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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.
Single-center retrospective cohort study of all post-cardiac arrest patients over one 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 6 hours after ROSC: (1) Exposures – two or more systolic blood pressures (SBP) <100 mmHg or (2) Non-exposures – less than two SBP <100 mmHg. 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.
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), early exposure to hypotension was a strong independent predictor of death (OR 3.5 [95% CI 1.3–9.6]).
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.
The post-cardiac arrest syndrome is a period of critical illness that follows return of spontaneous circulation (ROSC) from cardiac arrest.1 In recent years, new therapeutic interventions applied after ROSC (i.e. therapeutic hypothermia2, 3) have dramatically improved survival, and these findings raised awareness that events in the post-ROSC phase of therapy can have a striking impact on outcome for cardiac arrest victims.4 Given the fact that a minority of patients survive to hospital discharge, even after cardiopulmonary resuscitation (CPR) and Advanced Cardiac Life Support are successful in achieving ROSC5, 6, identifying new therapeutic targets in post-ROSC care is of paramount importance.
The post-cardiac arrest syndrome can be characterized by reversible myocardial stunning,7–9 a severe systemic pro-inflammatory response,10 and adrenal axis suppression,11, 12 all of which are byproducts of a global ischemia-reperfusion insult. These pathophysiologic derangements can induce post-ROSC hemodynamic alterations that render patients at high risk for acute organ hypoperfusion and multi-organ system dysfunction, repeat cardiac arrest, and death. However, the strength of association between post-ROSC hemodynamic derangements and clinical outcome is insufficiently studied and remains poorly understood. Recently, the International Liason Committee on Resuscitation (ILCOR) identified this as a “knowledge gap” and one of the high priority areas for cardiac arrest research in the future.13
Arterial hypotension is the most overt manifestation of major hemodynamic perturbations, and arterial blood pressure is a hemodynamic parameter that all clinicians can access routinely in clinical care. Although the degree and duration of arterial hypotension has been strongly associated with clinical outcome in other acutely ill populations14 including those with acute cardiovascular emergencies,15, 16 there is a paucity of data regarding the strength of the relationship between post-ROSC hypotension and survival has not been studied in a post-cardiac arrest population. The purpose of this study was to test the hypotheses that (1) arterial hypotension occurs commonly (>50%) within the first 6 hours after ROSC, and (2) the presence of early arterial hypotension is an independent predictor of in-hospital mortality. If arterial hypotension is common in the early hours after ROSC and associated with adverse outcome, then these findings could warrant further investigation of arterial pressure optimization as a therapeutic target in early post-ROSC care.
Single center retrospective study.
Urban academic medical center (Cooper University Hospital, Camden, New Jersey).
All post-cardiac arrest patients over a one year period (July, 2006 – July, 2007).
(1) age>17 years; (2) non-trauma; (3) sustained ROSC (defined as greater than 20 minutes17) after any in-hospital or out-of-hospital cardiac arrest [defined as (a) documented pulselessness and (b) received cardiopulmonary resuscitation (CPR)] regardless of initial cardiac rhythm.
We identified out-of-hospital cardiac arrest patients via the electronic logs and “code sheets” from the only two Emergency Medical Services (EMS) that transport patients to our ED: (a) University of Medicine and Dentistry of New Jersey EMS, and (b) Virtua Health Mobile Intensive Care Unit. We identified in-hospital cardiac arrest patients by reviewing every “code blue” event sheet from the study period, copies of which are stored in a central repository for administrative review, quality assurance, and charge processing. As mandated by hospital policy, every in-hospital cardiac arrest victim will have a standardized “code blue” sheet generated at the time of the cardiac arrest. We screened all cardiac arrest patients identified through these sources for inclusion criteria. Figure 1 displays a flow diagram of the search inclusion process.
Induced mild hypothermia (HT) for neuroprotection after ROSC was provided based on clinician discretion using a standardized physician order set for HT induction and maintenance. We previously demonstrated that, using our standardized HT order set, our clinicians could achieve HT target temperature (33–34°) in routine post-cardiac arrest care with efficiency comparable to that demonstrated in randomized controlled trials.18 Our HT order set did not include orders for hemodynamic support, which was entirely guided by individual clinician judgment.
Three investigators abstracted the data. We conducted a formal training session for data abstractors, used standardized abstraction forms and definitions of variables, monitored abstractor performance, and blinded abstractors to the study hypothesis and primary outcome measures.19 We calculated inter-observer agreement (Κ) among the three abstractors based on a 10% sample of cases selected at random.
We captured all data points according to the Utstein style for uniform reporting of cardiac arrest research, including all recommended elements of reporting post-cardiac arrest care.17, 20 In addition, we captured all documented arterial blood pressure recordings (including all cuff and arterial line measurements) for the first six hours after ROSC, and the highest and lowest recorded values for arterial blood pressure for the following time intervals after ROSC: 6–24 hours, 24–48 hours, and 48–72 hours. We also captured the highest and lowest values for heart rate, respiratory rate, and all hemodynamic parameters derived from invasive monitoring (if applicable) over one hour intervals (hour 0–1, 1–2, 2–3, etc.) for the first six hours after ROSC and then the following time intervals: 6–24 hours, 24–48 hours, and 48–72 hours. We entered all data into a dedicated Access database (Microsoft Corporation, Redmond, WA).
