When to Transfuse Blood in Sickle Cell Disease?

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 24, No. 5 Copyright 1994, Institute for Clinical Science, Inc. When to Transfuse Blood in Sickle Cell Disease? Lessons from Jehovah s Witnesses*! EUGENE S. PEARLMAN, M.D. and SAMIR K. BALLAS, M.D. Cardeza Foundation fo r Hematologic Research, and Thomas Jefferson University H ospital Blood Bank, Department o f Medicine, Jefferson Medical College, Philadelphia, PA ABSTRACT Hemoglobin concentration of 7 to 8 g/dl has been considered an indication for transfusion in the general adult population and has also been frequently applied to patients with sickle cell disease (SCD). Through a review of the case histories of two patients with SCD who were also Jehovah s Witnesses and developed severe anemia, and, considering as well the clinical characteristics of this population and the basic physiology of oxygen transport, the appropriateness is questioned of this transfusion trigger in patients with SCD. It is suggested for the latter that a Hb of 5.5 g/dl be used as an indication for transfusion except in very specific clinical circumstances. risks attendant upon such a policy including alloantibody formation, iron overload, and infectious disease transmission. These considerations led us to consider the question of how well patients with SCD can tolerate severe anemia and then to query what Hb should be an indication for transfusion in this population. This issue has been approached by reviewing two patients with sickle cell anemia who were Jehovah s Witnesses and, hence, refused blood products. One of them also refused dialysis. The patients presented the opportunity to observe their response to severe anemia without the confounding effect of concurrent transfusion therapy /94/ $00.90 Institute for Clinical Science, Inc. Introduction At present there appears to exist a concensus supporting a Hb of 7.0 to 8.0 g/dl as an indication for transfusion.1 2,3,4 This criterion has also generally been applied to individuals with sickle cell disease (SCD). Since the Hb in this population is normally 7 to 8 g/dl,5,6 application of this criterion would result in frequent transfusion of patients with SCD with all the * Presented in part at the Annual Meeting of the American Society of Hematology, D ecem ber 6, f Address reprint requests to: Samir K. Balias, M.D., Cardeza Foundation, 1015 W alnut Street, Philadelphia, PA

2 Case H istories C a s e R e p o r t 1 WHEN TO TRANSFUSE BLOOD IN SICKLE CELL DISEASE? 397 L.J. was a 25-year-old female admitted to Thomas Jefferson University Hospital (TJUH) on 5/23/89 with a 3-day history of fatigue and dizziness. The patient s medical history was significant for the diagnosis of sickle cell disease requiring occasional hospitalizations for management of painful crises. As an outpatient, her most recent Hb had been 8.5 g/dl on 3/14/89. From observations during preceding and subsequent admissions, her base line Hb and heart rate (HR) were estimated as 7.5 to 8.5 g/dl and 80 to 90/min, respectively. At the time of her current admission, the patient s HR was 104/min and jugular venous distension (7 cm) was noted, indicating congestive heart failure. Although chest film on admission showed mild cardiomegaly, an ultrasound study of the heart done two days after admission was normal. Her Hb was 3.2 g/dl with a reticulocyte count of 0.9 percent. A diagnosis of aplastic crisis, possibly secondary to infection, was made and the patient was placed on 2 L/min of Oa by nasal cannula. The patient s daily Hb, peak HR, 0 2 therapy, and other hematologic parameters are presented in table I. After the 5th day of hospitalization the patient started to im prove gradually; by the 12th day, she was ambulating without difficulty and without supplem ental 0 2. One hundred days post discharge, the patient s Hb was 7.0 g/dl, and reticulocyte count was 17.7 percent. Ten days later, her Hb TABLE I increased to 7.8 g/dl while her reticulocyte count fell to 9.9 percent. In a subsequent admission to TJUH for treatment of painful crisis in February, 1991, her predischarge Hb and HR were 8.7 g/dl and 86/min respectively. C a s e R e p o r t 2 C.M. was first seen at TJUH in 1959 at age 5 months at which time the diagnosis of sickle cell disease (SCD) was made. The patient had 6 pediatric adm issions for infectious problem s but no admissions to TJUH were noted betw een 1966 and Between 1978 and her demise in October, 1987, the patient had 56 admissions to TJUH. The patient s cardiac silhouette on chest x-ray was unremarkable as was her electrocardiogram (EKG) until 8/86 when her Hb dropped below 5 g/dl. At that time the EKG was interpreted as suggesting left ventricular hypertrophy w hile the chest x-ray was read as showing an enlarged cardiac silhouette without congestive heart failure. Subsequent chest films were unchanged up to the time of the patient s demise. The patient s serum creatinine (Cr) was within the reference range until 4/86 at which time it rose to 2.2 mg/dl while urinalysis revealed 4 + proteinuria. The Cr was stable until 4/87 when it rose to 4.5 mg/dl and then rose continuously, reaching 21.2 mg/dl in 10/87. The patient was fully ambulatory until the admission of 6/4/87 when she was noted to be lethargic with a wide shuffling gait. At that time the Hb was 3.3 g/dl, the Cr was 6.4 mg/dl, and the Heart Rate and Hematologic Parameters for Patient L.J. Hospital Day Hb Hct Reticulocyte Count % WBC Platelet Heart Rate 02 Therapy , ,000 n.d ,600 n.d , , L/min , , L/min , , L/min n.d. n.d L/min ,000 n.d L/min n.d. n.d L/min , L/min , , L/min n.d n.d. n.d L/min ,800 n.d L/min ,200 n.d ,200 n.d , ,000 n.d , ,000 n.d. 0 n.d. = not determined.

