Development and validation of novel sepsis subphenotypes using trajectories of vital signs

Abstract

Purpose: Sepsis is a heterogeneous syndrome and identification of sub-phenotypes is essential. This study used trajectories of vital signs to develop and validate sub-phenotypes and investigated the interaction of sub-phenotypes with treatment using randomized controlled trial data.

Methods: All patients with suspected infection admitted to four academic hospitals in Emory Healthcare between 2014-2017 (training cohort) and 2018-2019 (validation cohort) were included. Group-based trajectory modeling was applied to vital signs from the first 8 h of hospitalization to develop and validate vitals trajectory sub-phenotypes. The associations between sub-phenotypes and outcomes were evaluated in patients with sepsis. The interaction between sub-phenotype and treatment with balanced crystalloids versus saline was tested in a secondary analysis of SMART (Isotonic Solutions and Major Adverse Renal Events Trial).

Results: There were 12,473 patients with suspected infection in training and 8256 patients in validation cohorts, and 4 vitals trajectory sub-phenotypes were found. Group A (N = 3483, 28%) were hyperthermic, tachycardic, tachypneic, and hypotensive. Group B (N = 1578, 13%) were hyperthermic, tachycardic, tachypneic (not as pronounced as Group A) and hypertensive. Groups C (N = 4044, 32%) and D (N = 3368, 27%) had lower temperatures, heart rates, and respiratory rates, with Group C normotensive and Group D hypotensive. In the 6,919 patients with sepsis, Groups A and B were younger while Groups C and D were older. Group A had the lowest prevalence of congestive heart failure, hypertension, diabetes mellitus, and chronic kidney disease, while Group B had the highest prevalence. Groups A and D had the highest vasopressor use (p < 0.001 for all analyses above). In logistic regression, 30-day mortality was significantly higher in Groups A and D (p < 0.001 and p = 0.03, respectively). In the SMART trial, sub-phenotype significantly modified treatment effect (p = 0.03). Group D had significantly lower odds of mortality with balanced crystalloids compared to saline (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.23-0.67, p < 0.001).

Conclusion: Sepsis sub-phenotypes based on vital sign trajectory were consistent across cohorts, had distinct outcomes, and different responses to treatment with balanced crystalloids versus saline.

Keywords: Intravenous fluids; Phenotypes; Sepsis; Sub-phenotypes; Vital signs.

Fig. 1

Group-based trajectory modeling of vital signs in the training and validation cohorts. Using group-based trajectory modeling, four vitals trajectory sub-phenotypes were identified in the training and validation cohorts. Group A patients (N = 3483, 28%) were hyperthermic, tachycardic, and tachypneic and had relatively lower systolic and diastolic blood pressure. Group B (N = 1578, 13%) were also hyperthermic, tachycardic and tachypneic, but not as pronounced as Group A, and were hypertensive. Group C (N = 4044, 32%) and Group D (N = 3368, 27%) had lower temperatures, heart rates, and respiratory rates, with Group C normotensive and Group D being the most hypotensive sub-phenotype

Fig. 2

Laboratory values compared between vitals trajectory sub-phenotypes in sepsis patients in the training cohort. Laboratory values (most abnormal values in the first 24 h of hospitalization) were compared between the vitals trajectory sub-phenotypes using ANOVA testing. All laboratory values presented were significantly different between sub-phenotypes after multiple testing correction either in the training or validation cohorts. Group A had the highest white blood cell count, neutrophil-to-lymphocyte ratio, and lactic acid levels (p < 0.001). Group B had the highest creatinine and BNP levels (p < 0.001). Group D had the lowest hemoglobin (p < 0.001). These relative distributions of labs were similar in the validation cohort. NLR neutrophil-to-lymphocyte ratio, INR international normalized ratio, BNP Brain natriuretic peptide

Fig. 3

Odds ratio for 30-day hospital mortality compared between vitals trajectory sub-phenotypes in patients with sepsis. The vitals trajectory sub-phenotypes were evaluated for association with 30-day hospital mortality. Logistic regression was performed adjusting for age, sex, race, and comorbidities, with Group C as the reference group since this was the most prevalent sub-phenotype. 30-day mortality was significantly higher in Group A (Training cohort: OR 1.96, 95% CI 1.32–2.91, p < 0.001; Validation cohort: OR 2.50, 95% CI 1.31–4.77, p = 0.005). Mortality was also significantly higher in Group D (Training cohort: OR 1.54, 95% CI 1.05–2.24, p = 0.03; Validation cohort: OR 2.51, 95% CI 1.35–4.68, p = 0.004)

Fig. 4

Heterogeneity of treatment effect to balanced crystalloids (BC) and saline. In this secondary analysis of the Isotonic Solutions and Major Adverse Renal Events Trial (SMART), Group D had a significantly lower OR of 30-day mortality with balanced crystalloid treatment compared to saline (OR 0.39, 95% CI 0.23–0.67, p < 0.001). The other sub-phenotypes were not significantly associated with mortality: Group A OR 0.75 (95% CI 0.40–1.39, p = 0.4); Group B OR 2.60 (95% CI 0.54–12.53, p = 0.2); Group C OR 0.60 (95% CI 0.21–1.76, p = 0.4). Since the entire confidence interval for Group B could not be presented in the figure, the arrow signifies that the confidence interval extends beyond the axis. There was significant heterogeneity of treatment effect between sub-phenotypes and treatment assignment in predicting 30-day mortality (p = 0.03)