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CRITICAL CARE OUTCOMES: Edited by Stephen Brett

Making sense of clinical outcomes following cardiac arrest

Patel, Jignesh K.; Chabra, Vikram; Parnia, Sam

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Current Opinion in Critical Care: October 2015 - Volume 21 - Issue 5 - p 453-459
doi: 10.1097/MCC.0000000000000237
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Abstract

INTRODUCTION

Cardiac arrest is common in the USA with an annual incidence of 350 000 out-of-hospital and 750 000 in-hospital events [1]. Over the past 40 years, overall cardiac arrest survival has remained relatively unchanged at 20% for in-hospital and 5–9% for out-of-hospital cardiac arrest. Furthermore, anoxic brain injury still remains a major health burden for survivors with only 3–7% recovering to their precardiac arrest functional status [1,2]. These outcomes reflect the finale to a two-step brain injury process: ischemia during cardiac arrest followed by secondary reperfusion injury leading to organ failure and death in the hours to days after successful return of spontaneous circulation (ROSC) and initial survival [1–3]. As overall survival and favorable neurological outcomes reflect the impact of patient-specific factors in combination with cardio-pulmonary resuscitation related, and postresuscitative-related factors, here we will review data from recent published studies that have examined the impact of these factors on clinical outcomes following adult cardiac arrest.

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PATIENT-SPECIFIC FACTORS

A number of patient-specific factors have been shown to impact overall cardiac arrest outcomes [3–6]. In particular, these can be categorized on the basis of age, initial cardiac rhythm, and comorbid states at the time of cardiac arrest. Specifically, younger age (<60 years) and an initial rhythm of ventricular tachycardia/fibrillation are associated with improved rates of survival to hospital discharge following in-hospital cardiac arrest (IHCA) [3,4]. In a study of 2121 IHCA, survival rates were highest for patients younger than 60-years old (61% 24-h survival, and 40% survival to hospital discharge), compared with patients at least 60-year olds (30% 24-h survival, and 16.6% survival to discharge). Patients who had an initial rhythm of ventricular tachycardia/fibrillation also had a higher survival to discharge (32%) compared with patients with asystole (7.2%) or Pulseless Electrical Activity (4.8%) [3]. Comorbid risk factors for poor survival and neurological outcomes include hepatic failure, renal insufficiency, sepsis, and malignancy [4]. These have been validated in older studies utilizing the pre-arrest morbidity index – a multifactorial scoring system to evaluate prearrest morbidity [5,6].

FACTORS ASSOCIATED WITH CARDIOPULMONARY RESUSCITATION

Impact of duration of cardio-pulmonary resuscitation

A number of recent studies have demonstrated that prolonged cardio-pulmonary resuscitation (CPR) is associated with poor survival and neurological outcomes [4,7–9]. In a study of 725 patients, Xue et al. demonstrated that 97.8% of patients with CPR lasting at least 15 min achieved ROSC, with a 36% survival to discharge and 20.2% favorable neurological outcomes. CPR more than 15 min was, however, associated with ROSC in only 15.7%, with a 2.5% survival to discharge and 0.8% favorable neurological outcomes [7]. A cutoff of 15 min as a predictor of ROSC and longer-term survival has been observed in many other studies. In a recent study, Iqbal et al. further demonstrated that survival with favorable functional outcomes falls exponentially with every minute of CPR. Consequently, in this study after 30 min only 2.5% of patients achieved survival with favorable functional outcomes [8]. In a newly developed and validated prediction tool using 42 957 cardiac arrest patients, duration of CPR was found to have the strongest predictive ability (greater than initial rhythm, age, and comorbid states) for survival with favorable neurological outcomes [4]. In a study of 64 339 patients across 435 hospitals that examined resuscitation practices across the USA, Goldberger et al.[9] demonstrated that the median CPR time to achieve ROSC was 12 min; however, in hospitals that routinely perform CPR for longer periods of time (median 25 min), ROSC, and survival to hospital discharge rates are increased by 12%. These observations suggest that although the majority of ‘CPR responders’ are likely to achieve ROSC within the first 15–20 min of CPR, some require prolonged CPR (up to >60 min) [9]. As it is not possible to predict which patients require prolonged CPR, the study by Goldberger et al.[9] suggests that performing CPR for longer than is customary in most institutions may help improve overall rates of survival with favorable neurological outcomes.

