Chapter 108. Sickle Cell Disease

• Sickle cell disease causes a chronic hemolytic anemia associated with acute and chronic vaso-occlusion.
• Baseline hemodynamic and laboratory values in patients with sickle cell disease can be confused with sepsis.
• Serum creatinine levels of 1 to 1.5 mg/dL often indicate significant renal dysfunction.
• The most common intensive care management problems in patients with sickle cell disease include the acute chest syndrome, very severe anemia, sepsis, stroke, priapism, and splenic sequestration.
• Secondary pulmonary hypertension occurs in 30% of patients with sickle cell disease, often unrecognized.
• Red cell transfusion is an important treatment for most patients with sickle cell disease requiring intensive care management.
• Rapid exchange transfusion is indicated for central nervous system events, serious respiratory disease, or multiorgan failure.
• Transfusion management in patients with sickle cell disease requires investigation of alloimmunization history.
• Preoperative red cell transfusion and detailed supportive care are advisable for significant surgery in patients with sickle cell disease.

Sickle cell disease is a highly prevalent disease in the United States, affecting 1 in 500 African American infants. It is common in individuals of African, Caribbean, Mediterranean, Arab, and other Middle Eastern descent. It is a genetic disorder with an autosomal recessive inheritance pattern. Sickle cell disease is often called “the first molecular disease” because the biochemical alteration in sickle hemoglobin described by Linus Pauling in 1948 was one of the first lesions identified at the molecular level for a human disease. Sickle hemoglobin forms rod-like polymers in deoxygenated red cells in areas of the circulation, with low oxygen tension, acidosis, or hyperosmolarity. Sickle hemoglobin polymerization causes a host of secondary molecular and cellular changes, many of which impair blood flow and contribute to tissue damage. The microcirculation can be acutely or chronically impaired in virtually any organ in the body, resulting in the characteristic crisis pattern of intermittent pain and acute organ injury superimposed on the gradual development of chronic organ failure.

Despite the early progress in a molecular understanding of sickle cell disease, its treatment remained largely palliative for many decades. In recent years, the longevity of patients with sickle cell disease has been prolonged by the institution of prophylactic penicillin treatment and immunization to decrease mortality rate from pneumococcal sepsis. Chronic transfusion therapy for selected patients has improved outcome, and acute transfusion therapy is the central intervention for most complications requiring admission to the intensive care unit (ICU). Hydroxyurea, the first treatment approved by the Food and Drug Administration for sickle cell disease, decreases disease severity and mortality rate.1,2 Most recently, new paradigms have emerged regarding the pathophysiology of secondary complications of sickle cell disease, with much of this involving impairment of normal intravascular signaling via the nitric oxide (NO) pathway3–5 (Fig. 108-1). These new paradigms have triggered a wave of research seeking to translate these basic science advances into clinical practice.6 This chapter reviews general aspects of the genetics and pathophysiology of sickle cell disease, common clinical problems with an emphasis on those faced in a critical care setting, and contemporary therapeutic approaches to these complications of sickle cell disease.

In 1910, James Herrick first reported the observation of sickle-shaped red cells from the blood of an anemic Chicago dental student from Grenada. Subsequently, in 1949, Linus Pauling and his colleagues demonstrated a difference in the electrophoretic pattern of sickle hemoglobin compared with normal hemoglobin and introduced the label of “molecular disease.” Marotta and colleagues in 1977 showed that the hemoglobin alteration was due to a single nucleotide change in the gene encoding the β subunit of hemoglobin A.

Sickle cell disease is inherited in a classic Mendelian autosomal recessive pattern, with homozygous individuals demonstrating complications of hemolytic anemia and impaired microvascular blood flow. Usually the heterozygous carrier state, sickle trait, is completely asymptomatic, although rarely vaso-occlusive events, splenic infarction, renal papillary necrosis, or sudden death can occur, usually under high-altitude hypoxic conditions. Several other mutant β-globin alleles can induce sickling disorders when inherited in combination with the sickle trait, the most common of which are β thalassemia and hemoglobin C. Although the homozygous state typically results in severe disease, the sickle trait appears to confer resistance to severe malaria, leading to an evolutionary selection for this carrier state in geographic regions with a high prevalence of malaria.7 The sickle trait allele appears to have independently arisen at least three times in Africa and once in the Arab-Indian region. Migration from these regions has brought sickle cell disease to all parts of the world, particularly the Caribbean, Mediterranean, and the North and South American regions. Some variation in disease severity has been attributed to distinct haplotypes surrounding these alleles; additional polymorphisms in several other genes appear to modify disease severity, including those affecting expression of the α- and β-globin (thalassemia mutations) and γ-globin (fetal hemoglobin) genes.

Homozygous sickle cell disease is also referred to as SS disease or sickle cell anemia, to distinguish it from hemoglobin SC disease, a compound heterozygous combination of sickle trait and hemoglobin C trait. Hemoglobin SC disease is clinically similar in scope to SS, but hemoglobin SC disease on average presents milder or less frequent vaso-occlusive complications. The spectrum of SC disease overlaps considerably with SS. Another compound heterozygous form of sickle cell disease is that of S-β-thalassemia. A combination of a β-globin S allele with a nonexpressing β-globin allele, called S-β0-thalassemia, results in production of only hemoglobin S, and the clinical phenotype closely resembles SS. If the thalassemia allele of β globin permits partial expression of a normal β-globin protein, the combination is called S-β+-thalassemia, and like hemoglobin SC, the disease tends to be milder. There are several additional combinations of the β-globin S allele with rare variant hemoglobins that can result in different severities of sickle cell disease.

