J. Hope Kilgannon

Association Between Arterial Hyperoxia Following Resuscitation From Cardiac Arrest and In-Hospital Mortality

CONTEXT Laboratory investigations suggest that exposure to hyperoxia after resuscitation from cardiac arrest may worsen anoxic brain injury; however, clinical data are lacking. OBJECTIVE To test the hypothesis that postresuscitation hyperoxia is associated with increased mortality. DESIGN, SETTING, AND PATIENTS Multicenter cohort study using the Project IMPACT critical care database of intensive care units (ICUs) at 120 US hospitals between 2001 and 2005. Patient inclusion criteria were age older than 17 years, nontraumatic cardiac arrest, cardiopulmonary resuscitation within 24 hours prior to ICU arrival, and arterial blood gas analysis performed within 24 hours following ICU arrival. Patients were divided into 3 groups defined a priori based on PaO(2) on the first arterial blood gas values obtained in the ICU. Hyperoxia was defined as PaO(2) of 300 mm Hg or greater; hypoxia, PaO(2) of less than 60 mm Hg (or ratio of PaO(2) to fraction of inspired oxygen <300); and normoxia, not classified as hyperoxia or hypoxia. MAIN OUTCOME MEASURE In-hospital mortality. RESULTS Of 6326 patients, 1156 had hyperoxia (18%), 3999 had hypoxia (63%), and 1171 had normoxia (19%). The hyperoxia group had significantly higher in-hospital mortality (732/1156 [63%; 95% confidence interval {CI}, 60%-66%]) compared with the normoxia group (532/1171 [45%; 95% CI, 43%-48%]; proportion difference, 18% [95% CI, 14%-22%]) and the hypoxia group (2297/3999 [57%; 95% CI, 56%-59%]; proportion difference, 6% [95% CI, 3%-9%]). In a model controlling for potential confounders (eg, age, preadmission functional status, comorbid conditions, vital signs, and other physiological indices), hyperoxia exposure had an odds ratio for death of 1.8 (95% CI, 1.5-2.2). CONCLUSION Among patients admitted to the ICU following resuscitation from cardiac arrest, arterial hyperoxia was independently associated with increased in-hospital mortality compared with either hypoxia or normoxia.

Relationship Between Supranormal Oxygen Tension and Outcome After Resuscitation From Cardiac Arrest

Background— Laboratory and recent clinical data suggest that hyperoxemia after resuscitation from cardiac arrest is harmful; however, it remains unclear if the risk of adverse outcome is a threshold effect at a specific supranormal oxygen tension, or is a dose-dependent association. We aimed to define the relationship between supranormal oxygen tension and outcome in postresuscitation patients. Methods and Results— This was a multicenter cohort study using the Project IMPACT database (intensive care units at 120 US hospitals). Inclusion criteria were age >17 years, nontrauma, cardiopulmonary resuscitation preceding intensive care unit arrival, and postresuscitation arterial blood gas obtained. We excluded patients with hypoxia or severe oxygenation impairment. We defined the exposure by the highest partial pressure of arterial oxygen (PaO2) over the first 24 hours in the ICU. The primary outcome measure was in-hospital mortality. We tested the association between PaO2 (continuous variable) and mortality using multivariable logistic regression adjusted for patient-oriented covariates and potential hospital effects. Of 4459 patients, 54% died. The median postresuscitation PaO2 was 231 (interquartile range 149 to 349) mm Hg. Over ascending ranges of oxygen tension, we found significant linear trends of increasing in-hospital mortality and decreasing survival as functionally independent. On multivariable analysis, a 100 mm Hg increase in PaO2 was associated with a 24% increase in mortality risk (odds ratio 1.24 [95% confidence interval 1.18 to 1.31]. We observed no evidence supporting a single threshold for harm from supranormal oxygen tension. Conclusion— In this large sample of postresuscitation patients, we found a dose-dependent association between supranormal oxygen tension and risk of in-hospital death.

Early arterial hypotension is common in the post-cardiac arrest syndrome and associated with increased in-hospital mortality

AIM After return of spontaneous circulation (ROSC) from cardiac arrest, profound myocardial stunning and systemic inflammation may cause hemodynamic alterations; however, the prevalence of post-ROSC hemodynamic instability and the strength of association with outcome have not been established. We tested the hypothesis that exposure to arterial hypotension after ROSC occurs commonly (>50%) and is an independent predictor of death. METHODS Single-center retrospective cohort study of all post-cardiac arrest patients over 1 year. INCLUSION CRITERIA (1) age >17; (2) non-trauma; (3) sustained ROSC after cardiac arrest. Using the Jones criteria, subjects were assigned to one of two groups based on the presence of hypotension within 6h after ROSC: (1) exposures-two or more systolic blood pressures (SBPs) <100mmHg or (2) non-exposures-less than two SBP <100mmHg. The primary outcome was in-hospital mortality. We compared mortality rates between groups and used multivariate logistic regression to determine if post-ROSC hypotension independently predicted death. RESULTS 102 subjects met inclusion criteria. In-hospital mortality was 75%. Exposure to hypotension occurred in 66/102 (65%) and was associated with significantly higher mortality (83%) compared to non-exposures (58%, p=0.01). In a model controlling for common confounding variables (age, pre-arrest functional status, arrest rhythm, and provision of therapeutic hypothermia (HT)), early exposure to hypotension was a strong independent predictor of death (OR 3.5 [95% CI 1.3-9.6]). CONCLUSIONS Early exposure to arterial hypotension after ROSC was common and an independent predictor of death. These data suggest that post-ROSC hypotension could potentially represent a therapeutic target in post-cardiac arrest care.

Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome.

Objectives:Recent guidelines for the treatment of postcardiac arrest syndrome recommend optimization of vital organ perfusion after return of spontaneous circulation to reduce the risk of postresuscitation multiple organ injury. However, the prevalence of extracerebral multiple organ dysfunction in postcardiac arrest patients and its association with in-hospital mortality remain unclear. Design:Single-center, prospective observational study. Setting:Urban academic medical center. Patients:Postcardiac arrest patients. Inclusion criteria were as follows: age older than 17 years, nontrauma cardiac arrest, and comatose after return of spontaneous circulation. Interventions:We prospectively captured all extracerebral components of the Sequential Organ Failure Assessment score over the first 72 hours after return of spontaneous circulation. The primary outcome measure was in-hospital mortality. We used multivariate logistic regression to determine if multiple organ dysfunction (defined as the highest extracerebral Sequential Organ Failure Assessment score) was an independent predictor of death, after adjustment for the presence of cerebral injury (defined as not following commands at any point over 0–72 hr). Measurements and Main Results:We enrolled 203 postcardiac arrest patients; 96% had some degree of extracerebral organ dysfunction and 66% had severe dysfunction in two or more extracerebral organ systems. The most common extracerebral organ failures were cardiovascular (i.e., vasopressor dependence) and respiratory (i.e., oxygenation impairment). The highest extracerebral Sequential Organ Failure Assessment score over 72 hours had an independent association with in-hospital mortality (odds ratio 1.95 [95% CI, 1.15–3.29]). Of the individual organ systems, only the cardiovascular and respiratory Sequential Organ Failure Assessment scores had an independent association with in-hospital mortality. Conclusions:The results of this study support the hypothesis that extracerebral organ dysfunction is common and associated with mortality in postcardiac arrest syndrome. This association appears to be driven by postresuscitation hemodynamic dysfunction and oxygenation impairment. Further research is needed to determine the value of hemodynamic and oxygenation optimization as a part of treatment strategies for patients with postcardiac arrest syndrome.

Goal-directed hemodynamic optimization in the post-cardiac arrest syndrome: a systematic review

AIMS The treatment recommendations from the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science (hosted by the American Heart Association) advocate a goal-directed treatment strategy for hemodynamic optimization after return of spontaneous circulation (ROSC) in post-cardiac arrest care. We performed a systematic review to (1) examine the available evidence for goal-directed hemodynamic support in the post-cardiac arrest syndrome, (2) determine the effect of such a treatment strategy on survival, and (3) define the specific hemodynamic goals, if any, that have been tested in clinical trials of post-cardiac arrest patients. METHODS We conducted a systematic review of the Cochrane Library, MEDLINE, CINAHL, conference proceedings, clinical practice guidelines, and other sources using a comprehensive strategy to identify randomized controlled trials and quasi-experimental studies of goal-directed hemodynamic optimization in patients with ROSC after cardiac arrest. RESULTS The comprehensive search yielded a total of 1184 potential publications and after a relevance screen, five studies were eligible for full article review. None of the studies were eligible for inclusion in the final analysis. CONCLUSIONS To date, no clinical trials have examined hemodynamic optimization in post-cardiac arrest patients. Although clinical acumen may support the concept that hemodynamic derangements after ROSC should be normalized, there is currently no evidence available to indicate the best strategy for goal-directed hemodynamic support. The current study indicates the need for future clinical investigations designed to determine both the efficacy of hemodynamic optimization in post-cardiac arrest patients and the best endpoints to target as part of a goal-directed strategy.

Nitric Oxide Donor Agents for the Treatment of Ischemia/reperfusion Injury in Human Subjects: A Systematic Review

ABSTRACT In animal models, administration of nitric oxide (NO) donor agents has been shown to reduce ischemia/reperfusion (I/R) injury. Our aim was to systematically analyze the biomedical literature to determine the effects of NO-donor agent administration on I/R injury in human subjects. We hypothesized that NO-donor agents reduce I/R injury. We performed a search of Cochrane Library, PubMed, CINAHL, conference proceedings, and other sources with no restriction to language using a comprehensive strategy. Study inclusion criteria were as follows: (a) human subjects, (b) documented periods of ischemia and reperfusion, (c) treatment arm composed of NO-donor agent administration, and (d) use of a control arm. We excluded secondary reports, reviews, correspondence, and editorials. We performed a qualitative analysis to collate and summarize treatment effects according to the recommended methodology from the Cochrane Handbook. Twenty-six studies involving multiple etiologies of I/R injury (10 cardiopulmonary bypass, six organ transplant, seven myocardial infarction, three limb tourniquet) met all inclusion and no exclusion criteria. Six (23%) of 26 were considered high-quality studies as per the Cochrane criteria for assessing risk of bias. In 20 (77%) of 26 studies and four (67%) of six high-quality studies, patients treated with NO-donor agents experienced reduced I/R injury compared with controls. Zero clinical studies to date have tested NO-donor agent administration in patients with cerebral I/R injury (e.g., cardiac arrest, stroke). Despite a paucity of high-quality clinical investigations, the preponderance of evidence to date suggests that administration of NO-donor agents may be an effective treatment for I/R injury in human subjects.

