Baseline characteristics and outcomes of end-stage renal disease patients after in-hospital sudden cardiac arrest: a national perspective

End-stage renal disease (ESRD) is a well-recognized risk factor for the development of sudden cardiac arrest (SCA). There is limited data on baseline characteristics and outcomes after an in-hospital SCA event in ESRD patients. For the purpose of this study, data were obtained from the National Inpatient Sample from January 2007 to December 2017. In-hospital SCA was identified using the International Classification of Disease, 9th Revision, Clinical Modification and International Classification of Disease, 10th Revision, Clinical Modification codes of 99.60, 99.63, and 5A12012. ESRD patients were subsequently identified using codes of 585.6 and N18.6. Baseline characteristics and outcomes were compared among ESRD and non-ESRD patients in crude and propensity score (PS)–matched cohorts. Predictors of mortality in ESRD patients after an in-hospital SCA event were analyzed using a multivariate logistic regression model. A total of 1,412,985 patients sustained in-hospital SCA during our study period. ESRD patients with in-hospital SCA were younger and had a higher burden of key co-morbidities. Mortality was similar in ESRD and non-ESRD patients in PS-matched cohort (70.4% vs. 70.7%, p = 0.45) with an overall downward trend over our study years. Advanced age, Black race, and key co-morbidities independently predicted increased mortality while prior implantable defibrillator was associated with decreased mortality in ESRD patients after an in-hospital SCA event. In the context of in-hospital SCA, mortality is similar in ESRD and non-ESRD patients in adjusted analysis. Adequate risk factor modification could further mitigate the risk of in-hospital SCA among ESRD patients.


Introduction
Sudden cardiac arrest (SCA) is a prevalent entity in patients with end-stage renal disease (ESRD) contributing to nearly one-quarter of deaths in this patient population [1]. The mortality rate after a SCA event exceeds 52% in ESRD patients [2]. ESRD patients are at risk of the development of SCA since majority of these patients have left ventricular hypertrophy (LVH) which provides an underlying substrate for SCA perpetuation in settings of rapid fluid and electrolyte fluctuations during dialysis sessions [3][4][5][6]. ESRD patients also require frequent hospitalizations due to associated co-morbid conditions [7]. Recent evidence points to improved outcomes in patients with in-hospital SCA over the past two decades [8]. Limited data, however, exist in the context of ESRD patients after in-hospital SCA, and whether these improved outcomes have also been witnessed in this patient population is currently unknown. In this paper, we aimed to study baseline characteristics, trends, and outcomes of ESRD patients after they sustained in-hospital SCA from a nationally representative contemporary cohort of US population.

Methods
Data from the National Inpatient Sample (NIS) were used for this study. NIS database has been made possible through sponsorship of the federal Agency for Healthcare Research and Quality (AHRQ). The main purpose of AHRQ is to enhance the quality, appropriateness, and effectiveness of health care services [9]. NIS is a publicly available all-payer administrative claims-based database. National estimates of the entire US hospitalized population were calculated using the Agency for Healthcare Research and Quality sampling and weighting method. Institutional review board approval was not required for this study, given the de-identified nature of the NIS and its public availability.
We analyzed the NIS data from January 2007 to December 2017 using the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) and International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM) codes. Patients who sustained in-hospital SCA were identified by applying ICD-9-CM and ICD-10-CM codes of 99.60, 99.63, and 5A12012, respectively, to any procedure field. These codes indicate utilization of cardiopulmonary resuscitation (CPR) and well representative of in-hospital SCA from administrative datasets as shown by the earlier studies [10][11][12]. ESRD patients were then subsequently identified using ICD-9-CM and ICD-10-CM codes of 585.6 and N18.6, respectively. Patients were excluded if they were less than 18 years of age or had acute kidney injury (AKI) and prior history of renal transplantation. Baseline characteristics and outcomes were compared in ESRD patients who sustained in-hospital SCA to non-ESRD patients with in-hospital SCA. Propensity score matching was also done to balance confounding variables, and outcomes were again assessed in both groups. Trends in in-patient mortality and length of stay (LOS) were also assessed. Predictors of in-patient mortality in ESRD patients after a SCA event were also analyzed.
Age, race, median income, urban/rural hospital, US region, and Elixhauser co-morbidities were selected for analysis. Descriptive statistics were presented as frequencies with percentages for categorical variables and as means with standard deviations or median with interquartile range as appropriate for continuous variables. Baseline characteristics were compared using Pearson's chi-squared test for categorical variables and independent samples t test or non-parametric tests for continuous variables as appropriate. Median LOS, median cost of stay, and mortality were calculated. The median cost of stay was adjusted for inflation (in comparison to December 2017). Simple linear regression or chi-square test was used for trend analysis over the study years as appropriate. To mitigate the risk of confounding and selection bias, a nearest-neighbor 1:1 propensity score (PS) matching was done using a caliper width of 0.2. In this way, ESRD and non-ESRD patients were well matched with respect to demographic variables as shown in Table 1. Predictors of mortality in ESRD patients who sustained in-hospital SCA were analyzed using a logistic regression model. A forward stepwise entry model was used for this purpose. Initially, all variables, which were significantly associated with mortality with a p value of less than 0.05 in univariate analysis, were entered in the model from the baseline table. Subsequently, only those variables are retained in the model which were associated with mortality with a p value of less than 0.10 during forward entry. A type I error of less than 0.05 was considered statistically significant. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) (version 26, IBM Corp) and R (version 3.5).
Crude and propensity score-matched outcomes are shown in Table 2. A total of 1,035,037 (73.2%) patients died in our cohort after sustaining an in-hospital SCA. No difference in mortality was noted in PS-matched analysis among ESRD and non-ESRD patients with in-hospital SCA (70.4% vs. 70.7%, p = 0.45). The prevalence of new defibrillator (ICD) implantation at discharge continued to be low in ESRD patients who survived an in-hospital SCA compared to non-ESRD patients in both crude and propensity score-matched cohorts ( Over our study period from 2007 to 2017, the proportion of ESRD and non-ESRD patients who sustained in-hospital SCA was similar (please see Fig. 2). In-patient mortality showed a downward trend for both ESRD and non-ESRD patients with in-hospital SCA after an initial spike in the year 2009 (please see Fig. 3). Median LOS showed a stable trend over our study years (please see Fig. 4).
Predictors of mortality in ESRD patients after they sustained SCA are shown in Fig. 5