The single nucleotide mutation in the sixth codon of the β-globin gene changes the corresponding amino acid in β globin from valine to glutamic acid. This induces a conformational change in the hemoglobin tetramer that renders it susceptible to polymerization with deoxygenation in hypoxic, hyperosmolar, or acidic regions of the circulation. The rod-like polymer bundles distort the red cell membrane into the characteristic sickle shape. Intracellular hemoglobin S polymerization and “sickling” are associated with a complex combination of pathophysiologic changes (Table 108-1 and Fig. 108-2). It is likely that adhesion of erythrocytes and leukocytes to endothelial receptors such as vascular cellular adhesion molecule 1 (VCAM-1) combines with physical rigidity and distortion (“sickling”) of the red blood cells to occlude the microvascular circulation. Additional involved cell adhesion molecules include intercellular adhesion molecule 1, E selectin, and P selectin. The resulting tissue ischemia-reperfusion drives tissue and organ injury, generalized inflammation, and ultimately produces tissue infarction. These pathophysiologic events produce clinical and biochemical perturbations, such as fever and leukocytosis, which can mimic sepsis. Tissue ischemia and infarction produce severe pain attacks called acute pain crisis or vaso-occlusive crisis (VOC) and specific end-organ pathophysiology, such as the acute chest syndrome (ACS), an acute lung injury syndrome similar to acute respiratory distress syndrome (ARDS), discussed in greater detail below.

Steady-state sickle cell disease is characterized by intense inflammation that accelerates during VOC, likely secondary to nearly constant tissue ischemia-reperfusion. This is illustrated by frequent fever during VOC and the ACS and by increased leukocyte, platelet, and endothelial cell activation, with increased circulating mediators and markers of oxidant stress and inflammation. Examples of these inflammatory markers include elevated levels of C-reactive protein, cytokines (tumor necrosis factor α, interleukin 1β, and granulocyte-macrophage colony-stimulating factor), chemokines (interleukin 8), integrins (α4β1), selectins (E and P), adhesion molecules (VCAM-1 and intracellular adhesion molecule 1), markers of oxidant stress and inflammation (isoprostanes and tyrosine nitration), and vasoconstrictors (endothelin 1).4,5

Associated with this inflammation is a state of endothelial dysfunction, with impaired NO bioavailability. Strong evidence points to intravascular consumption of NO by cell-free plasma hemoglobin liberated from red cells by intravascular hemolysis and by radical-radical inactivation reactions with superoxide produced by xanthine oxidase.8,9 Impairment of NO signal transduction leads to many adverse consequences, including increased inflammation and impaired microcirculatory blood flow.10,11 It may also lead to platelet activation and acute and chronic pulmonary hypertension.12,13

Sickle cell disease is fundamentally a severe hemolytic anemia. This is characterized by a normocytic, normochromic anemia with reticulocytosis at baseline. Characteristic laboratory profiles for patients with SS and SC without hydroxyurea treatment are presented in Table 108-2. Hemolysis is mostly but not exclusively extravascular and is due primarily to mechanical injury and destruction of erythrocytes rendered rigid by intracellular hemoglobin S polymerization. Baseline leukocytosis is commonly present and should not necessarily be construed as evidence of infection. Nucleated red blood cells commonly are miscounted in the complete blood count as white cells, although the overall counting error is usually relatively small. The diminished oxygen-carrying capacity due to chronic anemia is compensated by increased cardiac output (Table 108-3). Cardiomegaly and biventricular chamber dilation due to constant increased cardiac output are common (Table 108-4). Splenic dysfunction due to subclinical infarction is almost universal by late childhood in patients with homozygous sickle cell disease; on computed tomography, the spleen appears typically as a small calcified mass (Fig. 108-3). As discussed below, patients with SC disease or S thalassemia may retain their spleens and present with acute splenic sequestration or infarction. Likewise, gradual infarction of the renal medulla by adolescence leads to isosthenuria (iso-osmolar urine), with increased urination because of diminished urinary concentrating capacity, mimicking a nephrogenic diabetes insipidus phenotype. Aside from increasing maintenance fluid requirements, these changes mean that urine specific gravity is not closely indicative of hydration status. The increased cardiac output and higher plasma content of each milliliter of blood present the renal glomeruli with a volume of plasma per minute up to twice that of patients without sickle cell disease. This leads to baseline glomerular hyperfiltration (up to 200 mL/min) and a low baseline serum creatinine range of approximately 0.5 to 0.6 mg/dL (see Table 108-2). Serum creatinine levels above this level actually imply renal insufficiency. A serum creatinine level of 1.0 mg/dL may often be associated with other consequences of renal insufficiency, such as hyperkalemia, hyperuricemia, and increased anemia due to a partial defect in erythropoietin secretion. Importantly, these features of renal insufficiency may arise even when the glomerular filtration rate may be in the 80-mL/min range.

