Metabolic Manipulation and Therapeutic Hypothermia.

Hypothermia has multiple physiological effects, including decreasing metabolic rate and oxygen consumption (VO2). There are few human data about the magnitude of change in VO2 with decreases in core temperature. We aimed to quantify to magnitude of reduction in resting VO2 as we reduced core temperature in lightly sedated healthy individuals. After informed consent and physical screening, we cooled participants by rapidly infusing 20 mL/kg of cold (4°C) saline intravenously and placing surface cooling pads on the torso. We attempted to suppress shivering using a 1 mcg/kg intravenous bolus of dexmedetomidine followed by titrated infusion at 1.0 to 1.5 µg/(kg·h). We measured resting metabolic rate VO2 through indirect calorimetry at baseline (37°C) and at 36°C, 35°C, 34°C, and 33°C. Nine participants had mean age 30 (standard deviation 10) years and 7 (78%) were male. Baseline VO2 was 3.36 mL/(kg·min) (interquartile range 2.98-3.76) mL/(kg·min). VO2 was associated with core temperature and declined with each degree decrease in core temperature, unless shivering occurred. Over the entire range from 37°C to 33°C, median VO2 declined 0.7 mL/(kg·min) (20.8%) in the absence of shivering. The largest average decrease in VO2 per degree Celsius was by 0.46 mL/(kg·min) (13.7%) and occurred between 37°C and 36°C in the absence of shivering. After a participant developed shivering, core body temperature did not decrease further, and VO2 increased. In lightly sedated humans, metabolic rate decreases around 5.2% for each 1°C decrease in core temperature from 37°C to 33°C. Because the largest decrease in metabolic rate occurs between 37°C and 36°C, subclinical shivering or other homeostatic reflexes may be present at lower temperatures.

A longitudinal assessment of posttraumatic stress symptoms and pain catastrophizing after injury.

PURPOSE/OBJECTIVE: Identifying individuals with high levels of pain catastrophizing (PC) may inform early psychological interventions to prevent the transition from acute to chronic post-injury pain. We examined whether pre-and post-injury posttraumatic stress symptoms (PTSS) predict post-injury PC among emergency department (ED) patients following acute motor vehicle crash (MVC). RESEARCH METHOD/DESIGN: This study represents secondary data analysis of a randomized clinical trial (NCT03247179) examining the efficacy of the PTSD Coach app on post-injury PTSS (PTSSpost). Among 63 injured ED patients (63% female; 57% non-White; average age = 37) with moderate pain (≥4 of 10), we assessed recall of pre-injury PTSS (PTSSrecall: stemming from preexisting exposures) and baseline PC within 24 hr post-MVC; PTSSpost stemming from the MVC was assessed 30-days later, and the outcome of PC was assessed at 90-days post-injury. We controlled for group assignment (intervention vs. control) in all analyses. RESULTS: Results revealed that at baseline and 90-days, PC was higher among non-White versus White participants. After adjusting for relevant covariates, PTSSrecall uniquely predicted post-injury PC and each subscale of PC (helplessness, magnification, and rumination). Similarly, after controlling for PTSSrecall and relevant covariates, PTSSpost uniquely predicted total and subscale post-injury PC. Intervention group participants reported less rumination than control group participants. CONCLUSIONS/IMPLICATIONS: These novel findings highlight that injured Black patients may be vulnerable to post-injury PC, and that both PTSSrecall and PTSSpost significantly predict post-injury PC. Brief PTSS assessment in the ED can identify high-risk patients who may benefit from early intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

One-year outcomes in individual domains of the cerebral performance category extended.

