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(Stroke. 1997;28:1-5.)
© 1997 American Heart Association, Inc.

Articles

Early Hemorrhage Growth in Patients With Intracerebral Hemorrhage

Thomas Brott, MD; Joseph Broderick, MD; Rashmi Kothari, MD; William Barsan, MD; Thomas Tomsick, MD; Laura Sauerbeck, RN; Judith Spilker, RN; John Duldner, MD Jane Khoury, MS

the University of Cincinnati (Ohio) Medical Center (T.B., J.B., R.K., T.T., L.S., J.S., J.K.); University of Michigan Medical Center, Ann Arbor (W.B.); and MetroHealth Medical Center, Cleveland, Ohio (J.D.).

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The goal of the present study was to prospectively determine how frequently early growth of intracerebral hemorrhage occurs and whether this early growth is related to early neurological deterioration.

Methods We performed a prospective observational study of patients with intracerebral hemorrhage within 3 hours of onset. Patients had a neurological evaluation and CT scan performed at baseline, 1 hour after baseline, and 20 hours after baseline.

Results Substantial growth in the volume of parenchymal hemorrhage occurred in 26% of the 103 study patients between the baseline and 1-hour CT scans. An additional 12% of patients had substantial growth between the 1- and 20-hour CT scans. Hemorrhage growth between the baseline and 1-hour CT scans was significantly associated with clinical deterioration, as measured by the change between the baseline and 1-hour Glasgow Coma Scale and National Institutes of Health Stroke Scale scores. No baseline clinical or CT prediction of hemorrhage growth was identified.

Conclusions Substantial early hemorrhage growth in patients with intracerebral hemorrhage is common and is associated with neurological deterioration. Randomized treatment trials are needed to determine whether this early natural history of ongoing bleeding and frequent neurological deterioration can be improved.

Key Words: computed tomography • intracerebral hemorrhage • prognosis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Intracerebral hemorrhage, which affects an estimated 37 000 persons in the United States annually,¹ has a 30-day mortality rate of 35% to 52%.^{2 3 4 5} Half of these deaths occur within the first 2 days.⁶ Only one fifth of the survivors are independent at 6 months.⁵ No surgical or medical treatment has proved effective,^{7 8 9 10 11 12 13 14} although an estimated 7000 operations to remove ICH are performed in the United States each year.¹⁵

One key to developing an effective treatment is improved understanding of the pathophysiology and early natural history of ICH. Until recently, bleeding in patients with ICH was thought to be completed within minutes of onset.¹⁶ Frequently observed neurological deterioration during the first day was attributed to developing cerebral edema and mass effect surrounding the hemorrhage.¹⁷ Recently, several small retrospective series described a few patients who had an increase in the volume of parenchymal hemorrhage on repeated CT scans of the head.^{18 19 20 21 22} None of these studies examined prospectively how commonly early growth of ICH occurs and whether this early growth is related to early neurological deterioration. This prospective study of patients with ICH addresses this question.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Objectives
The primary objective of this prospective observational study was to determine the proportion of patients with a primary spontaneous ICH who have ongoing intracerebral bleeding, as measured by serial CT scanning during the first 20 hours after onset of symptoms. Secondary objectives included the following: (1) to determine whether early hemorrhage growth is significantly associated with early neurological deterioration, as measured by changes in GCS and NIH Stroke Scale scores; (2) to determine which factors (particularly initial blood pressure, coagulation parameters, and location of hemorrhage) are significantly associated with hemorrhage growth; and (3) to determine whether patients with early hemorrhage growth have a significantly higher mortality and poorer functional outcome than patients without early hemorrhage growth.

Recruitment of Patients: The Greater Cincinnati–Northern Kentucky Stroke Network
The Greater Cincinnati Stroke Network is composed of one university and 11 community hospitals throughout Greater Cincinnati and northern Kentucky. During the 6 years of the study (1989 to 1994), all of these hospitals participated in acute stroke studies of thrombolytic therapy as well as the present study of ICH. If a patient with signs and symptoms of an acute stroke presented to a study hospital within several hours of onset, the hospital would page a university-based team of physician investigators (two neurologists and two emergency physicians). One of these investigators would respond immediately to the page and discuss the patient with the referring emergency department physician. If the patient appeared to be a possible candidate for either the acute hemorrhagic stroke study or the thrombolytic study for ischemic stroke, the physician investigator would leave immediately for the hospital. At the hospital, the physician investigator would examine the patient and obtain a definite time of stroke onset, review the patient's emergency CT scan, and determine whether the patient was a candidate for either acute stroke study. If the patient was thought to be eligible for the acute hemorrhagic stroke study, the investigator would discuss the study with the patient and family and obtain informed consent from the patient or the patient's legal representative.