Therapeutic hypothermia and vasopressor dependency after cardiac arrest

OBJECTIVE Clinical trials of therapeutic hypothermia (TH) after cardiac arrest excluded patients with persistent hemodynamic instability after return of spontaneous circulation (ROSC), and thus equipoise may exist regarding use of TH in these patients. Our objective was to determine if TH is associated with worsening hemodynamic instability among patients who are vasopressor-dependent after ROSC. METHODS We performed a prospective observational study in vasopressor-dependent post-cardiac arrest patients. Inclusion criteria were age >17, non-trauma cardiac arrest, comatose after ROSC, and persistent vasopressor dependence. The decision to initiate TH (33-34 ° C) was made by the treating physician. We measured cumulative vasopressor index (CVI) and mean arterial pressure (MAP) every 15 min during the first 6h after ROSC. The outcome measures were change in CVI (primary outcome) and MAP (secondary outcome) over time. We graphed median CVI and MAP over time for the treated and not treated cohorts, and used propensity adjusted repeated measures mixed models to test for an association between TH induction and change in CVI or MAP over time. RESULTS Seventy-five post-cardiac arrest patients were included (35 treated; 40 not treated). We observed no major differences in CVI or MAP over time between the treated and not treated cohorts. In the mixed models we found no statistically significant association between TH induction and changes in CVI or MAP. CONCLUSION In patients with vasopressor-dependency after cardiac arrest, the induction of hypothermia was not associated with a decrease in mean arterial pressure or increase in vasopressor requirement.

Emergency Department inter-hospital transfer for post-cardiac arrest care: Initial experience with implementation of a regional cardiac resuscitation center in the United States

OBJECTIVE The American Heart Association recently recommended regional cardiac resuscitation centers (CRCs) for post-resuscitation care following out-of-hospital cardiac arrest (OHCA). Our objective was to describe initial experience with CRC implementation. METHODS Prospective observational study of consecutive post-resuscitation patients transferred from community Emergency Departments (EDs) to a CRC over 9 months. Transfer criteria were: OHCA, return of spontaneous circulation (ROSC), and comatose after ROSC. Incoming patients were received and stabilized in the ED of the CRC where advanced therapeutic hypothermia (TH) modalities were applied. Standardized post-resuscitation care included: ED evaluation for cardiac catheterization, TH (33-34 °C) for 24h, 24h/day critical care physician support, and evidence-based neurological prognostication. Prospective data collection utilized the Utstein template. The primary outcome was survival to hospital discharge with good neurological function [Cerebral Performance Category 1 or 2]. RESULTS Twenty-seven patients transferred from 11 different hospitals were included. The majority (21/27 [78%]) had arrest characteristics suggesting poor prognosis for survival (i.e. asystole/pulseless electrical activity initial rhythm, absence of bystander cardiopulmonary resuscitation, or an unwitnessed cardiac arrest). The median (IQR) time from transfer initiation to reaching TH target temperature was 7(5-13)h. Ten (37%) patients survived to hospital discharge, and of these 9/10 (90% of survivors, 33% of all patients) had good neurological function. CONCLUSIONS Despite a high proportion of patients with cardiac arrest characteristics suggesting poor prognosis for survival, we found that one-third of CRC transfers survived with good neurological function. Further research to determine if regional CRCs improve outcomes after cardiac arrest is warranted.

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study

Background: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. Methods: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (PaO2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a PaO2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between PaO2 and poor neurological outcome. To assess whether there was an association between other supranormal PaO2 levels and poor neurological outcome, we used other PaO2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). Results: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1–23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11–1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02–1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. Conclusions: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge.

Reply to Letters Regarding Article, “Relationship Between Supranormal Oxygen Tension and Outcome After Resuscitation From Cardiac Arrest”

We thank Drs Cornet and Bellomo and colleagues for their interest in the topic of hyperoxia exposure after resuscitation from cardiac arrest. Regarding the letter from Cornet et al, we used a different definition of hypoxia as a result of the peer review process, in which we were asked by a reviewer to liberalize the definition of normoxia in order to minimize restriction of the sample and thus yield results that were generalizable to as many post–cardiac arrest patients as possible. Regarding the letter from Bellomo et al, we decided a priori to base the analysis on the measured partial pressure of arterial oxygen (Pao2), which we feel is the true “exposure” in this type of study, and not on the reported fraction of inspired oxygen (Fio2) on the grounds that Fio2 and Pao2 must exhibit collinearity, and thus including both variables in the …