Quality of cardio-pulmonary resuscitation:– first, manual versus mechanical cardio-pulmonary resuscitation, second, the use of active compression–decompression cardio-pulmonary resuscitation and impedance threshold device, and third, airway management

Together with patient-specific factors and duration of CPR, the quality of CPR plays a major role in cardiac arrest outcomes. Poor quality CPR is associated with reduced rates of ROSC, survival and favorable neurological outcomes [10–14]. As provider fatigue is a significant contributor to poor quality CPR [10,11], multiple mechanical chest compression devices using a variety of load-distributing bands, pistons, and pneumatic vests have been developed [15]. A number of observational studies in the past decade raised the possibility of improved rates of ROSC and short-term survival using mechanical CPR [12,13]. A recent meta-analysis of 1166 patients from six randomized controlled trials, however, demonstrated that although mechanical CPR is associated with increased rates of ROSC, it may not lead to improved cardiac arrest survival to discharge [14]. The recent prehospital randomized assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial of mechanical CPR versus conventional CPR did not demonstrate improvement in either ROSC or longer-term survival [16▪▪]. One of the limitations of these studies has been the fact that most enrolled patients received relatively short periods of CPR (<20 min), whereas some patients may require prolonged CPR [9]. When considered in the context that CPR is associated with provider fatigue [10,11], it is unclear whether mechanical CPR devices may be of benefit for a subgroup of patients who require prolonged CPR.

Active compression–decompression resuscitation and impedance threshold device (ITD) have been proposed to improve cardiac arrest survival by lowering intrathoracic pressure and increasing cardiac output. Results of clinical studies of active compression–decompression and ITD have, however, been controversial. A recent meta-analysis incorporating 15 RCTs (16 088 patients) demonstrated no improvement in ROSC, survival or neurological outcome at hospital discharge. A meta-regression indicated that after adjustment of two important prognostic factors (witnessed status and response time) ITD appeared to improve ROSC, which could be further augmented by advanced airway use [17].

Endotracheal intubation traditionally has been the mainstay for airway management in the setting of cardiac arrest. There has been growing support for the utilization of supraglottic airway devices as first-line airways for patients with out-of-hospital cardiac arrest (OHCA), primarily to ensure fewer interruptions in chest compressions during the early stages of CPR. Analyses comparing supraglottic airway devices to other modes of airway management (e.g., endotracheal intubation, bag-valve mask) have produced conflicting results [18–20]. The ongoing airway management in cardiac arrest (AIRWAYS-2) trial is a cluster randomized trial of the clinical and cost-effectiveness of the i-gel supraglottic airway device versus endotracheal intubation in the initial airway management of OHCA.

Role of vasopressors

Epinephrine has remained the mainstay of therapy in cardiac arrest for decades [21,22]. Although epinephrine increases coronary perfusion pressure and the likelihood of ROSC during CPR [21,23], concerns have been raised regarding potential harmful effects on the microcirculation, leading to myocardial dysfunction, and cerebral hypoperfusion [22,24]. Despite the higher rates of ROSC and 1-month survival noted with epinephrine administration in observational propensity-based studies and limited clinical trials of patients with OHCA, the impact of epinephrine on long-term clinical outcomes has remained unclear [22,25–27]. A recent meta-analysis of 14 randomized controlled trials with over 12 000 patients with OHCA assessed differences in outcomes with the following: first, standard dose epinephrine (defined as 0.01 mg/kg or 1 mg) versus placebo; second, high dose epinephrine (defined as 0.2 mg/kg or 5–15 mg) versus standard-dose epinephrine; third, standard-dose epinephrine alone versus vasopressin (dose of 40 IU) and standard-dose epinephrine; and fourth, standard-dose epinephrine to vasopressin alone. No differences in survival to discharge or neurological outcomes were noted in any of the comparison groups [22]. Standard-dose epinephrine was associated with nearly three-fold higher rates of ROSC compared with placebo but a 15% lower rate of ROSC compared with high-dose epinephrine. No differences in ROSC were, however, noted between standard-dose epinephrine and vasopressin alone or in combination with epinephrine [22]. The ongoing PARAMEDIC-2 trial is examining the association of epinephrine with outcomes in patients with OHCA.

Extracorporeal membrane oxygenation

Veno-arterial extracorporeal membrane oxygenation (ECMO) provides rapid temporal circulatory assistance to patients with shock or cardiac arrest [28]. To date, there have been no randomized controlled trials investigating the impact of ECMO for adults with cardiac arrest. Most data retrieved on outcomes have been from observational studies and propensity analyses. In studies of adults with in-hospital cardiac arrest, ECMO use has been associated with a nearly two-fold to six-fold improvement in survival and/or minimal neurologic impairment to hospital discharge at 6 months and 1 year [29,30]. Others have reported a four-fold higher survival with minimal neurological impairment at 2 years in patients receiving ECMO with CPR compared with those receiving conventional CPR alone [31]. ECMO has also been suggested as a means to extend the duration of CPR for adult IHCA patients [32].

