- Email: [email protected]
Plasma exchange in critically ill patients with sickle cell disease
Transfusion and Apheresis Science 37 (2007) 17–22 intl.elsevierhealth.com/journals/tras
Plasma exchange in critically ill patients with sickle cell disease C. Boga
a,*
, I. Kozanoglu
b,1
, H. Ozdogu
a,1
, Emel Ozyurek
c,1
a
Department of Hematology, Baskent University Faculty of Medicine, 06490 Ankara, Turkey Department of Physiology, Baskent University Faculty of Medicine, 06490 Ankara, Turkey Department of Pediatric Hematology, Baskent University Faculty of Medicine, 6490 Ankara, Turkey b
c
Received 21 November 2006; accepted 23 December 2006
Abstract Red cell exchange transfusion is the recommended therapy for patients with sickle cell disease who have complicated vaso-occlusive episodes. However, the role of the therapeutic plasma exchange in the management of the potentially life-threatening complications in patients with sickle cell disease is not well known. To determine whether plasma exchange had a cumulative effect on the red cell exchange in patients with sickle cell disease who developed multi-organ failure during the post red cell exchange period, we performed plasma exchange in the nine episodes of multi-organ failure of 7 patients with sickle cell anemia. The median age of those patients was 21 years (range, 9–50 years). The criterion of the multi-organ failure was defined as organ failure of two or more organs i.e. lung, liver, or renal, established according to Acute Physiological and Chronic Health Evaluation-II (APACHE-II) criteria. The average total plasma exchange volume was 1.0 times the patient’s plasma volume. The patients had a good outcome, with a survival rate at 86% after one year of follow-up. Plasma exchange may have cumulative benefits in the treatment of severe illness in patients with sickle cell disease who underwent automatic red cell exchange therapy. 2007 Elsevier Ltd. All rights reserved. Keywords: Sickle cell disease; Plasma exchange; Automatic red cell exchange; Vaso-occlusive crisis; Apheresis
1. Introduction The term ‘‘sickle cell syndrome’’ refers to a group of diseases characterized by the presence of hemo*
Corresponding author. Present address: Baskent University Adana Teaching and Medical Research Center, Dadaloglu Mahallesi, Serin Evler Sokak 39, No. 6 Yuregir, 01250 Adana, Turkey. Tel.: +90 322 327 27 27 2164; fax: +90 322 328 51 59. E-mail addresses: [email protected] (C. Boga), ipa [email protected] (I. Kozanoglu), hakanozdogu@hotmail. com (H. Ozdogu), [email protected] (E. Ozyurek). 1 Tel.: +90 322 327 27 27 2164; fax: +90 322 328 51 59.
globin S, but sickle cell disease (SCD) is the result of homozygosity for hemoglobin S, which causes rigid sickled erythrocytes. SCD is characterized by chronic hemolysis, frequent infections, and recurrent occlusion of the microcirculation, all of which cause painful crises and can result in chronic organ damage and organ failure [1–3]. However, it is not only the cellular component of the peripheral blood which contributes to the development of complications. Plasma factors such as cytokines, chemokines, other factors that can alter endothelial apoptosis and acute-phase proteins seem to be involved with
1473-0502/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2006.12.009
18
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
possible mechanisms of action in the vaso-occlusive phenomena of SCD [4–8]. Transfusion remains an essential component of care for patients with SCD [9]. In patients with SCD, transfusions are most readily accomplished via automatic red cell apheresis [10]. The purpose of this report was to describe 7 patients with SCD who underwent plasma exchange because their critical clinical condition failed to respond to automatic red cell apheresis. 2. Materials and methods We enrolled 7 patients (2 women and 5 men; age range, 9–50 years) with SCD who developed multiorgan failure during sickle cell crisis. Studies involving patients with SCD, >6 months of follow up, no treatment with hydroxyurea, and outcome measures on physical status or pain were included. Nine episodes of multi-organ failure were identified in these patients and defining criteria of organ failure of two or more organs that is lung, liver, or renal was established according to Acute Physiological and Chronic Health Evaluation-II (APACHE-II) criteria [11]. The median (range) hospitalization duration of the patients was 7 days (range, 2–31 days). During their hospital stay, the patients underwent red cell exchange because of indications such as painful crises (for 3 patients), stroke/TIA (for 1 patient), or hepatic necrosis (for 3 patients). When the signs of multi-organ dysfunction occurred in these patients after red cell exchange, the patients underwent