Sean M. Forsythe

Near-fatal heat stroke during the 1995 heat wave in Chicago

Chicago sustained a heat wave from 12 July to 20 July 1995 that resulted in more than 600 excess deaths [1] and 3300 excess emergency department visits [2]. Daily temperatures ranged from 33.9 to 40.0 C, and on 13 July, the heat index peaked at 48.3 C [1]; the maximum number of emergency department visits occurred 24 hours later. The medical examiners office reported the maximum number of deaths on 15 July [1, 2]. The peak number of admissions to area intensive care units occurred on 15 July (Figure 1). Critically ill persons were admitted with classic heat stroke, defined by a body temperature greater than 40.6 C in the presence of altered mental status and anhidrosis [1]. Figure 1. Relation between admissions to the intensive care unit (ICU) (bar graph) and the heat index (line chart) during the height of the heat wave. Heat stroke has been classified as exertional or classic. Exertional heat stroke is precipitated by heavy exertion in very hot and humid climates and is usually seen in otherwise healthy young persons [3]. Classic heat stroke results from unabated exposure to high temperatures and humidity. Elderly persons with premorbid conditions are likely to experience classic heat stroke. Despite the high incidence of heat-related deaths reported annually in the United States [4], the literature on the clinical features of classic heat stroke is limited. Lactic acidosis, renal failure, rhabdomyolysis, and disseminated intravascular coagulation, well described in exertional heat stroke, are reported as uncommon or of minor consequence in classic heat stroke [3, 5-7]. The numerous persons who presented with near-fatal classic heat stroke during the Chicago heat wave provided an opportunity to analyze the clinical course of this condition. We sought to describe the course of patients admitted to the intensive care unit with classic heat stroke. Excessive functional disability identified in survivors of the acute phase of the illness prompted a 1-year follow-up to assess delayed functional outcome and mortality. Methods Medical Record Review Twelve of 24 area hospitals permitted us access to patient records. We obtained institutional review board approval, which allowed us to contact patients for 1-year follow-up. Patients were identified by review of emergency department records, intensive care unit logs, and medical records discharge codes. Records of all patients admitted to each intensive care unit from 12 July to 20 July 1995 were reviewed. Enrollment criteria were 1) absence of vigorous physical activity during the heat wave; 2) alteration of mental status [coma, delirium, lethargy, disorientation, or seizures documented by paramedics and emergency department physicians]; 3) recorded core body temperature of more than 40.6 C or documented evidence of cooling before the first recorded temperature and a reliable history of compatible environmental exposure [1, 5, 8, 9]; and 4) hot, dry, flushed skin. Data were recorded by using a predesigned data collection form. Major components of this form were demographic characteristics, Glasgow coma score, temperature, and clinical condition at presentation; maximum Acute Physiology and Chronic Health Evaluation (APACHE) II score in the first 24 hours; length of intensive care unit and hospital stay; functional level and disposition at discharge; laboratory data; and results of radiography, electrocardiography, and echocardiography. Data on the presence or absence of air conditioning was obtained from paramedic encounter sheets. Information about when the patient was last seen was obtained from paramedic reports or emergency department history. The medical history was obtained from admission history and physical examination and was verified by the medical records of the patients personal physician, when available, or outpatient prescription medication, as recorded on the paramedic report. Organ system dysfunction was assessed by evaluation of serial laboratory results. The chart reviewer assessed neurologic impairment at discharge from documentation of the patients neurologic status at discharge. Follow-up A modified Stanford Health Assessment Questionnaire was used to score functionality [10, 11]. Components of this tool assess performance of activities of daily living. Survivors were contacted 1 year after discharge and were interviewed by telephone to complete the modified Stanford Health Assessment Questionnaire. If the patient was unable to respond, a caretaker estimated their level of function by using the same questionnaire. If telephone contact could not be made, tracking was attempted through mail, health care providers, or acquaintances identified in the medical record. Deaths were investigated in the aforementioned manner and by a search of the Cook County Medical Examiner logs. Data that allowed completion of the modified Stanford Health Assessment Questionnaire at the time of hospital discharge were abstracted