab446e-2c5b-4521-a31d-b54f9be73a4f","order_by":13,"name":"James McCullough","email":"","orcid":"","institution":"Griffith University","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"McCullough","suffix":""},{"id":433721395,"identity":"5cf3d5e9-ca88-4c55-a446-55685bbeb49f","order_by":14,"name":"Andrew Udy","email":"","orcid":"","institution":"The Alfred Hospital","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Udy","suffix":""},{"id":433721398,"identity":"efa99b2c-325a-4ce8-b906-a7893039733b","order_by":15,"name":"Glenn Eastwood","email":"","orcid":"","institution":"Austin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Glenn","middleName":"","lastName":"Eastwood","suffix":""},{"id":433721399,"identity":"fc7cf7b1-6372-4bbe-8ce9-f72cf4c99d34","order_by":16,"name":"Rinaldo Bellomo","email":"","orcid":"","institution":"Austin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rinaldo","middleName":"","lastName":"Bellomo","suffix":""},{"id":433721401,"identity":"f461058b-281c-41c7-9127-8328590dcd3b","order_by":17,"name":"Anis Chaba","email":"","orcid":"","institution":"Austin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anis","middleName":"","lastName":"Chaba","suffix":""}],"badges":[],"createdAt":"2025-02-08 14:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5988212/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5988212/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13054-025-05401-y","type":"published","date":"2025-05-12T15:58:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79323522,"identity":"a1645a6f-485f-4b1e-8180-f9a42045bcaf","added_by":"auto","created_at":"2025-03-27 04:55:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129587,"visible":true,"origin":"","legend":"\u003cp\u003eEstimated 30-day potential drug-induced mortality risk under a treatment strategy that allows to start vasopressin in the first 6h versus an intervention that never allows for vasopressin start\u003c/p\u003e\n\u003cp\u003eParametric regression models were fitted from the 3,105 patients to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history (Usual care). This joint distribution was then used in 5000 Monte Carlo simulations to estimate the risk of the outcome if every body received vasopressin within 6 hours of septic shock, and to compare it with the observed risk under the intervention with no vasopressin allowed. Non-parametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/54ac2512581a324491c9341d.png"},{"id":79322488,"identity":"532c20d6-21f5-46db-99cf-51c22ac3132d","added_by":"auto","created_at":"2025-03-27 04:39:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21773,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of risk difference of 30-day ICU mortality for each of the interventions tested against an intervention that never allows for vasopressin start\u003c/p\u003e\n\u003cp\u003eParametric regression models were fitted from the 3,105 patients to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history (Usual care). This joint distribution was then used in 5000 Monte Carlo simulations to estimate the risk of the outcome if every body received vasopressin at different timepoint from septic shock onset, and to compare it with the observed risk under the intervention with no vasopressin allowed. Non-parametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/7057a5a711506cd45561073d.png"},{"id":79322874,"identity":"19b7248c-a2e2-46f9-9ed7-ff4979378213","added_by":"auto","created_at":"2025-03-27 04:47:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39084,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of risk difference of 30-day ICU mortality for each of the interventions that allows to start vasopressin in the first 6h versus an intervention that never allows for vasopressin start according to subgroups\u003c/p\u003e\n\u003cp\u003eParametric regression models were fitted from the number of patients in each subrgoup to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history (Usual care). This joint distribution was then used in 5000 Monte Carlo simulations to estimate the risk of the outcome if every body received vasopressin within 6 hours of septic shock, and to compare it with the observed risk under the intervention with no vasopressin allowed. Non-parametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/4393fd2a2a355808b3e177ff.png"},{"id":79322875,"identity":"b11db179-62a9-4aa0-a75b-197629f6870e","added_by":"auto","created_at":"2025-03-27 04:47:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":76189,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of risk difference of 30-day ICU mortality according to norepinephrine equivalent dose threshold for vasopressin introduction versus an intervention that never allows for vasopressin start\u003c/p\u003e\n\u003cp\u003eParametric regression models were fitted from the 3,105 patients to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history (Usual care). This joint distribution was then used in 5000 Monte Carlo simulations to estimate the risk of the outcome if every body received vasopressin at a specific noradrenaline equivalende dose threshold, and to compare it with the observed risk under the intervention with no vasopressin allowed. Non-parametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/1417f95d7bf763994cc58042.png"},{"id":79323523,"identity":"802aa9f4-182e-4cd5-839b-51a43439e4f4","added_by":"auto","created_at":"2025-03-27 04:55:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":87351,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution over the study period of\u003cstrong\u003e \u003c/strong\u003ea: vasopressin administration; b: noradrenaline equivalent dose at vasopressin start time; c: Total SOFA score at vasopressin start