TSH Trajectories During Levothyroxine Treatment in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Cohort.

CONTEXT: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. OBJECTIVE: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. METHODS: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. RESULTS: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. CONCLUSION: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

Thyroid hormone homeostasis in levothyroxine-treated patients: Findings from ELSA-Brasil.

CONTEXT: The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. OBJECTIVE: To assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. METHODS: The ELSA-Brasil study follows 15,105 adult Brazilians (aged 35 to 74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. RESULTS: Initiation of therapy with LT4 resulted in a 11-19% decrease in TSH, a ∼19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and anti-diabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and, a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least one serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least one serum FT3 below the reference range (<0.23 ng/dL). CONCLUSION: The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.

A Cross-Sectional Analysis of Cardiovascular and Bone Health Care Utilization During Treatment With Thyroid Hormone.

CONTEXT: Combination therapy with levothyroxine and liothyronine (LT4 + LT3) and desiccated thyroid extract (DTE) make up >10% of new thyroid hormone (TH) prescriptions in the United States. OBJECTIVE: To assess health care utilization related to cardiovascular disease (CVD) and bone health (BH) events (atrial fibrillation [AF], heart failure [HF], myocardial infarction [MI], stroke, and osteoporosis/fractures [FX]) in participants taking LT4+LT3 or DTE surveyed in the Medical Expenditure Panel Survey database. MATERIALS AND METHODS: Multi-year cross-sectional analysis examining 5437 participants (≥18 years old) treated with LT4, LT4+LT3, or DTE between 2016 and 2020. Health care utilization was assessed through outpatient, emergency, and hospital visits for AF, HF, MI, stroke, FX, and a composite index. A weighted analysis provided national estimates of health care utilization parameters. Utilization was re-analyzed following propensity score-based matching to balance sociodemographic and clinical covariates between treatment groups. Additionally, provider type and specialty data were obtained from visits associated with TH prescriptions. RESULTS: 5106 participants were treated with LT4 monotherapy, 252 with DTE, and 79 with LT4 + LT3. Prevalence of combined outpatient CVD and BH-related care utilization was lower among DTE/LT4+LT3 vs LT4 users (3.5% vs 7.7%; P = .008). There were no differences in emergency/hospital events. After covariate balancing, CVD and BH-related care utilization was similar between groups in outpatient and emergency/hospital settings. LT3 and DTE made up 7.6% of all TH prescriptions. For visits associated with DTE prescriptions, nurse practitioners and alternative medicine professionals were more likely to be identified as the primary provider type. CONCLUSION: No significant differences in CVD- and BH-related health care utilization were identified between LT4 and DTE/LT4+LT3 users after covariate balancing. Non-MD providers were more likely to prescribe DTE.

The Effects of Patient Characteristics on the Management of Subclinical Hypothyroidism: A Survey of Faculty and Trainees.

OBJECTIVE: There is no universal approach to the management of subclinical hypothyroidism (SCH). This study was designed to determine the impact of patient characteristics on management decisions in SCH amongst physician faculty members and trainees. METHODS: An online survey was distributed to faculty members and medical trainees (ie, interns, residents, and fellows) at multiple academic medical centers. The survey included 9 clinical scenarios describing women with SCH with 5 management options sequenced from most "conservative" (no further treatment or monitoring) to most "aggressive" (treatment with levothyroxine). RESULTS: Of the 194 survey respondents, 95 (49.0%) were faculty members and 99 (51.0%) were trainees. Faculty members were more likely to report being "confident" or "very confident" in making the diagnosis of SCH compared to trainees (95.8% vs 46.5%, P < .001). Faculty members were also more likely to consider patient preference for treatment (60.0% vs 32.3%, P < .001). Among all respondents, the clinical factors that resulted in the highest predicted probability of treatment were hypothyroid symptoms (predicted probability [PP] 68.8%, 95% CI [65.7%-71.9%]), thyroid stimulating hormone >10 mIU/L in a 31-year-old (PP 63.9%, 95% CI [60.3%-67.3%]), and the desire for fertility (PP 52.2%, 95% CI [48.6%-56.0%]). In general, faculty members favored more aggressive treatment across all clinical scenarios. CONCLUSION: The presence of symptoms, thyroid stimulating hormone >10 mIU/L, and desire for fertility were most predictive of the decision to treat in SCH. In several clinical scenarios, both trainee and faculty decision-making demonstrated discordance with general SCH management principles.

