Relationship between norepinephrine dose and outcome in septic shock: a retrospective study

Relationship between norepinephrine dose and outcome in septic shock: a retrospective study | 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 Relationship between norepinephrine dose and outcome in septic shock: a retrospective study Lorenzo Antonino Calabrò, Marco Pasetto, Stefano Zorzi, Martina Polato, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9022011/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background High-dose norepinephrine (NE) is frequently required in septic shock, but the association of NE dose with outcome remains incompletely characterized. We aimed to evaluate the relationship between NE dosing, mortality and ischemic complications, and to identify clinically relevant NE dose ranges. Methods This retrospective single-center cohort study included adult patients admitted to the ICU with septic shock between 2016 and 2022. NE dosing variables, including initial dose, highest dose within 24 hours, and peak dose during ICU stay, were collected. An adjusted optimal binning approach was used to identify NE peak-dose ranges associated with ICU and in-hospital mortality. Multivariable logistic regression models were adjusted for age, APACHE II, and SOFA score at admission. Time-dependent Cox models were used to assess the association between NE peak dose and secondary ischemic outcomes. Results A total of 506 patients were included. Median NE peak dose was 0.5 [0.2–1.2] µg/kg*min. Four NE peak-dose ranges were identified: 0.05–0.6, 0.61–1.2, 1.2–3.0, and > 3.0 µg/kg*min. ICU and in-hospital mortality increased stepwise across these ranges, from 20.7% and 32.4% in the lowest group to 100% in patients receiving > 3.0 µg/kg*min. This association persisted after exclusion of patients with withdrawal of life-sustaining therapies. Adjusted odds ratios for ICU mortality were 1.88 [0.97–3.64] and 2.55 [1.38–5.57] in the 0.61–1.2 and 1.2–3.0 µg/kg*min groups, respectively. NE peak dose showed fair discrimination for ICU mortality (Area Under the Receiver Operating Characteristic curve of 0.75), with an optimal threshold of 0.78 µg/kg*min. Most ischemic complications were infrequent and not dose-dependent, except for myocardial ischemia and unexpected cardiac arrest, which were significantly associated with higher NE doses. Conclusions In septic shock, increasing NE peak doses are associated with a marked, stepwise increase in ICU and in-hospital mortality across four distinct dose ranges. Ischemic complications are uncommon and largely independent of NE dose. NE dose stratification may improve risk assessment and harmonization of outcome reporting in future studies. Vasopressor therapy Mortality thresholds Adverse events Hemodynamic support Dose-response relationship Figures Figure 1 Figure 2 Figure 3 Background Septic shock is a leading cause of intensive care unit (ICU) admissions and a major contributor to mortality and morbidity worldwide. Despite advances in critical care, mortality rates remain high, with recent data from Europe and North America varying between 30% and 50%, depending on patient severity and regional differences [ 1 ]. Septic shock is characterized by profound vasodilation and impaired tissue perfusion, driven by a dysregulated host response to infection, necessitating aggressive hemodynamic support to restore cardiovascular stability and organ function [ 2 ]. Current management guidelines emphasize the importance of early fluid resuscitation and vasopressor therapy to achieve and maintain adequate mean arterial pressure and tissue perfusion. Norepinephrine (NE) is widely regarded as the first-line vasopressor in septic shock, due to its potent vasoconstrictive properties mediated through α-adrenergic receptors and its modest β-adrenergic activity, which supports cardiac output [ 3 ]. While norepinephrine is effective in reversing hypotension, its use at high doses has been associated with worse clinical outcomes, including arrhythmias, stress cardiomyopathy, peripheral ischemia and immunosuppression [ 4 , 5 ]. However, it remains unclear whether high norepinephrine doses directly contribute to mortality due to these adverse events or merely reflect greater disease severity. Defining what constitutes a "high dose" of NE remains a subject of debate. The literature defines high dose variably, with thresholds ranging from 0.5 µg/kg*min to 2 µg/kg*min [ 6 , 7 ]. This lack of unanimity reflects differences in patient populations, disease severity, and institutional practices and is compounded by the arbitrary nature of some cut-off definitions. These inconsistencies make it challenging to generalize findings and establish universally accepted thresholds, complicating the interpretation of existing evidence and highlighting the need for a clearer understanding of how dosing thresholds impact outcomes. Furthermore, NE doses are reported variously in the literature, rarely specifying the conjugated NE salt, thereby making hard to compare and interpret the available results [ 8 ]. In this study, we sought to evaluate the correlation between NE doses during ICU stay and patient outcomes in patients suffering from septic shock. By adjusting for baseline severity and comorbidities, we aimed to identify clinically relevant dose thresholds associated with increased risk of mortality and adverse events. METHODS Study Design This is a retrospective cohort, single-centre study including adult (> 18 years of age) patients consecutively admitted to the general ICU at Hôpital Universitaire de Bruxelles (HUB) in Brussels, Belgium, for septic shock between January 2016 and December 2022. Inclusion criteria were the presence of septic shock, according to standard criteria at ICU admission [ 9 ], complete available data on dose of NE, hospital length of stay, and mortality at ICU discharge. Patients undergoing mechanical circulatory support were excluded. The study protocol was approved by the local Ethical Committee (P2023-332), which waived the need for an informed consent due to the retrospective nature of the study. Data Collection Demographics, clinical, hemodynamic, and laboratory data were collected on admission, as well as severity scores, including the Acute Physiologic Assessment and Chronic Health Evaluation Scoring System II (APACHE II) [ 10 ] and the Sepsis-related Organ Failure Assessment (SOFA) [ 11 ] scores. For each patient, the initial dose of NE, the highest dose of NE during the first 24-hours from the onset of septic shock and the peak dose during the entire observational period were collected. The peak dose and the highest 24-hour dose were recorded if administered for at least one hour. Additionally, the intervals between the various doses of NE, the time to halve the NE dose and the time to wean off NE from its highest value were calculated. Prescription of inotropes, intravenous hydrocortisone and a second-line vasopressors were also recorded. All NE doses are reported as base formulation equivalents for standardization purposes, although the NE used in our ICU corresponds to the tartrate formulation (Laboratoire Aguettant, Lyon, France). Primary and secondary outcomes The primary outcome of this study was to identify NE dose cut-offs that are statistically associated with an increased risk of mortality in patients with septic shock, adjusted for age, APACHE II and SOFA score at patient admission. Secondary outcomes include the relationship between the NE peak dose and the development of different ischemic complications (i.e. cutaneous or soft tissue ischemia; intestinal ischemia confirmed by contrast-enhanced abdominal CT scan; acute myocardial ischemia, defined according to the European Society of Cardiology guidelines [ 12 ]; new-onset atrial fibrillation in patients without a prior history of chronic atrial fibrillation, identified by continuous ECG monitoring; unexpected cardiac arrest, defined as a cardiac arrest occurring outside the context of withdrawal of life-sustaining therapy). Data collectors performed manual revision of ICU and hospital electronic records. Anonymized data (including demographic, clinical, microbiological, biochemical, ICU and hospital outcomes) were entered into a password-protected database. Statistical Analysis Statistical analyses were performed using IBM SPSS Statistics 28 for Windows (IBM Corporation, Somers, NY). Kolmogorov-Smirnov test was used to verify the normality of continuous variables distribution. Categorical variables are presented as number (n) and percentage (%). Continuous variables are expressed as mean with standard deviation (SD) or median with interquartile range (IQR). Groups were compared using t Student test, Mann- Whitney U test, paired t test, Chi-square test or Fisher’s exact test, as appropriate. Optimal binning [ 13 ], a method used to select a binning that maximizes predictive information for a target outcome, was employed to identify NE levels based on significant changes in ICU mortality percentages. Odds ratios were adjusted for age, APACHE II and SOFA score at hospital admission. Logistic regression was used to estimate the risk of death in intensive care and in hospital in terms of the identified NE levels. Unadjusted and adjusted odds ratios (ORs, using variables being associated with mortality in the univariate analysis) along with their 95% confidence intervals (CIs) were hence calculated. Area under the receiver operating characteristics (AUROC) curve was computed and the optimal value was determined using the Youden method. All tests were two-tailed, and a p-value less than 0.05 was considered statistically significant. We performed time-dependent Cox proportional hazards models to evaluate the association between NE peak dose and secondary outcomes, including peripheral ischemia, peripheral ischemia persisting after shock resolution, intestinal ischemia, myocardial ischemia, and cardiac arrest. NE dose was included as a continuous time-dependent variable, dividing each patient’s follow-up into pre- and post-peak intervals. Death and discharge were treated as a censoring event. All models were adjusted for age and SOFA score at ICU admission, and robust standard errors were used to account for repeated intervals. Potential sources of bias, including selection and information bias, were considered and minimized by consecutive patient inclusion, standardized data extraction from electronic medical records, and multivariable adjustment for disease severity. Residual confounding and treatment decision bias (e.g., withdrawal of life-sustaining therapy) could not be completely excluded. A sensitivity analysis was