These baseline physiologic perturbations result in a hyperdynamic cardiovascular state with relatively low blood pressure, low systemic and pulmonary vascular resistances, high cardiac output. and renal hyperfiltration (see Tables 108-3 and 108-4). These findings are similar to other high cardiac output states such as pregnancy and thyrotoxicosis. These hemodynamic parameters combined with significant baseline inflammation in patients with sickle cell disease, characterized by leukocytosis and increased serum ferritin, often can be mistaken for sepsis in the absence of a true infectious insult (see Table 108-4).

Common and significant clinical problems in patients with sickle cell disease are summarized in Fig. 108-1.

Vaso-Occlusive Pain Crisis

VOC is perhaps the most characteristic manifestation of sickle cell disease. These severe painful attacks, most commonly affecting the extremities and back, result from acutely impaired microvascular blood flow. Most commonly affected are bones, due primarily to ischemia and infarction of the bone marrow and inflammation of the periosteum, with intense bone pain due to the resulting edema and tissue swelling in the inelastic compartment of the bone marrow medulla. Most often, pain affects the lumbosacral vertebrae and the long bones, although any bone may be affected. Joint effusions of the elbows and knees are common. At times, especially in children, there is difficulty in distinguishing painful crisis from osteomyelitis. The mainstays of treatment for pain crisis are analgesics, in particular nonsteroidal anti-inflammatory drugs and opioids. Correction of dehydration or hypoxemia is important, as is careful monitoring for development of ACS (see below). Clinicians frequently undertreat the severe pain of sickle cell crisis. Opioid tolerance due to recurrent or chronic opioid treatment may dramatically increase the dosage required in individual patients. There is little, if any, risk for developing opioid dependency with short courses of large-dose opioids for VOC.

Stroke

Ischemic stroke is a frequent complication of sickle cell disease, occurring at any age, but mainly in children. This topic is discussed in detail below in the section on special problems in the ICU.

Eye Disease

A proliferative retinopathy develops in 10% of patients with SS disease and at least twice as often in patients with SC disease. This chronic complication may be treated with laser photocoagulation. Two acute complications present ophthalmologic emergencies. The first is vision loss due to acute occlusion of the central retinal artery. This may resolve with emergency exchange transfusion before retinal infarction occurs. The second emergency is traumatic hyphema in a patient with sickle cell disease or sickle trait. The environment of the anterior chamber of the eye promotes sickling, and this can readily cause acute glaucoma. Evacuation of the blood should be undertaken for hyphema without delay to avoid vision loss.14

Lung Disease

Sickle cell disease is associated with a high incidence of acute and chronic lung complications. The ACS is a lung injury syndrome and, in cases of extensive lung involvement, is similar to ARDS. It is defined by a new pulmonary infiltrate secondary to alveolar consolidation, not atelectasis, in a patient with sickle cell disease accompanied by chest pain, fever, tachypnea, wheezing, or cough. It is caused frequently by pulmonary fat embolism syndrome from severe vaso-occlusion of the bone marrow or by an excessive pulmonary inflammatory response to common respiratory pathogens. Its pathogenesis and treatment are discussed in detail in the section on special ICU problems. Chronic complications can include the development of restrictive lung disease, pulmonary fibrosis, or pulmonary hypertension, with the latter occurring in up to 30% of adults with sickle cell disease.15 Pulmonary hypertension appears to be the most serious risk factor for early mortality in adult patients with sickle cell disease and, in the past, may have been under-recognized by clinicians. Reactive airway disease or asthma occurs with increased frequency in children with sickle cell disease.16

Heart Disease

Although vaso-occlusion of the coronary microcirculation can produce myocardial infarction, acute wall motion abnormalities, and cardiac enzyme release, coronary atherosclerosis is essentially nonexistent in patients with sickle cell disease for reasons that are poorly understood, possibly owing to low levels of low-density lipoprotein cholesterol, early mortality of males, and increased heme oxygenase activity. Cardiomegaly and biventricular chamber dilation are nearly universal due to a long-term high cardiac output state as compensation for severe chronic anemia. High-output cardiac failure, diastolic dysfunction, and pulmonary hypertension are common cardiac complications of sickle cell disease (see Tables 108-3 and 108-4).

Hepatobiliary

Up to 42% of patients with sickle cell disease have calcium bilirubinate gallstones by age 18 years, although only a fraction of these patients are symptomatic. Stones develop due to the very high rate of bilirubin excretion in bile as a breakdown product of hemoglobin turnover. In cases of acute cholecystitis, awaiting its resolution decreases perioperative complications. Acute vaso-occlusion in the liver can cause pain, elevated transaminases, and extreme hyperbilirubinemia, generally responding well to supportive care. Rarely, the liver may acutely sequester peripheral blood cells, clinically analogous to splenic sequestration syndrome (see Special Problems in the ICU).

