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. 2022 Apr 5;98(14):e1470–e1478. doi: 10.1212/WNL.0000000000200018

Association of Acute Alteration of Consciousness in Patients With Acute Ischemic Stroke With Outcomes and Early Withdrawal of Care

Ayham Alkhachroum 1, Antonio J Bustillo 1, Negar Asdaghi 1, Hao Ying 1, Erika Marulanda-Londono 1, Carolina M Gutierrez 1, Daniel Samano 1, Evie Sobczak 1, Dianne Foster 1, Mohan Kottapally 1, Amedeo Merenda 1, Sebastian Koch 1, Jose G Romano 1, Kristine O'Phelan 1, Jan Claassen 1, Ralph L Sacco 1, Tatjana Rundek 1
PMCID: PMC8992606  PMID: 35169010

Abstract

Background and Objectives

Early consciousness disorder (ECD) after acute ischemic stroke (AIS) is understudied. ECD may influence outcomes and the decision to withhold or withdraw life-sustaining treatment.

Methods

We studied patients with AIS from 2010 to 2019 across 122 hospitals participating in the Florida Stroke Registry. We studied the effect of ECD on in-hospital mortality, withholding or withdrawal of life-sustaining treatment (WLST), ambulation status on discharge, hospital length of stay, and discharge disposition.

Results

Of 238,989 patients with AIS, 32,861 (14%) had ECD at stroke presentation. Overall, average age was 72 years (Q1 61, Q3 82), 49% were women, 63% were White, 18% were Black, and 14% were Hispanic. Compared to patients without ECD, patients with ECD were older (77 vs 72 years), were more often female (54% vs 48%), had more comorbidities, had greater stroke severity as assessed by the National Institutes of Health Stroke Scale (score ≥5 49% vs 27%), had higher WLST rates (21% vs 6%), and had greater in-hospital mortality (9% vs 3%). Using adjusted models accounting for basic characteristics, patients with ECD had greater in-hospital mortality (odds ratio [OR] 2.23, 95% CI 1.98–2.51), had longer hospitalization (OR 1.37, 95% CI 1.33–1.44), were less likely to be discharged home or to rehabilitation (OR 0.54, 95% CI 0.52–0.57), and were less likely to ambulate independently (OR 0.61, 95% CI 0.57–0.64). WLST significantly mediated the effect of ECD on mortality (mediation effect 265; 95% CI 217–314). In temporal trend analysis, we found a significant decrease in early WLST (<2 days) (R2 0.7, p = 0.002) and an increase in late WLST (≥2 days) (R2 0.7, p = 0.004).

Discussion

In this large prospective multicenter stroke registry, patients with AIS presenting with ECD had greater mortality and worse discharge outcomes. Mortality was largely influenced by the WLST decision.

Stroke is the second most common cause of death and the third leading cause of disability worldwide.1-3 Among patients admitted to the intensive care unit with severe acute ischemic stroke (AIS), only 25% reach minimal to no disability at 12 months follow-up.4 About 29% of patients who undergo tracheostomy during hospitalization reach independence.5 Many patients with severe stroke with uncertain prognosis die in the setting of withholding or withdrawal of life-sustaining treatment (WLST), leading to self-fulfilling prophecies.6-8 Early consciousness disorder (ECD) after AIS is common (4%–38%) and is underinvestigated.9-13 Altered consciousness after brain injury may affect the WLST decision after cardiac arrest and traumatic brain injury.14,15 However, the effect of ECD on outcomes and the WLST decision is not well studied in patients with AIS. In a single study, ECD was associated with higher complications, increased mortality, and worse functional outcomes at 3 months follow-up.9

In this study, we aimed to evaluate the effect of ECD after AIS on outcomes using data from Florida Stroke Registry hospitals participating in the American Heart Association (AHA) Get with the Guidelines–Stroke (GWTG-S). We also aimed to report the temporal trends of WLST between 2010 and 2019 by the presence or absence of ECD status. We hypothesized that ECD is associated with higher mortality and worse discharge outcomes, influenced by the decision to withhold or withdraw life-sustaining treatment.

