The Intracerebral Hemorrhage Score: Changing Perspectives on Mortality and Disability

Journal Pre-proof The ICH Score: Changing Perspectives on Mortality and Disability Andrew LA. Garton, MD, Vivek P. Gupta, MD, Saurabh Sudesh, BA, MS, Henry Zhou, BA, MS, Brandon R. Christophe, BA, E. Sander Connolly, Jr., MD PII:

S1878-8750(19)33103-1

DOI:

https://doi.org/10.1016/j.wneu.2019.12.074

Reference:

WNEU 13921

To appear in:

World Neurosurgery

Received Date: 22 October 2019 Accepted Date: 12 December 2019

Please cite this article as: Garton AL, Gupta VP, Sudesh S, Zhou H, Christophe BR, Connolly Jr. ES, The ICH Score: Changing Perspectives on Mortality and Disability, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2019.12.074. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

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The ICH Score: Changing Perspectives on Mortality and Disability Andrew LA Garton MD1, Vivek P Gupta MD2, Saurabh Sudesh BA, MS3, Henry Zhou BA, MS3, Brandon R Christophe BA3, E. Sander Connolly Jr. MD3 1

Department of Neurosurgery, NewYork-Presbyterian Hospital / Weill Cornell Medical Center Department of Neurosurgery, Washington University in St. Louis School of Medicine 3 Department of Neurosurgery, Columbia University, Vagelos College of Physicians and Surgeons 2

Grant Support: The authors have no grants or financial conflicts of interest to disclose. Corresponding Author: Andrew Garton, Department of Neurosurgery NewYork-Presbyterian Hospital / Weill Cornell Medical Center 525 E 68th St. New York, NY 10065, USA [email protected]

Short Title: ICH Score, Mortality, and Disability Keywords: intracerebral hemorrhage; ICH Score; mortality; disability; functional outcomes; surgery; withdrawal of care Abstract Word Count: 241 Manuscript Word Count: 2,920 Number of References: 42

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Abstract: Background: Intracerebral hemorrhage (ICH) remains a devastating diagnosis. While the ICH

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Score continues to be utilized in the clinical setting to prognosticate outcomes,

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contemporary improvements in management have reduced mortality rates have for each

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scoring tier.

6 7 8 9

Objective: 1) Examine mortality rates within ICH Score strata and 2) examine if these findings are stable if major disability is included in categorizing poor outcomes Methods: Five hundred and eighty-two patients were extracted from a single-institution cohort built between 2009 – 2016 based on the criteria for complete ICH Score, discharge

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mortality, and functional status for survivors. Mortality rates were stratified by ICH Score

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and compared to both historical and similar contemporary cohorts. Poor outcome was

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defined as severe disability (mRS = 5) in addition to death, stratified by ICH Score, and

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compared. A secondary analysis of patients with ICH Scores of 2 was performed in light

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of the primary results.

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Results: The mortality rates stratified by ICH Score were notably lower than expected for mild

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and moderate grade ICH when compared to the original cohort. However, when defining

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a poor outcome as includinng severe disability (mRS = 5) in addition to death, the rates

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for poor outcomes were higher for ICH Scores of 2, (2: 51.16% vs. 26%, p = 0.017) and

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no different for any other score group when compared to the original cohort.

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Conclusion: Though the original ICH Score overestimates mortality for low- and moderate-grade hemorrhages, it may under-predict severe disability.

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Introduction: Intracerebral hemorrhage (ICH) is a serious condition accounting for 10-15% of all stroke

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presentations worldwide.1 Thirty-day, one-year, and ten-year mortality rates are as high as 48%,

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59%, and 82%.2 Although ICH incidence may be declining, the rate of hospital admissions for

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ICH has increased since the early 2000s, theoretically due to an aging population and the

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increased use of anticoagulants, thrombolytics, and antiplatelet agents.1, 3, 4 Morbidity rates for

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ICH remain high: in the early 2000s, it was found that 43% of ICH patients were alive with

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significant impairment at thirty days after ICH5; a more contemporary review found that fewer

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than 50% of patients with ICH survive to 1 year6. Furthermore, of all the various stroke subtypes,