BACKGROUND: Physical and cognitive impairments are common after cardiac arrest, and recovery varies. This study assessed recovery of individual domains of the Cerebral Performance Category- Extended (CPC-E) 1-year after cardiac arrest. We hypothesized patients would have recovery in all CPC-E domains 1-year after the index cardiac arrest. METHODS: Prospective cohort study of cardiac arrest survivors evaluating outcome measures mRS, CPC, and CPC-E. Outcomes were assessed at discharge, 3-months, 6-months, and 1-year. We defined recovery of a CPC-E domain when >90% of patients had scores of 1-2 in that domain. RESULTS: Of 156 patients discharged, 57 completed the CPC-E at discharge, and were included in the analysis. 37 patients had follow-up at 3-months, and 23 patients had follow-up at 6 and 12 months. Only 16 patients had assessments at all four timepoints. Domains of alertness (N = 56, 98%) logical thinking (N = 56; 98%), and attention (N = 55; 96%) recovered by hospital discharge. BADL (N = 34; 92%) and motor skills (N = 36; 97%) recovered by 3-months. Most patients (N = 20; 87%) experienced slight-to-no disability or symptoms (mRS 0-2/CPC 1-2) at 1-year follow up. CPC-E domains of short term memory (78%), mood (87%), fatigue (22%), complex ADL (78%), and return to work (65%) did not recover by 1-year. CONCLUSIONS: CPC-E domains of alertness, logical thinking, and attention recover rapidly, while domains of short term memory, mood, fatigue, complex ADL and return to work remain chronically impaired 1-year after cardiac arrest. These deficits are not detected by mRS and CPC. Interventions to improve recovery in these domains are needed.

The role of specific sources of social support on postinjury psychological symptoms.

PURPOSE/OBJECTIVE: The role of perceived social support from specific sources (e.g., families, friends, and significant others) on the development of postinjury posttraumatic stress disorder (PTSD) and associated psychological symptoms (e.g., depression and anxiety) remains relatively unexplored. We examined the predictive role of social support from specific sources on psychological symptoms among emergency department (ED) patients following motor vehicle crash (MVC). Research Methods/Design: Sixty-three injured patients (63.5% female; 37 years old on average) with moderately painful complaints were recruited in the EDs of two Level-1 trauma centers within 24 hr post-MVC. In the ED, participants completed surveys of baseline psychological symptoms and perceived social support; follow-up surveys were completed at 90 days postinjury. RESULTS: Most of the sample (84.1%) was discharged home from the ED with predominantly mild injuries and did not require hospitalization. After adjusting for race, sex, age, and baseline symptoms, hierarchical regression analyses demonstrated that lower perceived social support in the ED predicted higher PTSD symptoms and depressive symptoms (but not anxiety) at 90 days. This effect seemed to be specific to significant others and friends but not family. CONCLUSIONS/IMPLICATIONS: MVC-related injuries are robust contributors to psychological sequelae. These findings extend prior work by highlighting that perceived social support, particularly from significant others and friends, provides unique information regarding the development of psychological symptoms following predominantly mild MVC-related injuries. This data may serve to inform recovery expectations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Pain Appraisals in Patients with Physical Injury: Assessing the Role of Distress Tolerance in the Relationship between Depression and Pain Catastrophizing.

Pain is a complex construct contributing to significant impairment, particularly among physically injured patients seeking treatment in trauma and orthopedic surgery settings in which social workers are an integral component of care. The biopsychosocial theory, fear-avoidance, and cognitive mediation models of pain suggest that psychological factors (for example, depression) affect one's ability to tolerate distress, leading to negative pain appraisals, such as catastrophizing. This study examined whether distress tolerance serves as a mechanism by which depression is associated with pain catastrophizing. We administered a health survey to outpatient trauma and orthopedic surgery clinic patients who were using opioid medications; 84 patients were included in the final analysis; 39.3 percent screened positive for depression. A multilevel mediation model using structural equation modeling revealed a significant direct effect from depression to pain catastrophizing (ß = .31, z = 3.96, p < .001) and a significant indirect effect by distress tolerance (Δß = .27, z = 3.84, p < .001). These results, which suggest that distress tolerance partially mediated the path from depression to pain catastrophizing, can inform social workers and other members of the multidisciplinary team about both the critical role of psychosocial factors after injury and interventions to improve postinjury recovery.

Glycopyrrolate does not ameliorate hypothermia associated bradycardia in healthy individuals: A randomized crossover trial.

