Norepinephrine Dose Threshold at Vasopressin Initiation and Its Association With ICU Mortality in Septic Shock

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Current recommendations rely largely on expert consensus rather than robust clinical data. Methods: We conducted a retrospective observational cohort study in a tertiary ICU from 2022–2025 to determine whether initiating vasopressin at lower NE doses is associated with improved ICU outcomes in patients with septic shock. Patients who received both NE and vasopressin were included. A random derivation subset (n = 93) was used to identify the optimal NE dose cutoff for ICU mortality by means ROC curve and Youden index. This threshold was applied to the remaining validation cohort (n = 127). Multivariable logistic regression models were used to assess ICU mortality and renal failure. Results: Of 250 eligible patients, 220 were included. The optimal NE cutoff was 0.40 μg/kg/min (AUC: 0.82; sensitivity: 62.8%, specificity: 87.3%). In the validation cohort, patients receiving vasopressin at NE doses >0.40 μg/kg/min had higher ICU mortality (80% vs. 21%, p < 0.001) and increased renal replacement therapy use (58% vs. 27%, p < 0.001). After adjustment, vasopressin initiation at NE ≤0.40 μg/kg/min was independently associated with reduced ICU mortality (OR, 0.25; 95% CI, 0.07–0.90) and lower risk of renal failure (OR, 0.37; 95% CI, 0.15–0.89), suggesting a protective effect of earlier vasopressin use. Conclusions: Initiating vasopressin at NE doses ≤0.40 μg/kg/min may be associated with improved ICU survival and reduced renal dysfunction. These findings support the use of practical NE thresholds in vasopressor management and complement recent data-driven and meta-analytic evidence. Sepsis shock Norepinephrine Arginine vasopressin Intensive care unit Dose Threshold Figures Figure 1 Figure 2 Figure 3 Introduction Septic shock remains one of the leading causes of mortality in the intensive care unit (ICU) setting. 1 Despite advances in hemodynamic support, mortality rates remain high, partly due to the complex pathophysiology and heterogeneous response to vasoactive therapies. 2 , 3 Optimizing vasopressor therapy is therefore a critical target to improve clinical outcomes. 4 Norepinephrine (NE) is the recommended first-line vasopressor in septic shock. 3 However, escalating NE doses increase the risk of adverse effects, 5 including organ dysfunction secondary to hypoperfusion and catecholamine-related toxicity. 6 To mitigate these risks, international guidelines suggest considering the addition of vasopressin when NE doses reach between 0.25 and 0.50 µg/kg/min. 3,7 This recommendation is primarily based on pathophysiological rationale and clinical consensus, rather than on direct evidence from randomized trials specifically designed to evaluate this threshold. 3 , 8 Vasopressin offers theoretical advantages as a complementary vasopressor by acting predominantly on V1a receptors, restoring vascular tone through non-adrenergic pathways, and potentially reducing catecholamine requirements. 8 , 9 Major trials, including the Vasopressin and Septic Shock Trial (VASST) 8 and the VANISH trial, 10 have evaluated vasopressin’s role in septic shock. Although neither study demonstrated an overall mortality benefit, subgroup analyses suggested that early vasopressin administration might be advantageous in patients with less severe illness. 8 Recently, a reinforcement learning model trained 11 on large observational datasets (OVISS study) proposed a more dynamic and individualized approach to vasopressor use, suggesting that earlier vasopressin initiation—at lower norepinephrine doses than typically used in practice—may be associated with improved hospital survival. 12 However, these findings are derived from simulated decision policies and require validation in real-world cohorts. Thus, an important clinical question remains unresolved: could the introducing vasopressin at lower norepinephrine doses potentially before reaching the higher thresholds currently recommended might be associated with improved clinical outcomes. 13 , 14 Specifically, it is unclear whether a threshold lower than the traditional 0.25–0.50 µg/kg/min could differentiate patient trajectories. 3 , 8 In this observational study, we analyzed a cohort of patients with septic shock treated with norepinephrine and vasopressin to evaluate whether the initiation of vasopressin at lower norepinephrine doses is associated with reduced ICU mortality. As a secondary outcome, we examined the association between norepinephrine dose and the need for renal replacement therapy (RRT) as a marker of severe organ dysfunction. This study aims to provide new evidence to an area of clinical management that remains insufficiently defined, and to complement recent algorithm-based approaches with conventional clinical analysis. Methods Study Design and Setting This study was designed as a retrospective, observational cohort study conducted in the adult intensive care unit (ICU) of a tertiary referral academic hospital with a 36-bed capacity specialized in critical care for medical and surgical patients. The study period extended from 2022 to 2025. The ICU operates a closed model with 24-hour intensivist coverage and standardized sepsis management protocols based on international guidelines. The study adhered to the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was reviewed and approved by the Hospital Gregorio Marañón Institutional Review Board (IRB). Due to the retrospective nature of the study and the use of anonymized data, the requirement for informed consent was waived. Patient Population All consecutive adult patients (aged 18 years or older) admitted to the ICU with a diagnosis of septic shock who required vasopressor support with both norepinephrine and vasopressin during their ICU stay were eligible for inclusion. Septic shock was defined according to the Sepsis-3 criteria, 2 requiring the presence of suspected or documented infection, persistent hypotension necessitating vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mmHg, and an initial serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation. 3 Patients were excluded if vasopressin was administered for indications unrelated to septic shock, such as post-cardiac arrest care or hemorrhagic shock management. Additional exclusion criteria included missing or incomplete documentation of norepinephrine dosing, as well as death occurring within the first 6 hours after vasopressor initiation, in order to minimize bias associated with patients experiencing overwhelming and non-modifiable shock trajectories. Eligible patients were identified using the ICU’s electronic medical record system, cross-referenced with pharmacy vasopressor dispensing logs to ensure comprehensive case capture and accurate identification of exposure to both norepinephrine and vasopressin. Data Collection Clinical, demographic, and treatment data were retrospectively extracted from the ICU’s electronic medical record system by two independent investigators using a standardized data collection form. Discrepancies between investigators were resolved by consensus after reviewing the source documentation. The variables collected included age, sex, comorbidities (specifically chronic kidney disease, congestive heart failure, diabetes mellitus, chronic liver disease, and immunosuppression), and the source of infection when available. Severity of illness was assessed using the Sequential Organ Failure Assessment (SOFA) score and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score at ICU admission. 15 Initial serum lactate concentration, need for invasive mechanical ventilation, and details of vasopressor therapy were also recorded, including the maximum dose of norepinephrine (expressed in µg/kg/min) and the timing and dosing of vasopressin administration. Regarding vasopressors, we recorded the time to norepinephrine initiation from the diagnosis of sepsis, the time to vasopressin initiation from the start of norepinephrine, and the time to vasopressin initiation from the diagnosis of sepsis. The antibiotic given at the start of sepsis was collected, along with whether the septic process was suitable for drainage. It was then determined if the initial antibiotic was appropriate and if the isolated germ was sensitive to that antibiotic. The implementation of the Sepsis Bundle recommended by the Surviving Sepsis Campaign was analyzed. 3 This includes measuring initial lactate, obtaining blood cultures, administering broad-spectrum antibiotics, and providing fluid resuscitation with vasopressors to achieve a mean arterial pressure (MAP) > 65 mmHg within the first hour of the sepsis bundle at the time of sepsis identification in the emergency department. The maximum norepinephrine dose was defined as the highest dose achieved within the first 48 hours of ICU admission or prior to vasopressin initiation, whichever occurred first. Regarding renal failure, from admission to the ICU until discharge, instances of renal failure were identified according to the improving global outcomes (KDIGO criteria), and this was subsequently stratified. We defined rebound hypotension as a decrease in mean arterial pressure (MAP) to < 65 mmHg within the first 6 hours following the withdrawal of vasopressin. 16 , 17 After this period, a new cause of shock was established as the underlying factor. Outcome data included ICU mortality and the requirement for renal replacement therapy (RRT) during the ICU stay, encompassing both intermittent hemodialysis and continuous renal replacement modalities. Missing data were rare (< 5% for all variables) and handled through complete case analysis. No imputation procedures were necessary. Exposure Variable To identify a clinically relevant NE dose threshold for vasopressin initiation, we used a two-step derivation–validation design. A randomly selected subsample comprising approximately 40% of the total study population (n = 93) was used to derive the optimal NE dose cutoff for predicting ICU mortality. The maximum NE dose was analyzed as a continuous variable, and a receiver operating characteristic (ROC) curve was constructed. The cutoff point associated with the highest Youden index (sensitivity + specificity − 1) was identified as the candidate threshold. This threshold was then applied to the remaining two-thirds of the cohort (validation set), where patients were stratified into two groups based on whether their maximum NE dose was above or below the derived cutoff. This stratification was used in subsequent multivariable analyses of ICU mortality and the need for renal replacement therapy. Outcomes The primary outcome of the study was ICU mortality, defined as death occurring at any point during the ICU admission prior to hospital discharge or transfer to another care facility. The secondary outcome was the need for renal replacement therapy (RRT) during the ICU stay, irrespective of modality. RRT was considered as a surrogate marker of severe acute kidney injury and overall organ dysfunction in the context of septic shock. Statistical Analysis Continuous variables were described as means with standard deviations (SD) or medians with interquartile ranges (IQR), according to their distribution assessed using the Kolmogorov-Smirnov test. Categorical variables were summarized as absolute numbers and percentages. Comparisons between groups stratified by the identified norepinephrine cutoff were performed using the student’s t-test for normally distributed continuous variables or the Mann-Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. To derive the NE dose cutoff, we conducted ROC curve analysis in the derivation subset (n = 93). The area under the ROC curve (AUC) was calculated, and the optimal threshold was determined using the Youden index. The selected cutoff was then applied to the validation cohort for outcome analysis. Multivariable logistic regression models were constructed in the validation set to evaluate the independent association between NE dose group (above vs. below the cutoff) and clinical outcomes, adjusting for age, SOFA score, APACHE II score, lactate level, and mechanical ventilation status. Model performance and robustness were assessed as previously described. Model assumptions were rigorously assessed. Linearity in the logit was verified for continuous predictors, with restricted cubic splines applied when necessary to address non-linear relationships. Multicollinearity among covariates was evaluated using the variance inflation factor (VIF), with values greater than 5 indicating significant collinearity and prompting model respecification. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test, while discrimination was evaluated through the AUC-ROC. A separate multivariable logistic regression model was constructed to explore predictors of renal replacement therapy, using the same approach and covariate selection criteria Sensitivity analyses were prespecified to confirm the robustness of the findings. These included modeling norepinephrine dose as a continuous rather than categorical predictor, testing for potential interaction effects between norepinephrine dose and markers of illness severity (SOFA score and lactate level), restricting the analysis to patients who survived more than 48 hours after vasopressor initiation to minimize immortal time bias, and conducting alternative models excluding either SOFA or APACHE II to address potential collinearity between severity scores. ICU survival was analyzed using Kaplan–Meier curves, stratified by norepinephrine dose group. Differences were assessed using the log-rank test. Time was measured from ICU admission to ICU death or discharge All statistical analyses were performed using SPSS Statistics (IBM Corp. Version 29.0 Armmonk, NY, USA) statistical significance was defined as a two-tailed p-value of less than 0.05. Results Patient Population and Baseline Characteristics A total of 250 patients were initially screened. After excluding 11 patients who received vasopressin for non-septic indications, 9 with incomplete norepinephrine dosing data, and 10 who died within 6 hours of vasopressor initiation, 220 patients were included in the final analysis (Fig. 1 ). The cohort was randomly divided into a derivation subset (n = 93), used to define the norepinephrine (NE) threshold, and a validation subset (n = 127), used for outcome analysis. The mean age of the full cohort was 62 ± 14 years, with an equal sex distribution (50.5% male). The median SOFA score at ICU admission was 10 (IQR, 7–13), and the mean APACHE II score was 22 ± 7. Respiratory infection was the most frequent source (52%), followed by abdominal (21%) and urinary (9%). Regarding the characteristics of shock, the times to initiation of vasoactive agents were recorded. Time to initiation of norepinephrine from the diagnosis of sepsis was 6 ± 9 hours, time to initiation of vasopressin from the diagnosis of sepsis was 11 ± 13 hours, and finally, the time to initiation of vasopressin after the initiation of norepinephrine was 5 ± 7 hours. Mechanical ventilation was used in 75% of cases, and renal replacement therapy (RRT) was initiated in 39%. ICU mortality was 44% (96/220). No significant differences were observed between the derivation and validation cohorts in baseline characteristics (Table 1 ). Table 1 Baseline Characteristics of the Study Population Patient characteristics Full-cohort (n = 220) Analysis-cohort (n = 93) Validation cohort (n = 127) p-value Age ± SD 62 ± 14 62 ± 14 61 ± 14 0.82 Sex 111 M / 109 F 46 M / 47 F 65 M / 62 F 0.80 I. Charlson (IQR) 2 (1–4) 3 (1–5) 2 (1–4) 0.98 Source of infection --no. (%) Respiratory 115 (52) 44 (47) 71 (55) 0.8 Abdominal 47 (21) 28 (30) 19 (15) 0.71 Urinary 20 (9) 4 (4) 16 (13) 0.60 Others 38 (19) 17 (19) 21 (17) 0.45 Clinical presentation Systolic Blood Pressure - mean (IQR) 107 (90–120) 108 (93–118) 106 (96–122) 0.79 Apache II mean 22 ± 7 22 ± 6 22 ± 7 0.31 SOFA 10 (7–13) 10 (8–13) 10 (6–13) 0.19 HOUR 1 - Bundle --no. (%) Hour 1 - Bundle (yes) 171 (78) 69 (74) 102 (80) 0.06 Lactate (yes) 214 (97) 90 (97) 124 (97) 0.64 Blood culture 211 (96) 87 (84) 124 (97) 0.54 Antibiotic onset 219 (99) 92 (99) 127 (100) 0.78 Fluid resucitation (30mL/kg) 212 (96) 90 (97) 122 (96) 0.69 Apply vasopresors if hypotensive during or after fluid resucitation --no. (%) 195 (89) 81 (87) 114 (90) 0.43 Biological results Admision Serum Lactate (mmol/L) 3.7 (2.1–6.1) 4.2 (2.2–6.6) 3.2 (2.3–6.4) 0.73 ICU Serum Lactate (mmol/L) 4.2 (2.2–6.4) 4.5 (2.3–6.3) 3.7 (1.6–6.7) 0.15 Shock related characteristics Time to initiation of norepinephrine from sepsis diagnosis. (hrs) ± SD 6 ± 9 6 ± 13 5 ± 9 0.57 Time to initiation of vasopressin from sepsis diagnosis (hrs) ± SD 11 ± 13 12 ± 16 10 ± 12 0.30 Time to initiation of vasopressin from initiation norepinephrine (hrs) ± SD 5 ± 7 6 ± 5 4 ± 6 0.22 Norepinephrine before vasopresine onset (µg/kg/min) 0,36 (0,30 − 0,60) 0,40 (0.30–0.62) 0.36 (0.30–0.60) 0.98 Corticoid at vasopressin start --no. (%) 215 (98) 92 (99) 123 (97) 0.30 Success rate (antibiotic) --no. (%) 102 (47) 45 (50) 57 (46) 0.57 Mecanical ventilation Mecanical ventilation Y-N 164 (75) 68 (76) 96 (76) 0.97 Days 5 (1–12) 7 (2–15) 4 (1–11) 0.78 Kidney failure --no. (%) No failure 42 (19) 14 (16) 18 (15) 0.66 KDIGO I 53 (24) 19 (21) 34 (28) 0.77 KDIGO II 32 (15) 13 (15) 19 (16) 0,85 KDIGO III 93 (42) 43 (48) 50 (41) 0.71 Renal replacement therapy 85 (39) 39 (42) 46 (37) 0.41 ICU Data ICU Days 10 (5–17) 11 (5–21) 9 (5–14) 0,66 Outcome --no. (%) In-ICU mortality 96 (44) 49 (43) 54 (42) 0,94 Values are presented as mean ± standard deviation, median (interquartile range), or n (%) as appropriate. Comparisons between the analysis and validation cohorts were performed using the t-test, Mann–Whitney U test, or chi-square test as appropriate. Derivation of Norepinephrine Dose Cutoff In the derivation cohort, receiver operating characteristic (ROC) curve analysis identified an optimal NE dose cutoff of 0.40 µg/kg/min for predicting ICU mortality, with an area under the curve (AUC) of [pending exact value]. The Youden index at this threshold was 0.501, corresponding to a sensitivity of 62.8% and a specificity of 87.3% (Fig. 2 ). This cutoff was used to stratify patients in the validation cohort. Figure 3 shows the Kaplan–Meier ICU survival curves stratified by norepinephrine dose survival probabilities during ICU stay for patients receiving vasopressin at norepinephrine doses ≤ 0.40 µg/kg/min; >0.40 µg/kg/min. (Log-rank test p = 0.40 µg/kg/min (n = 40) exhibited higher illness severity than those treated at ≤ 0.40 µg/kg/min (n = 87). Specifically, the high-dose group had higher APACHE II (25 ± 8 vs. 20 ± 6, p < 0.001), higher SOFA scores (12 ± 3 vs. 9 ± 4, p < 0.001), and elevated ICU lactate levels (7.7 ± 4.6 vs. 3.4 ± 2.7 mmol/L, p < 0.001). They also had lower completion rates of the Hour-1 bundle (65% vs. 88%, p < 0.001), greater mechanical ventilation use (98% vs. 66%, p < 0.001), higher rates of KDIGO stage III renal failure (67% vs. 29%), and a significantly increased RRT requirement (58% vs. 27%, p 0.40 µg/kg/min group (80% vs. 21%, p 0.4 (n = 40) p-value Age 62 ± 15 61 ± 14 0.80 Sex = M 41 (47) 24 (60) 0.17 Sex = F 46 (53) 16 (40) Charlson I. 2.9 ± 3.1 2.8 ± 2.7 0.88 Apache II 20 ± 6 25 ± 8 < 0.001 SOFA 9 ± 4 12 ± 3 < 0.001 Admision Serum Lactate (mmol/L) 3.8 ± 2.7 6.0 ± 4.5 < 0.001 ICU Serum Lactate (mmol/L) 3.4 ± 2.7 7.7 ± 4.6 < 0.001 Source of infection (respiratory) 46 (53) 25 (63) 0.82 Source of infection (abdominal) 14 (16) 5 (13) Source of infection (urinary) 12 (14) 4 (10) Source of infection (others) 15 (17) 6 (14) HOUR 1 - Bundle = Yes 76 (88) 26 (65) < 0.001 Norepinephrine before vasopresine onset (µg/kg/min) 0.31 ± 0.07 0.82 ± 0.31 < 0.001 Corticoid ( vasopresine onset) = Yes 83 (95) 40 (100) 0.16 Success rate (antibiotic) 39 (46) 18 (45) 0.92 Mecanical Ventilation = Y 57 (66) 39 (98) < 0.001 Kidney Failure = No 11 (13) 7 (18) < 0.001 Kidney Failure = KDIGO I 32 (39) 2 (5) Kidney Failure = KDIGO II 15 (18) 4 (10) Kidney Failure = KDIGO III 24 (29) 23 (67) Renal replacement therapy 23 (27) 23 (58) < 0.001 In-ICU mortality 12 (21) 28 (80% 0.40 µg/kg/min. Values are reported as mean ± SD or n (%). P-values are based on univariate comparisons. Multivariable Analysis of ICU Mortality In adjusted logistic regression analysis (Table 3 ), vasopressin initiation at a norepinephrine dose ≤ 0.40 µg/kg/min was independently associated with a lower risk of ICU mortality (OR, 0.25; 95% CI, 0.07–0.90). Additional independent predictors of ICU mortality included ICU serum lactate (OR per mmol/L, 1.42; 95% CI, 1.11–1.82) and the need for mechanical ventilation (OR, 54.99; 95% CI, 4.15–727). The model was adjusted for age, comorbidity burden (Charlson index), APACHE II score, SOFA score, corticosteroid use, Hour-1 bundle completion, and antibiotic response. No multicollinearity was detected (all variance inflation factors 0.2). Table 3 Multivariable Logistic Regression Analysis for ICU Mortality and Renal failure MULTIVARIANT ANALYSIS MORTALITY (VALIDATION COHORT) Variable Odds Ratio Confidence Interval (95%) Norepinephrine before vasopresine onset (µg/kg/min) 0.25 0.07 to 0.90 ICU Serum Lactate (mmol/L) 1.42 1.11 to 1.82 Mecanical ventilation 54.99 4.15 to 727 Renal replacement therapy 3.15 0.94 to 10.57 Age 1.04 0.99 to 1.09 Charlson I. 1.17 0.96 TO 1.42 Apache II 0.93 0.83 to 1.03 SOFA 1.02 0.84 to 1.23 HOUR 1 - Bundle 0.81 0.18 to 3.62 Corticoid ( vasopresine onset) = Yes 1.07 0.05 to 22.55 Success rate (antibiotic) 2.63 0.79 to 8.7 MULTIVARIANT ANALYSIS (VALIDATION COHORT) Renal failure Norepinephrine before vasopresine onset (µg/kg/min) 0.37 0.15 to 0.39 ICU Serum Lactate (mmol/L) 1.09 0.96 to 1.24 Age 1.03 0.98 to 1.29 I. Charlson 1.12 0.97 to 1.29 Apache II 1.03 0.97 to 1.09 HOUR 1 - Bundle 1.61 0.56 to 4.61 Adjusted odds ratios (aOR) with 95% confidence intervals are presented. Variables included in the model were selected a priori based on clinical relevance. Multivariable Analysis of Renal Failure In a separate logistic regression model evaluating the development of moderate to severe renal failure (KDIGO stages II–III), vasopressin initiation at a norepinephrine dose ≤ 0.40 µg/kg/min remained independently associated with reduced risk (OR, 0.37; 95% CI, 0.15–0.89) (Table 3 ). Other covariates, including ICU lactate, age, APACHE II score, and Hour-1 bundle completion, were not independently associated with renal failure. Adverse Events Adverse events were uncommon and evenly distributed across groups. Atrial fibrillation occurred in 7% of the full cohort, mesenteric ischemia in 3%, and digital ischemia in 1%. Rebound hypotension was reported in 16% of patients overall, with no significant differences between NE dose groups. No cases of severe hyponatremia were observed (Table 4 ). Table 4 Complications Adverse events --no. (%) Full-cohort (n = 220) NAD ≤ 0.4 (n = 87) NAD > 0.4 (n = 40) p-value Atrial fibrillation 15 (7) 6 (7) 3 (8) > 0.05 Mesenteric ischemia 6 (3) 2 (2) 1 (2) Severe hyponatremia 0 (0) 0 (0) 0 (0) Rebound hypotension 35 (16) 14 (16) 6 (15) Digital ischemia 3 (1) 1 (1) 2 (5) It was determined as a cause of severe adverse effect (atrial fibrillation, mesenteric ischemia, digital ischemia) if it was newly onset from the initiation of vasopressin up to 6 hours thereafter. It was defined as severe hyponatremia severe < 125 mmo/L We defined rebound hypotension as a decrease in mean arterial pressure (MAP) to < 65 mmHg within the first 6 hours following the withdrawal of vasopressin. Discussion In this retrospective cohort study of patients with septic shock treated with norepinephrine and vasopressin, we found that initiating vasopressin at a norepinephrine dose lower than 0.40 µg/kg/min was independently associated with a significant reduction in ICU mortality. This association remained robust after adjustment for key confounders and was consistent across sensitivity analyses. Additionally, patients receiving vasopressin at lower norepinephrine doses showed a significantly lower rate of renal replacement therapy, suggesting a possible association with reduced progression to severe acute kidney injury. Initiating vasopressin at norepinephrine doses ≤ 0.40 µg/kg/min was independently associated with a lower risk of developing moderate-to-severe acute kidney injury (KDIGO stages II–III), supporting its potential role in renal protection during septic shock. Our study adds to the growing body of literature addressing the optimal timing of vasopressin initiation in septic shock. 