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The Independent Association of Renal Dysfunction and Arrhythmias in Critically Ill Patients^*

^* From the Department of Internal Medicine (Drs. Soman and Lee), Division of Hypertension and Nephrology, and Henry Ford Heart and Vascular Institute (Ms. Sandberg, and Drs. Borzak and Hudson), Detroit, MI; and Cardiology Section (Dr. McCullough), Departments of Basic Science and Internal Medicine, University of Missouri-Kansas City School of Medicine, Truman Medical Center, Kansas City, MO.

Correspondence to: Peter A. McCullough, MD, MPH, FCCP, Associate Professor of Medicine, Cardiology Section Chief, University of Missouri-Kansas City School of Medicine, Truman Medical Center, 2301 Holmes St, Kansas City, MO 64108; e-mail: mcculloughp{at}umkc.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Conclusion References

 
Study objectives: The purpose of this study was to quantify the impact of baseline renal dysfunction on incidence and occurrence of cardiac arrhythmias in the coronary ICU.

Background: Renal dysfunction is an established predictor of all-cause mortality in the ICU setting. We set out to evaluate the independent contributory effect of renal dysfunction to arrhythmias and mortality in this population.

Design and setting: We analyzed a prospective coronary care unit registry of 12,648 admissions by 9,557 patients over 8 years at a single, tertiary center. An admission serum creatinine level was available for 9,544 patients. Those patients not receiving long-term dialysis were classified into quartiles of corrected creatinine clearance with cutpoints of 46.2 mL/min/72 kg (group 1), 63.1 mL/min/72 kg, and 81.5 mL/min/72 kg. Dialysis patients (n = 527) were considered as a fifth comparison group (group 5).

Measurements and results: Baseline characteristics including older age, African-American race, diabetes, hypertension, history of previous coronary disease, and heart failure were incrementally more common with increasing renal dysfunction strata. There were graded, independent increased risks for accelerated idioventricular rhythm (relative risk [RR], 2.43; 95% confidence interval [CI], 1.40 to 4.20; p = 0.002), sustained ventricular tachycardia (RR, 2.07; 95% CI, 1.02 to 4.22; p = 0.04), ventricular fibrillation (RR, 2.42; 95% CI, 1.13 to 5.15; p = 0.02), and complete heart block (RR, 3.64; 95% CI, 1.77 to 7.48; p = 0.0004, group 5 vs group 1).

Conclusions: We conclude that baseline renal function is a powerful, independent predictor of cardiac arrhythmias in the coronary ICU population.

Key Words: arrhythmias • complications • coronary care unit • renal failure • survival

	Introduction

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We and others^{1 2 3 4} have shown a graded, independent risk of acute renal failure after percutaneous coronary intervention, coronary artery bypass surgery, and other cardiac events driven in part by baseline renal function. The consequences of acute renal failure developing de novo after hospital admission requiring dialysis include high rates of in-hospital mortality and shortened long-term survival, whether or not dialysis becomes permanent.^{1 5} In addition, increased arrythmogenicity documented by ECG has been described in patients during hemodialysis, as well as in patients with left ventricular hypertrophy (LVH) and hypertension in the setting of renal dysfunction.^{6 7 8} Increased risk for arrhythmias was reported with mildly impaired renal function in patients undergoing cardiac valve replacement surgery.⁹

These investigations have been limited by the various definitions used to categorize and describe the degrees of renal dysfunction, and by the exclusion of patients with more advanced renal insufficiency, including those receiving dialysis treatment. We sought to evaluate the independent risk of baseline renal dysfunction on cardiac arrhythmia events in the cardiac ICU (CICU).

	Materials and Methods

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Setting, Data Collection, Follow-up
Henry Ford Hospital is a 903-bed tertiary-care center located in the urban core of the Detroit metropolitan area, and receives patients whose care is provided primarily within Henry Ford Health System, a vertically integrated, mixed-model managed care organization with an advanced information technology infrastructure.^{10 11 12} The Henry Ford CICU database has been previously described.² In brief, this was a registry in which every admission to this 16-bed unit had clinical data (approximately 250 discrete elements) prospectively recorded on case report forms by trained research assistants. Data collected from May 1, 1990, to August 22, 1998, included baseline demographics, laboratory values, and events occurring during the unit stay, including arrhythmias. Trained research nurses prospectively assessed arrhythmias with daily checks of telemetry, 12-lead ECGs, and hospital charts. Once an arrhythmia occurred, it was recorded. Multiple occurrences of the same arrhythmia were only counted once. The data collection period was stopped after discharge from the unit, either to another floor or to home. In-hospital events were also recorded and detailed, and only the first CICU admission was used in the analysis. Subsequent CICU admissions by the same patients were excluded to avoid double counting.