3 398 PEARLMAN AND BALLAS first appearance of facial and periorbital edem a was noted. T he patient consistently refused dialysis and succumbed to uremia on 10/16/87. In 53 of 56 admissions to TJUH, patient C.M. had a predischarge Hb of 3=4.0 g/dl. The Hb was 3*7.0 g/dl in 34 admissions (average = 7.9 g/dl) and 3*4.0 but <7.0 g/dl in 19 admissions (average = 5.7 g/dl). No difference in average predischarge HR was noted between these two groups of admissions (90/ m in and 88/min, respectively). An approximately inverse linear relationship betw een HR and Hb, when the latter was less than or equal to 4.0 g/dl, could be described by the following equation: (1) HR = [Hb] (r2 = 0.905, p < 0.05) which was derived by ordinary least squares techniques. No obvious relationship betw een these variables was noted for Hb between 4.0 and 9.1 g/dl. There was no EKG or radiologic evidence of ventricular hypertrophy until this patient s Hb was below 5 g/dl and clinical symptoms related to her degree of anemia were not apparent until her Hb dropped below 4 g/dl. C.M. s predischarge Hb is plotted as a function of time (days from the initial Hb determination) in figure 1. Although the data points are not equally spaced in time and considerable scatter is noted, there is a suggestion of a decrease in Hb beginning in 7/84, approximately 2 years prior to the onset of obvious renal failure. From 4/78 through 5/84, C.M. s Hb averaged 8.08 g/dl ± 0.49 (mean ± SD; n = 22) while from 7/84 through 1/86, the mean Hb dropped to 6.86 g/dl ±0.77 (n = 24). This decrease was statistically significant (p < 0.01 by Student s t-test) and contrasts with the view that in the absence of other disease the degree of anemia in patients with SCD is stable.2 No explanation is immediately available, and, unfortunately, erthropoietin assays were not available when these Hb data were collected. Discussion As previously noted, there appears at present to be a concensus favoring an Hb of 7 to 8 g/dl as an indication for transfusion in the general adult population. For patients with SCD whose baseline Hb is usually between 7 to 8 g/dl, application of such a standard would result in frequent transfusion and consequent increased exposure of this population to the hazards associated with transfusion. Because of the relative difficulty of recruiting minority blood donors, patients with SCD may be at risk for the development of alloantibodies.7,8,9 These considerations argue for a conservative approach to blood transfusion and critical assessment of the Hb concentration which should trigger transfusion in patients with SCD. Observations on the two patients suggest that individuals with SCD are able to tolerate a severe degree of anemia w ithout obvious clin ical seq u elae. Whether in the recovery phase of aplastic crisis or in the context of increasing ane F i g u r e 1. Longitudinal changes in Hb for patient C.M. The arrow in d ic a te s th e tim e o f onset of renal failure. Hb DAYS