Criteria for Enrollment in the Study
Subjects for this study were selected from patients who presented with an ICH at one of 12 study hospitals. Inclusion criteria were as follows: the patient was aged 18 or older, had evidence of ICH on a CT of the head performed within 3 hours of symptom onset, and had provided informed consent. Exclusion criteria included hemorrhage due to trauma, ruptured aneurysm, arteriovenous malformation, tumor, or use of anticoagulants. Subarachnoid hemorrhage could be present but had to be thought by the study neuroradiologist to be secondary to the ICH. Patients with isolated IVH were excluded. A definite time of onset was obtained for all study patients. For patients who awoke with a stroke, the time of onset was considered to be when they were last seen awake and without symptoms.

Study Design
Upon arrival to the emergency department, each patient underwent a baseline CT of the head and neurological evaluation as measured by the GCS²³ and the NIH Stroke Scale.²⁴ A baseline complete blood count, prothrombin time, and partial thromboplastin time were also obtained. The CT scan and neurological evaluation were repeated approximately 1 hour and 20 hours after the baseline CT and neurological evaluation. Blood pressure, pulse, and level of consciousness were obtained every 30 minutes for the first 2 hours after baseline CT and then every hour for 24 hours. Functional status at 4 to 6 weeks was measured by the Barthel Index,²⁵ Modified Rankin Scale,²⁶ and Glasgow Outcome Scale.²⁷

CT scans were performed on scanners with a 512x512 matrix with 8- to 10-mm slices and the standard imaging protocol for a given study hospital. Repeated CT scans were obtained with the same standard imaging protocol at a given hospital. The study neuroradiologist identified and circled each region of ICH, IVH, and subarachnoid hemorrhage separately on each study film and then reviewed these films with the image analysis technician. Each film image was then photographed and digitized into a computerized image analysis system and analyzed according to a previous population-based study of ICH and subarachnoid hemorrhage in Greater Cincinnati during 1988.⁶

Hemorrhage growth was operationally defined as an increase in the volume of intraparenchymal hemorrhage of >33% as measured by image analysis on the 1- or 20-hour CT compared with the baseline CT scan. The conservative number of 33% was chosen prospectively for two reasons. First, a 33% change in the volume of a sphere corresponds to a 10% increase in diameter, a clear difference to the naked eye of a physician viewing serial CT scans of a patient with ICH. Secondly, before this study, preliminary measurement of serial CTs in patients with ICH indicated that some patients had up to a third less volume of hemorrhage on the 1-hour CT than on the baseline CT. We thought that this "decrease" was due to different positioning and angles of the CT slice images in the baseline and 1-hour CTs rather than to an actual decrease in hemorrhage volume. This observation was particularly true for small hemorrhages. Thus, we were confident that our CT definition of growth represented true hemorrhage growth and not variability in CT imaging.

Statistical Analysis
The primary study hypothesis to be tested was that >33% of patients with an ICH who have a CT scan within 3 hours of symptom onset have growth in volume of parenchymal hemorrhage on subsequent CT scans. A ² test was used to test this hypothesis by comparing the actual proportion of patients in the study who had hemorrhage growth of >33%. ² and nonpaired t tests were used to compare patients with and without hemorrhage growth as to the following variables: age, sex, race, current smoking, prior stroke, use of antiplatelet agents before hemorrhage, diabetes, history of hypertension, mean initial blood pressure, mean blood pressure during the first hour, initial systolic blood pressure 230 mm Hg, initial diastolic blood pressure 125 mm Hg, location of hemorrhage, volume of ICH on baseline CT, volume of IVH on baseline CT, time to first CT scan, baseline platelet count, and baseline prothrombin and partial thromboplastin times. The Wilcoxon rank sum test was used to compare the initial GCS score in patients with and without hemorrhage growth. The Wilcoxon rank sum test was also used to compare patients with and without hemorrhage growth as to the change in the NIH Stroke Scale score and GCS score from baseline to 1 hour, as well as the Rankin, Barthel, and Glasgow Outcome scores at 4 to 6 weeks. Mortality at 4 to 6 weeks for the two groups was compared by a ² test. Logistic regression was used to investigate possible multiple risk factors for growth in hemorrhage volume from baseline to 1 hour. All statistical tests were two-tailed, and P.05 was considered significant. Data are presented as mean±SD.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of the 142 patients who underwent a baseline CT and neurological examination, 7 patients were excluded because of anticoagulant use, 5 for an associated ruptured aneurysm or suggested aneurysm, 4 for an associated arteriovenous malformation, 1 because of head trauma, and 10 because of incomplete clinical or CT data. Failure to obtain the 1-hour CT scan occurred in 10 patients because of patient care issues, and in 2 patients informed consent was unobtainable. These patients are not included in the following analyses of the remaining 103 patients.

