Acute chest syndrome in adult patients with sickle cell disease: The relationship with the time to onset after hospital admission

Data on acute chest syndrome (ACS) in adult sickle cell disease patients are scarce. In this study, we describe 105 consecutive ACS episodes in 81 adult patients during a 32-month period and compare the characteristics as a function of the time to onset after hospital admission for a vaso-occlusive crisis (VOC), that is early-onset episodes (time to onset ≤24 h, 42%) versus secondary episodes (>24 h, 58%; median [interquartile range] time to onset: 2 [2–3] days). The median age was 27 [22–34] years, 89% of the patients had an S/S or S/β⁰-thalassaemia genotype; 81% of the patients had a history of ACS (median: 3 [2–5] per patient), only 61% were taking a disease-modifying treatment at the time of the ACS. Fever and chest pain were noted in respectively 54% and 73% of the episodes. Crackles (64%) and bronchial breathing (32%) were the main abnormal auscultatory findings. A positive microbiological test was found for 20% of episodes. Fifty percent of the episodes required a blood transfusion; ICU transfer and mortality rates were respectively 29% and 1%. Secondary and early-onset forms of ACS did not differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high.     

Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia

Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of outcome could guide clinical care. To determine whether early vaso-occlusive complications predicted subsequent adverse outcomes in the Dallas Newborn Cohort, we studied all members with SS or sickle-beta0-thalassemia who presented in their first year of life and had 5 years or more of follow-up. We defined 3 potential early predictors: hospitalizations in the first 3 years of life for (1) painful events other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We studied the associations of these predictors with the following late adverse outcomes (occurring after the third birthday): death, first overt stroke, use of disease-modifying therapy, and hospitalizations for pain events and ACS. None of the early events predicted death or stroke. Early pain and ACS both predicted a modest, temporary increase in the number of later painful episodes, but early ACS strongly increased the odds of more frequent ACS throughout childhood. Dactylitis had limited utility as a predictor. Although we still lack a useful prognostic framework for young children with SS, those who experience early ACS might be candidates for higher risk interventions to mitigate or cure their disease.     

Acute chest syndrome in adults with sickle cell disease

STUDY OBJECTIVES: Acute chest syndrome (ACS) is a frequent and potentially severe pulmonary illness in sickle cell disease (SCD). The aim of the study was to report the clinical features and outcome of consecutive ACS episodes in adult patients in a French SCD center. All patients were treated according to an uniform therapeutic protocol applying transfusion only in the more severe clinical form of ACS. RESULTS: There were 107 consecutive episodes in 77 adult patients (mean age, 29 +/- 7 years; 78% hemoglobin [Hb] SS; 14% Hb SC; and 8% Hb Sbeta + thalassemia) over a 6-year period. Seventy-eight percent of our patients had an associated vaso-occlusive crisis that preceded the chest signs in half of the cases. Comparison between acute and baseline levels showed a statistically significant difference in Hb levels (drop of 1.6 to 2. 25 g/dL depending on Hb genotype), WBC count (increase of 9.2 +/- 8. 3 x 10(9)/L); platelet count (increase of 67 +/- 209 x 10(9)/L); and lactate dehydrogenase values (increase of 358 +/- 775 IU/L) in ACS patients. Hypercapnia was detected in 42% of patients without sign of narcotic abuse. We identified a high percentage of alveolar macrophages containing fat droplets in 31 of 43 (77%) patients who underwent BAL. Bacterial culture findings were almost always negative, but were performed after starting antibiotic therapy that was administered in 96 episodes. Transfusion was required in 50 of 107 ACS events (47%). Five patients died, and all were transfused. CONCLUSIONS: These results confirm that fat embolism is probably a frequent mechanism of ACS in adult patients. However, fat embolism was not associated with a more severe clinical course, suggesting that bronchoscopy and BAL have little impact on the management of these patients. Restricting transfusion to the most severe ACS cases does not seem to increase the mortality rate.     

