Intracerebral Hemorrha

ge with Hypothyroidism

Alexandra Czap, MD,* John P. Shoup, BA,* Jonathan Winkler, BA,* Ilene Staff, PhD,†

Gil Fortunato, MBA,† Carl Malchoff, MD, PhD,* Louise D. McCullough, MD, PhD,*†

and Lauren H. Sansing, MD, MSTR*†

From the *University

Connecticut; and †Hartfo

Received January 8, 20

July 27, 2013.

Grant support: Hartfo

Hartford Hospital, and T

Center, University of Con

Disclosure: None.

Address corresponden

Neurology, University of

Ave, Farmington, CT 060

1052-3057/$ - see front

� 2013 by National Str

http://dx.doi.org/10.1

e602

Background: Hypothyroidism is associated with increased ischemic stroke risk but

paradoxically results in more favorable outcomes once a stroke occurs. Whether

a similar pattern emerges in patients with primary intracerebral hemorrhage

(ICH) is unknown. Methods: A retrospective analysis of a prospective stroke center

database was performed to analyze the clinical presentation and outcomes of hypo-

thyroid patients with spontaneous ICH. Patients were classified into groups with no

history of thyroid disease (n5 491) versus those with hypothyroidism (n5 72). Hy-

pothyroid patients were further classified into patients receiving thyroid replace-

ment on admission or those without replacement. The Glasgow Coma Scale, ICH

score, and the National Institutes of Health Stroke Scale (NIHSS) were used to assess

the initial severity. Outcome was assessed by admission to discharge change in the

NIHSS and modified Barthel Index (mBI), in-hospital mortality, discharge disposi-

tion andmortality, and the mBI at 3 and 12 months. Results: There were 563 patients

in the analysis. Seventy-two patients had a history of hypothyroidism, and of these,

63% received thyroid hormone replacement. Patients receiving replacement had sig-

nificantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either

the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replace-

ment (median 9 [IQR 3.8, 15.5]; P 5 .004). There was no difference in in-hospital

and 3-month mortality or functional outcomes at 3 and 12 months among the

groups. Conclusions: This study suggests that the history of hypothyroidism does

not affect clinical severity or outcome after ICH. Key Words: Intracerebral

hemorrhage—severity—outcomes—hypothyroidism—retrospective studies.

� 2013 by National Stroke Association

Introduction

Intracerebral hemorrhage (ICH) accounts for 10%-15%

of all strokes annually, resulting in devastating morbidity

and mortality.1,2 Hospital admissions for ICH have

of Connecticut Health Center, Farmington,

rd Hospital, Hartford, Connecticut.

13; revision received July 8, 2013; accepted

rd Hospital Research Endowment Funds,

he Lowell P. Weicker, Jr, Clinical Research

necticut Health Center.