The mean time from onset of symptoms to baseline CT scan was 89±37 minutes. Growth in the volume of parenchymal hemorrhage of >33% occurred in 27 (26%) of the 103 study patients between the baseline and 1-hour CTs (Table 1). The mean volume of parenchymal hemorrhage was 26±29 mL on the baseline CT scan and 32±32 mL on the 1-hour CT scan. The mean combined volume of ventricular and parenchymal hemorrhage was 35±35 mL on the baseline CT scan and 44±44 mL on the 1-hour CT scan. An additional 12 patients (12%) who did not have >33% growth between the baseline and 1-hour CTs had >33% growth between the 1- and 20-hour CT scans. Thus, we identified 39 (38%) of the 103 study patients who had >33% growth in the volume of parenchymal hemorrhage during the first 20 hours after the baseline CT scan.

View this table: [in this window] [in a new window]   Table 1. Hemorrhage Growth of >33% Between Baseline, 1-Hour, and 20-Hour CT Scans by Location

Hemorrhage growth between the baseline and 1-hour CT scans was significantly associated with clinical deterioration as measured by the change between the baseline and 1-hour GCS and NIH Stroke Scale scores (Table 2). However, individual patients had significant hemorrhage growth without neurological deterioration (Fig 1). There was a nonsignificant trend toward poorer functional outcome and higher mortality at 4 to 6 weeks in patients with hemorrhage growth (Table 2).

View this table: [in this window] [in a new window]   Table 2. Hemorrhage Growth at 1-Hour CT and Neurological Outcome

View larger version (44K): [in this window] [in a new window]   Figure 1. This 66-year-old white man with a baseline GCS score of 14 and NIH Stroke Scale score of 20 had a putaminal hemorrhage with a baseline ICH volume of 10 mL (top row). The ICH volume on the 1-hour CT was 27 mL (bottom row). However, the 17-mL increase in ICH volume was not accompanied by any change in the 1-hour GCS (14) and NIH Stroke Scale (20) scores.

We found no significant predictor of hemorrhage growth on serial CTs, although a higher but nonsignificant growth rate was seen in thalamic hemorrhages (Tables 1 and 3, Figs 2 through 4).

View this table: [in this window] [in a new window]   Table 3. Comparison of Baseline Variables and Hemorrhage Growth Between Baseline and 1-Hour CTs

View larger version (19K): [in this window] [in a new window]   Figure 2. Patients with putaminal hemorrhages who had >33% growth in ICH volume by 1-hour CT (excludes 20-hour CTs for patients with surgical procedure between 1- and 20-hour CTs or patients who died or who could not undergo scan).

View larger version (18K): [in this window] [in a new window]   Figure 3. Patients with thalamic hemorrhages who had >33% growth in ICH volume by 1-hour CT (excludes 20-hour CTs for patients with surgical procedure between 1- and 20-hour CTs or patients who died or who could not undergo scan).

View larger version (14K): [in this window] [in a new window]   Figure 4. Patients with lobar hemorrhages who had >33% growth in ICH volume by 1-hour CT (excludes 20-hour CTs for patients with surgical procedure between 1- and 20-hour CTs or patients who died or who could not undergo scan).

Of the 103 patients, 13 underwent an operation to remove the hemorrhage and 12 had placement of an intraventricular catheter after the 1-hour CT and before the 20-hour CT. The mean time from symptom onset to operation in these patients was 6.3±4.8 hours. An additional 9 patients underwent an operation after the first 24 hours. The earliest surgical intervention was at 1.25 hours after symptom onset, 0.9 hour after arrival to the hospital. Medical treatment during the first 20 hours included antihypertensive medication in 76% of patients, intubation in 38%, and mannitol for increased intracranial pressure in 20%.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
At least 38% of patients had >33% growth in the volume of parenchymal hemorrhage during the first 24 hours after symptom onset. This percentage is an underestimate since we did not include 20-hour CT scans from 35 of the 103 patients who had a surgical procedure after the 1-hour CT (n=13), who died before the 20-hour CT (n=6), or who were too moribund to undergo the 20-hour CT (n=16). Most of the ongoing bleeding occurred within the first 3 to 4 hours after hemorrhage onset and was associated with early neurological deterioration. These data contradict pre-CT studies that bleeding in ICH is completed within minutes after onset¹⁶ and confirm several small retrospective CT series of ICH that showed ongoing bleeding during the first several hours.^{18 19 20 21 22}