Are We Restoring Thyroid Hormone Signaling in Levothyroxine-Treated Patients With Residual Symptoms of Hypothyroidism?

INTRODUCTION: Levothyroxine (LT4) at doses that maintain the serum thyroid-stimulating hormone levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates the signs and symptoms of overt hypothyroidism in the majority of patients, owing to the endogenous activation of thyroxine to triiodothyronine, the biologically active thyroid hormone. Still, a small percentage of the patients (10%-20%) exhibit residual symptoms, despite having normal serum thyroid-stimulating hormone levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life. OBJECTIVE: To provide a summary of progress in the approach of patients with hypothyroidism that exhibit residual symptoms despite treatment. METHODS: We reviewed the current literature and here we focused on the mechanisms leading to a deficiency of T3 in some LT4-treated patients, the role of residual thyroid tissue and the rationale for combination therapy with LT4 + liothyronine (LT3). RESULTS: A score of clinical trials comparing therapy with LT4 versus LT4 + LT3 concluded that both are safe and equally effective (neither is superior); however, these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4 + LT3; desiccated thyroid extract has also been used with similar results. A practical approach to patients with residual symptoms and on initiation of combination therapy with LT4 + LT3 is provided. CONCLUSION: A recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4.

Cardiovascular outcomes in subclinical thyroid disease: an update.

PURPOSE OF REVIEW: Subclinical thyroid disease is defined by a thyroid stimulating hormone (TSH) level outside of the normal range with normal circulating thyroid hormone levels. Excess adverse cardiovascular outcomes have been observed in certain patient populations with subclinical hypothyroidism (SCH) and hyperthyroidism (SCHr). The role of thyroid hormone and antithyroid treatments for subclinical thyroid disease remains debated. RECENT FINDINGS: Cardiovascular disease appears to be a major mediator of all-cause mortality in patients with SCH, in particular those aged at least 60 years of age. In contrast, pooled clinical trial results did not find that levothyroxine reduced the incidence of cardiovascular events or mortality in this patient population. The association between SCHr and atrial fibrillation is well established; however, a 5-year follow-up of older patients with mild (TSH 0.1-0.4 mIU/l) SCHr found no increased incidence of atrial fibrillation. Separately, SCHr was associated with derangements in endothelial progenitor cell function that may underlie vascular disease independent from effects on cardiac function. SUMMARY: The impact of treatment of subclinical thyroid disease on cardiovascular outcomes remains uncertain. Additional prospective and trial data are needed to evaluate treatment effects on cardiovascular outcomes in younger populations.

Demographic, Healthcare Access, and Dietary Factors Associated With Thyroid Hormone Treatments for Hypothyroidism.

CONTEXT: Clinical guidelines have recommended a trial of liothyronine (LT3) with levothyroxine (LT4) in select patients with hypothyroidism. However, little is known about the real-world use of LT3 and desiccated thyroid extract (DTE) and the characteristics of patients treated with LT3 and DTE. OBJECTIVES: (1) Determine national trends of new LT4, LT3, and DTE prescriptions in the United States; (2) determine whether sociodemographic, healthcare access, and dietary factors are associated with different thyroid hormone (TH) therapies. METHODS: Parallel cross-sectional studies were conducted using 2 datasets: (1) a national patient claims dataset (2010-2020) and (2) the National Health and Nutrition Examination Study (NHANES) dataset (1999-2016). Included participants had a diagnosis of primary or subclinical hypothyroidism. Study outcomes included the impact of demographics and healthcare access on differences in the proportion of TH therapies consisting of LT4, LT3, and DTE (patient claims) and differences in dietary behaviors between DTE-treated participants and LT4-treated matched controls (NHANES). RESULTS: On an average annual basis, 47 711 adults received at least 1 new TH prescription, with 88.3% receiving LT4 monotherapy, 2.0% receiving LT3 therapy, and 9.4% receiving DTE therapy. The proportion receiving DTE therapy increased from 5.4% in 2010 to 10.2% in 2020. In the analysis between states, high primary care and endocrinology physician densities were associated with increased use of LT4 monotherapy (odds ratio 2.51, P < .001 and odds ratio 2.71, P < .001). DTE-treated NHANES participants (n = 73) consumed more dietary supplements compared to LT4-treated participants (n = 146) (4.7 vs 2.1, P < .001). CONCLUSIONS: The proportion of new TH therapies containing DTE for hypothyroidism doubled since 2010 while LT3 therapies remained stable. DTE treatment was associated with decreased physician density and increased dietary supplement use.

