Henderson et al described significant neurologic syndromes associated with severe chest syndrome in children with sickle cell disease.1 All patients are described as being hospitalized and shortly thereafter developing respiratory distress and pain. The authors then report all patients “required” cytapheresis and intubation, often for prolonged periods. We wonder whether an early simple transfusion might have prevented the severe pulmonary decompensation seen in all of these patients. While some recommend exchange over simple transfusion for treatment of sickle cell complications,2 these recommendations are based primarily on in vitro laboratory data suggesting simple transfusion is deleterious from a viscosity standpoint.3 The only clinical trial comparing the 2 modalities was a study of preoperative transfusion,4 which demonstrated no benefit to exchange and in fact increased complications in the group that received them. In the recent comprehensive study of acute chest syndrome by Vichinsky et al,5 the authors reported no difference in clinical course whether exchange or simple transfusion was used initially. We commonly use simple transfusion therapeutically, have been very impressed with efficacy, and several years ago reported dramatic improvement in indices of oxygenation after transfusions, 18 of 21 of which were simple.6 We are concerned that delay in implementing exchange transfusion, particularly if cytapheresis is used, may be critical in allowing irreversible progression of acute chest syndrome, progression that might be circumvented by early simple transfusion.
Secondly, the authors mention “silent infarction” prominently in their discussion. Most define silent infarction as a lesion on brain magnetic resonance imaging (MRI) of a patient who has not had a cerebrovascular accident,7 and the Cooperative Study of Sickle Cell Disease (CSSCD) has identified risk factors for these lesions (low hemoglobin, high white count, elevated “pocked” red cell count, and Senegal haplotype; notably, rate of acute chest syndrome was not a risk factor),8 as well as an association with neuropsychologic deficits9 and overt stroke.10 Given the impressive clinical neurologic findings that occurred in several of the patients reported by Henderson et al, we feel it is not appropriate to classify the MRI abnormalities subsequently discovered as “silent.”
Finally, the CSSCD previously reported an association of cerebrovascular accident not only with proximate acute chest syndrome but also in patients with recurrent acute chest syndrome,11 suggesting perhaps pathophysiologic similarities. The recent description of pulmonary hypertension and pulmonary vascular changes similar to that seen in cerebrovascular disease12 suggests a pathologic link between these complications now further documented clinically.
In summary, we urge physicians taking care of children with acute chest syndrome and respiratory difficulty to consider simple transfusion as early therapy. We agree that risk of cerebral injury during these episodes is real, but are not convinced that an association with silent infarction has been demonstrated.
Response: Neurologic morbidity and severe acute chest syndrome
We appreciate the interest in neurologic morbidity in children with sickle cell disease and acute chest syndrome (ACS). In response to the comments by Drs Miller and Rao regarding our manuscript describing neurologic manifestations of severe ACS in 5 patients,1 all of our patients were initially managed with at least one simple blood transfusion. Despite transfusion therapy, all of the patients clinically deteriorated, developing respiratory failure requiring intubation and mechanical ventilation with transfer to the Pediatric Intensive Care Unit. Currently, the standard of care for ACS at our institution includes monitoring the hemoglobin level and administering a simple blood transfusion in patients with a decreasing hemoglobin level and/or symptoms of worsening respiratory failure. This case series was a description of our observations and experiences with 5 patients who progressed to respiratory failure after receiving blood transfusion early in their ACS course.
Despite the assertion by Miller and Rao, the evidence to support a simple transfusion over erythrocytapheresis early in the course of ACS is lacking. To our knowledge, no randomized control trial exists comparing simple transfusion therapy with erythrocytapheresis for ACS. Further, the potential benefits versus risks of repeated simple transfusions in this patient population should be evaluated carefully. Of 5 patients, 4 had a positive fluid balance prior to their neurologic event, 3 with subsequent hypertension and reversible posterior leukoencephalopathy syndrome.
In regard to our definition of silent cerebral infarct, we defined a silent infarct as a lesion consistent with infarction on magnetic resonance imaging without evidence of a focal neurologic finding lasting longer than 24 hours. This definition is based on the one used by a standard neurologic textbook that defines a stroke as a “sudden occurrence of a nonconvulsive, focal neurologic deficit” and distinguishes strokes from reversible transient ischemic attacks based upon duration of symptoms lasting less than 24 hours.2 Additionally, our definition of silent cerebral infarct is one that we have used previously.3 In our case series, none of the 3 patients determined to have a silent cerebral infarct had evidence of a focal neurologic deficit persisting longer than 24 hours. Patient 1 had a headache (a nonfocal neurologic symptom); patient 2 had generalized and multifocal seizures and transient, mild right-arm weakness and left-eye deviation lasting less than one hour (focal findings resolved in one hour); and patient 3 had evidence of diffuse deconditioning (nonfocal) after being intubated for several months. All patients had normal neurologic examination after being examined by a pediatric neurologist.
Regardless of the definition of silent cerebral infarcts, children with sickle cell anemia and ACS have a high incidence of cerebral infarcts, placing them at increased risk for further neurologic morbidity4,5 and associated cognitive impairment.6 In the setting of severe ACS following erythrocytapheresis, we recommend consideration be given for assessment of occult neurologic morbidity.
Correspondence: Michael R. DeBaun, Washington University School of Medicine, St Louis Children's Hospital, Box 8116, One Children's Place, St Louis, MO 63110
