Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
Background— The effect of prearrest left ventricular ejection fraction (LVEF) on outcome after cardiac arrest is unknown.
Methods and Results— During a 26-month period, Utstein-style data were prospectively collected on 800 consecutive inpatient adult index cardiac arrests in an observational, single-center study at a tertiary cardiac care hospital. Prearrest echocardiograms were performed on 613 patients (77%) at 11±14 days before the cardiac arrest. Outcomes among patients with normal or nearly normal prearrest LVEF (≥45%) were compared with those of patients with moderate or severe dysfunction (LVEF <45%) by χ2 and logistic regression analyses. Survival to discharge was 19% in patients with normal or nearly normal LVEF compared with 8% in those with moderate or severe dysfunction (adjusted odds ratio, 4.8; 95% confidence interval, 2.3 to 9.9; P<0.001) but did not differ with regard to sustained return of spontaneous circulation (59% versus 56%; P=0.468) or 24-hour survival (39% versus 36%; P=0.550). Postarrest echocardiograms were performed on 84 patients within 72 hours after the index cardiac arrest; the LVEF decreased 25% in those with normal or nearly normal prearrest LVEF (60±9% to 45±14%; P<0.001) and decreased 26% in those with moderate or severe dysfunction (31±7% to 23±6%, P<0.001). For all patients, prearrest β-blocker treatment was associated with higher survival to discharge (33% versus 8%; adjusted odds ratio, 3.9; 95% confidence interval, 1.8 to 8.2; P<0.001).
Conclusions— Moderate and severe prearrest left ventricular systolic dysfunction was associated with substantially lower rates of survival to hospital discharge compared with normal or nearly normal function.
Received September 13, 2007; accepted February 7, 2008.
In-hospital cardiac arrest is a major public health problem. In 2005, >20 000 in-hospital cardiac arrests were reported in the American Heart Association’s National Registry of Cardiopulmonary Resuscitation (NRCPR), representing ≈10% of the hospitals in the United States. Only 18% of these adults with in-hospital arrests survive to hospital discharge.1–4 Although patients surviving to hospital admission after an out-of-hospital cardiac arrest frequently die before hospital discharge because of neurological injury, <25% of patients with initially successful resuscitation after an in-hospital cardiac arrest die as a result of neurological injury.5
Clinical Perspective p 1872
Post–cardiac arrest myocardial dysfunction occurs commonly after successful resuscitation and is a major contributor to poor outcome.5–8 Although pre-event left ventricular ejection fraction (LVEF) is well established as a major prognostic factor in many cardiac conditions,9–14 the effect of prearrest LVEF on outcome after cardiac arrest is unknown.
The Heart Institute (InCor) is a large cardiac hospital in Sao Paulo, Brazil. Echocardiographic left ventricular function is commonly evaluated on admission, allowing a unique longitudinal evaluation of the effect of baseline prearrest left ventricular function on the outcome after in-hospital cardiac arrest. We hypothesized that patients with poor prearrest LVEF would be less likely to attain return of spontaneous circulation (ROSC) and survive to hospital discharge.
The InCor is a 420–adult bed tertiary cardiac care hospital. Most of the admitted patients are severely ill with long-standing medical or surgical heart diseases. The Institutional Committee on Human Research approved this observational study with waiver of informed consent.
A member of the research team responded to all cardiac arrests and entered data on a Portuguese translation of the NRCPR data collection form during and immediately after the resuscitation. This data form contains precisely defined variables derived from the Utstein-style guidelines.1,15 Specifically included are patient demographic, prearrest, arrest, process of care, and outcome data. The data were entered by a member of the research team during and immediately after the resuscitation, and then the patient data were tracked prospectively. Prearrest echocardiographic data and prearrest medication usage were attained by chart review.
From April 2004 to June 2006, all adult patients (≥18 years of age) with in-hospital cardiac arrests were evaluated and followed up prospectively until hospital discharge or in-hospital death. Cardiac arrest was defined as cessation of cardiac mechanical activity determined by the absence of palpable central pulse, unresponsiveness, and apnea. Patients whose resuscitation was initiated out of hospital were excluded. Among patients with >1 cardiac arrest, only the first arrest was analyzed.
The study included only patients with a documented prearrest echocardiogram performed during the in-hospital admission or within 3 months before cardiac arrest. Patients with preadmission echocardiograms were excluded if they became clinically unstable between the echocardiogram and hospital admission. Patients with myocardial infarction with or without ST elevation were excluded if their event occurred after the last echocardiogram and before the arrest.