Cost-effectiveness of adenotonsillectomy in reducing obstructive sleep apnea,cerebrovascular ischemia,vaso-occlusive pain,and ACS episodes in pediatric sickle cell disease

In children with sickle cell disease (SCD), adenotonsillar hypertrophy or recurrent tonsillitis are frequently linked with an increased risk of obstructive sleep apnea, cerebrovascular ischemia, or frequent pain episodes and often require an adenoidectomy and/or tonsillectomy. Interventions designed to prevent these complications, control vaso-occlusive pain episodes, and avoid hospitalizations may reduce the significant personal and economic burden of SCD. This study compares episode recurrence and treatment costs for cerebrovascular ischemia, vaso-occlusive pain, acute chest syndrome (ACS), and obstructive sleep apnea in children who had an adenotonsillectomy (A/T surgery, N = 256; 11.7%) and a matched cohort of those who did not (N = 512; 23.3%) from a cohort of 2,194 children and adolescents with SCD from South Carolina’s Medicaid system. A/T surgery was associated with a significantly reduced rate of visits over time for obstructive sleep apnea and cerebrovascular ischemia (e.g., stroke, transient ischemic attacks), but not with any change in the rate of visits for vaso-occlusive pain or ACS/pneumonia visits. The rate of mean acute (emergency and inpatient) service costs was significantly decreasing over time after an increase about the time the A/T surgery was performed. The cost-effectiveness of adenoidectomy and/or tonsillectomy for treating obstructive sleep apnea and preventing cerebrovascular ischemia without increasing vaso-occlusive pain episodes or long-term acute service costs in routine clinical practice settings was demonstrated. The matched control group of SCD patients without A/T surgery contained more patients with severe vaso-occlusive pain episodes, ACS visits, and higher mean total costs over time and appears to represent a different phenotype of children with SCD.     

Carence en vitamine B12 par toxicité du protoxyde d’azote : une cause méconnue de sclérose combinée de la moelle

Introduction

Nitrous oxide is widely used in anesthesia. It is usually safe but may be associated with severe side effects when it is used repeatedly or on a prolonged time. Here, we report a case of drug-induced subacute combined spinal cord degeneration related to cobalamin deficiency.

Case report

A 20-year-old man with sickle-cell disease (SS) who was followed for severe recurrent vaso-occlusive crisis with repeated hospital admissions presented with ascending motor and sensitive neurological deficits that were later associated with bladder dysfunction. He was first considered to develop Guillain-Barre syndrome. However, persisting neurological signs despite adequate treatment lately led to diagnose subacute combined medullar degeneration due to abnormal cobalamin (vitamin B12) metabolism induced by repeated use of nitrous oxide during painful episodes of sickle-cell disease.

Conclusion

Inhaled nitric oxide is widely used in the treatment of vaso-occlusive crisis. Clinicians should be aware of possible severe neurologic side effects.     

Unusual causes of abdominal pain: sickle cell anemia

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crises. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestation of the disease. Abdominal pain is an important component of vaso-occlusive painful crises. It often represents a substantial diagnostic challenge in this population of patients. These episodes are often attributed to micro-vessel occlusion and infarcts of mesentery and abdominal viscera. Abdominal pain due to sickle cell vaso-occlusive crisis is often indistinguishable from an acute intra-abdominal disease process such as acute cholecystitis, acute pancreatitis, hepatic infarction, ischemic colitis and acute appendicitis. In the majority of cases, however, no specific cause is identified and spontaneous resolution occurs. This chapter will focus on etiologies, pathophysiology and management of abdominal pain in patients with sickle cell disease.     

Asthma and acute chest in sickle-cell disease

Our objective was to determine if physician-diagnosed asthma increases the risk of acute chest syndrome (ACS) in children with sickle-cell disease (SCD) hospitalized for pain. Our study design was a retrospective case-control study of all SCD patients, aged 2-21 years, hospitalized for pain during the interval 1999-2000. Medical records of first admissions during the interval were reviewed to determine the presence of ACS during the admission. Cases were defined as patients with ACS, and controls were patients without ACS. Independently, medical records of admissions prior to the study interval were reviewed for evidence of physician-diagnosed asthma. Sixty-three cases with ACS and 76 controls without ACS were identified. No significant differences in gender, age, and hemoglobin phenotype were found. Patients with physician-diagnosed asthma were 4.0 times (95% CI, 1.7, 9.5) more likely to develop ACS during the admission than patients without asthma. Individuals with physician-diagnosed asthma had a longer hospitalization for ACS, i.e., 5.6 days vs. 2.6 days, respectively (P = 0.01). In conclusion, our preliminary data suggest that asthma in children with SCD admitted to the hospital for pain may be a risk factor for ACS and may increase the duration of hospitalization when compared to children with SCD and without asthma.     

