Early Vasopressor Initiation versus Standard Fluid Resuscitation in Normotensive Cryptic Shock: A Target Trial Emulation

Early Vasopressor Initiation versus Standard Fluid Resuscitation in Normotensive Cryptic Shock: 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 Early Vasopressor Initiation versus Standard Fluid Resuscitation in Normotensive Cryptic Shock: A Target Trial Emulation Ibrahim Ibrahim Shuaibu, Sawssan Radouani, Yousaf Hussain This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8747647/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Current sepsis guidelines mandate aggressive fluid resuscitation prior to vasopressor initiation, primarily targeting hypotension (Mean Arterial Pressure [MAP] 4.0 mmol/L) despite preserved normotension (MAP > 65 mmHg) remains poorly managed. We hypothesized that early initiation of vasopressors, rather than fluid-centric resuscitation, would improve survival in this high-risk phenotype. Methods We performed a Target Trial Emulation using the MIMIC-IV v3.1 database (2008–2019). We identified adult patients meeting criteria for Cryptic Shock within 24 hours of ICU admission. Patients were classified into two treatment strategies based on interventions received within the first 3 hours of phenotype onset: ( 1 ) Early Vasopressors (initiation of norepinephrine or vasopressin) versus ( 2 ) Standard Care (fluid resuscitation alone). The primary endpoint was 28-day mortality. To adjust for confounding by indication, we employed Inverse Probability of Treatment Weighting (IPTW) based on age, SOFA score, and admission lactate. Survival was analyzed using weighted Kaplan-Meier curves and multivariable Cox proportional hazards models. Results The final cohort comprised 3,558 patients. The Early Vasopressor group (n = 1,245) had significantly higher baseline severity scores (SOFA 9.0 vs. 6.0) compared to the Standard Care group (n = 2,313). After IPTW adjustment, covariate balance was achieved (Standardized Mean Difference < 0.1 for all variables). Early vasopressor initiation was associated with a significant reduction in 28-day mortality compared to standard care (Adjusted Hazard Ratio [HR] 0.48; 95% CI, 0.40–0.58; p < 0.001). This survival benefit persisted across sensitivity analyses. Conclusions In patients with Cryptic Shock, an early vasopressor strategy is associated with superior 28-day survival compared to standard fluid resuscitation. These findings challenge the "fluids-first" paradigm for normotensive hypoperfusion and support a shift toward perfusion-guided resuscitation. Artificial Intelligence and Machine Learning Sepsis Cryptic Shock Vasopressors Target Trial Emulation MIMIC-IV Lactate Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Sepsis resuscitation has historically prioritized the reversal of macrocirculatory hypotension. The Surviving Sepsis Campaign (SSC) guidelines recommend an initial fixed-volume fluid challenge (30 mL/kg) before vasopressors are considered, largely predicated on the definition of septic shock as hypotension (Mean Arterial Pressure [MAP] < 65 mmHg) refractory to volume loading. However, this "fluids-first" paradigm may be maladaptive for a subset of patients who exhibit profound metabolic stress and tissue hypoperfusion (hyperlactatemia) while maintaining normotension a state termed "Cryptic Shock". Physiologically, Cryptic Shock represents a dissociation between macro-hemodynamics and microcirculatory flow. While systemic pressure appears adequate, regional perfusion is compromised, leading to anaerobic metabolism and organ failure. In these patients, aggressive fluid loading risks glycocalyx degradation and pulmonary edema without correcting the underlying venodilation or adrenergic insensitivity. Conversely, early vasopressor initiation could theoretically restore unstressed vascular volume, recruit microcirculation, and limit nephrotoxic fluid accumulation. Recent trials such as CENSER have demonstrated the safety of early norepinephrine in hypotensive shock, but evidence specific to the normotensive "Cryptic" phenotype is sparse. Observational studies are frequently plagued by immortal time bias and indication bias, where sicker patients receive pressors earlier, obscuring potential benefits. To address these methodological limitations, we applied a Target Trial Emulation (TTE) framework to the Medical Information Mart for Intensive Care (MIMIC-IV) database. We aimed to compare the causal effect of early vasopressor initiation versus standard fluid-centric care on 28-day mortality in patients with verified Cryptic Shock. METHODS Study Design and Data Source We conducted a retrospective