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.
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).
Table 108–6. Pathogenesis of the Acute Chest Syndrome ||Download (.pdf)
Table 108–6. Pathogenesis of the Acute Chest Syndrome
|Bone infarction leads to atelectasis and regional hypoxia||Rib, vertebral, and sternal bone infarctions result in pain, hypoventilation, atelectasis, and subsequent hypoxia |
|Incentive spirometry decreases radiographic atelectasis in patients with sickle cell anemia and VOC |
|Fat emboli||Evidence of bone marrow embolization found in 9%–75% of autopsy series|
|Lipid-laden alveolar macrophages can be recovered from 20%–60% of patients with ACS; sPLA2 levels are elevated in ACS; sPLA2 may liberate free fatty acids from bone marrow lipid, releasing arachidonic acid and promulgating inflammation|
|Infection||Microbiological, serologic, or PCR evidence of pathogensa|
|Chlamydia pneumoniae||29%||Haemophilus influenzae||2%|
|Respiratory syncytial virus||10%||Influenza A virus||2%|
|Staphylococcus aureus||5%||Legionella pneumophila||2%|
|Streptococcus pneumoniae||4%||Escherichia coli||1%|
|Mycoplasma hominis||4%||Epstein-Barr virus||1%|
|Parvovirus||4%||Herpes simplex virus||1%|
|Vascular occlusion||Increased adherence of erythrocytes to endothelial cells|
|In animal models, regional pulmonary hypoxia results in entrapment of sickle erythrocytes|
|Vascular obstruction indicated by ventilation/perfusion scan|
|Pulmonary emboli documented by autopsy series|
|Vascular injury and inflammation||Endothelin 1 levels are elevated during VOC and ACS|
|Elevated levels of inflammatory mediators such as sPLA2|
|Clinical progression to adult respiratory distress syndrome (noncardiogenic pulmonary edema)|
Table 108–7. Causes of Acute Chest Syndromea ||Download (.pdf)
Table 108–7. Causes of Acute Chest Syndromea
|Cause||Cases with Identified Etiology|
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
Acute chest syndrome of sickle cell disease. A 27-year-old male with sickle cell disease presented with fever, shortness of breath, and vaso-occlusive crisis with left chest wall pain. A chest radiograph on day 3, initially normal on day 1, demonstrates the development of a bilateral lower lobe infiltrate and bilateral pulmonary volume loss. Chest computed tomographic images on day 3 show bilateral basilar infiltrates, with dense consolidation of left lower lobe, and small bilateral pleural effusions. Micrographs after oil red O staining (which stains fat red) of specimens obtained by bronchoalveolar lavage showed lipid-laden macrophages consistent with the acute chest syndrome caused by bone marrow fat embolism to lung. (Haley M, Gladwin MT, unpublished observations.)
Model of acute chest syndrome pathophysiology. Vaso-occlusive crisis mediated though increased polymerization of hemoglobin S, erythrocyte rigidity, deformation, mechanical obstruction, and blood cell adherence to vascular cell adhesion molecule 1 (VCAM-1) leads to infarction of a variety of tissues, most characteristically the marrow of bones, causing severe bone pain. In some cases, fat droplets from necrotic marrow appear to slough into the venous circulation of the bone medulla, where the droplets embolize to the pulmonary circulation and increase the amount of secretory phospholipase A2 in blood plasma. Hydrolysis of these fat emboli releases proinflammatory free fatty acids that can induce VCAM-1 expression in the pulmonary microvasculature, leading to adhesion of red and white blood cells. The pulmonary microvascular occlusion can lead to ventilation-perfusion mismatch, generalized hypoxemia, and increased systemic hemoglobin S polymerization. Alternatively, the cycle may be initiated by hypoventilation due to chest wall pain, causing localized hypoxia and pulmonary microvascular hemoglobin S polymerization, or by a pulmonary infection, which generates local hypoxia with shunting and inflammation to induce VCAM-1. The cycle may be broken by exchange transfusion or possibly by glucocorticoids. The potential therapeutic effect of inhaled nitric oxide on ventilation-perfusion matching, which decreases pulmonary artery pressure and inhibits adhesion events, is currently being studied. (Reproduced with permission from Gladwin and Rodgers.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
Table 108–8. Therapy of the Acute Chest Syndrome of Sickle Cell Disease ||Download (.pdf)
Table 108–8. Therapy of the Acute Chest Syndrome of Sickle Cell Disease
- Judicious hydration
- 1–1.5 times daily requirement; fluid restriction may be indicated in patients with severe acute chest syndrome and capillary leak or in renal insufficiency
- Indicated to maintain adequate oxygenation; does not offer benefit for vaso-occlusive crisis in the absence of hypoxemia
- Pain management
- Mild pain
- Oral codeine, acetaminophen or ibuprofen
- Moderate to severe pain
- Medication can be administered on a fixed time schedule with interval analgesics to obtain adequate pain control (see Table 108–9)
- Consider patient controlled analgesia (see Table 108–10)
- Prevent atelectasis
- Incentive spirometry: 10 maximum inspirations q 2 h while awake
- Empiric antibiotics
- Cephalosporin to cover Streptococcus pneumoniae
- Include macrolide or quinolone for coverage of atypical pathogens Chlamydia pneumoniae and Mycoplasma pneumoniae
- Cultures should include nasal washings for viral pathogens (influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, cytomegalovirus, and parvovirus)
- Diagnose and treat reactive airways disease
- Consider occult lack of positive end-expiration pressure and its complications
- Consider exchange transfusion or simple transfusion (see Table 108–12)
- Inhaled nitric oxide
- May prove efficacious but cannot be recommended routinely at this time
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
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.
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.
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 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.
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