performed to account. Missing values were assessed for all variables before analysis. For descriptive and univariate analyses, available-case data were used. For multivariable logistic regression models, a complete-case approach was primarily applied, as the overall rate of missingness for key variables was below 10%. RESULTS Study Population Between 2016 and 2022, 541 patients were admitted to ICU with septic shock, 35 were excluded due to incomplete records, 506 were included in the analysis (Figure S1 ). The median age was 66 [55–75] years, and 331 (65.4%) were male. The most frequent comorbidities were arterial hypertension (n = 273, 54.0%), diabetes mellitus (n = 182, 36.0%) and oncologic disease (n = 184, 36.4%). On admission, median APACHE II and SOFA scores were 24 [19–30] and 10 [ 8 – 13 ], respectively, with initial lactate levels of 3.6 [2.1–6.4] mmol/L. The main source of sepsis was abdominal in 234 (46.2%) patients, followed by pulmonary in 130 (25.7%) patients and urological in 54 (10.7%) patients (Table 1 ). The median time to antibiotic start from sepsis onset was 1 [0–3] hours, 101 (20.0%) patients received antibiotic prior to ICU admission. The median length of stay in ICU was 6 [ 3 – 11 ] days, while the median length of stay in hospital was 21 [10–45] days. During hospitalization 301 (59.5%) patients required mechanical ventilation. The ICU mortality rate was 36.2% (n = 183), while the hospital mortality rate was 44.5% (n = 225); in 76 non-survivors, the cause of death was the withdrawal of life support therapies (Table 2 ). There was a significant association between year of inclusion and in hospital mortality (p = 0.03) with a trend toward lower mortality over time (coeff. -0.015; p = 0.02). Table 1 Characteristics of the study population, according to ICU mortality. Data are presented as count (%) or median (IQR). All Survivors Non-Survivors p value (n = 506) (n = 322) (n = 184) Age, years 66 (55;75) 64 (53;74) 68 (58;76) 0.046 † Male gender, n (%) 331 (65,4) 215 (67) 116 (63) 0.39 †† Weight, Kg 77 (63;90) 76 (64;90) 78 (60;89) 0.96* Height, m 1.7 (1.62;1,78) 1.7 (1.62;1.78) 1.71 (1.62;1.78) 0.83* BMI, Kg/m 2 25.9 (22.5;29.7) 25.5 (22.5;29.7) 26.5 (22.7;30.0) 0.61* BSA, m 2 1.77 (1.46;1.99) 1.87 (1.69;2.06) 1.88 (1.69;2.04) 0.90* Scores at admission APACHE II 24 (18,8;30) 22 (17;27) 28 (22,5;33) < .001 † RASS -2 (-5;0) -1 (-5;0) -5 (-5;1) < .001 † SOFA 10 (8;13) 10 (7;12) 12 (10;14) < .001 † Comorbidities HF, n (%) 133 (26.3) 78 (25) 55 (30) 0.14 †† HFpEF, n (%) 53 (10.5) 34 (11) 19 (11) 0.95 †† HFrEF, n (%) 71 (14) 39 (13) 32 (18) 0.09 †† AF, n (%) 89 (18) 47 (15) 42 (23) 0.01 †† CMP, n (%) 121 (23.9) 73 (23) 48 (27) 0.33 †† CAD, n (%) 87 (17.2) 55 (17) 32 (18) 0.88 †† CABG/PCI, n (%) 51 (10.1) 30 (10) 21 (12) 0.45 †† CKD, n (%) 135 (26.7) 78 (24) 57 (31) 0.08 †† COPD, n (%) 116 (22.9) 76 (24) 40 (22) 0.67 †† HTA 273 (54) 177 (55) 96 (53) 0.63 †† DM, n (%) 182 (36) 127 (39) 55 (30) 0.04 †† Cirrhosis, n (%) 125 (24.7) 67 (21) 58 (32) 0.005 †† Malignancy, n (%) 184 (36.4) 124 (39) 60 (33) 0.22 †† Immunodeficiency, n (%) 127 (25.1) 78 (24) 49 (27) 0.48 †† Admitted from Emergency Department, n (%) 182 (35.8) 124 (38) 58 (31) Medical ward, n (%) 142 (27.9) 78 (24) 64 (35) Surgical ward, n (%) 58 (11.7) 41 (13) 17 (10) 0.06* From another hospital, n (%) 81 (15.8) 50 (15) 32 (17) Operating room, n (%) 42 (8.1) 29 (10) 13 (7) BMI, body mass index; BSA, body surface area; APACHE II, Acute Physiologic Assessment and Chronic Health Evaluation II; RASS, Richmond Agitation Sedation Scale; SOFA, sequential organ failure assessment; HF, heart failure; HFpEF heart failure with preserved ejection faction; HFrEF, heart failure with reduced ejection fraction; AF, chronic atrial fibrillation; CMP, cardiomyopathy; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; LOS, length of stay; WLST, withdrawal of life support treatment; (†)= Mann-Whitney test (††) = Chi square test. (*) = T student test Table 2 Main outcomes. Data are presented as count (%) or median (IQR). All Survivors Non-Survivors p value ICU LOS (days) 6 (3;10,8) 6 (4;10) 5 (3;11) 0.85 † Hospital LOS (days) 21 (10;45) 31(16;60) 5 (3;11) < .001 † In ICU mortality, n (%) 184 (36,3) - - NA In hospital mortality, n (%) 225 (44,5) 41(13) - NA WLST, n (%) 76 (15) - 76 (41) NA ICU= intensive care unit; LOS= length of stay; WLST= withdrawal of life support; (†)= Mann-Whitney test Norepinephrine and haemodynamic support Vasopressors were initiated at ICU admission, or during surgery for patients admitted after surgery. The median NE initial dose was 0.2 [0.1–0.5] µg/kg*min, the median NE highest dose at 24hr was 0.4 [0.2–0.9] µg/kg*min, the median NE peak dose was 0.5 [0.2–1.2] µg/kg*min, reached after a median of 8 [ 2 – 18 ] hours since the introduction of NE. The median time to NE halving from peak was 7 [ 3 – 14 ] hours, while the median time to NE weaning from peak was 46 [27–80] hours. An additional vasopressor was used in 29 (5.7%) patients (n = 23 vasopressin, n = 6, terlipressin). Inotropes were used in 119 (23.5%) patients (n = 93 dobutamine, n = 29 epinephrine), while hydrocortisone was administered in 208 (41.1%) patients (Table 3 ). Table 3 Main norepinephrine (NE) kinetics, according to ICU mortality. Data are presented as count (%) or median (IQR). ALL Survivors Non-Survivors P value (n = 506) (n = 322) (n = 184) NE initial dose, µg/kg*min 0.2 (0.1–0.5) 0.1 (0.1–0.3) 0.3 (0.1–0.7) < .001 † NE highest dose at 24hr, µg/kg*min 0.4 (0.2–0.9) 0.3 (0.1–0.6) 0.8 (0.2–1.7) < .001 † NE peak dose, µg/kg*min 0.5 (0.2–1.2) 0.3 (0.2–0.8) 1.1 (0.5-2.0) < .001 † NE time to peak, hours 8 (2–18) 5 (1–15) 14 (5–24) < .001 † Peak dose to halving, hours 7 (3–13) 7 (4–14) 6 (3–12) 0.44† Peak to weaning, hours 46 (27–80) 45 (26–76) 67 (30–134) 0.02 † Adjunctive therapy Added vasopressors, n (%) 29 (5.7) 9 (2.8) 20 (10.9) < .001 †† Inotropes, n (%) 119 (23.5) 55 (17.1) 64 (34.8) < .001 †† Hydrocortisone, n (%) 208 (41.1) 102 (31.7) 106 (57.6) < .001 †† Persistence of shock Still in shock at 24 hours, n (%) 379 (75.0) 210 (65.2) 169 (91.8) < .001 †† NE, noreprinephrine (†)= Mann-Whitney test (††) = Chi square test. Primary Outcome In ICU non-survivors, the NE initial dose and the NE peak dose were significantly higher, while the NE time to peak and the time from NE peak to NE weaning longer when compared to survivors, in unadjusted univariate analysis. NE highest dose at 24hr and NE peak dose were associated with ICU and in-hospital mortality at univariate analysis (p < 0.001), as well as age, APACHE II and SOFA scores, history of atrial fibrillation, liver cirrhosis and diabetes. Adjusted optimal binning procedure allowed identification of four patient groups with statistically significant difference in risk of death according to NE dose. (Figs. 1 and 2 , SM) After excluding patients for whom a decision had been made to withdraw life-sustaining therapies, both ICU and in-hospital mortality increased across the NE peak-dose groups. (SM) In the multivariable analysis, adjusted odds ratios for ICU mortality in the 0.61 and 1.2 µg/kg*min and the 1.2 and 3 µg/kg*min groups were 1.88 [0.97–3.64] and 2.55 [1.38–5.57], compared to the lower ranges group, used as reference. Similar results were obtained for in-hospital mortality (9.43 [4.06–21.90] and 6.21 [2.70–14.30], respectively). The AUROC analysis (0.75 [0.70–0.79]) identified the optimal cut-off value of 0.78 [0.7–0.79] µg/kg*min to predict ICU mortality, with a sensitivity of 60.1% and a specificity of 75.9% (Fig. 3 ). Secondary Outcomes Peripheral ischemia occurred in 21 patients (4.2%) at a median of 3 days (IQR 2–6) after shock onset and was not associated with peak NE dose (HR 1.06, 95% CI 0.91–1.24; p = 0.42), including cases persisting after shock resolution in 14 patients (2.8%) occurring at 4 days (IQR 3–7) (HR 1.01, 95% CI 0.79–1.28; p = 0.92). Intestinal ischemia occurred in 12 patients (2.4%) at 5 days (IQR 3–6) and was not associated with peak NE dose (HR 1.10, 95% CI 0.94–1.29; p = 0.22). Myocardial ischemia occurred in 5 patients (1.0%) early after shock onset (median 1 [ 1 – 3 ] days) and was associated with higher peak NE dose (HR 1.25, 95% CI 1.02–1.54; p = 0.04). New-onset atrial fibrillation occurred in 79 patients (15.6%) after a median of 2 ( 1–4) days and was not associated with peak NE dose (HR 0.96, 95% CI 0.75–1.22; p = 0.73). Unexpected cardiac arrest occurred in 14 patients (2.8%) after a median of 3 (2–8) days and was strongly associated with higher peak NE dose (HR 1.32, 95% CI 1.15–1.51; p < 0.01 - Table 4 ). Table 4 Adjusted time-dependent Cox proportional hazards models between NE peak dose and secondary outcomes. Peripheral ischemia n (%) Days from shock onset Peak NE dose µg/kg*min Robust S.E. Hazard ratio (C.I.) P value 21 (4.2) 3 (2–6) 1.1 (0.5–1.3) 0.08 1.06 (0.91–1.24) 0.42 Peripheral ischemia persisting after shock resolution 14 (2.8) 4 (3–7) 1.0 (0.4–1.2) 0.12 1.01 (0.79–1.28) 0.92 Intestinal ischemia 12 (2.4) 5 (3–6) 1.3 (0.5–1.4) 0.09 1.10 (0.94–1.29) 0.22 Myocardial ischemia 5 (1.0) 1 (1–3) 0.5 (0.5–0.6) 0.13 1.25 (1.02–1.54) 0.04 New onset AF 79 (15.6) 2 (1–4) 0.53 (0.26–1.07) 0.12 0.96 (0.75–1.22) 0.73 Unexpected CA 14 (2.8) 3 (2–8) 2.0 (1.3–2.5) 0.09 1.32 (1.15–1.51) < 0.01 NE= norepinephrine; S.E. = Standard Error; C.I.