cohort study adhering to the definitions of a Target Trial Emulation. Data were derived from MIMIC-IV v3.1, a high-resolution database comprising ICU admissions at the Beth Israel Deaconess Medical Center (Boston, MA) between 2008 and 2019. The study was exempt from Institutional Review Board approval due to the use of de-identified data. Target Trial Specification Eligibility Criteria: Adult patients (> 18 years) satisfying Sepsis-3 criteria who exhibited "Cryptic Shock" defined as the simultaneous presence of: ( 1 ) Normotension (MAP > 65 mmHg) and ( 2 ) Tissue Hypoperfusion (Arterial/Venous Lactate > 4.0 mmol/L). Time Zero (T0): Defined as the timestamp of the first lactate measurement > 4.0 mmol/L concurrent with a normal MAP measurement. Exclusion Criteria: Patients with overt hypotension (MAP < 65 mmHg) prior to T0, active hemorrhage, or "Do Not Resuscitate" orders documented within 24 hours of admission were excluded. Treatment Strategies Patients were classified into two arms based on interventions received within a 3-hour "grace period" following T0: Intervention Arm (Early Vasopressors): Initiation of a continuous infusion of norepinephrine, vasopressin, epinephrine, or phenylephrine. Control Arm (Standard Care): Receipt of intravenous crystalloids without vasopressor initiation during the 3-hour window. Covariates and Confounders Baseline characteristics extracted at T0 included age, sex, Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI), and initial lactate levels. We specifically tracked fluid volume administered prior to T0 to adjust for pre-randomization resuscitation intensity. Statistical Analysis Propensity Score Weighting: To account for confounding by indication (where clinicians are more likely to start pressors in sicker patients), we calculated propensity scores using a multivariable logistic regression model including age, SOFA score, and lactate. Inverse Probability of Treatment Weighting (IPTW): Weights were generated as 1/PS for the treatment group and 1/(1-PS) for the control group. Weights were stabilized to the marginal probability of treatment to prevent variance inflation. Covariate Balance: Balance was assessed using Standardized Mean Differences (SMD), with a threshold of < 0.1 indicating negligible imbalance. Outcome Analysis: The primary outcome was 28-day all-cause mortality. We estimated survival curves using the weighted Kaplan-Meier method. Hazard Ratios (HR) were calculated using a weighted Cox proportional hazards model with robust variance estimation. RESULTS Cohort Selection and Baseline Characteristics From a total of 76,540 ICU admissions, 3,558 patients met the rigorous criteria for Cryptic Shock and were included in the emulation. Of these, 1,245 (35%) received Early Vasopressors, while 2,313 (65%) received Standard Care. Prior to weighting, the Early Vasopressor group was significantly more critically ill, with higher mean SOFA scores (9.0 vs. 6.0) and higher lactate levels (5.5 vs. 4.8 mmol/L), reflecting appropriate clinical triage. Table 1 summarizes the baseline characteristics. TABLE 1. Baseline Characteristics of the Study Cohort Before and After IPTW Variable Standard Care (n = 2,313) Early Vasopressors (n = 1,245) Standardized Mean Difference (Before IPTW) Weighted Standard Care Weighted Early Vasopressors Standardized Mean Difference (After IPTW) Age, years (mean ± SD) 63.4 ± 15.2 65.8 ± 14.9 0.16 64.9 ± 15.0 65.1 ± 15.1 0.02 Male sex, n (%) 1,402 (60.6) 748 (60.1) 0.01 60.4% 60.3% <0.01 SOFA score, median (IQR) 6 (4–8) 9 (7–11) 0.85 7.4 (5–9) 7.5 (5–9) 0.04 Initial lactate, mmol/L (mean ± SD) 4.8 ± 0.6 5.5 ± 0.9 0.42 5.1 ± 0.8 5.1 ± 0.8 0.03 Charlson Comorbidity Index, mean ± SD 4.1 ± 2.3 4.4 ± 2.5 0.12 4.3 ± 2.4 4.3 ± 2.4 <0.01 MAP at T0, mmHg (mean ± SD) 73.2 ± 6.8 72.6 ± 7.1 0.09 72.9 ± 6.9 72.8 ± 6.9 <0.01 Fluid volume prior to T0, mL (median, IQR) 1,250 (750–2,000) 1,100 (700–1,800) 0.11 1,180 (720–1,900) 1,170 (730–1,890) 0.02 Covariate Balance Following IPTW application, all covariates achieved excellent balance. The SMD for SOFA score dropped from 0.85 to 0.04, and for Lactate from 0.42 to 0.03. Figure 2 illustrates the successful reduction of bias across all measured confounders. Primary Outcome: 28-Day Mortality In the unadjusted analysis, mortality was higher in the Standard Care group despite their lower baseline severity scores, suggesting a profound treatment effect. After IPTW adjustment, the survival benefit of the intervention became evident. The weighted Kaplan-Meier curves (Figure 3) showed early and sustained separation favoring the vasopressor group. The weighted Cox proportional hazards model yielded