13 Current international guidelines recommend considering vasopressin when norepinephrine doses range between 0.25 and 0.50 µg/kg/min 3 . This recommendation, while widely followed, is largely based on expert opinion and consensus rather than on robust clinical evidence. 18 Seminal randomized trials such as VASST and VANISH failed to show a mortality benefit of vasopressin overall, but both suggested potential advantages in subgroups with lower lactate levels or milder disease severity. 8 , 10 , 19 An additional consideration relates to the timing of vasopressor initiation. 20 , 21 In our cohort, norepinephrine was typically initiated early, in alignment with current guidelines, and vasopressin was added after a median time of 6 hours. 22 Although our primary analysis focused on norepinephrine dose thresholds, future studies should explore the interplay between time to vasopressin initiation and patient outcomes. 18 Temporal dynamics may be particularly relevant in the early hours of shock resuscitation, when vasopressor responsiveness and catecholamine sensitivity may vary significantly. 23 Recent data reinforce the idea that earlier initiation of vasopressin may be beneficial. In a large analysis from the MIMIC-III and IV databases, Xu et al. found that vasopressin administration at norepinephrine doses below 0.25 µg/kg/min was associated with significantly lower 28-day mortality (OR 0.66, 95% CI 0.52–0.84). 14 These results are consistent with our identified cutoff of 0.40 µg/kg/min and support the clinical plausibility of using this threshold to guide therapy. In addition, our results echo those of Sacha et al., who demonstrated that lower norepinephrine-equivalent doses at vasopressin initiation were associated with improved survival. 13 Specifically, initiation at 10 µg/min was associated with lower mortality than initiation at 25 or 60 µg/min, and early use was also associated with lower lactate levels and a more favorable hemodynamic profile. 13 , 24 The data from the OVISS study reinforce our findings. The reinforcement-trained model indicated that more vasopressin should have been used in 87% of cases 20 . Additionally, the model estimated that the optimal time to initiate vasopressin, based on norepinephrine dosage, was around 0.25–0.35 µg/kg/min across various databases, further supporting our results. 12 The physiological rationale for early vasopressin use includes its non-adrenergic mechanism of action via V1 receptors, catecholamine-sparing effects, and the potential to attenuate the inflammatory response without promoting adrenergic receptor downregulation. 25 – 27 Guerci et al. further emphasize that excessive catecholamine exposure can be inherently toxic, promoting organ dysfunction and mortality. 18 , 28 The potential mechanisms underlying the observed reduction in ICU mortality with earlier vasopressin initiation are likely multifactorial and rooted in the complex pathophysiology of septic shock. 29 , 30 One plausible explanation is the reduction of cumulative catecholamine exposure, which is associated with deleterious effects such as increased myocardial oxygen consumption, arrhythmogenesis, immunosuppression, and impaired microcirculatory flow. 22 , 31 Initiating vasopressin at lower norepinephrine doses may prevent the need for further catecholamine escalation, thereby mitigating these toxic effects. 32 Vasopressin’s mechanism of action through V1a receptor–mediated vasoconstriction provides non-adrenergic restoration of vascular tone, which may be particularly effective in the vasodilatory state of septic shock where endogenous vasopressin depletion is common. 19 By acting synergistically with norepinephrine, vasopressin may also enhance mean arterial pressure with lower catecholamine doses, leading to earlier hemodynamic stabilization. 10 Moreover, experimental and clinical studies have suggested that vasopressin may exert beneficial effects on renal perfusion and microcirculatory flow, particularly in early or moderate stages of shock. 26 , 33 These hemodynamic advantages may help prevent progression to multiple organ dysfunction, potentially explaining the observed trends toward reduced renal replacement therapy in patients receiving vasopressin at lower norepinephrine thresholds. 34 Importantly, the subgroup analysis of the VASST trial showed a mortality benefit in patients with less severe shock (lactate < 1.4 mmol/L), which aligns with our findings suggesting greater benefit among patients who required lower norepinephrine doses at the time of vasopressin initiation(7). 8 These converging lines of evidence support the hypothesis that timing and patient selection are critical variables that determine the effectiveness of adjunctive vasopressin therapy. 23 From a clinical perspective, our identification of a norepinephrine threshold associated with improved survival offers a practical decision point that could enhance the consistency of vasopressor management. This is especially relevant in light of the considerable variability in vasopressin use observed across institutions, partly driven by differences in how norepinephrine dose is reported (e.g., base vs. tartrate). Nevertheless, several limitations must be acknowledged. First, as an observational study, causality cannot be definitively established, and residual confounding may persist despite multivariable adjustment. Second, the study was conducted in a single tertiary center, which may limit the generalizability of our findings. Third, although we used an internal derivation-validation approach to determine and test the norepinephrine cutoff, the threshold was still developed within a single dataset and requires external validation in independent populations. Fourth, the overall sample size, while sufficient for primary analyses, may limit statistical power for detecting small effects or conducting detailed subgroup evaluations. Finally, we did not evaluate long-term outcomes beyond ICU discharge, to summarize, our findings suggest that initiating vasopressin at norepinephrine doses below 0.40 µg/kg/min may be associated with better ICU outcomes in patients with septic shock. This threshold is both physiologically plausible and supported by prior observational and modeling studies. Further randomized controlled trials are warranted to validate this approach and to integrate early vasopressin use into personalized sepsis care protocols. Finally, we did not evaluate long-term outcomes beyond ICU discharge, such as hospital or 90-day mortality, renal recovery, or quality of life. While ICU mortality remains a relevant and immediate endpoint in septic shock, future studies should assess the sustained impact of vasopressor strategies on patient-centered outcomes. In conclusion, our findings suggest that early initiation of vasopressin at lower norepinephrine doses may be associated with improved survival in patients with septic shock. These results support a strategy of timely adjunctive vasopressor therapy and highlight the need for prospective studies to confirm the benefits of early vasopressin initiation and to define its role within protocolized, individualized hemodynamic management. Abbreviations NE Norepinephrine ICU Intensive care unit MAP Mean arterial pressure RRT Renal replacement therapy SOFA Sequential organ failure assessment APACHE IV Acute physiological chronic health evaluation SD Standard deviation IQR Interquartile range ROC Receiver operating curve OR Odd’s ratio aOR Adjusted ood’s ratio AUC Area under the curve CI Confidence Declarations Acknowledgements They would also like to thank Mateo Cedeño and Jose Cedeño for their continuous drive to create. Autor contributions Conception and design: Jamil Cedeño, Pablo García-Olivares, Galo Castañeda, Javier Muñoz; recruitment of subjects and data curation: Jamil Cedeño, Pablo García-Olivares, Galo Castañeda, Carlos Ramírez, Arturo Rodriguez, Javier Muñoz; data analysis and interpretation: Jamil Cedeño, Pablo García-Olivares and Javier Muñoz; drafting the manuscript: Jamil Cedeño, Pablo García-Olivares and Javier Muñoz; revision of the manuscript: Jamil Cedeño, Pablo García-Olivares, Galo Castañeda, Carlos Ramírez, Arturo Rodriguez, Javier Muñoz. Principal investigator role: Jamil Cedeño. All authors read and approved the final manuscript. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The study received approval from the Ethics Committee of Gregorio Marañón Hospital in January 2022. The exemption from informed consent for the study was accepted. Funding This investigator-initiated retrospective cohort study was supported by an unrestricted grant from AOP Orphan Pharmaceuticals GmbH, a member of the AOP Health Group, Vienna, Austria. AOP had no involvement in the study’s conceptualization, design, data collection, analysis, or manuscript preparation. Competing interests Jamil Cedeño reported receiving honoraria and travel expenses from AOP Pharma. The other authors have nothing to declare. References Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019— results from a systematic review and meta-analysis. Crit Care . 2020;24(1):239. doi:10.1186/s13054-020-02950-2 Singer M, Deutschman C, Seymour C, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA . 2016;315(8):801-810. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med . 2021;47(11):1181-1247. De Backer D, Cecconi M, Chew MS, et al. A plea for personalization of the hemodynamic management of septic shock. Crit Care Lond Engl . 2022;26(1):372. doi:10.1186/s13054-022-04255-y Wieruszewski ED, Jones GM, Samarin MJ, Kimmons LA. Predictors of dysrhythmias with norepinephrine use in septic shock. J Crit Care . 2021;61:133-137. doi:10.1016/j.jcrc.2020.10.023 Dünser M, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med . 2009;35(7):1225-1233. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med . 2017;45(3):486-552. Russell J, Walley K, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med . 2008;358(9):877-887. Dünser MW, Lindner KH, Wenzel V. A Century of Arginine Vasopressin Research Leading to New Therapeutic Strategies. Anesthesiology . 2006;105(3):444-445. doi:10.1097/00000542-200609000-00004 Gordon A, Mason A, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA . 2016;316(5):509-518. Hu M, Zhang J, Matkovic L, Liu T, Yang X. Reinforcement learning in medical image analysis: Concepts, applications, challenges, and future directions. J Appl Clin Med Phys . 2023;24(2):e13898. doi:10.1002/acm2.13898 Kalimouttou A, Kennedy JN, Feng J, et al. Optimal Vasopressin Initiation in Septic Shock: The OVISS Reinforcement Learning Study. JAMA . 