Left Ventricular Ejection Fractions
Echocardiography was performed with commercial ultrasound scanners (Envisor-HD, SONOS 5500, or HDI 5000, Philips Medical Systems, Bothell, Washington). Linear measurements of cardiac chambers were obtained according to the recommendations of the American Society of Echocardiography.16 LVEF was calculated with the Teichholz formula or biplane method of disks (modified Simpson’s rule) for patients with wall motion abnormalities.16 According to American Society of Echocardiography guidelines, LVEF was classified as normal (≥55%), nearly normal (ie, mildly abnormal; <55% and ≥45%), moderately abnormal (<45% and ≥30%), or severely abnormal (<30%). We decided a priori to divide the patients into 2 prearrest groups: normal or nearly normal function (LVEF ≥45%) and moderate or severe dysfunction (LVEF <45%). If the endocardial border was not clearly delineated, qualitative left ventricular systolic function was estimated as normal or nearly normal function or moderate or severe dysfunction.
The prospectively selected primary outcome was survival to hospital discharge. Secondary outcome measures included ROSC >20 minutes, 24-hour survival, and survival to hospital discharge with favorable neurological outcome.
Neurological outcome was determined using cerebral performance category (CPC) scales; CPC 1 is normal, 2 is mild to moderate disability, 3 is severe disability, 4 is coma/vegetative state, and 5 is cerebral death.1,15,17,18 The neurological status before arrest and at discharge was determined by chart review. Favorable neurological outcome was defined as survival to hospital discharge with CPC 1 or 2. Septicemia during the cardiac arrest was defined as documented bloodstream infection and was grouped with other documented infections (eg, mediastinitis or urinary tract infections). Pneumonia without septicemia was a separate variable (Table 1).
Cause of postresuscitation death was determined (by M.M.G.) as described by Laver et al.5 Briefly, postresuscitation refractory shock as cause of death referred to blood pressure <90 mm Hg despite vasoactive medications. Neurological cause referred to Glasgow Coma Scale <5 in the absence of sedation, radiological evidence of hypoxic injury by computerized axial tomography or magnetic resonance, status epilepticus, or absence of brainstem function. Multiple organ failure referred to postresuscitation refractory shock or neurological cause of death plus previously described criteria for multiple organ failure.5
Continuous data are expressed as mean±SD. We report 2-sided 95% CIs and probability values. Continuous variables were compared by the use of paired or unpaired t tests. Continuous values with nongaussian distributions were compared by the Wilcoxon rank-sum or Mann-Whitney U test. Categorical variables were analyzed by χ2 analysis or Fisher’s exact test. Comparisons of groups were further assessed by multivariable logistic regression analyses. Patient and event variables associated with the relevant outcomes by univariate analysis (P<0.10) were included in the multivariable logistic regression analyses. Adjusted odds ratios (ORs) and 95% CIs were determined for variables that were associated with each outcome. In patients with quantitative LVEFs, a receiver-operating characteristic curve was performed to test the best cutoff for prediction of in-hospital survival and to address the validity of the separation between the 2 groups (normal or nearly normal function versus moderate or severe dysfunction). SPSS software (version 11.0, SPSS Inc, Chicago, Ill) was used for statistical analysis. A sample size was not planned.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Among 800 consecutive adults with in-hospital cardiac arrests, prearrest LVEF was documented by recent prearrest echocardiogram in 613 patients (77%; Figure). The echocardiograms were performed 11±14 days before the cardiac arrest. Of the 613 prearrest echocardiograms, 492 (80%) were performed during hospital admission and 121 (20%) within 3 months before the admission. Furthermore, 582 (95%) provided quantitative LVEFs, and 31 (5%) were limited to qualitative LVEFs. Prearrest LVEF was normal in 186 patients (30%), nearly normal in 49 (8%), moderately abnormal in 141 (23%), and severely abnormal in 237 (39%). Therefore, prearrest LVEF was categorized as normal or nearly normal for 235 patients (38%) and moderate or severe dysfunction in 378 (62%; Figure).
The area under the receiver-operating characteristic curve of LVEF in relation to the primary outcome was 0.61 (95% CI, 0.54 to 0.68; P=0.003). The best cutoff point associated with survival to discharge was LVEF ≥45.5%.