Assessment of Baseline Renal Function
The database was augmented with merged data from laboratory tables in order to obtain complete renal function data in 9,544 patients (99.9%). Because weight was not available in the database, the corrected creatinine clearance (CorrCrCl) [per 72 kg of body weight] was used as the best measure of baseline renal function as follows^{13 14} :

, where SCr = serum creatinine.

We have previously validated the predictive capabilities of CorrCrCl on all-cause mortality in the parent population.² The CorrCrCl was found to be unimodal and normally distributed. Therefore, patients were classified into quartiles at the cutpoints of 46.2, 63.1, and 81.5 mL/min/72 kg. Patients receiving long-term dialysis (n = 527) were considered again as a fifth comparison group. Tables were created with these groups as the column headings. There were no directional changes in the final calculated univariate and multivariate relative risks (RRs). Based on the established validity of estimated creatinine clearance as a surrogate for glomerular filtration rate and its frequency distribution in this data set, the investigators decided to retain the CorrCrCl as the measure of baseline renal function throughout the analysis.^{15 16}

Admitting Diagnoses
The admitting diagnosis categories ranked according to their increasing in-hospital mortality were as follows: coma, shock, noncardiac diagnoses, other cardiac diagnoses, congestive heart failure (CHF), acute myocardial infarction (AMI), arrhythmias, and unstable angina pectoris. This diagnosis rank code was used in multivariate modeling to account for the severity of illness on admission. Intubation and mechanical ventilation was performed in 1,355 patients (14.2%). In addition, sepsis was listed as a complicating factor in 1,504 patients (15.7%).

Outcome Validation
Eleven arrhythmic outcomes, including atrial flutter, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, asystole, junctional rhythm, and accelerated idioventricular rhythm, were selected for validation with blinded chart abstraction. A random sample (n = 20) from each outcome category was chosen, and each record was compared against chart abstraction by an independent team comprising an internist and a cardiologist for the development of the outcome during the ICU stay. Agreement statistics were computed for each outcome and then averaged over the seven categories. The mean percent agreement was 92.7% across the 11 outcomes.

Statistical Analysis
Baseline characteristics are reported with means ± SD or proportions with 95% confidence intervals (CIs), as appropriate, with exclusion of missing data points. Univariate comparisons were carried out using analysis of variance, or ² as appropriate. The ² test for linear trend was used for comparisons of baseline characteristics across ascending levels of renal dysfunction. Multiple logistic regression was performed for the outcomes of arrhythmias and in-hospital death, with independent RRs reported with 95% CIs. Multivariate risks were adjusted for age, gender, race, admission diagnosis, history of heart failure, previous aspirin, ß-blocker, and angiotensin-converting enzyme inhibitor use, diabetes, and baseline hemoglobin. All univariate significant predictors were entered in the model manually and removed at p > 0.10. All models were tested for interactions. Variables in the causal pathway, including the developing admission diagnosis (such as shock), were included in the final models. Cox proportional hazards model was used to derive the independent hazard of estimated renal function with cumulative, long-term survival. The log-rank test was used to evaluate the independent differences in survival across the strata. All p values are two tailed and considered significant at < 0.05.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Conclusion References

 
Baseline Characteristics
Table 1 shows baseline characteristics of the patient groups stratified by renal risk. The overall mean age was 63.4 ± 13.8 years (range, 15 to 98 years). The mean age for women and men was similar (63.6 ± 13.8 years and 63.3 ± 13.7 years, respectively; p = 0.22). The overall female-to-male ratio was 0.73, with male gender predominant in all groups. For the study group as a whole, 5,080 patients (53.2%) were white, 4,189 patients (43.9%) were African American, and 275 patients (2.9%) were categorized as "other" race. African-American race increased in proportion from group 1 to group 5, including 60% of those receiving long-term dialysis. Diabetes and hypertension were more common across the ascending risk groups 1 to 5 (p < 0.0001 for both trends). Conversely, smoking and hyperlipidemia were more common in the lower risk groups (p < 0.0001 for both trends). Previous coronary artery disease increased only slightly over the renal strata from 27 to 37% for a prior history of angina, and 20.6 to 31.7% for a previous AMI (p < 0.0001 for both). Rates of prior coronary revascularization were similar among the groups. There was, however, a graded increase from 13.8 to 45.0% in the frequency of prior CHF from group 1 to 5 (p < 0.0001). Rates of CHF medications including angiotensin-converting enzyme inhibitors, diuretics, and digoxin also increased over the strata, consistent with the CHF and hypertension frequencies observed. A history of prior atrial fibrillation (either chronic or paroxysmal) was collected only in a later group of cases (n = 373) from March 1, 1997, to August 22, 1998, and the frequencies for renal risk groups 1 to 5 were 4 of 130 cases (3.0%), 6 of 75 cases (8.0%), 7 of 76 cases (9.2%), 9 of 80 cases (11.3%), and 1 of 8 cases (12.5%), respectively (p = 0.26 for group 1 vs 5; p = 0.05 for trend).