ce to Alexandra Czap, MD, Department of

Connecticut Health Center, 263 Farmington

30. E-mail: alexandra.czap@gmail.com.

matter

oke Association

016/j.jstrokecerebrovasdis.2013.07.040

Journal of Stroke and Cerebrovasc

increased 18% in the past 10 years, most likely because of

an increase in the elderly population.3,4 With no specific

treatment for ICH, it is important to understand

comorbidities that can potentially affect outcomes, so

appropriate prevention and management strategies can

be implemented. Established clinical risk factors for

ICH include arterial hypertension, cerebral amyloid

angiopathy, older age, male gender, bleeding disorders,

anticoagulant medication, and chronic alcoholism.2,5-8

Radiologic predictors of mortality and functional outcome

include hematoma volume, midline shift, intraventricular

extension, location, and hydrocephalus.9-12

Approximately 5% of the US population is affected

by hypothyroidism.13 Both overt and subclinical hy-

pothyroidism can lead to hypertension, hyperchole-

sterolemia, and cardiac dysfunction, thus generally

conferring an increased risk of atherosclerosis and vas-

cular diseases.14-18 Depending on the degree of thyroid

ular Diseases, Vol. 22, No. 8 (November), 2013: pp e602-e609

INTRACEREBRAL HEMORRHAGE WITH HYPOTHYROIDISM e603

deficiency, hypothyroidism is also associated with

either increased risk of bleeding because of hypo-

coagulability or increased risk of thrombosis because of

hypercoagulability.19 These hemostatic changes are

mediated through disturbances in platelet function,

coagulation factors action, and changes in blood viscos-

ity.19,20 Interestingly, in contrast to these detrimental

effects of hypothyroidism on vascular function,21-24

elderly populations with subclinical and untreated

hypothyroidism unexpectedly show extended life spans

and better functional recovery after ischemic stroke,25,26

suggesting that the physiological effects of hypothy-

roidism are not yet completely understood.

Several studies have shown that changes occur in

the hypothalamic–pituitary–thyroid axis during stress

and systemic illness, known as the ‘‘nonthyroidal illness

syndrome (NTIS)’’ or low T3 syndrome.27,28 This is

manifested by low serum tri-iodothyronine (T3), normal

to low thyroxine (T4), and a high reverse T3 (rT3). These

changes may be observed in up to 75% of hospitalized pa-

tients28 and can arise without an intrinsic abnormality in

thyroid function. Paradoxical effects of hypothyroidism

have been well documented in patients with ischemic

stroke. Patients with hypothyroidism are at increased

risk for ischemic stroke29 yet appear protected once

a stroke occurs.25,26,30 Mechanisms for these beneficial

effects are unknown, but several have been proposed,

including the possibility that hypothyroidism could

serve as a ‘‘preconditioning’’ stimulus (a sublethal

stimulus that protects the brain from a subsequent more

severe injury) or could lead to a blunted response

to physical stress through reduced adrenergic

sensitivity.26,30 Although the effects of hypothyroidism

have been studied in patients with ischemic stroke,

acute coronary syndromes, sepsis, and renal failure,

studies in patients with ICH are lacking. The goal

of this work was to determine the effects of hypo-

thyroidism on the clinical presentation and outcomes in

patients with ICH.

Methods

Study Design

A retrospective review was performed on consecutive

patients diagnosed with ICH between January 2004 and

May 2011.

Study Setting and Population

This study was conducted at an 868-bed community-

based teaching hospital with a Neurology Residency

Program and a tertiary stroke center with an annual

stroke admission rate of approximately 1000. This center

is a Joint Commission approved comprehensive stroke

center. This study was approved by the Institutional

Review Board.

Study Protocol

ICH patients were identified from a prospectively

collected stroke center database and analysis of medical

records (n 5 848). Inclusion criteria were all consecutive

patients of 18 years old or more admitted for nontrau-

matic ICH and included patients with hypertension,

amyloid angiopathy, and coagulopathies as presumed

etiologies. After excluding traumatic hemorrhages,

tumor-related hemorrhages, vascular malformation-

related hemorrhages (arterial venous malformation and

aneurysm related), hemorrhagic conversion of ischemic

stroke, and subarachnoid hemorrhages, a spontaneous

ICH patient population (n 5 563) was identified. Hypo-

thyroid patients were identified by International Classifica-

tion of Diseases, Ninth Revision, code for hypothyroidism in

the medical history section of previous electronic medical

records confirmed with documentation of hypothyroid-

ism in the stroke admission medical record. Hypothyroid

patients were further subdivided into 2 groups: those

who received in-hospital thyroid replacement medication

as recorded in their electronic medical record and those

without in-hospital thyroid medication. In-hospital thy-

roid status was not considered a criteria for determining

hypothyroidism so that patients with NTIS were not mis-

classified with hypothyroidism. Hyperthyroid patients

were excluded from the study.