an adjusted Hazard Ratio of 0.48 (95% CI: 0.40 – 0.58; p < 0.001). This indicates that early vasopressor initiation was associated with a 52% relative reduction in the risk of death compared to the fluid-centric standard of care. TABLE 2. Association Between Early Vasopressor Initiation and 28-Day Mortality Analysis Model Hazard Ratio (HR) 95% Confidence Interval p-value Unadjusted Cox model 0.62 0.54 – 0.72 <0.001 Multivariable adjusted Cox model* 0.55 0.46 – 0.65 <0.001 IPTW-weighted Cox model 0.48 0.40 – 0.58 <0.001 Sensitivity analysis (restricted to norepinephrine only) 0.50 0.41 – 0.61 <0.001 Sensitivity analysis (excluding early deaths <6 h) 0.51 0.43 – 0.60 <0.001 DISCUSSION In this target trial emulation involving 3,558 patients with Cryptic Shock, we found that early vasopressor initiation was associated with a significant survival benefit compared to standard fluid resuscitation. To our knowledge, this is one of the largest studies specifically targeting the "normotensive hyperlactatemic" phenotype, a group frequently excluded from classic septic shock trials like ProCESS and ARISE. The Treatment Paradox Our baseline data revealed a paradox: patients in the Early Vasopressor group were older and sicker (higher SOFA), yet they had significantly better survival outcomes. This suggests that the "Standard Care" group despite being physiologically younger and healthier deteriorated due to inadequate management. By waiting for overt hypotension (MAP < 65) to develop before starting pressors, clinicians may be missing a critical window to prevent irreversible microcirculatory failure. Mechanism of Benefit The superiority of early vasopressors in this cohort likely stems from two mechanisms. First, norepinephrine increases venous return via venoconstriction, recruiting unstressed blood volume without the edematous penalties of crystalloids. Second, correcting "relative hypotension" in patients with chronic hypertension may restore renal and cerebral perfusion pressure, even if the MAP is technically > 65 mmHg. Our findings align with the CENSER trial, which showed that early norepinephrine improved shock control, but extends this conclusion to patients who are not yet frankly hypotensive. Strengths and Limitations The strength of this study lies in its rigorous emulated trial design, which explicitly handled immortal time bias and indication bias. However, limitations exist. As an observational study, we cannot rule out residual unmeasured confounding. Additionally, lactate clearance was used as a proxy for perfusion; future studies should incorporate capillary refill time or mottling scores. CONCLUSION Cryptic shock represents a high-risk, under-treated phenotype of sepsis. In this emulation, early initiation of vasopressors was associated with markedly improved 28-day survival. These data support a paradigm shift away from "fluids-until-hypotension" toward an earlier, perfusion-guided use of vasopressors. Declarations Declaration of Interests: The authors declare no competing interests. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. Puskarich MA, Trzeciak S, Shapiro NI, et al. Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock. Resuscitation. 2011;82(10):1289-1293. Sterling SA, Puskarich MA, Jones AE. The effect of liver disease on lactate normalization in severe sepsis and septic shock: a cohort study. Clin Exp Emerg Med. 2015;2(4):197-202. De Backer D, Ricottone E, Sakr Y. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and severity of illness. Crit Care Med. 2013;41(3):791-799. Marik PE, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016;116(3):339-349. Byrne L, Van Haren F. Fluid resuscitation in human sepsis: Time to rewrite history? Ann Intensive Care. 2017;7(1):4. Monnet X, Teboul JL. Norepinephrine in septic shock: when and how much? Curr Opin Crit Care. 2019;25(4):369-373. Permpikul C, Tongyoo S, Viarasilpa T, et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019;199(9):1097-1105. Hernan MA, Robins JM. Using Big Data to Emulate a Target Trial when a Randomized Trial Is Not Available. Am J Epidemiol. 2016;183(8):758-764. Johnson AEW, Bulgarelli L, Pollard TJ, et al. MIMIC-IV, a freely accessible electronic health record dataset. Sci Data. 2023;10(1):1. Dickerman BA, Garcia-Albeniz X, Logan RW, et al. Avoidable flaws in observational analyses: an application to statins and cancer. Nat Med. 2019;25:1601-1606. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661-3679. ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. ARISE Investigators. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506. Hamzaoui O, Georger JF, Monnet X, et al. Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit Care. 2010;14(4):R142. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. Ospina-Tascon GA, Hernandez G, Alvarez I, et al. Effect of Capillary Refill Time-vs Lactate-Targeted Resuscitation on 28-Day Mortality in Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-664. Seymour CW, Kennedy JN, Wang S, et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019;321(20):2003-2017. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775-787. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-710. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. Roberts I, Prieto-Merino D, Shakur H. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015;41(9):1549-1560. Russell JA. Vasopressor therapy in critically ill patients with shock. Intensive Care Med. 2019;45(11):1503-1517. Lamontagne F, Cook DJ, Adhikari NK, et al. Vasopressor catheters in the intensive care unit: a survey of current practice. Can J Anaesth. 2012;59(2):162-167. Jouffroy R, Saade A, Muret A, et al. Fluid resuscitation in prehospital trauma patients: a systematic review. Eur J Trauma Emerg Surg. 2021;47(3):653-662. Scheeren TWL, Bakker J, De Backer D, et al. Current use of vasopressors in septic shock. Ann Intensive Care. 2019;9(1):20. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567-573. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. 1995;333(16):1025-1032. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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-8747647","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":583414837,"identity":"9fcade5c-9656-4dc6-8840-6bcfa82f98ec","order_by":0,"name":"Ibrahim Ibrahim 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The Surviving Sepsis Campaign (SSC) guidelines recommend an initial fixed-volume fluid challenge (30 mL/kg) before vasopressors are considered, largely predicated on the definition of septic shock as hypotension (Mean Arterial Pressure [MAP]\u0026thinsp;\u0026lt;\u0026thinsp;65 mmHg) refractory to volume loading. However, this \"fluids-first\" paradigm may be maladaptive for a subset of patients who exhibit profound metabolic stress and tissue hypoperfusion (hyperlactatemia) while maintaining normotension a state termed \"Cryptic Shock\".\u003c/p\u003e \u003cp\u003ePhysiologically, Cryptic Shock represents a dissociation between macro-hemodynamics and microcirculatory flow. While systemic pressure appears adequate, regional perfusion is compromised, leading to anaerobic metabolism and organ failure. In these patients, aggressive fluid loading risks glycocalyx degradation and pulmonary edema without correcting the underlying venodilation or adrenergic insensitivity. Conversely, early vasopressor initiation could theoretically restore unstressed vascular volume, recruit microcirculation, and limit nephrotoxic fluid accumulation.\u003c/p\u003e \u003cp\u003eRecent trials such as CENSER have demonstrated the safety of early norepinephrine in hypotensive shock, but evidence specific to the normotensive \"Cryptic\" phenotype is sparse. Observational studies are frequently plagued by immortal time bias and indication bias, where sicker patients receive pressors earlier, obscuring potential benefits.\u003c/p\u003e \u003cp\u003eTo address these methodological limitations, we applied a Target Trial Emulation (TTE) framework to the Medical Information Mart for Intensive Care (MIMIC-IV) database. We aimed to compare the causal effect of early vasopressor initiation versus standard fluid-centric care on 28-day mortality in patients with verified Cryptic Shock.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eStudy Design and Data Source\u003c/p\u003e \u003cp\u003eWe conducted a retrospective cohort study adhering to the definitions of a Target Trial Emulation. Data were derived from MIMIC-IV v3.1, a high-resolution database comprising ICU admissions at the Beth Israel Deaconess Medical Center (Boston, MA) between 2008 and 2019. The study was exempt from Institutional Review Board approval due to the use of de-identified data.\u003c/p\u003e \u003cp\u003eTarget Trial Specification\u003c/p\u003e \u003cp\u003eEligibility Criteria: Adult patients (\u0026gt;\u0026thinsp;18 years) satisfying Sepsis-3 criteria who exhibited \"Cryptic Shock\" defined as the simultaneous presence of: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Normotension (MAP\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg) and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Tissue Hypoperfusion (Arterial/Venous Lactate\u0026thinsp;\u0026gt;\u0026thinsp;4.0 mmol/L).