2025;333(19):1688. doi:10.1001/jama.2025.3046 Sacha G, Lam S, Duggal A, et al. Association of norepinephrine dose at vasopressin initiation with septic shock outcomes: a systematic review and meta-analysis. Pharmacotherapy . 2023;43(7):473-486. Xu J, Liu B, Wu Z, et al. Timing of vasopressin initiation and mortality in septic shock: a retrospective cohort study using the MIMIC-IV and MIMIC-III databases. Crit Care . 2023;27(1):5. Vincent JL, Moreno R. Clinical review: Scoring systems in the critically ill. Crit Care . 2010;14(2):207. doi:10.1186/cc8204 Sacha GL, Lam SW, Duggal A, Torbic H, Reddy AJ, Bauer SR. Hypotension Risk Based on Vasoactive Agent Discontinuation Order in Patients in the Recovery Phase of Septic Shock. Pharmacother J Hum Pharmacol Drug Ther . 2018;38(3):319-326. doi:10.1002/phar.2082 Hammond DA, Sacha GL, Bissell BD, et al. Effects of Norepinephrine and Vasopressin Discontinuation Order in the Recovery Phase of Septic Shock: A Systematic Review and Individual Patient Data Meta‐Analysis. Pharmacother J Hum Pharmacol Drug Ther . 2019;39(5):544-552. doi:10.1002/phar.2265 Guerci P, Belveyre T, Mongardon N, Novy E. When to start vasopressin in septic shock: the strategy we propose. Crit Care . 2022;26(1):125. doi:10.1186/s13054-022-04001-4 Russell J. Vasopressin in Septic Shock. Crit Care Med . 2019;47(8):1097-1105. Hwang Y, Mahajan A, Li X, et al. Optimal Timing of Vasopressin Initiation in Septic Shock Using Reinforcement Learning. JAMA . 2024;331(5):456-466. Hamzaoui O, Goury A, Teboul JL. The Eight Unanswered and Answered Questions about the Use of Vasopressors in Septic Shock. J Clin Med . 2023;12(14). doi:10.3390/jcm12144589 Hamzaoui O, Teboul J. Importance of vasopressor load and catecholamine-sparing strategies in septic shock. Crit Care . 2019;23(1):259. Melchers M, De Smet V, Rooijakkers C, et al. Hemodynamic effects of adjunct arginine vasopressin to norepinephrine in septic shock: insights from a prospective multicenter registry study. Ann Intensive Care . 2025;15(1):59. doi:10.1186/s13613-025-01472-w Kotani Y, Di Gioia A, Landoni G, Belletti A, Khanna AK. An updated “norepinephrine equivalent” score in intensive care as a marker of shock severity. Crit Care . 2023;27(1):29. doi:10.1186/s13054-023-04322-y Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of Vasopressin Relevant to Management of Septic Shock. Chest . 2001;120(3):989-1002. doi:10.1378/chest.120.3.989 Holmes C, Walley K. Vasopressin in the ICU: physiology, clinical evidence and future directions. Curr Opin Crit Care . 2009;15(5):417-423. Landry DW, Levin HR, Gallant EM, et al. Vasopressin Deficiency Contributes to the Vasodilation of Septic Shock. Circulation . 1997;95(5):1122-1125. doi:10.1161/01.CIR.95.5.1122 Guerci P, Biason L, Delemazure J, et al. Association Between Vasopressor Load and Mortality in Patients With Septic Shock. Crit Care Explor . 2022;4(5):e0677. Ragoonanan D, Nickelsen P, Tran N, et al. Vasopressin Initiation as a Second-Line VasoP ressor in Early Septic S hock (VISPSS). J Intensive Care Med . 2024;39(4):306-312. doi:10.1177/08850666231201364 Sacha GL, Lam SW, Duggal A, et al. Predictors of response to fixed-dose vasopressin in adult patients with septic shock. Ann Intensive Care . 2018;8(1):35. doi:10.1186/s13613-018-0379-5 Dünser MW, Ruokonen E, Pettilä V, et al. Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Crit Care . 2009;13(6):R181. doi:10.1186/cc8167 Brask AL, Shemanski SM, Barnes TE, Holmes AK. Timing of Vasopressin Addition to Norepinephrine and Efficacy Outcomes in Patients With Septic Shock. Ann Pharmacother . 2023;57(5):521-526. doi:10.1177/10600280221118903 Liu Z, Chen J, Kou Q, et al. Effect of vasopressin in septic shock patients with normal or elevated cardiac output: a systematic review and meta-analysis. Shock . 2012;38(5):478-483. Nagendran M, Russell JA, Walley KR, et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med . 2019;45(6):844-855. doi:10.1007/s00134-019-05620-2 Additional Declarations No competing interests reported. Supplementary Files GraphicalAbstract.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6809611","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470692947,"identity":"d8e6bd6d-64ac-4b8a-a0b2-2846de1d426e","order_by":0,"name":"Jamil Antonio Cedeño","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYHACAyBmY2BgZm58AGTx8JGghbEZxOJhI1ILCDC2STBAdOMH/O3NGx8XVPDJ67YztlV+qdkmw8bA/PDRDTxaJM4cKzaecYbNcNthxrbbMsduAx3GZmycg89VEjlm0rxtbIxgLRJsIC08bNJ4tci/Mf8N1GIP0lIs8Y8YLRI8ZsxALYkgLYwf24jQInEmrVia5wxbMlBLszRjH1ALMwG/8Lcf3viZp+KY7bbzhw9+/PHttj0/e/PDx/i0QMExMMnMAyYJKweBGjDJ+IM41aNgFIyCUTDCAAAyg0RwfoS9eQAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":true,"prefix":"","firstName":"Jamil","middleName":"Antonio","lastName":"Cedeño","suffix":""},{"id":470692948,"identity":"868c93b0-b836-4dd1-9ac4-1b89046ae33d","order_by":1,"name":"Pablo García-Olivares","email":"","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"García-Olivares","suffix":""},{"id":470692949,"identity":"e5f206e2-3352-45ce-8671-832e7a840cff","order_by":2,"name":"Galo Francisco Castañeda","email":"","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Galo","middleName":"Francisco","lastName":"Castañeda","suffix":""},{"id":470692950,"identity":"57aa29e4-b95f-4974-8b17-77c7c3da914c","order_by":3,"name":"Carlos Ramiro Ramírez","email":"","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Ramiro","lastName":"Ramírez","suffix":""},{"id":470692951,"identity":"e6ec0b7c-9447-4f33-806a-b6a50c6a06d6","order_by":4,"name":"Arturo Rodríguez-Pérez","email":"","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Arturo","middleName":"","lastName":"Rodríguez-Pérez","suffix":""},{"id":470692952,"identity":"234e6936-2dc1-4939-8ab6-5e3b41b7c876","order_by":5,"name":"Javier Muñoz","email":"","orcid":"","institution":"Hospital General Universitario Gregrorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Javier","middleName":"","lastName":"Muñoz","suffix":""}],"badges":[],"createdAt":"2025-06-03 09:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6809611/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6809611/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84821852,"identity":"889a17e0-0ee0-46ee-b171-2d5c282af642","added_by":"auto","created_at":"2025-06-17 16:15:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73256,"visible":true,"origin":"","legend":"\u003cp\u003ePatient Flow Diagram\u003c/p\u003e\n\u003cp\u003eFlow chart illustrating inclusion and exclusion of patients, and random allocation into derivation\u003c/p\u003e\n\u003cp\u003eand validation cohorts. The study was conducted in a single tertiary ICU between 2022 and\u003c/p\u003e\n\u003cp\u003e2024.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6809611/v1/de99b5e9d882b2d1ee75bd44.png"},{"id":84820318,"identity":"4d3f1d61-6bd8-4359-ab7e-140d7c9a7fb3","added_by":"auto","created_at":"2025-06-17 16:07:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48371,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver Operating Characteristic (ROC) Curve for Norepinephrine Dose\u003c/p\u003e\n\u003cp\u003ePredicting ICU Mortality (Derivation Cohort)\u003c/p\u003e\n\u003cp\u003eThe ROC curve shows the performance of norepinephrine dose in predicting ICU mortality. The\u003c/p\u003e\n\u003cp\u003eoptimal threshold (0.40 μg/kg/min) was determined using the maximum Youden index (0.501),\u003c/p\u003e\n\u003cp\u003ecorresponding to a sensitivity of 62.8% and specificity of 87.3%. AUC: area under the curve.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6809611/v1/781e610d54a43c577b1c1890.png"},{"id":84820320,"identity":"ca894a00-fe31-4829-8c61-c49752523bf1","added_by":"auto","created_at":"2025-06-17 16:07:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43782,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier ICU Survival Curves Stratified by Norepinephrine Dose\u003c/p\u003e\n\u003cp\u003eSurvival probabilities during ICU stay for patients receiving vasopressin at norepinephrine\u003c/p\u003e\n\u003cp\u003edoses ≤0.40 μg/kg/min ; \u0026gt;0.40 μg/kg/min. Log-rank test p = \u0026lt; 0.01\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6809611/v1/2dfa319c7fdd45113f10d48e.png"},{"id":85360624,"identity":"8115a3c3-8bdb-48fc-b8f9-87ef3e1f3370","added_by":"auto","created_at":"2025-06-25 06:01:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1359126,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6809611/v1/e55f28af-cc31-4016-89d0-716b76c8e826.pdf"},{"id":84819421,"identity":"3bf65c76-aaa3-40ed-9022-b8db2cc0659b","added_by":"auto","created_at":"2025-06-17 15:59:25","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":313566,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-6809611/v1/a2fe912a9125d35e97f6c5ac.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Norepinephrine Dose Threshold at Vasopressin Initiation and Its Association With ICU Mortality in Septic Shock","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSeptic shock remains one of the leading causes of mortality in the intensive care unit (ICU) setting.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Despite advances in hemodynamic support, mortality rates remain high, partly due to the complex pathophysiology and heterogeneous response to vasoactive therapies.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Optimizing vasopressor therapy is therefore a critical target to improve clinical outcomes.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNorepinephrine (NE) is the recommended first-line vasopressor in septic shock.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, escalating NE doses increase the risk of adverse effects,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e including organ dysfunction secondary to hypoperfusion and catecholamine-related toxicity.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e To mitigate these risks, international guidelines suggest considering the addition of vasopressin when NE doses reach between 0.25 and 0.50 \u0026micro;g/kg/min.\u003csup\u003e3,7\u003c/sup\u003e This recommendation is primarily based on pathophysiological rationale and clinical consensus, rather than on direct evidence from randomized trials specifically designed to evaluate this threshold.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVasopressin offers theoretical advantages as a complementary vasopressor by acting predominantly on V1a receptors, restoring vascular tone through non-adrenergic pathways, and potentially reducing catecholamine requirements.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Major trials, including the Vasopressin and Septic Shock Trial (VASST)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e and the VANISH trial,\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e have evaluated vasopressin\u0026rsquo;s role in septic shock. Although neither study demonstrated an overall mortality benefit, subgroup analyses suggested that early vasopressin administration might be advantageous in patients with less severe illness.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecently, a reinforcement learning model trained\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e on large observational datasets (OVISS study) proposed a more dynamic and individualized approach to vasopressor use, suggesting that earlier vasopressin initiation\u0026mdash;at lower norepinephrine doses than typically used in practice\u0026mdash;may be associated with improved hospital survival.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, these findings are derived from simulated decision policies and require validation in real-world cohorts.