Measurements

Clinical and patient information was prospectively col-

lected by trained nursing staff and entered into the Stroke

Center’s database, which has been accumulating informa-

tion regarding patient presentation, etiology, and out-

come since 2001. Baseline demographic information

(age, sex, medical history, medication use), baseline labo-

ratory data (complete blood count, electrolyte panel, and

coagulation panel (prothrombin time, international nor-

malized ratio, and partial thromboplastin time)), and thy-

roid function tests, if available, were collected. Initial and

follow-up head computed tomography and magnetic res-

onance imaging scans were analyzed for volume of ICH,

calculated by the ABC/2 formula.31 Scans were also as-

sessed for location and intraventricular extension of hem-

orrhage. Risk factors such as a history of hypertension,

atrial fibrillation, previous stroke or transient ischemic at-

tack, coronary artery disease, cigarette smoking, diabetes

mellitus, and hypercholesterolemia were also collected.

Severity of stroke on admission was assessed using clini-

cal and radiographic prognostic markers and outcome

variables, including age, Glasgow Coma Scale (GCS),

ICH score,32 and the National Institutes of Health Stroke

Scale (NIHSS)33,34 on admission and discharge. The

primary outcome was in-hospital mortality. Secondary

outcomes included admission to discharge changes in

the NIHSS, admission to discharge changes in the modi-

fied Barthel Index (mBI),35 and discharge disposition.

Figure 1. Flow chart for selection of spontane-

ous ICH patient population.

A. CZAP ET AL.e604

Outcome measures included mortality during hospitali-

zation and at 3 and 12months and a ‘‘poor outcome’’ com-

posite measure defined as death or disabled with mBI less

than 15 at 3 and 12 months after ICH. Treatment medica-

tion list included levothyroxine, liothyronine, porcine

thyroid, and liotrix for thyroid replacement.

Statistical Analysis

Descriptive comparisons were made between 3 groups:

euthyroid, hypothyroid receiving replacement medica-

tion, and hypothyroid without replacement therapy

during the inpatient hospitalization. Continuous data,

such as age, are presented as mean (standard deviation).

Differences among the 3 groups were assessed with 1-

way analysis of variance with a post hoc Scheffe analysis

as appropriate. Non-normally distributed continuous and

ordinal variables (eg, ICH score, ICH volume, GCS,

NIHSS at admission and discharge, and mBI scores) are

presented as median (interquartile range) and analyzed

with nonparametric tests. Differences among the 3 groups

were assessed with Kruskal–Wallis. For those showing

significance differences, Wilcoxon rank sum tests were

conducted to determine which groups differed with

a Bonferroni correction. Categorical data, such as mortal-

ity, are presented as proportions and group differences as-

sessed with chi-square tests of proportion. In addition to

the ordinal analyses, several of the variables with non-

normal distributions were dichotomized and analyzed

with chi-square tests of proportions. These included the

mBI, dichotomized into independent (scoring 15 or

greater) or dependent (14 or less), and ICH volume,

GCS, etc., dichotomized based on the ICH score criteria.36

Mortality and the composite outcomes were also ana-

lyzed using multivariable logistic regression to control

for all significant confounding variables identified in uni-

variate analyses. The criterion of statistical significance

was set at .05. All analyses were performed using Statisti-

cal Package for the Social Sciences v14.

Results

Five hundred sixty-three patients with complete neuro-

logic documentation and available laboratory data met

inclusion criteria (see Fig 1). Four hundred ninety-one

patients had no history of hypothyroid abnormality and

72 patients had a diagnosis of hypothyroidism. Of these,

45 patients received in-hospital thyroid medication and

27 did not.

Clinical and laboratory characteristics of these 3 groups

were analyzed. Patient demographics are shown in

Table 1. Patients in the euthyroid control group were sig-

nificantly younger than hypothyroid patients without

thyroid replacement. There were more men in the euthy-

roid group. Patients with hypothyroidism without re-

placement therapy were more likely to have baseline

disability (by mBI) at presentation. There was no differ-

ence among the 3 groups of patients in regards to other

vascular risk factors including hypertension, diabetes

mellitus, smoking, and history of heart disease, stroke,

or transient ischemic attack. The 3 patient groups also

presented with similar admission blood pressures, white

blood cell count, glucose, and coagulation profiles. There

was a higher rate of aspirin use in the patients who were

Table 1. Patient demographics by thyroid status

Euthyroid (n 5 491)