Splenic

Nearly all patients with sickle cell disease develop progressive loss of splenic function secondary to its microvascular vaso-occlusion and infarction, beginning at birth and complete by age 10 years. This manifests primarily as a marked susceptibility to sepsis and meningitis due to encapsulated organisms, particularly in children younger than 5 years. The incidence of serious infection is dramatically decreased by penicillin prophylaxis and immunization against Haemophilus influenzae and Streptococcus pneumoniae. However, splenic dysfunction still causes a modest lifelong risk of overwhelming sepsis. The spleen is atrophic and nonfunctional in 98% of adults with SS sickle cell disease (see calcified spleen in Fig. 108-3B). A dramatic acute complication of sickle cell disease is splenic sequestration crisis, described in detail in the section on special problems in the ICU. This complication occurs frequently in pediatric patients with functioning spleens, primarily young children with homozygous SS disease, and adults with hemoglobin SC sickle cell disease or S-β+-thalassemia because approximately 50% of these patients retain their spleen into adulthood. It is conceivable that hydroxyurea therapy in children with sickle cell disease might lead to prolongation of splenic function.

Renal

Isosthenuria develops in most patients by age 10 years, with increasing maintenance fluid and sodium requirements. Hematuria due to papillary necrosis is an occasional complication, usually self-resolving. A nephropathy with nephrotic-grade proteinuria can frequently progress to uremia. Early signs include the normally low serum creatinine exceeding 0.6 mg/dL, progressively severe anemia, and a rise in the serum uric acid level. Angiotensin-converting enzyme inhibitors can decrease proteinuria and potentially slow progression of renal insufficiency. Uremia has been treated with dialysis and with renal transplantation.

Skeletal

Bone marrow infarcts are frequent causes of pain. These may be detected on magnetic resonance imaging or radionuclide imaging with technetium sulfur colloid, although it is not normally clinically helpful to ascertain these by imaging. The heads of the femur and humerus are susceptible to avascular necrosis, a potential source of constant pain and disability. Ischemic bone becomes susceptible to bacterial osteomyelitis. Staphylococcus aureus is the most common organism in sickle cell osteomyelitis episodes. Salmonella species are frequently encountered, which very rarely cause bone sepsis in patients without sickle cell disease. Joint effusions and occasionally hemarthrosis may be seen adjacent to infarcted bones. Septic arthritis is seen less commonly.

Skin

Leg ulcers, a clinical feature of this and other hemolytic disorders, are usually limited to adolescence and adulthood. They heal very slowly and can cause very severe pain. They rarely develop acute cellulitis. They are best treated with scrupulous wound care.

The demographics of adult patients with sickle cell disease admitted to the medical ICU at a single institution over a 10-year span are presented in Table 108-5. Specific issues in management of patients with sickle cell disease admitted to the ICU are discussed in detail below.

Acute Chest Syndrome

The ACS of sickle cell disease is an all-inclusive lung injury syndrome, akin to ARDS. The largest clinical study of ACS defined ACS on the basis of the finding of a new pulmonary infiltrate involving at least one complete lung segment that was consistent with the presence of alveolar consolidation but excluding atelectasis. In addition, the case definition required chest pain, a temperature higher than 38.5°C, tachypnea, wheezing, or cough.17 Implicit in this definition is the acknowledgment that lung injury from a wide variety of causes can induce pulmonary microvascular sickling to a greater or lesser extent.

Identified etiologies of the ACS include infection, vascular infarction, and fat emboli (Table 108-6). Vichinsky and colleagues found that infections account for about one-half of cases with identified etiologies, with identified pathogens in order of frequency: Chlamydia, Mycoplasma, respiratory syncytial virus, Staphylococcus aureus, Streptococcus pneumoniae, and Parvovirus (Table 108-7). Approximately one-third of cases were presumed due to pulmonary infarction from vaso-occlusion.17 Some of these cases may have resulted from pulmonary atelectasis due to hypoventilation caused by painful infarction of ribs or vertebrae. Localized hypoxemia due to ventilation-perfusion mismatch of any cause may result in intrapulmonary sickling and vaso-occlusion (see Table 108-6).

Fat embolism appears to play a large role in episodes of ACS developing after the onset of a pain crisis. In the study by Vichinsky et al, oil droplets in pulmonary macrophages were found in bronchoalveolar lavage fluid from approximately one-sixth of all cases, indicative of fat embolism.18 The mechanism appears to involve infarction of bone marrow, with sloughing of fat droplets from necrotic marrow into the venous circulation, resulting in pulmonary fat emboli resembling those classically seen in patients with femur and pelvic fractures after trauma (Figs. 108-4 and 108-5). Serum levels of secretory phospholipase A2 rise before the clinical onset of ACS associated with painful crisis.19 This enzyme can hydrolyze phospholipids into potent inflammatory mediators such as free fatty acids and lysophospholipids. Liberation of arachidonic acid may lead to production of leukotrienes, thromboxanes, and prostaglandins, all of which mediate inflammation and affect endothelial function. Inflammation leads to endothelial cell surface expression of cell adhesion molecules, especially VCAM-1. Expression of VCAM-1 may be further increased by depletion of NO and its precursor arginine, which normally suppress VCAM-1 expression.20,21 This receptor, normally involved in the recruitment of inflammatory cells, may bind erythrocytes and leukocytes, contributing to pulmonary vaso-occlusion. This pulmonary microvascular obstruction worsens ventilation-perfusion mismatch, thereby aggravating hypoxemia, which increases sickling and leads to a vicious cycle (see Fig. 108-5). The ACS can evolve to a common end point of acute lung injury resembling that of ARDS, regardless of the initial etiology.22

