Antioxidant supplementation and atrial arrhythmias in critically ill trauma patients.

BACKGROUND: The purpose of this study is to determine if antioxidant supplementation influences the incidence of atrial arrhythmias in trauma intensive care unit (ICU) patients. MATERIALS AND METHODS: In this retrospective pre-post study, critically ill injured patients aged ≥18 years, admitted to a single-center trauma ICU for ≥48 hours were eligible for inclusion. The control group consists of patients admitted from January 2000 to September 2005, before routine antioxidant supplementation in our ICU. The antioxidant group consists of patients admitted from October 2005 to June 2011 who received an antioxidant protocol for ≥48 hours. The primary outcome is the incidence of atrial arrhythmias in the first 2 weeks of hospitalization or before discharge. RESULTS: Of the 4699 patients, 1622 patients were in the antioxidant group and 2414 patients were in the control group. Adjusted for age, sex, year, injury severity, past medical history, and medication administration, the unadjusted incidence of atrial arrhythmias was 3.02% in the antioxidant group versus 3.31% in the control group, with no adjusted difference in atrial arrhythmias among those exposed to antioxidants (odds ratio: 1.31 [95% confidence interval: 0.46, 3.75], P = 0.62). Although there was no change in overall mortality, the expected adjusted survival of patients in those without antioxidant therapy was lower (odds ratio: 0.65 [95% confidence interval: 0.43, 0.97], P = 0.04). CONCLUSIONS: ICU antioxidant supplementation did not decrease the incidence of atrial arrhythmias, nor alter the time from admission to development of arrhythmia. A longer expected survival time was observed in the antioxidant group compared with the control group but without a change in overall mortality between groups.

Increasing blood glucose variability heralds hypoglycemia in the critically ill.

BACKGROUND: Control of hyperglycemia improves outcomes, but increases the risk of hypoglycemia. Recent evidence suggests that blood glucose variability (BGV) is more closely associated with mortality than either isolated or mean BG. We hypothesized that differences in BGV over time are associated with hypoglycemia and can be utilized to estimate risk of hypoglycemia (<50 mg/dL). MATERIALS AND METHODS: Patients treated with intravenous insulin in the Surgical Intensive Care Unit of a tertiary care center formed the retrospective cohort. Exclusion criteria included death within 24 h of admission. We describe BGV in patients over time and its temporal relationship to hypoglycemic events. The risk of hypoglycemia for each BG measurement was estimated in a multivariable regression model. Predictors were measures of BGV, infusions of dextrose and vasopressors, patient demographics, illness severity, and BG measurements. RESULTS: A total of 66,592 BG measurements were collected on 1392 patients. Hypoglycemia occurred in 154 patients (11.1%). Patient BGV fluctuated over time, and increased in the 24 h preceding a hypoglycemic event. In crude and adjusted analyses, higher BGV was positively associated with a hypoglycemia (OR 1.41, P < 0.001). Previous hypoglycemic events and time since previous BG measurement were also positively associated with hypoglycemic events. Severity of illness, vasopressor use, and diabetes were not independently associated with hypoglycemia. CONCLUSIONS: BGV increases in the 24 h preceding hypoglycemia, and patients are at increased risk during periods of elevated BG variability. Prospective measurement of variability may identify periods of increased risk for hypoglycemia, and provide an opportunity to mitigate this risk.

Colon anastomosis after damage control laparotomy: recommendations from 174 trauma colectomies.

BACKGROUND: Primary colonic anastomosis in trauma patients has been demonstrated to be safe. However, few studies have investigated this in the setting of damage control laparotomy. We hypothesized that colonic anastomosis for trauma patients requiring an open abdomen (OA) would have a higher anastomotic leak (AL) rate when compared with patients having an immediate abdominal closure following trauma laparotomy. METHODS: We performed a cohort comparison study of all trauma patients who underwent colectomy, between the years 2004 and 2009. Exclusion criteria were mortality within 24 hours of admission or colectomy for indications unrelated to injury. Data collected included age, gender, injury severity score, mechanism, length of stay, and mortality. Multivariable logistic regression was performed to assess the relationship of OA to our primary outcome measure, AL. RESULTS: Totally, 174 patients met study criteria. Fecal diversion was performed in 58 patients, and colonic anastomosis was performed in the remaining 116 patients. Patients with OA had a clinically significant increase in AL rate compared with immediate abdominal closure (6% vs. 27%, p=0.002). Logistic regression demonstrated that OA was independently associated with AL, with OA patients having more than a sixfold increase in odds of AL compared with those who were closed (odds ratio=6.37, p=0.002, area under the receiver operator curve=0.72). Transfusion requirement and left-sided anastomosis were risk factors for leak. CONCLUSIONS: Patients with a colonic anastomosis and an OA have an unacceptably high leak rate compared with those who undergo reconstruction with immediate closure. Given the significant risk of AL, colonic anastomosis should not be routinely performed in patients with OA.