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Adjusted RR for life-threatening arrhythmias and death in critically ill patients with renal dysfunction. Multivariate risks are adjusted for age, gender, race, admission diagnosis, history of heart failure, previous aspirin, ß-blocker, and angiotensin-converting enzyme inhibitor use, diabetes, and baseline hemoglobin. VT = sustained ventricular tachycardia; VF = ventricular fibrillation; CHB = complete heart block; corrected creatinine clearance (CrCl) is presented in mL/min/72 kg (p < 0.0001 for all trends except death).

	Discussion

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There were significant ethnic differences across the renal risk groups with higher proportions of African Americans in the higher risk groups, including 60.0% of those receiving long-term dialysis compared to 37.6% of those in the lowest risk group. The impact of baseline comorbidities across the renal strata was evident. Those patients receiving long-term dialysis therapy had, as expected, significantly higher rates of diabetes, hypertension, and CHF. Patients with renal dysfunction were more likely to be admitted to the hospital with CHF than acute ischemic syndromes. Although measurement of left ventricular (LV) function was not done routinely on patients, when it was evaluable by indexes such as cardiothoracic ratio, echocardiography, and radionucleotide ventriculography, it was lower in the higher risk strata consistent with higher rates of history and hospital admission diagnoses of CHF. The multivariate analysis, however, indicates that not all the risk observed in the upper strata can be explained by decreased LV function alone and confirmed, in a consistent manner, the independent relation between renal function and the development of arrhythmias. Another confounder, baseline hemoglobin, was found to be lower as renal failure advanced across the groups. This finding is consistent with the anemia associated with renal dysfunction and was appropriately accounted for in all the multivariate analyses of this population.

Potential Mediators of Cardiac Arrhythmias in Renal Dysfunction
This study suggests that there are other unmeasured intermediate factors present that mediate risk for arrhythmias and death. We describe a wide range of arrhythmias to highlight potentially different relative associations, or different mechanisms for various arrhythmias. For instance, changes in the intracellular matrix and fibrous replacement of the cardiac tissue over time are thought to be related to the development of heart block. Conversely, electrolyte disturbances and LVH are thought to trigger and facilitate, respectively, re-entrant ventricular arrhythmias such as ventricular tachycardia. In addition, the likely structural and physiologic substrates for arrhythmias in renal dysfunction include diastolic dysfunction, volume overload, electrolyte abnormalities, and adverse pharmacologic interactions.^{17 18 19} Ample evidence from the literature exists to expect a high rate of LVH in the predialysis and dialysis populations by echocardiography.²⁰ In these groups, LVH has been related to higher rates of asymptomatic ventricular arrhythmias, and cardiac events including AMI, revascularization, CHF, and cardiac death.^{21 22 23} Volume overload is anticipated in groups 4 and 5, with the distinct possibility that the volume excess is better handled by dialysis than by high-dose diuretics in those with significant impairment in renal function. This may explain, in part, the plateau in risk seen in group 4 for many of the adverse arrhythmias.

In addition to the structural and physiologic substrates, there are likely to be components of autonomic dysfunction, myocyte dysfunction, and altered electrolyte metabolism that impact on the cellular electrophysiology. There are several lines of evidence that suggest a role for the autonomic nervous system in the pathogenesis of arrhythmias in renal failure.²⁴ Cardiac ß-adrenergic responses are blunted in uremia due to reduced isoprenaline-dependent activation of adenylate cyclase. This is thought to be due to an uncoupling of the receptor or by an inhibition of the receptor by the uremic toxins.²⁵ In chronic uremic rats, the density of ₁ and ₂ receptors in the cerebral cortex was found to be significantly increased, while the ß-adrenergic and muscarinergic receptors in the heart as well as cardiac ₁ adrenoceptors were unchanged.^{26 27 28} The reduced chronotropic responsiveness in the uremic heart may be partly related to the reduced activity of adenylate cyclase.²⁹ Studies in uremic rats have shown a significant decrease in contraction of isolated myocytes along with a decrease in the velocity of shortening and relaxation.³⁰ However, this was not reproduced in an experimental model involving foxhounds, wherein there was no anemia, hypertension, or heart failure.^{31 32} It has been postulated that altered calcium metabolism may result in the decreased contractility in rat myocytes perfused with uremic serum. There is also activation of cellular metabolism and of both energy production and consumption.^{33 34} Increased regional and transmyocardial dispersion of ventricular depolarization in ESRD patients may be a contributory factor in the pathogenesis of increased cardiac arrhythmias and mortality.³⁵ Renal failure is associated with rapid inactivation of cardiac ventricular myocyte L-type Ca2+ currents, which may reduce Ca2+ influx and contribute to shortening of the action potential duration.³⁶ There is also a decrease in the sodium pump number in cardiac myocytes in chronic uremia, though the functional significance of this is unclear as intracellular sodium is unchanged and active cation flux rates are maintained.³⁷ Lastly, parathyroid hormone-mediated intermyocardiocytic fibrosis has been demonstrated in patients with ESRD.^{38 39 40} This potentially unique form of fibrosis may lead to differential rates of conduction, and hence be a setup for re-entrant rhythms.^{41 42}