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ICH leads to the longest duration of disability and long-term care needs.7

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Predictors of mortality in ICH have been studied thoroughly. Thirty-day mortality is

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significantly predicted by Glascow Coma Scale (GCS) score8, 9, hemorrhage volume8, 9,

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location10, intraventricular hemorrhage extension8, 11, expansion of perihematomal edema12, and

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age13, among other variables. Over a dozen prognostic models have been developed; arguably

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the most robust of these, according to a recent meta-analysis, is the ICH Score.5, 10, 14-17

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Developed in 2001, the ICH Score was derived from a single-institution cohort of patients, and

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identified GCS, age older than 80 years, infratentorial location, volume, and presence of

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intraventricular hemorrhage.10 However, recent studies suggest that the ICH Score may no longer

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be an accurate predictor of mortality. A retrospective study of 554 patients with spontaneous

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ICH found that the mortality rates predicted by the historical, original ICH Score cohort failed to

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reflect the groups’ observed mortality rates, suggesting that the previously described ICH Score

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mortality models tend to overestimate mortality in modern patient cohorts.18

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Modern advances in the treatment of patients with moderate to high-grade ICH have

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likely contributed to the observed improvement in mortality rates. A higher proportion of the

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population is on statins, theoretically associated with better ICH outcomes.19 Advancements in

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techniques, such as minimally invasive surgery in combination with thrombolytic agents, are

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promising additional strategies.20 Some treatments, such as aggressive blood pressure lowering,

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have been shown to reduce hematoma expansion and 3-month mortality rates, though

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importantly have not been shown to impact functional outcomes.21 These recent advancements in

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ICH critical care may have played a large role in decreasing mortality, but may not necessarily

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correlate with improved disability metrics.

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While mortality will always be of paramount importance in assessing intervention

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efficacy, it is also essential that other poor outcomes be considered during clinical decision-

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making. The ICH Score, for example, was originally devised with 30-day mortality as the

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measured outcome, but severe disability is another important outcome in ICH.22, 23 The ICH

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Score has since been validated for stratifying clinical outcomes (inspiring derivative scores such

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as ICH-FOS), and other studies have also indicated growing interest in measuring functional

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outcomes such as severe disability.24-27 The modified Rankin Scale (mRS), a commonly used

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scale ranging from 0 (no symptoms) to 6 (dead), is one method of codifying disability,

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particularly in stroke patients (a score of 5 typically indicates very severe disability).27-29 Given

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the increased awareness of outcomes as well as mortality, it is important to also analyze the

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shifting ICH Score mortality rates for concomitant changes in functional outcomes and

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disability.

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In this study, we sought to confirm previous descriptions that the original ICH Score

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cohort mortality rates have shifted over time as well as evaluate the rates of poor outcomes when

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accounting for severe disability as well as death.

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Methods:

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Data Collection:

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Between 2009-2017, 661 patients were prospectively enrolled in the Columbia University

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Medical Center Intracerebral Hemorrhage Outcomes Project (ICHOP) (IRB-AAAD4775). Data

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collected by trained clinicians and researchers included patient identifiers, admission scores,

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laboratory tests, etiology, imaging correlates, procedures and interventions, and discharge data.

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Follow-up information was collected by trained laboratory personnel via phone interviews with

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patients or caregivers; analysis presented here includes data from 6 and 12 months. Patients were

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excluded from final analysis if either ICH Scores, discharge mortality, or functional status were

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missing. Five hundred and eight-two patients were included in the final analysis.

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Measures: ICH Score: The ICH Score was first designed as a clinical grading scale that would allow

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for mortality prediction in patients with ICH.10 The five variables of interest are Glasgow Coma

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Score (GCS) (+2 points for GCS: 3-4, +1 point for GCS: 5-12), Age (+1 for ≥ 80), ICH volume

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(+1 for ICH ≥ 30cc), intraventricular hemorrhage (+1 for present), and location (+1 for

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infratentorial origin). A score of 0 correlates with 0% 30-day mortality, 1 – 13% mortality, 2 –

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26% mortality, 3 – 72% mortality, 4 – 94% mortality, 5 – 100% mortality, and 6 – 100%

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mortality10, 16, 18.