The dynamic nature of ICH during the first several hours represents an opportunity and a challenge to physicians. Our patients with hemorrhage growth had a mean initial GCS score of 12. However, nearly a third of our patients deteriorated in the hour after the first CT scan, and an additional 25% deteriorated within the next 20 hours. Thus, nearly half of patients with hemorrhage growth deteriorated significantly during the first 20 hours after arrival at the hospital. Even 34% of patients without hemorrhage growth had significant neurological deterioration during the first 24 hours.

If one could stop the bleeding during the first few hours and remove the accumulated blood without significant additional brain trauma from the operation, neurological deterioration and poor outcome could be prevented in some patients. Unfortunately, operative removal of blood clot and hemostasis within the first 3 to 4 hours are extremely rare at present. In this series, the earliest surgical intervention among the operated patients was 1.25 hours. Operative removal of ICH at later time periods has not been shown to improve patient outcome, although an estimated 7000 operations to remove ICH are performed annually in the United States¹⁵ A multicenter, randomized trial of very early surgery for ICH is currently being organized (the STITCH Study, Dr James Grotta, Principal Investigator).

Prediction of hemorrhage growth at baseline would be a first step toward an effective therapy. We were disappointed to find no clinical or CT predictor of hemorrhage growth, such as marked elevations in the baseline blood pressure. However, the frequent very early treatment of moderately or severely elevated blood pressure in 76% of the 103 study patients obscures any relationship between sustained elevated blood pressure and hemorrhage growth.

A trend toward more frequent hemorrhage growth was seen in patients with thalamic hemorrhage. Small retrospective series have also reported that a relative preponderance of patients with early hemorrhage growth had a thalamic, putaminal, or brain stem hemorrhage.^{18 22} We speculate that hemorrhages originating in the periventricular regions are more likely to expand toward the nearby ventricular fluid spaces because the fluid spaces are more compressible than surrounding brain parenchyma.²⁸ Of the 27 parenchymal hemorrhages that grew during the first hour, 52% also had hemorrhage into the ventricles.

There was a trend toward earlier arrival to the hospital for patients who had hemorrhage growth (a mean of 1.3 hours) compared with those patients without growth (1.5 hours). In addition, the volume of parenchymal hemorrhage on the baseline CT was larger in the patients without hemorrhage growth, whereas the parenchymal hemorrhage volume at 1 hour was greater for patients with hemorrhage growth. These two groups of patients, those with and without growth by our definition, probably represent "snapshots" of hemorrhage patients at two different time points along the hemorrhage growth curve.

Are our findings generalizable to spontaneous ICHs in the population at large? Table 4 compares the patient characteristics of the 103 study patients recruited during 1989 to 1994 and all 163 patients who had an ICH among the Greater Cincinnati population during 1988 and for whom CT films were available for review. Patients in the present study were significantly younger, more likely to be male and black, more likely to have a deep hemorrhage, and less likely to have a prior stroke. More patients in the present study were admitted to hospitals that cared for neighborhoods with a higher proportion of black patients. Finally, patients in the present study arrived earlier at the hospital. However, the mean baseline GCS score and the mean volumes of ICH and IVH on the 1-hour CT in our present study were similar to baseline findings in the 1988 epidemiological study.

View this table: [in this window] [in a new window]   Table 4. Comparison of Present Prospective Observational Study and 1988 Epidemiological Study of ICH

In conclusion, substantial early hemorrhage growth in patients with ICH is common and is associated with neurological deterioration. Randomized treatment trials of very early surgery are needed to determine whether the frequent early neurological deterioration and long-term poor outcome for patients with ICH can be improved.

	Selected Abbreviations and Acronyms

 

GCS = Glasgow Coma Scale ICH = intracerebral hemorrhage IVH = intraventricular hemorrhage NIH = National Institutes of Health

	Acknowledgments

 
This study was supported by National Institute of Neurological Disorders and Stroke grant NS26933. We would like to acknowledge the following persons for their contributions to this manuscript: George Korkoris, MD; Rosie Miller, RN, CCRC; Kari Dunning, MSPT; and Preeti Rao, MD.