time; d: time from vasopressor start to first vasopressin administration\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/debfe05f24ff438fa173c1f1.png"},{"id":83067857,"identity":"bf12eca1-145a-4ba7-aa92-c60bcb91b291","added_by":"auto","created_at":"2025-05-19 16:07:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1209159,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/fac34b54-e2fc-4bf7-b2a2-15061bb26182.pdf"},{"id":79322490,"identity":"6a28ab66-5ba8-4015-9a19-1a84b3619b71","added_by":"auto","created_at":"2025-03-27 04:39:23","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2249038,"visible":true,"origin":"","legend":"","description":"","filename":"20250202vasopressinttesupplementalmaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5988212/v1/c029cea590f98d1684cc167c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Early Adjunctive Vasopressin Initiation for Septic Shock Patients: A Target Trial Emulation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThere is increasing interest in catecholamine-sparing vasopressor strategies in the management of septic shock [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The Surviving Sepsis Campaign guidelines currently recommend norepinephrine as the first-line agent for this condition, with a weak recommendation for commencing adjunctive vasopressin when the dose of norepinephrine base is in the range of 0.25\u0026ndash;0.5 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Thus, clinicians may regard vasopressin as a \u0026lsquo;rescue\u0026rsquo; therapy rather than an essential component of a multimodal vasopressor strategy. Furthermore, current sepsis guidelines do not recommend a timing threshold for vasopressin initiation despite randomized and observational data suggesting that timing may be an important consideration [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAn individual patient data meta-analysis of four randomized controlled trials of vasopressin in septic shock suggested potential benefit when vasopressin is commenced in less severe shock states (i.e., lower lactate levels, lower norepinephrine dose), and in the absence of established acute kidney injury [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Earlier initiation of adjunctive vasopressin in patients with less severe shock, therefore, warrants further investigation.\u003c/p\u003e \u003cp\u003eAccordingly, we conducted a target trial emulation using a large, multicentre database to estimate the effect of early vasopressin initiation on mortality in septic shock patients. We aimed to test the primary hypothesis that early (\u0026le;\u0026thinsp;6 hours) vasopressin initiation would be associated with lower hospital mortality compared with no vasopressin adjunction. Our secondary hypothesis was that late (\u0026gt;\u0026thinsp;6 hours) vasopressin therapy would be associated with worse outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe conducted a target trial emulation (TTE) of early vasopressin in septic shock patients. We used routinely collected electronic medical record clinical data from twelve intensive care units (ICU) in Queensland, Australia. The study sites comprised five tertiary, three outer metropolitan, and four regional ICUs and included most of Queensland\u0026rsquo;s state-wide ICU capacity.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePopulation\u003c/h3\u003e\n\u003cp\u003eWe included all adult ICU patients (\u0026ge;\u0026thinsp;18 years) admitted with a diagnosis of septic shock within the first six hours of admission. We excluded patients transferred from another ICU or were admitted solely for palliative care or organ donation. In addition, we excluded patients who commenced vasopressin within the first hour of ICU admission. We reasoned that such patients might have had vasopressin started before or within the first hour of ICU admission, introducing uncertainty about the real start time.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003ePatients were assigned by TTE to treatment groups if they met eligibility criteria in the first six hours of ICU admission. In the primary analysis, patients in the treatment group commenced adjunctive vasopressin within six hours of septic shock. Patients in the control group did not commence adjunctive vasopressin at all. In secondary analyses, vasopressin was started either at a prespecified time or norepinephrine-equivalent dose (NED) threshold.\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003eThe norepinephrine formulation used in all centres was norepinephrine tartrate [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Vasopressors other than vasopressin were converted to norepinephrine-equivalent doses according to previously published conversion tables [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Sepsis and septic shock were defined according to the Sepsis-3 consensus definition using previously published methodology [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome of this study was to assess the impact of early timing (\u0026le;\u0026thinsp;6 hours since septic shock) of vasopressin initiation on 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of vasopressin start within 6 hours of ICU admission with peak NED at 6 hours, APACHE score, peak lactate at 6 hours and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality, effect of NED at vasopressin start on 30-day ICU mortality. Exploratory outcomes were changes in vasopressin administration over the study period (prevalence of prescription, NED at vasopressin start, total SOFA score at vasopressin start and time from ICU admission to vasopressin start).