The clinical severity of ACS is highly variable. Common physical findings include fever, tachypnea, rales, and wheezing. Laboratory findings often include leukocytosis, an acute decrease in hemoglobin level (∼1.6 g/dL), and hypoxemia. Pulmonary infiltrates are often found in the upper lobes in children and lower lobes in adults. Multilobar disease suggests a worse prognosis. In addition to a new pulmonary infiltrate or consolidation, pleural effusions develop in up to half of the episodes during the course of hospitalization (see Fig. 108-4). In the study by the National Acute Chest Syndrome Study Group, 22% of ACS episodes in adults and 10% of episodes in children required management with mechanical ventilation. Risk factors for requiring mechanical ventilation were decreased platelet count (<200,000/mm3), multilobar disease, a history of cardiac problems, and neurologic complications. Total mortality rates were 9% in adults but lower than 1% in children. Other than pain (especially abdominal pain), the most common complications are neurologic (11% of episodes), including seizures or stroke. Cardiac, gastrointestinal, or renal complications are infrequent. Mean duration of hospitalization was 10.5 days, as compared with 3 to 4 days for uncomplicated ACS.17

Treatment of ACS involves careful supportive care, empiric antibiotic therapy, and transfusion therapy (Table 108-8). Pain should be treated aggressively, and often patient-controlled analgesia is best. Relief of chest pain may improve tidal volume and improve oxygenation, although it is important to avoid excessive sedation and respiratory suppression. Incentive spirometry also helps to reduce atelectasis. Because an infectious etiology in practice can rarely be ruled out, initial management should include empiric antibiotic coverage for Chlamydia pneumoniae, Mycoplasma pneumoniae, and Streptococcus pneumoniae, frequently encountered organisms in ACS.17 Commonly a third-generation cephalosporin is combined with a macrolide or quinolone antibiotic. Patients may respond to inhaled bronchodilator therapy, especially if they have a history of reactive airway disease.16

Pulse oximetry is a useful tool to monitor the severity of hypoxemia. Due to difficulties in interpretation caused by sickle cell disease, the data from pulse oximetry is only approximate.23–25 Pulse oximetry while the patient is on room air should be followed, with consideration of arterial blood gas sampling while the patient is on room air if the oxygen saturation is below 92%. An increase in the alveolar-arterial oxygen gradient is the best predictor of ACS severity. The magnitude of the gradient and rate at which it develops determine the need for ICU admission, emergency transfusion, and aggressive respiratory support.26

Transfusion therapy is an important consideration in any case of ACS. Simple transfusion of 2 to 4 U of packed red blood cells should be considered early when ACS is diagnosed. Simple transfusion appears to be as effective as a more complete red blood cell exchange, but hemoglobin must be maintained below 10 g/dL.27 This is usually possible because hemoglobin levels decrease during ACS. In the event of rapid progression of respiratory distress, more severe hypoxemia, multilobar disease, or requirement for mechanical ventilation, exchange transfusion is more definitive and the current standard of care (see section on transfusion therapy). Simple transfusion can be performed as a temporizing maneuver until manual or automated exchange transfusion can be performed.

Other treatments for ACS have been reported in the literature. Dexamethasone pulse therapy (0.3 mg/kg intravenously every 12 hours in four doses) has been reported to be effective in decreasing the severity of ACS in children. However, the rate of rebound pain or ACS progression when dexamethasone is stopped may exceed 25%, thus preventing widespread acceptance of this treatment.28 Our own anecdotal experience indicates that a steroid taper does not alleviate this rebound. Dexamethasone may be useful in clinical settings in which transfusion therapy is not available or as a temporizing measure pending definitive therapy with exchange transfusion. Two case series have suggested that inhaled NO might provide clinical benefit, but this cannot be recommended without further clinical investigation in patients with sickle cell disease.28a,28b

Pulmonary Hypertension

This frequent but previously underreported complication of sickle cell disease is associated with a high mortality rate. In a current prospective study of the prevalence and severity of pulmonary hypertension in adult patients with sickle cell disease, our group found a prevalence of 33%, and affected patients had a significantly lower survival rate at 21 months of follow up than did patients with sickle cell disease without pulmonary hypertension.28c A retrospective analysis suggested a 2-year mortality rate of 50%, comparable to that of primary pulmonary hypertension.15 Sudden death from sickle cell disease may be linked to pulmonary hypertension. Severity of pulmonary hypertension in patients with sickle cell disease in steady state is mild to moderate and associated with a high cardiac output and low pulmonary vascular resistance compared with control subjects with sickle cell disease without pulmonary hypertension (see Tables 108-3 and 108-4). In our experience, pulmonary vasculature remains vaso-responsive to prostacyclin and NO in approximately 80% of patients.

Our data indicated that endogenous NO is consumed in the plasma of patients with sickle cell disease by the cell-free hemoglobin liberated from red cells by intravascular hemolysis.8 The increase in plasma hemoglobin commonly observed during VOC may heighten NO consumption during crisis and cause decompensation of previously moderate pulmonary hypertension. This is exacerbated by an apparent depletion of the substrate for NO synthesis, the amino acid L-arginine.29,30 Elevated plasma levels of endothelin 1, an extremely potent vasoconstrictor, are found in patients with sickle cell disease during VOC, potentially increasing pulmonary artery pressures in VOC.