plasma exchange. The following information was extracted from the patients’ medical records: age; sex; symptoms at presentation; the results of physical examination, microbiologic cultures and serologic tests; treatment; comorbid medical conditions; and the outcome of treatment. The patients were followed for one year. Good outcome of the plasma exchange was defined as Glasgow–Pittsburgh Cerebral Performance category 1 or 2 for neurologic events, improvement of renal function and liver function (to achieve a postapheresis creatinine and bilirubin value that is the same as the steady state one), or normalization of arterial blood pressure and partial oxygen pressure [12]. Homozygous SCD was identified by the results of hemoglobin electrophoresis performed with high-performance liquid chromatography (BioRad Laboratories, Irvine, California, USA). The clinical diagnosis of painful crisis was based on the
following criteria: widespread pain typically involving the limbs, vertebrae, or ribs that could be ascribed to vascular occlusion and/or ischemic tissue damage and the relief of symptomatic pain after the administration of an analgesic medication. Stroke/TIA was defined by criteria from the American Neurological Association [13]. Finally, hepatic necrosis was defined by signs of basic biochemical examination. Microbiologic samples were collected and processed according to well-established published guidelines [14]. Laboratory measurements for the periodic quality control program were made by Bio-Rad Laboratories External Quality Assurance Services (Bio-Rad Laboratories, Catalog 3517, Irvine, California, USA). The institutional review board of the Baskent University in Ankara, Turkey, approved the study. 2.1. Automated red cell exchange procedure A 20-gauge Intracath catheter was used to access the peripheral vein and to provide an exit route from the opposite arm. An automated system (Cobe Spectra 7.0, Lakewood, CO, USA) that separates cells via continuous blood flow was used to exchange 60–70% of the patients’ red cells with new red cells of the same blood type and crossmatch. As a result, the hemoglobin S level in the peripheral blood was reduced to less than 30% of the total hemoglobin content. Leukofiltered red cell suspensions preserved for 1–7 days by citrate phosphate dextrose and with a hematocrit level of about 75% were used. Target hematocrit was guided by a complicated pain episode (clinical deterioration; a hemoglobin level of less than 7 g per deciliter; leukocytosis in the absence of infection; an underlying pulmonary or cardiac disease) and the steady state hematocrit level that was noted in sickle cell patients attending outpatient regularly [15]. The patients required a target hematocrit of 30–34% after the red cell exchange was arranged in order to get a safe patient outcome. The inlet pump flow rate and centrifugation speed were automatically adjusted according to parameters preset by patient data (weight, height, sex, and hematocrit level) during red cell exchange. In those procedures, cells were exposed to 930 g during a maximum centrifugation speed of 2400 rpm (Cobe Spectra Apheresis System Essential Guide). In some patients, the inlet pump flow rate was regulated manually. The flow rate was selected for a range of 15–60 mL/min, and the centrifuge speed was established at 400–2400 rpm
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
(up to 930 g). The mean centrifugation time was 90.38 ± 37.58 min for all procedures. The total blood volume was calculated according to body weight (70–75 mL/kg), and the calculation of the red cell volume was based on hematocrit values [2]. All procedures used acid-citrate-dextrose A solution (ACD-A) (whole blood to ACD-A ratio = 14:1). 2.2. Plasma exchange A 20-gauge Intracath catheter was used to access the peripheral vein and to provide exit route from the opposite arm. Total blood and plasma volumes were calculated via the standard formulation [15]. At each session, approximately 1–1.5 L of plasma was exchanged by means of an automated system (Cobe Spectra 7.0, Lakewood, CO, USA). Fresh frozen plasma was chosen as the replacement fluid because of prevention of unwanted effects on plasma viscosity and replacement of coagulation factors. One plasma volume exchange with fresh frozen plasma of the patient’s blood type was performed. The procedure was performed with 50% plasma and 50% albumin in patients whose albumin was under 3 gr/dL. Total protein and calcium levels were measured before and after all procedures in all patients. Each apheresis procedure took about 2– 3 h. 3. Results Nine procedures were performed in 7 patients, in patient 2 and patient 5, plasma exchanges were performed in more than one episode. The time period between the episodes in these patients was 1 year for patient 2 and 41 days for patient 5. They were represented separately (Table 1). Symptoms at the time of the plasma exchange procedures included dyspnea in 67% of the patients, progressive jaundice (55%), pleuritic chest pain (11%), hematuria (33%), oliguria (22%), painful crisis (33%), palpitation (100%), coma (44%), and fever (44%). The median duration of symptoms before the plasma exchange procedures was 4 days (range, 1–9 days). The median time interval between automatic red cell apheresis and plasma exchange was 3 days (range, 1–9 days). The mean (range) hematocrit was 29 (27–33%), platelet 224 (216–474 · 109/L) and hemoglobin S 29 (18.5–35.5%) before plasma exchange. Patient 2