BACKGROUND: Hypothermia improves outcomes following ischemia-reperfusion injury. Shivering is common and can be mediated by agents such as dexmedetomidine. The combination of dexmedetomidine and hypothermia results in bradycardia. We hypothesized that glycopyrrolate would prevent bradycardia during dexmedetomidine-mediated hypothermia. METHODS: We randomly assigned eight healthy subjects to premedication with a single 0.4 mg glycopyrrolate intravenous (IV) bolus, titrated glycopyrrolate (0.01 mg IV every 3 min as needed for heart rate <50), or no glycopyrrolate during three separate sessions of 3 h cooling. Following 1 mg/kg IV dexmedetomidine bolus, subjects received 20 ml/kg IV 4 °C saline and surface cooling (EM COOLS, Weinerdorf, Austria). We titrated dexmedetomidine infusion to suppress shivering but permit arousal to verbal stimuli. After 3 h of cooling, we allowed subjects to passively rewarm. We compared heart rate, core temperature, mean arterial blood pressure, perceived comfort and thermal sensation between groups using Kruskal-Wallis test and ANOVA. RESULTS: Mean age was 27 (SD 6) years and most (N = 6, 75%) were male. Neither heart rate nor core temperature differed between the groups during maintenance of hypothermia (p > 0.05). Mean arterial blood pressure was higher in the glycopyrrolate bolus condition (p < 0.048). Thermal sensation was higher in the control condition than the glycopyrrolate bolus condition (p = 0.01). Bolus glycopyrrolate resulted in less discomfort than titrated glycopyrrolate (p = 0.04). CONCLUSIONS: Glycopyrrolate did not prevent the bradycardic response to hypothermia and dexmedetomidine. Mean arterial blood pressure was higher in subjects receiving a bolus of glycopyrrolate before induction of hypothermia. Bolus glycopyrrolate was associated with less intense thermal sensation and less discomfort during cooling.

A Pilot Randomized Controlled Trial of the PTSD Coach App Following Motor Vehicle Crash-related Injury.

OBJECTIVE: Posttraumatic stress disorder (PTSD) symptoms (PTSS) are common after minor injuries and can impair recovery. We sought to understand whether an evidence-based mobile phone application with self-help tools (PTSD Coach) could be useful to improve recovery after acute trauma among injured emergency department (ED) patients. This pilot study examined the feasibility, acceptability, and potential benefit of using PTSD Coach among acutely injured motor vehicle crash (MVC) patients. METHODS: From September 2017 to September 2018, we recruited adult patients within 24 hours post-MVC from the EDs of two Level I trauma centers in the United States. We randomly assigned 64 injured adults to either the PTSD Coach (n = 33) or treatment as usual (TAU; n = 31) condition. We assessed PTSS and associated symptoms at 1 month (83% retained) and 3 months (73% retained) postenrollment. RESULTS: Enrollment was feasible (74% of eligible subjects participated) but usability and engagement were low (67% used PTSD Coach at least once, primarily in week 1); 76% of those who used it rated the app as moderately to extremely helpful. No differences emerged between groups in PTSS outcomes. Exploratory analyses among black subjects (n = 21) indicated that those in the PTSD Coach condition (vs. TAU) reported marginally lower PTSS (95% CI = -0.30 to 37.77) and higher PTSS coping self-efficacy (95% CI = -58.20 to -3.61) at 3 months. CONCLUSIONS: We demonstrated feasibility to recruit acutely injured ED patients into an app-based intervention study, yet mixed evidence emerged for the usability and benefit of PTSD Coach. Most patients used the app once and rated it favorably in regard to satisfaction with and helpfulness, but longitudinal engagement was low. This latter finding may explain the lack of overall effects on PTSS. Additional research is warranted regarding whether targeting more symptomatic patients and the addition of engagement and support features can improve efficacy.

Cardiac arrest survivors lost to follow-up after 3-Months, 6-Months and 1-Year.

BACKGROUND: Long-term assessment of global functional outcomes in cardiac arrest (CA) survivors allows for evaluation of acute care practices and referral to rehabilitation services. Given that many post-CA patients are lost to follow-up (LTFU), we explored whether these patients are systematically different from those who complete follow-up based on demographic, resuscitation and outcome characteristics. METHODS: We conducted a prospective cohort study of 168 English-speaking CA survivors between 9/25/2016 and 5/31/2018. We measured demographic data and global functional outcomes using Modified Rankin Scale (mRS), and Cerebral Performance Category (CPC) in-person at hospital discharge, and via telephone at 3-, 6-months, and 1-year. We compared patients LTFU (e.g., failure to contact or refused to follow-up) with those contacted. Patients who were hospitalized, in a rehabilitation facility, missed by the research team, or dead were considered not eligible for follow-up. RESULTS: Of the 116 patients eligible for follow-up at 3-months, the majority completed follow-up (n = 69; 59.5%) and 47 (40.5%) were LTFU. Conversely, at 6-months and 1-year, fewer subjects were assessed (42% and 47%) compared to those who were LTFU (58% and 53%), respectively. At 3-months, LTFU patients were younger, unmarried, and had longer ICU stay. At 6-months and 1-year, LTFU patients were primarily male, had a non-shockable primary rhythm, and non-cardiac arrest etiologies. CONCLUSIONS: Over one-third of patients are LTFU during the first year after CA, and differences emerged for demographics and characteristics of the event. Future research should account for the informative, non-random distribution of patients LTFU.