Systems initiatives reduce healthcare-associated infections: a study of 22,928 device days in a single trauma unit.

BACKGROUND: "Implementation research" promotes the systematic conversion of evidence-based principles into routine practice to improve the quality of care. We hypothesized a system-based initiative to reduce nosocomial infection would lower the incidence of ventilator-associated pneumonia (VAP), urinary tract infection (UTI), and bloodstream infection (BSI). METHODS: From January 2006 to April 2008, 7,364 adult trauma patients were admitted, of which 1,953 (27%) were admitted to the trauma intensive care unit and comprised the study group. Tight glycemic control was maintained using a computer algorithm for continuous insulin administration based on every 2-hour blood glucose testing. Centers for Disease Control and Prevention definitions of nosocomial infections were used. Evidence-based infection reduction strategies included the following: a VAP bundle (spontaneous breathing, Richmond Agitation-Sedation Scale, oral hygiene, bed elevation, and deep vein thrombosis/stress ulcer prophylaxis), UTI (expert insertion team and Foley removal/change at 5 days), and BSI (maximum barrier precautions, chlorhexidine skin prep, line management protocol). An electronic dashboard identified the at-risk population, and designated auditors monitored the compliance. Infection rates (events per 1,000 device days) were measured over time and compared annually using Fisher's exact test. RESULTS: The study group had 22,928 device exposure days: 6,482 ventilator days, 9,037 urinary catheter days, and 7,399 central line days. Patient acuity, demographics, and number of device days did not vary significantly year-to-year. Annual infection rates declined between 2006 and 2008, and decreases in UTI and BSI rates were statistically significant (p < 0.05). These decreases pushed UTI and BSI rates below Centers for Disease Control and Prevention norms. CONCLUSIONS: Over 28 months, a systems approach to reducing nosocomial infection rates after trauma decreased nosocomial infections: UTI (76.3%), BSI (74.1%), and VAP (24.9%). Our experience suggests that infection reduction requires (1) an evidence-based plan; (2) MD and staff education/commitment; (3) electronic documentation; and (4) auditors to monitor and ensure compliance.

Personalized medicine: genetic variation and loss of physiologic complexity are associated with mortality in 644 trauma patients.

OBJECTIVE: Personalized medicine merges genetics, physiology, and patient outcome. Loss of physiologic complexity (heart rate [HR] variability) is a bedside biomarker for autonomic nervous system (ANS) dysfunction. We hypothesized that variability in ANS receptor proteins (genetics) and loss of complexity (physiology) are independently associated with mortality in critical illness. SUMMARY BACKGROUND DATA: Decreased HR complexity has been associated with increased mortality and morbidity in trauma and other critically ill populations. Genetic variations in alpha-1A and beta-2 adrenergic receptors (ADRA1A, ADRB2) have been associated with changes in smooth muscle tone in various tissues, and implicated in bronchial hyper-responsiveness, metabolic syndrome, and other disorders. METHODS: A cohort of 644 trauma intensive care unit (ICU) admissions had complexity data and genetic samples. Two ANS receptor polymorphisms (rs1048101, Alpha ADRA1A and rs1042714, Beta ADRB2) were genotyped. Physiologic complexity at various points in the ICU stay was measured using previously-studied integer HR multiscale entropy (MSE) over 6-hour intervals (~21,600 HR data points/interval/patient). Logistic regression assessed the concurrent relationship of genotypes, complexity, and probability of survival, an acuity score incorporating age, injury mechanism/severity, and admission vitals, to risk of death. RESULTS: Of total, 96 patients (15%) died. Nonsurvivors had lower complexity at early, middle, and late portions of ICU stay (median MSE at least 25% less in nonsurvivors, P < 0.001) and lower incidence of the GG ADRB2 genotype (7.5% vs. 18.3%, P < 0.001). In multivariable logistic regression, the GG ADRB2 genotype carried ~3-fold decrease in mortality odds (odd ratio [OR] = 0.33, P = 0.01), independent of significant effects in HR MSE (OR = 0.93, P < 0.001), and probability of survival (OR = 0.22, P < 0.001). CONCLUSIONS: This first study to simultaneously examine ANS genetics, the biomarker complexity, and mortality concludes: (1) ANS genetics and physiologic complexity are independently related to mortality; (2) Genetics and complexity add information over traditional acuity scoring (probability of survival); and (3) Simultaneous assessment of ANS physiology and genetics may yield novel research, diagnostic, and therapeutic opportunities in critical illness.