Sepsis and Meningitis

Due primarily to splenic dysfunction, patients with sickle cell disease are at particular risk for sepsis. Children younger than 6 years are at greatest risk, especially for meningitis. Advances in immunizations are improving these risks, but these patients remain at higher risk for sepsis and meningitis than the general population. Although sepsis and meningitis may be caused by any organisms pathogenic in the general population, patients with sickle cell disease are particularly susceptible to infection with encapsulated organisms, especially Streptococcus pneumoniae. This organism may be resistant to β-lactam antibiotics due to long-term penicillin prophylaxis or recurrent courses of empiric antibiotics. Empiric antibiotic coverage with ceftriaxone or cefotaxime should be considered for fever in children younger than 6 years and in patients of all ages who appear toxic or have fever with high-grade leukocytosis. These antibiotics have rarely been associated with immune-mediated hemolytic anemia, and appropriate caution and monitoring should be undertaken. Cerebrospinal fluid pleocytosis or strongly suspected bacterial meningitis should be treated initially with vancomycin in addition to large doses of ceftriaxone or cefotaxime. Antimicrobial management of ACS was discussed earlier.

Stroke

Approximately 7% of patients with sickle cell disease will develop clinically detected cerebral infarction, with much of this risk occurring in early childhood. Young children are at risk of ischemic stroke, with a peak incidence between ages 2 and 5 years, and another peak is seen in adults older than 53 years.31 These strokes are commonly in large vessel distributions, in contrast to the microvascular infarcts incurred in other organs. The infarctions are commonly multifocal and can be clinically overt or subclinical in nature. Population screening with transcranial Doppler ultrasonography is performed prospectively to identify those at high risk for strokes because prophylactic transfusion therapy can prevent these strokes. Patients at risk are those with time-averaged mean blood flow velocity over 200 cm/second in the internal or middle carotid arteries.32 Clinical strokes can manifest during acute illness or as isolated neurologic events. Children with acute neurologic events should be rapidly assessed clinically for the likelihood of ischemic stroke versus bacterial meningitis, with the latter normally presenting with features of sepsis. Ischemic clinical stroke mandates rapid treatment with exchange transfusion to limit the extent of the infarction and prevent recurrences. Emergency exchange transfusion should be considered in children with sickle cell disease and acute neurologic disability even before neuroimaging studies. Without continued chronic transfusion, two of three patients will have a recurrence. The required duration of long-term transfusion remains unclear, although most children with stroke are transfused into adulthood. Issues in stroke in sickle cell disease have recently been reviewed.33

Hemorrhagic stroke predominates over nonhemorrhagic stroke in adults with sickle cell disease, primarily during the third decade.31 They are usually intracerebral hemorrhages but may occur as subarachnoid hemorrhages, with the latter often following rupture of aneurysms. Hemorrhages occur apparently due to chronic vasculopathy, and there is no published evidence to indicate whether or not its course is modified by transfusion therapy. Unfortunately, there is a dearth of published experience to guide therapy in these patients, and treatment is largely supportive, with consideration of exchange transfusion. Surgical intervention may be indicated for aneurysms.

Splenic Sequestration and Infarction

Splenic sequestration involves acute engorgement of the spleen, presumably due to obstruction of its venous outflow by sickled erythrocytes.34 The volume of blood acutely sequestered from the circulation can cause severe anemia and life-threatening hypotension. Because most patients with homozygous sickle cell disease have splenic atrophy by age 10 years due to gradual microinfarction, this complication occurs only in those patients with significant residual splenic parenchyma, namely young children with sickle cell disease and individuals at all ages with less severe sickling syndromes, such as hemoglobin SC disease and hemoglobin S-β-thalassemia. Splenic sequestration when acute and severe should be treated with rapid red cell transfusion, analogous to the treatment of acute severe traumatic blood loss. Overtransfusion should be avoided because, during resolution, sequestered red cells can be abruptly released, potentially causing hyperviscosity. When this syndrome occurs in adolescents or adults with hemoglobin SC disease, it may be associated with acute splenic infarction. This clinically impressive syndrome can present with very high-grade fever, extraordinary splenic pain and tenderness, and enormous splenomegaly. Sonography or computed tomography may depict inhomogeneity representative of hemorrhagic infarction, which should be differentiated from possible splenic abscess. Patients with acute splenic infarction can be managed medically with transfusions and supportive care.35

Recurrence of splenic infarction indicates a risk of multiple future recurrences, and some have recommended splenectomy. If this is done, it should probably be done electively after medical management and clinical resolution of the acute episode to avoid undue operative risk.

Priapism

Priapism refers to pathologically prolonged erection of the penis, which is often extremely painful.36 Although its pathophysiologic mechanism remains to be elucidated, it seems likely that penile venous outflow is obstructed by sickled erythrocytes. Case reports of many therapeutic approaches have been proposed based on experience in limited numbers of patients, but these have rarely proved to be of benefit in larger clinical experiences. The most widely recommended acute treatment for severe episodes is exchange transfusion, although evidence of its efficacy is limited. Therapies of questionable value have included adrenergic agonists, nitrates, and a surgical approach known as a Winter shunt. Only one therapy has shown some benefit in a relatively large single-institution study involving percutaneous drainage and irrigation of the corpus cavernosum initiated within 3 hours of onset.37 The value of this approach has not been validated in other institutions, but it may have the clearest evidence of benefit in absence of a well-established standard of care. One very interesting, counterintuitive approach has been reported. Sildenafil, normally used clinically to treat erectile dysfunction, given in single 50-mg doses as needed, rapidly relieved several episodes of priapism in three patients with sickle cell disease.38 Because of the possibility that this drug might also be capable of inducing priapism, its use cannot be recommended until further research is conducted.

