Influence of bundled care treatment on functional outcome in patients with intracerebral hemorrhage

Abstract

Background and aims: General guideline recommendations in patients with intracerebral hemorrhage (ICH) include blood pressure-, temperature- and glucose management. The therapeutic effect of such a "care bundle" (blood pressure lowering, glycemic control, and treatment of pyrexia) on clinical outcomes becomes increasingly established. For the present study, we aimed to investigate associations of strict bundled care treatment (BCT) with clinical outcomes and characterize associations with key outcome effectors such as hematoma enlargement (HE) and peak perihemorrhagic edema (PHE).

Methods: We screened consecutive ICH patients (n = 1,322) from the prospective UKER-ICH cohort study. BCT was defined as achieving and maintaining therapeutic ranges for systolic blood pressure (110-160 mmHg), glucose (80-180 mg/dL), and body temperature (35.5-37.5°C) over the first 72 h. The primary outcome was the functional outcome at 12 months (modified Rankin Scale (mRS) 0-3). Secondary outcomes included mortality at 12 months, the occurrence of hematoma enlargement, and the development of peak perihemorrhagic edema. Confounding was addressed by a doubly robust methodology to calculate the absolute treatment effect (ATE) and by calculating e-values.

Results: A total of 681 patients remained for analysis, and 182 patients fulfilled all three BCT criteria and were compared to 499 controls. The ATE of BCT to achieve the primary outcome was 9.3%, 95% CI (1.7 to 16.9), p < 0.001; e-value: 3.1, CI (1.8). Mortality at 12 months was significantly reduced by BCT [ATE: -12.8%, 95% CI (-19.8 to -5.7), p < 0.001; e-value: 3.8, CI (2.2)], and no association was observed for HE or peak PHE. Significant drivers of BCT effect on the primary outcome were systolic blood pressure control (ATE: 15.9%) and maintenance of normothermia (ATE: 10.9%).

Conclusion: Strict adherence to this "care bundle" over the first 72 h during acute hospital care in patients with ICH was independently associated with improved functional long-term outcome, driven by systolic blood pressure control and maintenance of normothermia. Our findings strongly warrant prospective validation to determine the generalizability especially in Western countries.Clinical trial registration:ClinicalTrials.gov, identifier [ID: NCT03183167].

Keywords: HE; ICH; PHE; bundle; treatment.

Figure 1

Flow chart of study participants. Overall, 1,322 patients with spontaneous ICH (years 2006–2015) were screened for analysis. 641 patients were excluded because of (i) symptom onset >8 h before admission (n = 317), (ii) withdrawal of therapy within the first 24 h (n = 185), and (iii) missing patient data (n = 139). 681 patients remained for primary and secondary outcome analyses. 182 fulfilled the bundle care treatment criteria, and 499 patients remained as controls. *Missing data consist of (i) more than 33.3% of maximum or minimum values of each BCT parameter over all 6-h intervals or (ii) follow-up imaging (dicom data for detailed analysis). BCT, bundled care treatment; ICH, intracerebral hemorrhage; UKER, Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage.

Figure 2

Systolic blood pressure, temperature, and glucose levels in 6-h intervals during the first 72 h mean values for (A) systolic blood pressure, mmHg, (B) temperature, °C, and (C) glucose levels, mg/dL measured in 6-h intervals since admission during the first 72 h separated for patients who fulfilled the bundle care treatment criteria (black) and for control patients (gray), maximum values were used. I bars indicated 95% confidence intervals. Asterisks mark significance *p ≤ 0.05.

Figure 3

Associations of single BCT components to the absolute treatment effect. Results for the primary (modified Rankin Scale score 0–3 at 12 months) and secondary outcomes (mortality at 12 months), occurrence of hematoma enlargement, volume of peak perihemorrhagic edema, dichotomized according to median split (<25 cm³) are shown as adjusted absolute treatment effects separated for each target parameter: systolic blood pressure, temperature, and blood sugar, as well as BCT effect for categorized outcomes (bold), n = 681. Abbreviations/scores: BCT: bundled care treatment; hematoma enlargement was defined as an ICH volume increase of more than 33% (relative) or 6 mL from initial to follow-up imaging; peak perihemorrhagic edema was defined as maximum perihemorrhagic edema volume measured during hospitalization and dichotomized according to the median split method.

Figure 4

Exploratory subgroup analyses of the primary outcome. The results for the primary outcome (modified Rankin Scale score 0–3 at 12 months) are shown as crude frequency data and adjusted absolute treatment effects (n = 681). Interactions of exploratory subgroup analyses were analyzed by the subgroup-defining variable (variable×intervention) and were considered significant for p < 0.05. Abbreviations/scores: ICH: intracerebral hemorrhage; ICH volume was dichotomized according to median split (≥16.0 cm³). NIHSS, National Institutes of Health Stroke Scale. Hematoma enlargement defined as an ICH volume increase of more than 33% (relative) or 6 mL from initial to follow-up imaging; peak perihemorrhagic edema was defined as maximum perihemorrhagic edema volume measured during hospitalization and dichotomized according to the median split method (≥25.0cm³).