19
and patient 4 received fresh frozen plasma and albumin as a replacement fluid. Potential sources or predisposing conditions for deteriorating clinical and metabolic states were identified during the nine episodes of the 7 patients (Table 1). The results of microbiologic studies failed to reveal the pathogens most likely to have caused fever. Abnormalities were noted in 3 of the patients whose chest radiographs were available for current review. The radiographs demonstrated patchy alveolar infiltrates and/or peripheral reticular opacities and peripheral ground-glass opacities in the lower lobes in patient 1; those findings were bilateral in patient 2 and patient 3. Serologic markers of inflammation, such as the erythrocyte sedimentation rate and the level of C-reactive protein, were found to be elevated in all patients. Renal, respiratory, cardiovascular, cerebral, and hepatic status are presented in the Table 1. All but 2 patients received parenteral antibacterial therapy, and the remaining patient was treated only with oral antimicrobial treatment. Ceftriaxone (Rocephine, Roche, Basel, Switzerland) and clotrimazole (Klacid, Abbott Lab, Abbott, France) were the most preferred antimicrobial agents. The duration of antibacterial therapy ranged from 1 to 3 weeks. One patient was treated with prednisolone (Deltacortril, Pfizer, Switzerland) 5 mg per day for intrahepatic cholestasis, which was in the ductular phase. Only 1 patient demonstrated paresthesia caused by hypocalcemia during apheresis, and 2 patients experienced a venous access problem. No complication occurred during the other apheresis procedures. The outcome of the plasma exchange procedures were summarized in Table 1. One patient (patient 3) died on the subsequent day of plasma exchange because of multi-organ failure. In the other patients, good outcome was achieved approximately two weeks after plasma exchange, with a survival rate at 86% after one year of follow-up. 4. Discussion Homozygous SCD is prevalent among the people who live in the Mediterranean region of southern Turkey. It has been reported that the rate of hemoglobin S is 3.9% in the entire population of Turkey if ethnic groups are not considered [16]. The main clinical features of SCD are caused by chronic hemolysis, microvascular ischemia, and organ
20
Table 1 Clinical characteristics of patients with sickle cell disease who were eligible for plasma exchange Age (y), sex
Predisposing condition
Flare in renal activity
Acute chest syndrome
Stroke
Heart failure
Hepatic necrosis and/or intrahepatic cholestasis
Exchanged plasma (mL)
Red cell transfusion need/no. units after PE
Outcome/ hospital stay (day) after PE
1/1
30, F
IBT UI
Cr > 2 mg/dL
Hypoxemia
–
–
2500
6
2/2
50, M
HN
Coma
–
HN
Coma
EF < 55%
3850
–
Good outcome/ 3
4/3
21, F
P
–
Coma
EF < 55% Shock
3467
2
Death/1
5/4
22, M
HN
Cr > 2 mg/dL Hematuria
Coma
EF < 55% Shock
6/5
17, M
OP
–
Hypoxemia Pulmonary infiltrates Hypoxemia Pulmonary infiltrates Hypoxemia
ALT: 66 IU/L AST: 171 IU/L Bil: 44 (total 35 mg/dL) ALP: 289 IU/L ALT: 19 IU/L AST: 15 IU/L Bil: 69 (total 52 mg/dL) ALP: 193 IU/L –
3520
50, M
Pulmonary infiltrates Hypoxemia Hypoxemia
Good outcome/ 3 Good outcome/ 7
3/2
Cr > 2 mg/dL ATN Hematuria Cr > 2 mg/dL Oliguria
EF < 55% Shock EF < 55%
–
7/5
17, M
OP,IU
Cr > 2 mg/dL
–
–
EF < 55% Shock Shock
8/6
9, M
HN
Cr > 2 mg/dL Hematuria
–
–
Shock
9/7
18, M
P,IBT,HN
Cr > 2 mg/dL
–
–
EF < 55% Shock
ALT: 41 IU/L AST: 40 IU/L Bil: 84 (total 52 mg/dL) ALP: 154 IU/L –
2980
–
Good outcome/ 12
3742
7
–
3658
–
ALT: 183 IU/L AST: 120 IU/L Bil: 28 (total 20 mg/dL) ALP: 367 IU/L ALT: 183 IU/L AST: 120 IU/L Bil: 28 (total 20 mg/dL) ALP: 367 IU/L
1121
–
Good outcome/ 3 Good outcome/ 11 Good outcome/ 4
4076
–
Good outcome/ 4
PE, Plasma exchange; F, female; IBT, incompatible blood transfusion; UI, urinary infection; M, male; HN, hepatic necrosis; P, pregnancy; OP, operation; Cr, creatinine; ATN, acute tubular necrosis; EF, ejection fraction; Bil, bilurubin: ALP, alkaline phosphatase.
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
Episode no./ Case no.