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mRS: The modified Rankin Scale (mRS) is a commonly used scale for measuring

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disability and/or dependence in stroke survivors as well as other neurologically disabled

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populations.28 The scale ranges from 0-6, where 0 indicates no functional dependence, 5

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indicates severe disability, and 6 indicates death. We define poor outcome in our study as severe

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disability or death, operationalized as an mRS of 5 or 6, which we use as the primary outcome

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metric in our analysis. The mRS has been widely validated and used as an operationalization of

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functional outcome in patients with ICH.29 This metric was obtained both during initial

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presentation as a baseline, either directly from the patient or from the individual providing the

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official history, as well as at discharge and during follow-up interviews.

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The ICHOP database does not record 30-day mortality rates. Instead, discharge mortality

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and functional status were available. Therefore, caution was used to only describe discharge

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mortality: when patients were discharged in under 30 days, care was used to correlate the

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discharge mRS with 3-month mRS. There were 3 cases in which a patient discharged in under 30

101

days was deceased by 3 months post-discharge without a clear date of death. After excluding

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these three patients, we feel confident that our record of discharge mortality does not

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underestimate 30-day mortality rates.

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Statistical Methods:

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After implementing exclusion criteria, the data were stratified by ICH Score and

107

compared to historical and contemporary cohorts. Analyses were conducted using R software

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(version 3.3.0, 2016, R Foundation for Statistical Computing, Vienna, Austria) and Microsoft

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Excel 2016 (version 15.29). Statistical significance was assessed at the P < 0.05 level unless

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otherwise noted. Descriptive statistics were calculated for variables of interest, including means

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and standard deviations or medians and ranges as needed. Characteristics of outcomes for

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patients with ICH Scores of 2 were compared using Chi-square tests for categorical variables and

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logistic regression for continuous variables.

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5 115 116

Results: In this cohort of patients, 582 patients were included in final analysis. Of this group,

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46.2% were female, 29.4% were white, and 35.7% were Hispanic; 52.1% presented with ICH

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involving the basal ganglia or the thalamus. The median ICH Score was 2. A histogram of ICH

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score distribution is shown in Figure 1. An EVD was required in 27.9% of patients, while 7.7%

120

required a hemicraniectomy. Additional relevant summary statistics are summarized in Table 1.

121 122

Mortality and Disability Rates:

123

Our first objective was to examine mortality rates after stratifying by ICH Score, as

124

shown in Table 2. The mortality rates increased with each increment in the ICH Score: 0 = 1.2%,

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1 = 5.06%, 2 = 13.18%. 3 = 45.05%, 4 = 67.65%, 5 = 86.67%, and 6 = 100%. Although

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mortality rates increased for each subsequent tier in the ICH Score, it was not to the extent

127

described by the original study; rates were significantly lower for scores 2-4 (Table 3).10 These

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mortality rates were, however, in agreement with a recent cohort published by McCracken et al.

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(2019), with the exception of ICH Scores of 2: 13.18% in the ICHOP cohort compared to

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30.30% in the McCracken et al. cohort (p = 0.0015).

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Poor outcome was defined as discharge mRS scores of 5 (severe disability) and 6 (death).

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These rates are displayed in Table 3. The only tier in which the rates of poor outcome differed

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from the original mortality rate was for ICH Scores of 2: 51.2% of our cohort with an ICH Score

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of 2 had a poor outcome compared to 26% mortality in the original ICH Score cohort (p =

135

0.026).10

136

Withdrawal-of-care (WOC) rates are described in Table 2; rates increased across ICH

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Score strata in a stepwise fashion such that while only 1-13% of patients with scores of 0-2 had

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care withdrawn, the rates for an ICH score of 3 and 4 were 45% and 68% respectively. Sixty

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percent of patients with an ICH Score of 5 had care withdrawn, while another 28% ultimately

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passed away despite maximal medical intervention.30

141

In order to evaluate the long-term outcome of patients who were left severely disabled

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(mRS = 5), functional outcomes were assessed at 6- and 12-months (Table 4). Nearly half of

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these patients had passed away by 6 (46%) and 12 months (48%). However, by 6 months after

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their initial presentation, 38% of patients that were described as severely disabled upon discharge

145

had at least some functional recovery (mRS 0 – 4), a number that dropped to 31% by 12 months.