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eBaseline characteristics are reported as absolute values with percentages for categorical variables or medians with the interquartile interval for quantitative variables. Annual proportion with a 95% confidence interval was calculated out of the yearly number of included ICU admissions. Changes in annual incidence were performed by testing its interaction with time via linear regression. To quantify the causal effect of early vasopressin start on 30-day ICU mortality, we used a target trial emulation protocol (electronic supplementary material, \u003cb\u003eESM, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e) and the parametric g-formula [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This method allows for the reliable estimation of the risk of outcomes under sustained interventions (analogous to a per-protocol analysis in a randomized controlled trial), adjusted for both pre-and post-baseline prognostic factors, which themselves might be influenced by preceding treatments (\u003cb\u003eESM, Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e-S3\u003c/b\u003e). This framework has demonstrated high stability and the ability to obtain precise adjustment in various situations [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Briefly, during g-modelling, parametric regression models are fitted to estimate the complete joint distribution of the outcome and time-varying covariates given previous treatment and covariate history (\u003cb\u003eESM, Table S2\u003c/b\u003e) and tested for fit with estimation of usual care (\u003cb\u003eFigure S3)\u003c/b\u003e. This joint distribution is then used in Monte Carlo simulations to estimate the risk of the outcome if all patients have had early vasopressin initiation and to compare such risk with the observed risk under an intervention that never allows for vasopressin initiation. In addition, nonparametric bootstrapping with 500 resamples was used to estimate 95% confidence intervals (CIs). The results are reported as absolute risk, risk differences and risk ratios with 95% CIs. Statistical analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] with the packages \u0026lsquo;dplyr\u0026rsquo;[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], \u0026lsquo;ggplot2\u0026rsquo;[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], \u0026lsquo;ggpubr\u0026rsquo; [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], \u0026lsquo;gtsummary\u0026rsquo; [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], \u0026lsquo;mice\u0026rsquo; [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and \u0026lsquo;gfoRmula\u0026rsquo; [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Sensitivity analyses, description of how missing data were handled, and details on missing data patterns are described in detail in the Online Data Supplement (\u003cb\u003eESM, Table S3, Figure S4\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData access and storage\u003c/h3\u003e\n\u003cp\u003eWe obtained hospital administrative data and intensive care data from the clinical information systems eCritical MetaVisionTM (iMDsoft, Boston, MA, USA) and the Australia and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE) Adult Patient Database (APD). The data were stored in a password-protected file in a non-identifiable format.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n \u003cp\u003eWithin the 7-year study period, there were 74,851 unique admissions to the twelve study ICUs. Within this population, 3,105 patients presented with septic shock within six hours of ICU admission and were eligible for the target trial (\u003cstrong\u003eSupplemental Figure S5\u003c/strong\u003e). Their baseline characteristics are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The majority of patients were male (60%), with a mean age of 62 years and a mean APACHE III score of 83. Approximately half were admitted from the emergency department and one-third from the ward. Among patients admitted from the emergency department, the median length of stay before ICU admission was 5 hours (2.5\u0026ndash;7.8). In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated, and 109 (3.5%) received renal replacement therapy. The maximum NED was 0.15 (0.06\u0026ndash;0.28) \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and the mean peak lactate was 4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Vasopressin was initiated in 1,209 (39%) patients and started at a mean time of 5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1 hours from vasopressor start. Median NED at vasopressin initiation was 0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (0.15\u0026ndash;0.39).\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics and intervention of eligible cohort\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3,105\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDemographic\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex female, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,230 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody mass index (kg.m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdmission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eICU admission source, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmergency department\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,433 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOperating Theatre\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e505 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e237 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWard\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e877 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic respiratory disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic cardiovascular disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic liver disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e177 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic immunosuppression, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e543 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemopathy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e221 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastatic cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrognosis scores\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAPACHE III score, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83\u0026thinsp;\u0026plusmn;\u0026thinsp;29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAPACHE III risk of death (%), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSOFA score, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime of randomization (0h to 6h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaximum noradrenaline equivalent dose (\u0026micro;g.kg-1.min-1) at 6h, Median (Q1 - Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15 (0.06\u0026ndash;0.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive ventilation at 6h, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,864 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRRT at 6h, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e109 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak lactate at 6h, mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNadir pH at 6h, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak serum creatinine at 6h, \u0026micro;mol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Median (Q1 - Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e142 (94\u0026ndash;222)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak white cell count at 6h, 10\u003csup\u003e9\u003c/sup\u003e.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay of vasopressor start (0h to 24h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive ventilation at 24h, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,920 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRRT at 24h, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e317 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaximum noradrenaline dose (\u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) at 24h, Median (Q1 - Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17 (0.07\u0026ndash;0.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak lactate at 24h, mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNadir pH at 24h, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak serum creatinine at 24h, \u0026micro;mol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194\u0026thinsp;\u0026plusmn;\u0026thinsp;156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak white cell count at 24h, 10\u003csup\u003e9\u003c/sup\u003e.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrocortisone, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,545 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of vasopressor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNoradrenaline, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,013 (97)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdrenaline, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e676 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVasopressin, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,209 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNoradrenaline equivalent dose at vasopressin start (\u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), Median (Q1 - Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25 (0.15\u0026ndash;0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime from vasopressor start to vasopressin start (hrs), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDopamine, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetaraminol, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e767 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDobutamine, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e256 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMilrinone, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eContinuous values are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (Q1 - Q3), categorical variables are presented as n (%)\u003c/p\u003e\n \u003cp\u003eAbbreviations: ICU, Intensive care unit; APACHE, Acute Physiology And Chronic Health Evaluation, SOFA, Sequential organ failure assessment; CRRT, Continuous renal replacement therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cdiv class=\"gridtable\"\u003e\u003cbr\u003e\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary analysis \u0026ndash; Vasopressin start within 6 hours of septic shock\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, in 3,105 patients analysed in the target trial emulation, the estimated 30-day ICU mortality was 19.34% (95% CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95% CI, 16.26 to 20.63) in the early vasopressin start within 6 hours group; relative risk 0.95 (95% CI, 0.93 to 0.98).\u003c/p\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, there was a time effect when comparing an approach that never allowed vasopressin use (\u003cstrong\u003eSupplemental Figure S6-S8\u003c/strong\u003e) with vasopressin start within 6 hours showing the lowest relative risk for mortality.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eSubgroup and threshold analysis\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, vasopressin start within 6 hours of septic shock diagnosis was associated with a decreased likelihood of 30-day ICU mortality in all sub-groups explored. As shown in in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cstrong\u003eFigure S9-S10\u003c/strong\u003e, the estimated 30-day ICU mortality effect of starting vasopressin at lower doses of norepinephrine was stronger.