Opioid use patterns and risk characteristics among injured patients.

Background: Injured patients are at risk for prolonged opioid use after discharge from care. Limited evidence exists regarding how continued opioid use may be related to opioid medication misuse and opioid use disorder (OUD) following injury. This pilot study characterized opioid consumption patterns, health characteristics, and substance use among patients with active prescriptions for opioid medications following injury care. Methods: This study was a cross-sectional screening survey combined with medical record review from February 2017 to March 2018 conducted among outpatient trauma and orthopedic surgery clinic patients. Eligible patients were 18-64 years of age, admitted/discharged for an injury or trauma-related orthopedic surgery, returning for clinic follow-up ≤6 months post hospital discharge after the index injury, prescribed opioid pain medication at discharge, and currently taking an opioid medication (from discharge or a separate prescription post discharge). Data collected included demographic, substance use, mental health, and physical health information. Descriptive and univariate statistics were calculated to characterize the population and opioid-related risks. Results: Seventy-one participants completed the survey (92% response). Most individuals (≥75%) who screened positive for misuse or OUD reported no nonmedical/illicit opioid use in the year before the index injury. A positive depression screen was associated with a 3.88 times increased likelihood for misuse or OUD (95% confidence interval [CI] = 1.1-13.5). Nonopioid illicit drug use (odds ratio [OR] = 1.89, 95% CI = 1.1-3.4) and opioid craving (OR = 1.29, 95% CI = 1.1-1.5) were also associated with increased likelihood for misuse or OUD. Number of emergency department visits in the 3 years previous to the index injury was associated with a 22% likelihood of being misuse or OUD positive (95% CI = 1.0-1.5). Conclusions: Patients with behavioral health concerns and greater emergency department utilization may have heightened risk for experiencing adverse opioid-related outcomes. Future research must further establish these findings and possibly develop protocols to identify patients at risk prior to pain management planning.

Cooling to Facilitate Metabolic Suppression in Healthy Individuals.

BACKGROUND: Carbon dioxide (CO2) toxicity could be catastrophic for astronauts. Suppressing metabolism by lowering body temperature decreases CO2 production and may facilitate rescue in the event of a crippled ship. Lowering body temperature requires shivering suppression. We evaluated dexmedetomidine to facilitate cooling of healthy individuals.METHODS: Following consent, we administered a 1 mcg · kg-1 bolus of dexmedetomidine followed by continuous infusion (0.5-1.4 mcg · kg-1 · h-1) for 3 h of cooling. We cooled subjects using a bolus of 30 cc · kg-1 of 4°C saline followed by surface cooling. We measured vital signs, thermal and comfort scales, sedation, and shivering for 3 h and during recovery. ANOVA evaluated changes in measures over time.RESULTS: Nine subjects completed the study. Mean age was 31 (SD 8) yr, mean mass was 71 (SD 14) kg, height of 168 (SD 9) cm, and body mass index of 25 (SD 3). Median time to 1°C drop in core temperature was 16 (IQR 15, 32) min. Temperature changed over time with median lowest temperature being 33.1°C (IQR 32.8°C, 34.1°C). Neither heart rate nor diastolic blood pressures changed over time. Systolic blood pressure decreased over time. Subjects responded to verbal stimuli and completed tasks throughout the protocol. During cooling and maintenance, subjects reported discomfort and the sensation of being cold.CONCLUSION: Dexmedetomidine facilitates shivering suppression during prolonged cooling in healthy individuals. Subjects are easily roused, have mild decreases in systolic blood pressure, and note sensations of discomfort and cold. Cooling to suppress metabolism is a feasible countermeasure to prolong astronaut endurance.Rittenberger JC, Flickinger KL, Weissman A, Repine M, Elmer J, Guyette FX, Callaway CW. Cooling to facilitate metabolic suppression in healthy individuals. Aerosp Med Hum Perform. 2019; 90(5):475-479.