Hypothyroid with

replacement (n 5 45)

Hypothyroid no replacement

(n 5 27) P

Age (y) 70.5 6 14.0 75.5 6 11.9 78.3 6 9.4 .002

Gender .005

Male 53.7% 31.1% 37.0%

Female 46.3% 68.9% 63.0%

History of

HTN 78.2% 75.6% 81.5% NS

DM 25.5% 20.0% 40.7% NS

Heart disease 31.6% 28.9% 33.0% NS

Stroke 16.9% 8.9% 22.2% NS

TIA 6.1% 8.9% 14.8% NS

Smoking 16.5% 13.5% 13.0% NS

Prior medications

Aspirin 32.3% 25.6% 57.7% .015

Warfarin 16.3% 16.3% 15.4% NS

Statins 33.6% 47.7% 50.0% NS

ACE I 24.3% 6.8% 19.2% .027

Origin location NS

Home 79.9% 84.4% 74.0%

Home with services 8.4% 4.4% 7.4%

ALF 4.9% 4.4% 3.7%

ECF 4.9% 6.7% 11.1%

Other 0.4% 0.0% 0.0%

Blood pressure (mm Hg)

Systolic 178.5 6 36.2 180.4 6 44.6 173.4 6 36.9 NS

Diastolic 96.0 6 22.3 91.9 6 27.3 94.7 6 29.5 NS

WBC count (3103/mL) 9.6 6 3.9 10.7 6 5.5 9.7 6 3.3 NS

Glucose (mg/dL) 148.0 6 66.7 151.3 6 80.9 136.1 6 47.6 NS

Coagulation studies

INR 1.0 (.9, 1.1) 1.0 (1.0, 1.2) 1.1 (1.0, 1.2) NS

PT (s) 12.1 (11.5, 13) 12.1 (11.3, 13.3) 12.5 (11.8, 13) NS

PTT (s) 26.0 (24.0, 29.0) 26.3 (23.9, 29.8) 26.0 (29.3, 27.7) NS

TSH (mIU/mL) 2.0 6 2.8 3.5 6 4.4 2.4 6 3.3 NS

Number of patients with TSH n 5 83 (17%) n 5 26 (58%) n 5 12 (44%)

Modified Barthel PreAdmit 20.0 (19.0, 20.0) 20.0 (19.0, 20.0) 19.0 (17.0, 19.0) ,.001

Abbreviations: ACE I, angiotensin-converting enzyme inhibitor; ALF, assisted living facility; DM, diabetes mellitus; ECF, extended care fa-

cility; HTN, hypertension; INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time; TIA, transient ischemic

attack; WBC, white blood cell; TSH, thyroid-stimulating hormone, normal 0.4-4 mIU/mL.

INTRACEREBRAL HEMORRHAGE WITH HYPOTHYROIDISM e605

hypothyroid without hormone replacement. ACE inhibi-

tor use was more common among euthyroid patients.

No significant difference was found between the reported

thyroid-stimulating hormone (TSH) values among the 3

groups, although samples were drawn at variable time in-

tervals from admission. Recorded TSH measurements

were found to retrospectively correlate with NIHSS on

admission with Spearman rho (.004).

Measures of initial clinical severity are listed in Table 2.

All 3 patient groups presented with similar total ICH

scores although the hypothyroid patients without re-

placement therapy were more likely to be older than

80 years. In addition, a greater number of hypothyroid re-

ceiving replacement therapy had hemorrhages in the

brain stem or cerebellum. Hemorrhage volume was not

significantly different among the groups nor was there

a difference in the number of deep versus lobar hemor-

rhages among the groups. Although all 3 groups pre-

sented with similar GCS and mBI scores, the NIHSS on

admission was significantly lower in the patients with hy-

pothyroidism given replacement therapy indicating less

severe initial focal deficits.

Univariate outcome parameters are shown in Table 3.

