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Intracerebral Hemorrhage with Hypothyroidism
Intracerebral Hemorrhage 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*†
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 hypothyroid patients with spontaneous ICH. Patients were classified into groups with no history of thyroid disease (n 5 491) versus those with hypothyroidism (n 5 72). Hypothyroid patients were further classified into patients receiving thyroid replacement 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 disposition and mortality, 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 significantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replacement (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. Ó 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
From the *University of Connecticut Health Center, Farmington, Connecticut; and †Hartford Hospital, Hartford, Connecticut. Received January 8, 2013; revision received July 8, 2013; accepted July 27, 2013. Grant support: Hartford Hospital Research Endowment Funds, Hartford Hospital, and The Lowell P. Weicker, Jr, Clinical Research Center, University of Connecticut Health Center. Disclosure: None. Address correspondence to Alexandra Czap, MD, Department of Neurology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.07.040
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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 hypothyroidism can lead to hypertension, hypercholesterolemia, and cardiac dysfunction, thus generally conferring an increased risk of atherosclerosis and vascular diseases.14-18 Depending on the degree of thyroid
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deficiency, hypothyroidism is also associated with either increased risk of bleeding because of hypocoagulability 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 viscosity.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 hypothyroidism 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 patients28 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 hypothyroidism 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 communitybased 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.
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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 nontraumatic ICH and included patients with hypertension, amyloid angiopathy, and coagulopathies as presumed etiologies. After excluding traumatic hemorrhages, tumor-related hemorrhages, vascular malformationrelated 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. Hypothyroid patients were identified by International Classification of Diseases, Ninth Revision, code for hypothyroidism in the medical history section of previous electronic medical records confirmed with documentation of hypothyroidism 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 thyroid status was not considered a criteria for determining hypothyroidism so that patients with NTIS were not misclassified with hypothyroidism. Hyperthyroid patients were excluded from the study.
Measurements Clinical and patient information was prospectively collected by trained nursing staff and entered into the Stroke Center’s database, which has been accumulating information regarding patient presentation, etiology, and outcome since 2001. Baseline demographic information (age, sex, medical history, medication use), baseline laboratory data (complete blood count, electrolyte panel, and coagulation panel (prothrombin time, international normalized ratio, and partial thromboplastin time)), and thyroid function tests, if available, were collected. Initial and follow-up head computed tomography and magnetic resonance imaging scans were analyzed for volume of ICH, calculated by the ABC/2 formula.31 Scans were also assessed for location and intraventricular extension of hemorrhage. Risk factors such as a history of hypertension, atrial fibrillation, previous stroke or transient ischemic attack, coronary artery disease, cigarette smoking, diabetes mellitus, and hypercholesterolemia were also collected. Severity of stroke on admission was assessed using clinical 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 modified Barthel Index (mBI),35 and discharge disposition.
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Figure 1. Flow chart for selection of spontaneous ICH patient population.
Outcome measures included mortality during hospitalization and at 3 and 12 months and a ‘‘poor outcome’’ composite measure defined as death or disabled with mBI less than 15 at 3 and 12 months after ICH. Treatment medication list included levothyroxine, liothyronine, porcine thyroid, and liotrix for thyroid replacement.
GCS, etc., dichotomized based on the ICH score criteria.36 Mortality and the composite outcomes were also analyzed using multivariable logistic regression to control for all significant confounding variables identified in univariate analyses. The criterion of statistical significance was set at .05. All analyses were performed using Statistical Package for the Social Sciences v14.