Patient, prearrest, and arrest characteristics are described in Tables 1 and 2⇓. Patients with moderate or severe prearrest left ventricular dysfunction were more likely to be male and to have medical or cardiac illnesses, including diabetes mellitus, chronic coronary artery disease, acute coronary syndrome, previous coronary intervention, dilated cardiomyopathy, and Chagas’ disease. In contrast, arrest characteristics and process of care were similar in the 2 groups. The most common cause of the arrest was hypotension in nearly one third of both groups. Furthermore, the first documented arrest rhythm was ventricular fibrillation or ventricular tachycardia in about one fourth of the arrests in both groups.
Of patients with normal or nearly normal LVEF (≥45%), 19% survived to hospital discharge compared with 8% of patients with moderately or severely abnormal LVEF (adjusted OR, 4.8; 95% CI, 2.3 to 9.9; P<0.001; Table 3). However, the 2 groups did not differ in regard to ROSC >20 minutes (59% versus 56%; P=0.468) or 24-hour survival (39% versus 36%; P=0.550). When all 4 LVEF subgroups were considered separately, survival to hospital discharge occurred in 32 of 186 patients (17%) with normal function, 12 of 49 (24%) with nearly normal function, 13 of 141 (9%) with moderate dysfunction, and 19 of 237 (8%) with severe dysfunction (P<0.001).
Notably, 41 of 44 survivors (93%) in the normal or nearly normal LVEF group had favorable neurological outcomes: 27 of 44 (61%) with CPC 1 and 14 of 44 (32%) with CPC 2. Similarly, 29 of 32 survivors (91%) in the moderately or severely abnormal LVEF group had favorable neurological outcomes (17 of 32 [53%] with CPC 1 and 12 of 32 [38%] with CPC 2). Hence, prearrest left ventricular function did not affect the CPC of survivors. Only 3 patients in each group were discharged with poor neurological outcome (CPC 3), and none were in a coma/vegetative state.
The mean prearrest LVEFs in relevant groups of patients are shown in Table 4 for the 582 patients with documented prearrest quantitative echocardiograms. Among all 84 patients who had quantitative postarrest echocardiograms within 72 hours, LVEF decreased 26% (43±17% before arrest to 32±15% after arrest; P<0.001). These postarrest echocardiograms were performed on 35 of 66 patients (53%) with normal or nearly normal prearrest function who survived 72 hours after arrest and 49 of 81 patients (61%) with moderate or severe prearrest dysfunction who survived 72 hours after arrest. The LVEF decreased by 25% in the 35 patients with normal or nearly normal prearrest function (60±9% before arrest to 45±14% after arrest; P<0.001) and decreased by 26% in the 49 patients with moderate or severe prearrest ventricular dysfunction (31±7% to 23±6%; P<0.001).
In addition to prearrest LVEF, other factors associated with higher rates of survival to discharge included use of β-blockers within 24 hours before arrest, initial rhythm of ventricular fibrillation or ventricular tachycardia, and age <65 years (Table 3). Factors associated with lower survival to discharge rates included preexisting renal failure, septicemia/other infections, administration of >3 doses of epinephrine during the arrest, atropine during the arrest, and need for mechanical ventilation before arrest. Of these 9 factors associated with survival to discharge, only administration of >3 doses of epinephrine and atropine and prearrest need for mechanical ventilation also were associated with rates of ROSC >20 minutes and 24-hour survival (Table 3 and the online Data Supplement).
Prearrest LVEF did not differ between patients who did and did not receive β-blockers within 24-hours before arrest (41±18% and 41±19%, respectively; P=0.960; Table 4). For the 84 survivors who had postarrest echocardiograms, LVEF changed from 38±15% before arrest to 29±13% after arrest (P<0.001) among those with β-blocker use (n=22) and from 45±17% to 33±16% (P<0.001) among those without β-blocker use (n=62). The relative decrease in LVEF in these 2 groups did not differ (24% versus 27%; P=0.359).
The cause of in-hospital deaths among the 274 of 350 study patients with initial ROSC >20 minutes and subsequent hospital death was postresuscitation refractory shock in 93 of 274 (34%), neurological failure in 7 of 274 (3%), multiple organ failure with neurological failure in 31 of 274 (11%), multiple organ failure without neurological failure in 138 of 274 (50%), and other causes in 5 of 274 (2%; Table 5). Only 14% of these patients died of neurological failure with or without multiple organ failure. The group with moderate or severe dysfunction before arrest was more likely to die of postresuscitation refractory shock (39% versus 25%; P=0.038) than the group with normal or nearly normal prearrest LVEF.
