Number of Circulating CD 73-Expressing Lymphocytes Correlates With Survival After Cardiac Arrest.

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia-reperfusion injuries. After the initial hypoxic-ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5'-nucleotidase), production of tumor necrosis factor-α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73-expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post- CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor-α production and generation of reactive oxygen species. This effect was blocked by adenosine 5'-(α, ß-methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP -dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73-expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.

Hemodynamic, Biochemical, and Ventilatory Parameters are Independently Associated with Outcome after Cardiac Arrest.

BACKGROUND: Hypotension, hyperglycemia, dysoxia, and dyscarbia may contribute to reperfusion injury, and each is independently associated with poor outcome (PO) after cardiac arrest. We investigated whether the combined effects of these physiological derangements are associated with cardiac arrest outcomes. METHODS: This institutional review board-approved retrospective cohort study included consecutive resuscitated cardiac arrest patients that received targeted temperature management at Maine Medical Center from 2013 to 2015. We abstracted demographics, intra-arrest factors, and physiological parameters. The primary outcome was dichotomized cerebral performance category (CPC 1-2 vs 3-5) at hospital discharge. After comparing demographics, clinical factors, and persistent post-arrest physiological derangements in patients with good and PO, we constructed a logistic regression model comprised of clinical and demographic factors separately associated with severity, and physiology variables, attempting to evaluate the independent effects of persistent physiological derangements on outcome. RESULTS: Sixty-eight of 222 (31%) patients had CPC 1-2 (good outcome [GO]) at discharge. In bivariate analysis, factors associated with PO included increased time from collapse to resuscitation, non-shockable rhythm, and age-combined Charlson comorbidity index. In multivariate analysis, each persistent physiological derangement incrementally decreased the likelihood of GO [OR GO per derangement 0.71 (interquartile range [IQR] 0.51-0.99), p = 0.042, area under the curve (AUC) for final model 0.769]. CONCLUSIONS: Uncorrected physiological derangements in the first 24 h after cardiac arrest are independently associated with PO. Although causality cannot be established, these findings support preclinical models suggesting that aggressive normalization of physiology after resuscitation may be a reasonable strategy to decrease reperfusion injury.

Derivation and Validation of the CREST Model for Very Early Prediction of Circulatory Etiology Death in Patients Without ST-Segment-Elevation Myocardial Infarction After Cardiac Arrest.

BACKGROUND: No practical tool quantitates the risk of circulatory-etiology death (CED) immediately after successful cardiopulmonary resuscitation in patients without ST-segment-elevation myocardial infarction. We developed and validated a prediction model to rapidly determine that risk and facilitate triage to individualized treatment pathways. METHODS: With the use of INTCAR (International Cardiac Arrest Registry), an 87-question data set representing 44 centers in the United States and Europe, patients were classified as having had CED or a combined end point of neurological-etiology death or survival. Demographics and clinical factors were modeled in a derivation cohort, and backward stepwise logistic regression was used to identify factors independently associated with CED. We demonstrated model performance using area under the curve and the Hosmer-Lemeshow test in the derivation and validation cohorts, and assigned a simplified point-scoring system. RESULTS: Among 638 patients in the derivation cohort, 121 (18.9%) had CED. The final model included preexisting coronary artery disease (odds ratio [OR], 2.86; confidence interval [CI], 1.83-4.49; P≤0.001), nonshockable rhythm (OR, 1.75; CI, 1.10-2.77; P=0.017), initial ejection fraction<30% (OR, 2.11; CI, 1.32-3.37; P=0.002), shock at presentation (OR, 2.27; CI, 1.42-3.62; P<0.001), and ischemic time >25 minutes (OR, 1.42; CI, 0.90-2.23; P=0.13). The derivation model area under the curve was 0.73, and Hosmer-Lemeshow test P=0.47. Outcomes were similar in the 318-patient validation cohort (area under the curve 0.68, Hosmer-Lemeshow test P=0.41). When assigned a point for each associated factor in the derivation model, the average predicted versus observed probability of CED with a CREST score (coronary artery disease, initial heart rhythm, low ejection fraction, shock at the time of admission, and ischemic time >25 minutes) of 0 to 5 was: 7.1% versus 10.2%, 9.5% versus 11%, 22.5% versus 19.6%, 32.4% versus 29.6%, 38.5% versus 30%, and 55.7% versus 50%. CONCLUSIONS: The CREST model stratified patients immediately after resuscitation according to risk of a circulatory-etiology death. The tool may allow for estimation of circulatory risk and improve the triage of survivors of cardiac arrest without ST-segment-elevation myocardial infarction at the point of care.