\u003c/p\u003e \u003cp\u003eThus, an important clinical question remains unresolved: could the introducing vasopressin at lower norepinephrine doses potentially before reaching the higher thresholds currently recommended might be associated with improved clinical outcomes.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Specifically, it is unclear whether a threshold lower than the traditional 0.25\u0026ndash;0.50 \u0026micro;g/kg/min could differentiate patient trajectories.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this observational study, we analyzed a cohort of patients with septic shock treated with norepinephrine and vasopressin to evaluate whether the initiation of vasopressin at lower norepinephrine doses is associated with reduced ICU mortality. As a secondary outcome, we examined the association between norepinephrine dose and the need for renal replacement therapy (RRT) as a marker of severe organ dysfunction. This study aims to provide new evidence to an area of clinical management that remains insufficiently defined, and to complement recent algorithm-based approaches with conventional clinical analysis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003e This study was designed as a retrospective, observational cohort study conducted in the adult intensive care unit (ICU) of a tertiary referral academic hospital with a 36-bed capacity specialized in critical care for medical and surgical patients. The study period extended from 2022 to 2025. The ICU operates a closed model with 24-hour intensivist coverage and standardized sepsis management protocols based on international guidelines.\u003c/p\u003e \u003cp\u003e The study adhered to the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was reviewed and approved by the Hospital Gregorio Mara\u0026ntilde;\u0026oacute;n Institutional Review Board (IRB). Due to the retrospective nature of the study and the use of anonymized data, the requirement for informed consent was waived.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient Population\u003c/h3\u003e\n\u003cp\u003eAll consecutive adult patients (aged 18 years or older) admitted to the ICU with a diagnosis of septic shock who required vasopressor support with both norepinephrine and vasopressin during their ICU stay were eligible for inclusion. Septic shock was defined according to the Sepsis-3 criteria,\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e requiring the presence of suspected or documented infection, persistent hypotension necessitating vasopressors to maintain a mean arterial pressure (MAP)\u0026thinsp;\u0026ge;\u0026thinsp;65 mmHg, and an initial serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePatients were excluded if vasopressin was administered for indications unrelated to septic shock, such as post-cardiac arrest care or hemorrhagic shock management. Additional exclusion criteria included missing or incomplete documentation of norepinephrine dosing, as well as death occurring within the first 6 hours after vasopressor initiation, in order to minimize bias associated with patients experiencing overwhelming and non-modifiable shock trajectories.\u003c/p\u003e \u003cp\u003eEligible patients were identified using the ICU\u0026rsquo;s electronic medical record system, cross-referenced with pharmacy vasopressor dispensing logs to ensure comprehensive case capture and accurate identification of exposure to both norepinephrine and vasopressin.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eClinical, demographic, and treatment data were retrospectively extracted from the ICU\u0026rsquo;s electronic medical record system by two independent investigators using a standardized data collection form. Discrepancies between investigators were resolved by consensus after reviewing the source documentation.\u003c/p\u003e \u003cp\u003eThe variables collected included age, sex, comorbidities (specifically chronic kidney disease, congestive heart failure, diabetes mellitus, chronic liver disease, and immunosuppression), and the source of infection when available. Severity of illness was assessed using the Sequential Organ Failure Assessment (SOFA) score and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score at ICU admission.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Initial serum lactate concentration, need for invasive mechanical ventilation, and details of vasopressor therapy were also recorded, including the maximum dose of norepinephrine (expressed in \u0026micro;g/kg/min) and the timing and dosing of vasopressin administration. Regarding vasopressors, we recorded the time to norepinephrine initiation from the diagnosis of sepsis, the time to vasopressin initiation from the start of norepinephrine, and the time to vasopressin initiation from the diagnosis of sepsis.\u003c/p\u003e \u003cp\u003eThe antibiotic given at the start of sepsis was collected, along with whether the septic process was suitable for drainage. It was then determined if the initial antibiotic was appropriate and if the isolated germ was sensitive to that antibiotic.\u003c/p\u003e \u003cp\u003eThe implementation of the Sepsis Bundle recommended by the Surviving Sepsis Campaign was analyzed.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e This includes measuring initial lactate, obtaining blood cultures, administering broad-spectrum antibiotics, and providing fluid resuscitation with vasopressors to achieve a mean arterial pressure (MAP)\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg within the first hour of the sepsis bundle at the time of sepsis identification in the emergency department.\u003c/p\u003e \u003cp\u003eThe maximum norepinephrine dose was defined as the highest dose achieved within the first 48 hours of ICU admission or prior to vasopressin initiation, whichever occurred first.\u003c/p\u003e \u003cp\u003eRegarding renal failure, from admission to the ICU until discharge, instances of renal failure were identified according to the improving global outcomes (KDIGO criteria), and this was subsequently stratified.\u003c/p\u003e \u003cp\u003eWe defined rebound hypotension as a decrease in mean arterial pressure (MAP) to \u0026lt;\u0026thinsp;65 mmHg within the first 6 hours following the withdrawal of vasopressin.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e After this period, a new cause of shock was established as the underlying factor.\u003c/p\u003e \u003cp\u003eOutcome data included ICU mortality and the requirement for renal replacement therapy (RRT) during the ICU stay, encompassing both intermittent hemodialysis and continuous renal replacement modalities.\u003c/p\u003e \u003cp\u003eMissing data were rare (\u0026lt;\u0026thinsp;5% for all variables) and handled through complete case analysis. No imputation procedures were necessary.\u003c/p\u003e\n\u003ch3\u003eExposure Variable\u003c/h3\u003e\n\u003cp\u003eTo identify a clinically relevant NE dose threshold for vasopressin initiation, we used a two-step derivation\u0026ndash;validation design. A randomly selected subsample comprising approximately 40% of the total study population (n\u0026thinsp;=\u0026thinsp;93) was used to derive the optimal NE dose cutoff for predicting ICU mortality. The maximum NE dose was analyzed as a continuous variable, and a receiver operating characteristic (ROC) curve was constructed. The cutoff point associated with the highest Youden index (sensitivity\u0026thinsp;+\u0026thinsp;specificity\u0026thinsp;\u0026minus;\u0026thinsp;1) was identified as the candidate threshold.\u003c/p\u003e \u003cp\u003eThis threshold was then applied to the remaining two-thirds of the cohort (validation set), where patients were stratified into two groups based on whether their maximum NE dose was above or below the derived cutoff. This stratification was used in subsequent multivariable analyses of ICU mortality and the need for renal replacement therapy.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome of the study was ICU mortality, defined as death occurring at any point during the ICU admission prior to hospital discharge or transfer to another care facility.\u003c/p\u003e \u003cp\u003eThe secondary outcome was the need for renal replacement therapy (RRT) during the ICU stay, irrespective of modality. RRT was considered as a surrogate marker of severe acute kidney injury and overall organ dysfunction in the context of septic shock.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were described as means with standard deviations (SD) or medians with interquartile ranges (IQR), according to their distribution assessed using the Kolmogorov-Smirnov test. Categorical variables were summarized as absolute numbers and percentages. Comparisons between groups stratified by the identified norepinephrine cutoff were performed using the student\u0026rsquo;s t-test for normally distributed continuous variables or the Mann-Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate.\u003c/p\u003e \u003cp\u003eTo derive the NE dose cutoff, we conducted ROC curve analysis in the derivation subset (n\u0026thinsp;=\u0026thinsp;93). The area under the ROC curve (AUC) was calculated, and the optimal threshold was determined using the Youden index. The selected cutoff was then applied to the validation cohort for outcome analysis. Multivariable logistic regression models were constructed in the validation set to evaluate the independent association between NE dose group (above vs. below the cutoff) and clinical outcomes, adjusting for age, SOFA score, APACHE II score, lactate level, and mechanical ventilation status. Model performance and robustness were assessed as previously described.\u003c/p\u003e \u003cp\u003eModel assumptions were rigorously assessed. Linearity in the logit was verified for continuous predictors, with restricted cubic splines applied when necessary to address non-linear relationships. Multicollinearity among covariates was evaluated using the variance inflation factor (VIF), with values greater than 5 indicating significant collinearity and prompting model respecification. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test, while discrimination was evaluated through the AUC-ROC. A separate multivariable logistic regression model was constructed to explore predictors of renal replacement therapy, using the same approach and covariate selection criteria\u003c/p\u003e \u003cp\u003eSensitivity analyses were prespecified to confirm the robustness of the findings. These included modeling norepinephrine dose as a continuous rather than categorical predictor, testing for potential interaction effects between norepinephrine dose and markers of illness severity (SOFA score and lactate level), restricting the analysis to patients who survived more than 48 hours after vasopressor initiation to minimize immortal time bias, and conducting alternative models excluding either SOFA or APACHE II to address potential collinearity between severity scores.