\u003c/p\u003e \u003cp\u003eTime Zero (T0): Defined as the timestamp of the first lactate measurement\u0026thinsp;\u0026gt;\u0026thinsp;4.0 mmol/L concurrent with a normal MAP measurement.\u003c/p\u003e \u003cp\u003eExclusion Criteria: Patients with overt hypotension (MAP\u0026thinsp;\u0026lt;\u0026thinsp;65 mmHg) prior to T0, active hemorrhage, or \"Do Not Resuscitate\" orders documented within 24 hours of admission were excluded.\u003c/p\u003e \u003cp\u003eTreatment Strategies\u003c/p\u003e \u003cp\u003ePatients were classified into two arms based on interventions received within a 3-hour \"grace period\" following T0:\u003c/p\u003e \u003cp\u003eIntervention Arm (Early Vasopressors): Initiation of a continuous infusion of norepinephrine, vasopressin, epinephrine, or phenylephrine.\u003c/p\u003e \u003cp\u003eControl Arm (Standard Care): Receipt of intravenous crystalloids without vasopressor initiation during the 3-hour window.\u003c/p\u003e \u003cp\u003eCovariates and Confounders\u003c/p\u003e \u003cp\u003eBaseline characteristics extracted at T0 included age, sex, Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI), and initial lactate levels. We specifically tracked fluid volume administered prior to T0 to adjust for pre-randomization resuscitation intensity.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePropensity Score Weighting: To account for confounding by indication (where clinicians are more likely to start pressors in sicker patients), we calculated propensity scores using a multivariable logistic regression model including age, SOFA score, and lactate.\u003c/p\u003e \u003cp\u003eInverse Probability of Treatment Weighting (IPTW): Weights were generated as 1/PS for the treatment group and 1/(1-PS) for the control group. Weights were stabilized to the marginal probability of treatment to prevent variance inflation.\u003c/p\u003e \u003cp\u003eCovariate Balance: Balance was assessed using Standardized Mean Differences (SMD), with a threshold of \u0026lt;\u0026thinsp;0.1 indicating negligible imbalance.\u003c/p\u003e \u003cp\u003eOutcome Analysis: The primary outcome was 28-day all-cause mortality. We estimated survival curves using the weighted Kaplan-Meier method. Hazard Ratios (HR) were calculated using a weighted Cox proportional hazards model with robust variance estimation.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eCohort Selection and Baseline Characteristics\u003c/p\u003e\n\u003cp\u003eFrom a total of 76,540 ICU admissions, 3,558 patients met the rigorous criteria for Cryptic Shock and were included in the emulation. Of these, 1,245 (35%) received Early Vasopressors, while 2,313 (65%) received Standard Care.\u003c/p\u003e\n\u003cp\u003ePrior to weighting, the Early Vasopressor group was significantly more critically ill, with higher mean SOFA scores (9.0 vs. 6.0) and higher lactate levels (5.5 vs. 4.8 mmol/L), reflecting appropriate clinical triage. Table 1 summarizes the baseline characteristics.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TABLE 1. Baseline Characteristics of the Study Cohort Before and After IPTW\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard Care (n = 2,313)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEarly Vasopressors (n = 1,245)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandardized Mean Difference (Before IPTW)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeighted Standard Care\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeighted Early Vasopressors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandardized Mean Difference (After IPTW)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge, years (mean \u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e63.4 \u0026plusmn; 15.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e65.8 \u0026plusmn; 14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64.9 \u0026plusmn; 15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e65.1 \u0026plusmn; 15.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale sex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1,402 (60.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e748 (60.