Statistical Analysis Descriptive comparisons were made between 3 groups: euthyroid, hypothyroid receiving replacement medication, 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 1way 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 mortality, are presented as proportions and group differences assessed with chi-square tests of proportion. In addition to the ordinal analyses, several of the variables with nonnormal 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,
Results Five hundred sixty-three patients with complete neurologic 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 significantly younger than hypothyroid patients without thyroid replacement. There were more men in the euthyroid group. Patients with hypothyroidism without replacement therapy were more likely to have baseline disability (by mBI) at presentation. There was no difference 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
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Table 1. Patient demographics by thyroid status
Age (y) Gender Male Female History of HTN DM Heart disease Stroke TIA Smoking Prior medications Aspirin Warfarin Statins ACE I Origin location Home Home with services ALF ECF Other Blood pressure (mm Hg) Systolic Diastolic WBC count (3103/mL) Glucose (mg/dL) Coagulation studies INR PT (s) PTT (s) TSH (mIU/mL) Number of patients with TSH Modified Barthel PreAdmit
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid no replacement (n 5 27)
70.5 6 14.0
75.5 6 11.9
78.3 6 9.4
53.7% 46.3%
31.1% 68.9%
37.0% 63.0%
78.2% 25.5% 31.6% 16.9% 6.1% 16.5%
75.6% 20.0% 28.9% 8.9% 8.9% 13.5%
81.5% 40.7% 33.0% 22.2% 14.8% 13.0%
NS NS NS NS NS NS
32.3% 16.3% 33.6% 24.3%
25.6% 16.3% 47.7% 6.8%
57.7% 15.4% 50.0% 19.2%
.015 NS NS .027 NS
79.9% 8.4% 4.9% 4.9% 0.4%
84.4% 4.4% 4.4% 6.7% 0.0%
74.0% 7.4% 3.7% 11.1% 0.0%
178.5 6 36.2 96.0 6 22.3 9.6 6 3.9 148.0 6 66.7
180.4 6 44.6 91.9 6 27.3 10.7 6 5.5 151.3 6 80.9
173.4 6 36.9 94.7 6 29.5 9.7 6 3.3 136.1 6 47.6
NS NS NS NS
1.0 (.9, 1.1) 12.1 (11.5, 13) 26.0 (24.0, 29.0) 2.0 6 2.8 n 5 83 (17%) 20.0 (19.0, 20.0)
1.0 (1.0, 1.2) 12.1 (11.3, 13.3) 26.3 (23.9, 29.8) 3.5 6 4.4 n 5 26 (58%) 20.0 (19.0, 20.0)
1.1 (1.0, 1.2) 12.5 (11.8, 13) 26.0 (29.3, 27.7) 2.4 6 3.3 n 5 12 (44%) 19.0 (17.0, 19.0)
NS NS NS NS
P .002 .005
,.001
Abbreviations: ACE I, angiotensin-converting enzyme inhibitor; ALF, assisted living facility; DM, diabetes mellitus; ECF, extended care facility; 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.
hypothyroid without hormone replacement. ACE inhibitor 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 intervals 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 replacement therapy were more likely to be older than 80 years. In addition, a greater number of hypothyroid receiving 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 hemorrhages among the groups. Although all 3 groups presented with similar GCS and mBI scores, the NIHSS on admission was significantly lower in the patients with hypothyroidism 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 inhospital and 3-month mortality rate. Hypothyroid patients and the euthyroid control group were discharged with similar NIHSS scores and similar proportions to facilities or home locations. No differences were found between 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
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Table 2. Severity parameters in patients with ICH
ICH score Volume $ 30 mL (%) Intraventricular (%) Age $ 80 y (%) Infratentorial (%) GCS , 13 (%) ICH volume (cc) Location of bleed Deep (%) Lobar (%) GCS score NIHSS admit Modified Barthel admit
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid with no replacement (n 5 27)
1.0 (1.0, 2.25) 37.1 43.5 30.8 11.5 34.4 34.6 6 42.5
1.0 (1.0, 2.75) 22.7 37.8 42.2 24.4 25.6 20.5 6 21.5
2.0 (1.0, 3.0) 34.6 42.3 55.6 7.7 33.3 33.8 6 41.6
63.2 36.8 14.0 (10.0, 15.0) 8.0 (3.0, 16.0) 11.0 (3.0, 18.0)
59.1 40.9 15.0 (13.0, 15.0) 4.0 (1.0, 11.0) 12.0 (1.5, 19.0)
64.0 36.0 14.0 (12.0, 15.0) 9.0 (3.8, 15.5) 9.5 (1.25, 11.75)
P NS NS NS .011 .032 NS NS NS
NS .016 NS
Abbreviations: ICH, intracerebral hemorrhage; GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale.