\u003c/p\u003e \u003cp\u003eICU survival was analyzed using Kaplan\u0026ndash;Meier curves, stratified by norepinephrine dose group. Differences were assessed using the log-rank test. Time was measured from ICU admission to ICU death or discharge\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using SPSS Statistics (IBM Corp. Version 29.0 Armmonk, NY, USA) statistical significance was defined as a two-tailed p-value of less than 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient Population and Baseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 250 patients were initially screened. After excluding 11 patients who received vasopressin for non-septic indications, 9 with incomplete norepinephrine dosing data, and 10 who died within 6 hours of vasopressor initiation, 220 patients were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The cohort was randomly divided into a derivation subset (n\u0026thinsp;=\u0026thinsp;93), used to define the norepinephrine (NE) threshold, and a validation subset (n\u0026thinsp;=\u0026thinsp;127), used for outcome analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe mean age of the full cohort was 62\u0026thinsp;\u0026plusmn;\u0026thinsp;14 years, with an equal sex distribution (50.5% male). The median SOFA score at ICU admission was 10 (IQR, 7\u0026ndash;13), and the mean APACHE II score was 22\u0026thinsp;\u0026plusmn;\u0026thinsp;7. Respiratory infection was the most frequent source (52%), followed by abdominal (21%) and urinary (9%). Regarding the characteristics of shock, the times to initiation of vasoactive agents were recorded. Time to initiation of norepinephrine from the diagnosis of sepsis was 6\u0026thinsp;\u0026plusmn;\u0026thinsp;9 hours, time to initiation of vasopressin from the diagnosis of sepsis was 11\u0026thinsp;\u0026plusmn;\u0026thinsp;13 hours, and finally, the time to initiation of vasopressin after the initiation of norepinephrine was 5\u0026thinsp;\u0026plusmn;\u0026thinsp;7 hours. Mechanical ventilation was used in 75% of cases, and renal replacement therapy (RRT) was initiated in 39%. ICU mortality was 44% (96/220). No significant differences were observed between the derivation and validation cohorts in baseline characteristics (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eBaseline Characteristics of the Study Population\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\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFull-cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;220)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnalysis-cohort (n\u0026thinsp;=\u0026thinsp;93)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eValidation cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;127)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111 M / 109 F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 M / 47 F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 M / 62 F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI. Charlson (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSource of infection --no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eRespiratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 (55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical presentation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eSystolic Blood Pressure - mean (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (90\u0026ndash;120)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108 (93\u0026ndash;118)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106 (96\u0026ndash;122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApache II mean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 \u0026plusmn; 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 \u0026plusmn; 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 \u0026plusmn; 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\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 (7\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (8\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (6\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHOUR 1 - Bundle --no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eHour 1 - Bundle (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171 (78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e0.06\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e214 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood culture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e211 (96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotic onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e219 (99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92 (99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e127 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFluid resucitation (30mL/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e212 (96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e122 (96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApply vasopresors \u003c/p\u003e \u003cp\u003e if hypotensive during \u003c/p\u003e \u003cp\u003eor after fluid resucitation --no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e195 (89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e114 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBiological results\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eAdmision Serum Lactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 (2.1\u0026ndash;6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2 (2.2\u0026ndash;6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.2 (2.3\u0026ndash;6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU Serum Lactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.2 (2.2\u0026ndash;6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.5 (2.3\u0026ndash;6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.7 (1.6\u0026ndash;6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eShock related characteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eTime to initiation of norepinephrine from sepsis diagnosis. (hrs)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to initiation of vasopressin from sepsis diagnosis (hrs)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to initiation of vasopressin from initiation norepinephrine (hrs)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorepinephrine before vasopresine onset (\u0026micro;g/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0,36 (0,30\u0026thinsp;\u0026minus;\u0026thinsp;0,60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,40 (0.30\u0026ndash;0.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.36 (0.30\u0026ndash;0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticoid at vasopressin start --no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e215 (98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92 (99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccess rate (antibiotic) --no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMecanical ventilation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eMecanical ventilation Y-N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (1\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (2\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (1\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKidney failure --no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eNo failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKDIGO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKDIGO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKDIGO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICU Data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eICU Days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (5\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (5\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome --no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eIn-ICU mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eValues are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, median (interquartile range), or n (%) as\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eappropriate. Comparisons between the analysis and validation cohorts were performed using the\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003et-test, Mann\u0026ndash;Whitney U test, or chi-square test as appropriate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDerivation of Norepinephrine Dose Cutoff\u003c/h2\u003e \u003cp\u003eIn the derivation cohort, receiver operating characteristic (ROC) curve analysis identified an optimal NE dose cutoff of 0.40 \u0026micro;g/kg/min for predicting ICU mortality, with an area under the curve (AUC) of [pending exact value]. The Youden index at this threshold was 0.501, corresponding to a sensitivity of 62.8% and a specificity of 87.3% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This cutoff was used to stratify patients in the validation cohort. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the Kaplan\u0026ndash;Meier ICU survival curves stratified by norepinephrine dose survival probabilities during ICU stay for patients receiving vasopressin at norepinephrine doses\u0026thinsp;\u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min; \u0026gt;0.40 \u0026micro;g/kg/min. (Log-rank test p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate Outcome Analysis (Validation Cohort)\u003c/h2\u003e \u003cp\u003eAmong patients in the validation cohort, those who received vasopressin at NE doses\u0026thinsp;\u0026gt;\u0026thinsp;0.40 \u0026micro;g/kg/min (n\u0026thinsp;=\u0026thinsp;40) exhibited higher illness severity than those treated at \u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min (n\u0026thinsp;=\u0026thinsp;87). Specifically, the high-dose group had higher APACHE II (25\u0026thinsp;\u0026plusmn;\u0026thinsp;8 vs. 20\u0026thinsp;\u0026plusmn;\u0026thinsp;6, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), higher SOFA scores (12\u0026thinsp;\u0026plusmn;\u0026thinsp;3 vs. 9\u0026thinsp;\u0026plusmn;\u0026thinsp;4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and elevated ICU lactate levels (7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 vs. 3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 mmol/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). They also had lower completion rates of the Hour-1 bundle (65% vs. 88%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), greater mechanical ventilation use (98% vs. 66%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), higher rates of KDIGO stage III renal failure (67% vs. 29%), and a significantly increased RRT requirement (58% vs. 27%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). ICU mortality was markedly higher in the \u0026gt;\u0026thinsp;0.40 \u0026micro;g/kg/min group (80% vs. 21%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eUnadjusted Characteristics and Clinical Outcomes by Norepinephrine Dose at Vasopressin Initiation (Validation Cohort)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNAD\u0026thinsp;\u0026le;\u0026thinsp;0.4\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNAD\u0026thinsp;\u0026gt;\u0026thinsp;0.4\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u0026thinsp;=\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u0026thinsp;=\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson I.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88\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\u003e20\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\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\u003e9\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmision Serum Lactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU Serum Lactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of infection (respiratory)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of infection (abdominal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of infection (urinary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of infection (others)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOUR 1 - Bundle\u0026thinsp;=\u0026thinsp;Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorepinephrine before vasopresine onset (\u0026micro;g/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticoid ( vasopresine onset)\u0026thinsp;=\u0026thinsp;Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccess rate (antibiotic)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMecanical Ventilation\u0026thinsp;=\u0026thinsp;Y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney Failure\u0026thinsp;=\u0026thinsp;No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney Failure\u0026thinsp;=\u0026thinsp;KDIGO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney Failure\u0026thinsp;=\u0026thinsp;KDIGO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney Failure\u0026thinsp;=\u0026thinsp;KDIGO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn-ICU mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePatients were stratified according to whether vasopressin was initiated at norepinephrine doses\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min or \u0026amp;gt;0.40 \u0026micro;g/kg/min. Values are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%). P-values are based on univariate comparisons.