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
damage. The most common complication is vasoocclusive crisis [2,3]. Most patients with SCD receive transfusions at some point in their life to reduce the incidence of complications from their disease. The indications for red cell exchange transfusion include acute stroke, acute chest syndrome with severe hypoxia, acute multi-organ failure, and (possibly) priapism [2,9,10]. It is generally accepted that red cell exchange transfusion is indicated before extensive surgery as a prophylactic measure against recurrent cerebrovascular accidents [2,9,10]. The goals of the erythrocyte exchange procedure are to decrease the concentration of hemoglobin S to a value below 30% of the total hemoglobin level in the peripheral blood and to lower the levels of erythrocyte-expressed integrin a4b1 and surface glycoprotein IV (thrombospondin receptor, CD36) to prevent interactions between red cells, endothelial cells, and platelets [1,4,5]. On their surface, reticulocytes express the integrin complex a4b1, which binds to plasma and endothelial membrane fibronectin and to an adhesive molecule on the surface of the endothelial cell vascular cell adhesion molecule-1 [4,5]. In that way, tissue oxygenation can be restored and nitric oxygen production can be increased to maintain vasodilatation and modulate hemostasis [17]. However, the adhesiveness of reticulocytes and young (reversibly sickled) red cell to the vascular endothelium and the initiation of endothelial activation are associated with the production of cytokines (tumor necrosis factor, interleukin-1, interleukin-6, and interleukin-8) [1,4]. These cytokines (particularly tumor necrosis factor) can be found in plasma, and interleukin-6 can stimulate the liver to produce acute-phase proteins such as C-reactive protein [4,7]. Other plasma factors such as endothelin-1, endotoxins associated with infections, and chemokines can alter the apoptosis of endothelial cells and neutrophils [4–8]. This derangement in apoptosis probably contributes to endothelial damage and tissue ischemia [4]. Plasma exchange conducted by new-generation machines is rapid and safe, although an experienced team must perform that procedure. With an automated system that separates cells from plasma by means of continuous blood flow, 60–70% of a patient’s plasma can be exchanged for donor plasma during a single procedure [15]. In a brief report on plasma exchange in patients with SCD, Svarch and colleagues observed a dramatic improvement in a child with SCD in whom acute cholestasis and a neu-
21
rologic syndrome developed after a plasma exchange [18]. For use in our patients, we first preferred automated red cell exchange. Plasma exchange was performed after the onset of the multi-organ failure during post red cell apheresis period. Our data suggest that in some patients with SCD whose clinical condition is critical, plasma exchange exerts a cumulative effect on erythrocyte exchange and restores microcirculation to deteriorated tissue. Although we did not achieve data regarding what types of plasma components are eliminated, our findings indicate that plasma exchange may play a role in the recovery of critically ill patients with SCD who have not benefited from automated red cell exchange. References [1] Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762–9. [2] Saunthararajah Y, Vichinsky PE, Embury HS. Sickle cell disease. In: Hoffman R, Benz Jr EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, et al., editors. Hematology: basic principles and practice. Philadelphia: Elsevier; 2005. p. 605–44. [3] Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–44. [4] Makis AC, Hatzimichael EC, Bourantas KL. The role of cytokines in sickle cell disease. Ann Hematol 2000;79: 407–413. [5] Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest 1997;99:2561–4. [6] Schroder JM, Christophers E. Secretion of novel and homologous neutrophil-activating peptides by LPS-stimulated human endothelial cells. J Immunol 1989;142:244–51. [7] Hedo CC, Aken’ova YA, Okpala IE, Durojaiye AO, Salimonu LS. Acute phase reactants and severity of homozygous sickle cell disease. J Intern Med 1993;233:467–70. [8] Hebert MJ, Gullans SR, Mackenzie HS, Brady HR. Apoptosis of endothelial cells is associated with paracrine induction of adhesion molecules: Evidence for an interleukin-1beta-dependent paracrine loop. Am J Pathol 1998;152:523–32. [9] Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am 2005;19:803–26. [10] Singer ST, Quirolo K, Nishi K, Hackney-Stephens E, Evans C, Vichinsky EP. Erythrocytapheresis for chronically transfused children with sickle cell disease: An effective method for maintaining a low hemoglobin S level and reducing iron overload. J Clin Apher 1999;14:122–5. [11] Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India 2005;53:19–22. [12] Idris AH, Berg RA, Bierens J, Bossaert L, Branche CM, Gabrielli A, et al. Recommended guidelines for uniform reporting of data from drowning. Circulation 2003;108:2565.
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[13] Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation 2006;113:409–49. [14] Miler J. Bacteriology. In: Murray PR, Baron EJ, Phaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. Washington, DC: ASM Press; 1999. p. 33–104.
[15] McLeod BC. In: Bethesda MD, editor. Apheresis: principles and practice. AABB Press; 2003. [16] Kocak R, Alparslan ZN, Agridag G, Baslamisli F, Aksungur PD, Koltas S. The frequency of anaemia, iron deficiency, hemoglobin S and beta thalassemia in the south of Turkey. Eur J Epidemiol 1995;11:181–4. [17] Uchida K, Rackoff WR, Ohene-Frempong K, Kim HC, Reilly MP, Asakura T. Effect of erythrocytapheresis on arterial oxygen saturation and hemoglobin oxygen affinity in patients with sickle cell disease. Am J Hematol 1998;59:5–8. [18] Svarch E, Gonzalez A, Villaescusa R, Basanta P. Plasma exchange for acute cholestasis in homozygous sickle cell disease. Haematologia (Budap) 1986;19:49–51.