Another very important superimposed factor may be clinically overt or silent ischemia in patients with renal dysfunction leading to arrhythmias. Autopsy studies of ESRD patients who received dialysis have shown lower length density of myocardial capillaries, and increased myocyte diameter and volume density of myocardial interstitial tissue. Diminished LV capillary supply in renal failure increases critical oxygen diffusion distance in the myocardium, thus exposing cardiomyocytes to the risk of hypoxia.^{42 43} In addition, because of LVH, as well as an inflammatory state that may exist with uremia, the oxygen supply becomes diminished, while the demand generally stays high, creating an imbalance to the heart.⁴¹

Impact of Dialysis
We found an increased hazard with respect to some arrhythmias for those with reduced CorrCrCl < 46.2 mL/min/72 kg, but not yet receiving dialysis. This suggests that dialysis therapy, whether by selection or biological action, has at least a stabilizing effect on arrhythmias. This is at variance from other studies done in the outpatient setting, which describe a higher incidence of arrhythmias in ESRD especially during dialysis related to potassium flux and changes in repolarization.^{44 45 46 47} Our study did record arrhythmias during dialysis which occurred within the CICU, and hence was unlikely to miss this component of the arrhythmia event rate. The protective effect of hemodialysis on some cardiac arrhythmias likely relates to the correction of volume-overload electrolyte disturbances such as hyperkalemia.

Study Limitations
We acknowledge the limitations of this study, as it was a retrospective analysis of prospectively collected data. Misclassification bias concerning the exposure, renal function, was an important issue. Since we did not have body weight in the database, we used a measure that takes into account age, gender, and serum creatinine level measured on the first blood draw in the emergency department. Since the unit of measure was mL/kg/min/72 kg, we recognize the value will underestimate renal function for individuals > 72 kg, and underestimate for those < 72 kg. We would expect that a Cockroft-Gault value, another calculation such as the Modification in Diet in Renal Disease equation, or actual measurement of glomerular filtration, would have reduced variance, and by eliminating random misclassification bias, would have elevated the RRs reported in the tables and figure of this article. We did not have detailed information about the use of antiarrhythmics, the clinical response to an arrhythmia event, or the use of devices such as pacemakers or implantable defibrillators. In addition, we did not have critical electrolyte information such as pH, potassium, calcium, magnesium, or phosphorus at the time of the arrhythmia event collected in the database, and we anticipate electrolyte disturbance likely played a major role. Although acute renal failure and the initiation of dialysis was not an event captured on our registry, we expect this factor may have influenced group 4, a predialysis group, but not the other groups, where new dialysis was an unlikely clinical issue. Lastly, we did not have a detailed ECG analysis, and information such has the QT interval, QT dispersion, and other variables would have been of considerable interest in explaining our findings. The multivariate analysis could have been strengthened by temporal capture of data, which was not possible given the retrospective study design. For example, in the immediate time of the arrhythmia several important critical care events such as intubation, acid-base status, electrolytes, fever, and other contributors could be noted. We acknowledge that with a large database, small differences in characteristics, eg, serum sodium, across the groups may not be clinically significant, but are found to be statistically significant.

	Conclusion

TOP Abstract Introduction Materials and Methods Results Discussion Conclusion References

 
Baseline CorrCrCl derived from the serum creatinine, age, and gender is a significant, independent risk factor for acute arrhythmic complications in critically ill patients. We conclude that renal dysfunction is integrally related to the occurrence of arrhythmias and death, hence, further research into the clinical and biological mechanisms, as well as potential preventative and curative measures, for this relation are warranted.

	Footnotes

 
Abbreviations: AMI = acute myocardial infarction; CHF = congestive heart failure; CI = confidence interval; CICU = cardiac ICU; CorrCrCl = corrected creatinine clearance; ESRD = end-stage renal disease; LV = left ventricular; LVH = left ventricular hypertrophy; RR = relative risk

Presented in parts at the American College of Chest Physicians, CHEST 2000, October 22–26, 2000, San Francisco, CA.

Received for publication September 7, 2001. Accepted for publication January 17, 2002.

	References

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