4 WHEN TO TRANSFUSE BLOOD IN SICKLE CELL DISEASE? 399 mia secondary to concurrent chronic renal failure, no deviation from baseline HR was noted until the Hb reached 4 g/dl. In patient C.M. no EKG or radiological evidence of left ventricular hypertrophy was noted until the Hb decreased below 5.0 g/dl, and no evidence of congestive heart failure was ever noted. Although exercise tolerance data are not available for either patient, both appeared to be fully ambulatory until their Hb dropped below 4.0 g/dl. There is, therefore, some grounds for believing that anemia with Hb less than 7.0 to 8.0 g/dl could be sustained. From the standpoint of 0 2 transport, there is also some basis for thinking that a Hb of less than 7.0 to 8.0 g/dl could be well tolerated, at least in the absence of other disease conditions (vide infra). Elementary physiological considerations10 lead to the following equation for the Hb concentration required to ensure a fixed oxygen delivery rate to tissue: where A is the rate of 0 2 delivery to tissue (ml/min), S is the fractional hemoglobin saturation by 0 2, C is the 0 2 carrying capacity of the Hb (ml/g), E is the 0 2 extraction ratio (arterio-venous 0 2 difference divided by the arterial 0 2 content and Q is the cardiac output ml/min). Increases in E and Q occur in the presence of anemia; in patients with SCD in whom an exchanged Bohr effect has been noted, a set of reasonable values for the parameters in equation 2 would appear to be S = 0.95, C = 1.37 ml/g, E = 0.50 and Q = 8800 ml/min.11,12 This value of Q is 1.6 times the cardiac output of a 70 kg individual at rest; it is much less than the increases in Q achieved during heavy exercise and in the absence of intrinsic cardiac disease should be sustainable for a prolonged period and probably indefinitely. With respect to the parameter A, it is not clear why tissue 0 2 requirement should increase above baseline (240 to 250 ml/min for a 70 kg individual at rest) secondary to anemia per se but a 15 percent increase above baseline is assumed to account for increased cardiac work. Hence, A is taken as 290 ml/min. Inserting these values into equation 2 yields a required Hb of 5.06 g/dl to ensure adequate 0 2 delivery to a 70 kg individual at rest. This approach does not consider possible increased efficiency of 0 2 utilization or the decreased use of 0 2 for heat generation.13,14 The clinical observations and physiological considerations argue that patients with SCD are capable of tolerating a Hb below 7 to 8 g/dl, and, in our view, suggest a Hb of 5.5 g/dl as a transfusion trigger in this population. This suggestion has to be placed, however, in the wider context of a cost-benefit analysis of transfusion in these patients. Reference has already been made to the risks of transfusion in this population, especially given the difficulty in minority donor recruitment. It is also well established that ordinary transfusion does not alter the course of vaso-occlusive crisis in patients with SCD.2 Transfusion in patients with SCD and Hb 2=5.5 g/dl is justified only in specific clinical circumstances which include acute bleeding, central nervous system complications, acute chest syndrome, severe hypoxia, or heart failure. Acknowledgment Support in part by the Sickle Cell Program of the Commonwealth of Pennsylvania and in part by the NIH Comprehensive Sickle Cell Grant # HL References 1. M enitove JE. Transfusion practices in the 1990 s. Ann Rev Med 1991;42: Wyngaarden JB, Smith LH, Bennett JC. Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992;893-8.

5 400 PEARLMAN AND BALLAS 3. Simon TL. Evolution in indications for blood fied transfusion program for prevention of component transfusion. Clin Lab Med 1992;12: stroke in sickle cell disease. Blood 1992;79: Office of Medical Applications of Research, 10. Naylor-Shepherd MF, Fuhs DW, Angaran DM. NIH, Bethesda, MD. Consensus Conference: Oxygen homeostasis: theory, m easurem ent, Perioperative Red Blood C ell Transfusion. and therapeutic implications. Drug Intell Clin JAMA 1933;260: Pharm 1990;24: Balias SK, Lewis CN, Noone AM, et al. Clinical, 11. Seakins M, Gibbs WN, Milner PF, Bertles JF. hematological and biochemical features of Hb Erythrocyte Hb-S concentration: an important SC disease. Am J Hematol 1982;13: factor in the low oxygen affinity of blood in 6. Balias SK, Larner J, Smith ED, et al. Rheologic sickle cell anemia. J Clin Invest 1973;52:422 predictors of the severity of the painful sickle 32. cell crises. Blood 1988;72: Ueda Y, Nagel RL, Bookchin RM. An increased 7. Vichinsky EP, Earles A, Johnson RA, et al. Bohr effect in sickle cell anemia. Blood 1979; Alloimmunization in sickle anemia and transfusion of racially unmatched blood. New Eng J 13. Whalen WJ. Intracellular P 0 2: a limiting factor 53: Med 1990;322: in cell respiration. Am J Physiol 1966;211: 8. Rosse WF, Gallagher D, Kinney TR, et al Transfusion and alloimmunization in sickle cell 14. Robin ED. Of men and mitochondria: coping disease. Blood 1990;76: with hypoxic dysoxia. Am Rev Resp Dis 1980; 9. Cohen AR, Martin MB, Silber JH, et al. A modi 122: