Jon C. Rittenberger

Out-of-hospital cardiac arrest survival improving over time: Results from the Resuscitation Outcomes Consortium (ROC).

BACKGROUND Out-of-hospital cardiac arrest (OHCA) remains a leading cause of death and a 2010 meta-analysis concluded that outcomes have not improved over several decades. However, guidelines have changed to emphasize CPR quality, minimization of interruptions, and standardized post-resuscitation care. We sought to evaluate whether OHCA outcomes have improved over time among agencies participating in the Resuscitation Outcomes Consortium (ROC) cardiac arrest registry (Epistry) and randomized clinical trials (RCTs). METHODS Observational cohort study of 47,148 EMS-treated OHCA cases in Epistry from 139 EMS agencies at 10 ROC sites that participated in at least one RCT between 1/1/2006 and 12/31/2010. We reviewed patient, scene, event characteristics, and outcomes of EMS-treated OHCA over time, including subgroups with initial rhythm of pulseless ventricular tachycardia or ventricular fibrillation (VT/VF). RESULTS Mean response interval, median age and male proportion remained similar over time. Unadjusted survival to discharge increased between 2006 and 2010 for treated OHCA (from 8.2% to 10.4%), as well as for subgroups of VT/VF (21.4% to 29.3%) and bystander witnessed VT/VF (23.5% to 30.3%). Compared with 2006, adjusted survival to discharge was significantly higher in 2010 for treated cases (OR = 1.72; 95% CI 1.53, 1.94), VT/VF cases (OR = 1.69; 95% CI 1.45, 1.98) and bystander witnessed VT/VF cases (OR = 1.65; 95% CI 1.36, 2.00). Tests for trend in each subgroup were significant (p < 0.001). CONCLUSIONS ROC-wide survival increased significantly between 2006 and 2010. Additional research efforts are warranted to identify specific factors associated with this improvement.

Coronary Angiography Predicts Improved Outcome Following Cardiac Arrest: Propensity-adjusted Analysis

Objectives: Determine if clinical parameters of resuscitated patients predict coronary angiography (CATH) performance and if receiving CATH after cardiac arrest is associated with outcome. Introduction: CATH is associated with survival in patients suffering out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation or ventricular tachycardia(VF/VT). Its effect on outcome in other cohorts is unknown. Methods: Chart review of resuscitated cardiac arrest patients between 2005 and 2007. Exclusion criteria: immediate withdrawal of care, hemodynamic collapse, or neurologic exam under sedation. Clinical parameters included Glasgow Coma Scale (GCS) arrest location, presenting rhythm, age, and acute ischemic ECG changes (new left bundle branch block or ST-elevation myocardial infarction-STEMI). Logistic regression identified clinical parameters predicting CATH. The association between CATH and good outcome (discharge home or to acute rehabilitation facility) was determined using logistic regression adjusting for likelihood of receiving CATH via propensity score. Result: Of the 241 patients, 96 (40%) received CATH. Significant disease (≥70% stenosis) of ≥1 coronary arteries was identified in 69% of patients including 57% of patients without acute ischemic ECG changes. Unadjusted predictors of CATH were sex, method of arrival, OHCA, presenting rhythm, acute ischemic ECG changes, and GCS. Propensity adjusted logistic regression demonstrated an association between CATH and good outcome (OR 2.16; 95% CI 1.12, 4.19; P < 0.02). Conclusion: CATH is more likely to be performed in certain patients and identifies a significant number of high-grade stenoses in this population. Receiving CATH was independently associated with good outcome.

Duration of Resuscitation Efforts and Functional Outcome After Out-of-Hospital Cardiac Arrest When Should We Change to Novel Therapies?

Background— Functionally favorable survival remains low after out-of-hospital cardiac arrest. When initial interventions fail to achieve the return of spontaneous circulation, they are repeated with little incremental benefit. Patients without rapid return of spontaneous circulation do not typically survive with good functional outcome. Novel approaches to out-of-hospital cardiac arrest have yielded functionally favorable survival in patients for whom traditional measures had failed, but the optimal transition point from traditional measures to novel therapies is ill defined. Our objective was to estimate the dynamic probability of survival and functional recovery as a function of resuscitation effort duration to identify this transition point. Methods and Results— Retrospective cohort study of a cardiac arrest database at a single site. We included 1014 adult (≥18 years) patients experiencing nontraumatic out-of-hospital cardiac arrest between 2005 and 2011, defined as receiving cardiopulmonary resuscitation or defibrillation from a professional provider. We stratified by functional outcome at hospital discharge (modified Rankin scale). Survival to hospital discharge was 11%, but only 6% had a modified Rankin scale of 0 to 3. Within 16.1 minutes of cardiopulmonary resuscitation, 89.7% (95% confidence interval, 80.3%–95.8%) of patients with good functional outcome had achieved return of spontaneous circulation, and the probability of good functional recovery fell to 1%. Adjusting for prehospital and inpatient covariates, cardiopulmonary resuscitation duration (minutes) is independently associated with favorable functional status at hospital discharge (odds ratio, 0.84; 95% confidence interval, 0.72–0.98; P=0.02). Conclusions— The probability of survival to hospital discharge with a modified Rankin scale of 0 to 3 declines rapidly with each minute of cardiopulmonary resuscitation. Novel strategies should be tested early after cardiac arrest rather than after the complete failure of traditional measures.

Receiving Hospital Characteristics Associated with Survival after Out-of-Hospital Cardiac Arrest

AIM Survival after out-of-hospital cardiac arrest (OOHCA) varies between regions, but the contribution of different factors to this variability is unknown. This study examined whether survival to hospital discharge was related to receiving hospital characteristics, including bed number, capability of performing cardiac catheterization and hospital volume of OOHCA cases. MATERIAL AND METHODS Prospective observational database of non-traumatic OOHCA assessed by emergency medical services was created in 8 US and 2 Canadian sites from December 1, 2005 to July 1, 2007. Subjects received hospital care after OOHCA, defined as either (1) arriving at hospital with pulses, or (2) arriving at hospital without pulses, but discharged or died > or =1 day later. RESULTS A total of 4087 OOHCA subjects were treated at 254 hospitals, and 32% survived to hospital discharge. A majority of subjects (68%) were treated at 116 (46%) hospitals capable of cardiac catheterization. Unadjusted survival to discharge was greater in hospitals performing cardiac catheterization (34% vs. 27%, p=0.001), and in hospitals that received > or =40 patients/year compared to those that received <40 (37% vs. 30%, p=0.01). Survival was not associated with hospital bed number, teaching status or trauma center designation. Length of stay (LOS) for surviving subjects was shorter at hospitals performing cardiac catheterization (p<0.01). After adjusting for all variables, there were no independent associations between survival or LOS and hospital characteristics. CONCLUSIONS Some subsets of hospitals displayed higher survival and shorter LOS for OOHCA subjects but there was no independent association between hospital characteristics and outcome.

Association between a quantitative CT scan measure of brain edema and outcome after cardiac arrest

BACKGROUND Cerebral edema is one physical change associated with brain injury and decreased survival after cardiac arrest. Edema appears on computed tomography (CT) scan of the brain as decreased X-ray attenuation by gray matter. This study tested whether the gray matter attenuation to white matter attenuation ratio (GWR) was associated with survival and functional recovery. METHODS Subjects were patients hospitalized after cardiac arrest at a single institution between 1/1/2005 and 7/30/2010. Subjects were included if they had non-traumatic cardiac arrest and a non-contrast CT scan within 24h after cardiac arrest. Attenuation (Hounsfield Units) was measured in gray matter (caudate nucleus, putamen, thalamus, and cortex) and in white matter (internal capsule, corpus callosum and centrum semiovale). The GWR was calculated for basal ganglia and cerebrum. Outcomes included survival and functional status at hospital discharge. RESULTS For 680 patients, 258 CT scans were available, but 18 were excluded because of hemorrhage (10), intravenous contrast (3) or technical artifact (5), leaving 240 CT scans for analysis. Lower GWR values were associated with lower initial Glasgow Coma Scale motor score. Overall survival was 36%, but decreased with decreasing GWR. The average of basal ganglia and cerebrum GWR provided the best discrimination. Only 2/58 subjects with average GWR<1.20 survived and both were treated with hypothermia. The association of GWR with functional outcome was completely explained by mortality when GWR<1.20. CONCLUSIONS Subjects with severe cerebral edema, defined by GWR<1.20, have very low survival with conventional care, including hypothermia. GWR estimates pre-treatment likelihood of survival after cardiac arrest.

Early coronary angiography and induced hypothermia are associated with survival and functional recovery after out-of-hospital cardiac arrest

BACKGROUND The rate and effect of coronary interventions and induced hypothermia after out-of-hospital cardiac arrest (OHCA) are unknown. We measured the association of early (≤24h after arrival) coronary angiography, reperfusion, and induced hypothermia with favorable outcome after OHCA. METHODS We performed a secondary analysis of a multicenter clinical trial (NCT00394706) conducted between 2007 and 2009 in 10 North American regions. Subjects were adults (≥18 years) hospitalized after OHCA with pulses sustained ≥60min. We measured the association of early coronary catheterization, percutaneous coronary intervention, fibrinolysis, and induced hypothermia with survival to hospital discharge with favorable functional status (modified Rankin Score≤3). RESULTS From 16,875 OHCA subjects, 3981 (23.6%) arrived at 151 hospitals with sustained pulses. 1317 (33.1%) survived to hospital discharge, with 1006 (25.3%) favorable outcomes. Rates of early coronary catheterization (19.2%), coronary reperfusion (17.7%) or induced hypothermia (39.3%) varied among hospitals, and were higher in hospitals treating more subjects per year. Odds of survival and favorable outcome increased with hospital volume (per 5 subjects/year OR 1.06; 95%CI: 1.04-1.08 and OR 1.06; 95%CI: 1.04, 1.08, respectively). Survival and favorable outcome were independently associated with early coronary angiography (OR 1.69; 95%CI 1.06-2.70 and OR 1.87; 95%CI 1.15-3.04), coronary reperfusion (OR 1.94; 95%CI 1.34-2.82 and OR 2.14; 95%CI 1.46-3.14), and induced hypothermia (OR 1.36; 95%CI 1.01-1.83 and OR 1.42; 95%CI 1.04-1.94). INTERPRETATION Early coronary intervention and induced hypothermia are associated with favorable outcome and are more frequent in hospitals that treat higher numbers of OHCA subjects per year.