Perioperative Management

Patients with sickle cell disease have a high risk of perioperative complications, with 10% to 50% developing a VOC or ACS postoperatively. Careful preoperative anesthesiology consultation should be undertaken. Many sickle cell centers have traditionally performed serial transfusion or exchange transfusion preoperatively with a goal of preventing postoperative complications by reducing the hemoglobin S fraction to less than 30%, with a final total hemoglobin level of at least 10 gm/dL. A randomized study by Vichinsky et al showed that preoperative simple transfusion with a goal of raising the total hemoglobin concentration to 10 gm/dL, without a specific goal for hemoglobin S percentage, has similar efficacy. However, this study included predominantly patients with less invasive surgical procedures, such as tympanostomy tube placement or laparoscopic cholecystectomy. Some centers still prefer to perform exchange transfusion before major surgery in patients with sickle cell disease, although many transfuse less aggressively. A careful risk-benefit evaluation must be applied to each case, especially in patients with a history of red blood cell alloimmunization.

Supportive care should include careful attention to avoiding dehydration, overhydration, deoxygenation, vascular stasis, low temperature, acidosis or infection. The operating room should be kept warm, and warming devices should be used for the patient. Oxygenation status should be closely monitored intraoperatively and postoperatively, and incentive spirometry should be prescribed postoperatively. The literature regarding perioperative management of patients with sickle cell disease has been reviewed in more detail by Marchant and Walker.39

Oxygen and Fluids

Because hypoxemia and dehydration can trigger sickling, it is important to prevent these from developing. Contrary to traditional teaching in many medical training programs, there is no indication of benefit from aggressive hydration in patients who are not dehydrated or from oxygen therapy in the absence of hypoxemia. Excessive fluid resuscitation may even compromise some older patients who have some degree of congestive heart failure or renal insufficiency.

Analgesics

At times, acetaminophen can suffice for mild pain. More severe pain often requires addition of an oral opioid analgesic such as codeine, hydromorphone, morphine, or oxycodone; morphine and oxycodone are available as short-acting or sustained-release preparations (Table 108-9). Severe pain episodes are best treated with intravenous opioids, usually morphine or hydromorphone, with considerable added convenience to patient and clinician when administered via a patient-controlled analgesia pump (Table 108-10). Patients with severe pain may also benefit from the parenteral nonsteroidal anti-inflammatory drug ketorolac, although questions have been raised about potential impairment of renal blood flow. Ketorolac also presents a risk of gastrointestinal hemorrhage, particularly if used for 5 days or longer. We recommend that nonsteroidal anti-inflammatory agents be withheld in patients with sickle cell disease with pulmonary hypertension or serum creatinine level above 0.8 mg/dL. Clinicians should consider the baseline narcotics the patient is using for determining an adequate dose of narcotics. Opioid tolerance due to previous chronic or frequent opioid administration may be an indication for much larger doses of opioids for acute pain control. Elderly or debilitated patients may require smaller doses of opioids to reduce toxicity. Opioid therapy may result in constipation, nausea, or pruritus. A laxative such as Senokot should be administered prophylactically. Nausea may be treated with diphenhydramine, hydroxyzine, promethazine, ondansetron, or dolasetron. Pruritus may be treated with diphenhydramine or hydroxyzine. Very severe pruritus may respond to naloxone 1 μg/kg per hour as a continuous intravenous infusion. This small dose can block opioid receptors associated with pruritus without blocking those associated with analgesia. Detailed recommendations for analgesia in patients with sickle cell disease have been published.40

Incentive Spirometry

Bedrest during a pain crisis may lead to pulmonary atelectasis. This can trigger ACS (see below). Bedside incentive spirometry during pain crisis has been shown to prevent the development of pulmonary infiltrates.

Transfusion

Although there is probably no indication for treatment of the acute pain crisis, most other acute serious complications of sickle cell disease can be stabilized through the use of transfusions to diminish the percentage of circulating hemoglobin S. Table 108-11 lists indications for transfusion therapy. It is clear from reviewing this list that almost any patient who requires an ICU visit is likely to require a simple or exchange transfusion. As such, the intensivist must be well versed in the indications, complications, and pitfalls of transfusion therapy in this population.

Patients with sickle cell disease have severe chronic anemia, and they generally tolerate transient episodes of at least a 20% decrease in their baseline hemoglobin level quite well, if the reticulocyte count remains high. Knowledge of a given patient's baseline parameters can help to determine the need for transfusion for exacerbation of anemia. The most severe and life-threatening anemia and reticulocytopenia occurs during aplastic crisis resulting from infection with the parvovirus B19, otherwise known as erythema infectiosum, fifth disease, or slapped-cheek disease. Life-threatening anemia and hypovolemia due to splenic sequestration are other such indications, discussed in more detail below.

