Platt et al reported in 1994 a median age of death of 42 years in adult patients with SCD(9
). In contrast to Platt’s study, where age of death was determined from birth, patients in our study had to have survived to the age of 18 years to be included. Therefore, the patients in Platt et al’s work and our study represent two different populations and our median survival age cannot truly be compared. More recently based on an analysis from birth, Powars reported a median age of survival of 36.3 years for female patients and 38.7 years for male patients with SCD(5
). The median survival ages from our study agree fairly well with the results by Platt et al and Powars, if 95% confidence intervals are considered. Further, Steiner el al have reported that in-hospital deaths and death rate in United States hospitals remained stable for adult patients with SCD from 1998–2004 as compared to 1994–1997(34
). A likely explanation is that the causes of death are shifting from acute to chronic sickle-related complications.
Our results, representing an institution that specializes in the care of adult patients with SCD, show that a large proportion of the deaths were not from classic acute sickle-related complications. The most common known causes of death in our patient population while related to SCD were cardiopulmonary in nature, totaling 17 of 43 patients (39.5%) and the most prevalent was pulseless electrical activity arrest. This is likely in part secondary to hypoxia, myocardial infarction, CHF, and pulmonary disorders,. The other known causes of death included single or multi-organ failure (6 patients) and stroke (4 patients). Our findings are compatible with Steinberg et al(11
), who showed that 21 of their 75 deaths were due to pulmonary diseases, with SCD crisis and stroke each accounting for an additional 9 and 6 patients. Steiner and Miller(34
) also reported that of 113,098 hospital stays in the United States during which SCD was noted, cardiac and respiratory conditions accounted for 15% of deaths. Powars and colleagues reported that of 232 patients that died, the most common cause of death was chronic lung disease with pulmonary HTN and cor pulmonale in 47 patients (20%), and 12 of those patients had evidence of myocardial ischemia and fibrosis. An additional 7 patients (3%) died from cardiovascular disease(5
). These studies collectively suggest that in the post-hydroxyurea era, acute non-sickle-related complications leading to death may become the most prevalent.
Three of the deceased patients in our study had a history of myocardial infarction, suggesting that a small proportion of SCD patients will develop this lethal disease; however, its clinical manifestations appear to be different than in patients without SCD. Exercise testing has a low positive predictive value of myocardial ischemia(35
). Sickle vasculopathy has been shown to have many parallels with atherosclerosis, including endothelial activation and dysfunction, platelet activation, in situ thrombosis, and disordered apolipoproteins(36
). Still, patients with SCD who are found to have evidence of myocardial infarction on autopsy generally have no signs of coronary atherosclerotic disease(35
). This lack of atheroma formation may be due to the significantly decreased total cholesterol and low-density lipoprotein levels that occur in patients with SCD(36
The cause of death for six of the patients remains unknown. In addition, the cause of death listed on death certificates for three patients was “sickle cell anemia.” In past clinical series, the cause of death was stated as “unknown” or as “sickle cell disease” in 7–75% of cases(5
). This high proportion of ill-defined causes of death is thought to be secondary to the absence of uniformity in data collection and analyses among medical centers, lack of morphological evidence of some fatal physiological event, and insufficient interest, time, and/or resources for a more in-depth evaluation of the specific causes of death(24
). From our experience, even when the exact circumstances surrounding death were detailed, the exact cause of death was frequently difficult to decipher.
The pattern of pre-morbid conditions of SCD seen in our deceased patients () were similar to previous reports, with ACS/pneumonia, cholethiasis, pHTN, and avascular necrosis at the top of the list. However, chronic conditions such as proteinuria, renal insufficiency, systemic HTN, and CHF were also very common. Further, many cardiopulmonary complications such as pHTN, CHF, myocardial infarction, and atrial fibrillation, and chronic conditions such as sickle cell nephropathy occurred significantly more commonly in deceased as compared to living patients. These observations suggest that while hydroxyurea may reduce acute sickle-related complications, end-organ damage continues to be very prevalent in this patient population.