from the charts of patients whose outcomes were known at 1 year. Data Analysis Data are presented as the mean SD except when they did not fit tests for normality and the mean did not accurately describe the data. In these instances, data are presented as the median and interquartile range. We used n to denote the number of values averaged when data were not available on all 58 study patients. Nominal data were compared by using chi-square analysis or the Fisher exact test of contingency tables. Continuous data were compared and correlations were made by using analysis of variance, the t-test, the Spearman rank test, and the Wilcoxon signed-rank test. Admission laboratory values and follow-up values were compared, and correlations were performed between laboratory tests to determine whether abnormalities were related. To determine the effect of functional disability and age on survival, survival analysis was performed by using Kaplan-Meier plots with the Mantel-Cox log-rank test and the Cox proportional-hazards model. Statistical analysis was performed by using StatView 4.5 (Abacus Concepts, Berkeley, California). Role of Funding Source Neither of our funding sources, the Park Ridge Health Foundation or the University of Chicago Clinical Research Center, participated in collection, analysis, and interpretation of the data or in preparation of the manuscript. The decision to publish this report was not influenced by the funding sources. Results Epidemiology Fifty-eight patients met the inclusion criteria. Patients who met the case definition of classic heat stroke but were not admitted to the intensive care unit were excluded from further analysis. Demographic characteristics of the patients are presented in Table 1. Forty-seven patients (83%) were found at home, and 77% were last seen within 12 hours of rescue (range, 2 to 42 hours; n = 39). The environments in which patients were found lacked air conditioning in 40 instances (69%). Three patients had air conditioners that were turned off, and 1 patient had the unit on at the time of rescue. In 14 cases, the presence or absence of air conditioning was not documented. Forty-three of 50 patients had medical insurance (Medicare [44%], private insurance [18%], private insurance and Medicare [14%], Medicaid [10%], and self-pay [14%]). Insurance data were not available for eight patients. Table 1. Demographic Characteristics of the 58 Study Patients Chronic medical conditions were documented in 52 patients (Table 2). The most common comorbid conditions were hypertension and alcohol abuse. Before admission, 47 patients were taking at least 1 of 18 medications (Table 2). Sixteen patients were found to be taking medications that predispose to the development of heat stroke (diuretics [13 patients], phenothiazines [2 patients], or both [1 patient]). An additional 2 patients tested positive for cocaine, a substance known to increase heat production. Table 2. Preexisting Medical Conditions (52 Patients) and Medications (47 Patients) Presenting temperature, time to cooling, and APACHE II scores are shown in Table 3. Methods of cooling in the emergency department included antipyretic agents (15 patients), water or fan (24 patients), groin and axillary ice packs (34 patients), cooling blanket (19 patients), gastric lavage with cool saline (6 patients), cold intravenous fluids (17 patients), and ice bath (1 patient). The median hospital stay was 9 days (interquartile range, 13 days), and the median intensive care unit stay was 4 days (interquartile range, 5 days). Twelve patients died (20.7%). Table 3. Presenting Body Temperature, Time to Cooling, and APACHE II Data in 58 Patients* Organ System Dysfunction Cardiovascular Findings Presenting electrocardiography showed sinus tachycardia (71%), normal sinus rhythm (8.5%), supraventricular tachycardia (8.5%), atrial fibrillation (8.5%), and multifocal atrial tachycardia (3%). Hypovolemic shock was suggested by physical examination in 17 of 58 patients. In the first 24 hours, 3.8 2.1 L (range, 0.6 to 13.5 L) of fluid was infused. Six patients had central venous pressure measured within the first 24 hours; the mean was 12 6 cm H2O (range, 7 to 20 cm H2O). Fourteen of 43 patients underwent echocardiography early in the hospital course. Among these 14 patients, findings included normal left ventricular systolic function (7 patients), concentric left ventricular hypertrophy (4 patients), mild left ventricular dysfunction (1 patient), moderate to severe left ventricular dysfunction (4 patients), left-sided chamber enlargement (4 patients), and mitral regurgitation (3 patients). Six patients had one of the following findings: right ventricular hypertrophy, aortic insufficiency, tricuspid regurgitation, pericardial effusion, paradoxical septal-wall movement, and aneurysm. Two patients underwent follow-up echocardiography; one had normalization of previously noted moderate to severe left ventricular dysfunction and resolution of pericardial effusion. This patient also und