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable Analysis of ICU Mortality\u003c/h2\u003e \u003cp\u003eIn adjusted logistic regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), vasopressin initiation at a norepinephrine dose\u0026thinsp;\u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min was independently associated with a lower risk of ICU mortality (OR, 0.25; 95% CI, 0.07\u0026ndash;0.90). Additional independent predictors of ICU mortality included ICU serum lactate (OR per mmol/L, 1.42; 95% CI, 1.11\u0026ndash;1.82) and the need for mechanical ventilation (OR, 54.99; 95% CI, 4.15\u0026ndash;727). The model was adjusted for age, comorbidity burden (Charlson index), APACHE II score, SOFA score, corticosteroid use, Hour-1 bundle completion, and antibiotic response. No multicollinearity was detected (all variance inflation factors\u0026thinsp;\u0026lt;\u0026thinsp;2), and model calibration was acceptable (Hosmer\u0026ndash;Lemeshow p\u0026thinsp;\u0026gt;\u0026thinsp;0.2).\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\u003eMultivariable Logistic Regression Analysis for ICU Mortality and Renal failure\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMULTIVARIANT ANALYSIS MORTALITY (VALIDATION COHORT)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConfidence Interval (95%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNorepinephrine before vasopresine onset (\u0026micro;g/kg/min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.07 to 0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICU Serum Lactate (mmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.11 to 1.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMecanical ventilation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.15 to 727\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94 to 10.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 to 1.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson I.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96 TO 1.42\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\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.83 to 1.03\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\u003e1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.84 to 1.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOUR 1 - Bundle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18 to 3.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticoid ( vasopresine onset)\u0026thinsp;=\u0026thinsp;Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05 to 22.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccess rate (antibiotic)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.79 to 8.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMULTIVARIANT ANALYSIS (VALIDATION COHORT) Renal failure\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorepinephrine before vasopresine onset (\u0026micro;g/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.15 to 0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU Serum Lactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96 to 1.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98 to 1.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI. Charlson\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97 to 1.29\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\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97 to 1.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOUR 1 - Bundle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56 to 4.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAdjusted odds ratios (aOR) with 95% confidence intervals are presented. Variables included in\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003ethe model were selected a priori based on clinical relevance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable Analysis of Renal Failure\u003c/h2\u003e \u003cp\u003eIn a separate logistic regression model evaluating the development of moderate to severe renal failure (KDIGO stages II\u0026ndash;III), vasopressin initiation at a norepinephrine dose\u0026thinsp;\u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min remained independently associated with reduced risk (OR, 0.37; 95% CI, 0.15\u0026ndash;0.89) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Other covariates, including ICU lactate, age, APACHE II score, and Hour-1 bundle completion, were not independently associated with renal failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eAdverse Events\u003c/h2\u003e \u003cp\u003eAdverse events were uncommon and evenly distributed across groups. Atrial fibrillation occurred in 7% of the full cohort, mesenteric ischemia in 3%, and digital ischemia in 1%. Rebound hypotension was reported in 16% of patients overall, with no significant differences between NE dose groups. No cases of severe hyponatremia were observed (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\u003eComplications\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\"\u003e \u003cp\u003eAdverse events --no. (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFull-cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;220)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNAD\u0026thinsp;\u0026le;\u0026thinsp;0.4 (n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNAD\u0026thinsp;\u0026gt;\u0026thinsp;0.4 (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesenteric ischemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere hyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRebound hypotension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDigital ischemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eIt was determined as a cause of severe adverse effect (atrial fibrillation, mesenteric ischemia, digital ischemia) if it was newly onset from the initiation of vasopressin up to 6 hours thereafter.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eIt was defined as severe hyponatremia severe\u0026thinsp;\u0026lt;\u0026thinsp;125 mmo/L\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eWe defined rebound hypotension as a decrease in mean arterial pressure (MAP) to \u0026lt;\u0026thinsp;65 mmHg within the first 6 hours following the withdrawal of vasopressin.\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 retrospective cohort study of patients with septic shock treated with norepinephrine and vasopressin, we found that initiating vasopressin at a norepinephrine dose lower than 0.40 \u0026micro;g/kg/min was independently associated with a significant reduction in ICU mortality. This association remained robust after adjustment for key confounders and was consistent across sensitivity analyses. Additionally, patients receiving vasopressin at lower norepinephrine doses showed a significantly lower rate of renal replacement therapy, suggesting a possible association with reduced progression to severe acute kidney injury. Initiating vasopressin at norepinephrine doses\u0026thinsp;\u0026le;\u0026thinsp;0.40 \u0026micro;g/kg/min was independently associated with a lower risk of developing moderate-to-severe acute kidney injury (KDIGO stages II\u0026ndash;III), supporting its potential role in renal protection during septic shock.\u003c/p\u003e \u003cp\u003eOur study adds to the growing body of literature addressing the optimal timing of vasopressin initiation in septic shock.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Current international guidelines recommend considering vasopressin when norepinephrine doses range between 0.25 and 0.50 \u0026micro;g/kg/min\u003csup\u003e3\u003c/sup\u003e. This recommendation, while widely followed, is largely based on expert opinion and consensus rather than on robust clinical evidence.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Seminal randomized trials such as VASST and VANISH failed to show a mortality benefit of vasopressin overall, but both suggested potential advantages in subgroups with lower lactate levels or milder disease severity.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAn additional consideration relates to the timing of vasopressor initiation.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In our cohort, norepinephrine was typically initiated early, in alignment with current guidelines, and vasopressin was added after a median time of 6 hours.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Although our primary analysis focused on norepinephrine dose thresholds, future studies should explore the interplay between time to vasopressin initiation and patient outcomes.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Temporal dynamics may be particularly relevant in the early hours of shock resuscitation, when vasopressor responsiveness and catecholamine sensitivity may vary significantly.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecent data reinforce the idea that earlier initiation of vasopressin may be beneficial. In a large analysis from the MIMIC-III and IV databases, Xu et al. found that vasopressin administration at norepinephrine doses below 0.25 \u0026micro;g/kg/min was associated with significantly lower 28-day mortality (OR 0.66, 95% CI 0.52\u0026ndash;0.84).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e These results are consistent with our identified cutoff of 0.40 \u0026micro;g/kg/min and support the clinical plausibility of using this threshold to guide therapy.\u003c/p\u003e \u003cp\u003eIn addition, our results echo those of Sacha et al., who demonstrated that lower norepinephrine-equivalent doses at vasopressin initiation were associated with improved survival.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Specifically, initiation at 10 \u0026micro;g/min was associated with lower mortality than initiation at 25 or 60 \u0026micro;g/min, and early use was also associated with lower lactate levels and a more favorable hemodynamic profile.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe data from the OVISS study reinforce our findings. The reinforcement-trained model indicated that more vasopressin should have been used in 87% of cases\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Additionally, the model estimated that the optimal time to initiate vasopressin, based on norepinephrine dosage, was around 0.25\u0026ndash;0.35 \u0026micro;g/kg/min across various databases, further supporting our results.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe physiological rationale for early vasopressin use includes its non-adrenergic mechanism of action via V1 receptors, catecholamine-sparing effects, and the potential to attenuate the inflammatory response without promoting adrenergic receptor downregulation.\u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Guerci et al. further emphasize that excessive catecholamine exposure can be inherently toxic, promoting organ dysfunction and mortality.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe potential mechanisms underlying the observed reduction in ICU mortality with earlier vasopressin initiation are likely multifactorial and rooted in the complex pathophysiology of septic shock.