logistic regression model was used to control for the potential confounders identified in univariate analysis and other known predictors of outcome after ICH. After controlling for potential confounding variables, thyroid status, 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-
tient’s functional outcome at 3 and 12 months postevent. Retrospective studies have demonstrated a relationship between the severity of ischemic stroke and a history of hypothyroidism.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 surges during the critical 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
Table 3. Outcomes in patients with ICH based on thyroid status
Mortality In hospital 3 mo 12 mo Modified Barthel Index , 15 3 mo 12 mo Discharge location Home with or without services Acute rehab Subacute rehab ECF, hospice, death NIHSS discharge Change in NIHSS Improved Same Worsened
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid with no replacement (n 5 27)
P
31.0% 39.1% 41.8%
20.0% 35.6% 42.2%
25.9% 40.7% 44.4%
NS NS NS
27.2% 22.6%
33.3% 30.0%
41.7% 0.0%
NS NS NS
19.0% 13.6% 29.8% 37.6% 3.0 (0.0, 8.0)
25.0% 6.8% 38.6% 29.5% 1.0 (0.0, 9.0)
7.4% 18.5% 40.7% 33.3% 2.0 (.5, 6.5)
30.4% 11.6% 58.0%
26.9% 26.9% 46.2%
25.0% 25.0% 50.0%
NS NS
Abbreviations: ECF, extended care facility; NIHSS, National Institutes of Health Stroke Scale; rehab, rehabilitation; NS, nonsignificant.
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Table 4. Hypothyroidism and mortality after ICH In-hospital mortality (n 5 454)
3-Mo mortality (n 5 409)
12-Mo mortality (n 5 366)
Variable
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
Thyroid status (compared with euthyroid) Hypothyroid with replacement Hypothyroid without replacement
.95 (.30-3.00) .86 (.24-3.12)
.93 .82
2.33 (.80-6.79) 1.06 (.28-3.93)
.12 .94
2.47 (.94-6.52) 1.28 (.41-6.03)
.07 .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 Coumadin, 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.
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 replacement 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
3 time points, long-term functional outcome, and discharge 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 hypothyroidism does not meaningfully contribute to patient outcomes and should not enter prognostication discussions. 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 variable time points during a patient’s hospitalization, ranging 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 usefulness of classifying acutely ill patients with TSH levels. Although only a subset of patients in each group had TSH levels drawn, it is unclear whether inpatient measurements of TSH levels in all patients would have aided in the diagnosis of hypothyroidism in this ill population.
Table 5. Hypothyroidism and poor long-term outcome after ICH Poor outcome at 3 mo (n 5 374)
Poor outcome at 12 mo (n 5 285)
Variable
OR (95% CI)
P
OR (95% CI)
P
Thyroid status (compared with euthyroid) Hypothyroid with replacement Hypothyroid without replacement
2.12 (.78-5.78) 1.27 (.34-4.71)
.14 .72
1.23 (.41-3.66)
.71 .998
Abbreviations: CI, confidence interval; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; mBI, modified Barthel Index; 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 Coumadin, ICH volume, and infratentorial location. Poor outcome defined as death or disability with mBI , 15. OR not shown for the hypothyroid without replacement group as the number of patients was small leading to a 95% CI of 0 to infinity. 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.
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In NTIS, the most 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 outcomes. However, the number and timing of thyroid hormone 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 quality 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 classify thyroid status at controlled time intervals. Because of the instability of the hypothalamic–pituitary–thyroid axis during acute illness and markedly different thyroid hormone half lives, a single set of thyroid function measurements 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 replacement therapy limited our determination of functional 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 dysfunction of the hypothalamic-pituitary-adrenal axis and whether this correlates with outcome. If ICH-induced decline 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 provides 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 outcomes in this devastating disease.
Conclusions We found no association with reported hypothyroidism and outcomes after ICH, regardless of ongoing replacement 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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a factor analysis. NINDS tPA Stroke Trial Investigators. Stroke 1999;30:2347-2354. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864-870. Shah S, Vanclay F, Cooper B. Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol 1989;42:703-709. Hemphill JC III, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891-897. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab 2009;94:1853-1878. Elijovich L, Patel PV, Hemphill JC III. Intracerebral hemorrhage. Semin Neurol 2008;28:657-667. Agnihotri S, Czap A, Staff I, et al. Peripheral leukocyte counts and outcomes after intracerebral hemorrhage. J Neuroinflammation 2011;8:160. Broderick JP, Diringer MN, Hill MD, et al. Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke 2007;38:1072-1075. Sansing LH, Messe SR, Cucchiara BL, et al. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology 2009;72:1397-1402. Bello G, Ceaichisciuc I, Silva S, et al. The role of thyroid dysfunction in the critically ill: a review of the literature. Minerva Anestesiol 2010;76:919-928. Stathatos N, Levetan C, Burman KD, et al. The controversy of the treatment of critically ill patients with thyroid hormone. Best Pract Res Clin Endocrinol Metabol 2001;15:465-478. Slag MF, Morley JE, Elson MK, et al. Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA 1981;245:43-45. Kaptein EM, Weiner JM, Robinson WJ, et al. Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol 1982;16:565-574. Zetterling M, Engstr€ om BE, Arnardottir S, et al. Somatotropic and thyroid hormones in the acute phase of subarachnoid haemorrhage. Acta Neurochir 2013; [Epub ahead of print]. Grad A, Kiauta T, Osredkar J. Effect of elevated plasma norepinephrine on electrocardiographic changes in subarachnoid hemorrhage. Stroke 1991;22:746-749. Dilraj A, Botha JH, Rambiritch V, et al. Levels of catecholamine in plasma and cerebrospinal fluid in aneurysmal subarachnoid hemorrhage. Neurosurgery 1992; 31:42-51. Cruickschank JM, Neil-Dwyer G, Stott AW. Possible role of catecholamines, corticosteroids, and potassium in production of electrocardiographic abnormalities associated with subarachnoid hemorrhage. Br Heart J 1974; 36:697-706. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955-1969. McIntyre LA, Fergusson DA, Hebert PC, et al. Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003; 289:2992-2999.