=confidence interval; AF= atrial fibrillation; CA= cardiac arrest DISCUSSION In this large single-center cohort of patients with septic shock, NE exposure was strongly associated with ICU and in-hospital mortality, with a clear gradient of risk across four predefined NE peak-dose ranges. Using an adjusted optimal binning approach, four dose ranges were identified, with progressively increasing and statistically different mortality rates. ICU and in-hospital mortality rose from 20.7% and 32.4% in the lowest dose range to 39.1% and 45.5% in the intermediate range, and further to 59.0% and 64.0% in the higher range, reaching 100% in patients requiring peak NE doses above 3.0 µg/kg/min. This stepwise increase in mortality persisted after exclusion of patients with withdrawal of life-sustaining therapies. In addition, NE peak dose demonstrated a fair discriminatory performance for ICU mortality, with an AUROC of 0.75 and an optimal threshold of 0.78 µg/kg/min. Both time to peak NE dose and duration of vasopressor therapy were significantly longer in patients with unfavourable outcomes. Secondary analyses showed that most ischemic complications were infrequent, with myocardial ischemia and unexpected cardiac arrest being the only events significantly associated with higher NE doses. The definition of high-dose NE varies widely across the published studies, largely due to differences in patient cohort severity, NE formulations, and resuscitation practices across institutions [ 14 , 15 ]. In several previous studies, an NE dose of 1 µg/kg/min was selected a priori to define high-dose exposure, and mortality was subsequently compared between patients above and below this threshold, with reported mortality rates of 80–90% in patients receiving doses exceeding 1 µg/kg/min. While pragmatic, this approach relies on an arbitrary cut-off that was not derived from outcome-driven analyses within the studied cohorts [ 6 , 16 , 17 ]. Other studies have reported 28-day mortality rates of 60–65% in patients receiving high-dose NE [ 7 , 18 ]. These outcomes are consistent with the hospital mortality rates observed in our cohort for patients receiving 1.2–3.0 or > 3.0 µg/kg*min. A large multicenter study reported a mortality rate of 61.4% for patients receiving NE doses above 0.3 µg/kg*min [ 19 ], although this likely reflects aggregated subgroups with heterogeneous risk profiles. Sato et al. further explored the relationship between maximum NE dose at 24 hours and in-hospital mortality, but did not define a specific high-dose threshold or assess dose kinetics and related complications [ 20 ]. Auchet et al. evaluated outcomes in patients receiving high-dose vasopressor therapy (≥ 1 µg/kg/min for ≥ 1 h) but focused solely on predefined thresholds without exploring dose kinetics or its association with complications [ 7 ]. None of these studies specified the NE formulation used, limiting interpretability. This issue has been explicitly raised by Morales et al. [ 14 ], who emphasized that the choice of NE formulation significantly affects the interpretation and definition of what constitutes a “high” dose. The lack of standardization and clarity regarding NE formulation limits comparability across studies and may contribute to inconsistent risk stratification. While the association between NE dose and mortality appears to be continuous rather than categorical, reliance on a single predefined threshold is insufficient to capture meaningful differences in risk. In this context, the NE dose ranges identified in our study were not arbitrarily selected but derived from an outcome-driven analysis aimed at maximizing separation between patient groups with distinct mortality risk, to provide a pragmatic framework for clinical interpretation. Two studies have reported that the total cumulative dose of NE administered during septic shock was not independently associated with mortality [ 7 , 21 ]. This suggests that the temporal kinetics of NE administration may be more clinically relevant than the absolute total dose. Specifically, patients who experience a rapid escalation followed by prompt de-escalation of NE therapy tend to have lower peak doses and higher survival rates compared to those with slower dose escalation and prolonged tapering. The latter pattern may reflect a more indolent, treatment-resistant, or poorly controlled septic state, characterized by persistent vasoplegia and delayed hemodynamic stabilization. In our cohort, complications traditionally associated with NE use, including peripheral ischemia, and acute intestinal ischemia, were relatively infrequent and not clearly dose-dependent. New onset atrial fibrillation occurred in 15.6% of patients, but was neither dose-dependent nor significantly associated with mortality. Unexpected cardiac arrest and myocardial ischemia arrest were observed in 14 (2.8%) and 5 (1.0%) patients respectively and were strongly associated with exposure to high NE peak doses. Our findings are generally consistent with those reported by Anantasit et al., who observed slightly lower complication rates in a comparable population [ 4 ]. It is important to acknowledge that the overall complication rate associated with NE may be underestimated, particularly for less severe or transient events such as reversible peripheral ischemia, which are often underreported in observational studies. Overall, our data suggest that complications typically attributed to NE are relatively uncommon and, with the notable exception of cardiac arrest and myocardial ischemia, appear to be largely independent of dose. The contribution of NE mediated complications to overall mortality appears to remain limited and does not fully account for the excess mortality observed at high NE doses. These findings suggest that high-dose NE may have a less significant role as a direct contributor to poor outcomes in septic shock than previously proposed [ 17 ]. Experimental studies have proposed that NE may exert immunomodulatory effects, including anti-inflammatory actions that could, paradoxically, promote bacterial proliferation and worsen infection control [ 5 , 22 ]. However, the clinical relevance of these preclinical observations remains unproven. It is also possible that NE anti-inflammatory properties could confer beneficial effects, by attenuating the deleterious consequences of an excessive inflammatory response. Additionally, we observed that dobutamine was administered in 18.4% of patients in our cohort. As a beta-adrenergic agent, dobutamine may also influence the host immune response and inflammatory pathways, although its precise role in modulating outcomes in septic shock warrants further investigation. This study has several limitations. Its single-center design may limit generalizability to institutions with different resuscitation protocols, although it also ensured greater consistency in treatment strategies and strengthened internal validity. The retrospective nature of the study may have led to underreporting of mild or transient complications, while major events are likely to have been reliably captured. Mortality patterns during the COVID-19 period may have influenced outcomes, although the overall temporal trend toward decreasing mortality remained unchanged. Time from shock onset to vasopressor initiation was not systematically recorded, representing a potential source of bias, although early vasopressor administration is routinely implemented in our institution. Finally, most patients receiving NE doses > 3.0 µg/kg/min died following withdrawal of life-sustaining therapy, which may introduce treatment-decision bias, although sensitivity analyses were consistent with the primary results. All NE doses were reported as base formulation equivalents, limiting direct comparison with studies using other formulations. CONCLUSIONS In septic shock, increasing NE peak doses were associated with a stepwise increase in ICU and in-hospital mortality across four dose ranges. Ischemic complications were uncommon and largely independent of dose, except for myocardial ischemia and unexpected cardiac arrest. Norepinephrine dose stratification may improve risk assessment and standardization in future studies. Abbreviations ICU Intensive care unit NE norepinephrine APACHE II acute physiology and chronic health evaluation II SOFA sequential organ failure assessment AUROC area under the receiver operator curve CI confidence interval OR odds ratio SD standard deviation IQR interquartile range Declarations Clinical trial number Not applicable Human Ethics and Consent to Participate declarations This study was approved by the local ethical committee, which waived the need for an informed consent due to the retrospective nature of the study. Consent for publication Not applicable. Competing interests We declare no competing interests. Funding The authors declare no specific funding for this research Author Contribution L.A.C. conceived and designed the study and drafted the manuscript. M.P. and S.Z. contributed to the study conception, data collection, and critical revision of the manuscript. Ma.P., E.V., C.F., and S.C. contributed to data collection and revision. H.N. provided statistical support and contributed to data analysis. K.D., L.G., and F.A. contributed to critical revision of the manuscript. F.S.T. supervised the study and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Vincent JL, Jones G, David S, Olariu E, Cadwell KK: Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Critical care 2019, 23(1):196. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC et al : Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021, 47(11):1181–1247. Hernandez G, Teboul JL, Bakker J: Norepinephrine in septic shock. Intensive Care Med 2019, 45(5):687–689. Anantasit N, Boyd JH, Walley KR, Russell JA: Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock. Crit Care Med 2014, 42(8):1812–1820. Stolk RF, van der Pasch E, Naumann F, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth MM, van der Hoeven JG et al : Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis. Am J Respir Crit Care Med 2020, 202(6):830–842. Brown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, Miller RR, 3rd, Hirshberg EL, Grissom CK, Morris AH: Survival after shock requiring high-dose vasopressor therapy. Chest 2013, 143(3):664–671. Auchet T, Regnier MA, Girerd N, Levy B: Outcome of patients with septic shock and high-dose vasopressor therapy. Ann Intensive Care 2017, 7(1):43. Wieruszewski PM, Leone M, Kaas-Hansen BS, Dugar S, Legrand M, McKenzie CA, Bissell Turpin BD, Messina A, Nasa P, Schorr CA et al : Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force. Crit Care Med 2024, 52(4):521–530. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM et al : The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315(8):801–810. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985, 13(10):818–829. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996, 22(7):707–710. Rao SV, O'Donoghue ML, Ruel M, Rab T, Tamis-Holland JE, Alexander JH, Baber U, Baker H, Cohen MG, Cruz-Ruiz M et al : 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2025, 151(13):e771-e862. Fayyad UM, Irani KB: Multi-Interval Discretization of Continuous-Valued Attributes for Classification Learning. In: International Joint Conference on Artificial Intelligence : 1993; 1993. Morales S, Wendel-Garcia PD, Ibarra-Estrada M, Jung C, Castro R, Retamal J, Cortinez LI, Severino N, Kiavialaitis GE, Ospina-Tascon G et al : The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients. Critical care 2024, 28(1):216. Antonucci E, Polo T, Giovini M, Girardis M, Martin-Loeches I, Nielsen ND, Lozsan FJC, Ferrer R, Lakbar I, Leone M: Refractory septic shock and alternative wordings: A systematic review of literature. Journal of critical care 2023, 75:154258. Chotalia M, Matthews T, Arunkumar S, Bangash MN, Parekh D, Patel JM: A time-sensitive analysis of the prognostic utility of vasopressor dose in septic shock. Anaesthesia 2021, 76(10):1358–1366. Martin C, Medam S, Antonini F, Alingrin J, Haddam M, Hammad E, Meyssignac B, Vigne C, Zieleskiewicz L, Leone M: Norepinephrine: Not Too Much, Too Long. Shock 2015, 44(4):305–309. Dopp-Zemel D, Groeneveld AB: High-dose norepinephrine treatment: determinants of mortality and futility in critically ill patients. Am J Crit Care 2013, 22(1):22–32. Domizi R, Calcinaro S, Harris S, Beilstein C, Boerma C, Chiche JD, D'Egidio A, Damiani E, Donati A, Koetsier PM et al : Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation. Journal of critical care 2020, 57:185–190. Sato R, Duggal A, Sacha GL, Rudoni MA, Yataco AC, Khanna AK, Dugar S: The Relationship Between Norepinephrine Equivalent Dose of Vasopressors Within 24 Hours From the Onset of Septic Shock and In-Hospital Mortality Rate. Chest 2023, 163(1):148–151. Yamamura H, Kawazoe Y, Miyamoto K, Yamamoto T, Ohta Y, Morimoto T: Effect of norepinephrine dosage on mortality in patients with septic shock. Journal of intensive care 2018, 6:12. Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M: Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis. Am J Respir Crit Care Med 2016, 194(5):550–558. Additional Declarations No competing interests reported. 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Calabrò","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie3Rv0oDMRzA8V8I5JbgrTkC9RVSAkXp4Kskiy6HfzYHwUrguhS7VnwVh0ig0z1ApTdYhGxCXeS6iHflNonc2CHf4TeEfPgFAhCLHWBH7XgHC5DMAO+PEjxppg0S0g7VXqBlRzDqS1jem+DNVt1VV2n2ueQ3L07PMXrY1FANwoRIppb+9On58pwvvJOZQUZS8DJMKDBFnBDrfMSpdQPhUMEBnJ6ECa7VT0Peyj2hZw5NdzW4+38IYbpoyIp2WzAqmtVOBR+GyehEP3qRzXI5XtgLyRwynAo/DG1JE/Ox2n5XIk3K4frajvV8al6/6tvqOLSl+4s/iSCIxWKxWI9+ATOCU1rJr4wLAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":true,"prefix":"","firstName":"Lorenzo","middleName":"Antonino","lastName":"Calabrò","suffix":""},{"id":609969974,"identity":"a06b9a72-4011-469b-9d07-373e0b441c63","order_by":1,"name":"Marco Pasetto","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Pasetto","suffix":""},{"id":609969975,"identity":"7efd8f9a-2417-4d6c-a559-2575b0b4dde7","order_by":2,"name":"Stefano Zorzi","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Zorzi","suffix":""},{"id":609969979,"identity":"b26ce0c2-ace5-44d8-a5c4-13d6f9e6bedb","order_by":3,"name":"Martina Polato","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Polato","suffix":""},{"id":609969980,"identity":"b47389ad-b1c8-4a40-9f8b-3790f5777ac3","order_by":4,"name":"Eva Vitali","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Vitali","suffix":""},{"id":609969981,"identity":"aa0af6d3-9c19-45bb-be79-2d87f261cf4f","order_by":5,"name":"Chiara Faso","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Faso","suffix":""},{"id":609969982,"identity":"22502b27-b426-4fa9-b421-bdd7b34695fd","order_by":6,"name":"Sofia Castellani","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Castellani","suffix":""},{"id":609969983,"identity":"2dc55721-7676-4ebc-aa4a-5b18044f1eec","order_by":7,"name":"Hassane Njimi","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Hassane","middleName":"","lastName":"Njimi","suffix":""},{"id":609969984,"identity":"255ceb00-46d3-4690-8d0e-fd9c0059807f","order_by":8,"name":"Katia Donadello","email":"","orcid":"","institution":"Department of Surgery, Dentistry, Gynaecology and Paediatrics, University of Verona","correspondingAuthor":false,"prefix":"","firstName":"Katia","middleName":"","lastName":"Donadello","suffix":""},{"id":609969987,"identity":"1fa5378f-e298-4366-b1cd-22586c1b0f0e","order_by":9,"name":"Leonardo Gottin","email":"","orcid":"","institution":"Department of Surgery, Dentistry, Gynaecology and Paediatrics, University of Verona","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"","lastName":"Gottin","suffix":""},{"id":609969988,"identity":"47e2f0e1-ef80-4427-8f93-69d01635e65d","order_by":10,"name":"Filippo Annoni","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"","lastName":"Annoni","suffix":""},{"id":609969990,"identity":"4ec6cdf1-a447-4a6d-bd00-bf462ba0d835","order_by":11,"name":"Fabio Silvio Taccone","email":"","orcid":"","institution":"Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles","correspondingAuthor":false,"prefix":"","firstName":"Fabio","middleName":"Silvio","lastName":"Taccone","suffix":""}],"badges":[],"createdAt":"2026-03-03 15:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9022011/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9022011/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105564586,"identity":"7f187f44-5b0f-479d-ab7d-de796a4cc2ad","added_by":"auto","created_at":"2026-03-27 12:50:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":135468,"visible":true,"origin":"","legend":"\u003cp\u003ePredicted probability of ICU mortality and norepinephrine peak dose.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9022011/v1/a25d224d47e92d7540b50d3b.jpg"},{"id":105259490,"identity":"6cd2987c-5049-472a-bb0c-466cd701a048","added_by":"auto","created_at":"2026-03-24 05:51:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":137961,"visible":true,"origin":"","legend":"\u003cp\u003ePredicted probability of in hospital mortality and norepinephrine peak dose.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9022011/v1/970eb428cc9ecc51809d6d40.jpg"},{"id":105259494,"identity":"585c3659-9ad5-4175-b52d-e9f3bf1af390","added_by":"auto","created_at":"2026-03-24 05:51:20","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":55013,"visible":true,"origin":"","legend":"\u003cp\u003eArea under the receiver operating characteristics (AUROC) curve of norepinephrine peak dose (µg/kg*min) to predict ICU mortality.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9022011/v1/4ce248a12146c330630fca9c.jpg"},{"id":106401602,"identity":"c5f6fa0f-0a41-4eb2-8735-afbd7ef95a11","added_by":"auto","created_at":"2026-04-08 09:07:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1308821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9022011/v1/7f65e78f-074d-4f3c-88f2-fa7d649173c7.pdf"},{"id":105564615,"identity":"aef1f412-9bd9-4b47-8d53-41807499c702","added_by":"auto","created_at":"2026-03-27 12:50:12","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2119168,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial.doc","url":"https://assets-eu.researchsquare.com/files/rs-9022011/v1/7fde47edff7d9ea07a0be26e.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Relationship between norepinephrine dose and outcome in septic shock: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eSeptic shock is a leading cause of intensive care unit (ICU) admissions and a major contributor to mortality and morbidity worldwide. Despite advances in critical care, mortality rates remain high, with recent data from Europe and North America varying between 30% and 50%, depending on patient severity and regional differences [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Septic shock is characterized by profound vasodilation and impaired tissue perfusion, driven by a dysregulated host response to infection, necessitating aggressive hemodynamic support to restore cardiovascular stability and organ function [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Current management guidelines emphasize the importance of early fluid resuscitation and vasopressor therapy to achieve and maintain adequate mean arterial pressure and tissue perfusion. Norepinephrine (NE) is widely regarded as the first-line vasopressor in septic shock, due to its potent vasoconstrictive properties mediated through α-adrenergic receptors and its modest β-adrenergic activity, which supports cardiac output [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While norepinephrine is effective in reversing hypotension, its use at high doses has been associated with worse clinical outcomes, including arrhythmias, stress cardiomyopathy, peripheral ischemia and immunosuppression [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, it remains unclear whether high norepinephrine doses directly contribute to mortality due to these adverse events or merely reflect greater disease severity.\u003c/p\u003e \u003cp\u003eDefining what constitutes a \"high dose\" of NE remains a subject of debate. The literature defines high dose variably, with thresholds ranging from 0.5 \u0026micro;g/kg*min to 2 \u0026micro;g/kg*min [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This lack of unanimity reflects differences in patient populations, disease severity, and institutional practices and is compounded by the arbitrary nature of some cut-off definitions. These inconsistencies make it challenging to generalize findings and establish universally accepted thresholds, complicating the interpretation of existing evidence and highlighting the need for a clearer understanding of how dosing thresholds impact outcomes. Furthermore, NE doses are reported variously in the literature, rarely specifying the conjugated NE salt, thereby making hard to compare and interpret the available results [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we sought to evaluate the correlation between NE doses during ICU stay and patient outcomes in patients suffering from septic shock. By adjusting for baseline severity and comorbidities, we aimed to identify clinically relevant dose thresholds associated with increased risk of mortality and adverse events.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis is a retrospective cohort, single-centre study including adult (\u0026gt;\u0026thinsp;18 years of age) patients consecutively admitted to the general ICU at H\u0026ocirc;pital Universitaire de Bruxelles (HUB) in Brussels, Belgium, for septic shock between January 2016 and December 2022. Inclusion criteria were the presence of septic shock, according to standard criteria at ICU admission [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], complete available data on dose of NE, hospital length of stay, and mortality at ICU discharge. Patients undergoing mechanical circulatory support were excluded. The study protocol was approved by the local Ethical Committee (P2023-332), which waived the need for an informed consent due to the retrospective nature of the study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eDemographics, clinical, hemodynamic, and laboratory data were collected on admission, as well as severity scores, including the Acute Physiologic Assessment and Chronic Health Evaluation Scoring System II (APACHE II) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and the Sepsis-related Organ Failure Assessment (SOFA) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] scores. For each patient, the initial dose of NE, the highest dose of NE during the first 24-hours from the onset of septic shock and the peak dose during the entire observational period were collected. The peak dose and the highest 24-hour dose were recorded if administered for at least one hour. Additionally, the intervals between the various doses of NE, the time to halve the NE dose and the time to wean off NE from its highest value were calculated. Prescription of inotropes, intravenous hydrocortisone and a second-line vasopressors were also recorded. All NE doses are reported as base formulation equivalents for standardization purposes, although the NE used in our ICU corresponds to the tartrate formulation (Laboratoire Aguettant, Lyon, France).