Sickle-cell disease and malaria: evaluation of seasonal intermittent preventive treatment with sulfadoxine-pyrimethamine in Senegalese patients—a randomized placebo-controlled trial

Sickle-cell disease (SCD) patients are at high risk of developing malaria which is a major contributor to morbidity and mortality in this disease. In Senegal, malaria transmission is high during rainy season, between July and October, and it was noted that sickle-cell crisis are frequent during this period. Then we carried out a double-blind randomized controlled trial to compare the impact of monthly sulfadoxine-pyrimethamine (SP) during the high-transmission season versus placebo on malaria incidence and morbidity of sickle-cell anemia. Sixty (60) SCD patients were randomized either to receive three intermittent preventive treatment (ITP) with SP or placebo using the random permutation table with nine elements. The drug was administrated as follows: sulfadoxine 25 mg/kg and pyrimethamine 1.25 mg/kg and this treatment was given once during the following months: September, October, and November. Overall four episodes of malaria disease were diagnosed, all these cases in the placebo arm. Thus, overall prevalence was 6.6% and there was no other case of malaria in the SP arm during the study period. Parasitological diagnosis confirmed the presence of Plasmodium falciparum in all four cases. No patient death was encountered during the study. SP treatment was well tolerated as only one patient (1.6%) in the SP arm reported pruritis. A significant reduction of patients' complaints (p = 002) and blood requirements (p = 0.001) was noted in the SP group; whereas, no impact was observed on vaso-occlusive crisis and hospitalization occurrence. Malaria prophylaxis by monthly intake of SP during the transmission period of the parasite reduced the prevalence of malaria and was safe in SCD patients leaving in malaria endemic area.     

Role of phlebotomy in the management of hemoglobin SC disease: case report and review of the literature

Marked variability is a keynote in the disease course of patients with hemoglobin SC (Hb SC) and hemoglobin S/beta(+)-thalassemia (Hb S/beta(+)-thal), with some patients having a frequency of complications and painful episodes similar to patients with homozygous sickle cell (Hb SS) disease. One possible explanation is that the higher hematocrit in these syndromes may contribute to an increase in blood viscosity, leading to vaso-occlusive pain episodes as well as an increased incidence of thromboembolic complications and retinopathy. We present a patient with Hb SC disease with an excellent baseline functional status who developed splenic infarction at a high altitude. Following splenectomy, the patient developed a sustained increase in hematocrit, an increase in the frequency of painful episodes, as well as new-onset dizziness and malaise. We initiated a therapeutic phlebotomy program in order to lower the hematocrit to pre-splenectomy values, as well as to induce iron deficiency. Repeated phlebotomy resulted in a dramatic decrease in symptoms. Our patient no longer requires narcotic analgesics for pain, has resolution of constitutional symptoms, and has not required further hospitalizations for vaso-occlusive pain crises. The correlation between symptoms and hematocrit levels supports the importance of blood viscosity in contributing to this patient's symptoms. A trial of phlebotomy to reduce viscosity in patients with higher hematocrit values should be considered as an intervention for symptomatic patients with sickle cell disease.     

Clinical significance of circulating blood and endothelial cell microparticles in sickle-cell disease

Increased thrombocyte activation leads to a higher likelihood of coagulation in sickle-cell disease. On the other hand, chronic inflammation and endothelial cell activation promote vaso-occlusion. The effect of circulating microparticles derived from erythrocytes, monocytes, thrombocytes, and endothelial cells on the vaso-occlusive process is unclear. This study aims to analyze the relationship between sickle-cell disease and miscellaneous organ complications by defining the circulating microparticles during the steady-state and painful crisis periods in 45 patients with sickle-cell disease. Microparticle analysis was conducted using an eight-parameter flow cytometric method, using CD61 PERCP, CD142PE, CD106 FITC, CD14 APC-H7, CD235a FITC, and Annexin-V APC monoclonal antibodies. Microparticle levels of sickle-cell patients were found to be significantly higher during both painful crisis and steady-state situations compared with the control group (for all, p < 0.001). Among these microparticles, levels of erythrocyte microparticles (eMPs) were significantly higher during crisis than in the steady-state period (eMP steady state vs. painful crisis: 7.59 ± 12.24 vs. 7.59 ± 12.24, respectively; p < 0.01). Microparticles, including eMPs, were not affected by hydroxyurea treatment. Their level did not reflect the high frequency of crisis (>3 times/year). Thrombocyte microparticle levels were found to be higher in patients with nephropathia than in those without (48.05 ± 40.23 vs. 7.67 ± 6.75, respectively; p < 0.049). Circulating microparticles seem to be involved in the pathogenesis of sickle-cell disease. eMPs may help with the management of crisis. Thrombocyte microparticles might predict renal damage induced by vaso-occlusion.     