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eExploratory analyses\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, vasopressin administration progressively increased over the study period, from 35.2 (95% CI, 30.0 to 40.5) in 2015 to 45.1 (95% CI, 40.7 to 49.6) in 2021 (\u0026szlig; = +1.3% per year; 95% CI, +\u0026thinsp;0.46 to +\u0026thinsp;2.16, p\u0026thinsp;=\u0026thinsp;0.011). Patients had progressively lower NED (\u0026szlig; = -0.05 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e per year; 95% CI, -0.09 to -0.002, p\u0026thinsp;=\u0026thinsp;0.038) and lower total SOFA score (\u0026szlig; = -0.1 point per year; 95% CI, -0.18 to -0.07, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) at vasopressin start.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eKey findings\u003c/h2\u003e \u003cp\u003eIn this study, we emulated a hypothetical target trial and found that, after adjustments, patients with septic shock who received early adjunctive vasopressin therapy (\u0026le;\u0026thinsp;6 hours) had a lower risk ratio for 30-day ICU mortality than patients who never received vasopressin or who received late vasopressin therapy (\u0026gt;\u0026thinsp;6 hours). Moreover, this effect was progressively diminished as vasopressin start occurred after 12 hours, 18 hours and 24 hours. Similarly, the beneficial mortality effect was strongest when the NED was 0.1 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and diminished as the NED at the start of vasopressin moved to 0.125 and then 0.2 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and was absent at 0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e or above. The beneficial effect of vasopressin was pervasive and significant in all groups (high or low lactate, ventilated or not ventilated, APACHE score\u0026thinsp;\u0026lt;\u0026thinsp;80 or \u0026ge;\u0026thinsp;80).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eRelationship to previous studies\u003c/h2\u003e \u003cp\u003eThere are limited data available on outcomes relating to early initiation of adjunctive vasopressin therapy in septic shock patients. The only multicentre randomised controlled trial to consider a timing threshold, the VANISH study, enrolled patients within six hours of shock onset [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Similar to our patient cohort, these patients had a \u0026lsquo;low dose\u0026rsquo; vasopressor requirement with a median norepinephrine dose of 0.16 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Furthermore, in the VANISH study, less than 60% of patients were mechanically ventilated and the median lactate was 2.3 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. This study did not identify any significant difference in mortality rates between the examined groups, in contrast with our results. However, the VANISH study included vasodilatory shock patients who are known to have different outcomes when compared to septic shock [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, the study was underpowered, limiting the reliability of its conclusions. Notably, the study did not observe a beneficial effect of hydrocortisone treatment, a finding that contrasts with results from larger randomized controlled trials such as APPROACHS and ADRENAL, which have suggested its beneficial effects regarding ICU length of stay, duration of shock, and duration of mechanical ventilation [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA signal of benefit for early adjunctive vasopressin use compared with late initiation has been assessed in retrospective studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. White et al. showed that, among septic shock patients, later time to vasopressin initiation was independently associated with hospital mortality [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This is consistent with our finding of higher mortality risk with late vasopressin initiation. However, in our study, we extended such findings by target trial emulation and found that compared to no vasopressin use, early vasopressin was associated with a decreased risk of death.\u003c/p\u003e \u003cp\u003eSacha et al\u0026rsquo;s study showed a linear association between hospital mortality and lactate concentration at time of vasopressin initiation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, the odds of death increased with increasing lactate concentration at vasopressin initiation when time from shock onset to vasopressin initiation increased. However, there was no independent association between hospital mortality and timing of vasopressin initiation. These results suggest a longer duration of hyperlactatemia without adjunctive treatment (and possibly \u0026lsquo;decatecholaminisation\u0026rsquo; ) may be detrimental [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Similarly, in our study, the beneficial effect of early vasopressin was particularly strong when the lactate was \u0026gt;\u0026thinsp;4 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Thus, a lactate\u0026thinsp;\u0026gt;\u0026thinsp;4 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, despite a norepinephrine-equivalent infusion dose\u0026thinsp;\u0026le;\u0026thinsp;0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, may be an important clinical trigger to commence adjunctive vasopressin in the first six hours of septic shock management.