\u003c/p\u003e\n\u003ch3\u003ePrimary and secondary outcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome of this study was to identify NE dose cut-offs that are statistically associated with an increased risk of mortality in patients with septic shock, adjusted for age, APACHE II and SOFA score at patient admission. Secondary outcomes include the relationship between the NE peak dose and the development of different ischemic complications (i.e. cutaneous or soft tissue ischemia; intestinal ischemia confirmed by contrast-enhanced abdominal CT scan; acute myocardial ischemia, defined according to the European Society of Cardiology guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]; new-onset atrial fibrillation in patients without a prior history of chronic atrial fibrillation, identified by continuous ECG monitoring; unexpected cardiac arrest, defined as a cardiac arrest occurring outside the context of withdrawal of life-sustaining therapy). Data collectors performed manual revision of ICU and hospital electronic records. Anonymized data (including demographic, clinical, microbiological, biochemical, ICU and hospital outcomes) were entered into a password-protected database.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics 28 for Windows (IBM Corporation, Somers, NY). Kolmogorov-Smirnov test was used to verify the normality of continuous variables distribution. Categorical variables are presented as number (n) and percentage (%). Continuous variables are expressed as mean with standard deviation (SD) or median with interquartile range (IQR). Groups were compared using t Student test, Mann- Whitney U test, paired t test, Chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Optimal binning [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], a method used to select a binning that maximizes predictive information for a target outcome, was employed to identify NE levels based on significant changes in ICU mortality percentages. Odds ratios were adjusted for age, APACHE II and SOFA score at hospital admission. Logistic regression was used to estimate the risk of death in intensive care and in hospital in terms of the identified NE levels. Unadjusted and adjusted odds ratios (ORs, using variables being associated with mortality in the univariate analysis) along with their 95% confidence intervals (CIs) were hence calculated. Area under the receiver operating characteristics (AUROC) curve was computed and the optimal value was determined using the Youden method. All tests were two-tailed, and a p-value less than 0.05 was considered statistically significant. We performed time-dependent Cox proportional hazards models to evaluate the association between NE peak dose and secondary outcomes, including peripheral ischemia, peripheral ischemia persisting after shock resolution, intestinal ischemia, myocardial ischemia, and cardiac arrest. NE dose was included as a continuous time-dependent variable, dividing each patient\u0026rsquo;s follow-up into pre- and post-peak intervals. Death and discharge were treated as a censoring event. All models were adjusted for age and SOFA score at ICU admission, and robust standard errors were used to account for repeated intervals.\u003c/p\u003e \u003cp\u003ePotential sources of bias, including selection and information bias, were considered and minimized by consecutive patient inclusion, standardized data extraction from electronic medical records, and multivariable adjustment for disease severity. Residual confounding and treatment decision bias (e.g., withdrawal of life-sustaining therapy) could not be completely excluded. A sensitivity analysis was performed to account. Missing values were assessed for all variables before analysis. For descriptive and univariate analyses, available-case data were used. For multivariable logistic regression models, a complete-case approach was primarily applied, as the overall rate of missingness for key variables was below 10%.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eBetween 2016 and 2022, 541 patients were admitted to ICU with septic shock, 35 were excluded due to incomplete records, 506 were included in the analysis (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). The median age was 66 [55\u0026ndash;75] years, and 331 (65.4%) were male. The most frequent comorbidities were arterial hypertension (n\u0026thinsp;=\u0026thinsp;273, 54.0%), diabetes mellitus (n\u0026thinsp;=\u0026thinsp;182, 36.0%) and oncologic disease (n\u0026thinsp;=\u0026thinsp;184, 36.4%). On admission, median APACHE II and SOFA scores were 24 [19\u0026ndash;30] and 10 [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], respectively, with initial lactate levels of 3.6 [2.1\u0026ndash;6.4] mmol/L. The main source of sepsis was abdominal in 234 (46.2%) patients, followed by pulmonary in 130 (25.7%) patients and urological in 54 (10.7%) patients (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median time to antibiotic start from sepsis onset was 1 [0\u0026ndash;3] hours, 101 (20.0%) patients received antibiotic prior to ICU admission. The median length of stay in ICU was 6 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] days, while the median length of stay in hospital was 21 [10\u0026ndash;45] days. During hospitalization 301 (59.5%) patients required mechanical ventilation. The ICU mortality rate was 36.2% (n\u0026thinsp;=\u0026thinsp;183), while the hospital mortality rate was 44.5% (n\u0026thinsp;=\u0026thinsp;225); in 76 non-survivors, the cause of death was the withdrawal of life support therapies (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was a significant association between year of inclusion and in hospital mortality (p\u0026thinsp;=\u0026thinsp;0.03) with a trend toward lower mortality over time (coeff. -0.015; p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population, according to ICU mortality. Data are presented as count (%) or median (IQR).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvivors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-Survivors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;506)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;322)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (55;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (53;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (58;76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.046\u003c/b\u003e\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e331 (65,4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, Kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (63;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (64;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (60;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.96*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight, m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7 (1.62;1,78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.7 (1.62;1.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.71 (1.62;1.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.83*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, Kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.9 (22.5;29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.5 (22.5;29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.5 (22.7;30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.61*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA, m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.77 (1.46;1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.87 (1.69;2.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.88 (1.69;2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eScores at admission\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (18,8;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (17;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (22,5;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRASS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-2 (-5;0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1 (-5;0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5 (-5;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (8;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (10;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHF, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFpEF, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.95\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFrEF, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMP, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.88\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCABG/PCI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116 (22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e177 (55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCirrhosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e184 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunodeficiency, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 (25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003cem\u003e\u0026dagger;\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdmitted from\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency Department, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical ward, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64\u0026nbsp;(35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical ward, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrom another hospital, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperating room, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eBMI, body mass index; BSA, body surface area; APACHE II, Acute Physiologic Assessment and Chronic Health Evaluation II; RASS, Richmond Agitation Sedation Scale; SOFA, sequential organ failure assessment; HF, heart failure; HFpEF heart failure with preserved ejection faction; HFrEF, heart failure with reduced ejection fraction; AF, chronic atrial fibrillation; CMP, cardiomyopathy; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; LOS, length of stay; WLST, withdrawal of life support treatment; (\u0026dagger;)= Mann-Whitney test (\u0026dagger;\u0026dagger;)\u0026thinsp;=\u0026thinsp;Chi square test. (*)\u0026thinsp;=\u0026thinsp;T student test\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain outcomes. Data are presented as count (%) or median (IQR).