Early loss of heart rate complexity predicts mortality regardless of mechanism, anatomic location, or severity of injury in 2178 trauma patients.

BACKGROUND: Reduced heart rate (HR) complexity (e.g., a lack of randomness or unpatterned variability) is an established predictor of trauma patient mortality. However, this finding has not been validated across the diverse spectrum of traumatic injury, and underlying mechanisms of this relationship are poorly understood. MATERIALS AND METHODS: Two thousand one hundred seventy-eight trauma patients were admitted directly to the intensive care unit (ICU), and had sufficient (>6h) continuous integer heart rate data within the first d. Patients were stratified by location of isolated severe injury (head, torso, both, or neither), primary mechanism (blunt or penetrating), and probability of survival, an accepted scoring system based on age, admission vital signs, and injury type and severity. HR multiscale entropy (MSE) was calculated (sum of scales, Costa's algorithm, physionet.org, m=2, r=0.15) to estimate complexity. Univariate analysis was performed by comparing MSE between survivors and nonsurvivors in each subgroup. Multivariate analysis incorporated logistic regression to characterize the relationship between MSE and risk of death, controlling for probability of survival. The MSE odds ratios (OR) and area under the receiver operator curve (AUC) were calculated. RESULTS: Reduced MSE was significantly associated with increasing mortality, and was independent of probability of survival in all multivariate analyses (OR 0.87-0.94). This range of odds ratios implies that a patient with an MSE of 15 has roughly a 2- to 6-fold increase in odds of death versus a patient with an MSE of 25. The relationship between MSE and death was moderately stronger in patients with isolated severe head injury versus torso injury, and significantly stronger in patients with penetrating versus blunt mechanism of injury. MSE measured early in the hospital stay remained a robust predictor of mortality in all subgroups, even stratified by narrow ranges of probability of survival. CONCLUSIONS: Early reduction of heart rate complexity is an important risk factor across diverse injury etiology. This suggests common underlying physiologic mechanisms linking the loss of biologic complexity to death.

Genetic variation in complement component 2 of the classical complement pathway is associated with increased mortality and infection: a study of 627 patients with trauma.

BACKGROUND: Trauma is a disease of inflammation. Complement Component 2 (C2) is a protease involved in activation of complement through the classical pathway and has been implicated in a variety of chronic inflammatory diseases. We hypothesized that genetic variation in C2 (E318D) identifies a high-risk subgroup of patients with trauma reflecting increased mortality and infection (ventilator-associated pneumonia [VAP]). Consequently, genetic variation in C2 may stratify patient risk and illuminate underlying mechanisms for therapeutic intervention. METHODS: DNA samples from 702 patients with trauma were genotyped for C2 E318D and linked with covariates (age: mean 42.8 years, gender: 74% male, ethnicity: 80% white, mechanism: 84% blunt, injury severity score: mean 25.0, admission lactate: mean 3.13 mEq/L) and outcomes: mortality 9.9% and VAP: 18.5%. VAP was defined by quantitative bronchoalveolar lavage (> 10). Multivariate regression analysis determined the relationship of genotype and covariates to risk of death and VAP. However, patients with injury severity score > or = 45 were excluded from the multivariate analysis, as magnitude of injury overwhelms genetics and covariates in determining outcome. RESULTS: Fifty-two patients (8.3%) had the high-risk heterozygous genotype, associated with a significant increase in mortality and VAP. CONCLUSION: In 702 patients with trauma, 8.3% had a high-risk genetic variation in C2 associated with increased mortality (odds ratio = 2.65) and infection (odds ratio = 2.00). This variation: (1) identifies a previously unknown high-risk group for infection and mortality; (2) can be determined at admission; (3) may provide opportunity for early therapeutic intervention; and (4) requires validation in a distinct cohort of patients.