There are several important transfusion issues unique to patients with sickle cell disease to consider. First, transfused red cells should be negative by Sickledex or another rapid screening test to exclude blood from sickle trait donors. Second, the detailed red cell phenotype should be ascertained in the blood bank, particularly for patients who will be chronically transfused, such as children with a new stroke. This permits more directed management of alloimmunization to red cell antigens, although the actual approach is controversial. The rate of alloimmunization to red cell antigens in patients with sickle cell disease is 18% to 36%, most often involving the D, C, and E antigens in the Rh system and less often the Kell, Kidd and Duffy blood groups. This is attributable in large part to discrepancy in allele frequency between these patients of African descent and the blood pool from donors of mostly European descent. One workshop report has recommended the use of red cell units prophylactically matched to prevent sensitization to the Rh antigens D, C, and E and the Kell antigen K.41 However, others have advocated matching these antigens only after the patient has become immunized to antigens.42 The high rate of alloimmunization in patients with sickle cell disease promotes a higher incidence (3%) of delayed hemolytic transfusion reactions. These are defined as premature clearance of transfused red cells, usually several days after transfusion. In some cases, the hemoglobin level may decrease to below the pretransfusion level, with the immune reaction to transfused cells apparently generalizing to also involve the patient's own red cells, a phenomenon that has been called “bystander hemolysis.”

Because of this complication, it is critical to obtain a transfusion antibody history from blood banks where a patient was previously transfused. Over several months, alloantibody titers to red blood cell antigens may become undetectable on a routine type and cross-match but remain capable of mediating a transfusion reaction. The resulting delayed transfusion reaction in an acutely ill hospitalized patient can be catastrophic, with hemoglobin levels decreasing to 2 to 3 g/dL.

Simple transfusion is sufficient for correcting severe anemia, but exchange transfusion can more rapidly dilute sickle hemoglobin to less than 40% of circulating hemoglobin, which is desirable in acute life-threatening sickle cell complications, in particular stroke, ACS, and multiorgan failure syndrome. Exchange transfusion may be accomplished rapidly and isovolumetrically by erythrocytapheresis, when this procedure is available (Table 108-12). This requires upper extremity veins sufficient for two large-bore needles, placement of a Quinton or similar apheresis, or hemodialysis venous catheter in a central vein (femoral, internal jugular, or subclavian). Alternatively, manual exchange transfusion may be performed by using one of several protocols, with a goal of replacing 70% of the sickle red cell mass with transfused red cells. One simplified approach for adults is presented in Table 108-12. Another approach useful in children and adults is to exchange the red cell mass twice, as calculated below:

This volume may be transfused while whole blood is being withdrawn from a high-flow site, often an arterial or central venous line. The transfusion may be accomplished as rapidly as the inflow and outflow catheters allow, as long as care is taken to maintain balanced hourly inflow and outflow rates for the duration of the procedure. If the hemoglobin level exceeds 10 gm/dL or hematocrit exceeds 30% during the first half of the exchanged volume, the red cell hourly infusion rate should be halved, and the reduced red cell rate replaced with normal saline, so that the hourly inflow rate continues to equal the outflow rate. The final target hemoglobin level should be 10 gm/dL. Higher hemoglobin levels can cause hyperviscosity problems at the microvascular level in patients with sickle cell disease.

Hydroxyurea

This agent was first widely used to treat chronic myeloid leukemia and has found a place in the prophylactic treatment of sickle cell disease. At least in adults with more severe than average sickle cell disease, it decreases the incidence of significant pain episodes, ACS, and transfusions by approximately 50% and significantly prolongs lifespan. Its favorable effects are mediated through its elevation of fetal hemoglobin, which inhibits sickle hemoglobin polymerization. Its use may be complicated by myelosuppression, and administration is commonly interrupted during sepsis or serious infection, although it is unclear whether this is truly necessary in the absence of drug-induced neutropenia. Hydroxyurea is contraindicated in pregnancy due to its potential teratogenicity, and a potential carcinogenic effect after long-term use has not been completely excluded.

Glucocorticoids

Methylprednisolone (15 mg/kg per day intravenously IV in two doses) and dexamethasone (0.3 mg/kg every 12 hours intravenously in four doses) have produced statistically significant improvements in painful crisis and ACS, respectively, but this treatment is troubled by significant rebound symptoms in at least 25% of patients. The partial success of these agents indicates the probable role that inflammatory pathways play in acute vaso-occlusive phenomena.

Investigational

Inhaled NO at 80 ppm for 4 hours produces a trend toward significant improvement in the duration of crisis and pain scores in a preliminary study in children with VOC.43 Case reports have documented its effect on increasing arterial oxygenation and decreasing pulmonary pressures during the ACS.28a,28b Its use in secondary pulmonary hypertension in sickle cell disease is being studied. The natural NO donor L-arginine often is depleted from the blood of patients with sickle cell disease in crisis, and its supplementation is being evaluated.44 Inhibitors of the red cell Gardos channel enhance water transport into normally dehydrated sickle cells, thereby decreasing hemoglobin S polymerization, and these are in clinical trial.45 Poloxamer 188 (Flocor) is a rheological agent that has shortened the duration of VOC under some circumstances.46