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A Systematic Review of the Incidence and Outcomes of In-Hospital Cardiac Arrests in Patients With Coronavirus Disease 2019*

Lim, Zheng Jie MBBS1; Ponnapa Reddy, Mallikarjuna MB BS, FCICM, DCH, DECMO, MCTR, MD, MPH2; Curtis, J. Randall PhD3,4; Afroz, Afsana PhD5,6; Billah, Baki MD5; Sheth, Vishad MD7; Hayek, Salim S. MD, MMSc8; Leaf, David E. MD9; Miles, Jeremy A. MD, MPH, FACC10; Shah, Priyank BSc(Hons), MB BS, FRACP, FCICM, MD, PhD11; Yuriditsky, Eugene MD12; Jones, Daryl MB BS, FCICM, FCCCM, PhD, MB BS, MMed, FRACP, FCICM5,13; Shekar, Kiran MB BS, FCICM, FCCCM, PhD14–16; Subramaniam, Ashwin MB BS, MMed, FRACP, FCICM17,18

Author Information
doi: 10.1097/CCM.0000000000004950

Abstract

The severe acute respiratory syndrome coronavirus 2 has spread worldwide, resulting in a global pandemic. The clinical manifestation and outcomes of patients infected with coronavirus disease 2019 (COVID-19) vary widely (1). Although most patients experience mild disease, critically ill patients often suffer from significant respiratory and cardiac complications, which can cause malignant arrhythmias and severe hypoxia, leading to cardiac arrest and eventually death (2).

Upon identification of in-hospital cardiac arrest (IHCA), cardiopulmonary resuscitation (CPR) is a key element of basic and advanced life support, with the aim of achieving a return of spontaneous circulation (ROSC) (3). Unfortunately, outcomes following ROSC are often poor, with only one in three critically ill patients with pneumonia or sepsis surviving to hospital discharge (4). Such interventions are more complex in patients with COVID-19 due to the staff requirement to don personal protective equipment and due to larger patient volumes creating resource constraints.

Recent cross-sectional studies have reported cardiac arrest as an important cause of death among patients with COVID-19 (5,6). The aim of this systematic review was to determine the incidence, characteristics, and outcomes of patients with COVID-19 experiencing IHCA with a resuscitation attempt. In addition, we sought to evaluate the differences in characteristics and outcomes between patients cared for in the ICU versus those in non-ICU locations, and whether patient age was associated with mortality after IHCA.

METHODS

The protocol for this systematic review was registered with Prospective Register of Systematic Reviews (CRD42020203371). The study was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (7). Figure 1 illustrates the consort flow diagram.

Figure 1.
Figure 1.:
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of study inclusions and exclusions. COVID = coronavirus disease, IHCA = in-hospital cardiac arrest, OHCA = out-of-hospital cardiac arrest.

Eligibility Criteria

Studies reporting on consecutive IHCA incidence, characteristics, and events among patients who tested positive for COVID-19 were included. Studies were excluded if results were reported only among deceased patients.

Search Strategy, Information Sources, and Study Selection

Two authors (Z.J.L., A.S.) independently searched the publicly available COVID-19 living systematic review (8). This living systematic review is updated daily and provides a dynamic database of research papers related to COVID-19 that are indexed by PubMed, EMBASE, MedRxiv, and BioRxiv. This approach has been validated and used in previously published COVID-19–related research (9–11). Due to the rapidly evolving pandemic, preprint studies that were yet to be peer reviewed were included to capture as much data as possible. Studies were extracted between January 1, 2020, and December 10, 2020, using the search terms, “in-hospital cardiac arrest,” “arrest,” “IHCA,” and “arrhythmia” within the title and the abstract columns of the systematic review list. These terms were combined with the Boolean operator “OR.” Preprint and non-English language articles were included. The bibliography of each study was examined to identify studies that may have been missed during the literature search.

Quality Assessment and Risk of Bias in Individual Studies

The Newcastle-Ottawa Scale (NOS) is a quality assessment tool used to evaluate nonrandomized studies based on an eight-item score divided into three domains (12). These domains assess selection, comparability, and ascertainment of the outcome of interest. The NOS was used by the two reviewers (Z.J.L., M.P.R.) to independently evaluate the quality of included studies and assess for risk of bias. The same set of decision rules was used by each reviewer to score the studies. Any discrepancies from the NOS were reviewed and resolved by a third author (A.S.).

Definitions

A cardiac arrest was defined by the absence of a pulse, measurable blood pressure, unresponsiveness, and the commencement of CPR. CPR was defined as the initiation of basic and/or advanced life support. Cardiac arrest was defined in three studies (13–15), and CPR was defined in two studies (13,15).