	Footnotes

 
Reprint requests to Joseph P. Broderick, MD, University of Cincinnati Medical Center, Department of Neurology, PO Box 670525, Cincinnati, OH 45267-0525. E-mail JBRODER@UC.EDU.

Received August 5, 1996; revision received October 14, 1996; accepted October 15, 1996.

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				H. B. Huttner, P. D. Schellinger, M. Hartmann, M. Kohrmann, E. Juettler, J. Wikner, S. Mueller, U. Meyding-Lamade, R. Strobl, U. Mansmann, et al. Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy: Comparison of Acute Treatment Strategies Using Vitamin K, Fresh Frozen Plasma, and Prothrombin Complex Concentrates Stroke, June 1, 2006; 37(6): 1465 - 1470. [Abstract] [Full Text] [PDF]

				D. A. Godoy, G. Pinero, and M. Di Napoli Predicting Mortality in Spontaneous Intracerebral Hemorrhage: Can Modification to Original Score Improve the Prediction? Stroke, April 1, 2006; 37(4): 1038 - 1044. [Abstract] [Full Text] [PDF]

				R.D. Zimmerman, J.A. Maldjian, N.C. Brun, B. Horvath, and B.E. Skolnick Radiologic Estimation of Hematoma Volume in Intracerebral Hemorrhage Trial by CT Scan AJNR Am. J. Neuroradiol., March 1, 2006; 27(3): 666 - 670. [Abstract] [Full Text] [PDF]

				M O McCarron, P McCarron, and M J Alberts Location characteristics of early perihaematomal oedema. J. Neurol. Neurosurg. Psychiatry, March 1, 2006; 77(3): 378 - 380. [Abstract] [Full Text] [PDF]

				M. A. Ewanchuk and D. A. Hudson Best evidence in anesthetic practice: Recombinant activated factor VII for acute intracerebral hemorrhage: a promising therapy for a devastating problem? Can J Anesth, March 1, 2006; 53(3): 250 - 251. [Full Text] [PDF]

				C Foerch, I Curdt, B Yan, F Dvorak, M Hermans, J Berkefeld, A Raabe, T Neumann-Haefelin, H Steinmetz, and M Sitzer Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke J. Neurol. Neurosurg. Psychiatry, February 1, 2006; 77(2): 181 - 184. [Abstract] [Full Text] [PDF]

				S. Tuhrim Aspirin-Use Before ICH: A Potentially Treatable Iatrogenic Coagulopathy? Stroke, January 1, 2006; 37(1): 4 - 5. [Full Text] [PDF]

				J. N. Goldstein, S. H. Thomas, V. Frontiero, A. Joseph, C. Engel, R. Snider, E. E. Smith, S. M. Greenberg, and J. Rosand Timing of Fresh Frozen Plasma Administration and Rapid Correction of Coagulopathy in Warfarin-Related Intracerebral Hemorrhage Stroke, January 1, 2006; 37(1): 151 - 155. [Abstract] [Full Text] [PDF]

				P. Saloheimo, M. Ahonen, S. Juvela, J. Pyhtinen, E.-R. Savolainen, and M. Hillbom Regular Aspirin-Use Preceding the Onset of Primary Intracerebral Hemorrhage is an Independent Predictor for Death Stroke, January 1, 2006; 37(1): 129 - 133. [Abstract] [Full Text] [PDF]

				M. L. Flaherty, D. Woo, M. Haverbusch, C. J. Moomaw, P. Sekar, L. Sauerbeck, B. Kissela, D. Kleindorfer, and J. P. Broderick Potential Applicability of Recombinant Factor VIIa for Intracerebral Hemorrhage Stroke, December 1, 2005; 36(12): 2660 - 2664. [Abstract] [Full Text] [PDF]

				K. Toyoda, Y. Okada, K. Minematsu, M. Kamouchi, S. Fujimoto, S. Ibayashi, and T. Inoue Antiplatelet therapy contributes to acute deterioration of intracerebral hemorrhage Neurology, October 11, 2005; 65(7): 1000 - 1004. [Abstract] [Full Text] [PDF]

				K W Muir and C Santosh Imaging of acute stroke and transient ischaemic attack J. Neurol. Neurosurg. Psychiatry, September 1, 2005; 76(suppl_3): iii19 - iii28. [Full Text] [PDF]

				J. P. Broderick The STICH Trial: What Does It Tell Us and Where Do We Go From Here? Stroke, July 1, 2005; 36(7): 1619 - 1620. [Full Text] [PDF]

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