Divergent differentiation paths in airway smooth muscle culture: induction of functionally contractile myocytes

We tested the hypothesis that prolonged serum deprivation would allow a subset of cultured airway myocytes to reacquire the abundant contractile protein content, marked shortening capacity, and elongated morphology characteristic of contractile cells within intact tissue. Passage 1 or 2 canine tracheal smooth muscle (SM) cells were grown to confluence, then serum deprived for up to 19 days. During serum deprivation, two differentiation pathways emerged. One-sixth of the cells developed an elongated morphology and aligned into bundles. Elongated myocytes contained cables of contractile myofilaments, dense bodies, gap junctions, and membrane caveoli, ultrastructural features of contractile SM in tissue. These cells immunostained intensely for SM alpha-actin, SM myosin heavy chain (MHC), and SM22 (an SM-specific actin-binding protein), and Western analysis of culture lysates disclosed 1.8 (SM alpha-actin)-, 7.7 (SM MHC)-, and 5.8 (SM22)-fold protein increases during serum deprivation. Immunoreactive M3 muscarinic receptors were present in dense foci distributed throughout elongated, SM MHC-positive myocytes. ACh (10(-3) M) induced a marked shortening (59.7 +/- 14.4% of original length) in 62% of elongated myocytes made semiadherent by gentle proteolytic digestion, and membrane bleb formation (a consequence of contraction) occurred in all stimulated cells that remained adherent and so did not shorten. Cultured airway myocytes that did not elongate during serum deprivation instead became short and flattened, lost immunoreactivity for contractile proteins, lacked the M3 muscarinic-receptor expression pattern seen in elongated cells, and exhibited no contractile response to ACh. Thus we demonstrate that prolonged serum deprivation induces distinct differentiation pathways in confluent cultured tracheal myocytes and that one subpopulation acquires an unequivocally functional contractile phenotype in which structure and function resemble contractile myocytes from intact tissue.

Physiological control of smooth muscle-specific gene expression through regulated nuclear translocation of serum response factor.

Prolonged serum deprivation induces a structurally and functionally contractile phenotype in about 1/6 of cultured airway myocytes, which exhibit morphological elongation and accumulate abundant contractile apparatus-associated proteins. We tested the hypothesis that transcriptional activation of genes encoding these proteins accounts for their accumulation during this phenotypic transition by measuring the transcriptional activities of the murine SM22 and human smooth muscle myosin heavy chain promoters during transient transfection in subconfluent, serum fed or 7 day serum-deprived cultured canine tracheal smooth muscle cells. Contrary to our expectation, SM22 and smooth muscle myosin heavy chain promoter activities (but not viral murine sarcoma virus-long terminal repeat promoter activity) were decreased in long term serum-deprived myocytes by at least 8-fold. Because serum response factor (SRF) is a required transcriptional activator of these and other smooth muscle-specific promoters, we evaluated the expression and function of SRF in subconfluent and long term serum-deprived cells. Whole cell SRF mRNA and protein were maintained at high levels in serum-deprived myocytes, but SRF transcription-promoting activity, nuclear SRF binding to consensus CArG sequences, and nuclear SRF protein were reduced. Furthermore, immunocytochemistry revealed extranuclear redistribution of SRF in serum-deprived myocytes; nuclear localization of SRF was restored after serum refeeding. These results uncover a novel mechanism for physiological control of smooth muscle-specific gene expression through extranuclear redistribution of SRF and consequent down-regulation of its transcription-promoting activity.

Low vitamin D levels are associated with increased rejection and infections after lung transplantation

BACKGROUND The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation. METHODS Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant). RESULTS In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04]. CONCLUSIONS Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.

Retrospective utility of bronchoscopy after hematopoietic stem cell transplant.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is thought to be the procedure of choice to evaluate pulmonary infiltrates in hematopoietic stem cell transplant (HSCT) recipients. We retrospectively reviewed 91 bronchoscopies performed on 190 in-patient HSCT recipients admitted or treated for pneumonia from January 1994 to December 2004. These yielded a diagnosis 49% of the time with an overall survival of 35 days post-bronchoscopy. We were unable to detect any survival benefit from an addition to the treatment regimen after a positive result from analysis of the BAL fluid or transbronchial biopsy. The most common bacteria isolated was Pseudomonas that was often resistant to the patients current antibiotics, suggesting that in lieu of this diagnostic procedure, changes to better cover resistant Gram-negative bacteria are reasonable. Although transbronchial biopsies provided an additional diagnosis in one out of 21 biopsies performed, six of the seven complications in our series were directly related to the transbronchial biopsy. With approximately a 50% yield from a bronchoscopy, additional treatment given after only 20% of all bronchoscopies, and no detectable survival benefit with a bronchoscopy that yielded a diagnosis, the utility of a bronchoscopy in this patient population is questioned by these data.