Valproate for agitation in critically ill patients: A retrospective study.

PURPOSE: The purpose was to describe the use of valproate therapy for agitation in critically ill patients, examine its safety, and describe its relationship with agitation and delirium. MATERIALS AND METHODS: This retrospective cohort study evaluated critically ill adults treated with valproate for agitation from December 2012 through February 2015. Information on valproate prescribing practices and safety was collected. Incidence of agitation, delirium, and concomitant psychoactive medication use was compared between valproate day 1 and valproate day 3. Concomitant psychoactive medication use was analyzed using mixed models. RESULTS: Fifty-three patients were evaluated. The median day of valproate therapy initiation was ICU day 7, and it was continued for a median of 7 days. The median maintenance dose was 1500 mg/d (23 mg/kg/d). The incidence of agitation (96% vs 61%, P < .0001) and delirium (68% vs 49%, P = .012) significantly decreased by valproate day 3. Treatment with opioids (77% vs 65%, P = .02) and dexmedetomidine (47% vs 24%, P = .004) also decreased. In mixed models analyses, valproate therapy was associated with reduced fentanyl equivalents (-185 µg/d, P = .0003) and lorazepam equivalents (-2.1 mg/d, P = .0004). Hyperammonemia (19%) and thrombocytopenia (13%) were the most commonly observed adverse effects. CONCLUSIONS: Valproate therapy was associated with a reduction in agitation, delirium, and concomitant psychoactive medication use within 48 hours of initiation.

Inadequacy of Headache Management After Subarachnoid Hemorrhage.

BACKGROUND: Headache profoundly affects management of spontaneous subarachnoid hemorrhage but is poorly characterized. OBJECTIVE: To characterize headache after spontaneous subarachnoid hemorrhage. METHODS: Medical records of patients with Hunt and Hess grades I-III subarachnoid hemorrhage admitted from 2011 to 2013 were reviewed. Demographics, clinical and radiographic features, medications, and pain scores were recorded through day 14 after hemorrhage. Headache pain was characterized on the basis of a numeric rating scale and analgesic use. Severe headache was defined as 2 or more days with maximum pain scores of 8 or greater or need for 3 or more different analgesics for 2 or more days. Univariate and multivariable models were used to analyze factors associated with severe headache. RESULTS: Of the 77 patients in the sample, 57% were women; median age was 57 years. Severe headache (73% overall) was associated nonlinearly with Hunt and Hess grade: grade I, 58%; grade II, 88%; and grade III, 56% (P = .01), and with Hijdra score: score 0-10, 56%; score 11-20, 86%; score 21-30, 76% (P = .03). By univariate analysis, patients with low Hijdra scores were less likely to have severe headache (27% vs 57%; P = .02). In a multivariable model, younger age and higher Hijdra score tended to be associated with severe headache. CONCLUSIONS: Headache after spontaneous subarachnoid hemorrhage was often severe, necessitating multiple opioid and nonopioid analgesics. Many patients reported persistent headache and inadequate pain control.

Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.

OBJECTIVES: To evaluate the outcomes of cardiac arrest survivors with myoclonus receiving modern postresuscitation care. DESIGN: Retrospective review of registry data. SETTING: Cardiac arrest receiving centers in Europe and the United States from 2002 to 2012. PATIENTS: Two thousand five hundred thirty-two cardiac arrest survivors 18 years or older enrolled in the International Cardiac Arrest Registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-eight percent of patients underwent therapeutic hypothermia and 471 (18%) exhibited myoclonus. Patients with myoclonus had longer time to professional cardiopulmonary resuscitation (8.6 vs 7.0 min; p < 0.001) and total ischemic time (25.6 vs 22.3 min; p < 0.001) and less often presented with ventricular tachycardia/ventricular fibrillation, a witnessed arrest, or had bystander cardiopulmonary resuscitation. Electroencephalography demonstrated myoclonus with epileptiform activity in 209 of 374 (55%), including status epilepticus in 102 of 374 (27%). Good outcome (Cerebral Performance Category 1-2) at hospital discharge was noted in 9% of patients with myoclonus, less frequently in myoclonus with epileptiform activity (2% vs 15%; p < 0.001). Patients with myoclonus with good outcome were younger (53.7 vs 62.7 yr; p < 0.001), had more ventricular tachycardia/ventricular fibrillation (81% vs 46%; p < 0.001), shorter ischemic time (18.9 vs 26.4 min; p = 0.003), more witnessed arrests (91% vs 77%; p = 0.02), and fewer "do-not-resuscitate" orders (7% vs 78%; p < 0.001). Life support was withdrawn in 330 of 427 patients (78%) with myoclonus and poor outcome, due to neurological futility in 293 of 330 (89%), at 5 days (3-8 d) after resuscitation. With myoclonus and good outcome, median ICU length of stay was 8 days (5-11 d) and hospital length of stay was 14.5 days (9-22 d). CONCLUSIONS: Nine percent of cardiac arrest survivors with myoclonus after cardiac arrest had good functional outcomes, usually in patients without associated epileptiform activity and after prolonged hospitalization. Deaths occurred early and primarily after withdrawal of life support. It is uncertain whether prolonged care would yield a higher percentage of good outcomes, but myoclonus of itself should not be considered a sign of futility.

