Continuous Electrocardiographic Monitoring in Patients with Sickle- Cell Anemia During Pain Crisis

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1 Clin. Cardiol. 6, (1 983) 0 Clinical Cardiology Publishing Co., Inc. Continuous Electrocardiographic Monitoring in Patients with Sickle- Cell Anemia During Pain Crisis A. MAISEL, M.D., H. FRIEDMAN, M.D., L. FLINT, M.D., M. KOSHY, M.D., R. PRABHU, M.D. Department of Medicine, Michael Reese Hospital and Medical Center, Chicago, Illinois, USA Summary: Electrocardiographic studies in patients with sickle-cell anemia have been performed during the normal resting state with routine twelve-lead ECGs. We studied 30 patients with sickle-cell disease in acute crisis with 24-hour continuous electrocardiographic monitoring. The standard ECG demonstrated a high incidence of abnormalities, but only three patients had arrhythmias. These findings contrasted sharply with the results of continuous monitoring, during which arrhythmias were detected in 24 of 30 patients. They were fairly evenly split between atrial (60%) and ventricular (67%). Nine of the patients had complex arrhythmias including two with episodes of ventricular tachycardia. Seventeen patients subsequently underwent equilibrium gated-blood pool scans. Eight patients had abnormal contractility and tended to have more arrhythmias on monitoring than those with normal contractility. Thus, continuous electrocardiographic monitoring of sickle-cell patients during crisis revealed a higher incidence of arrhythmias than previously thought. Key words: sickle-cell anemia, arrhythmia, Holter monitor Introduction Cardiovascular abnormalities are a significant part of the clinical picture of sickle-cell anemia (Klinefelter, 1942). However, precise definitions of the pathophysiologic mechanisms of sickle-cell heart disease are unknown. Low oxygen tension, acidosis, and stasis are thought to cause sickling and subsequent infarction in the lungs, spleen, kidney, liver, and bone marrow (Murphy and Shapiro, 1945; Rimmelstiel, 1948). Whether similar vaso-occlusive phenenomena could produce ischemia or injury to the heart remains speculative (Baroldi, 1976, 1973; Desforges and Wang, 1966; Finch, 1976). Electrocardiographic changes are frequent and have generally been nonspecific (Jones et al., 1945; Nyg, 1967; Shubin, 1960; Vzoynk, 1964; Windsor and Burch, 1945). Left ventricular hypertrophy (LVH) is present in perhaps half the patients and PR interval prolongation is found in up to 10%. Cardiovascular arrhythmias however have been sparsely reported. The purpose of this study was twofold. First, to evaluate the standard ECG changes during active crisis, something not often reported, and second, to detect and define with continuous electrocardiographic monitoring the incidence of arrhythmias during the crisis state. Address for reprints: Alan Maisel, M.D. Division of Cardiology (H8 1 1 A) University Hospital 225 Dickinson San Diego, California 92103, USA Received: November 4, 1982 Accepted with revision: April 2, 1983 Method Patient Selection Thirty consecutive patients with sickle-cell anemia followed at Michael Reese Hospital Sickle-Cell Clinic were studied in the 24-hour observation area of the