Data Collection and Analysis

Data analysis was conducted using Stata SE Version 16 (Statacorp, College Station, TX). Categorical variables are presented as percentages, with between-group differences compared using Fisher exact tests. A two-tailed p value of less than 0.05 was considered significant. Equality of two proportions was evaluated using Z test. The pooled prevalence and odds ratios (ORs) were calculated across studies using random-effects models of restricted maximum-likelihood method. The original OR was obtained by taking antilog of the calculated OR. In the presence of heterogeneity (as expected and observed), random-effect models have superior properties and are more conservative than fixed-effect models (16). Heterogeneity across the studies was evaluated using the Cochran Q test and quantified using I2 statistic. Heterogeneity among studies was categorized as high (I2: 76–100%), moderate (I2: 26–75%), and low (I2: 0–25%) (17). Subgroup analyses and meta-regression were not conducted to explore the possible reasons of heterogeneity due to the relatively small number of studies and patients.

Study Aims

The primary aim was to evaluate the incidence of IHCA in patients with COVID-19, characteristics, and outcomes following resuscitation attempt of these patients. Corresponding authors of selected studies were contacted for additional information relating to the primary outcome, if the data were not complete in the original publication. All studies included in this review obtained ethics approval from their individual ethics review committee. Additional information sought was already collected as part of each study’s ethics approval. Additional secondary aims included 1) an analysis of the incidence, characteristics, and outcomes of IHCA in the ICU versus non-ICU setting and 2) examining the frequency and outcomes based on age.

RESULTS

Frequency, Characteristics, and Outcomes of IHCA

A total of 696 studies were extracted from the living systematic review. Fifty full text articles were assessed for eligibility. Eight studies across two countries (United States and China) reporting on 847 patients with COVID-19 with an IHCA were included in the qualitative and quantitative analysis (13–15,18–22) (Fig. 1). Four studies provided additional data to enable further analysis (13,19,20,22). Based on the NOS, two studies were of good quality (13,15), whereas the other six were of fair quality (14,18–22) (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/G229).

Supplementary Table 2 (Supplemental Digital Content 2, http://links.lww.com/CCM/G230) summarizes the study features and the characteristics of COVID-19 patients suffering an IHCA event. Mean age for each study was derived using an estimation formula (Supplementary Table 3, Supplemental Digital Content 3, http://links.lww.com/CCM/G231) to convert median to mean values (23). This was conducted for three studies (14,20,21). The pooled mean (sd) age was 63.7 (14.1) years. The majority of the IHCA events occurred in males (65.6%; n = 556). The most common comorbidities were hypertension (60.9%; n = 431) and diabetes mellitus (45.8%; n = 388). Six studies reported the incidence of IHCA. This ranged between 8.0% and 11.4% among patients with COVID-19 admitted to ICU (13,18) and 1.5% and 5.8% among all hospitalized patients with COVID-19 (14,21,22). Shao et al (15) reported an incidence of 17.9% among patients with severe COVID-19, based on interim World Health Organization guidelines. The most common initial rhythm was pulseless electrical activity (PEA, 47.6%; n = 400), followed by asystole (36.4%; n = 306). Ventricular arrhythmias (ventricular fibrillation [VF], ventricular tachycardia [VT], and torsades de pointes) were uncommon (9.2%; n = 77). Across all studies, 282 (33.3%) patients achieved ROSC, and 777 (91.7%) died in hospital.

All patients in the study by Sheth et al (20) (n = 31), Shah et al (14) (n = 63), and Thapa et al (21) (n = 54) died in the hospital (Supplementary Table 4, Supplemental Digital Content 4, http://links.lww.com/CCM/G232). In the study by Shao et al (15) (n = 136), of the four patients who survived to day 30, only one patient had a favorable neurologic outcome. In the study by Bhatla et al (18) (n = 9), five patients were reported as alive at the time of study conclusion, with three continuing to receive inpatient care and two patients discharged. As reported by Hayek et al (13) (n = 400), of 48 patients surviving to hospital discharge, 20 (41.7%) suffered from moderate or severe neurologic impairment. In the study by Miles et al (19), among 99 patients with IHCA, only two patients (2%) were discharged from the hospital following IHCA. Finally, Yuriditsky et al (22) reported five patients (9.1%) who had a cerebral performance category of 1 or 2.