Preliminary experience with point-of-care EEG in post-cardiac arrest patients.

OBJECTIVE: Abnormal electroencephalography (EEG) patterns are common after resuscitation from cardiac arrest and have clinical and prognostic importance. Bedside continuous EEGs are not available in many institutions. We tested the feasibility of using a point-of-care system for EEG acquisition. METHODS: We prospectively enrolled a convenience sample of post-cardiac arrest patients between 9/2015-1/2017. Upon hospital arrival, a limited EEG montage was applied. We tested both continuous EEG (cEEG) and this point-of-care EEG (eEEG). A board-certified epileptologist and a board-certified neurointensivist jointly reviewed all EEGs. Cohen's kappa coefficient evaluated agreement between eEEG and cEEG and Fisher's exact test evaluated their associations with survival to hospital discharge and proximate cause of death. RESULTS: We studied 95 comatose post-cardiac arrest patients. Mean age was 59 (SD17) years. Most (61%) were male, few (N = 22; 23%) demonstrated shockable rhythms, and PCAC IV illness severity was present in 58 (61%). eEEG was interpretable in 57 (60%) subjects. The most common eEEG interpretations were: continuous (21%), generalized suppression (14%), burst-suppression (12%) and burst-suppression with identical bursts (10%). Seizures were detected in 2 eEEG subjects (2%). No patient with seizure or burst-suppression with identical bursts survived. cEEG demonstrated generalized suppression (31%), burst-suppression with identical bursts (27%), continuous (18%) and seizure (4%). The eEEG and cEEG demonstrated fair agreement (kappa = 0.27). Neither eEEG nor cEEG was associated with survival (p = 0.19; p = 0.11) or proximate cause of death (p = 0.14; p = 0.8) CONCLUSIONS: eEEG is feasible, although artifact often precludes interpretation. eEEG is fairly associated with cEEG and may facilitate post-cardiac arrest care.

Quantitative sensory testing measures individual pain responses in emergency department patients.

BACKGROUND: Refining and individualizing treatment of acute pain in the emergency department (ED) is a high priority, given that painful complaints are the most common reasons for ED visits. Few tools exist to objectively measure pain perception in the ED setting. We speculated that variation in perception of fixed painful stimuli would explain individual variation in reported pain and response to treatment among ED patients. MATERIALS AND METHODS: In three studies, we 1) describe performance characteristics of brief quantitative sensory testing (QST) in 50 healthy volunteers, 2) test effects of 10 mg oxycodone versus placebo on QST measures in 18 healthy volunteers, and 3) measure interindividual differences in nociception and treatment responses in 198 ED patients with a painful complaint during ED treatment. QST measures adapted for use in the ED included pressure sensation threshold, pressure pain threshold (PPT), pressure pain response (PPR), and cold pain tolerance (CPT) tests. RESULTS: First, all QST measures had high inter-rater reliability and test-retest reproducibility. Second, 10 mg oxycodone reduced PPR, increased PPT, and prolonged CPT. Third, baseline PPT and PPR revealed hyperalgesia in 31 (16%) ED subjects relative to healthy volunteers. In 173 (88%) ED subjects who completed repeat testing 30 minutes after pain treatment, PPT increased and PPR decreased (Cohen's dz 0.10-0.19). Verbal pain scores (0-10) for the ED complaint decreased by 2.2 (95% confidence intervals [CI]: 1.9, 2.6) (Cohen's dz 0.97) but did not covary with the changes in PPT and PPR (r=0.05-0.13). Treatment effects were greatest in ED subjects with a history of treatment for anxiety or depression (Cohen's dz 0.26-0.43) or with baseline hyperalgesia (Cohen's dz 0.40-0.88). CONCLUSION: QST reveals individual differences in perception of fixed painful stimuli in ED patients, including hyperalgesia. Subgroups of ED patients with hyperalgesia and psychiatric history report larger treatment effects on ED pain and QST measures.