Serum Thyrotropin and Triiodothyronine Levels in Levothyroxine-treated Patients.

CONTEXT: Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. OBJECTIVE: This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. METHODS: This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. RESULTS: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. CONCLUSION: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

Evaluating health outcomes in the treatment of hypothyroidism.

Clinical hypothyroidism is defined by the inadequate production of thyroid hormone from the thyroid gland to maintain normal organ system functions. For nearly all patients with clinical hypothyroidism, lifelong treatment with thyroid hormone replacement is required. The primary goal of treatment is to provide the appropriate daily dose of thyroid hormone to restore normal thyroid function for each individual patient. In current clinical practice, normalization of thyrotropin (TSH) level is the primary measure of effectiveness of treatment, however the use of a single biomarker to define adequate thyroid hormone replacement is being reevaluated. The assessment of clinical health outcomes and patient-reported outcomes (PROs), often within the context of intensity of treatment as defined by thyroid function tests (i.e., undertreatment, appropriate treatment, or overtreatment), may play a role in evaluating the effectiveness of treatment. The purpose of this narrative review is to summarize the prominent health outcomes literature in patients with treated hypothyroidism. To date, overall mortality, cardiovascular morbidity and mortality, bone health and cognitive function have been evaluated as endpoints in clinical outcomes studies in patients with treated hypothyroidism. More recent investigations have sought to establish the relationships between these end results and thyroid function during the treatment course. In addition to clinical event outcomes, patient-reported quality of life (QoL) has also been considered in the assessment of adequacy of hypothyroidism treatment. From a health care quality perspective, treatment of hypothyroidism should be evaluated not just on its effectiveness for the individual patients but also to the extent to which patients of different sociodemographic groups are treated equally. Ultimately, more research is needed to explore differences in health outcomes between different sociodemographic groups with hypothyroidism. Future prospective studies of treated hypothyroidism that integrate biochemical testing, PROs, and end result clinical outcomes could provide a more complete picture into the effectiveness of treatment of hypothyroidism.

Suboptimal Thyroid Hormone Replacement Is Associated With Worse Hospital Outcomes.

CONTEXT: Many patients with hypothyroidism receive suboptimal treatment that may affect hospital outcomes. OBJECTIVE: This work aimed to identify differences in hospital outcomes between patients with and without hypothyroidism. METHODS: A retrospective cohort study, using the propensity score-based fine stratification method to balance covariates, was conducted using a large, US-based, commercial claims database from January 1, 2008 to December 31, 2015. Participants included patients aged 64 years and younger who had a thyrotropin (TSH) level collected before a hospital admission. Covariates included age, sex, US region, type of admission, year of admission, and comorbidities. Exposure included clinical hypothyroidism, which was divided into 4 subgroups based on prehospitalization TSH level: low (TSH < 0.40 mIU/L), normal (TSH 0.40-4.50 mIU/L), intermediate (TSH 4.51-10.00 mIU/L), and high (TSH > 10.00 mIU/L). MAIN OUTCOME MEASURES INCLUDED: length of stay (LOS), in-hospital mortality, and readmission outcomes. RESULTS: A total of 43 478 patients were included in the final study population, of whom 8873 had a diagnosis of hypothyroidism. Those with a high prehospitalization TSH level had an LOS that was 1.2 days longer (95% CI, 1.1-1.3; P = .003), a 49% higher risk of 30-day readmission (relative risk [RR] 1.49; 95% CI, 1.20-1.85; P < .001), and a 43% higher rate of 90-day readmission (RR 1.43; 95% CI, 1.21-1.67; P < .001) compared to balanced controls. Patients with normal TSH levels exhibited decreased risk of in-hospital mortality (RR 0.46; 95% CI, 0.27-0.79; P = .004) and 90-day readmission (RR 0.92; 95% CI, 0.85-0.99; P = .02). CONCLUSION: The results suggest suboptimal treatment of hypothyroidism is associated with worse hospital outcomes, including longer LOS and higher rate of readmission.