The outcomes stratified by initial arrest rhythm are outlined in Table 1. Data are reported across 581 patients from seven studies (13–15,18–20,22). The highest survival rates to hospital discharge were observed in patients with VF/VT (12/75 [16.0%]) and PEA (43/356 [12.1%]) as the initial rhythm. Among 63 patients who lived after achieving ROSC, the initial rhythm was shockable in 12 patients (19.0%) and nonshockable in 51 patients (81.0%; PEA in 43 patients and asystole in eight patients).

TABLE 1. - Initial Arrest Rhythm and Outcome as Reported Across Seven Studies (13–15,18–20,22 )
Arrest Rhythm Initial Rhythm, n = 729, n Died, n = 666 Return of Spontaneous Circulation, Alive, n = 63
Ventricular arrhythmia—ventricular tachycardia, ventricular fibrillation, torsades de pointes 75 63 (84.0, 73.7–91.4) 12 (16.0, 8.6–26.3)
Pulseless electrical activity 356 313 (87.9, 84.1–91.1) 43 (12.1, 8.9–15.9)
Asystole 298 290 (97.3, 94.8–98.8) 8 (2.7, 1.2–5.2)
Data published as n (%, 95% CI).

IHCA in the ICU Compared With Non-ICU Locations

The differences in characteristics and outcomes of patients following IHCA in ICU versus non-ICU locations are presented in Table 2. A total of seven studies were included (13–15,18–20,22), with five studies reporting both ICU and non-ICU locations (14,15,19,20,22). There were more male patients in ICU as compared to non-ICU locations (65.7% vs 47.8%; p < 0.001) and more patients with cancer (16.3% vs 4.1%; p < 0.001) or respiratory diseases (38.2% vs 8.0%; p < 0.001) in non-ICU locations. Ventricular arrhythmias (11.7% vs 3.4%; p < 0.001) and PEA (51.3% vs 27.9%; p < 0.001) were more frequent in the ICU, whereas asystole was more common in non-ICU locations (27.1% vs 68.6%; p < 0.001). ROSC was more frequent in the ICU (36.6% vs 18.7%; p < 0.001) with a lower risk of in-hospital mortality in ICU patients (88.7% vs 98.1%; p < 0.001) compared with patients in non-ICU locations.

TABLE 2. - Characteristics and Outcomes Among Coronavirus Disease 2019 Patients Following In-Hospital Cardiac Arrest in ICU (n = 7 studies) (13–15,18–20,22) Versus Non-ICU Locations (n = 5 studies) (14,15,19,20,22)
Characteristics and Outcomes IHCA Among ICU Patients IHCA Among Non-ICU Patients p
Male, n (%) 378/575 (65.7) 100/209 (47.8) < 0.001
Comorbidities
 Obesity 144/462 (31.2, 27.0–35.6) 5/10 (50.0, 18.7–81.3) 0.3
 Hypertension 332/499 (66.5, 62.2–70.7) 16/19 (84.2, 60.4–96.6) 0.14
 Diabetes mellitus 266/537 (49.5, 45.2–53.8) 53/113 (46.9, 37.5–56.5) 0.68
 Congestive heart disease 130/537 (24.2, 20.6–28.1) 22/113 (19.5, 12.6–28.0) 0.33
 Cancer 20/491 (4.1, 2.5–6.2) 17/104 (16.3, 9.8–24.9) < 0.001
 Asthma or chronic obstructive  lung disease 37/462 (8.0, 5.7–10.9) 13/34 (38.2, 22.2–56.4) < 0.001
 Chronic kidney disease 113/537 (21.0, 17.7–24.7) 33/113 (29.2, 21.0–38.5) 0.06
Initial rhythm
 Ventricular arrhythmia 68/583 (11.7, 9.2–14.6) 7/204 (3.4, 1.4–6.9) < 0.001
 Pulseless electrical activity 299/583 (51.3, 47.1–55.4) 57/204 (27.9, 21.9–34.6) < 0.001
 Asystole 158/583 (27.1, 23.5–30.9) 140/204 (68.6, 61.8–74.9) < 0.001
Return of spontaneous circulation 214/584 (36.6, 32.7–40.7) 39/209 (18.7, 13.6–24.6) < 0.001
Mortality 518/584 (88.7, 85.8–91.2) 205/209 (98.1, 95.2–99.5) < 0.001
IHCA = in-hospital cardiac arrest.
Data published as n (%, 95% CI).
Boldface values are significant p values.

OR analysis of similarities/differences in characteristics and outcomes in these patients in ICU versus non-ICU areas was conducted across five studies (Table 3) (14,15,19,20,22). The likelihood of male gender, ROSC after IHCA, etiology of arrest (cardiac or respiratory), and initial rhythm (VF/VT, asystole, or PEA) were similar in patients managed in ICU and non-ICU areas.