Discussion
In this investigation of in-hospital SCA patients stratified on the basis of ESRD status or not, we report several key findings. (1) The mortality in patients with in-hospital SCA was similar in PS-matched analysis regardless of ESRD status (70.4% vs. 70.7%, p = 0.45). (2) Over the study period from 2007 to 2017, there was a reduced trend of mortality after a SCA event in both ESRD and non-ESRD patients after an initial spike in the year 2009. (3) ESRD patients who suffered in-hospital SCA were younger and had a higher burden of key co-morbidities when compared to non-ESRD patients with inhospital SCA. (4) The utilization of invasive procedures was lower in ESRD patients compared to non-ESRD patients after an in-hospital SCA.
In-hospital SCA affects nearly 290,000 adult patients in the USA each year [13]. The clinical trajectory of ESRD patients is frequently complicated by SCA which contributes to nearly a quarter of deaths in this patient population [1]. ESRD patients have an underlying vulnerable myocardial substrate for SCA since most of these patients are found to have LVH that can prolong ventricular repolarization, a well-recognized risk factor for induction of malignant arrhythmias [3,4]. patients when compared to their non-ESRD counterparts. In our study, we also demonstrated similar mortality rates in ESRD and non-ESRD patients after in-hospital SCA in PSmatched cohorts. Additionally, in our trend analysis, we have also shown improved mortality in both ESRD and non-ESRD patients after in-hospital SCA over our study years despite an initial spike in the year 2009 (Fig. 3). American Heart Association (AHA)/Emergency Cardiovascular Care (ECC) CPR guidelines were updated in 2010 and focused primarily on early chest compressions (chest compression-airwaybreathing rather than airway-breathing-chest compressions as recommended by earlier guidelines), chest compressions of at least 2 in. with a rate of at least 100/min, eradication of atropine use for non-shockable SCA, and prompt institution of targeted temperature management in eligible patients [16,17]. It is plausible that improved mortality trend witnessed in our study in both ESRD and non-ESRD patients especially after   Our analysis showed mortality was in excess of 70% in ESRD patients who suffered in-hospital SCA. The first step in reducing this mortality in ESRD patients is to adequately identify risk factors that are associated with in-hospital SCA so that targeted risk modification can be done. Shastri et al. [18] assessed 1745 dialysis patients from the non-cardiac deaths in the hemodialysis (HEMO) study and found that prior history of diabetes, peripheral vascular disease, and ischemic heart disease were independently associated with SCA events in dialysis patients. After incorporating these variables in a SCA prediction model, they found good discrimination (C-statistic of 0.75, 95% CI 0.70-0.79) and calibration of the model at 3 years of follow-up. Our study also showed increased prevalence of diabetes (32.5% vs. 8.4%, p < 0.01), peripheral vascular disease (19.9% vs. 9.9%, p < 0.01), and coronary artery disease (39.4% vs. 30.8%, p < 0.01) in ESRD patients who sustained in-hospital SCA when compared to non-ESRD patients. Additionally, in our predictor analysis, both diabetes (OR 1.046, 95% CI 1.009-1.084) and peripheral vascular disease (OR 1.079, 95% CI 1.044-1.115) were associated with increased mortality after in-hospital SCA among ESRD patients.
The current data on therapeutic interventions that can prevent SCA or improve outcomes after a SCA event in ESRD patients are limited. In a randomized, placebo-controlled trial on 114 consecutive dialysis patients with history of dilated cardiomyopathy, carvedilol administration was associated with 24% reduction in mortality at 2 years and a trend towards reduced incidence of SCA [19]. On the contrary, a secondary analysis of HEMO study did not show any benefit of beta- Fig. 3 Trends in mortality in endstage renal disease and non-endstage renal disease patients after in-hospital sudden cardiac arrest over the study years Fig. 2 Proportion of end-stage renal disease and non-end-stage renal disease patients with inhospital sudden cardiac arrest over the study years blocker utilization in reducing incidence of SCA [20]. The utilization of calcium channel blockers of dihydropyridine class is associated with improved survival at 24 h after an index SCA event [21]. Implantable cardioverter defibrillators have been shown to improve outcomes when utilized for secondary prevention purposes; however, they are often underutilized in ESRD patients due to a multitude of factors [22]. Indeed, our study has shown that the presence of prior ICD was associated with reduced mortality in ESRD patients who suffered an in-hospital SCA event. Additionally, dialysis prescription offers several opportunities to reduce risk of SCA among ESRD patients. Large fluctuations in serum electrolytes and fluids have been demonstrated as inciting factors for initiation of SCA in ESRD patients. Low potassium and calcium dialysates are especially associated with an increased risk of SCA as they increase the risk of hypokalemia and hypocalcemia during a dialysis session that disperse myocardial repolarization which is a well-recognized prerequisite for initiation of malignant arrhythmias [5,23,24]. Our data, unfortunately, do not inform on these patient and dialysis-related Fig. 4 Length of stay trends in end-stage renal disease and nonend-stage renal disease patients after in-hospital sudden cardiac arrest over the study years Fig. 5 Predictors of mortality in end-stage renal disease patients after in-hospital sudden cardiac arrest characteristics. However, prompt attention to these measures can result in prevention of SCA events in ESRD patients and result in improved outcomes after such events have occurred.