Methods

Study Population

Using the Florida Stroke Registry, we identified patients with a final diagnosis of AIS between 2010 and 2019. The presence of ECD was identified using one of the GWTG-S questions on the presence or absence of altered level of consciousness on initial examination findings. Altered level of consciousness may include somnolence, stupor, coma, confusion, or delirium states. Centers were instructed to select altered level of consciousness on initial physical assessment on arrival to the hospital among a list of other neurologic findings: weakness/paresis, aphasia, and other neurologic signs/symptoms.

Case Identification and Data Abstraction

Originally funded by the National Institute of Neurologic Disorders, the stroke registry included data from GWTG-S participating hospitals in Florida and Puerto Rico (2010–2017) and was referred to as the Florida–Puerto Rico Collaboration to Reduce Stroke Disparities (FL-PR CReSD).16,17 Since 2017, the registry continued as the Florida Stroke Registry with funding support through the state of Florida (COHAN-A1). Deidentified data from hospitalized patients with the primary diagnosis of ischemic stroke, TIA, subarachnoid hemorrhage, intracerebral hemorrhage, or stroke not otherwise specified are included in the registry.

The University of Miami's institutional review board approved this study. Each participating center received institutional ethics approval to enroll patients in the registry without requiring individual patient consent under the common rule or a waiver of authorization and exemption from subsequent review by the institutional review board.

This study was restricted to patients with a final diagnosis of AIS. Data collected included patient demographics (age, sex, race/ethnicity, insurance status), comorbidities (prior history of smoking, alcohol/drug use, hypertension, diabetes, obesity, atrial fibrillation or flutter, coronary artery disease, peripheral vascular disease, prior stroke, heart failure), head trauma on presentation, prior ambulation status, stroke etiology (cardioembolic, cryptogenic, large vessel atherosclerosis, small vessel disease, other etiologies), IV thrombolysis or endovascular treatment, statin use on discharge, the presence of aphasia or language disturbance, time from stroke onset to arrival in the emergency department, time to the initial head CT (door to CT), hospital level characteristics (academic status, stroke center type—comprehensive, primary, or thrombectomy capable), and disease severity (as measured by the National Institutes of Health Stroke Scale [NIHSS]).18-20

We identified the WLST status through a question during hospitalization on whether the patient underwent comfort measures only or WLST as documented in GWTG-S as a discrete data element. We identified the timing of WLST as follows: day 0 or 1, day 2 or after, or timing unclear. Outcomes included in-hospital mortality, ambulation status on discharge (independent, need assistance, unknown), hospital length of stay (<4 or ≥4 days), and discharge disposition (home/inpatient rehabilitation or other).

Statistical Analysis

The primary outcome was to determine the risk of in-hospital mortality by ECD status after AIS. Our secondary outcomes included ambulation status on discharge, hospital length of stay, and discharge disposition status by ECD status. We also evaluated temporal trends in the proportion of mortality and WLST by the ECD status.

For patient characteristics, continuous variables were summarized as median with first and third quartiles (Q1 and Q3). Pearson χ2 and Kruskal-Wallis tests were used to compare descriptive statistics. A multivariable logistic regression with generalized estimating equations (GEEs) accounted for basic demographics (age, sex, race/ethnicity, insurance status), comorbidities (prior history of smoking, alcohol/drug use, hypertension, diabetes, obesity, atrial fibrillation or flutter, coronary artery disease, peripheral vascular disease, prior stroke, heart failure), disease severity (defined as NIHSS >5), stroke location (vascular distribution [middle cerebral artery, basilar artery, carotid artery, vertebral artery, more than one vessel]), and hospital size and teaching status and was calculated to test the association of ECD and the different outcomes on discharge. GEE models were utilized for analysis to account for potential clustering of outcomes within different hospitals. We calculated E values for the estimate and the CI to explain the effect of the unmeasured confounders in our model. Mediation analysis was conducted by the product of coefficients method21 in order to determine whether WLST and the timing of WLST mediate in-hospital mortality in patients with ECD. Logistic models were fitted by first regressing the dichotomized mediator “WLST” on the exposure “ECD” (path A) and then regressing the outcome “in-hospital mortality” on WLST after adjusting for ECD (path B). The product of the standardized regression coefficients was itself standardized and a z test was conducted to determine whether the mediation effect was significantly different from zero. We adjusted for basic demographics in the mediation analysis model (age, sex, race/ethnicity) and for disease severity as measured by NIHSS. R2 values were reported for early and late WLST in the regression trend analysis.