There were no differences among the 3 groups in the in-

hospital and 3-month mortality rate. Hypothyroid pa-

tients and the euthyroid control group were discharged

with similar NIHSS scores and similar proportions to

facilities or home locations. No differences were found be-

tween the groups in regards to their NIHSS change from

admission to discharge among the groups. In addition,

there were no differences in functional outcomes at 3

and 12 months among the groups. A multivariable

Table 2. Severity parameters in patients with ICH

Euthyroid (n 5 491)

Hypothyroid with

replacement (n 5 45)

Hypothyroid with no

replacement (n 5 27) P

ICH score 1.0 (1.0, 2.25) 1.0 (1.0, 2.75) 2.0 (1.0, 3.0) NS

Volume $ 30 mL (%) 37.1 22.7 34.6 NS

Intraventricular (%) 43.5 37.8 42.3 NS

Age $ 80 y (%) 30.8 42.2 55.6 .011

Infratentorial (%) 11.5 24.4 7.7 .032

GCS , 13 (%) 34.4 25.6 33.3 NS

ICH volume (cc) 34.6 6 42.5 20.5 6 21.5 33.8 6 41.6 NS

Location of bleed NS

Deep (%) 63.2 59.1 64.0

Lobar (%) 36.8 40.9 36.0

GCS score 14.0 (10.0, 15.0) 15.0 (13.0, 15.0) 14.0 (12.0, 15.0) NS

NIHSS admit 8.0 (3.0, 16.0) 4.0 (1.0, 11.0) 9.0 (3.8, 15.5) .016

Modified Barthel admit 11.0 (3.0, 18.0) 12.0 (1.5, 19.0) 9.5 (1.25, 11.75) NS

Abbreviations: ICH, intracerebral hemorrhage; GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale.

A. CZAP ET AL.e606

logistic regression model was used to control for the po-

tential confounders identified in univariate analysis and

other known predictors of outcome after ICH. After con-

trolling for potential confounding variables, thyroid sta-

tus, regardless of use of replacement therapy during the

hospitalization, was not associated with mortality

(Table 4) or functional outcome (Table 5).

Discussion

The results of the present study show that hypothyroid

status did not influence mortality after an ICH during

hospital stay or at 3 and 12 months after the event.

Similarly, hypothyroid dysfunction did not influence pa-

Table 3. Outcomes in patients with

Euthyroid (n 5 491)

H

rep

Mortality

In hospital 31.0%

3 mo 39.1%

12 mo 41.8%

Modified Barthel Index , 15

3 mo 27.2%

12 mo 22.6%

Discharge location

Home with or without services 19.0%

Acute rehab 13.6%

Subacute rehab 29.8%

ECF, hospice, death 37.6%

NIHSS discharge 3.0 (0.0, 8.0)

Change in NIHSS

Improved 30.4%

Same 11.6%

Worsened 58.0%

Abbreviations: ECF, extended care facility; NIHSS, National Institutes

tient’s functional outcome at 3 and 12 months postevent.

Retrospective studies have demonstrated a relationship be-

tween the severity of ischemic stroke and a history of hypo-

thyroidism.25,30 The relationship between ICH and thyroid

status has not been previously investigated, leading to

a lack of understanding of how thyroid hormone status

may affect the clinical severity and outcomes after

ICH. We hypothesized that hypothyroidism would be

a favorable factor for ICH patients because of decreased

metabolic and sympathetic surgesduring thecritical illness.

Most of the hypothyroid patients in this study were

older adult females, which mirrors the epidemiology of

thyroid disease in the general population.37 Patients

among the 3 groups presented with similar vitals and

ICH based on thyroid status

ypothyroid with

lacement (n 5 45)

Hypothyroid with no

replacement (n 5 27) P

20.0% 25.9% NS

35.6% 40.7% NS

42.2% 44.4% NS

33.3% 41.7% NS

30.0% 0.0% NS

NS

25.0% 7.4%

6.8% 18.5%

38.6% 40.7%

29.5% 33.3%

1.0 (0.0, 9.0) 2.0 (.5, 6.5) NS

NS

26.9% 25.0%

26.9% 25.0%

46.2% 50.0%

of Health Stroke Scale; rehab, rehabilitation; NS, nonsignificant.