Plasma exchange in critically ill patients with sickle cell disease C. Boga
a,*
, I. Kozanoglu
b,1
, H. Ozdogu
a,1
, Emel Ozyurek
c,1
a
Department of Hematology, Baskent University Faculty of Medicine, 06490 Ankara, Turkey Department of Physiology, Baskent University Faculty of Medicine, 06490 Ankara, Turkey Department of Pediatric Hematology, Baskent University Faculty of Medicine, 6490 Ankara, Turkey b
c
Received 21 November 2006; accepted 23 December 2006
Abstract Red cell exchange transfusion is the recommended therapy for patients with sickle cell disease who have complicated vaso-occlusive episodes. However, the role of the therapeutic plasma exchange in the management of the potentially life-threatening complications in patients with sickle cell disease is not well known. To determine whether plasma exchange had a cumulative effect on the red cell exchange in patients with sickle cell disease who developed multi-organ failure during the post red cell exchange period, we performed plasma exchange in the nine episodes of multi-organ failure of 7 patients with sickle cell anemia. The median age of those patients was 21 years (range, 9–50 years). The criterion of the multi-organ failure was defined as organ failure of two or more organs i.e. lung, liver, or renal, established according to Acute Physiological and Chronic Health Evaluation-II (APACHE-II) criteria. The average total plasma exchange volume was 1.0 times the patient’s plasma volume. The patients had a good outcome, with a survival rate at 86% after one year of follow-up. Plasma exchange may have cumulative benefits in the treatment of severe illness in patients with sickle cell disease who underwent automatic red cell exchange therapy. 2007 Elsevier Ltd. All rights reserved. Keywords: Sickle cell disease; Plasma exchange; Automatic red cell exchange; Vaso-occlusive crisis; Apheresis
1. Introduction The term ‘‘sickle cell syndrome’’ refers to a group of diseases characterized by the presence of hemo*
Corresponding author. Present address: Baskent University Adana Teaching and Medical Research Center, Dadaloglu Mahallesi, Serin Evler Sokak 39, No. 6 Yuregir, 01250 Adana, Turkey. Tel.: +90 322 327 27 27 2164; fax: +90 322 328 51 59. E-mail addresses: [email protected] (C. Boga), ipa [email protected] (I. Kozanoglu), hakanozdogu@hotmail. com (H. Ozdogu), [email protected] (E. Ozyurek). 1 Tel.: +90 322 327 27 27 2164; fax: +90 322 328 51 59.
globin S, but sickle cell disease (SCD) is the result of homozygosity for hemoglobin S, which causes rigid sickled erythrocytes. SCD is characterized by chronic hemolysis, frequent infections, and recurrent occlusion of the microcirculation, all of which cause painful crises and can result in chronic organ damage and organ failure [1–3]. However, it is not only the cellular component of the peripheral blood which contributes to the development of complications. Plasma factors such as cytokines, chemokines, other factors that can alter endothelial apoptosis and acute-phase proteins seem to be involved with
1473-0502/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2006.12.009
18
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
possible mechanisms of action in the vaso-occlusive phenomena of SCD [4–8]. Transfusion remains an essential component of care for patients with SCD [9]. In patients with SCD, transfusions are most readily accomplished via automatic red cell apheresis [10]. The purpose of this report was to describe 7 patients with SCD who underwent plasma exchange because their critical clinical condition failed to respond to automatic red cell apheresis. 2. Materials and methods We enrolled 7 patients (2 women and 5 men; age range, 9–50 years) with SCD who developed multiorgan failure during sickle cell crisis. Studies involving patients with SCD, >6 months of follow up, no treatment with hydroxyurea, and outcome measures on physical status or pain were included. Nine episodes of multi-organ failure were identified in these patients and defining criteria of organ failure of two or more organs that is lung, liver, or renal was established according to Acute Physiological and Chronic Health Evaluation-II (APACHE-II) criteria [11]. The median (range) hospitalization duration of the patients was 7 days (range, 2–31 days). During their hospital stay, the patients underwent red cell exchange because of indications such as painful crises (for 3 patients), stroke/TIA (for 1 patient), or hepatic necrosis (for 3 patients). When the signs of multi-organ dysfunction occurred in these patients after red cell exchange, the patients underwent plasma exchange. The following information was extracted from the patients’ medical records: age; sex; symptoms at