Most variables had missing values in fewer than 5% of patients, except for NIHSS (26% missing and 86% for NIHSS 1A), door to CT time (30% missing), and onset to arrival time (50% missing). The missing indicator approach was used to include the full sample for variables with a large proportion of missingness as previously described.22 Adding or removing door to CT and onset to arrival had no effect on our model’s results, thus they were not included in the final models. The level of statistical significance was set at p < 0.05. All statistical analyses were performed using SAS version 9.4 software (SAS Institute).

Standard Protocol Approvals, Registrations, and Patient Consents

The University of Miami's institutional review board approved this study (IRB 20120987). Each GWTG-S participating center received institutional ethics approval to enroll patients in the FL-PR CReSD and subsequently Florida Stroke Registry without requiring individual patient consent under the common rule or a waiver of authorization and exemption from subsequent review by the institutional review board.

Data availability

Florida Stroke Registry analyses are available per request sent to the Florida Stroke Registry Biostatistics Core and after approval of the Florida Stroke Registry Publication Committee.

Results

Study Population

We studied 238,989 patients between 2010 and 2019, of whom ECD was found in 32,862 (14%) patients at stroke presentation. Median age was 71 years (Q1, Q3; 61, 82); 49% were women, 63% were White, 18% Black, and 14% Hispanic. Seventy percent of patients had hypertension, 31% diabetes, 27% a prior history of stroke or TIA, 22% coronary artery disease, 18% atrial fibrillation or flutter, and 16% were smokers. Patients with ECD were older (77 vs 71 years, p < 0.001), had more comorbidities (including hypertension, diabetes, atrial fibrillation or flutter, coronary artery disease, and prior stroke), had higher NIHSS (defined as NIHSS >5), and were more likely to be aphasic on presentation (Table).

Table.

Characteristics of Patients With Acute Ischemic Stroke by Early Consciousness Disorder

graphic file with name WNL-2022-200317T1.jpg

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Mortality, Ambulation Status on Discharge, Hospital Length of Stay, Discharge Disposition, and WLST

In-hospital mortality was observed in 8,110 (3%) patients, and WLST in 20,115 (8%) patients. In-hospital mortality was higher in patients with ECD (9% vs 3%, p < 0.001) with higher rates of WLST (21% vs 6%, p < 0.001). In 30% of patients, WLST occurred on day 0 or 1, and in 67% on day 2 or after (Table). Forty-three percent of patients with ECD were discharged to home or to rehabilitation and a quarter were independent at discharge in comparison to 41% of those without ECD (Table).

In models adjusted for demographics, comorbidities, NIHSS, stroke location, and hospital size and teaching status, patients with ECD had greater in-hospital mortality (OR 2.23, 95% CI 1.98–2.51) (E value for the estimate is 3.89, and for CI 3.96), had longer hospitalization (OR 1.37, 95% CI 1.33–1.44) (E value for the estimate is 2.08, and for the CI 1.99), were less likely to be discharged home or to rehabilitation (OR 0.54, 95% CI 0.52–0.57) (E value for the estimate is 3.1, and for the CI 3.25), and were less likely to ambulate independently at discharge (OR 0.61, 95% CI 0.57–0.64) (E value for the estimate is 2.66, and for the CI 2.9). Even when NIHSS was removed from the model, patients with ECD had higher mortality (OR 3.95, 95% CI 3.47–4.49), had longer hospitalization (OR 1.71, 95% CI 1.59–1.83), were less likely to be discharged home or to rehabilitation (OR 0.38, 95% CI 0.36–0.40), and were less likely to ambulate independently at discharge (OR 0.40, 95% CI 0.36–0.43).