6 146 147

Figure 2 displays the mortality and poor outcome rates for the present cohort, original ICH score derivation group, and the recent McCracken et al. (2019) study18.

148 149 150

Procedure Rates: Rates of surgical intervention (EVD placement, evacuation, and hemicraniectomy) were

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greatest in patients with ICH Scores of 2-3, subsequently declining as scores increased (Table 2).

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The rates of EVD placement and hemicraniectomy were significantly different across ICH Score

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strata (p = 1.78 x 10-9, p = 0.006, respectively), though surgical evacuation was not (p = 0.076).

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In multivariate analyses controlling for covariates (smoking status, anticoagulation history, age,

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ICH score, NIHSS on admission), only surgical evacuation was associated with reduced odds of

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mortality (OR: 0.88, p < 0.01); EVD placement and hemicraniectomies were not significantly

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associated with death. However, multivariate analysis for poor outcomes including severe

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disability revealed that, while surgical evacuation was associated with improved outcomes (OR:

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0.85, p = 0.002), EVD placement (OR: 1.19, p < 0.001) and hemicraniectomies (OR: 1.22, p =

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0.002) were associated with poorer outcomes, i.e. severe disability as well as death.

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Secondary Analysis of Mortality and Disability in ICH Scores of 2 Given the disparity between the mortality rate and disability rate in the subset of patients

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with ICH scores of 2, these patients were subsequently examined further. Within the cohort of

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patients with ICH scores of 2, (n = 129), 14.7% had mRS scores of 0-3 at discharge, 34.1% had

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mRS scores equal to 4, 38.0% equal to 5, and 13.2% died (therefore with a poor outcome rate of

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51.2%). Given the disparity between the rate of mortality, along with the above findings that

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EVD placement and hemicraniectomies were associated with severe disability but not

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necessarily with mortality, the multivariate analysis was re-performed. After controlling for

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smoking status, NIHSS, and age, only EVD placement was associated with mortality (OR: 1.14,

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p = 0.05). However, the same analysis for poor outcomes indicated that hemicraniectomies were

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associated with greater disability and death (OR: 1.42, p = 0.020), while EVD placement (OR:

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1.20, p = 0.07) and surgical evacuation (OR: 0.78, p = 0.07) were not related to poor outcomes.

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Discussion:

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Our study reinforces other recent studies showing a marked decrease in mortality now as

177

compared to the original ICH Score cohort.18 We provide further evidence that the original 30-

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day mortality predictions specified by the original ICH Score may no longer be entirely accurate.

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However, if instead of using the ICH Score to predict mortality in our cohort ,we use it to predict

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short term poor outcome (defined as mRS of 5 or greater), we find that the rates of poor outcome

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are nearly identical to the 30-day mortality projections in the original ICH Score cohort (Figure

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2). This suggests that in the time since the creation of the original ICH score, we have become

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more adept at keeping patients alive, but have not yet been able to reduce the burden of

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functional disability in the patients that are now surviving ICH events that previously would have

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been fatal.

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This distinction between overall survival and severe disability is an important one in

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outcomes research, particularly in stroke and ICH.31, 32 Although the emphasis on mortality is

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helpful in that it creates an objective, binary outcome, disability drives quality of life33, mental

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health34-36, and systemic costs.37 As alluded to above, there are numerous scoring systems for

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prognosticating ICH, yet the focus for many, if not most, of these scales is death.17, 38 However if

191

there were a shift towards “treating to functional outcomes,” then acknowledging the high rates

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of severe disability, as demonstrated here, becomes of paramount importance in shifting

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prognostication metrics. We have previously shown that attempts to predict 3-month and 12-

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month functional outcomes, while incorporating similar variables to the ICH Score, ends up

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emphasizing pre-morbid functional status and acute physiological measurements (i.e. the Acute

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Physiology, Age, Chronic Health Evaluation (APACHE) II score).29 Additional validated score

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systems have simply taken the original ICH score and shown that the NIH stroke scale and blood

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glucose are independent, robust predictors of functional outcome at one year.25 Perihematomal

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edema has been shown to correlate with functional outcomes39, and although with mixed

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success, there are ongoing clinical directed at reducing this prognosticator.40, 41 In short, we

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believe that this data contributes to an ongoing shift towards treating functional outcomes

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including severe disability rather than mortality.