2 340 Clin. Cardiol. Vol. 6, July 1983 TABLE 1 Population description (30 patients) Mean Range Standard deviation Age (yr) f3 Emergency room visits/yr f3 Time monitored (h) f4 Hemoglobin (g/dl) I.2 f2 Reticulocyte count (mm3) f5 Serum sodium (meq/liter) I36.' f3 Serum potassium (meq/liter) f0.4 emergency room during a painful crisis. Criteria for exclusion from the study were as follows: (I) Presence of known cardiac disease, (2) Holter monitoring for less than I2 hours, (3) refusal by the patient to participate, and (4) treatment with medications other than analgesics. Protocol Prior to continuous monitoring, a medical history and physical exam were performed with emphasis on the cardiovascular system. A standard 12-lead electrocardiogram was obtained, along with routine electrolytes and CBC. The tracings of 30 subjects were recorded by a two-channel 24-h portable ECG tape recorder (Avionics Model 650). Monitoring was done for a minimum of 12 and a maximum of 24 hours. Patients admitted to the general medical floor kept the unit in place for the complete 24-h period. Electrocardiographic recordings were scanned visually for the presence of arrhythmias (Model 650 Electrocardio Scanner, Avionics). The ventricular arrhythmias were graded according to the Lown classification as follows: No ventricular premature contractions (VPCs), LO; unifocal VPCs, L,; unifocal VPCs greater than 10/h, Lz; multifocal VPCs, L3; paired VPCs, Lq; and ventricular tachycardia, Ls. This classification has been used to evaluate patients after myocardial infarction and may have prognostic significance in terms of sudden death as well as correlation with the severity of the disease (Lown, 1976). Atrial arrhythmias were graded similarly and designated by the letter K. K5 included atrial fibrillation, paroxysmal atrial tachycardia, and atrial flutter. Category K6 was assigned for multifocal atrial tachycardia. Results The population description is given in Table 1. Fourteen of the thirty patients were women. There was no significant difference between the type of the arrhythmia and the number of emergency room visits per year, time monitored, hemoglobin, reticulocyte count, or serum sodium or potassium. Eleven subjects had palpitations, and nine complained of shortness of breath. Although chest pain was noted by 50%, it was described as a typical manifestation of sickle crisis rather than angina pectoris. Twenty subjects had a systolic ejection murmur, and twenty had either an S3 or Sq gallop. The pulmonic component of Sz was increased in one-half of the subjects. The standard 12-lead electrocardiograms demonstrated frequent morphologic abnormalities, yet only three patients (10%) had evidence of arrhythmias (Table 11). These findings contrasted sharply with the results of Holter monitoring (Table 111) which detected arrhythmias in 24 patients (80%). The arrhythmias were equally divided into atrial (67%) and ventricular (60%). All three patients with ectopy on the standard electrocardiogram had both high-grade atrial and ventricular arrhythmias on monitoring (Table IV, Fig. I). Figure 2 reveals the recording of one typical case illustrating that patients without rhythm disturbance on the normal standard electrocardiogram may have complex arrhythmias as recorded by the Holter monitor. The distribution of K and L classification numbers is shown in Table V. Seven patients (24%) had K values of 3 or above and seven (24%) had L values of 3 or above. Two patients had episodes of ventricular tachycardia. TABLE II Characteristics of standard ECG Morphology Left ventricular hypertrophy Nonspecific abnormalities Normal I O A-V block Rhythm Sinus tachycardia Atrial premature contractions Ventricular premature contractions Patients

3 ~ A. Maisel et al.: Arrhythmias in sickle-cell crisis 34 I TABLE 111 Comparison of the incidence of arrhythmias detected by ECG and by Holter monitoring Absent Present Atrial Ventricular Standard ECG Holter TABLE IV Results of Holter recordings in 5 patients with arrhythmias on standard ECG Patient Age (yr) Standard ECG Holter Atrial b Ventricular OCC, APC APC, OCC, VPC occ, VPC FIG. 1 Holter monitor showing high grade ventricular arrhythmias in a patient whose standard ECG demonstrated arrhythmia Finally, 17 of the 30 patients were subsequently hospitalized and had resting cardiac gated-blood pool studies. Comparing the arrhythmias of those with normal wall motion to those with abnormal wall motion, it appears, though not statistically significant, that there is a trend toward more atrial and ventricular arrhythmias in patients with ventricular dysfunction. Discussion Cardiovascular abnormalities have played a prominent part in sickle-cell anemia since the condition was first described by James Herrick in 1910 (Herrick, 191 1). Although investigators have focused their studies of the clinical features of the cardiovascular system on

4 342 Clin. Cardiol. Vol. 6, July 1983 FIG. High grade ventricular arrhythmias in patients whose standard ECG showed no arrhythmias and leads ~ stanr-.d ECG showing no arrhythmias. and V, of TABLE V Distribution of atrial (K) and ventricular (L) arrhythmias observed by holter monitoring Arrhythmia grade No. of patients K I L the electrocardiogram, little diagnostic information has been gained (Hardison and Rogers, 1980; Klinefelter, 1942; Lindsay et al., 1974; Nyg, 1967; Shubin, 1960; Windsor and Burch, 1945). The appearance of LVH in 57% of our patients agrees with the 50% figure given by others (Klinefelter, 1942; Shubin, 1960; Windsor and Burch, 1945). However, 40% of our subjects had first degree A-V block as compared to approximately 10% elsewhere (Klinefelter, 1942; Shubin, 1960; Windsor and Burch, 1945). We have no explanation for this discrep- ancy except that our patient population was older than most previously studied. The present study indicates that atrial and ventricular arrhythmias are common during sickle-cell crisis and are present despite a normal standard ECG. Furthermore, long-term monitoring reveals an 80% incidence of arrhythmias compared to only 10% with routine electrocardiography. Moreover, an enhanced sensitivity of monitoring has been amply demonstrated in ambulatory patients.