Effect of low-dose warfarin on D-dimer levels during sickle cell vaso-occlusive crisis: a brief report

OBJECTIVE: To evaluate the activation of clotting systems in patients with sickle cell disease (SCD) by measuring the plasma D-dimer level and to determine the effect of low-dose warfarin on D-dimer level during vaso-occlusive crisis. METHODS: Plasma D-dimer level was measured in 65 blood samples of 37 adult patients with SCD who were hospitalized for vaso-occlusive painful crisis. D-dimer level of patients who were on low-dose warfarin was compared with those patients who were not on any anticoagulation treatment. Analysis of variance (anova) was carried out to determine factors significantly associated with low D-dimer level in patients with SCD. The following factors were included in the anova model; warfarin, homozygous hemoglobin S, history of blood transfusion in past 3 months, hydroxyurea, hemoglobin S%, hemoglobin F%, white blood cell counts, hemoglobin level, platelet count, and plasma fibrinogen level. RESULTS: Overall median D-dimer level in 65 samples was 2.7 microg fibrinogen equivalent units (FEU)/mL (0.34-4). Patients who were on low-dose warfarin had a median D-dimer level of 0.81 microg FEU/mL (0.34-1.8) compared with 3.1 microg FEU/mL (0.94-4) in those patients who were not on anticoagulation treatment. Using anova to model D-dimer levels, only warfarin was significantly correlated with low D-dimer levels after controlling for other variables. CONCLUSIONS: Patients with SCD during vaso-occulsive painful crisis have an elevated D-dimer level. Low-dose anticoagulation treatment is associated with a significant reduction in the D-dimer levels.     

Phospholipase A2 levels in acute chest syndrome of sickle cell disease

Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non- SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100- fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS.     

Urinary markers of bone resorption, pyridinoline and deoxypyridinoline, are increased in sickle cell patients with further increments during painful crisis

The painful crisis is the hallmark of sickle-cell disease (SCD). Bone resorption, as part of physiological bone turnover, results in release into the circulation with subsequent urinary excretion of the collagen cross-links pyridinoline (PYD) and deoxypyridinoline (DPD). Urinary PYD and DPD concentrations could reflect the extent of bone infarction during painful sickle-cell crisis. Urinary concentrations of PYD and DPD, adjusted for urine creatinine, were measured in sickle-cell patients (38 clinically asymptomatics and 27 during painful crisis) and healthy controls (n 5 25) using high-performance liquid chromatography(HPLC). PYD and DPD concentrations were higher in asymptomatic HbSS/HbSb0-thalassemia patients compared to controls (P <0.05) with further increments during painful crisis in both HbSS/HbSb0-thalassemia and HbSC/HbSb1-thalassemia patients (P < 0.05). In the asymptomatic HbSS/HbSb0-thalassemia patients, there was a statistically significant positive correlation between DPD and hemolytic rate.Based on urinary PYD and DPD concentrations, bone degradation is increased in asymptomatic sickle-cell patients, with further increments during painful crisis. Urinary PYD and DPD concentrations are potentially diagnostic and prognostic tools in SCD.     

Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea

The multicenter study of hydroxyurea (MSH) in sickle-cell anemia (SCA) demonstrated that patients treated with hydroxyurea (HU) had a 44% decrease in hospitalizations when compared with those taking placebo. A subsequent study looking at the cost-effectiveness of HU showed that decreased hospitalizations for painful crisis accounted for the majority of cost savings in those taking HU. The purpose of this study was to examine whether the expected decrease in hospital utilization occurred after the approval of HU in Maryland. We used data collected by the Maryland Health Services Cost Review Commission to obtain SCA discharge data for Maryland from FY1995 through FY2003. We also reviewed the inpatient and outpatient charts of all adults with SCA admitted to a large university hospital during 2003. Hospitalization rates for adults with SCA in Maryland have increased significantly since approval of HU. While the total costs of inpatient care in Maryland are estimated to have increased by 31% above inflation from 1995 to 2003, the costs of inpatient care for adult SCA patients has increased by almost 60% above inflation. By comparison, there has been no significant increase in the pediatric hospitalization rate. We found that 70% of patients in one hospital who were appropriate candidates for HU were not taking the medication. Hospital utilization among adults with SCA has increased significantly. There are likely many factors that have played a role in this increase. One factor that appears to be involved is the underutilization of HU.     

Sickle cell disease in adults: which emergency care by the internists?