Comparison of three cognitive exams in cardiac arrest survivors.

BACKGROUND: Cognitive deficits may detract from quality of life after cardiac arrest. Their pattern and prevalence are not well documented. We used the Computer Assessment of Mild Cognitive Impairment (CAMCI), the Montreal Cognitive Assessment (MOCA) and the 41 Cent Test (41CT) to assess cognitive impairment in cardiac arrest survivors and examine the exams' diagnostic accuracy. We hypothesized that the scores of these exams would indicate the presence of cognitive impairment in arrest survivors, that the overall scores on the three study assessments would correlate with one another, and that the 41CT, MOCA, and executive function element of the CAMCI would vary independently from other non-executive CAMCI components, reflecting executive function impairment after cardiac arrest. METHODS: Four researchers administered the CAMCI, MOCA, and/or the 41CT to cardiac arrest survivors after discharge from the intensive care unit between 2010 and 2015. Physicians screened patients with the Mini-Mental State Exam to determine when this cognitive testing was feasible, generally when the patient was able to score 20-25 points on the MMSE. We performed pairwise correlations between the different subscales' and tests' scores. RESULTS: One hundred and fourteen participants completed the CAMCI, of which 38 (33.3%) participants additionally completed the MOCA and 41CT. The median (IQR) percentile score for CAMCI for all 114 participants was 33.5 (18.3, 49.8), which corresponds to moderately low risk of impairment. The median (IQR) for the MOCA was 22.0 (19, 24.8) out of a possible 30, which is considered indicative of abnormal cognitive function, and for the 41CT was 6 (5, 7) out of a possible 7 points when all 38 participants were included. MOCA correlated strongly with the overall CAMCI score (r=0.71); the CAMCI correlated moderately strongly with the 41CT (r=0.62) and the MOCA and 41CT were moderately strongly correlated with each other (r=0.56). When all 114 CAMCI scores were considered, the Executive Accuracy subscale was strongly correlated with the overall CAMCI score (r=0.81). CONCLUSION: The CAMCI detects cognitive impairment after cardiac arrest. The MOCA correlates strongly with the overall CAMCI and the executive function subscale of the CAMCI. The 41CT as appears less effective than the MOCA in detecting cognitive deficits.

Success Rates for Notification of Enrollment in Exception From Informed Consent Clinical Trials.

OBJECTIVES: Exception from informed consent (EFIC) for research in emergency settings requires investigators to notify enrolled subjects, family members, or legally authorized representatives about inclusion in the study. We examined the success rate of a notification strategy including mail services for subjects enrolled in EFIC trials. METHODS: We describe notification attempts for subjects in three out-of-hospital cardiac arrest clinical trials in both urban and rural areas around Pittsburgh, Pennsylvania, between the years 2000 and 2014. We examined the time required to notify subjects and the success of contacting subjects or their representatives when notified in person (if alive), by mail (if alive and unable to reach in person), or by mail (if the subject was deceased). We characterized comments received from subjects or their representatives as positive, neutral, or negative. RESULTS: We attempted notification on a total of 1,912 subjects, 1,762 by mail, and 163 in person. Of these, 1,767 (92%) notification forms were successfully delivered, and 431 (24%) were signed and returned. Only 16 subjects or representatives (0.91%) requested to withdraw from the study. In-person notifications were more likely to be signed than mailed notifications (69% vs. 20%; p < 0.001). A total of 3.2% of recipients contacted investigators by phone or letter in response to notifications, but only five recipients expressed negative attitudes toward the trial. Ninety percent of subjects were notified within 35 days of the incident. Time to notification was shorter for in person (median = 5 days, interquartile range [IQR] = 2 to 10 days) than for deceased and mailed (11 days, IQR = 8 to 14 days) or alive and mailed (20 days, IQR = 14 to 29 days). CONCLUSIONS: It is possible to successfully notify recipients of enrollment in a study using EFIC over 90% of the time within 35 days, although only 24% of recipients will sign and return a form. Fewer than 1% of subjects withdraw from the study, and fewer than 5% contact investigators, usually for neutral reasons.

Dexmedetomidine Reduces Shivering during Mild Hypothermia in Waking Subjects.