These data demonstrate that patients with a prearrest LVEF <45% (ie, moderate or severe dysfunction) were substantially less likely to survive to hospital discharge than patients with prearrest LVEF ≥45%. Surprisingly, the 2 groups had similar rates of initially successful resuscitation (ie, ROSC >20 minutes and 24-hour survival). Among patients who had postarrest echocardiograms within 72 hours, LVEF decreased 25% (60±9% before arrest to 45±14% after arrest) in those with normal or nearly normal prearrest LVEF and a similar 26% (31±7% to 23±6%) in those with moderate or severe prearrest dysfunction. The resultant severe postarrest ventricular dysfunction in the latter group presumably contributed to the lower rate of survival to discharge in that group. Importantly, 84% of the hospital deaths after initially successful resuscitations were due to postresuscitation refractory shock with or without multiple organ failure.
Poor pre-event left ventricular systolic function is associated with worse outcomes from other heart diseases.9–14 Therefore, we hypothesized that poor prearrest LVEF would preclude successful resuscitation in many patients and would worsen postarrest left ventricular dysfunction in others, thereby resulting in lower ROSC rates and lower 24-hour survival rates. Nevertheless, the 2 groups did not differ in regard to ROSC >20 minutes (59% versus 56%; P=0.468) or 24-hour survival (39% versus 36%; P=0.550). Apparently, the poor postresuscitation myocardial performance in the group with worse prearrest and worse postarrest ventricular function often is adequate to initially maintain spontaneous circulation and short-term survival but generally inadequate to maintain myocardial and systemic blood flow sufficient to attain long-term survival. Importantly, 19% of patients with normal or nearly normal LVEF survived to hospital discharge compared with 8% of patients with moderately or severely abnormal systolic function (adjusted OR, 4.8; 95% CI, 2.3 to 9.9; P<0.001). Moreover, nearly all of the survivors in both groups had favorable neurological outcomes, and most of the patients in both groups were described as apparently neurologically normal. In contrast to out-of-hospital cardiac arrests, neurological injury was a relatively uncommon cause of death after these in-hospital cardiac arrests.
Most patients with initially successful resuscitations from cardiac arrests do not survive to hospital discharge. For example, among 36 902 in-hospital adult index cardiac arrests from the NRCPR, 47% attained ROSC, 30% were alive at 24 hours, and 18% survived to hospital discharge.1 Experimental and clinical data have established that postarrest left ventricular dysfunction is common and is a major contributor to postresuscitation mortality.5–8,19,20 It therefore should not be surprising that moderate and severe prearrest left ventricular dysfunction can lead to worse postarrest LVEF and ultimately worse survival rates. In the present study, among 350 survivors with initial ROSC >20 minutes, 147 patients were alive 72 hours after resuscitation, and postarrest quantitative echocardiograms were performed in 84 of them (57%). Although postarrest LVEF decreased in both prearrest LVEF groups, the group with moderate or severe prearrest left ventricular dysfunction had substantially lower postarrest LVEF (23±6% versus 45±14%; P<0.001). Not surprisingly, patients with these very low LVEFs more commonly died because of postresuscitation refractory shock.
Patients who received β-blockers within 24 hours before arrest were substantially more likely to survive to hospital discharge compared with patients who did not receive β-blockers (33% versus 8%; adjusted OR, 3.9; 95% CI, 1.8 to 8.2; P<0.001). Experimental investigations have established that β-blockade can improve myocardial bioenergetics during and after cardiopulmonary resuscitation21 and that postresuscitation myocardial dysfunction is a myocardial stunning phenomenon.6,22 Perhaps decreasing myocardial (and systemic) metabolic needs during and after cardiopulmonary resuscitation can improve myocardial (and systemic) bioenergetics in this setting of postresuscitation myocardial stunning.
A hyperadrenergic state characterized by hypertension, tachycardia, and ventricular ectopy can occur within minutes of successful resuscitation, especially when high doses of epinephrine are administered during the resuscitative efforts.23–27 This postresuscitation tachycardia and increased afterload can adversely affect hemodynamic status and myocardial bioenergetics. Furthermore, clinical studies have shown that neurological outcomes are worse among survivors who received more epinephrine during their resuscitation.28 In our cohort, administration of >3 doses of epinephrine was strongly associated with poor outcome. Although administration of more epinephrine may have simply been a marker of a prolonged or failed resuscitation, these findings raise the possibility that the β-adrenergic effects were harmful. Pretreatment with β-blockers may attenuate this potentially dangerous hyperadrenergic state. These findings also suggest that β-blockade may deserve consideration as a therapeutic intervention during advanced life support for cardiac arrests in humans.
The present has several potential limitations, including potential sampling biases, data integrity, and the choice of dichotomous LVEF grouping. Approaches to minimize sampling biases included strict inclusion and exclusion criteria, a large sample size, and comprehensive and redundant methods to ascertain all cases. We cannot exclude sampling biases in regard to which patients had echocardiograms within 72 hours after arrest because only 24% with ROSC >20 minutes had postarrest echocardiograms (based on the practitioner’s discretion). Nevertheless, postarrest LVEFs were attained from a similar proportion of 72-hour survivors from each group (53% and 60%), and the percentage decrease in LVEF from before to after arrest was similar in both groups (25% and 26%). Attempts to optimize data integrity included uniform data collection, consistent Utstein-style definitions, and a small, well-trained research staff blinded to the prearrest LVEF during the initial documentation of the arrest data. The dichotomous grouping of normal and nearly normal LVEF or moderate and severe dysfunction was chosen a priori and supported by receiver-operating characteristic curve analysis.
An important limitation is the difficulty in delineating whether the association between prearrest LVEF and outcome is causal or the result of other confounding variables. Although multivariable logistic regression analysis accounted for these potentially confounding factors, observational studies cannot fully address causality. Nevertheless, most of the nonsurvivors after attainment of a spontaneous circulation died as a result of refractory shock with or without multiple organ failure. Presumably, poor prearrest LVEF contributed to the worse postarrest LVEF and the higher rate of death from refractory shock.
These results confirm our hypothesis that patients with poor prearrest left ventricular systolic function are less likely to survive to hospital discharge than patients with normal or nearly normal prearrest function. The severe postarrest myocardial dysfunction in the patients with worse prearrest dysfunction was associated with and may have contributed to the worse outcomes.
Enriquez-Sarano M, Tajik AJ, Schaff HV, Orszulak TA, Bailey KR, Frye RL. Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation. 1994; 90: 830–837.
Sun JP, James KB, Yang XS, Solankhi N, Shah MS, Arheart KL, Thomas JD, Stewart WJ. Comparison of mortality rates and progression of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy and dilated versus nondilated right ventricular cavities. Am J Cardiol. 1997; 80: 1583–1587.
Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. 2007; 115: 1101–1108.
Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D’Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zideman D. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, Inter American Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004; 110: 3385–3397.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 1440–1463.
Kern KB, Hilwig RW, Berg RA, Rhee KH, Sanders AB, Otto CW, Ewy GA. Postresuscitation left ventricular systolic and diastolic dysfunction: treatment with dobutamine. Circulation. 1997; 95: 2610–2613.
Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation. 1995; 92: 3089–3093.
In-hospital cardiac arrest is a major public health problem. In 2005, >20 000 in-hospital cardiac arrests were reported in the American Heart Association’s National Registry of Cardiopulmonary Resuscitation, representing ≈10% of the hospitals in the United States. Only 18% of these adults with in-hospital arrests survived to hospital discharge. Importantly, postarrest myocardial dysfunction occurs commonly after successful resuscitation and is a major contributor to poor outcome. Although pre-event left ventricular ejection fraction (LVEF) is well established as a major prognostic factor in many cardiac conditions, the effect of prearrest LVEF on outcome after cardiac arrest has not been previously evaluated. In the present study of 613 in-hospital cardiac arrest patients with recent prearrest echocardiograms from the Heart Institute in Sao Paulo, the patients with a prearrest LVEF <45% (ie, moderate or severe dysfunction) were substantially less likely to survive to hospital discharge than patients with prearrest LVEF ≥45% (8% versus 19% survival rate). Among patients who had postarrest echocardiograms within 72 hours, LVEF decreased by 25% in both groups. Therefore, the mean postarrest LVEF was 23% in the patients with prearrest LVEF <45%. This resultant severe postarrest left ventricular dysfunction among patients with prearrest LVEF <45% presumably contributed to the lower rate of survival to discharge in that group. Importantly, 84% of the hospital deaths after initially successful resuscitations were due to postresuscitation refractory shock with or without multiple organ failure. Prearrest LVEF appears to be an important contributor to outcome after in-hospital cardiac arrest.
The online Data Supplement, which contains a table, can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.740167/DC1.