We divided the cohort into two groups based on the presence or absence of arterial hypotension within the first 6 hours after ROSC. We used the standardized criteria for defining hypotension that have been validated in three clinical studies including more than 15,000 subjects from Jones et al.14, 21, 22 The classifications of hypotension by these criteria are, (1) sustained – systolic blood pressure < 100 mm HG without recovery (no measurements > 100 mm Hg) for ≥ 60 minutes, (2) transient – systolic blood pressure < 100 mm Hg followed by at least 2 readings ≥ 100 mm Hg at least 15 minutes apart and no subsequent readings < 100 mm Hg, and (3) episodic – systolic blood pressure < 100 mm Hg not categorized as transient or sustained.14, 21, 22 For the purpose of analysis, we combined hypotension classifications to create a dichotomous exposure variable. We defined the “exposure” group by the presence of two or more systolic blood pressure (SBP) recordings <100 mmHg (i.e. episodic or sustained hypotension14, 21, 22). We defined the “non-exposure” group as less than two SBP recordings <100 mmHg (i.e. transient or no hypotension14, 21, 22).
The primary outcome measure was in-hospital mortality. The secondary outcome measure was re-arrest (defined as a repeat cardiac arrest treated with CPR) within 72 hours of ROSC from the index arrest. We used 72 hours as the time interval within which to measure the occurrence of re-arrest based on consensus guidelines for reporting post-resuscitation research.20 We analyzed the occurrence of the primary outcome (in-hospital mortality) and re-arrest in each exposure group with binomial test for difference in proportions. The Kaplan-Meier survival estimates and log-rank test for comparison were used for time-to-primary outcome analysis.
In order to account for potential confounding of several variables on mortality, we performed multivariate logistic regression to determine the relative strength of exposure to hypotension as an independent predictor of death. A priori, we determined that five candidate variables would be an optimal number of covariates for the model based on the following assumptions: (1) an event (death) per variable ratio of 10 to 1 necessary for multivariate modeling,23, 24 (2) prior years’ data from our institution showing 80–90 cardiac arrest survived events per year, and (3) an expected mortality rate after ROSC of 60%,5 which would yield approximately 50 cases with mortality after an initial survived event. We selected candidate variables for the regression model that were shown to impact mortality in prior studies3, 6, 25, 26: age, pre-arrest functional status [defined as the Overall Performance Category (OPC)27], initial cardiac arrest rhythm [defined as unfavorable (asystole and pulseless electrical activity) versus favorable (ventricular tachycardia/fibrillation)], achievement of therapeutic hypothermia target temperature, and early exposure to hypotension. In-hospital morality was the dependent variable. We calculated the Hosmer-Lemeshow statistic for goodness-of-fit. We used SigmaStat (Systat Software, San Jose, CA) for all analyses.
The Institutional Review Board approved this study with an exemption from written informed consent.
During the study period, 102 patients met inclusion criteria. Inter-observer agreement among data abstractors was excellent for all variables tested (κ >0.90) and specifically for determination of exposure versus non-exposure to hypotension (κ =0.93). Table 1 displays the baseline characteristics of all study subjects as well as the exposure and non-exposure groups. Early exposure to hypotension occurred in 66/102 (65%) subjects.
The overall in-hospital mortality rate for the entire cohort was 75%, and the re-arrest rate within 72 hours was 25%. Table 2 displays outcomes for the entire study cohort as well as the exposure and non-exposure groups. Sixty-six percent of in-hospital cardiac arrest victims and 60% of the out-of–hospital cohort had exposure to hypotension in the first 6 hours after ROSC.
Early exposure to hypotension was associated with a significantly higher mortality rate (83%) compared to non-exposures (58%, p=0.01) and a significantly higher re-arrest rate (32%) compared to non-exposures (11%, p=0.04). Figure 2 displays the Kaplan-Meier survival curves for patients with early exposure to hypotension versus non-exposures. The survival curves diverged significantly by log-rank test, p<0.001. Figure 3 displays in-hospital mortality among subjects stratified by duration of hypotension (absence of hypotension, episodic hypotension, and sustained hypotension as defined by the criteria from Jones et al. Similar to subjects with sustained hypotension, subjects with episodic hypotension had an in-hospital mortality rate of 83%.
In the multivariate logistic regression model controlling for confounding variables (age, pre-arrest functional status, initial arrest rhythm, and achievement of therapeutic hypothermia target temperature), early exposure to hypotension was an independent predictor of death (odds ratio 3.5 [95% CI 1.3 – 9.6]) (Table 3).