TABLE 3. - Odds Ratio Analysis Showing Differences Between ICU and Non-ICU Coronavirus Disease 2019 Patients Following an In-Hospital Cardiac Arrest Event Reported in Five Studies (14,15,19,20,22).
Comparison No. of Studies OR 95% CI p Heterogeneity
I 2 (%) P heterogeneity
Male 5 1.07 0.59-1.97 0.81 8.51 0.42
Cardiac etiology 3 1.14 0.34-3.86 0.84 0.00 0.91
Respiratory etiology 3 0.64 0.20-2.10 0.46 21.54 0.28
Initial rhythm ventricular fibrillation/ventricular tachycardia 5 2.11 0.52-8.67 0.30 52.81 0.07
Initial rhythm pulseless electrical activity 5 0.90 0.39-2.08 0.80 27.88 0.23
Initial rhythm asystole 5 0.90 0.28-2.94 0.87 63.34 0.05
Return of spontaneous circulation 5 2.44 0.91-6.49 0.08 64.89 0.02
Mortality 5 0.62 0.13-2.89 0.54 37.96 0.18
OR = odds ratio.
Heterogeneity among studies was categorized as high (I2: 76–100%), moderate (I2: 26–75%), and low (I2: 0–25%) (15).

Frequency of and Outcomes After IHCA Stratified by Age

Seven studies (n = 793) reported frequency of IHCA stratified by age (Fig. 2) (Supplementary Table 5, Supplemental Digital Content 5, http://links.lww.com/CCM/G233) (13–15,18–20,22). Two thirds (528/793; 66.6%) of the patients reported were greater than or equal to 60 years old (Fig. 2) (Supplementary Table 5, Supplemental Digital Content 5, http://links.lww.com/CCM/G233). These six studies also reported on the outcome following IHCA stratified by age (Supplementary Fig. 1, Supplemental Digital Content 6, http://links.lww.com/CCM/G234; and Supplementary Table 6, Supplemental Digital Content 7, http://links.lww.com/CCM/G235) (13–15,18–20,22). More patients greater than 60 years failed to achieve ROSC (70.6% vs 63.7%; p = 0.048), whereas patients less than or equal to 60 years were more likely to be alive at study conclusion following ROSC (12.1% vs 6.9%; p = 0.019).

Figure 2.
Figure 2.:
In-hospital cardiac arrest stratified by age.

DISCUSSION

To our knowledge, this is the first systematic review to report on the frequency, characteristics, and outcomes of patients with COVID-19 who have suffered an IHCA event. Among included studies, reported rates of IHCA were comparable. Nonshockable rhythms (asystole and PEA) were the most common initial rhythm at arrest, and ventricular arrhythmias were infrequent. Although ROSC was achieved a third of patients, less than one in 10 survived to hospital discharge. Patients managed in the ICU were more likely to achieve ROSC, whereas asystole and mortality were more frequent in patients managed in non-ICU locations. Most patients who survived were younger than 60 years old. This is similar to previously reported data before the COVID-19 pandemic (24). Among patients discharged, data about survival with good neurologic outcome are limited. It is difficult to make a comparison of COVID-19–related IHCA with historical epidemics or pandemics due to the sparse reported evidence: to our knowledge, there are limited data on the epidemiology of IHCA during past major outbreaks such as Middle East respiratory syndrome and severe acute respiratory syndrome.

Nonshockable rhythms were observed more frequently in patients with COVID-19 (83.9%) when compared with previously published data during nonpandemic periods which ranged from 66.0–75.9% (24,25). Possible explanations include the respiratory nature of most cardiac arrests from COVID-19 and the potential delays in IHCA detection and commencing CPR due to time taken to do appropriate protective equipment to minimize the risk of healthcare worker exposure to COVID-19 (26,27). Although the frequency of nonshockable rhythms observed in ICU patients (78.3%) in this review was comparable with pre-COVID era in ICU patients (80%) (28), the frequency was very high in non-ICU patients (96.6%) when compared with pre-COVID era (24,25,28). The overwhelming surge in critically ill COVID-19 patients and reduced staffing with increased provider-to-patient ratios during the COVID-19 pandemic may have resulted in delayed recognition of arrest (29,30).