WLST significantly mediated the effect of ECD on mortality (mediation effect 265, 95% CI 217–314, p < 0.001), even after adjusting for basic demographics (age, sex, race/ethnicity) and NIHSS. In addition, given the missingness of NIHSS, we performed unadjusted and adjusted for demographics only analyses. The mediation analysis remained significant in an unadjusted model (mediation effect 726, 95% CI 651–801, p < 0.001) and in an adjusted for demographics only model (mediation effect 586, 95% CI 518–654, p < 0.001).

Temporal Trend Analysis of Mortality and WLST Between 2010 and 2019

Using regression trend analysis in patients with ECD, we found a significant decrease in early WLST (on day 0 or 1 of admission) (R2 0.7, p = 0.002) and an increase in late WLST (≥2 days) (R2 0.7, p = 0.004). Overall, the change in temporal trends for WLST was not significant (R2 0.12, p = 0.4) (Figure).

Figure. Temporal Trends From 2010 to 2019 for In-Hospital Mortality and WLST Among Patients With AIS With and Without ECD.

Figure

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Bar graph and lines show trends of mortality and withholding or withdrawal of life-sustaining treatment (WLST) by level of consciousness on presentation (early consciousness disorder [ECD]) in patients with acute ischemic stroke (AIS) between 2010 and 2019 using the Florida Stroke Registry. The orange line shows actual trends of total WLST and the dotted orange line presents the predicted values using the regression trend analysis. The red line shows early (day 0 and 1) trends of WLST and the dotted red line presents the predicted values. The green line shows late (day 2 and after) WLST trends and the dotted green line show the predicted values.

Discussion

In this prospective large multicenter stroke registry reporting on patients with AIS from 2010 to 2019, 14% of patients with AIS presented with ECD. Patients with ECD had 3 times greater in-hospital mortality as well as WLST. ECD at AIS presentation was associated with worse outcomes (longer hospitalization, less likely to be discharged home or to rehabilitation, and less likely to ambulate independently at discharge). Greater mortality in patients with ECD was largely affected by the decision to withhold or withdraw life-sustaining treatment and less by demographics and disease severity. AIS regardless of ECD was associated with decrease in early WLST (<2 days) and increase in late WLST (≥2 days) during hospitalization in later years.

ECD is common in patients with AIS. The proportion of 14% in our study is within the range of 4%–38% reported by other stroke registries.9-13,23,24 Similar to other studies, patients with ECD had higher comorbidities (prior history of smoking, alcohol/drug use, hypertension, diabetes, obesity, atrial fibrillation or flutter, coronary artery disease, peripheral vascular disease, prior stroke, heart failure).9,25-27

In a prospective single-center study in China, ECD was reported in 35%.9 The authors found more complications, increased mortality, and worse functional outcomes at 3 months follow-up in 199 patients presenting with ECD as assessed by 2 experienced neurologists.9 In the same study, mortality in patients with ECD was 17% vs 0.5% in those without ECD, but the rates of WLST were not reported. In-hospital mortality in our study was 9% in those with ECD and 3% in those without ECD. Here we report more WLST than mortality (21% in patients with ECD and 6% without patients with ECD). Although the data lack the granular information on WLST, the greater risk of WLST than mortality highlights the uncertainty of the current prognostication models after ischemic strokes.

For a third of patients, the WLST occurred on day 0 or 1. We found a significant increase in the trends of late WLST and a significant decrease in the proportions of early WLST. This change might be explained by the evolving management for AIS. Multiple successful interventional trials for recanalization of large vessel occlusion have been reported in the past few years, offering early treatment options for severe AIS.28-32 In addition, more attention has been focused on the effect of self-fulfilling prophecy in patients with acute brain injury, leading to avoidance of early WLST. Unlike the intracerebral hemorrhage guidelines, the current AHA/American Stroke Association (ASA) guidelines for AIS lack any recommendations regarding WLST.33,34 In our study, 43% of patients with ECD were discharged to home or to rehabilitation and 26% were independent at discharge. More patients with AIS are therefore expected to recover over a longer follow-up period and better prognostic models for patients with AIS with ECD need to be developed.