Prophylactic antibiotics are associated with a lower incidence of pneumonia in cardiac arrest survivors treated with targeted temperature management.

INTRODUCTION: Prophylactic antibiotics (PRO) reduce the incidence of early-onset pneumonia in comatose patients with structural brain injury, but have not been examined in cardiac arrest survivors undergoing targeted temperature management (TTM). We investigated the effect of PRO on the development of pneumonia in that population. METHODS: We conducted a retrospective cohort study comparing patients treated with PRO to those not receiving PRO (no-PRO) using Northern Hypothermia Network registry data. Cardiac arrest survivors ≥ 18 years of age with a GCS<8 at hospital admission and treated with TTM at 32-34 °C were enrolled in the registry. Differences were analyzed in univariate analyses and with logistic regression models to evaluate independent associations of clinical factors with incidence of pneumonia and good functional outcome. RESULTS: 416 of 1240 patients (33.5%) received PRO. Groups were similar in age, gender, arrest location, initial rhythm, and time from collapse to return of spontaneous circulation. PRO patients had less pneumonia (12.6% vs. 54.9%, p < 0.001) and less sepsis (1.2 vs. 5.7%, p < 0.001) compared to no-PRO patients. ICU length of stay (98 vs. 100 h, p = 0.2) and incidence of a good functional outcome (41.1 vs. 36.6%, p = 0.19) were similar between groups. Backwards stepwise logistic regression demonstrated PRO were independently associated with a lower incidence of pneumonia (OR 0.09, 95% 0.06-0.14, p < 0.001) and a similar incidence of good functional outcome. CONCLUSIONS: Prophylactic antibiotics were associated with a reduced incidence of pneumonia but a similar rate of good functional outcome.

Feasibility of bispectral index monitoring to guide early post-resuscitation cardiac arrest triage.

INTRODUCTION: Triage after resuscitation from cardiac arrest is hindered by reliable early estimation of brain injury. We evaluated the performance of a triage model based on early bispectral index (BIS) findings and cardiac risk classes. METHODS: Retrospective evaluation of serial patients resuscitated from cardiac arrest, unable to follow commands, and undergoing hypothermia. Patients were assigned to a cardiac risk group: STEMI, VT/VF shock, VT/VF no shock, or PEA/asystole, and to a neurological dysfunction group, based on the BIS score following first neuromuscular blockade (BISi), and classified as BISi>20, BISi 10-20, or BISi<10. Cause of death was described as neurological or circulatory. RESULTS: BISi in 171 patients was measured at 267(±177)min after resuscitation and 35(±1.7)°C. BISi<10 suffered 82% neurological-cause and 91% overall mortality, BISi 10-20 35% neurological and 55% overall mortality, and BISi>20 12% neurological and 36% overall mortality. 33 patients presented with STEMI, 15 VT/VF-shock, 41 VT/VF-no shock, and 80 PEA/asystole. Among BISi>20 patients, 75% with STEMI underwent urgent cardiac catheterization (cath) and 94% had good outcome. When BISi>20 with VT/VF and shock, urgent cath was infrequent (33%), and 4 deaths (44%) were uniformly of circulatory etiology. Of 56 VT/VF patients without STEMI, 24 were BISi>20 but did not undergo urgent cath - 5(20.8%) of these had circulatory-etiology death. Circulatory-etiology death also occurred in 26.5% BIS>20 patients with PEA/asystole. When BISi<10, a neurological etiology death dominated independent of cardiac risk group. CONCLUSIONS: Neurocardiac triage based on very early processed EEG (BIS) is feasible, and may identify patients appropriate for individualized post-resuscitation care. This and other triage models warrant further study.