INTRODUCTION: Sickle cell disease is an inherited disease characterized by the presence of an abnormal haemoglobin. It is the most prevalent genetic disease at birth in the Ile-de-France area. Internists are involved in the management of acute complications, particularly acute vaso-occlusive crisis. CURRENT KNOWLEDGE AND KEY POINTS: Sickle cell disease can be complicated by acute vaso-occlusive crisis, chronic visceral involvement related to the ischaemic process, and infectious complications. In adults, acute vaso-occlusive crisis is the major clinical problem prompting admission to the hospital and the main cause of death. It mainly manifests by osteoarticular pain but other clinical complications can be observed such as acute chest syndrome, priapism, ischaemic or haemorrhagic stroke, abdominal pain and acute multivisceral failure. The treatment of acute vaso-occlusive crisis is symptomatic. Simple transfusion or partial exchange transfusion is required in the more severe form of vaso-occlusive crisis. FUTURE PROSPECTS AND PROJECTS: The management of adult patients with sickle cell disease must be based on a multidisciplinary approach. At the present time, more than 50% of patients survive beyond the fifth decade. This better and longer life in developed countries has resulted from basic investigations and symptomatic treatments.     

Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions

A prospective, randomized clinical trial compared the clinical effectiveness of syrup of ipecac and activated charcoal to that of activated charcoal alone in the treatment of acute toxic ingestions. Two hundred adult patients with mild to moderate oral overdoses were entered into the trial. Patients receiving only activated charcoal were discharged from the emergency department in significantly (P less than or equal to .05) less time than those receiving both syrup of ipecac and activated charcoal (6.0 +/- 0.3 vs 6.8 +/- 0.2 hours, respectively). The percentage of patients requiring nonpsychiatric hospitalizations was not significantly different between the two groups (11.2% vs 14.0%, respectively). For the hospitalized patients, the length of time spent in the ICU and in the hospital was not statistically different between the two groups. A complication rate of 5.4% was found with the ipecac and activated charcoal treatment compared with a 0.9% complication rate in the activated charcoal group (P less than or equal to .05). Three episodes of aspiration pneumonitis occurred after administration of ipecac and activated charcoal, while no episodes of aspiration were noted after treatment with only activated charcoal. Together, these data are consistent with the recommendation that ED treatment with activated charcoal alone be the gastrointestinal decontamination procedure of choice for the routine mildly-to-moderately orally poisoned adult patient.     

Hemoglobin oxygen saturation discrepancy using various methods in patients with sickle cell vaso-occlusive painful crisis

OBJECTIVE: To evaluate agreement among various methods for measuring oxyhemoglobin (O2Hb) saturation in adult hypoxic patients with sickle cell disease (SCD) during painful vaso-occlusive crisis and to compare those results with a control group. PATIENTS AND METHODS: The hemoglobin oxygen saturation was determined simultaneously by pulse oximetry (SpO2), co-oximetry [SO2 (functional oxyhemoglobin saturation) and FO2Hb (oxyhemoglobin fraction)] and by calculation (SaO2) using a normal O2Hb dissociation curve in 18 adult patients with SCD during vaso-occlusive crisis and 12 non-SCD patients with various cardiopulmonary diagnoses. The method proposed by Bland and Altman was used to evaluate agreement of various methods in each of the two groups. RESULTS: Mean differences between various methods in patients with SCD were significantly larger than the control group. Limits of agreement (LOA) were also wider in the SCD group than in the control group. Mean bias between SpO2 and SO2, and SpO2 and FO2Hb in patients with SCD were -3.1 +/- 4.4 (LOA: -11.9 to 5.7) and 2 +/- 4.1 (LOA: -6.2 to 10.2) respectively, compared with -1.4 +/- 1.4 (LOA: -4.2 to 1.4) and 1.2 +/- 1.5 (LOA: -1.9 to 4.3) in the control group. A mean bias of -4.5 +/- 4 (LOA: -12.5 to 3.5) between SpO2 and SaO2 was noted in patients with SCD compared with -0.1 +/- 2.1 (LOA: -4.3 to 4.1) in the control group. The width of LOA for various methods in patients with SCD ranged from 9.8 to 17.6 compared with 1.3 to 8.4 in the control group. CONCLUSION: Patients with SCD during vaso-occlusive crisis have discrepancies in O2Hb saturation measurements by various methods. Abnormal pulse oximetry values in these patients should be interpreted cautiously and supplemented by arterial blood gas analysis and co-oximetry.     

Continuous electrocardiographic monitoring in patients with sickle-cell anemia during pain crisis

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.