Table 4. Hypothyroidism and mortality after ICH

Variable

In-hospital mortality

(n 5 454)

3-Mo mortality

(n 5 409)

12-Mo mortality

(n 5 366)

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Thyroid status (compared with euthyroid)

Hypothyroid with replacement .95 (.30-3.00) .93 2.33 (.80-6.79) .12 2.47 (.94-6.52) .07

Hypothyroid without replacement .86 (.24-3.12) .82 1.06 (.28-3.93) .94 1.28 (.41-6.03) .51

Abbreviations: ACE, angiotensin-converting enzyme; CI, confidence interval; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage;

NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.

Multivariable logistic regression model adjusted for age, NIHSS, GCS, ICH score components, use of ACE inhibitors, aspirin, and/or Cou-

madin, ICH volume, and infratentorial location. Male sex, age, GCS, NIHSS, use of aspirin, ACE inhibitor, and Coumadin, ICH volume,

interventricular hemorrhage, and infratentorial hemorrhage location were factors that are considered potential confounders and consequently

included in the multivariable logistic regression as adjustment variables.

INTRACEREBRAL HEMORRHAGE WITH HYPOTHYROIDISM e607

laboratories including admission blood pressure, white

blood cell count, glucose, and coagulation profiles, all

of which influence hemorrhage size and outcome.38,39

ICH patients with a history of hypothyroidism given

hormone replacement therapy had less severe clinical

deficits on presentation including lower admission

NIHSS and a trend toward lower ICH volumes. The

reason for this is unclear. There was a similar

percentage of hypothyroid patients without replacement

therapy who subsequently had TSH levels drawn, and

there was no significant difference among the groups in

the percentage of patients who died in the hospital. This

suggests that thyroid hormone was not being withheld

because of comfort-only care in the most severely affected

patients. However, we do not have detailed data on the

goals of care for each patient, and this is a limitation in

the study. The hypothyroid patients not given replace-

ment therapy were more likely to be taking aspirin

at ICH onset, and although consistent with post hoc

analyses of clinical trials,40,41 aspirin use was not

associated with increased mortality or poor outcome in

the multivariable models. Furthermore, hypothyroid

patients had similar outcomes compared with euthyroid

patients, as shown by comparable mortality rates at

Table 5. Hypothyroidism and poor

Variable

Poor outcome at 3

OR (95% CI)

Thyroid status (compared with euthyroid)

Hypothyroid with replacement 2.12 (.78-5.78)

Hypothyroid without replacement 1.27 (.34-4.71)

Abbreviations: CI, confidence interval; GCS, Glasgow Coma Scale; IC

National Institutes of Health Stroke Scale; OR, odds ratio.

Multivariable logistic regression model adjusted for age, NIHSS, GCS,

madin, ICH volume, and infratentorial location. Poor outcome defined as d

without replacement group as the number of patients was small leading to a

ACE inhibitor, and Coumadin, ICH volume, interventricular hemorrhage, a

potential confounders and consequently included in the multivariable logi

3 time points, long-term functional outcome, and dis-

charge NIHSS. The lack of association of thyroid status

and outcome persisted after adjustment for potential

imbalances in the initial severity of presentation of the

patients (eg, admission NIHSS) and other confounding

variables. This suggests that historical report of hypothy-

roidism does not meaningfully contribute to patient

outcomes and should not enter prognostication discus-

sions.