Heart rate multiscale entropy at three hours predicts hospital mortality in 3,154 trauma patients.

Complexity is a measure of variation and randomness potentially indicating improvement or deterioration in critically ill patients. Previously, we have shown integer heart rate (HR) multiscale entropy (MSE), an indicator of complexity, predicts death based on long duration (12 h) and dense (>or=0.4 Hz) windows of HR data. However, such restrictions reduce the use of MSE in the clinical setting. We hypothesized MSE predicts death using HR data of shorter duration and lower density. During the initial 24 h of intensive care unit stay, 3,154 patients had at least 3 h of continuous integer HR sampled. The first continuous window of 3, 6, 9, and 12 h was selected for each patient regardless of density, and an open-source MSE algorithm was applied (M. Costa, www.physionet.org; m = 2; r = 0.15). Risk of death based on MSE, alone and with covariates (age, sex, injury severity score), was assessed using randomly selected logistic regression in half of the cases. Area under the receiver operator curve (AUC) was computed in the other half in subgroups having various durations and densities of HR data. At days 2.3 (median) and 4.9 (mean), 441 patients (14%) died. Multiscale entropy stratified patients by mortality and was an independent predictor of death using 3 h or more of data. Multiscale entropy alone (AUC = 0.66 - 0.71) predicted death comparably to covariates alone (AUC = 0.72). We conclude: (1) Heart rate MSE within hours of admission predicts death occurring days later. (2) Multiscale entropy is robust to variation in bedside data duration and density occurring in a working intensive care unit. (3) Complexity may be a new clinical biomarker of outcome.

Cardiac uncoupling and heart rate variability are associated with intracranial hypertension and mortality: a study of 145 trauma patients with continuous monitoring.

BACKGROUND: A noninvasive tool reflecting intracranial hypertension (ICH) should prompt early invasive monitoring and reduce secondary injury after traumatic brain injury. We hypothesized that integer heart rate variability (HRV) may be associated with rises in intracranial pressure (ICP); changes in HRV may precede changes in ICP; and both increases in ICP and cardiac uncoupling (low HRV) predict mortality. METHODS: Of 14,330 consecutive trauma admissions, 291 of these patients had an injury requiring intracranial monitoring. Of these patients 145 had simultaneous HRV and ICP monitoring with a Camino monitor. ICP and heart rate (HR) data were matched and divided into 5-minute intervals (N = 117,956, representing 24.4 million HR and ICP data points). In each interval, the median ICP, and SD of HR (HRSD5) were calculated. Cardiac uncoupling was defined as an interval with HRSD5 between 0.3 bpm and 0.6 bpm. Cardiac uncoupling was compared between ICP categories using the Wilcoxon Rank-Sum test, and logistic regression was used to assess the continuous relationship between ICP and risk of uncoupling. RESULTS: Cardiac uncoupling increases as ICP increases (p < 0.001). Uncoupling nearly doubles when comparing acceptable ICP (<20 mm Hg, 11% uncoupled) to ICH (31-50 mm Hg, 18% uncoupled), with uncoupling = 13% in the intermediate group (ICP 21-30 mm Hg). This trend continues at the level of malignant ICH (>50 mm Hg, 22% uncoupled). CONCLUSION: Cardiac uncoupling increases as ICP increases. Both cardiac uncoupling and ICH predict mortality. Cardiac uncoupling may precede ICH but is not yet an indication for invasive monitoring.

Adrenal insufficiency, heart rate variability, and complex biologic systems: a study of 1,871 critically ill trauma patients.

BACKGROUND: Reduction in integer heart rate variability (HRVi), one potential measurement of complex biologic systems, is common in ICU patients and is strongly associated with hospital mortality. Adrenal insufficiency (AI) and reduced HRVi are associated with autonomic dysfunction. Failure of the autonomic nervous system can be associated with loss of biologic complexity. We hypothesize decreased HRVi is associated with AI, and HRVi improves after treatment of AI, suggesting "recomplexification" (resumption of normal stress response to injury). STUDY DESIGN: Of 4,116 trauma ICU admissions from December 2000 to November 2005, 1,871 patients had sufficient physiologic, laboratory, pharmacy, and demographic data for analysis. Seventy-five patients failing cosyntropin-stimulation testing were defined as AI; the remaining 1,796 were defined as no AI. HRVi was calculated as integer heart rate standard deviation over 5-minute intervals. HRVi 10th, 50th (median), and 90th percentiles were calculated over the 72 hours pre-, or poststeroid, or both administration (AI). HRVi percentiles in non-AI patients were evaluated at the same interval and compared with AI using Wilcoxon's rank-sum test. In patients with AI, daily HRVi was computed 3 days before and after steroid administration, and compared between survivors and nonsurvivors. RESULTS: There were 2.9 million heart-rate intervals measured. HRVi stratified patients with AI (cosyntropin failure), and without AI. HRVi was similar in AI survivors and nonsurvivors before steroid treatment, but differed after treatment. HRVi increased substantially in survivors after steroid administration, yet did not change in nonsurvivors. HRVi does not increase in patients who are unresponsive to steroids and die. CONCLUSIONS: Reduced heart-rate variability, a potential measurement of complex biologic systems, is associated with cosyntropin-confirmed AI; improved in patients responding to steroid therapy; and is a noninvasive, real-time biomarker suggesting AI.

Beta-blocker exposure in patients with severe traumatic brain injury (TBI) and cardiac uncoupling.

BACKGROUND: Cardiac uncoupling and reduced heart rate (HR) variability are associated with increased mortality after severe traumatic brain injury (TBI). Recent data has shown beta-blocker (betaB) exposure is associated with improved survival in this patient population. The purpose of the present study was to evaluate the effect of betaB exposure on the mortality risk of patients with severe TBI and early cardiac uncoupling. METHODS: From December 2000 to October 2005, 4,116 patients were admitted to the trauma intensive care unit. Four hundred forty-six patients (12%) had head Abbreviated Injury Scale score >/= 5 without neck injury and had continuous HR data for the first 24 hours. One hundred forty-one patients (29%) received betaB. Cardiac uncoupling was calculated as the percent of time that 5-minute HR standard deviation was between 0.3 bpm and 0.6 bpm on postinjury day 1. RESULTS: A relationship between betaB and survival was observed when the population was considered irrespective of length of stay or betaB start time (p < 0.001). Cardiac uncoupling appears to stratify patients into groups who might receive additional benefit from betaB, and identifies patients with increasing mortality. However, the association of betaB with survival was attenuated when analyses accounted for selection bias in betaB administration. CONCLUSIONS: betaB exposure was associated with reduced mortality among patients with severe TBI. Though loss of HR variability has previously been associated with an increase in mortality, betaB exposure appears to be associated with increased survival across all stratifications of cardiac uncoupling.

Insulin Resistance in Critically Injured Adults: Contribution of Pneumonia, Diabetes, Nutrition, and Acuity.

PURPOSE: Changes in insulin resistance (IR) cause stress-induced hyperglycemia after trauma, but the numerous factors involved in IR have not been delineated clearly. We hypothesized that a statistical model could help determine the relative contribution of different clinical co-variates to IR in critically injured patients. PATIENTS AND METHODS: We retrospectively studied 726 critically injured patients managed with a computer-assisted glycemic protocol at an academic level I trauma center (639 ventilated controls without pneumonia (VWP) and 87 patients with ventilator-associated pneumonia (VAP). Linear regression using age, gender, body mass index (BMI), diabetes mellitus, pneumonia, and glycemic provision was used to estimate M, a marker of IR that incorporates both the serum blood glucose concentration (BG) and insulin dose. RESULTS: Increasing M (p<0.001) was associated with age (1.62%; 95% confidence interval [CI] 1.27%-1.97% per decade), male gender (9.78%; 95% CI 8.28%-12.6%), BMI (4.32% [95% CI 4.02%-4.62%] per 5 points), diabetes mellitus (21.2%; 95% CI 19.2%-23.2%), pneumonia (10.9%; 95% CI 9.31%-12.6%), and glycemic provision (27.3% [95% CI 6.6%-28.1%] per 100 g of glucose). Total parenteral nutrition was associated with a decrease in M of 10.3%; 95% CI 8.52%-12.1%; p<0.001. CONCLUSIONS: Clinical factors can be used to construct a model of IR. Prospective validation might enable early detection and treatment of infection or other conditions associated with increased IR.

A pilot study of the noninvasive assessment of the lung microbiota as a potential tool for the early diagnosis of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) remains a common complication in critically ill surgical patients, and its diagnosis remains problematic. Exhaled breath contains aerosolized droplets that reflect the lung microbiota. We hypothesized that exhaled breath condensate fluid (EBCF) in hygroscopic condenser humidifier/heat and moisture exchanger (HCH/HME) filters would contain bacterial DNA that qualitatively and quantitatively correlate with pathogens isolated from quantitative BAL samples obtained for clinical suspicion of pneumonia. METHODS: Forty-eight adult patients who were mechanically ventilated and undergoing quantitative BAL (n = 51) for suspected pneumonia in the surgical ICU were enrolled. Per protocol, patients fulfilling VAP clinical criteria undergo quantitative BAL bacterial culture. Immediately prior to BAL, time-matched HCH/HME filters were collected for study of EBCF by real-time polymerase chain reaction. Additionally, convenience samples of serially collected filters in patients with BAL-diagnosed VAP were analyzed. RESULTS: Forty-nine of 51 time-matched EBCF/BAL fluid samples were fully concordant (concordance > 95% by κ statistic) relative to identified pathogens and strongly correlated with clinical cultures. Regression analysis of quantitative bacterial DNA in paired samples revealed a statistically significant positive correlation (r = 0.85). In a convenience sample, qualitative and quantitative polymerase chain reaction analysis of serial HCH/HME samples for bacterial DNA demonstrated an increase in load that preceded the suspicion of pneumonia. CONCLUSIONS: Bacterial DNA within EBCF demonstrates a high correlation with BAL fluid and clinical cultures. Bacterial DNA within EBCF increases prior to the suspicion of pneumonia. Further study of this novel approach may allow development of a noninvasive tool for the early diagnosis of VAP.

Do models incorporating comorbidities outperform those incorporating vital signs and injury pattern for predicting mortality in geriatric trauma?

BACKGROUND: Geriatric trauma is becoming a significant public health concern. The most commonly used prediction models for mortality benchmarking are based on vital signs and injury pattern, including the Trauma and Injury Severity Score (TRISS), which is less accurate in the elderly. The ICD-9-based prediction models incorporating injuries and comorbidities, such as the University Health System Consortium Expected Mortality (UHC-EM), may be more accurate for the elderly. STUDY DESIGN: We retrospectively studied all trauma admissions from January 2005 to June 2012 at an academic level I adult trauma center. This was an observational study comparing expected to actual in-hospital mortality for both geriatric (age ≥65 years) and nongeriatric populations. Predictive ability for TRISS and UHC-EM was determined by the area under the receiver operator characteristic curve (AUC). RESULTS: Geriatric patients had higher median TRISS predicted mortality (8.4% [interquartile range (IQR) 4.8%, 27.4%] vs 2.8% [IQR 1.1%, 30.2%], p < 0.001). Geriatric patients had a median UHC-EM 5 times higher than nongeriatric patients (5.0% [IQR 1.0%, 19.0%] vs 1.0% [IQR 0%, 7.0%], p < 0.001). In-hospital mortality was 3 times higher in geriatric patients (18.1% vs 6.0%, p < 0.001). The UHC-EM had superior AUC to TRISS in both geriatric (0.89 [95% CI 0.87, 0.91] vs 0.81 [95% CI 0.78, 0.84], p < 0.05) and nongeriatric (0.93 [95% CI 0.92, 0.94] vs 0.90 [95% CI 0.89, 0.91], p < 0.05) patients. CONCLUSIONS: An ICD-9-based algorithm, such as the UHC-EM, which incorporates injuries and comorbidities, may be superior to algorithms based on vital signs and injury patterns without comorbidities in predicting mortality after trauma in the geriatric population.

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

BACKGROUND: Severe TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI. METHODS/DESIGN: The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications. DISCUSSION: The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322048.

Non-invasive detection of pulmonary pathogens in ventilator-circuit filters by PCR.

Ventilator associated pneumonia is a common and costly complication in critically ill and injured surgical patients. The diagnosis of pneumonia remains problematic and non-specific. Using clinical criteria, a diagnosis of pneumonia is typically not made until an infection is well established. Semi-quantitative cultures of endotracheal aspirate and broncho-alveolar lavage are employed to improve the accuracy of diagnosis but are invasive and require time for culture results to become available. We report data that show that an inexpensive, rapid and non-invasive alternative may exist. In particular we show that: 1). Bio-aerosols evolved in the breath of ventilated patients and captured in the hygroscopic condenser humidifier filter of the ventilator circuit contain pathogenic micro-organisms. 2). The number (CFU/ml) and identity (Genus, species) of the pathogens in the aerosol samples can rapidly and inexpensively be determined by PCR. 3). Data from a convenience sample of filters correlate with clinical findings from standard microbiological methods such as broncho-alveolar lavage. The evaluation of the bacterial load evolved in exhaled breath by PCR is amenable to repeated sampling. Since increasing bacterial burden is believed to correlate with the establishment of infection, the use of quantitative PCR may provide a method to rapidly, inexpensively, and effectively detect and diagnose the early onset of pneumonia and identify pathogens involved.

Core temperature variation is associated with heart rate variability independent of cardiac index: a study of 278 trauma patients.

PURPOSE: The purpose of this study is to determine if temperature extremes are associated with reduced heart rate variability (HRV) and "cardiac uncoupling." MATERIALS AND METHODS: This was a retrospective, observational cohort study performed on 278 trauma intensive care unit admissions that had continuous HR, cardiac index (CI), and core temperature data from "thermodilution" Swan-Ganz catheter. Dense (captured second-by-second) physiologic data were divided into 5-minute intervals (N = 136 133; 11 344 hours of data). Mean CI, mean temperature, and integer HR SD were computed for each interval. Critically low HRV was defined as HR SD from 0.3 to 0.6 beats per minute. Temperature extremes were defined as less than 36°C or greater than 39°C. RESULTS: Low HRV and CI vary with temperature. Temperature extremes are associated with increased risk for critically low HRV (odds ratio, >1.8). Cardiac index increases with temperature until hyperthermia (>40°C). At temperature extremes, changes in CI were not explained solely by changes in HR. CONCLUSIONS: The conclusions of this study are (1) temperature extremes are associated with low HRV, potentially reflecting cardiac autonomic dysfunction; (2) CI increases with temperature; and (3) HRV provides additional physiologic information unobtainable via current invasive cardiac monitoring and current vital signs.

Provision of balanced nutrition protects against hypoglycemia in the critically ill surgical patient.

BACKGROUND: Intensive insulin therapy lowers blood glucose and improves outcomes but increases the risk of hypoglycemia. Typically, insulin protocols require a dextrose solution to prevent hypoglycemia. The authors hypothesized that the provision of balanced nutrition (enteral nutrition [EN] or parenteral nutrition [PN]) would be more protective against hypoglycemia (≤50 mg/dL) than carbohydrate alone. METHODS: A retrospective analysis was performed of patients treated with intensive insulin therapy and surviving ≥24 hours. The computer-based insulin protocol requires infusion of D10W at 30 mL/h if EN or PN is not provided. Nutrition provision was assessed in 2-hour increments, comparing periods of blood glucose control with and without balanced nutrition. The risk of hypoglycemia for each blood glucose measurement was estimated by multivariable regression. RESULTS: In total, 66,592 glucose measurements were collected on 1392 patients. Hypoglycemic events occurred in 5.8/1000 glucose tests after 2 hours without balanced nutrition compared to 2.2/1000 tests when balanced nutrition was given in the preceding 2 hours. In multivariable regression models, balanced nutrition was the strongest protective factor against hypoglycemia. Patients who did not receive balanced nutrition in the preceding 2 hours had a 3 times increase in the odds of a hypoglycemic event at their next glucose check (odds ratio = 3.6, P < .001). Providing carbohydrate alone was not protective. CONCLUSIONS: Balanced nutrition is associated with reduced risk of hypoglycemia. These results suggest that balanced nutrition should be given when insulin therapy is initiated. Future studies should evaluate the efficacy of EN vs PN in preventing hypoglycemia.