presentation; the results of physical examination, microbiologic cultures and serologic tests; treatment; comorbid medical conditions; and the outcome of treatment. The patients were followed for one year. Good outcome of the plasma exchange was defined as Glasgow–Pittsburgh Cerebral Performance category 1 or 2 for neurologic events, improvement of renal function and liver function (to achieve a postapheresis creatinine and bilirubin value that is the same as the steady state one), or normalization of arterial blood pressure and partial oxygen pressure [12]. Homozygous SCD was identified by the results of hemoglobin electrophoresis performed with high-performance liquid chromatography (BioRad Laboratories, Irvine, California, USA). The clinical diagnosis of painful crisis was based on the
following criteria: widespread pain typically involving the limbs, vertebrae, or ribs that could be ascribed to vascular occlusion and/or ischemic tissue damage and the relief of symptomatic pain after the administration of an analgesic medication. Stroke/TIA was defined by criteria from the American Neurological Association [13]. Finally, hepatic necrosis was defined by signs of basic biochemical examination. Microbiologic samples were collected and processed according to well-established published guidelines [14]. Laboratory measurements for the periodic quality control program were made by Bio-Rad Laboratories External Quality Assurance Services (Bio-Rad Laboratories, Catalog 3517, Irvine, California, USA). The institutional review board of the Baskent University in Ankara, Turkey, approved the study. 2.1. Automated red cell exchange procedure A 20-gauge Intracath catheter was used to access the peripheral vein and to provide an exit route from the opposite arm. An automated system (Cobe Spectra 7.0, Lakewood, CO, USA) that separates cells via continuous blood flow was used to exchange 60–70% of the patients’ red cells with new red cells of the same blood type and crossmatch. As a result, the hemoglobin S level in the peripheral blood was reduced to less than 30% of the total hemoglobin content. Leukofiltered red cell suspensions preserved for 1–7 days by citrate phosphate dextrose and with a hematocrit level of about 75% were used. Target hematocrit was guided by a complicated pain episode (clinical deterioration; a hemoglobin level of less than 7 g per deciliter; leukocytosis in the absence of infection; an underlying pulmonary or cardiac disease) and the steady state hematocrit level that was noted in sickle cell patients attending outpatient regularly [15]. The patients required a target hematocrit of 30–34% after the red cell exchange was arranged in order to get a safe patient outcome. The inlet pump flow rate and centrifugation speed were automatically adjusted according to parameters preset by patient data (weight, height, sex, and hematocrit level) during red cell exchange. In those procedures, cells were exposed to 930 g during a maximum centrifugation speed of 2400 rpm (Cobe Spectra Apheresis System Essential Guide). In some patients, the inlet pump flow rate was regulated manually. The flow rate was selected for a range of 15–60 mL/min, and the centrifuge speed was established at 400–2400 rpm
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
(up to 930 g). The mean centrifugation time was 90.38 ± 37.58 min for all procedures. The total blood volume was calculated according to body weight (70–75 mL/kg), and the calculation of the red cell volume was based on hematocrit values [2]. All procedures used acid-citrate-dextrose A solution (ACD-A) (whole blood to ACD-A ratio = 14:1). 2.2. Plasma exchange A 20-gauge Intracath catheter was used to access the peripheral vein and to provide exit route from the opposite arm. Total blood and plasma volumes were calculated via the standard formulation [15]. At each session, approximately 1–1.5 L of plasma was exchanged by means of an automated system (Cobe Spectra 7.0, Lakewood, CO, USA). Fresh frozen plasma was chosen as the replacement fluid because of prevention of unwanted effects on plasma viscosity and replacement of coagulation factors. One plasma volume exchange with fresh frozen plasma of the patient’s blood type was performed. The procedure was performed with 50% plasma and 50% albumin in patients whose albumin was under 3 gr/dL. Total protein and calcium levels were measured before and after all procedures in all patients. Each apheresis procedure took about 2– 3 h. 3. Results Nine procedures were performed in 7 patients, in patient 2 and patient 5, plasma exchanges were performed in more than one episode. The time period between the episodes in these patients was 1 year for patient 2 and 41 days for patient 5. They were represented separately (Table 1). Symptoms at the time of the plasma exchange procedures included dyspnea in 67% of the patients, progressive jaundice (55%), pleuritic chest pain (11%), hematuria (33%), oliguria (22%), painful crisis (33%), palpitation (100%), coma (44%), and fever (44%). The median duration of symptoms before the plasma exchange procedures was 4 days (range, 1–9 days). The median time interval between automatic red cell apheresis and plasma exchange was 3 days (range, 1–9 days). The mean (range) hematocrit was 29 (27–33%), platelet 224 (216–474 · 109/L) and hemoglobin S 29 (18.5–35.5%) before plasma exchange. Patient 2