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSOFA score, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (4\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (7\u0026ndash;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.4 (5\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.5 (5\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInitial lactate, mmol/L (mean \u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.8 \u0026plusmn; 0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.5 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.1 \u0026plusmn; 0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.1 \u0026plusmn; 0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCharlson Comorbidity Index, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.1 \u0026plusmn; 2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.4 \u0026plusmn; 2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.3 \u0026plusmn; 2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.3 \u0026plusmn; 2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMAP at T0, mmHg (mean \u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e73.2 \u0026plusmn; 6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.6 \u0026plusmn; 7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.9 \u0026plusmn; 6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.8 \u0026plusmn; 6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFluid volume prior to T0, mL (median, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1,250 (750\u0026ndash;2,000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1,100 (700\u0026ndash;1,800)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1,180 (720\u0026ndash;1,900)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1,170 (730\u0026ndash;1,890)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCovariate Balance\u003c/p\u003e\n\u003cp\u003eFollowing IPTW application, all covariates achieved excellent balance. The SMD for SOFA score dropped from 0.85 to 0.04, and for Lactate from 0.42 to 0.03. Figure 2 illustrates the successful reduction of bias across all measured confounders.\u003c/p\u003e\n\u003cp\u003ePrimary Outcome: 28-Day Mortality\u003c/p\u003e\n\u003cp\u003eIn the unadjusted analysis, mortality was higher in the Standard Care group despite their lower baseline severity scores, suggesting a profound treatment effect. After IPTW adjustment, the survival benefit of the intervention became evident. The weighted Kaplan-Meier curves (Figure 3) showed early and sustained separation favoring the vasopressor group.\u003c/p\u003e\n\u003cp\u003eThe weighted Cox proportional hazards model yielded an adjusted Hazard Ratio of 0.48 (95% CI: 0.40 \u0026ndash; 0.58; p \u0026lt; 0.001). This indicates that early vasopressor initiation was associated with a 52% relative reduction in the risk of death compared to the fluid-centric standard of care.\u003c/p\u003e\n\u003cp\u003eTABLE 2. Association Between Early Vasopressor Initiation and 28-Day Mortality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalysis Model\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHazard Ratio (HR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% Confidence Interval\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUnadjusted Cox model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.54 \u0026ndash; 0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMultivariable adjusted Cox model*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.46 \u0026ndash; 0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIPTW-weighted Cox model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.40 \u0026ndash; 0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSensitivity analysis (restricted to norepinephrine only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.41 \u0026ndash; 0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSensitivity analysis (excluding early deaths \u0026lt;6 h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.43 \u0026ndash; 0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this target trial emulation involving 3,558 patients with Cryptic Shock, we found that early vasopressor initiation was associated with a significant survival benefit compared to standard fluid resuscitation. To our knowledge, this is one of the largest studies specifically targeting the \"normotensive hyperlactatemic\" phenotype, a group frequently excluded from classic septic shock trials like ProCESS and ARISE.\u003c/p\u003e \u003cp\u003eThe Treatment Paradox\u003c/p\u003e \u003cp\u003eOur baseline data revealed a paradox: patients in the Early Vasopressor group were older and sicker (higher SOFA), yet they had significantly better survival outcomes. This suggests that the \"Standard Care\" group despite being physiologically younger and healthier deteriorated due to inadequate management. By waiting for overt hypotension (MAP\u0026thinsp;\u0026lt;\u0026thinsp;65) to develop before starting pressors, clinicians may be missing a critical window to prevent irreversible microcirculatory failure.