Trends in estradiol during critical illness are associated with mortality independent of admission estradiol.

BACKGROUND: We have previously demonstrated that elevated serum estradiol (E(2)) at intensive care unit (ICU) admission is associated with death in the critically ill, regardless of sex. However, little is known about how changes in initial E(2) during the course of care might signal increasing patient acuity or risk of death. We hypothesized that changes from baseline serum E(2) during the course of critical illness are more strongly associated with mortality than a single E(2) level at admission. STUDY DESIGN: A prospective cohort of 1,408 critically ill or injured nonpregnant adult patients requiring ICU care for ≥48 hours with admission and subsequent E(2) levels was studied. Demographics, illness severity, and E(2) levels were examined, and the probability of mortality was modeled with multivariate logistic regression. Changes in E(2) were examined by both analysis of variance and logistic regression. RESULTS: Overall mortality was 14.1% [95% confidence interval (CI) 12.3% to 16%]. Both admission and subsequent E(2) levels were independently associated with mortality [admission E(2) odds ratio 1.1 (CI 1.0 to 1.2); repeat estradiol odds ratio 1.3 (CI 1.2 to1.4)], with subsequent values being stronger. Changes in E(2) were independently associated with mortality [odds ratio 1.1 (CI 1.0 to 1.16)] and improved regression model performance. The regression model produced an area under the receiver operating characteristic curve of 0.80 (CI 0.77 to 0.83). CONCLUSIONS: Although high admission levels of E(2) are associated with mortality, changes from baseline E(2) in critically ill or injured adults are independently associated with mortality. Future studies of E(2) dynamics may yield new indicators of patient acuity and illuminate underlying mechanisms for targeted therapy.

Genetic variation in the autonomic nervous system affects mortality: a study of 1,095 trauma patients.

BACKGROUND: We have previously demonstrated an unappreciated link between the autonomic nervous system and mortality, heart rate variability, and physiologic complexity. STUDY DESIGN: Genetic variation in adrenergic receptors or key enzymes in catecholamine degradation could be associated with, and potentially explain, autonomic nervous system dysfunction and its impact on mortality after severe trauma. Three genetic polymorphisms critical to the adrenergic pathway were evaluated: beta-2 adrenergic receptor (ADBR2: Q27E), alpha-1a adrenergic receptor (ADRA1A:R347C), and catechol-O-methyl transferase (COMT: V158M). The study population consisted of 1,095 trauma admissions between April 2005 and April 2007. These patients all had genotyping performed using mass spectrometric analysis (Sequenom, Inc). The genetic data were linked with detailed demographic and clinical data. Trauma Related Injury Severity Score (TRISS) probability of survival was used as a composite measure of injury severity, admission physiology, and demographic factors in the multivariate logistic regression analyses of mortality outcomes data. RESULTS: The overall mortality rate for the study population was 14.2% (155 of 1,095). Univariate comparisons of genotypes with mortality revealed a significant association with the ADBR2 polymorphism: CC=15.9%, GC=14.8% and GG=7.6%, p=0.02. The apparently protective ADBR2 GG genotype was seen in 15.5% (170 of 1,095) of the study population. In multivariate analysis, which included adjustment for TRISS, the ADBR2 GG genotype was associated with reduced mortality (odds ratio 0.36, p=0.002). CONCLUSIONS: Genetic variation in the beta-2 adrenergic receptor (ADBR2:Q27E) associated with bronchial constriction appears protective (odds ratio 0.36), perhaps by making the receptor resistant to downregulation. These genetic data support the emerging understanding of critical role of the autonomic nervous system in the response to injury.