19
and patient 4 received fresh frozen plasma and albumin as a replacement fluid. Potential sources or predisposing conditions for deteriorating clinical and metabolic states were identified during the nine episodes of the 7 patients (Table 1). The results of microbiologic studies failed to reveal the pathogens most likely to have caused fever. Abnormalities were noted in 3 of the patients whose chest radiographs were available for current review. The radiographs demonstrated patchy alveolar infiltrates and/or peripheral reticular opacities and peripheral ground-glass opacities in the lower lobes in patient 1; those findings were bilateral in patient 2 and patient 3. Serologic markers of inflammation, such as the erythrocyte sedimentation rate and the level of C-reactive protein, were found to be elevated in all patients. Renal, respiratory, cardiovascular, cerebral, and hepatic status are presented in the Table 1. All but 2 patients received parenteral antibacterial therapy, and the remaining patient was treated only with oral antimicrobial treatment. Ceftriaxone (Rocephine, Roche, Basel, Switzerland) and clotrimazole (Klacid, Abbott Lab, Abbott, France) were the most preferred antimicrobial agents. The duration of antibacterial therapy ranged from 1 to 3 weeks. One patient was treated with prednisolone (Deltacortril, Pfizer, Switzerland) 5 mg per day for intrahepatic cholestasis, which was in the ductular phase. Only 1 patient demonstrated paresthesia caused by hypocalcemia during apheresis, and 2 patients experienced a venous access problem. No complication occurred during the other apheresis procedures. The outcome of the plasma exchange procedures were summarized in Table 1. One patient (patient 3) died on the subsequent day of plasma exchange because of multi-organ failure. In the other patients, good outcome was achieved approximately two weeks after plasma exchange, with a survival rate at 86% after one year of follow-up. 4. Discussion Homozygous SCD is prevalent among the people who live in the Mediterranean region of southern Turkey. It has been reported that the rate of hemoglobin S is 3.9% in the entire population of Turkey if ethnic groups are not considered [16]. The main clinical features of SCD are caused by chronic hemolysis, microvascular ischemia, and organ
20
Table 1 Clinical characteristics of patients with sickle cell disease who were eligible for plasma exchange Age (y), sex
Predisposing condition
Flare in renal activity
Acute chest syndrome
Stroke
Heart failure
Hepatic necrosis and/or intrahepatic cholestasis
Exchanged plasma (mL)
Red cell transfusion need/no. units after PE
Outcome/ hospital stay (day) after PE
1/1
30, F
IBT UI
Cr > 2 mg/dL
Hypoxemia
–
–
2500
6
2/2
50, M
HN
Coma
–
HN
Coma
EF < 55%
3850
–
Good outcome/ 3
4/3
21, F
P
–
Coma
EF < 55% Shock
3467
2
Death/1
5/4
22, M
HN
Cr > 2 mg/dL Hematuria
Coma
EF < 55% Shock
6/5
17, M
OP
–
Hypoxemia Pulmonary infiltrates Hypoxemia Pulmonary infiltrates Hypoxemia
ALT: 66 IU/L AST: 171 IU/L Bil: 44 (total 35 mg/dL) ALP: 289 IU/L ALT: 19 IU/L AST: 15 IU/L Bil: 69 (total 52 mg/dL) ALP: 193 IU/L –
3520
50, M
Pulmonary infiltrates Hypoxemia Hypoxemia
Good outcome/ 3 Good outcome/ 7
3/2
Cr > 2 mg/dL ATN Hematuria Cr > 2 mg/dL Oliguria
EF < 55% Shock EF < 55%
–
7/5
17, M
OP,IU
Cr > 2 mg/dL
–
–
EF < 55% Shock Shock
8/6
9, M
HN
Cr > 2 mg/dL Hematuria
–
–
Shock
9/7
18, M
P,IBT,HN
Cr > 2 mg/dL
–
–
EF < 55% Shock
ALT: 41 IU/L AST: 40 IU/L Bil: 84 (total 52 mg/dL) ALP: 154 IU/L –
2980
–
Good outcome/ 12
3742
7
–
3658
–
ALT: 183 IU/L AST: 120 IU/L Bil: 28 (total 20 mg/dL) ALP: 367 IU/L ALT: 183 IU/L AST: 120 IU/L Bil: 28 (total 20 mg/dL) ALP: 367 IU/L
1121
–
Good outcome/ 3 Good outcome/ 11 Good outcome/ 4
4076
–
Good outcome/ 4
PE, Plasma exchange; F, female; IBT, incompatible blood transfusion; UI, urinary infection; M, male; HN, hepatic necrosis; P, pregnancy; OP, operation; Cr, creatinine; ATN, acute tubular necrosis; EF, ejection fraction; Bil, bilurubin: ALP, alkaline phosphatase.
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
Episode no./ Case no.