The patients who had an IHCA event were likely to have more comorbidities than those not suffering an ICHA, but comparable with previous IHCA literature in patients without COVID-19 (31,32). A recent review of patients prior to the COVID-19 pandemic observed that IHCA occurred more in men (58%), the initial rhythm was most often nonshockable (81%), and the cause of the cardiac arrest was most often cardiac (50–60%), followed by respiratory insufficiency (15–40%) (33). Some of the demographic characteristics, such as patient sex, were comparable with the findings in this current review. However, less than 10% of patients in this review were reported to have cardiac cause for the IHCA. Although there may be an underrecognition of cardiovascular causes such as myocarditis or pulmonary thromboembolism as a result of vascular injuries and coagulation derangements or drug toxicities which may precipitate a cardiac arrest in these patients (34–37), it appears that noncardiac causes predominated. It is likely that hypoxia may have played an important role given that hypoxic respiratory failure is one of the typical presentations in COVID-19 (22).

Patients with COVID-19 and IHCA managed in ICU have similar outcomes as compared to patients suffering an IHCA event before the pandemic. A recent study analyzed the outcomes following CPR among mechanically ventilated ICU patients with pneumonia and observed a mortality rate of 87.5% (38). Furthermore, a meta-analysis on the frequency and outcomes of cardiac arrest in ICU demonstrated a mortality rate of 83% (39), similar to the 88.7% mortality rate among ICU patients with COVID-19 observed in this review. Within ICU, close monitoring of patients and early intensive care for these critically ill patients potentially improved patient outcome (40).

Our findings suggest that mortality was significantly higher among IHCA events occurring in non-ICU locations. Studies prior to the COVID-19 pandemic from China and the United States reported mortality rates of 90.9% and 80.7–89.4% following an IHCA in non-ICU settings, respectively (28,41). The outcomes in our report should be interpreted in the context of an ongoing pandemic, wherein overall quality of care and outcomes may be compromised in many jurisdictions due to resource constraints and overwhelming caseloads. Although our data are not necessarily representative of the global COVID-19 disease burden, it is essential to consider the risk-to-benefit ratio of prolonged, resource-intensive resuscitation in a resource-constraint environment (42).

Our results lead to several considerations for healthcare systems. As with critically ill patients prior to the COVID-19 pandemic, advanced care planning targeting patients unlikely to benefit from a resuscitation has the opportunity to promote patient dignity and comfort in the event of an IHCA (43–45). Our finding of higher mortality in older patients following IHCA suggests this may be a group that would benefit from advance care planning prior to hospitalization and early goals-of-care discussions during hospitalization (43). Although it is possible that in some patients, rapid progression of COVID-19–related pulmonary and cardiac pathology led to rapid deterioration and cardiac arrest, other factors such as hospitals exceeding capacity during the pandemic may also contribute to the poor outcomes observed in this review. Further studies of factors contributing to these poor outcomes and interventions required to improve outcomes following IHCA in patients with COVID-19 are needed.

This systematic review has several important limitations. First, only a small number of studies, predominantly from the early part of pandemic, fulfilled our inclusion criteria. Given the dynamic nature of management of COVID-19 and the ongoing adaptation of health services to respond to the pandemic, some of our findings may not be generalizable and sustainable. Second, although 66.6% of IHCA happened in patients older than 60 years old, we were not able to examine results by age other than comparing less than to over 60 years old due to limited data available in the eligible studies. Third, the circumstances leading to IHCA were not clear, and there were no data available on response times and only sporadic data on major comorbidities that could influence survival after an IHCA. Fourth, limitations of the NOS in terms of interrater reliability and external validation should be acknowledged (46). Finally, there were also no data on the occurrence of healthcare worker infection as a result of a resuscitation attempt, which is an important consideration in this setting.

CONCLUSIONS

Approximately one in 20 patients with COVID-19 suffered an IHCA with a resuscitation attempt. Although a third of patients achieved ROSC, overall mortality after IHCA was high. Patients managed in non-ICU locations had lower frequency of ROSC and significantly higher mortality. Although hospital mortality after IHCA in the ICU was high, this mortality was comparable to prepandemic mortality rates for patients with nonshockable rhythms. Patients over age 60 had a significantly higher mortality than those under age 60. These data may provide guidance about the likelihood of successful resuscitation in the event of IHCA for patients with COVID-19 during this pandemic period. Further research that examines both the patient and system factors that may be contributing to poor outcomes in this high-risk population is urgently needed.

ACKNOWLEDGMENTS

Dr. Shekar acknowledges research support from Metro North Hospital and Health Service. We would like to acknowledge the work of all staff in supporting the health system and their patients.

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Keywords:

coronavirus disease 2019; in-hospital cardiac arrest; severe acute respiratory syndrome coronavirus 2

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