BACKGROUND AND PURPOSE: Reducing body temperature can prolong tolerance to ischemic injury such as stroke or myocardial infarction, but is difficult and uncomfortable in awake patients because of shivering. We tested the efficacy and safety of the alpha-2-adrenergic agonist dexmedetomidine for suppressing shivering induced by a rapid infusion of cold intravenous fluids. METHODS: Ten subjects received a rapid intravenous infusion of two liters of cold (4°C) isotonic saline on two separate test days, and we measured their core body temperature, shivering, hemodynamics and sedation for two hours. On one test day, fluid infusion was preceded by placebo infusion. On the other test day, fluid infusion was preceded by 1.0 µg/kg bolus of dexmedetomidine over 10 minutes. RESULTS: All ten subjects experienced shivering on placebo days, with shivering beginning at a mean (SD) temperature of 36.6 (0.3)°C. The mean lowest temperature after placebo was 36.0 (0.3)°C (range 35.7-36.5°C). Only 3/10 subjects shivered on dexmedetomidine days, and the mean lowest temperature was 35.7 (0.4)°C (range 35.0-36.3°C). Temperature remained below 36°C for the full two hours in 6/10 subjects. After dexmedetomidine, subjects had moderate sedation and a mean 26 (13) mmHg reduction in blood pressure that resolved within 90 minutes. Heart rate declined a mean 23 (11) bpm after both placebo and dexmedetomidine. Dexmedetomidine produced no respiratory depression. CONCLUSION: Dexmedetomidine decreases shivering in normal volunteers. This effect is associated with decreased systolic blood pressure and sedation, but no respiratory depression.

Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats.

Increased brain-derived neurotrophic factor (BDNF) levels and extracellular-signal regulated kinase (ERK) signaling are associated with reduced brain injury after cerebral ischemia. In particular, mild hypothermia after cardiac arrest increases BDNF and ERK signaling. This study tested whether intracerebroventricular infusions (0.025 microg/h x 3 days) of BDNF also improved recovery of rats resuscitated from cardiac arrest and maintained at 37 degrees C. BDNF infusions initiated at the time of cardiac arrest did not alter survival, neurological recovery, or histological injury. Separate experiments confirmed that BDNF infusions increased tissue levels of BDNF. However, these infusions did not increase ERK activation in hippocampus. These data suggest that increased BDNF levels are not sufficient to explain the beneficial effects of mild hypothermia after cardiac arrest, and that exogenous BDNF administration does not increase extracellular ERK signaling.

Delayed hypothermia preferentially increases expression of brain-derived neurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest.

Brain-derived neurotrophic factor (BDNF) protein levels increase in rats treated with a regimen of delayed, mild hypothermia that improve neurological recovery after asphyxial cardiac arrest. BDNF transcription in rat brain involves at least five different BDNF exons (exons I-V) that produce four different varieties of mRNA, each containing exon V paired with one of exons I-IV. This study examined whether these different BDNF transcripts are differentially affected by cardiac arrest and by therapeutic hypothermia in rat hippocampus using a reverse transcription and PCR-based method. At 24 h after asphyxial cardiac arrest, transcripts containing exons I and III increased. In rats treated with hypothermia after cardiac arrest, transcripts containing exon III were further increased. No significant alterations in transcripts from exons II or IV were observed, though there was a trend for hypothermia to decrease message from these exons. These data suggest that hypothermia after cardiac arrest produces exon-specific changes in BDNF transcription.

Regional changes in glial cell line-derived neurotrophic factor after cardiac arrest and hypothermia in rats.

Hypothermia after resuscitation from cardiac arrest reduces functional and histological brain injury. Stimulation of neurotrophic factors may contribute to the beneficial effects of hypothermia. This study examined the effects of cardiac arrest and induced hypothermia on regional levels of glial cell line-derived neurotrophic factor (GDNF) over the first 24 h after rat cardiac arrest. Hypothermia increased GDNF in hippocampus at 6 h, but did not prevent a subsequent decline in hippocampal GDNF. In contrast, hypothermia prevented early increases in cortical levels of GDNF at 3 and 6 h. Cerebellar GDNF increased slightly over 24 h in hypothermia-treated rats, but brainstem levels of GDNF did not change in response to cardiac arrest or hypothermia. These results suggest that temperature after resuscitation produces regionally specific changes of GNDF levels in brain.