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 hypothyroid patients with spontaneous ICH. Patients were classified into groups with no history of thyroid disease (n 5 491) versus those with hypothyroidism (n 5 72). Hypothyroid patients were further classified into patients receiving thyroid replacement 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 disposition and mortality, 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 significantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replacement (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. Ó 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
From the *University of Connecticut Health Center, Farmington, Connecticut; and †Hartford Hospital, Hartford, Connecticut. Received January 8, 2013; revision received July 8, 2013; accepted July 27, 2013. Grant support: Hartford Hospital Research Endowment Funds, Hartford Hospital, and The Lowell P. Weicker, Jr, Clinical Research Center, University of Connecticut Health Center. Disclosure: None. Address correspondence to Alexandra Czap, MD, Department of Neurology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.07.040
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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 hypothyroidism can lead to hypertension, hypercholesterolemia, and cardiac dysfunction, thus generally conferring an increased risk of atherosclerosis and vascular diseases.14-18 Depending on the degree of thyroid
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deficiency, hypothyroidism is also associated with either increased risk of bleeding because of hypocoagulability 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 viscosity.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 hypothyroidism 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 patients28 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 hypothyroidism 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 communitybased 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.
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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 nontraumatic ICH and included patients with hypertension, amyloid angiopathy, and coagulopathies as presumed etiologies. After excluding traumatic hemorrhages, tumor-related hemorrhages, vascular malformationrelated 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. Hypothyroid patients were identified by International Classification of Diseases, Ninth Revision, code for hypothyroidism in the medical history section of previous electronic medical records confirmed with documentation of hypothyroidism 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 thyroid status was not considered a criteria for determining hypothyroidism so that patients with NTIS were not misclassified with hypothyroidism. Hyperthyroid patients were excluded from the study.
Measurements Clinical and patient information was prospectively collected by trained nursing staff and entered into the Stroke Center’s database, which has been accumulating information regarding patient presentation, etiology, and outcome since 2001. Baseline demographic information (age, sex, medical history, medication use), baseline laboratory data (complete blood count, electrolyte panel, and coagulation panel (prothrombin time, international normalized ratio, and partial thromboplastin time)), and thyroid function tests, if available, were collected. Initial and follow-up head computed tomography and magnetic resonance imaging scans were analyzed for volume of ICH, calculated by the ABC/2 formula.31 Scans were also assessed for location and intraventricular extension of hemorrhage. Risk factors such as a history of hypertension, atrial fibrillation, previous stroke or transient ischemic attack, coronary artery disease, cigarette smoking, diabetes mellitus, and hypercholesterolemia were also collected. Severity of stroke on admission was assessed using clinical 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 modified Barthel Index (mBI),35 and discharge disposition.
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Figure 1. Flow chart for selection of spontaneous ICH patient population.
Outcome measures included mortality during hospitalization and at 3 and 12 months and a ‘‘poor outcome’’ composite measure defined as death or disabled with mBI less than 15 at 3 and 12 months after ICH. Treatment medication list included levothyroxine, liothyronine, porcine thyroid, and liotrix for thyroid replacement.
GCS, etc., dichotomized based on the ICH score criteria.36 Mortality and the composite outcomes were also analyzed using multivariable logistic regression to control for all significant confounding variables identified in univariate analyses. The criterion of statistical significance was set at .05. All analyses were performed using Statistical Package for the Social Sciences v14.
