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.

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.

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.

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.

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.