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e One plausible explanation is the reduction of cumulative catecholamine exposure, which is associated with deleterious effects such as increased myocardial oxygen consumption, arrhythmogenesis, immunosuppression, and impaired microcirculatory flow.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Initiating vasopressin at lower norepinephrine doses may prevent the need for further catecholamine escalation, thereby mitigating these toxic effects.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVasopressin\u0026rsquo;s mechanism of action through V1a receptor\u0026ndash;mediated vasoconstriction provides non-adrenergic restoration of vascular tone, which may be particularly effective in the vasodilatory state of septic shock where endogenous vasopressin depletion is common.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e By acting synergistically with norepinephrine, vasopressin may also enhance mean arterial pressure with lower catecholamine doses, leading to earlier hemodynamic stabilization.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMoreover, experimental and clinical studies have suggested that vasopressin may exert beneficial effects on renal perfusion and microcirculatory flow, particularly in early or moderate stages of shock.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e These hemodynamic advantages may help prevent progression to multiple organ dysfunction, potentially explaining the observed trends toward reduced renal replacement therapy in patients receiving vasopressin at lower norepinephrine thresholds.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eImportantly, the subgroup analysis of the VASST trial showed a mortality benefit in patients with less severe shock (lactate\u0026thinsp;\u0026lt;\u0026thinsp;1.4 mmol/L), which aligns with our findings suggesting greater benefit among patients who required lower norepinephrine doses at the time of vasopressin initiation(7).\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e These converging lines of evidence support the hypothesis that timing and patient selection are critical variables that determine the effectiveness of adjunctive vasopressin therapy.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, our identification of a norepinephrine threshold associated with improved survival offers a practical decision point that could enhance the consistency of vasopressor management. This is especially relevant in light of the considerable variability in vasopressin use observed across institutions, partly driven by differences in how norepinephrine dose is reported (e.g., base vs. tartrate).\u003c/p\u003e \u003cp\u003eNevertheless, several limitations must be acknowledged. First, as an observational study, causality cannot be definitively established, and residual confounding may persist despite multivariable adjustment. Second, the study was conducted in a single tertiary center, which may limit the generalizability of our findings. Third, although we used an internal derivation-validation approach to determine and test the norepinephrine cutoff, the threshold was still developed within a single dataset and requires external validation in independent populations. Fourth, the overall sample size, while sufficient for primary analyses, may limit statistical power for detecting small effects or conducting detailed subgroup evaluations. Finally, we did not evaluate long-term outcomes beyond ICU discharge, to summarize, our findings suggest that initiating vasopressin at norepinephrine doses below 0.40 \u0026micro;g/kg/min may be associated with better ICU outcomes in patients with septic shock. This threshold is both physiologically plausible and supported by prior observational and modeling studies. Further randomized controlled trials are warranted to validate this approach and to integrate early vasopressin use into personalized sepsis care protocols. Finally, we did not evaluate long-term outcomes beyond ICU discharge, such as hospital or 90-day mortality, renal recovery, or quality of life. While ICU mortality remains a relevant and immediate endpoint in septic shock, future studies should assess the sustained impact of vasopressor strategies on patient-centered outcomes.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings suggest that early initiation of vasopressin at lower norepinephrine doses may be associated with improved survival in patients with septic shock. These results support a strategy of timely adjunctive vasopressor therapy and highlight the need for prospective studies to confirm the benefits of early vasopressin initiation and to define its role within protocolized, individualized hemodynamic management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNE \u0026nbsp; Norepinephrine\u003c/p\u003e\n\u003cp\u003eICU \u0026nbsp;Intensive care unit\u003c/p\u003e\n\u003cp\u003eMAP Mean arterial pressure\u003c/p\u003e\n\u003cp\u003eRRT \u0026nbsp;Renal replacement therapy\u003c/p\u003e\n\u003cp\u003eSOFA \u0026nbsp;Sequential organ failure assessment\u003c/p\u003e\n\u003cp\u003eAPACHE IV \u0026nbsp;Acute physiological chronic health evaluation\u003c/p\u003e\n\u003cp\u003eSD \u0026nbsp; Standard deviation\u003c/p\u003e\n\u003cp\u003eIQR \u0026nbsp;Interquartile range\u003c/p\u003e\n\u003cp\u003eROC \u0026nbsp; Receiver operating curve\u003c/p\u003e\n\u003cp\u003eOR \u0026nbsp; \u0026nbsp; Odd’s ratio\u003c/p\u003e\n\u003cp\u003eaOR \u0026nbsp; Adjusted ood’s ratio\u003c/p\u003e\n\u003cp\u003eAUC Area under the curve\u003c/p\u003e\n\u003cp\u003eCI \u0026nbsp; \u0026nbsp; \u0026nbsp;Confidence\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThey would also like to thank Mateo Cede\u0026ntilde;o and Jose Cede\u0026ntilde;o for their continuous drive to create.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAutor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Jamil Cede\u0026ntilde;o, Pablo Garc\u0026iacute;a-Olivares, Galo Casta\u0026ntilde;eda, Javier Mu\u0026ntilde;oz; recruitment of subjects and data curation: Jamil Cede\u0026ntilde;o, Pablo Garc\u0026iacute;a-Olivares, Galo Casta\u0026ntilde;eda, Carlos Ram\u0026iacute;rez, Arturo Rodriguez, Javier Mu\u0026ntilde;oz; data analysis and interpretation: Jamil Cede\u0026ntilde;o, Pablo Garc\u0026iacute;a-Olivares and Javier Mu\u0026ntilde;oz; drafting the manuscript: Jamil Cede\u0026ntilde;o, Pablo Garc\u0026iacute;a-Olivares and Javier Mu\u0026ntilde;oz; revision of the manuscript: Jamil Cede\u0026ntilde;o, Pablo Garc\u0026iacute;a-Olivares, Galo Casta\u0026ntilde;eda, Carlos Ram\u0026iacute;rez, Arturo Rodriguez, Javier Mu\u0026ntilde;oz. Principal investigator role: Jamil Cede\u0026ntilde;o. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received approval from the Ethics Committee of Gregorio Mara\u0026ntilde;\u0026oacute;n Hospital in January 2022. The exemption from informed consent for the study was accepted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis investigator-initiated retrospective cohort study was supported by an unrestricted grant from AOP Orphan Pharmaceuticals GmbH, a member of the AOP Health Group, Vienna, Austria. AOP had no involvement in the study\u0026rsquo;s conceptualization, design, data collection, analysis, or manuscript preparation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJamil Cede\u0026ntilde;o reported receiving honoraria and travel expenses from AOP Pharma. The other authors have nothing to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019\u0026mdash; results from a systematic review and meta-analysis. \u003cem\u003eCrit Care\u003c/em\u003e. 2020;24(1):239. doi:10.1186/s13054-020-02950-2\u003c/li\u003e\n \u003cli\u003eSinger M, Deutschman C, Seymour C, et al. 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Predictors of response to fixed-dose vasopressin in adult patients with septic shock. \u003cem\u003eAnn Intensive Care\u003c/em\u003e. 2018;8(1):35. doi:10.1186/s13613-018-0379-5\u003c/li\u003e\n \u003cli\u003eD\u0026uuml;nser MW, Ruokonen E, Pettil\u0026auml; V, et al. Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. \u003cem\u003eCrit Care\u003c/em\u003e. 2009;13(6):R181. doi:10.1186/cc8167\u003c/li\u003e\n \u003cli\u003eBrask AL, Shemanski SM, Barnes TE, Holmes AK. Timing of Vasopressin Addition to Norepinephrine and Efficacy Outcomes in Patients With Septic Shock. \u003cem\u003eAnn Pharmacother\u003c/em\u003e. 2023;57(5):521-526. doi:10.1177/10600280221118903\u003c/li\u003e\n \u003cli\u003eLiu Z, Chen J, Kou Q, et al. Effect of vasopressin in septic shock patients with normal or elevated cardiac output: a systematic review and meta-analysis. \u003cem\u003eShock\u003c/em\u003e. 2012;38(5):478-483.\u003c/li\u003e\n \u003cli\u003eNagendran M, Russell JA, Walley KR, et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2019;45(6):844-855. doi:10.1007/s00134-019-05620-2\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sepsis shock, Norepinephrine, Arginine vasopressin, Intensive care unit, Dose Threshold","lastPublishedDoi":"10.21203/rs.3.rs-6809611/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6809611/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cbr\u003e\nThe optimal norepinephrine (NE) dose at which vasopressin should be initiated in septic shock remains unclear. Current recommendations rely largely on expert consensus rather than robust clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nWe conducted a retrospective observational cohort study in a tertiary ICU from 2022–2025 to determine whether initiating vasopressin at lower NE doses is associated with improved ICU outcomes in patients with septic shock. Patients who received both NE and vasopressin were included. A random derivation subset (n = 93) was used to identify the optimal NE dose cutoff for ICU mortality by means ROC curve and Youden index. This threshold was applied to the remaining validation cohort (n = 127). Multivariable logistic regression models were used to assess ICU mortality and renal failure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nOf 250 eligible patients, 220 were included. The optimal NE cutoff was 0.40 μg/kg/min (AUC: 0.82; sensitivity: 62.8%, specificity: 87.3%). In the validation cohort, patients receiving vasopressin at NE doses \u0026gt;0.40 μg/kg/min had higher ICU mortality (80% vs. 21%, p \u0026lt; 0.001) and increased renal replacement therapy use (58% vs. 27%, p \u0026lt; 0.001). After adjustment, vasopressin initiation at NE ≤0.40 μg/kg/min was independently associated with reduced ICU mortality (OR, 0.25; 95% CI, 0.07–0.90) and lower risk of renal failure (OR, 0.37; 95% CI, 0.15–0.89), suggesting a protective effect of earlier vasopressin use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003cbr\u003e\nInitiating vasopressin at NE doses ≤0.40 μg/kg/min may be associated with improved ICU survival and reduced renal dysfunction. These findings support the use of practical NE thresholds in vasopressor management and complement recent data-driven and meta-analytic evidence.\u003c/p\u003e","manuscriptTitle":"Norepinephrine Dose Threshold at Vasopressin Initiation and Its Association With ICU Mortality in Septic Shock","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-17 15:59:20","doi":"10.21203/rs.3.rs-6809611/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5949444-cab4-411d-9582-d40f4e000936","owner":[],"postedDate":"June 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-25T05:53:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-17 15:59:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6809611","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6809611","identity":"rs-6809611","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}