The benefits of ECMO following OHCA are less clear. Compared with IHCA, adults with OHCA undergoing ECMO have lower rates of survival and/or favorable neurological outcome at the time of discharge [33,34] and significantly lower rates (approximately seven-fold lower) of survival or favorable neurologic outcome at 6 months [35]. One small propensity-matched study of adults with witnessed OHCA noted a three-fold to four-fold higher neurologically intact survival rate in the matched ECMO with CPR group than in the matched conventional CPR group [36]. Multi-institutional data from the Extracorporeal Life Support Organization registry demonstrated 27% survival to hospital discharge in adults with OHCA in which ECMO was initiated alongside conventional CPR [37]. Complication rates following ECMO use for OHCA have been reported to be high – approximately 33–69%, mostly bleeding and ischemic events [34,38].

Early initiation of ECMO in OHCA has been associated with beneficial outcomes. Reports have also correlated delay in ECMO initiation to higher blood lactate levels in witnessed OHCA patients [39]. Patients with OHCA undergoing implementation of ECMO (and ongoing CPR) upon admission to the cardiac catheterization laboratory revealed an overall 30-day survival rate of 39% [40]. Nonsurvivors have been reported to have significantly longer (nearly two-fold) door-to-ECMO implantation wait times. Unlike nonsurvivors, ECMO treatment has been associated with improvements in left ventricular ejection fraction in survivors of OHCA [40]. Door-to-ECMO implantation time was independently predictive of 30-day mortality in adults with OHCA [40].

The combination of ECMO and intra-arrest percutaneous coronary intervention (PCI) has been associated with improved outcomes in cardiac arrest patients [41]. Rapid-response ECMO and intra-arrest PCI was associated with higher rates of 30-day survival (by three-fold), resumption of spontaneous beating, weaning from ECMO, and favorable neurological outcomes [41]. IHCA and shorter duration from collapse to initiation of ECMO were positively correlated with improved 30-day survival [41]. The recent Australian CHEER trial (mechanical CPR, hypothermia, ECMO, and early reperfusion), a single center, prospective, observational study, enrolled 26 patients with refractory IHCA and OHCA, involved mechanical CPR, rapid induction of therapeutic hypothermia, and initiation of veno-arterial ECMO [42▪]. Patients with suspected coronary artery occlusion were transferred to the cardiac catheterization laboratory for emergent coronary angiography. ROSC was achieved in 96% of patients and survival to hospital discharge with full neurological recovery occurred in 54% of patients [42▪]. Despite these promising studies, research is needed to better define the ideal cardiac arrest population for ECMO treatment.

POSTRESUSCITATION FACTORS

A significant organ injury continues during the postresuscitation period (up to 72 h after ROSC) because of reperfusion injury and ongoing ischemia [43,44]. The impact of number of postresuscitation factors and interventions against these has been studied recently.

Therapeutic hypothermia

Two randomized controlled trials published in 2002 demonstrated improved neurological outcomes following 12–24 h of therapeutic hypothermia at a range of 32–34 °C [45,46], as well as a greater than 25% mortality reduction in cardiac arrest patients with an initial rhythm of VF/VT [45]. A recent randomized controlled study comparing the effect of postresuscitation temperature management (36°C versus 33 °C) following OHCA irrespective of initial rhythm, however, demonstrated no significant difference in all-cause mortality and neurological outcomes at 6 months [47]. Another recent randomized controlled study examined the effect of early initiation of therapeutic hypothermia (during cardiac arrest in ambulances) compared with later initiation (after arrival in-hospital), and found no difference in survival or neurological outcomes [48▪▪]. These RCT's suggest that the primary beneficial effect of postresuscitation temperature management is the avoidance of postresuscitation fever. Further studies are needed to determine the optimal temperature target post-cardiac arrest. The ongoing Initiation of Cooling by Emergency Medical Services to Promote the Adoption of In-hospital Therapeutic Hypothermia in Cardiac Arrest Survivors Trial will evaluate the impact of early initiation of therapeutic hypothermia (i.e., target body temperature attained within 6 h of hospital arrival) on outcomes in patients with OHCA.