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One discrepancy in this pattern exists for patients in our cohort with an ICH Score of 2.

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Our mortality rate is lower (13.2%) compared to the original ICH Score cohort (26.0%) and the

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cohort described by McCracken et al (30.3%).18 However, 40% of this cohort has an mRS of 5 at

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discharge, bringing the total for poor outcomes to 53.2% for patients with an ICH Score of 2. As

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described in our results section, subgroup analysis for this cohort suggests that surgical

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evacuation is weakly associated with better outcomes while hemicraniectomy and EVD

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placement are associated with poorer outcomes, though only EVD placement is truly associated

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with actual mortality. This finding again suggests that these temporizing measures reduce

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mortality even in patients with a relatively low ICH Score, but that these patients instead

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encounter high morbidity and functional debilitation. This has always been true; a large series

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from 2008 showed that, at 90 days, only 26% of patients achieve functional independence on the

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Glasgow outcome scale.42 Therefore, it remains imperative to assess interventions from a more

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longitudinal perspective. The authors of McCracken et al. (2019) suggest that the ICH Score might be a self-

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fulfilling prophecy in the sense that once a patient has been assigned a score, the extent to which

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they are intervened upon is based mortality prognostication derived from the rates found in the

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original ICH Score paper.10 As an example, the ICH Score’s prognostication could influence the

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discussion that the physician and the patient’s family have which may result in withdrawal of

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care or absence of more invasive treatment methods. However, when we look at the data from

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our study, we see that while there are different rates of procedures between patients of differing

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ICH Scores, these differences are not statistically significant with the exception of patients with

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an ICH Score of 6 (of which our dataset only has one). This contradicts the notion that outcomes

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are a self-fulfilling prophecy, as patients were intervened upon at similar rates regardless of their

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clinical picture. Additionally, withdrawal of care rates increased with ICH Score, though rates were

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overall steady on a year by year basis, starting with 2009, the first year included in this database.

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This suggests that, despite the advancements in ICH treatment and care, changes in rates of

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withdrawal of care were not the primary contributing factor to the shift in outcomes from

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mortality to functional morbidity. Furthermore, for patients with an ICH Score of 2 through 5,

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the majority of deaths were directly attributable to withdrawal of care, suggesting that death in

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spite of maximal medical and surgical intervention may be even less common than indicated

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here.

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It is possible that this analysis is not sensitive enough to pick up more granular details that may impact the decision to invasively intervene, but suggests that further exploration of this

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discrepancy is warranted to help guide clinical decision in order to optimize patient selection and

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therefore outcome.

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Overall, our findings, combined with other recent studies, suggest that the original

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mortality predictions defined by the ICH Score in a cohort of patients back in 2001 are no longer

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absolutely accurate for present-day treatment, and could be updated to encompass advances in

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care contributing to reduced mortality in these patients. However, it should also be noted that

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reduced mortality is no longer the end goal in caring for patients with ICH, as functional

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outcome is just as important, if not more so. Thus, updates to the original ICH Score could

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consider prognosticated functional disability in ICH patients to facilitate discussions with

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patients and family members, improve communication between physicians regarding a patient’s

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status, and facilitate research endeavors in this area.

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Conclusion: Though the original ICH Score likely overestimates mortality for low- and moderate-

251

grade hemorrhages, it may under-predict severe disability. Surgical intervention rates varied by

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ICH Score group, and though there was no association with increased mortality, intervention did

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correlate with greater disability. These findings taken together suggest that ICH Score remains a

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useful metric in clinician decision making, especially when accounting for severe disability as

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well as mortality.