5 A. Maisel et al.: Arrhythmias in sickle-cell crisis 343 Although the routine electrocardiogram underestimated the prevalence of arrhythmias, the three patients whose standard ECG showed any ectopic activity had severe arrhythmias by monitoring. Furthermore, 28% had arrhythmias considered by some to be of poor prognostic significance (frequent PVCs, R or T, multifocal PVCs, bigeminy, and ventricular tachycardia). With a small sample size, the data should, however, be interpreted with caution. Moreover, several studies have indicated that continuous monitoring of disease- free populations will reveal frequent arrhythmias (Baroldi, 1969; Harrison et al., 1978; Kennedy and Underhill, 1976; Kennedy et al., 1978; Morganroth, 1978; Winkle, 1978, 1980) with up to 12% frequency of more serious arrhythmias. Our population is however, particularly young (average age 26) and arrhythmias would be expected to occur less frequently. Since the mechanism of arrhythmias occurring in sickle-cell crisis is unknown, it would be interesting to speculate on the possible role of ischemia or ventricular dysfunction. With the knowledge that many patients have cardiomegaly and congestive heart failure, it is possible to speculate that there is a specific myocardial abnormality. However, this remains unproven. At autopsy, the heart is diffusely hypertrophic and dilated (Klinefelter, 1942). Infarction is not found in the myocardium probably because the rapid flow rate that passes deoxygenated red blood cells through the myocardium does so before sickling has time to occur (Baroldi, 1969, 1973). In fact, the coronary arteries in patients with sickle-cell anemia are usually larger than normal as demonstrated by postmortem angiography (Gerry et al., 1978). Of interest though, are the observations of Windsor and Burch (1 945) and Oliviera and Gomez- Patino ( 1963). They detected the presence of an arteritis of the small coronary arteries. The latter investigators described occlusion of these vessels by agglutinated sickled red blood cells and organizing microthromboemboli. Oliviera and Gomez-Patino (1 963) suggested falcemic cardiomyopathy existed as a result of myocardial ischemia attributable to this process. However, the presence in autopsy material of blood vessels packed with sickled red blood cells does not necessarily indicate the presence of vascular occlusion antimortem. Thus, it is difficult to interpret such observations. In our study, 17 patients were subsequently admitted and underwent resting equilibrium gated-blood pool scans while still in crisis; 9 patients were found to have wall motion abnormalities. Of the 9 patients, 6 had atrial and 6 had ventricular arrhythmias on their monitor. This is compared to 8 normal ventricles where only 3 patients had atrial and 2 had ventricular arrhythmias. These are only preliminary findings, but it suggests the possibility of small vessel occlusion leading to ischemia causing ventricular dysfunction and arrhythmias. Thallium scanning during crisis might better be able to delineate these findings. Patients with beta-thalassemia and other transfusion-dependent congenital anemias are often found to have clinically apparent myocardial dysfunction and associated arrhythmias in their adolescent or early adult years (Engle, 1964; Engle et al., 1964). Several investigators have used noninvasive techniques to demonstrate cardiac abnormalities in these patients often prior to the development of clinically apparent heart disease (Hellenbrand et al., 1977; Henry et al., 1978; Leon et al., 1979). The relationship between these abnormalities and iron deposition is controversial but it appears that greater than one hundred units of transfused blood are needed to cause significant cardiac dysfunction (Buja and Roberts, 1971; Leon et al., 1979). As no subject in our study had over ten transfusions, iron overload as a cause of the abnormalities described seems unlikely. In conclusion, 30 patients with sickle-cell anemia underwent continuous electrocardiographic monitoring during pain crises. The results revealed a higher incidence of arrhythmias in this subgroup of patients than previously thought. More work is needed to evaluate fully the etiology of these arrhythmias. References Baroldi G: Relevance of thrombosis to infarction. Adu Cardiol9, 15 (1 973) Baroldi G: High resistance of the human myocardium to shock and red blood cell aggregation. Cardiologia 54, 271 (1969) Bashour FA, Jones E, Edmonson E: Cardiac arrhythmias with special reference to ventricular tachycardia. Dis Chest 5 I, 520 (1 967) Brodsky M, Wu D, Denes P, Kanakis C, et al: Arrhythmias documented by twenty-four hour continuous electrocardiographic monitoring in fifty male medical students without apparent heart disease. 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