Limitations
Our study results should be interpreted in the context of following key limitations: (1) NIS is an administrative, claimsbased database that relies on ICD coding system. These codes can be subjected to errors; however, HCUP quality control measures are routinely instituted that mitigate such concerns [9]. Additionally, the positive predictive value of ESRD codes is close to 96% [25]. (2) It is sometimes difficult to distinguish between co-morbidities and complications from NIS dataset as there is no specific "present at admission" indicator. It should, however, be pointed out that most co-morbidities analyzed for the present study are usually diagnosed in an outpatient setting and unlikely to be related to a SCA hospitalization. (3) There are no specific ICD codes for in-hospital arrest, and previous studies have utilized demonstration of CPR as evidence of in-hospital arrest and we have replicated the same methodology in our current analysis. (4) NIS does not inform on detailed management of SCA, and specifically, no data is collected on quality of CPR and other measures that are practiced as part of advanced life support. (5) NIS censors data gathering at discharge, and patients are not followed longitudinally. ESRD patients who sustained SCA have been shown to have poor survival on follow-up studies and that cannot be investigated from NIS dataset [21].

Conclusion
In our large nationally representative sample of in-hospital SCA patients, we have shown that in adjusted analysis, inpatient mortality is similar in ESRD and non-ESRD patients. ESRD patients who sustained an in-hospital SCA have higher burden of key co-morbidities in unadjusted analysis. After adjustment by propensity score matching, both ESRD and non-ESRD cohorts were well balanced in terms of key comorbidities. Mortality has been on the downward trend after an in-hospital SCA event in both ESRD and non-ESRD patients over our study years.
Data availability The data that support the finding of this study are available from the corresponding author (MBM) upon reasonable request.

Declarations
Ethics approval and consent to participate The need for these entities was waived due to the de-identified nature of National Inpatient Sample database and its public availability.

Conflict of interest
The authors declare no competing interests.