Geriatric experience following cardiac arrest at six interventional cardiology centers in the United States 2006-2011: interplay of age, do-not-resuscitate order, and outcomes.

OBJECTIVES: It is not known if aggressive postresuscitation care, including therapeutic hypothermia and percutaneous coronary intervention, benefits cardiac arrest survivors more than 75 years old. We compared treatments and outcomes of patients at six regional percutaneous coronary intervention centers in the United States to determine if aggressive care of elderly patients was warranted. DESIGN: Retrospective evaluation of registry data. SETTING: Six interventional cardiology centers in the United States. PATIENTS: Six hundred and twenty-five unresponsive cardiac arrest survivors aged 18-75 were compared with 129 similar patients aged more than 75. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cardiac arrest survivors aged more than 75 had more comorbidities (3.0 ± 1.6 vs 2.0 ± 1.6, p < 0.001), but were matched to younger patients in initial heart rhythm, witnessed arrests, bystander cardiopulmonary resuscitation, and total ischemic time. Patients aged more than 75 frequently underwent therapeutic hypothermia (97.7%), urgent coronary angiography (44.2%), and urgent percutaneous coronary intervention (24%). They had more sustained hyperglycemia (70.5% vs 59%, p = 0.015), less postcooling fever (25.2% vs 35.2%, p = 0.03), were more likely to have do-not-resuscitate orders (65.9% vs 48.2%, p < 0.001), and undergo withdrawal of life support (61.2% vs 47.5%, p = 0.005). Good functional outcome at 6 months (Cerebral Performance Category 1-2) was seen in 27.9% elderly versus 40.4% younger patients overall (p = 0.01) and in 44% versus 55% (p = 0.13) of patients with an initial shockable rhythm. Of 35 survivors more than 75 years old, 33 (94.8%) were classified as Cerebral Performance Category 1 or 2 at (mean) 6.5-month follow-up. In multivariable logistic regression modeling, age more than 75 was significantly associated with outcome only when the presence of a do-not-resuscitate order was excluded from the model. CONCLUSIONS: Elderly patients were more likely to have do-not-resuscitate orders and to undergo withdrawal of life support. Age was independently associated with outcome only when correction for do-not-resuscitate status was excluded, and functional outcomes of elderly survivors were similar to younger patients. Exclusion of patients more than 75 years old from aggressive care is not warranted on the basis of age alone.

Surface cooling after cardiac arrest: effectiveness, skin safety, and adverse events in routine clinical practice.

BACKGROUND: Effectiveness of cooling and adverse events (AEs) involving skin have not been intensively evaluated in cardiac arrest survivors treated with therapeutic hypothermia (TH) when induced and maintained with a servomechanism-regulated surface cooling system. METHODS: Retrospective review of sixty-nine cardiac arrest survivor-events admitted from April 2006-September 2008 who underwent TH using the Medivance Arctic Sun Temperature Management System. A TH database and medical records were reviewed, and nursing interviews conducted. Primary endpoint was time from initiation to target temperature (TT; 32-34 °C). Secondary endpoints were cooling rate, percentage of hypothermia maintenance phase at TT, effect of body-mass index (BMI) on rate of cooling, and AEs. RESULTS: Mean time to the target temperature (TT) was 2.78 h; 80% of patients achieved TT within 4 h; all did within 8 h. Patients were at TT for 96.7% of hypothermia maintenance; 17% of patients had >1 hourly temperature measurement outside TT range. Mean cooling rate during induction phase was 1.1 °C/h, and was not associated with BMI. Minor skin injury occurred in 14 (20%) patients; 4 (6%) were device-related. Skin injuries were associated with shock (P = 0.04), and decubitus ulcers were associated with left ventricular ejection fraction <45% (P = 0.004). AEs included shivering (94%), hypokalemia (81%), hyperglycemia (57%), pneumonia (23%), bleeding (22%), post-cooling fever (17%), and bacteremia (9%). CONCLUSIONS: The Arctic Sun Temperature Management System was an effective means of performing therapeutic hypothermia after cardiac arrest. Infrequent skin injuries were associated with vasopressor use and low ejection fraction.