Statistical Analysis Descriptive comparisons were made between 3 groups: euthyroid, hypothyroid receiving replacement medication, 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 1way 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 mortality, are presented as proportions and group differences assessed with chi-square tests of proportion. In addition to the ordinal analyses, several of the variables with nonnormal 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,
Results Five hundred sixty-three patients with complete neurologic 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 significantly younger than hypothyroid patients without thyroid replacement. There were more men in the euthyroid group. Patients with hypothyroidism without replacement therapy were more likely to have baseline disability (by mBI) at presentation. There was no difference 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
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Table 1. Patient demographics by thyroid status
Age (y) Gender Male Female History of HTN DM Heart disease Stroke TIA Smoking Prior medications Aspirin Warfarin Statins ACE I Origin location Home Home with services ALF ECF Other Blood pressure (mm Hg) Systolic Diastolic WBC count (3103/mL) Glucose (mg/dL) Coagulation studies INR PT (s) PTT (s) TSH (mIU/mL) Number of patients with TSH Modified Barthel PreAdmit
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid no replacement (n 5 27)
70.5 6 14.0
75.5 6 11.9
78.3 6 9.4
53.7% 46.3%
31.1% 68.9%
37.0% 63.0%
78.2% 25.5% 31.6% 16.9% 6.1% 16.5%
75.6% 20.0% 28.9% 8.9% 8.9% 13.5%
81.5% 40.7% 33.0% 22.2% 14.8% 13.0%
NS NS NS NS NS NS
32.3% 16.3% 33.6% 24.3%
25.6% 16.3% 47.7% 6.8%
57.7% 15.4% 50.0% 19.2%
.015 NS NS .027 NS
79.9% 8.4% 4.9% 4.9% 0.4%
84.4% 4.4% 4.4% 6.7% 0.0%
74.0% 7.4% 3.7% 11.1% 0.0%
178.5 6 36.2 96.0 6 22.3 9.6 6 3.9 148.0 6 66.7
180.4 6 44.6 91.9 6 27.3 10.7 6 5.5 151.3 6 80.9
173.4 6 36.9 94.7 6 29.5 9.7 6 3.3 136.1 6 47.6
NS NS NS NS
1.0 (.9, 1.1) 12.1 (11.5, 13) 26.0 (24.0, 29.0) 2.0 6 2.8 n 5 83 (17%) 20.0 (19.0, 20.0)
1.0 (1.0, 1.2) 12.1 (11.3, 13.3) 26.3 (23.9, 29.8) 3.5 6 4.4 n 5 26 (58%) 20.0 (19.0, 20.0)
1.1 (1.0, 1.2) 12.5 (11.8, 13) 26.0 (29.3, 27.7) 2.4 6 3.3 n 5 12 (44%) 19.0 (17.0, 19.0)
NS NS NS NS
P .002 .005
,.001
Abbreviations: ACE I, angiotensin-converting enzyme inhibitor; ALF, assisted living facility; DM, diabetes mellitus; ECF, extended care facility; 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.
hypothyroid without hormone replacement. ACE inhibitor 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 intervals 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 replacement therapy were more likely to be older than 80 years. In addition, a greater number of hypothyroid receiving 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 hemorrhages among the groups. Although all 3 groups presented with similar GCS and mBI scores, the NIHSS on admission was significantly lower in the patients with hypothyroidism 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 inhospital and 3-month mortality rate. Hypothyroid patients and the euthyroid control group were discharged with similar NIHSS scores and similar proportions to facilities or home locations. No differences were found between 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
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Table 2. Severity parameters in patients with ICH
ICH score Volume $ 30 mL (%) Intraventricular (%) Age $ 80 y (%) Infratentorial (%) GCS , 13 (%) ICH volume (cc) Location of bleed Deep (%) Lobar (%) GCS score NIHSS admit Modified Barthel admit
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid with no replacement (n 5 27)
1.0 (1.0, 2.25) 37.1 43.5 30.8 11.5 34.4 34.6 6 42.5
1.0 (1.0, 2.75) 22.7 37.8 42.2 24.4 25.6 20.5 6 21.5
2.0 (1.0, 3.0) 34.6 42.3 55.6 7.7 33.3 33.8 6 41.6
63.2 36.8 14.0 (10.0, 15.0) 8.0 (3.0, 16.0) 11.0 (3.0, 18.0)
59.1 40.9 15.0 (13.0, 15.0) 4.0 (1.0, 11.0) 12.0 (1.5, 19.0)
64.0 36.0 14.0 (12.0, 15.0) 9.0 (3.8, 15.5) 9.5 (1.25, 11.75)
P NS NS NS .011 .032 NS NS NS
NS .016 NS
Abbreviations: ICH, intracerebral hemorrhage; GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale.