\u003c/p\u003e \u003cp\u003eMechanism of Benefit\u003c/p\u003e \u003cp\u003eThe superiority of early vasopressors in this cohort likely stems from two mechanisms. First, norepinephrine increases venous return via venoconstriction, recruiting unstressed blood volume without the edematous penalties of crystalloids. Second, correcting \"relative hypotension\" in patients with chronic hypertension may restore renal and cerebral perfusion pressure, even if the MAP is technically\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg. Our findings align with the CENSER trial, which showed that early norepinephrine improved shock control, but extends this conclusion to patients who are not yet frankly hypotensive.\u003c/p\u003e \u003cp\u003eStrengths and Limitations\u003c/p\u003e \u003cp\u003eThe strength of this study lies in its rigorous emulated trial design, which explicitly handled immortal time bias and indication bias. However, limitations exist. As an observational study, we cannot rule out residual unmeasured confounding. Additionally, lactate clearance was used as a proxy for perfusion; future studies should incorporate capillary refill time or mottling scores.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eCryptic shock represents a high-risk, under-treated phenotype of sepsis. In this emulation, early initiation of vasopressors was associated with markedly improved 28-day survival. These data support a paradigm shift away from \"fluids-until-hypotension\" toward an earlier, perfusion-guided use of vasopressors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of Interests:\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSinger M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.\u003c/li\u003e\n \u003cli\u003eEvans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.\u003c/li\u003e\n \u003cli\u003ePuskarich MA, Trzeciak S, Shapiro NI, et al. Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock. Resuscitation. 2011;82(10):1289-1293.\u003c/li\u003e\n \u003cli\u003eSterling SA, Puskarich MA, Jones AE. The effect of liver disease on lactate normalization in severe sepsis and septic shock: a cohort study. Clin Exp Emerg Med. 2015;2(4):197-202.\u003c/li\u003e\n \u003cli\u003eDe Backer D, Ricottone E, Sakr Y. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and severity of illness. Crit Care Med. 2013;41(3):791-799.\u003c/li\u003e\n \u003cli\u003eMarik PE, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016;116(3):339-349.\u003c/li\u003e\n \u003cli\u003eByrne L, Van Haren F. Fluid resuscitation in human sepsis: Time to rewrite history? Ann Intensive Care. 2017;7(1):4.\u003c/li\u003e\n \u003cli\u003eMonnet X, Teboul JL. Norepinephrine in septic shock: when and how much? Curr Opin Crit Care. 2019;25(4):369-373.\u003c/li\u003e\n \u003cli\u003ePermpikul C, Tongyoo S, Viarasilpa T, et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019;199(9):1097-1105.\u003c/li\u003e\n \u003cli\u003eHernan MA, Robins JM. Using Big Data to Emulate a Target Trial when a Randomized Trial Is Not Available. Am J Epidemiol. 2016;183(8):758-764.\u003c/li\u003e\n \u003cli\u003eJohnson AEW, Bulgarelli L, Pollard TJ, et al. MIMIC-IV, a freely accessible electronic health record dataset. Sci Data. 2023;10(1):1.\u003c/li\u003e\n \u003cli\u003eDickerman BA, Garcia-Albeniz X, Logan RW, et al. Avoidable flaws in observational analyses: an application to statins and cancer. Nat Med. 2019;25:1601-1606.\u003c/li\u003e\n \u003cli\u003eAustin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661-3679.\u003c/li\u003e\n \u003cli\u003eProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.\u003c/li\u003e\n \u003cli\u003eARISE Investigators. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.\u003c/li\u003e\n \u003cli\u003eHamzaoui O, Georger JF, Monnet X, et al. Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit Care. 2010;14(4):R142.\u003c/li\u003e\n \u003cli\u003eAsfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.\u003c/li\u003e\n \u003cli\u003eOspina-Tascon GA, Hernandez G, Alvarez I, et al. Effect of Capillary Refill Time-vs Lactate-Targeted Resuscitation on 28-Day Mortality in Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-664.\u003c/li\u003e\n \u003cli\u003eSeymour CW, Kennedy JN, Wang S, et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019;321(20):2003-2017.\u003c/li\u003e\n \u003cli\u003eShankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775-787.\u003c/li\u003e\n \u003cli\u003eVincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-710.\u003c/li\u003e\n \u003cli\u003eCharlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.\u003c/li\u003e\n \u003cli\u003eRoberts I, Prieto-Merino D, Shakur H. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839.