In this study, we hypothesized that exposure to hypotension within six hours after ROSC would be associated with lower survival to hospital discharge. Using standardized criteria to classify arterial hypotension, we found that the presence of two or more systolic blood pressures below 100 mmHg in the first six hours after ROSC was associated with a greater than three fold increased odds of in-hospital death. Our group employs the concept of “exposure” to hypotension to emphasize the significance of the event as an independent predictor of death. Previously two large observational studies showed that in the general, non-traumatic patient population, early exposure to arterial hypotension was a strong independent predictor of long-range outcome including in-hospital mortality.21, 22 We sought to determine the strength of the relationship between early exposure to hypotension and mortality in this specific post-ROSC patient population. Our findings indicate that post-ROSC hypotension, especially in the early hours, may be an important determinant of outcome.
Although it may be an expected finding that patients with overt shock have worse clinical outcomes, Figure 2 highlights that even patients with episodic hypotension had high mortality risk and therefore our findings are not entirely driven by subjects who manifest sustained hypotension and suggest that any hypotension may be deleterious.
We acknowledge that our data have important limitations. Although all of our subjects had blood pressures measured early and frequently, the retrospective design did not permit measurements to be accrued at fixed time intervals, and therefore it is possible that some subjects with less frequent measurements had exposure to hypotension that was not detected. Due to the potential heterogeneity in number of blood pressures measurements, we also could not perform a cumulative analysis (i.e. area under the curve for exposure) over time. Therefore we cannot comment on the impact of the depth and duration of post-ROSC hypotension (i.e. akin to a dose-response effect). In addition, we recognize that it is possible that some subjects who were moribund or deemed non-salvagable by clinicians may have received less aggressive care and thus were more likely exposed to hypotension. However, this concern is attenuated by the fact that the exposure group actually received more repeat CPR in the first 72 hours post-ROSC compared to non-exposures.
We chose arterial hypotension as the hemodynamic variable of interest because it is a hallmark of circulatory insufficiency and is a readily available parameter for all clinicians. After ROSC, hypotension leads to persistent tissue hypoperfusion which may produce secondary cellular injury after the initial ischemic insult. Furthermore, the associated cardiovascular instability may increase the propensity to suffer repeat cardiac arrest. Post-cardiac arrest studies in animals have defined impaired myocardial function after cardiac arrest and shown that cardiovascular derangements in the hours after ROSC lead to poor neurologic outcome.28, 29 In humans, Laurent et al showed that persistent low cardiac index at 24 hours post-ROSC was associated with death and multiorgan failure.8 In addition, Mullner and colleagues found that hypotension in the first two hours after ROSC was related to poor neurologic outcome at 6 months.30 We know of no prior study specifically examining the relationship between arterial hypotension after ROSC and survival.
In the last decade scientific advances showed that interventions after ROSC can save lives.2, 3 In 2005, the European Resuscitation Council added ‘Post Resuscitation Care’ as the final link in the Chain of Survival paradigm for treating cardiac arrest.31 This change in the classical view denotes a new focus on the post-resuscitation period as a window of opportunity to intervene and develop treatments to change the trajectory of post-cardiac arrest syndrome. Although we now know that body temperature may play a significant role in determining outcomes,2, 3 little is known as to what other physiologic parameters may be important in the post-ROSC period. Specifically, although consensus recommendations advocate for hemodynamic optimization in the post-ROSC period, there is little empiric evidence on the association between post-ROSC hemodynamic derangements and outcome.32, 33
Identifying new target parameters in the post-ROSC period will be the next steps in the development of novel treatment strategies to improve survival after cardiac arrest. Therapeutic hypothermia for neuroprotection represents the first step in this process. In this study, we showed that arterial blood pressure may be a major determinant of outcome in this disease and therefore it may represent a new therapeutic target during post-ROSC treatment. Our findings provide scientific rationale for further investigation to determine the value of arterial blood pressure optimization as a part of an early goal-directed treatment strategy for post-cardiac arrest syndrome.
In this cohort of cardiac arrest patients with sustained ROSC we demonstrated that early exposure to arterial hypotension after ROSC was common and an independent predictor of death. These data indicate that future prospective investigation is warranted to determine the overall incidence of post-ROSC hypotension as well as the impact of the depth and duration of the hypotension on outcome. Post-ROSC hypotension could potentially represent a new therapeutic target in post-cardiac arrest care.
Dr. Kilgannon is supported by a grant from the Emergency Medicine Foundation. Dr. Trzeciak’s effort to this project was supported by a grant from the National Institutes of Health/National Institute of General Medical Sciences (K23GM83211). Dr. Jones’ effort to this project was supported by a grant from the National Institutes of Health/National Institute of General Medical Sciences (K23GM76652).
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POTENTIAL CONFLICTS OF INTEREST
Dr. Trzeciak has received research support from Biosite, Eli Lilly, and Novo Nordisk. None of the other authors have potential financial conflicts of interest to disclose.