Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients

Abstract

Background: A growing number of patients survive sepsis but remain chronically critically ill. We sought to define clinical outcomes and incidence of chronic critical illness (CCI) after sepsis and to determine whether selected biomarkers of inflammation, immunosuppression, and catabolism differ between these patients and those that rapidly recover (RAP).

Methods: This 3-year prospective observational cohort study (NCT02276417) evaluated 145 surgical intensive care unit patients with sepsis for the development of CCI (≥14 days of intensive care unit resource utilization with persistent organ dysfunction). Patient clinical demographics, outcomes, and serial serum/urine samples were collected for plasma protein and urinary metabolite analyses.

Results: Of 145 sepsis patients enrolled, 19 (13%) died during their hospitalization and 71 (49%) developed CCI. The CCI patients were significantly older (mean, 63 ± 15 vs. 58 ± 13 years, p = 0.006) and more likely to be discharged to long-term acute care facilities (32% vs. 3%, p < 0.0001), whereas those with RAP were more often discharged to home or a rehabilitation facility. Six-month mortality was significantly higher in CCI as compared with RAP cohort (37% vs. 2%; p < 0.01). Multivariate logistic regression modeling revealed delayed onset sepsis (>48 hours after admission; odds ratio [OR], 10.93; 95% confidence interval [CI], 4.15-28.82]), interfacility transfer (OR, 3.58; 95% CI, 1.43-8.96), vasopressor-dependent septic shock (OR, 3.75; 95% CI, 1.47-9.54), and Sequential Organ Failure Assessment score of 5 or greater at 72 hours (OR, 5.03; 95% CI, 2.00-12.62) as independent risk factors for the development of CCI. The CCI patients also demonstrated greater elevations in inflammatory cytokines (IL-6, IL-8, IL-10), and biomarker profiles are consistent with persistent immunosuppression (absolute lymphocyte count and soluble programmed death ligand 1) and catabolism (plasma insulin-like growth factor binding protein 3 and urinary 3-methylhistidine excretion).

Conclusion: The development of CCI has become the predominant clinical trajectory in critically ill surgical patients with sepsis. These patients exhibit biomarker profiles consistent with an immunocatabolic phenotype of persistent inflammation, immunosuppression, and catabolism.

Level of evidence: Prognostic, level II.

Figure 1. 6-month mortality after sepsis based on clinical trajectory

Six-month mortality was determined by prospective follow-up, with cross-check validation via the United States Social Security Death Index (SSDI). Trajectories were classified as Early Death (blue), Rapid Recovery (RAP; green) and chronic critical illness (CCI; red) as defined within the methods section. Kaplan-Meier survival curve shows significant difference between 3 groups (p<0.01) and also between CCI vs RAP (p<0.01). 6-month mortality rate for CCI cohort is 26/71 (37%), and 1/66 (2%) in RAP.

Figure 2. Biomarker concentrations for inflammation, immunosuppression and protein catabolism in patients with chronic critical illness (CCI) and rapid recovery (RAP)

Blood and urine samples were collected at 0.5, 1, 4, 7, 14, 21, and 28 days after sepsis management protocol onset. Plasma concentrations of IL-6, IL-8 and IL-10 were used to assess the inflammatory status of the subject (panel A), plasma sPDL-1 and absolute lymphocyte count to assess immune suppression (panel B), and urinary 3-methylhistidine excretion normalized to creatinine excretion and plasma IGFBP3 concentrations were used as markers of protein catabolism (panel C). Complete cases for laboratory results were binned to the closest time point. Differences in concentrations between CCI (●) and RAP (▲) cohorts at individual time points are identified with a (★) at a p-value <0.05 using non-parametric tests. The results of mixed model analyses reveal that the levels of all analytes over time were significantly different between groups (p<0.05). Patients with CCI had significantly increased early and late inflammation, as well as prolonged immune suppression and evidence of increased muscle protein catabolism (3-MH) and reduced anabolic signals (IGFBP3). (★) indicates p<0.05 at that time point; shaded areas are normal ranges.