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eImplications of study findings\u003c/h2\u003e \u003cp\u003eTo our knowledge, this is the first target trial emulation of early adjunctive vasopressin use in septic shock patients. This is an important cohort of patients to consider given the time critical nature of septic shock treatment and current international guidelines, which do not advocate adjunctive vasopressor therapies below a norepinephrine base infusion dose threshold of 0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study provides important findings to help better inform patient selection and interventions for a prospective randomised-control trial for early adjunctive vasopressin use in septic shock. It implies that early vasopressin therapy may be desirable. Moreover, it implies that initiation at lower doses of norepinephrine administration (\u0026gt;\u0026thinsp;0.125 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e but \u0026lt;\u0026thinsp;0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e of norepinephrine tartrate) than currently recommended by the Surviving Sepsis Campaign guidelines (between 0.25 and 0.50 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e of norepinephrine base) may also be desirable. In addition, it suggests that patients with a lactate\u0026thinsp;\u0026gt;\u0026thinsp;4 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and patients on mechanical ventilation may be easily identifiable candidates in whom early administration of vasopressin may be particularly beneficial. Finally, our results highlight the limited magnitude of effect that investigators should expect when designing such trials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThis study had several strengths. In particular, this target trial emulation cohort was sampled from a large, comprehensive ICU patient database covering nearly all ICU admissions in a large state of Australia. This population is generalisable to the wider Australian population and likely to other high-income countries. Moreover, our highly granular study data was electronically extracted from a mature clinical information system in daily clinical use at all twelve study sites. There were minimal missing data points. In addition, the methods to emulate a hypothetical target trial, selection and adjustment for confounding variables and strict eligibility criteria minimise immortal time bias and confounding by indication and prespecified sensitivity analyses were performed with results consistent with our primary analysis. Finally, our study design encompassed all patients with the condition of interest, avoiding the selection bias frequently found in randomized controlled trials.\u003c/p\u003e \u003cp\u003eWe acknowledge some limitations. First, the groups differed significantly at baseline, with the treatment group having a higher severity of illness. This raises the possibility of residual confounding. However, the adjustments performed with target trial emulation methodology are likely to have addressed such differences. Second, we do not have data to explain why clinicians commenced vasopressin early or late in this patient cohort. Therefore, despite being reduced by the study design, there may still be confounding factors due to vasopressin being given to patients whom clinicians judge most likely to survive. However, early initiation of vasopressin may also easily indicate greater illness severity and such indication bias may have actually decreased the true magnitude of the benefits associated with vasopressin. Third, although there is a significant effect across all subgroups, the severity of patients may impact outcomes. Fourth, we only admitted patients diagnosed with septic shock during the first six hours of their ICU stay, which limits the applicability of these results to other groups. Fifth, a time-related effect might have affected our results as we covered a six-year period. Finally, despite the imputation method we performed, missing values may have biased our results.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration even when the NED was low, the peak serum lactate was \u0026gt;\u0026thinsp;4 mmol.L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, or mechanical ventilation was being applied. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Metro South Hospital and Health Service Human Research Ethics Committee (HREC/2022/QMS/82024) with an individual waiver of consent granted.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData cannot be shared publicly due to institutional ethics, privacy, and confidentiality regulations. Data released for the purposes of research under section 280 of the Public Health Act 2005 requires an application to the Director-General of Queensland Health ([email protected])\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study conception and design (all authors); data acquisition (KW); analysis (AC, KW); interpretation of data (all authors); article drafting (RCP, AC, RB, KW), article revision for important intellectual content (all authors); final approval of the version submitted for publication (all authors); agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the ANZICS CORE management committee and the clinicians, data collectors and researchers at the following contributing sites: Caboolture Hospital, Cairns Hospital, Gold Coast University Hospital, Logan Hospital, Mackay Base Hospital, Princess Alexandra Hospital, Redcliffe Hospital, Rockhampton Hospital, Royal Brisbane and Women’s Hospital, Sunshine Coast University Hospital, The Prince Charles Hospital, and The Townsville Hospital. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCollaborators - Queensland Critical Care Research Network Group: Mahesh Ramanan, Prashanti Marella, Patrick Young, Phillipa McIlroy, Ben Nash, James McCullough, Kerina J Denny, Mandy Tallott, Andrea Marshall, David Moore, Hayden White, Sunil Sane, Aashish Kumar, Lynette Morrison, Pam Dipplesman, Jennifer Taylor, Stephen Luke, Anni Paasilahti, Ray Asimus, Jennifer Taylor, Kyle White, Jason Meyer, Rod Hurford, Meg Harward, James Walsham, Neeraj Bhadange, Wayne Stevens, Kevin Plumpton, Sainath Raman, Andrew Barlow, Alexis Tabah, Hamish Pollock, Stuart Baker, Kylie Jacobs, Antony G. Attokaran, David Austin, Jacobus Poggenpoel, Josephine Reoch, Kevin B. Laupland, Felicity Edwards, Tess Evans, Jayesh Dhanani, Marianne Kirrane, Pierre Clement, Nermin Karamujic, Paula Lister, Vikram Masurkar, Lauren Murray, Jane Brailsford, Todd Erbacher, Kiran Shekar, Jayshree Lavana, George Cornmell, Siva Senthuran, Stephen Whebell, Michelle Gatton, Sam Keogh\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWieruszewski PM, Khanna AK. Vasopressor Choice and Timing in Vasodilatory Shock. Critical Care. 2022;26:76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeone M, Einav S, Antonucci E, Depret F, Lakbar I, Martin-Loeches I, et al. Multimodal strategy to counteract vasodilation in septic shock. Anaesthesia Critical Care \u0026amp; Pain Medicine. 2023;42:101193.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181\u0026ndash;247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316:509\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSacha GL, Lam SW, Wang L, Duggal A, Reddy AJ, Bauer SR. Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock*. Critical Care Medicine. 2022;50:614\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrask AL, Shemanski SM, Barnes TE, Holmes AK. Timing of Vasopressin Addition to Norepinephrine and Efficacy Outcomes in Patients With Septic Shock. 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N Engl J Med. 2018;378:797\u0026ndash;808.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"vasopressin, sepsis, shock, hypotension, vasodilation, critical care","lastPublishedDoi":"10.21203/rs.3.rs-5988212/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5988212/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIn septic shock, the optimal timing of adjunctive vasopressin initiation shock is unknown. We aimed to assess the effect of its early initiation for patients with septic shock.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a multicenter target trial emulation to estimate the intensive care unit (ICU) mortality effect of early (\u0026le;\u0026thinsp;6 hours) adjunctive vasopressin compared with usual care. Eligible patients had septic shock diagnosed within 6 hours of ICU admission. The primary outcome of this study was 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of early vasopressin start with peak norepinephrine-equivalent dose (NED) at 6 hours, APACHE score, peak lactate at 6 hours and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality and effect of NED at vasopressin start on 30-day ICU mortality. We used the parametric g-formula to emulate a target trial.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOverall, 3,105 patients fulfilled the inclusion criteria. Mean age was 62 years and mean APACHE III score was 83. In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated. Estimated 30-day ICU mortality was 19.34% (95%CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95%CI, 16.26 to 20.63) in the early vasopressin group; relative risk 0.95 (95%CI, 0.93 to 0.98). The estimated 30-day ICU mortality effect of starting vasopressin was particularly strong at lower norepinephrine doses (\u0026lt;\u0026thinsp;0.25 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ) and significant at lower norepinephrine doses than recommended by the Surviving Sepsis Campaign Guidelines. Vasopressin administration progressively increased over the study period, from 35.2% (95%CI, 30.0 to 40.5) in 2015 to 45.1% (95%CI, 40.7 to 49.6) in 2021 (\u0026szlig; = +1.3% per year; 95%CI, +\u0026thinsp;0.46 to +\u0026thinsp;2.16, p\u0026thinsp;=\u0026thinsp;0.011). Patients had progressively lower norepinephrine equivalent dose (\u0026szlig; = -0.05 \u0026micro;g.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e per year; 95%CI, -0.09 to -0.002, p\u0026thinsp;=\u0026thinsp;0.038) and lower total SOFA score (\u0026szlig; = -0.1 point per year; 95%CI, -0.18 to -0.07, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) at vasopressin start.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock.\u003c/p\u003e","manuscriptTitle":"Effect of Early Adjunctive Vasopressin Initiation for Septic Shock Patients: A Target Trial Emulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:39:18","doi":"10.21203/rs.3.rs-5988212/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-27T05:55:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-25T11:23:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"143854798866490638475781952953038406227","date":"2025-03-25T11:20:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T10:02:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T06:18:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2025-03-22T13:54:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b3ea8ac3-8c48-4905-8534-3afe948e1100","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:02:36+00:00","versionOfRecord":{"articleIdentity":"rs-5988212","link":"https://doi.org/10.1186/s13054-025-05401-y","journal":{"identity":"critical-care","isVorOnly":false,"title":"Critical Care"},"publishedOn":"2025-05-12 15:58:01","publishedOnDateReadable":"May 12th, 2025"},"versionCreatedAt":"2025-03-27 04:39:18","video":"","vorDoi":"10.1186/s13054-025-05401-y","vorDoiUrl":"https://doi.org/10.1186/s13054-025-05401-y","workflowStages":[]},"version":"v1","identity":"rs-5988212","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5988212","identity":"rs-5988212","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}