The relevance of T3 in the management of hypothyroidism.

Levothyroxine monotherapy has been the standard of care for treatment of hypothyroidism for more than 40 years. However, patients treated with levothyroxine have relatively lower serum tri-iodothyronine (T3) concentrations than the general population, and symptoms of hypothyroidism persist for some patients despite normalisation of thyroid-stimulating hormone (TSH) concentrations. The understanding that maintenance of normal T3 concentrations is the priority for the thyroid axis has redirected the clinical focus to serum T3 concentrations in patients with hypothyroidism. This Personal View explores whether it is currently feasible to identify patients who could be considered for liothyronine supplementation in combination with levothyroxine. Genetic profiling stands out as a potential future tool to identify patients who do not respond well to levothyroxine due to suboptimal peripheral thyroxine (T4) activation. Moreover, new slow-release liothyronine preparations are being developed to be trialled in these symptomatic patients, in an attempt to restore T3 concentrations and provide conclusive results for the use of T4 plus T3 combination therapy.

Brain Fog in Hypothyroidism: Understanding the Patient's Perspective.

OBJECTIVE: Patient-centered studies have shown that several patients on thyroid hormone replacement therapy for hypothyroidism exhibit persistent symptoms, including "brain fog." Here, we aimed to determine which of these specific symptoms are associated with brain fog, identify patient-reported factors that modify these symptoms, and identify patient concerns related to brain fog not included in thyroid-specific questionnaires. METHODS: A survey on brain fog symptoms adapted from thyroid-specific patient-reported outcome was distributed online. Textual data analysis was performed to identify common areas of concern from open-ended survey responses. RESULTS: A total of 5170 participants reporting brain fog while being treated for hypothyroidism were included in the analysis. Of these, 2409 (46.6%) participants reported symptom onset prior to the diagnosis of hypothyroidism, and 4096 (79.2%) participants experienced brain fog symptoms frequently. Of the symptoms listed, participants associated fatigue and forgetfulness most frequently with brain fog. More rest was the most common factor provided for improving symptoms. The textual data analysis identified areas of concern that are not often included in thyroid-specific quality of life questionnaires, including a focus on the diagnosis of hypothyroidism, the types and doses of medications, and the patient-doctor relationship. CONCLUSION: Brain fog in patients treated for hypothyroidism was associated most frequently with fatigue and cognitive symptoms. Several additional areas of patient concern were found to be associated with brain fog, which are not typically addressed in thyroid-specific questionnaires.

Sociodemographic Disparities in the Treatment of Hypothyroidism: NHANES 2007-2012.

PURPOSE: Both undertreatment and overtreatment of hypothyroidism with thyroid hormone are associated with adverse clinical outcomes. Disparities in the treatment of hypothyroidism may lead to a higher risk of adverse outcomes for certain sociodemographic groups. Our objectives were to identify sociodemographic disparities between those with treated and untreated hypothyroidism, and between those who were adequately and inadequately treated. METHODS: This is a cross-sectional study of a representative sample of US adults aged 20 years and older with hypothyroidism (n = 698). The main measures were age, gender, race/ethnicity, education, income, and health care access differences among those with treated and untreated hypothyroidism. RESULTS: Of those with hypothyroidism, women were more likely than men to be taking thyroid hormone (odds ratio [OR] 2.66 [95% confidence interval (CI) 1.42-4.99]), as were older participants (45-69 years old vs 20-44 years old: OR 7.25 [95% CI 4.15-12.67]; 70 years of age and older: OR 11.00 [95% CI 5.30-22.79]). Health care access was strongly associated with thyroid hormone use (OR 14.32, 95% CI 3.63-56.58). Hispanic race/ethnicity was associated with inadequate treatment compared with non-Hispanic whites (OR 2.42, 95% CI: 1.14-5.14). MAIN CONCLUSIONS: Male gender, younger age, and lack of health care access were associated with untreated hypothyroidism, and Hispanic race was associated with inadequate treatment of hypothyroidism. Clinicians should be aware of these sociodemographic disparities in the hypothyroid population and consider strategies to improve treatment of hypothyroidism in men, younger adults, Hispanics, and those without routine health care access.

Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

CONTEXT: It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure. EVIDENCE ACQUISITION: This review is based on a collection of primary and review literature gathered from a PubMed search of "hypothyroidism," "levothyroxine," "liothyronine," and "desiccated thyroid extract," among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject. EVIDENCE SYNTHESIS: In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels. CONCLUSIONS: After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.

Roux-en-Y gastric bypass versus sleeve gastrectomy: risks and benefits.

INTRODUCTION: Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) are the most commonly performed metabolic surgeries and are highly effective for the treatment of obesity and related comorbidities. In this narrative review, recent studies of at least two years of follow-up directly comparing outcomes between GB and SG are reviewed to assess the efficacy of each procedure in weight loss and diabetes remission, as well as resulting quality of life (QoL) assessment and micronutrient deficiencies. EVIDENCE ACQUISITION: A systematic search of the literature of PubMed using MeSH terms and key words was performed. EVIDENCE SYNTHESIS: Forty recent studies comparing GB and SG including 208,556 patients are included in this narrative review. Most studies demonstrate significantly greater weight loss after GB compared to SG. There is some evidence that GB may lead to greater proportion of remission of diabetes mellitus (DM), but the majority of studies found no significant difference at longer follow-up. There is some evidence of greater rates of vitamin D and B12 deficiencies following GB. There were no significant differences in QoL assessments between SG and GB. CONCLUSIONS: A review of moderate and long-term studies directly comparing SG and GB suggests a greater degree of weight loss with GB. There is some but limited evidence the GB is more likely to induce DM remission, while increasing the risk of specific micronutrient deficiencies.

Hyperglycemia and insulin resistance in cardiac arrest patients treated with moderate hypothermia.

CONTEXT: It is unknown whether the hyperglycemia that follows cardiac arrest and during therapeutic hypothermia (TH) is due to the arrest or the TH, whether it is associated with adverse outcomes, or whether its treatment affects outcomes. OBJECTIVE: The objective of the study was to determine the effects of TH on the blood glucose (BG) levels in postcardiac arrest patients and the effects of hyperglycemia on mortality. DESIGN: This was a chart review of 62 patients undergoing TH after cardiac arrest between September 2005 and April 2008. BG levels from 72 hours before the arrest to 48 hours after TH and iv insulin infusion rates were analyzed and correlated with survival to discharge from hospital. SETTING: The study was conducted at a tertiary, university referral center. PATIENTS: PATIENTS undergoing TH after cardiac arrest participated in the study. INTERVENTIONS: TH consisted of cooling as rapidly as possible to 33°C, holding that temperature for 24 hours, and then controlled rewarming to 37°C over 8 or 16 hours. Hyperglycemia was managed with iv insulin drip protocols. MAIN OUTCOME MEASURE: The relationship of cardiac arrest and hypothermia to hyperglycemia, with a key secondary outcome being the relationship of hyperglycemia to survival to discharge, was measured. RESULTS: Analysis of glucose patterns showed no independent effect of TH on BG levels. Mean BG levels between cardiac arrest and the initiation of hypothermia were higher in nonsurvivors (253 ± 112 mg/dL, n = 48) than in survivors (192 ± 69 mg/dL, n = 24, P = .016). BG, insulin infusion rates, and insulin resistance during hypothermia, during rewarming, and 24-48 hours after hypothermia were not significantly different between the 2 groups. CONCLUSIONS: In patients treated with TH, the TH had no independent effect on BG levels. Mortality was associated with increased BG levels after cardiac arrest but before initiation of TH or an insulin drip. Likely, it is the severity of stress from the cardiac arrest that causes the hyperglycemia in these patients.