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eAll Survivors Non-Survivors p value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU LOS (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3;10,8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (4;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (3;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.85\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital LOS (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (10;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31(16;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (3;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003cem\u003e\u0026dagger;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn ICU mortality, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e184 (36,3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn hospital mortality, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e225 (44,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWLST, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eICU= intensive care unit; LOS= length of stay; WLST= withdrawal of life support; (\u0026dagger;)= Mann-Whitney test\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eNorepinephrine and haemodynamic support\u003c/h3\u003e\n\u003cp\u003eVasopressors were initiated at ICU admission, or during surgery for patients admitted after surgery. The median NE initial dose was 0.2 [0.1\u0026ndash;0.5] \u0026micro;g/kg*min, the median NE highest dose at 24hr was 0.4 [0.2\u0026ndash;0.9] \u0026micro;g/kg*min, the median NE peak dose was 0.5 [0.2\u0026ndash;1.2] \u0026micro;g/kg*min, reached after a median of 8 [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] hours since the introduction of NE. The median time to NE halving from peak was 7 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] hours, while the median time to NE weaning from peak was 46 [27\u0026ndash;80] hours. An additional vasopressor was used in 29 (5.7%) patients (n\u0026thinsp;=\u0026thinsp;23 vasopressin, n\u0026thinsp;=\u0026thinsp;6, terlipressin). Inotropes were used in 119 (23.5%) patients (n\u0026thinsp;=\u0026thinsp;93 dobutamine, n\u0026thinsp;=\u0026thinsp;29 epinephrine), while hydrocortisone was administered in 208 (41.1%) patients (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain norepinephrine (NE) kinetics, according to ICU mortality. Data are presented as count (%) or median (IQR).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvivors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-Survivors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;506)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;322)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE initial dose, \u0026micro;g/kg*min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.2 (0.1\u0026ndash;0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1 (0.1\u0026ndash;0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3 (0.1\u0026ndash;0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE highest dose at 24hr, \u0026micro;g/kg*min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.4 (0.2\u0026ndash;0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 (0.1\u0026ndash;0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8 (0.2\u0026ndash;1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE peak dose, \u0026micro;g/kg*min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 (0.2\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 (0.2\u0026ndash;0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.1 (0.5-2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE time to peak, hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (2\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (5\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak dose to halving, hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (4\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (3\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.44\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak to weaning, hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (27\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (26\u0026ndash;76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (30\u0026ndash;134)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdjunctive therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdded vasopressors, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInotropes, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydrocortisone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e208 (41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102 (31.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePersistence of shock\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStill in shock at 24 hours, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e379 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e169 (91.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u0026dagger;\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNE, noreprinephrine (\u0026dagger;)= Mann-Whitney test (\u0026dagger;\u0026dagger;)\u0026thinsp;=\u0026thinsp;Chi square test.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePrimary Outcome\u003c/h3\u003e\n\u003cp\u003eIn ICU non-survivors, the NE initial dose and the NE peak dose were significantly higher, while the NE time to peak and the time from NE peak to NE weaning longer when compared to survivors, in unadjusted univariate analysis. NE highest dose at 24hr and NE peak dose were associated with ICU and in-hospital mortality at univariate analysis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as well as age, APACHE II and SOFA scores, history of atrial fibrillation, liver cirrhosis and diabetes. Adjusted optimal binning procedure allowed identification of four patient groups with statistically significant difference in risk of death according to NE dose. (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, SM) After excluding patients for whom a decision had been made to withdraw life-sustaining therapies, both ICU and in-hospital mortality increased across the NE peak-dose groups. (SM)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the multivariable analysis, adjusted odds ratios for ICU mortality in the 0.61 and 1.2 \u0026micro;g/kg*min and the 1.2 and 3 \u0026micro;g/kg*min groups were 1.88 [0.97\u0026ndash;3.64] and 2.55 [1.38\u0026ndash;5.57], compared to the lower ranges group, used as reference. Similar results were obtained for in-hospital mortality (9.43 [4.06\u0026ndash;21.90] and 6.21 [2.70\u0026ndash;14.30], respectively). The AUROC analysis (0.75 [0.70\u0026ndash;0.79]) identified the optimal cut-off value of 0.78 [0.7\u0026ndash;0.79] \u0026micro;g/kg*min to predict ICU mortality, with a sensitivity of 60.1% and a specificity of 75.9% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003ePeripheral ischemia occurred in 21 patients (4.2%) at a median of 3 days (IQR 2\u0026ndash;6) after shock onset and was not associated with peak NE dose (HR 1.06, 95% CI 0.91\u0026ndash;1.24; p\u0026thinsp;=\u0026thinsp;0.42), including cases persisting after shock resolution in 14 patients (2.8%) occurring at 4 days (IQR 3\u0026ndash;7) (HR 1.01, 95% CI 0.79\u0026ndash;1.28; p\u0026thinsp;=\u0026thinsp;0.92). Intestinal ischemia occurred in 12 patients (2.4%) at 5 days (IQR 3\u0026ndash;6) and was not associated with peak NE dose (HR 1.10, 95% CI 0.94\u0026ndash;1.29; p\u0026thinsp;=\u0026thinsp;0.22). Myocardial ischemia occurred in 5 patients (1.0%) early after shock onset (median 1 [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] days) and was associated with higher peak NE dose (HR 1.25, 95% CI 1.02\u0026ndash;1.54; p\u0026thinsp;=\u0026thinsp;0.04). New-onset atrial fibrillation occurred in 79 patients (15.6%) after a median of 2 ( 1\u0026ndash;4) days and was not associated with peak NE dose (HR 0.96, 95% CI 0.75\u0026ndash;1.22; p\u0026thinsp;=\u0026thinsp;0.73). Unexpected cardiac arrest occurred in 14 patients (2.8%) after a median of 3 (2\u0026ndash;8) days and was strongly associated with higher peak NE dose (HR 1.32, 95% CI 1.15\u0026ndash;1.51; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 - Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdjusted time-dependent Cox proportional hazards models between NE peak dose and secondary outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePeripheral ischemia\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDays from shock onset\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePeak NE dose \u0026micro;g/kg*min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRobust S.E.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHazard ratio (C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (4.2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.1 (0.5\u0026ndash;1.3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.06 (0.91\u0026ndash;1.24)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral ischemia persisting after shock resolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0 (0.4\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.01 (0.79\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntestinal ischemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.5\u0026ndash;1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.10 (0.94\u0026ndash;1.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyocardial ischemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.5 (0.5\u0026ndash;0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.25 (1.02\u0026ndash;1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew onset AF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.53 (0.26\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.96 (0.75\u0026ndash;1.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnexpected CA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.3\u0026ndash;2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.32 (1.15\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eNE= norepinephrine; S.E. = Standard Error; C.I.