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Over 25 reports have found outpatient frequency of sudden cardiac death peaks between 6 am and noon; few studies, with inconsistent results, have examined circadian variation of death in hospitalized patients. This study assesses circadian variation in cardiopulmonary arrest of in-hospital patients across patient, hospital, and event variables and its effect on survival to discharge.
Methods
A retrospective, single institution registry included all admissions to the Medical Center of Central Georgia in which resuscitation was attempted between January 1987 and December 2000. The registry included 4692 admissions; only the first attempt was reported. Analyses of 1-, 2-, 4-, and 8-hour intervals were performed; 1- and 4-hour intervals are presented.
Results
Significant circadian variation was found at 1 hour (P=.01), but not at 4-hour intervals. Significant circadian variation was found for initial rhythms that were perfusing (P=.03) and asystole (P=.01). A significantly higher percentage of unwitnessed events were found as asystole during the overnight hours (P=.002). Using simple logistic regression, time in 4-hour intervals and rhythm were each significantly related to patient survival until hospital discharge (P=.003 and P <.0001). In multivariate analysis, only rhythm remained significant.
Conclusions
Circadian variation of cardiopulmonary arrest in this hospital has several temporal versions and is related to survival. Late night variation in witnessed events and rhythm suggests a delay between onset of clinical death and discovery, which contributes to poorer outcomes.
refinement of resuscitative technique and efforts to explain factors influencing cardiopulmonary arrest have been at the forefront of the medical literature. One area that has received attention is the circadian variation of acute illness and sudden death. Multiple clinical and epidemiological studies have focused on circadian variation in acute coronary syndrome,
Circadian variation of cardiopulmonary arrest does exist.
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Common variations seen in population and prehospital studies are not found.
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Late night arrests are less likely to be witnessed and are more frequently fatal.
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No differences were found between patients with heart disease and other illnesses.
In an attempt to create uniformity within a vast and increasing body of data on cardiopulmonary arrest, a stratification of convenience and practicality has emerged that subdivides resuscitative efforts into 2 main locations: events in a prehospital setting and events confined to emergency departments, hospital wards, and intensive care units. This organization allows for more uniform comparison of data collected in each venue, as factors influencing both events and outcome vary substantially based on location, expertise of responders, and availability of monitors/defibrillators and medications. Protocols for standardized reporting in each venue have been established.
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
and revealed a primary peak between 10 and 11 am and a second peak between 5 and 6 pm. Subsequently, over 25 reports on various aspects of circadian variation in out-of-hospital cardiopulmonary arrest have been published. Seven reports, with a cumulative total of more than 78,000 patients, demonstrated a peak of sudden cardiac death between 6 am and noon.
Belgian Cardiopulmonary Cerebral Resuscitation Study Group Further prospective evidence of a circadian variation in the frequency of call for sudden cardiac death.
Literature dedicated to inpatient circadian variation of cardiopulmonary arrest is limited and consistently nonuniform in overall findings. Only 7 single-institution, inpatient studies exist, with a cumulative total of only 1140 patients.
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
Variations in findings may result from small sample sizes, variable time periods, and a wide variability in populations; inpatient studies are clearly under-represented.
This is one of a series of reports from an ongoing study of in-hospital resuscitation designed to include an extensive range of variables for analysis over time. As suggested by the Utstein style,
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
hospital, patient demographics, arrest, and outcome variables have been incorporated into the database. The current report extends the previously reported data set
to encompass a 14-year time span. The objective of this study was to demonstrate the presence or absence of circadian variation in frequency of cardiopulmonary arrest in a hospital setting, across sex, age, diagnosis, witness of event, monitoring of an event, year of study, and rhythm. A second objective was to delineate any influence of circadian variation of cardiopulmonary arrest on survival to discharge.
Materials and methods
Data Collection
A more detailed description of methods has been reported.
This longitudinal registry (retrospective cohort) includes all resuscitation attempts, excluding those occurring in operating rooms and the neonatal intensive care unit, at the Medical Center of Central Georgia (MCCG), from January 1, 1987 through December 31, 2000. This study was reviewed and approved by the Institutional Review Boards of MCCG and Mercer University School of Medicine (MUSM). Events are identified through review of standardized resuscitation records (code sheets), hospital financial and diagnostic records, quality appraisal review, and hospital death records. Information from each code sheet is entered into a database and cross-referenced. Detailed chart review is completed for all questionable events. All registry entries are thoroughly reviewed.