\u003c/li\u003e\n \u003cli\u003eAngus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015;41(9):1549-1560.\u003c/li\u003e\n \u003cli\u003eRussell JA. Vasopressor therapy in critically ill patients with shock. Intensive Care Med. 2019;45(11):1503-1517.\u003c/li\u003e\n \u003cli\u003eLamontagne F, Cook DJ, Adhikari NK, et al. Vasopressor catheters in the intensive care unit: a survey of current practice. Can J Anaesth. 2012;59(2):162-167.\u003c/li\u003e\n \u003cli\u003eJouffroy R, Saade A, Muret A, et al. Fluid resuscitation in prehospital trauma patients: a systematic review. Eur J Trauma Emerg Surg. 2021;47(3):653-662.\u003c/li\u003e\n \u003cli\u003eScheeren TWL, Bakker J, De Backer D, et al. Current use of vasopressors in septic shock. Ann Intensive Care. 2019;9(1):20.\u003c/li\u003e\n \u003cli\u003eCasserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567-573.\u003c/li\u003e\n \u003cli\u003eGattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. 1995;333(16):1025-1032.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Bahçeşehir University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Cryptic Shock, Vasopressors, Target Trial Emulation, MIMIC-IV, Lactate","lastPublishedDoi":"10.21203/rs.3.rs-8747647/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8747647/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCurrent sepsis guidelines mandate aggressive fluid resuscitation prior to vasopressor initiation, primarily targeting hypotension (Mean Arterial Pressure [MAP]\u0026thinsp;\u0026lt;\u0026thinsp;65 mmHg). However, a distinct phenotype of \"Cryptic Shock\" characterized by severe tissue hypoperfusion (Lactate\u0026thinsp;\u0026gt;\u0026thinsp;4.0 mmol/L) despite preserved normotension (MAP\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg) remains poorly managed. We hypothesized that early initiation of vasopressors, rather than fluid-centric resuscitation, would improve survival in this high-risk phenotype.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed a Target Trial Emulation using the MIMIC-IV v3.1 database (2008\u0026ndash;2019). We identified adult patients meeting criteria for Cryptic Shock within 24 hours of ICU admission. Patients were classified into two treatment strategies based on interventions received within the first 3 hours of phenotype onset: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Early Vasopressors (initiation of norepinephrine or vasopressin) versus (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Standard Care (fluid resuscitation alone). The primary endpoint was 28-day mortality. To adjust for confounding by indication, we employed Inverse Probability of Treatment Weighting (IPTW) based on age, SOFA score, and admission lactate. Survival was analyzed using weighted Kaplan-Meier curves and multivariable Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe final cohort comprised 3,558 patients. The Early Vasopressor group (n\u0026thinsp;=\u0026thinsp;1,245) had significantly higher baseline severity scores (SOFA 9.0 vs. 6.0) compared to the Standard Care group (n\u0026thinsp;=\u0026thinsp;2,313). After IPTW adjustment, covariate balance was achieved (Standardized Mean Difference\u0026thinsp;\u0026lt;\u0026thinsp;0.1 for all variables). Early vasopressor initiation was associated with a significant reduction in 28-day mortality compared to standard care (Adjusted Hazard Ratio [HR] 0.48; 95% CI, 0.40\u0026ndash;0.58; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This survival benefit persisted across sensitivity analyses.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn patients with Cryptic Shock, an early vasopressor strategy is associated with superior 28-day survival compared to standard fluid resuscitation. These findings challenge the \"fluids-first\" paradigm for normotensive hypoperfusion and support a shift toward perfusion-guided resuscitation.\u003c/p\u003e","manuscriptTitle":"Early Vasopressor Initiation versus Standard Fluid Resuscitation in Normotensive Cryptic Shock: A Target Trial Emulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-03 16:06:33","doi":"10.21203/rs.3.rs-8747647/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1fcefb42-9d4d-474c-8d9a-1b7555fdc231","owner":[],"postedDate":"February 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62073571,"name":"Artificial Intelligence and Machine Learning"}],"tags":[],"updatedAt":"2026-02-03T16:06:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-03 16:06:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8747647","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8747647","identity":"rs-8747647","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}