=confidence interval; AF= atrial fibrillation; CA= cardiac arrest\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this large single-center cohort of patients with septic shock, NE exposure was strongly associated with ICU and in-hospital mortality, with a clear gradient of risk across four predefined NE peak-dose ranges. Using an adjusted optimal binning approach, four dose ranges were identified, with progressively increasing and statistically different mortality rates. ICU and in-hospital mortality rose from 20.7% and 32.4% in the lowest dose range to 39.1% and 45.5% in the intermediate range, and further to 59.0% and 64.0% in the higher range, reaching 100% in patients requiring peak NE doses above 3.0 \u0026micro;g/kg/min. This stepwise increase in mortality persisted after exclusion of patients with withdrawal of life-sustaining therapies. In addition, NE peak dose demonstrated a fair discriminatory performance for ICU mortality, with an AUROC of 0.75 and an optimal threshold of 0.78 \u0026micro;g/kg/min. Both time to peak NE dose and duration of vasopressor therapy were significantly longer in patients with unfavourable outcomes. Secondary analyses showed that most ischemic complications were infrequent, with myocardial ischemia and unexpected cardiac arrest being the only events significantly associated with higher NE doses.\u003c/p\u003e \u003cp\u003eThe definition of high-dose NE varies widely across the published studies, largely due to differences in patient cohort severity, NE formulations, and resuscitation practices across institutions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In several previous studies, an NE dose of 1 \u0026micro;g/kg/min was selected a priori to define high-dose exposure, and mortality was subsequently compared between patients above and below this threshold, with reported mortality rates of 80\u0026ndash;90% in patients receiving doses exceeding 1 \u0026micro;g/kg/min. While pragmatic, this approach relies on an arbitrary cut-off that was not derived from outcome-driven analyses within the studied cohorts [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Other studies have reported 28-day mortality rates of 60\u0026ndash;65% in patients receiving high-dose NE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These outcomes are consistent with the hospital mortality rates observed in our cohort for patients receiving 1.2\u0026ndash;3.0 or \u0026gt;\u0026thinsp;3.0 \u0026micro;g/kg*min. A large multicenter study reported a mortality rate of 61.4% for patients receiving NE doses above 0.3 \u0026micro;g/kg*min [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], although this likely reflects aggregated subgroups with heterogeneous risk profiles. Sato et al. further explored the relationship between maximum NE dose at 24 hours and in-hospital mortality, but did not define a specific high-dose threshold or assess dose kinetics and related complications [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Auchet et al. evaluated outcomes in patients receiving high-dose vasopressor therapy (\u0026ge;\u0026thinsp;1 \u0026micro;g/kg/min for \u0026ge;\u0026thinsp;1 h) but focused solely on predefined thresholds without exploring dose kinetics or its association with complications [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. None of these studies specified the NE formulation used, limiting interpretability. This issue has been explicitly raised by Morales et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], who emphasized that the choice of NE formulation significantly affects the interpretation and definition of what constitutes a \u0026ldquo;high\u0026rdquo; dose. The lack of standardization and clarity regarding NE formulation limits comparability across studies and may contribute to inconsistent risk stratification. While the association between NE dose and mortality appears to be continuous rather than categorical, reliance on a single predefined threshold is insufficient to capture meaningful differences in risk. In this context, the NE dose ranges identified in our study were not arbitrarily selected but derived from an outcome-driven analysis aimed at maximizing separation between patient groups with distinct mortality risk, to provide a pragmatic framework for clinical interpretation.\u003c/p\u003e \u003cp\u003eTwo studies have reported that the total cumulative dose of NE administered during septic shock was not independently associated with mortality [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This suggests that the temporal kinetics of NE administration may be more clinically relevant than the absolute total dose. Specifically, patients who experience a rapid escalation followed by prompt de-escalation of NE therapy tend to have lower peak doses and higher survival rates compared to those with slower dose escalation and prolonged tapering. The latter pattern may reflect a more indolent, treatment-resistant, or poorly controlled septic state, characterized by persistent vasoplegia and delayed hemodynamic stabilization.\u003c/p\u003e \u003cp\u003eIn our cohort, complications traditionally associated with NE use, including peripheral ischemia, and acute intestinal ischemia, were relatively infrequent and not clearly dose-dependent. New onset atrial fibrillation occurred in 15.6% of patients, but was neither dose-dependent nor significantly associated with mortality. Unexpected cardiac arrest and myocardial ischemia arrest were observed in 14 (2.8%) and 5 (1.0%) patients respectively and were strongly associated with exposure to high NE peak doses. Our findings are generally consistent with those reported by Anantasit et al., who observed slightly lower complication rates in a comparable population [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is important to acknowledge that the overall complication rate associated with NE may be underestimated, particularly for less severe or transient events such as reversible peripheral ischemia, which are often underreported in observational studies. Overall, our data suggest that complications typically attributed to NE are relatively uncommon and, with the notable exception of cardiac arrest and myocardial ischemia, appear to be largely independent of dose. The contribution of NE mediated complications to overall mortality appears to remain limited and does not fully account for the excess mortality observed at high NE doses. These findings suggest that high-dose NE may have a less significant role as a direct contributor to poor outcomes in septic shock than previously proposed [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExperimental studies have proposed that NE may exert immunomodulatory effects, including anti-inflammatory actions that could, paradoxically, promote bacterial proliferation and worsen infection control [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the clinical relevance of these preclinical observations remains unproven. It is also possible that NE anti-inflammatory properties could confer beneficial effects, by attenuating the deleterious consequences of an excessive inflammatory response. Additionally, we observed that dobutamine was administered in 18.4% of patients in our cohort. As a beta-adrenergic agent, dobutamine may also influence the host immune response and inflammatory pathways, although its precise role in modulating outcomes in septic shock warrants further investigation.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Its single-center design may limit generalizability to institutions with different resuscitation protocols, although it also ensured greater consistency in treatment strategies and strengthened internal validity. The retrospective nature of the study may have led to underreporting of mild or transient complications, while major events are likely to have been reliably captured. Mortality patterns during the COVID-19 period may have influenced outcomes, although the overall temporal trend toward decreasing mortality remained unchanged. Time from shock onset to vasopressor initiation was not systematically recorded, representing a potential source of bias, although early vasopressor administration is routinely implemented in our institution. Finally, most patients receiving NE doses\u0026thinsp;\u0026gt;\u0026thinsp;3.0 \u0026micro;g/kg/min died following withdrawal of life-sustaining therapy, which may introduce treatment-decision bias, although sensitivity analyses were consistent with the primary results. All NE doses were reported as base formulation equivalents, limiting direct comparison with studies using other formulations.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn septic shock, increasing NE peak doses were associated with a stepwise increase in ICU and in-hospital mortality across four dose ranges. Ischemic complications were uncommon and largely independent of dose, except for myocardial ischemia and unexpected cardiac arrest. Norepinephrine dose stratification may improve risk assessment and standardization in future studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enorepinephrine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPACHE II\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute physiology and chronic health evaluation II\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSOFA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esequential organ failure assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea under the receiver operator curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cb\u003eClinical trial number\u003c/b\u003e \u003c/p\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003cp\u003e \u003cb\u003eHuman Ethics and Consent to Participate declarations\u003c/b\u003e \u003c/p\u003e \u003cp\u003e This study was approved by the local ethical committee, which waived the need for an informed consent due to the retrospective nature of the study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eWe declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors declare no specific funding for this research\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.A.C. conceived and designed the study and drafted the manuscript. M.P. and S.Z. contributed to the study conception, data collection, and critical revision of the manuscript. Ma.P., E.V., C.F., and S.C. contributed to data collection and revision. H.N. provided statistical support and contributed to data analysis. K.D., L.G., and F.A. contributed to critical revision of the manuscript. F.S.T. supervised the study and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVincent JL, Jones G, David S, Olariu E, Cadwell KK: Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. \u003cem\u003eCritical care\u003c/em\u003e 2019, 23(1):196.