Our study has multiple limitations. We identified patients with ECD based on the presence of altered level of consciousness on initial examination findings, which might include patients with different levels of consciousness, including delirium. We did not have information on the etiology and the duration of ECD. Medications (such as sedation, stimulants, statin, and antiseizure medications) administered or withdrawn were not accounted for in our prognostication models as these data are not available in the registry. We had no details on clinical examination (brainstem reflexes, motor, and cognitive examination). We also had missing data for the ambulation status prior to hospitalization, thus prior functional status was not included in our model. Nevertheless, the proportions of ECD post AIS in our study are consistent with prior studies.9 Although NIHSS was missing in a quarter of our patients with AIS, we used the missing indicator approach in the analysis. ECD (including or excluding NIHSS) was associated with greater mortality, longer hospitalization, worse discharge disposition, and worse ambulation status. Data were also missing on the sub-item A1 of the NIHSS (level of consciousness) to validate the ECD ascertainment. In addition, the data lack the long-term cognitive and functional outcomes after AIS resulting in an insufficient indicator of overall outcomes in ECD post AIS. Long-term follow-up is an important measure to fully assess the effect of the self-fulfilling prophecy. We had no data on the withdrawal of specific treatments, such as mechanical ventilation, vasopressors use, feeding tube placement, and tracheostomy. Our data lack internal or external validation on the WLST measure during hospitalization.

Patients with AIS presenting with ECD had greater in-hospital mortality and worse discharge outcomes. Mortality risk was largely associated with the decision to withhold or withdraw life-sustaining treatment. The results of this study carry important clinical implications. Clinicians should make WLST decisions with caution as they may result in a self-fulfilling prophecy in managing patients with AIS and subsequently worse mortality and morbidity. The current AHA/ASA guidelines lack any recommendations regarding WLST in patients with AIS. More studies on long-term mortality and cognitive and functional outcomes are needed in patients with ECD after AIS.

Glossary

AHA

American Heart Association

AIS

acute ischemic stroke

ASA

American Stroke Association

ECD

early consciousness disorder

FL-PR CReSD

Florida–Puerto Rico Collaboration to Reduce Stroke Disparities

GEE

generalized estimating equation

GWTG-S

Get with the Guidelines–Stroke

NIHSS

National Institutes of Health Stroke Scale

WLST

withholding or withdrawal of life-sustaining treatment

Appendix. Authors

Appendix.

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Study Funding

The Florida Stroke Registry was funded by NINDS U54 NS081763 and is currently funded by the Florida Department of Health (COHAN A1).

Disclosure

A.J. Bustillo, N. Asdaghi, H. Ying, E. Marulanda-Londono, C. M. Gutierrez, D. Samano, E. Sobczak, D. Foster, M. Kottapally, A. Merenda, S. Koch, and K. O'Phelan report no disclosures relevant to the manuscript. A. Alkhachroum is supported by an institutional KL2 Career Development Award from the Miami CTSI NCATS UL1TR002736. J. Romano is supported by grant funding from NIH R01 NS084288, NIH R01 MD012467, and U24 NS107267. J. Claassen is supported by grant funding from NIH R01 NS106014 and R03 NS112760 and the DANA Foundation. R.L. Sacco is funded by the Florida Department of Health for work on the Florida Stroke Registry and by grants from the NIH (R01 NS029993, R01 MD012467, R01 NS040807, U10NS086528) and the National Center for Advancing Translational Sciences (UL1 TR002736 and KL2 TR002737) and receives compensation from the American Heart Association as Editor-In-Chief of Stroke. T. Rundek is funded by the Florida Department of Health for work on the Florida Stroke Registry and by the grants from the NIH (R01 MD012467, R01 NS029993, R01 NS040807, 1U24 NS107267) and the National Center for Advancing Translational Sciences (UL1 TR002736 and KL2 TR002737). This work represents the authors' independent analysis of local or multicenter data gathered using the AHA GWTG Patient Management Tool but is not an analysis of the national GWTG dataset and does not represent findings from the AHA GWTG National Program. Go to Neurology.org/N for full disclosures.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Florida Stroke Registry analyses are available per request sent to the Florida Stroke Registry Biostatistics Core and after approval of the Florida Stroke Registry Publication Committee.

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