These results could be the result of misclassification of

hypothyroid status by medical history or truly negative

findings. Interestingly, the ‘‘historical’’ classification

method of thyroid status did not correlate to the TSH

levels between groups. TSH levels were measured at vari-

able time points during a patient’s hospitalization, rang-

ing from time of admission to days after the acute

event. The NTIS, in which changes in thyroid hormone

concentration arise without pathologic thyroid disease

during times of critical illness and stress, limits the useful-

ness of classifying acutely ill patients with TSH levels. Al-

though only a subset of patients in each group had TSH

levels drawn, it is unclear whether inpatient measure-

ments of TSH levels in all patients would have aided in

the diagnosis of hypothyroidism in this ill population.

long-term outcome after ICH

mo (n 5 374) Poor outcome at 12 mo (n 5 285)

P OR (95% CI) P

.14 1.23 (.41-3.66) .71

.72 .998

H, intracerebral hemorrhage; mBI, modified Barthel Index; NIHSS,

ICH score components, use of ACE inhibitors, aspirin, and/or Cou-

eath or disability with mBI, 15. OR not shown for the hypothyroid

95% CI of 0 to infinity. Male sex, age, GCS, NIHSS, use of aspirin,

nd infratentorial hemorrhage location were factors that are considered

stic regression as adjustment variables.

A. CZAP ET AL.e608

In NTIS, themost significant changes in thyroid function

are seen in critically ill patients,32,42,43 and there is a direct

correlation between poor outcome and greater reductions

in the levels of thyroxine and tri-iodothyronine in critically

ill patients.44,45 After subarachnoid hemorrhage, low

concentrations of TSH and T3 were associated with

worse SAH grade and poor outcome.46 Generally, patients

with NTIS are not given exogenous hormone replacement.

NTIS has been seen by some to represent a protective

adaption of the body to cope with stress or counteract

the excessive catabolism that occurs during acute illness.41

The potential benefits of NTIS may be profound in ICH

as brain hemorrhage causes an acute activation of

the sympathetic nervous system that may contribute

to inflammation and systemic cardiac events.47-49 In

addition, the decreased metabolic rate of hypothyroid

patients may contribute to favorable functional outcomes

by providing protection to brain tissues at risk and

improved neuronal survival during injury, similar to

what is seen with hypothermia.50,51 Despite these

hypothesized mechanisms, our data did not find an

association of pre-ICH hypothyroidism and improved out-

comes. However, the number and timing of thyroid hor-

mone levels were insufficient to investigate the incidence

and importance of NTIS in our patients.

There are also several limitations to this study because

of the retrospective design. Results were based on a single

center, thereby decreasing this study’s external validity.

However, previously established outcome predictors

including hematoma volume, ICH location (infratentorial

versus supratentorial), and advanced age held true in our

multivariable models, increasing confidence in the qual-

ity of the data. Although assessment of outcomes was

blinded to thyroid status, subjects were not randomized

to replacement treatment. A major limitation of this study

was the lack of TSH, T3, and T4 laboratory data for most

of the patient population to objectively measure and clas-

sify thyroid status at controlled time intervals. Because of

the instability of the hypothalamic–pituitary–thyroid axis

during acute illness and markedly different thyroid hor-

mone half lives, a single set of thyroid function measure-

ments during the hospital admission may not be

indicative of true thyroid hormone status.32 In addition,

the lack of thyroid studies in patients taking thyroid re-

placement therapy limited our determination of func-

tional control of the patient’s hypothyroidism. The

degree of stabilization of thyroid hormone levels could

have an effect on stroke outcome. A prospective study

that includes serial measurements of thyroid function to

investigate dynamic changes in thyroid function in ICH

patients is needed to determine if ICH induces dysfunc-

tion of the hypothalamic-pituitary-adrenal axis and

whether this correlates with outcome. If ICH-induced de-

cline in thyroid hormone levels occurs and correlates with

outcome, a replacement trial could be considered. This

study is an initial step in understanding the complex in-

teraction between ICH and thyroid hormones and pro-

vides baseline data with which to design prospective

studies. Spontaneous ICH is the most devastating type

of stroke and a major cause of disability and mortality

worldwide. Understanding the role of thyroid hormone

status and ICH severity and outcome may improve out-

comes in this devastating disease.

Conclusions

We found no association with reported hypothyroidism

and outcomes after ICH, regardless of ongoing replace-

ment of thyroid hormone during admission. Further

study with structured testing of hormone levels will be

needed to determine if thyroid status is associated with

outcome.

Acknowledgment: None.

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