An early, novel illness severity score to predict outcome after cardiac arrest

BACKGROUND Illness severity scores are commonly employed in critically ill patients to predict outcome. To date, prior scores for post-cardiac arrest patients rely on some event-related data. We developed an early, novel post-arrest illness severity score to predict survival, good outcome and development of multiple organ failure (MOF) after cardiac arrest. METHODS Retrospective review of data from adults treated after in-hospital or out-of-hospital cardiac arrest in a single tertiary care facility between 1/1/2005 and 12/31/2009. In addition to clinical data, initial illness severity was measured using serial organ function assessment (SOFA) scores and full outline of unresponsiveness (FOUR) scores at hospital or intensive care unit arrival. Outcomes were hospital mortality, good outcome (discharge to home or rehabilitation) and development of multiple organ failure (MOF). Single-variable logistic regression followed by Chi-squared automatic interaction detector (CHAID) was used to determine predictors of outcome. Stepwise multivariate logistic regression was used to determine the independent association between predictors and each outcome. The Hosmer-Lemeshow test was used to evaluate goodness of fit. The n-fold method was used to cross-validate each CHAID analysis and the difference between the misclassification risk estimates was used to determine model fit. RESULTS Complete data from 457/495 (92%) subjects identified distinct categories of illness severity using combined FOUR motor and brainstem subscales, and combined SOFA cardiovascular and respiratory subscales: I. Awake; II. Moderate coma without cardiorespiratory failure; III. Moderate coma with cardiorespiratory failure; and IV. Severe coma. Survival was independently associated with category (I: OR 58.65; 95% CI 27.78, 123.82; II: OR 14.60; 95% CI 7.34, 29.02; III: OR 10.58; 95% CI 4.86, 23.00). Category was also similarly associated with good outcome and development of MOF. The proportion of subjects in each category changed over time. CONCLUSIONS Initial illness severity explains much of the variation in cardiac arrest outcome. This model provides prognostic information at hospital arrival and may be used to stratify patients in future studies.

Prevalence and effect of fever on outcome following resuscitation from cardiac arrest.

OBJECTIVE Evaluate the prevalence of fever in the first 48 h after cardiac arrest and its effect on outcomes. METHODS Review of patients treated between 1/1/2005 and 6/30/2010. Fever was defined as T ≥ 38.0°C. We classified categories of post-cardiac arrest illness severity as (I) awake, (II) coma+mild cardiopulmonary dysfunction (SOFA cardiac+respiratory score <4), (III) coma+moderate-severe cardiopulmonary dysfunction, and (IV) deep coma. Associations between fever and survival or good neurologic outcome were examined between hypothermia (TH) and non-TH groups. RESULTS In 336 patients, mean age was 60 years (SD 16), 63% experienced out-of-hospital cardiac arrest and 65% received TH. A shockable rhythm was present in 40%. Post arrest illness severity was category II in 38%, category III in 20%, and category IV in 42%. Fever was present in 42% of subjects, with a post-arrest median onset of 15 h in the non-TH cohort and 36 h in TH cohort. Fever was not associated with survival within the whole cohort (OR 0.32, CI 0.15, 0.68) or TH cohort (OR 1.21, CI 0.69, 2.14), but was associated with survival in non-TH cohort (OR 0.47, CI 0.20, 1.10). Fever was not associated with good outcomes in the whole cohort (OR 0.83, CI 0.49, 1.40), TH cohort (OR 1.09, CI 0.56, 2.12) or non-TH cohort (OR 0.34, CI 0.11, 1.06). CONCLUSIONS The development of fever within the first 48 h after ROSC is common. Fever is associated with death in non-TH patients. TH treatment appears to mitigate this effect, perhaps by delaying fever onset.

The development and implementation of cardiac arrest centers

In the last decade, many regionalized centers for the care of post-cardiac arrest patients (cardiac arrest centers) have all independently developed with a common goal of providing multi-disciplinary and organized care plans for this patient population. The American Heart Association recently issued support for regionalized and organized comprehensive care for post-arrest patients through a position paper as well as the 2010 American Heart Association BLS/ACLS guidelines. This paper outlines the formation, structure, and implementation of four cardiac arrest centers, and also discusses a statewide model of post-arrest center care. This paper may assist other potential clinical sites that are considering or actively developing cardiac arrest centers of their own.

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4°C saline infusions and 4°C saline + magnesium) and two normothermia groups (37°C saline infusions and 37°C saline + magnesium). The lowest temperatures achieved in the 4°C saline + magnesium and 4°C saline infusions were 35.4 ± 0.4 and 35.8 ± 0.3°C, respectively. A significant decrease in the formation clearance of the major metabolite 1′-hydroxymidazolam was observed during the 4°C saline + magnesium compared with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5°C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.