Emergent coronary angiography and percutaneous coronary intervention

In the 1990s, Spaulding et al.[49] demonstrated that more than 70% of OHCA patients have underlying coronary artery disease and 50% of these have an occluded coronary vessel. Among resuscitated patients without ST-segment elevation of electrocardiogram, 11% had an acutely occluded coronary artery [49]. It was further observed that chest pain and ST elevation on ECG were poor predictors of acute coronary occlusion in OHCA patients. Recent observational studies have examined the impact of coronary angiography on OHCA outcomes. A recent meta-analysis of 50 studies found that overall survival patients undergoing acute angiography group were 58.8% versus 30.9% in those without acute angiography (odds ratio 2.77, 95% confidence interval 2.06–3.72). Survival with good neurological outcome in the acute early angiography group was 58% versus 35.8% in the control group (odds ratio 2.20, 95% confidence interval 1.46–3.32) [50]. Further large-scale randomized control studies are needed to further evaluate the impact of early primary PCI in OHCA survival. The ongoing randomized parallel groups comparative Prague OHCA Study is randomizing patients with OHCA to a ‘hyperinvasive approach’ (i.e., utilization of mechanical chest compression device, prehospital intra-arrest cooling, extracorporeal life support, and early invasive assessment) compared with standard of care approach.

Role of oxygenation

Hyperoxia after ROSC is associated with neurological injury in animal models of cardiac arrest [51]. Data in humans have, however, been largely limited to observational studies. A recent meta-analysis of 14 human observational studies examined the effects of hyperoxia on outcomes of patients after ROSC demonstrated an association between hyperoxia and mortality [52]. This study had major limitation however, as the studies used in the analysis included varying treatment algorithms. One small human RCT has compared the effects of 30% (n = 14) versus 100% inspired oxygen concentrations (n = 14) for 1 h on patients with ROSC following witnessed OHCA with VF [53]. Using the level of neuronal injury serum marker, neuron-specific enolase as a marker for adverse neurological events, the authors demonstrated elevated serum markers in patients receiving 100% inspired oxygen. Given the small study and the fact that all patients were not treated with therapeutic hypothermia, the clinical significance of this finding is, however, unknown. Larger randomized clinical trials focusing on impact of oxygen concentration on outcomes in patients with ROSC following cardiac arrest are warranted.

Role of mean arterial pressure

Significant hemodynamic instability is often seen during the postresuscitation period as a result of myocardial stunning, oxidant damage, adrenal axis suppression, and systemic inflammation [54–65]. Alterations in systemic blood pressure following cardiac arrest may be associated with neurologic outcomes given that cerebral injury commonly occurs with impaired autoregulation of cerebral blood flow [66,67]. One prospective observational study, which analyzed postresuscitation patients from 2009 to 2012, demonstrated that mean arterial pressure (MAP) greater than 70 mmHg was associated with a four-fold higher rate of good neurologic outcome [68]. Another retrospective study examining the impact of higher MAP during postresuscitation treatment with therapeutic hypothermia, however, failed to show any correlation between higher MAP during therapeutic hypothermia and neurologically intact survival [69]. There remains a need for RCTs to further elucidate the optimal blood pressure target during the postresuscitation period.

Carbon dioxide tension following return of spontaneous circulation

Dysregulation of carbon dioxide (CO2) during the postresuscitation period is common [70]. Several studies have reported the adverse association of both hyper and hypocapnia on cerebral circulation and neurologic outcomes [70–73]. One recent systematic review of 17 studies involving different etiologies of cerebral injury examined the impact of hypo and hypercapnia [74]. Six of the 17 included studies specifically examined the impact of CO2 on postresuscitation outcomes following cardiac arrest. Although normocapnia was associated with improved neurological outcomes, hypocapnia and hypercapnia were associated with increased mortality and poor neurological outcomes [74]. As of 2010, international guidelines have recommended maintaining CO2 within the physiological range (PaCO2 40–45 mmHg) [75,76].

CONCLUSION

Despite the use of conventional CPR, rates of survival with minimal neurologic impairment remain low in adults with cardiac arrest. Factors related to patient comorbidities, quality of CPR, and postresuscitative care measures have been associated with ROSC, short-term and long-term survival, and neurological status according to mostly small randomized, nonrandomized, and observational studies. Larger RCTs assessing the impact of advanced therapies are warranted to evaluate their impact on survival and neurologic function in adults with cardiac arrest.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

cardiac arrest; outcomes; patient-specific factors

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