logistic regression model was used to control for the potential confounders identified in univariate analysis and other known predictors of outcome after ICH. After controlling for potential confounding variables, thyroid status, 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-
tient’s functional outcome at 3 and 12 months postevent. Retrospective studies have demonstrated a relationship between the severity of ischemic stroke and a history of hypothyroidism.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 surges during the critical 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
Table 3. Outcomes in patients with ICH based on thyroid status
Mortality In hospital 3 mo 12 mo Modified Barthel Index , 15 3 mo 12 mo Discharge location Home with or without services Acute rehab Subacute rehab ECF, hospice, death NIHSS discharge Change in NIHSS Improved Same Worsened
Euthyroid (n 5 491)
Hypothyroid with replacement (n 5 45)
Hypothyroid with no replacement (n 5 27)
P
31.0% 39.1% 41.8%
20.0% 35.6% 42.2%
25.9% 40.7% 44.4%
NS NS NS
27.2% 22.6%
33.3% 30.0%
41.7% 0.0%
NS NS NS
19.0% 13.6% 29.8% 37.6% 3.0 (0.0, 8.0)
25.0% 6.8% 38.6% 29.5% 1.0 (0.0, 9.0)
7.4% 18.5% 40.7% 33.3% 2.0 (.5, 6.5)
30.4% 11.6% 58.0%
26.9% 26.9% 46.2%
25.0% 25.0% 50.0%
NS NS
Abbreviations: ECF, extended care facility; NIHSS, National Institutes of Health Stroke Scale; rehab, rehabilitation; NS, nonsignificant.
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Table 4. Hypothyroidism and mortality after ICH In-hospital mortality (n 5 454)
3-Mo mortality (n 5 409)
12-Mo mortality (n 5 366)
Variable
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
Thyroid status (compared with euthyroid) Hypothyroid with replacement Hypothyroid without replacement
.95 (.30-3.00) .86 (.24-3.12)
.93 .82
2.33 (.80-6.79) 1.06 (.28-3.93)
.12 .94
2.47 (.94-6.52) 1.28 (.41-6.03)
.07 .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 Coumadin, 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.
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 replacement 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
3 time points, long-term functional outcome, and discharge 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 hypothyroidism does not meaningfully contribute to patient outcomes and should not enter prognostication discussions. 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 variable time points during a patient’s hospitalization, ranging 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 usefulness of classifying acutely ill patients with TSH levels. Although only a subset of patients in each group had TSH levels drawn, it is unclear whether inpatient measurements of TSH levels in all patients would have aided in the diagnosis of hypothyroidism in this ill population.
Table 5. Hypothyroidism and poor long-term outcome after ICH Poor outcome at 3 mo (n 5 374)
Poor outcome at 12 mo (n 5 285)
Variable
OR (95% CI)
P
OR (95% CI)
P
Thyroid status (compared with euthyroid) Hypothyroid with replacement Hypothyroid without replacement
2.12 (.78-5.78) 1.27 (.34-4.71)
.14 .72
1.23 (.41-3.66)
.71 .998
Abbreviations: CI, confidence interval; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; mBI, modified Barthel Index; 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 Coumadin, ICH volume, and infratentorial location. Poor outcome defined as death or disability with mBI , 15. OR not shown for the hypothyroid without replacement group as the number of patients was small leading to a 95% CI of 0 to infinity. 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.
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In NTIS, the most 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 outcomes. However, the number and timing of thyroid hormone 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 quality 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 classify thyroid status at controlled time intervals. Because of the instability of the hypothalamic–pituitary–thyroid axis during acute illness and markedly different thyroid hormone half lives, a single set of thyroid function measurements 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 replacement therapy limited our determination of functional 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 dysfunction of the hypothalamic-pituitary-adrenal axis and whether this correlates with outcome. If ICH-induced decline 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 provides 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 outcomes in this devastating disease.
Conclusions We found no association with reported hypothyroidism and outcomes after ICH, regardless of ongoing replacement 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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