C. Boga et al. / Transfusion and Apheresis Science 37 (2007) 17–22
damage. The most common complication is vasoocclusive crisis [2,3]. Most patients with SCD receive transfusions at some point in their life to reduce the incidence of complications from their disease. The indications for red cell exchange transfusion include acute stroke, acute chest syndrome with severe hypoxia, acute multi-organ failure, and (possibly) priapism [2,9,10]. It is generally accepted that red cell exchange transfusion is indicated before extensive surgery as a prophylactic measure against recurrent cerebrovascular accidents [2,9,10]. The goals of the erythrocyte exchange procedure are to decrease the concentration of hemoglobin S to a value below 30% of the total hemoglobin level in the peripheral blood and to lower the levels of erythrocyte-expressed integrin a4b1 and surface glycoprotein IV (thrombospondin receptor, CD36) to prevent interactions between red cells, endothelial cells, and platelets [1,4,5]. On their surface, reticulocytes express the integrin complex a4b1, which binds to plasma and endothelial membrane fibronectin and to an adhesive molecule on the surface of the endothelial cell vascular cell adhesion molecule-1 [4,5]. In that way, tissue oxygenation can be restored and nitric oxygen production can be increased to maintain vasodilatation and modulate hemostasis [17]. However, the adhesiveness of reticulocytes and young (reversibly sickled) red cell to the vascular endothelium and the initiation of endothelial activation are associated with the production of cytokines (tumor necrosis factor, interleukin-1, interleukin-6, and interleukin-8) [1,4]. These cytokines (particularly tumor necrosis factor) can be found in plasma, and interleukin-6 can stimulate the liver to produce acute-phase proteins such as C-reactive protein [4,7]. Other plasma factors such as endothelin-1, endotoxins associated with infections, and chemokines can alter the apoptosis of endothelial cells and neutrophils [4–8]. This derangement in apoptosis probably contributes to endothelial damage and tissue ischemia [4]. Plasma exchange conducted by new-generation machines is rapid and safe, although an experienced team must perform that procedure. With an automated system that separates cells from plasma by means of continuous blood flow, 60–70% of a patient’s plasma can be exchanged for donor plasma during a single procedure [15]. In a brief report on plasma exchange in patients with SCD, Svarch and colleagues observed a dramatic improvement in a child with SCD in whom acute cholestasis and a neu-
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rologic syndrome developed after a plasma exchange [18]. For use in our patients, we first preferred automated red cell exchange. Plasma exchange was performed after the onset of the multi-organ failure during post red cell apheresis period. Our data suggest that in some patients with SCD whose clinical condition is critical, plasma exchange exerts a cumulative effect on erythrocyte exchange and restores microcirculation to deteriorated tissue. Although we did not achieve data regarding what types of plasma components are eliminated, our findings indicate that plasma exchange may play a role in the recovery of critically ill patients with SCD who have not benefited from automated red cell exchange. References [1] Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762–9. [2] Saunthararajah Y, Vichinsky PE, Embury HS. Sickle cell disease. In: Hoffman R, Benz Jr EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, et al., editors. Hematology: basic principles and practice. Philadelphia: Elsevier; 2005. p. 605–44. [3] Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–44. [4] Makis AC, Hatzimichael EC, Bourantas KL. The role of cytokines in sickle cell disease. Ann Hematol 2000;79: 407–413. [5] Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest 1997;99:2561–4. [6] Schroder JM, Christophers E. Secretion of novel and homologous neutrophil-activating peptides by LPS-stimulated human endothelial cells. J Immunol 1989;142:244–51. [7] Hedo CC, Aken’ova YA, Okpala IE, Durojaiye AO, Salimonu LS. Acute phase reactants and severity of homozygous sickle cell disease. J Intern Med 1993;233:467–70. [8] Hebert MJ, Gullans SR, Mackenzie HS, Brady HR. Apoptosis of endothelial cells is associated with paracrine induction of adhesion molecules: Evidence for an interleukin-1beta-dependent paracrine loop. Am J Pathol 1998;152:523–32. [9] Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am 2005;19:803–26. [10] Singer ST, Quirolo K, Nishi K, Hackney-Stephens E, Evans C, Vichinsky EP. Erythrocytapheresis for chronically transfused children with sickle cell disease: An effective method for maintaining a low hemoglobin S level and reducing iron overload. J Clin Apher 1999;14:122–5. [11] Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India 2005;53:19–22. [12] Idris AH, Berg RA, Bierens J, Bossaert L, Branche CM, Gabrielli A, et al. Recommended guidelines for uniform reporting of data from drowning. Circulation 2003;108:2565.
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[13] Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation 2006;113:409–49. [14] Miler J. Bacteriology. In: Murray PR, Baron EJ, Phaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. Washington, DC: ASM Press; 1999. p. 33–104.
[15] McLeod BC. In: Bethesda MD, editor. Apheresis: principles and practice. AABB Press; 2003. [16] Kocak R, Alparslan ZN, Agridag G, Baslamisli F, Aksungur PD, Koltas S. The frequency of anaemia, iron deficiency, hemoglobin S and beta thalassemia in the south of Turkey. Eur J Epidemiol 1995;11:181–4. [17] Uchida K, Rackoff WR, Ohene-Frempong K, Kim HC, Reilly MP, Asakura T. Effect of erythrocytapheresis on arterial oxygen saturation and hemoglobin oxygen affinity in patients with sickle cell disease. Am J Hematol 1998;59:5–8. [18] Svarch E, Gonzalez A, Villaescusa R, Basanta P. Plasma exchange for acute cholestasis in homozygous sickle cell disease. Haematologia (Budap) 1986;19:49–51.