Hospital Variables
MCCG is a 634-bed tertiary care center located in Macon, Ga; it is the major teaching affiliate of MUSM. Resuscitation attempts are conducted by multidisciplinary teams trained in advanced cardiac life support (ACLS) and include residents, attending physicians, nurses, respiratory therapists, pharmacists, and ancillary staff. Code teams are notified by intercom and personal pagers.
Patient Variables
Approximately 53% (n=2439) of patients were male, and 47% (n=2202) were female. Patients ranged in age from 0 to 103 years (mean age of 63 years); ∼3% (n=133) were <20 years old, 31% (n=1437) were between the ages of 20 and 59 years, and the remaining 66% (n=3068) were aged >59 years; age was not available for 3 events.
Arrest Variables
A resuscitation attempt was defined, following Bedell
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
To consider an event a resuscitative effort, sudden changes in level of consciousness, respirations, or rhythm incompatible with spontaneous recovery were required. Initial rhythm for monitored patients was defined as rhythm displayed on the monitor when the code was called; initial rhythm for unmonitored patients was defined as the first identifiable rhythm after connecting a monitor. Events were considered witnessed if a change in rhythm was discovered on telemetry or a patient decompensated in the presence of a staff member or visitor. Rhythms are categorized into 6 groups, including supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, perfusing, pulseless electrical activity, and asystole, as previously cited.
Analysis of circadian variation is reported in simple frequencies. The sole outcome variable is survival to discharge. To ensure accuracy, outcomes on code sheets, hospital discharge status, and death logs were cross-validated.
Statistical Analysis
Statistical analyses were conducted via SAS/STAT version 9.1.
The frequencies of cardiopulmonary arrest were computed for the study population by 1-, 2-, 4-, and 8-hour intervals. We utilized χ2 tests for goodness-of-fit to detect differences in the frequency of arrest within these time intervals.
Focused analyses on 4-hour intervals were based on previous findings,
avoiding small cell sizes, and stability of analyses. Data were combined into 6 4-hour intervals with time beginning at 7 am to capture change of shifts in our institution. Simple categorical predictor variables were converted to contrast codes; eg, for sex, male and female were respectively coded 1 and −1. Comparisons were assessed using simple effects by χ2 analysis. Variables included in focused analysis are shown in Table 1.
Table 1χ2 Analyses of Event Frequency versus Other Variables
Frequencies of witnessed and unwitnessed events across rhythms were compared by χ2. Because unwitnessed supraventricular tachycardia and ventricular tachycardia were rare, these were excluded from this analysis.
Simple logistic regressions with survival to discharge as the outcome variable were completed for the following predictor variables: time in 1-hour and 4-hour intervals, and initial rhythm. Multiple logistic regression analyses were used to assess association between time and rhythm with survival as the outcome. Survival to discharge was treated as a dichotomous measure in all analyses.
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
(Figure 1). From January 1, 1987 through December 31, 2000, there were 354,763 total admissions and 4692 admissions in which resuscitation was attempted. Fifty-one calls were determined to be nonarrests, yielding a total study group of 4641. There were 1435 patients discharged alive (31%). Supraventricular tachycardia accounted for 2% of events (n=80), ventricular tachycardia 3% (n=143), ventricular fibrillation 14% (n=641), perfusing 31% (n=1422), pulseless electrical activity 35% (n=1634), and asystole 15% (n=714).
χ2 goodness-of-fit concerning frequency of events in 1-hour time periods was significant (χ2 [23]=41.2, P=.01) (Figure 2). The goodness-of-fit test for 4-hour time periods was not significant (χ2 [5]=7.2, P=.20), but the obvious variation exhibited in Figure 3 and previous reports of 4-hour periodicity
χ2 tests did not detect any significant relationships between 4-hour periodicity and the following variables: sex, age group, year of study, and monitored versus unmonitored. There was also no statistically significant relationship between frequency in 4-hour time intervals and cardiac diseases versus other diagnoses (Figure 4). The only significant relationship between 4-hour periodicity and patient variables was with initial rhythm (χ2 [25]=45.2, P=.008), which is displayed in Table 2. Further analysis of initial rhythms indicated that only perfusing rhythms (χ2 [5]=12.4, P=.03) and asystole (χ2 [5]=14.6, P=.01) exhibited circadian variation with the 4-hour periods (Figure 5, Figure 6, respectively).
Figure 4Cardiac disease event frequency versus other diagnoses. χ2=3.4; P <.75 for other diagnoses; χ2=8.9; .10<P <.25 for all cardiac disease.
Despite the fact that most events (84.6%) were witnessed, this institutional variable exhibited circadian variation within the 4-hour time periods (χ2 [5]=22.9, P=.0004) (Table 3). The greatest percentage of unwitnessed events occurs during 3:00-6:59 am (19.5%). The 4-hour periodicity of unwitnessed events was strongly related to initial rhythm (χ2 [15]=35.9, P=.002). As evidenced in Table 4, a significantly greater percentage of unwitnessed events were found as asystole during the time periods of 11:00 pm-2:59 am and 3:00-6:59 am. As depicted in Figure 7, there were more unwitnessed than witnessed events among those whose initial rhythm was asystole during the overnight hours (χ2 [5]=18.8, P=.002). There was also a significantly lower percentage of events in which the initial rhythm was ventricular fibrillation during the same 11:00 pm-2:59 am and 3:00-6:59 am time periods (χ2 [5]=11.1, P=.05).
Table 3Frequency of Events by Witnessed versus Unwitnessed Arrest
Using simple logistic regression, we identified a significant relationship between time in 1-hour intervals and survival to discharge (χ2 [1]=8.2, P=.004), as well as between time in 4-hour intervals and survival to discharge (χ2 [1]=8.6, P=.003). As depicted in Figure 8, there is clearly decreased survival in the overnight hours. Initial rhythm was significantly, and much more strongly, related to patient survival until hospital discharge (χ2 [1]=680.1, P <.0001). When both rhythm and 4-hour periodicity were entered simultaneously into logistic regression on survival, initial rhythm was the only significant predictor (χ2 [1]=669.9, P <.0001); 4-hour periodicity became nonsignificant (χ2 [1]=2.4, P=.12).
Figure 8Frequency of events by survival to discharge. χ2=9.0; P=.11.
Our results demonstrate circadian variation of cardiopulmonary arrest in a hospital setting. Nonuniform distribution of resuscitation attempts was clearly obtained for 1-hour periods, but not so clearly for 4-hour periods. The 4-hour period is most prevalent in previous in-hospital literature.
Although minor peaks and troughs were lost when focusing on 4-hour time intervals, the relationships between 4-hour periodicity and witnessed/unwitnessed, initial rhythm, and survival lead us to conclude this is the more useful time period for understanding circadian rhythm in an in-hospital population.
In contrast to numerous studies that have shown a morning peak of cardiopulmonary arrest,
Belgian Cardiopulmonary Cerebral Resuscitation Study Group Further prospective evidence of a circadian variation in the frequency of call for sudden cardiac death.
we obtained a broader distribution without a clear peak (Figure 2). Previous findings are consistent with physiology studies revealing circadian variation of factors influencing ischemic events such as cortisol secretion,
However, interventional studies with anti-ischemic medications, including beta-blockers and low-dose aspirin, have shown modification or abolition of the circadian distribution of cardiac arrhythmias, sudden cardiac death, and fatal myocardial infarction.
Population studies, multi-center reports, and meta-analyses of the circadian variation of cardiopulmonary arrest also have been completed. Mortality data from Framingham revealed a significant circadian variation of sudden cardiac death, with a peak incidence from 7 to 9 am and a decreased incidence from 9 am to 1 pm.
Analysis of the Multicenter Investigation of Limitation of Infarct Size database revealed a statistically greater incidence of myocardial infarction from 6 am to noon.
A meta-analysis of acute myocardial infarction and sudden cardiac death, which included 30 studies and 66,635 patients, revealed a significant peak of acute myocardial infarction between 6 am and noon.
The greatest advantage of meta-analyses is large sample sizes; however, each uses data collected in both inpatient and outpatient arenas. Disadvantages include lack of uniformity in definitions, reporting, statistical analysis, and population demographics across individual studies.
Resuscitation is a valid model to study sudden death; however, many studies that demonstrated diurnal variation restricted patients to sudden cardiac death or acute ischemia. We identified the events occurring among patients with cardiac disease and those with acute coronary syndromes. We found no significant diurnal variation among these groups. Comparison with subjects with other illnesses showed no differences.
There is significant circadian variation by rhythm. Subdivision into individual rhythms reveals significant circadian variation for only perfusing rhythms and asystole (Table 2). Asystole increases from a nadir of 12.4% during the 11:00 am-2:59 pm and 3:00-6:59 pm periods, to a peak of 20.1% from 3:00-6:59 am. Perfusing rhythms vary from a maximum of 33.4% during the 7:00-10:59 am period to a minimum of 28.1% during the 7:00-10:59 pm period. Perfusing rhythms represent an earlier stage of arrest. As discussed below, there are more witnessed arrests during the hours of 7:00-10:59 am, and as a result, patients are more likely to be found in earlier stages of arrest. Although circadian variation of ventricular fibrillation was not statistically significant, there was clearly a trend in its occurrence. The highest percentage of events (16.2%) recognized as ventricular fibrillation were during 7:00-10:59 pm and the lowest, only 11.7%, occurring during 3:00-6:59 am. The overall incidence of ventricular fibrillation in the hospital is low. Pulseless electrical activity, supraventricular tachycardia, and ventricular tachycardia were fairly uniformly distributed.
Previous research has emphasized the prognostic value of witnessed or unwitnessed events.
The majority of all events (∼85%) at our institution are witnessed, but there is a statistically significant difference in the likelihood of witnessed events as a function of time. From 7:00 am-10:59 pm, approximately 86% of all events are witnessed; this falls to 81% from 11:00 pm-2:59 am. When unwitnessed events are further stratified into rhythm categories, the rhythm distribution is significantly different from expected. As represented in Table 4, the occurrence of asystole during the overnight time period is significantly higher than expected, whereas the percentage of events recorded as ventricular fibrillation is significantly lower.
Perhaps of greatest interest is that circadian variation exists for survival to discharge, with significantly lower survival from 7:00 pm-6:59 am (Figure 8). Initial rhythm was a significant predictor of survival, consistent with previous reports.
Multiple logistic regression modeling demonstrated that the difference in survival was explained by circadian changes in initial rhythm. Coupled with the variation in witnessed events, it appears that the circadian variation of survival may reflect a higher proportion of patients discovered later in the dying process during the overnight hours, when fewer staff members are available for early detection.
Limitations of this study include the fact that this was an exploratory analysis, and data were assessed in a variety of ways to determine significant relationships. Variables were added to preliminary analyses to better understand initial findings. Multiple analyses may have contributed to positive findings. Variations in time intervals and methods of analysis occasionally led to differing results in statistical significance. Although the chosen time periods were clinically reasonable, further replication of the relevance of 4-hour periodicity to in-hospital resuscitation is needed. Perhaps more importantly, we were unable to obtain hourly census information, so we cannot determine whether the increased frequency of events resulted from a higher number of patients in the hospital during those time periods. Additionally, this study was completed within a single institution that is a referral center. Our facility receives many acute coronary syndromes from outlying facilities and completes a large number of open-heart surgeries. Medication effects were not assessable in this data set. This may limit generalizability of these findings to smaller institutions. Finally, this study follows the Utstein guidelines
American Heart Association Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the in-hospital “Utstein style”.
for reporting in-hospital resuscitation, which means that findings reported herein should consistently lend themselves to further study. However, because all previous in-hospital studies predated the standardized reporting recommendations, comparison warrants extreme caution.
We have found that circadian variation in hospital is strongly related to initial rhythm, which is different from previously reported population and outpatient studies. We obtained no circadian variation of cardiopulmonary arrest specific to patients with primary cardiac disease. The explanation for this is uncertain and merits further investigation. Clearly, as a referral center, with fluctuations in time of admissions and modification of acute coronary syndrome with medications, as well as interventions, differences should be expected. Finally, late night variation in witnessed events and initial rhythm suggest delay between onset of clinical death and discovery, which certainly contributes to negative outcome.
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