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC \u003cem\u003eet al\u003c/em\u003e: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. \u003cem\u003eIntensive Care Med\u003c/em\u003e 2021, 47(11):1181\u0026ndash;1247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHernandez G, Teboul JL, Bakker J: Norepinephrine in septic shock. \u003cem\u003eIntensive Care Med\u003c/em\u003e 2019, 45(5):687\u0026ndash;689.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnantasit N, Boyd JH, Walley KR, Russell JA: Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock. \u003cem\u003eCrit Care Med\u003c/em\u003e 2014, 42(8):1812\u0026ndash;1820.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStolk RF, van der Pasch E, Naumann F, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth MM, van der Hoeven JG \u003cem\u003eet al\u003c/em\u003e: Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis. \u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e 2020, 202(6):830\u0026ndash;842.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, Miller RR, 3rd, Hirshberg EL, Grissom CK, Morris AH: Survival after shock requiring high-dose vasopressor therapy. \u003cem\u003eChest\u003c/em\u003e 2013, 143(3):664\u0026ndash;671.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAuchet T, Regnier MA, Girerd N, Levy B: Outcome of patients with septic shock and high-dose vasopressor therapy. \u003cem\u003eAnn Intensive Care\u003c/em\u003e 2017, 7(1):43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWieruszewski PM, Leone M, Kaas-Hansen BS, Dugar S, Legrand M, McKenzie CA, Bissell Turpin BD, Messina A, Nasa P, Schorr CA \u003cem\u003eet al\u003c/em\u003e: Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force. \u003cem\u003eCrit Care Med\u003c/em\u003e 2024, 52(4):521\u0026ndash;530.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinger M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM \u003cem\u003eet al\u003c/em\u003e: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). \u003cem\u003eJAMA\u003c/em\u003e 2016, 315(8):801\u0026ndash;810.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. \u003cem\u003eCrit Care Med\u003c/em\u003e 1985, 13(10):818\u0026ndash;829.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. \u003cem\u003eIntensive Care Med\u003c/em\u003e 1996, 22(7):707\u0026ndash;710.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRao SV, O'Donoghue ML, Ruel M, Rab T, Tamis-Holland JE, Alexander JH, Baber U, Baker H, Cohen MG, Cruz-Ruiz M \u003cem\u003eet al\u003c/em\u003e: 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. \u003cem\u003eCirculation\u003c/em\u003e 2025, 151(13):e771-e862.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFayyad UM, Irani KB: Multi-Interval Discretization of Continuous-Valued Attributes for Classification Learning. In: \u003cem\u003eInternational Joint Conference on Artificial Intelligence\u003c/em\u003e: 1993; 1993.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorales S, Wendel-Garcia PD, Ibarra-Estrada M, Jung C, Castro R, Retamal J, Cortinez LI, Severino N, Kiavialaitis GE, Ospina-Tascon G \u003cem\u003eet al\u003c/em\u003e: The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients. \u003cem\u003eCritical care\u003c/em\u003e 2024, 28(1):216.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntonucci E, Polo T, Giovini M, Girardis M, Martin-Loeches I, Nielsen ND, Lozsan FJC, Ferrer R, Lakbar I, Leone M: Refractory septic shock and alternative wordings: A systematic review of literature. \u003cem\u003eJournal of critical care\u003c/em\u003e 2023, 75:154258.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChotalia M, Matthews T, Arunkumar S, Bangash MN, Parekh D, Patel JM: A time-sensitive analysis of the prognostic utility of vasopressor dose in septic shock. \u003cem\u003eAnaesthesia\u003c/em\u003e 2021, 76(10):1358\u0026ndash;1366.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartin C, Medam S, Antonini F, Alingrin J, Haddam M, Hammad E, Meyssignac B, Vigne C, Zieleskiewicz L, Leone M: Norepinephrine: Not Too Much, Too Long. \u003cem\u003eShock\u003c/em\u003e 2015, 44(4):305\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDopp-Zemel D, Groeneveld AB: High-dose norepinephrine treatment: determinants of mortality and futility in critically ill patients. \u003cem\u003eAm J Crit Care\u003c/em\u003e 2013, 22(1):22\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDomizi R, Calcinaro S, Harris S, Beilstein C, Boerma C, Chiche JD, D'Egidio A, Damiani E, Donati A, Koetsier PM \u003cem\u003eet al\u003c/em\u003e: Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation. \u003cem\u003eJournal of critical care\u003c/em\u003e 2020, 57:185\u0026ndash;190.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato R, Duggal A, Sacha GL, Rudoni MA, Yataco AC, Khanna AK, Dugar S: The Relationship Between Norepinephrine Equivalent Dose of Vasopressors Within 24 Hours From the Onset of Septic Shock and In-Hospital Mortality Rate. \u003cem\u003eChest\u003c/em\u003e 2023, 163(1):148\u0026ndash;151.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamamura H, Kawazoe Y, Miyamoto K, Yamamoto T, Ohta Y, Morimoto T: Effect of norepinephrine dosage on mortality in patients with septic shock. \u003cem\u003eJournal of intensive care\u003c/em\u003e 2018, 6:12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M: Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis. \u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e 2016, 194(5):550\u0026ndash;558.\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-anesthesia-analgesia-and-critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Anesthesia, Analgesia and Critical Care](https://janesthanalgcritcare.biomedcentral.com/)","snPcode":"44158","submissionUrl":"https://submission.nature.com/new-submission/44158/3","title":"Journal of Anesthesia, Analgesia and Critical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Vasopressor therapy, Mortality thresholds, Adverse events, Hemodynamic support, Dose-response relationship","lastPublishedDoi":"10.21203/rs.3.rs-9022011/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9022011/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHigh-dose norepinephrine (NE) is frequently required in septic shock, but the association of NE dose with outcome remains incompletely characterized. We aimed to evaluate the relationship between NE dosing, mortality and ischemic complications, and to identify clinically relevant NE dose ranges.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective single-center cohort study included adult patients admitted to the ICU with septic shock between 2016 and 2022. NE dosing variables, including initial dose, highest dose within 24 hours, and peak dose during ICU stay, were collected. An adjusted optimal binning approach was used to identify NE peak-dose ranges associated with ICU and in-hospital mortality. Multivariable logistic regression models were adjusted for age, APACHE II, and SOFA score at admission. Time-dependent Cox models were used to assess the association between NE peak dose and secondary ischemic outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 506 patients were included. Median NE peak dose was 0.5 [0.2\u0026ndash;1.2] \u0026micro;g/kg*min. Four NE peak-dose ranges were identified: 0.05\u0026ndash;0.6, 0.61\u0026ndash;1.2, 1.2\u0026ndash;3.0, and \u0026gt;\u0026thinsp;3.0 \u0026micro;g/kg*min. ICU and in-hospital mortality increased stepwise across these ranges, from 20.7% and 32.4% in the lowest group to 100% in patients receiving\u0026thinsp;\u0026gt;\u0026thinsp;3.0 \u0026micro;g/kg*min. This association persisted after exclusion of patients with withdrawal of life-sustaining therapies. Adjusted odds ratios for ICU mortality were 1.88 [0.97\u0026ndash;3.64] and 2.55 [1.38\u0026ndash;5.57] in the 0.61\u0026ndash;1.2 and 1.2\u0026ndash;3.0 \u0026micro;g/kg*min groups, respectively. NE peak dose showed fair discrimination for ICU mortality (Area Under the Receiver Operating Characteristic curve of 0.75), with an optimal threshold of 0.78 \u0026micro;g/kg*min. Most ischemic complications were infrequent and not dose-dependent, except for myocardial ischemia and unexpected cardiac arrest, which were significantly associated with higher NE doses.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn septic shock, increasing NE peak doses are associated with a marked, stepwise increase in ICU and in-hospital mortality across four distinct dose ranges. Ischemic complications are uncommon and largely independent of NE dose. NE dose stratification may improve risk assessment and harmonization of outcome reporting in future studies.\u003c/p\u003e","manuscriptTitle":"Relationship between norepinephrine dose and outcome in septic shock: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 05:51:13","doi":"10.21203/rs.3.rs-9022011/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-21T05:35:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T20:42:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T06:56:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-04T07:00:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225533227484987118660065818281240103258","date":"2026-03-30T21:38:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333620711004029158916817413960436338429","date":"2026-03-30T14:49:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20836175341233713107813299608189518730","date":"2026-03-30T10:49:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31714407911387084126891154284557712641","date":"2026-03-30T09:59:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23350388578850466610212778392712640248","date":"2026-03-21T19:56:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-18T13:21:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T15:25:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-16T15:25:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Anesthesia, Analgesia and Critical Care","date":"2026-03-03T15:39:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-anesthesia-analgesia-and-critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Anesthesia, Analgesia and Critical Care](https://janesthanalgcritcare.biomedcentral.com/)","snPcode":"44158","submissionUrl":"https://submission.nature.com/new-submission/44158/3","title":"Journal of Anesthesia, Analgesia and Critical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4df90797-d78b-4d84-91ff-0fa9b7413dfc","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-17T17:38:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 05:51:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9022011","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9022011","identity":"rs-9022011","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}