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Table 1. Summary statistics for all ICH patients. Age (mean +/- SD) 62.8 +/- 17.6 Sex (%) Female 46.2% Ethnicity (%) White 29.4% Black 25.0% Hispanic 35.7% Asian 5.6% Other/Unspecified 4.3% Location (%) Left-sided 47.4% Basal Ganglia 32.1% Thalamus 20.0% ICH Score and components (Median, IQR) ICH Score 2, 0-4 GCS 11, 7-15 IVH Present (%) 43.8% ICH Volume (mean, SD) 9.18, 18.17 Procedures (%) EVD Placement 27.9% Surgical Evacuation 12.6% Hemicraniectomy 7.7% Past Medical History (%) Smoking 29.6% Anticoagulants 12.8%

Table 2. Mortality and surgical intervention rates stratified by ICH score. Mortality Surgical Hemicrani Smoking Attributable EVD Hematoma Evacuation NIHSS ICH Mortality Withdrawal (%, n = (%, n = to (%, n Volume n, % (%, n = (mean) Score Rate (%) of Care (%) 585) 585) Withdrawal = 585) (mean) 585) of Care 83, 0% 0 1.2% 0, 0.0% 1.22% 7.23% 2.41% 26.51% 4.6 7.9 14.19% 178, 100% 1 5.06% 9, 5.06% 19.66% 8.43% 3.37% 33.71% 7.89 18.1 30.43% 129, 82.3% 2 14, 10.85% 35.66% 17.83% 14.73% 27.91% 14.53 19.86 13.18% 22.05% 52.0% 111, 26, 23.42% 41.44% 3 18.02% 10.81% 32.43% 23.93 43.25 45.05% 18.97% 68, 47.8% 4 22, 32.35% 32.35% 14.71% 8.82% 23.53% 30.33 55.57 67.65% 11.62% 15, 69.2% 5 86.67% 9, 60.00% 20.00% 13.33% 6.67% 20.00% 31.86 79.24 2.56% 1, 0% 6 100% 0, 0.00% 0.00% 0.00% 0.00% 0.00% 38 36 0.17%

Table 3. Comparison of mortality rates across cohorts, including disability rate for present sample. ICHOP Original ICH Score McCracken et al., 2019 mRS 5-6 ICH 12 17 Mortality Rate Rate Score Mortality Rate Mortality Rate Projection 0 1.2% 0.00% 0.60% 7.23% 1 5.06% 13.00% 6.60% 17.42% 2 26.00% 30.30% 13.18% 51.16% 3 72.00% 48.80% 78.38% 45.05% 4 97.00% 70.60% 95.59% 67.65% 5 86.67% 99.00% 100.00% 100.00% 6 100% 99.00% -100.00% Bolded values indicate statistically significant differences in mortality rates between present cohort and Hemphill et al., 2001.

Table 4. Long-term outcomes of patients left severely disabled (mRS = 5) at discharge. 6-month Outcomes 12-month Outcomes mRS = 0-4 mRS = 5 mRS = 6 mRS = 0-4 mRS = 5 mRS = 6 % of 37.86% 23.30% 45.63% 30.53% 21.05% 48.42% patients

Figure 1: Histogram of ICH Scores

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Figure 2. Mortality and poor outcome rates across cohorts. Expected mortality derived from original ICH score cohort. 100.00% 90.00% 80.00%

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Poor Outcome in Present Cohort

Highlights • Corroborates recent findings that ICH score mortality estimates are no longer accurate given contemporary management • Although mortality rates have declined, the percentage of patients with severe or debilitating outcomes remains high, indicating that those patients who would have previously suffered fatal outcomes are still sustaining very poor outcomes • However, 1/3rd of patients with mRS outcomes of 5 at discharge improve their outcomes at 6- and 12-month follow-up, indicating that ongoing rehabilitation offers these patients a better chance at improved quality of life

Abbreviations: GCS: Glasgow coma scale ICH: Intracerebral hemorrhage mRS: Modified Rankin scale EVD: External ventricular drain WOC: Withdrawal of care

The authors have no conflicts of interest to disclose.