In our study, seven patients had a history of significant cardiac arrhythmias, including five patients with atrial fibrillation, one with supraventricular tachycardia, and one with a history of ventricular fibrillation arrest. Inadequate blood supply to areas with fibromuscular dysplasia, microthrombosis, hypoxemia, and rheological abnormalities(41
) may lead to the development of fatal cardiac arrhythmias. The demonstration of both recent and old areas of fibrosis and degeneration near the cardiac conduction system suggests a chronic process. The risk of serious arrhythmia is increased during vasoocclusive crisis, as Maisel et al. demonstrated significant arrhythmias in 24 of 30 patients with continuous electrocardiographic monitoring during a vasoocclusive episode(31
). Further, they detected atrial and ventricular arrhythmias in 60 and 67% of patients, respectively, via 12-lead and 24-hour ambulatory electrocardiograms during vasoocclusive crisis. Nine of the 30 patients had “complex arrhythmias,” including two patients with ventricular tachycardia. Early detection of serious electrical disturbance may decrease the incidence of sudden cardiac death in patients with SCD.
Sudden cardiac death has been treated successfully in high-risk populations with implanted cardioverter defibrillators (ICD). Initial studies using the ICD focused on patients with ischemic cardiomyopathy and history of acute myocardial infarction(32
). More recently, the sudden cardiac death in heart failure trial (SCD HeFT) has extended the use of ICD therapy to patients without previous myocardial infarction(42
). These patients had heart failure due to left ventricular dysfunction and no other risk for sudden cardiac arrest. Nevertheless, ICD therapy was effective in preventing all cause mortality and sudden cardiac arrest. The key element in the success of ICD therapy has been the identification of a patient population at risk for sudden cardiac arrest and subsequent placement of an ICD. In our SCD patient population, usual risk factors for sudden cardiac death, including decreased ejection fraction and increased left ventricular size, were not significantly different between patients who were living and deceased. Further study is indicated to identify cardiac risk factors associated with increased mortality such that a select group of patients with SCD can be followed more closely and be exposed to more aggressive and invasive clinical interventions as deemed necessary if we hope to be successful in preventing premature death.
Increased anemia was found to be a risk factor for early death in our study. Sebastiani et al. have shown that an elevated lactate dehydrogenase level, due to hemolysis, contributed to an increased risk of death in patients with SCD(43
). Baseline WBC and oxygen saturations were not significantly different between deceased and living patients. The presence or absence of α-thalassemia was not available for our study groups. Platt and colleagues previously reported that α-thalassemia status was not associated with mortality in patients with SCD. Fourteen of the deceased patients had evidence of iron overload, with ferritin levels ≥ 1000 mcg/L, as a result of chronic transfusion therapy. Although our patients with history of cardiac complications had higher ferritin levels, this difference was not statistically significant. As ferritin levels do not correlate well with hepatic iron concentration and may not be a reliable marker of iron stores in patients with SCD(44
), our patients with cardiac complications may indeed have higher iron stores, contributing to the observed cardiac complications and premature mortality in our patients. In contrast to studies performed in patients with thalassemia(46
), severe iron overload has not been found to be associated with cardiac arrhythmias and CHF in patients with SCD. However, studies have shown that chronically transfused patients with SCD have increased mortality as compared to non-transfused patients with SCD(48
), though the contribution of iron overload to this increased mortality is difficult to decipher. Further, the ferritin level has been found to be a univariate predictor of death in patients with SCD(50
In conclusion, despite advances in medical therapy, patients with SCD continue to die prematurely. Our patients died most commonly from cardiopulmonary disease and multi-organ failure, shifting from the previously reported infectious and sickle cell-related causes of death. As acute complications of SCD are ameliorated by hydroxyurea, end-organ damage continues to accumulate. Further studies are indicated to determine which patients should be aggressively treated to prevent early fatal cardiopulmonary complications.