Acute Chest Syndrome Of Sickle Cell Anemia

Kevin J. Sullivan, M.D., FAAP and Niranjan Kissoon, M.D., FAAP, FCCM, FRCP(C)
Kevin J. Sullivan, M.D. is a Pediatric Anesthesiologist and Pediatric Intensivist
at the Nemours Children's Clinic/ Jacksonville.
Niranjan Kissoon, M.D. is Professor and Chief of the Division of Pediatric Critical Care Medicine
at the University of Florida Health Science Center / Jacksonville.

Introduction

Sickle cell anemia is an inherited disorder characterized by an amino acid substitution that renders the hemoglobin molecule susceptible to polymerization upon oxygen unloading. As a result of hemoglobin polymerization, erythrocytes become deformed, rigid, and are unable to traverse the microvaculature. The result is tissue ischemia or infarction distal to the occluded circulation. In this manuscript we discuss the manifestations of severe lung involvement in the acute chest syndrome of sickle cell disease.

Definitions And Epidemiology

The term acute chest syndrome (ACS) was coined because patients with sickle cell disease (SCD) are prone to repeated and severe episodes of pulmonary insult. Rapidly progressive pulmonary infiltrates, tachypnea, dyspnea, hypoxemia, and chest pain characterize ACS1-4. It has long been a subject of debate as to whether this clinical syndrome is the result of infarction, infection, or both. There is evidence to support a multifactorial etiology for the ACS.

Toddlers and school-aged children are more likely to suffer from ACS.1-3 In this population the etiology is more often felt to be infectious in nature.3,4 Adolescents and young adults have a lower incidence of ACS, but it tends to be more severe, and is often fatal.3 In this age group an infectious agent is less frequently isolated. Risk factors for the development of ACS include younger age, lower hemoglobin F concentration, higher steady state hemoglobin concentration, and higher steady state white blood cell count.3

The frequency, severity, and outcome of ACS differ depending upon the age of the patient. This may reflect different mechanisms for the initiation of the syndrome, and/or less physiologic reserve after repeated cardio-pulmonary insults in older children, or a combination of both. In any event, it is unclear whether primary parenchymal lung injury, pulmonary vascular injury, or a more remote insult precipitates ACS. It is likely that either can precipitate this syndrome with pulmonary parenchymal and pulmonary vascular injury serving as the final common pathway in this syndrome.

Pathogenesis

The exact pathogenesis of ACS is not fully delineated, however evidence points to multifactorial etiologies. Prior studies have demonstrated that sickle cell patients with numerous previous episodes of ACS suffer chronic lung injury.5-7 Peak expiratory flow rates are diminished in patients with a prior history of multiple episodes of ACS.7 This is hypothesized to be due to pulmonary fibrosis secondary to repeated bouts of pulmonary inflammation and supports the notion that pulmonary parenchyma is a site of direct injury in ACS.7 It does not, however, prove that the pulmonary parenchyma is the site of primary injury in cases of ACS. It is conceivable to imagine that any primary pulmonary infectious, or atelectatic process, could cause regional alveolar hypoxia and a spiral of erythrocyte "sickling" culminating in pulmonary microvascular occlusion.

Conversely, other investigators have implicated a primary pulmonary "vasculitis" as etiologic in ACS. Some have concluded that a primary pulmonary "vasculitis" might act independently of any parenchymal lung injury in producing pulmonary hypertension. Such a vasculitis might serve as a primary insult in the ACS cascade, with lung injury and infarction as secondary or concomitant injuries. In fact endothelium/platelet interactions may contribute to ACS, and support the belief that a primary "vasculitis" is a substantial contributor to the pathophysiology of ACS. Endothelin-1 is an intracellular endothelial protein that is liberated into the bloodstream when endothelial injury occurs. Studies of endothelin-1 levels in patients with SCD reveal that endothelin-1 levels are chronically elevated when compared with control patients.8 Additionally, endothelin-1 levels increase markedly immediately before or concomitantly with the onset of vaso-occlusive crisis and return to their baseline elevated state with clinical resolution of the illness.8 This evidence supports the notion that chronic endothelial injury takes place in SCD, and exacerbation of endothelial injury accompanies the onset of clinical crises in SCD. Radiographic evidence for intravascular thrombosis in the pulmonary circulation during episodes of ACS supports this notion.9

Recent evidence has pointed to pulmonary fat embolism as a cause, or contributor to ACS.10 Autopsy studies of children who died from ACS revealed numerous fat emboli in the pulmonary vasculature.10 Investigators hypothesized that medullary long bone fat liberated into the circulation during vaso-occlusive infarcts were responsible for the emboli. Indeed, serum levels of phospholipase A2 were found to be markedly elevated in patients with ACS.11 Phospholipase A2 may be responsible for increased pulmonary vascular permeability, bronchoconstriction, mucus secretion, and leukocyte chemotaxis.12

Platelet activity is known to be chronically increased in the setting of SCD.13 Mehta and colleagues have demonstrated that there are increased numbers of circulating platelet complexes in the setting of SCD.14 Additionally, platelet life is shorter, and the bone marrow produces more platelets per unit time to support this accelerated turnover.15 Markers of platelet activity such as b-thromboglobulin levels, as well as other platelet granule products are elevated chronically in patients with SCD, and likewise increase during periods of clinical disease.16-19 Platelets from SCD patients exhibit diminished in vitro activity, presumably as a result of chronic activation in vivo.20

It is clear that the pathogenesis of ACS is not known, and it is likely that many insults (atelectesis, pneumonia, fat emboli) result in regional hypoxemia and may lead to a final common patho-physiologic pathway of intravascular sickling with subsequent endothelial damage, platelet activation, and liberation of inflammatory mediators. The initiating insult as well as the underlying health of organ systems may differ in different age groups accounting for the difference in etiology, incidence and outcome observed across the spectrum of sickle cell patients.

Clinical Presentation And Differential Diagnosis

Acute chest syndrome may be the presenting diagnosis for a patient with SCD, but equally as often, develops while the patient has a vaso-occlusive crisis, bacterial infection, or after surgery.1-4,21,22 The classic presentation is that of a youngster with tachypnea and hypoxemia.1-4 Verbal children may complain of chest pain and difficulty breathing.1-4 Fever often accompanies the presentation.1-4 Chest radiography reveals the presence of a new pulmonary infiltrate, which usually progresses rapidly (over the course of hours to several days) to involve multiple lobes.1-4 It is usual to see a drop in hemoglobin concentration below expected values for the patient, and the platelet count can be decreased.1-4 Pulse-oximetry and arterial blood gas analysis demonstrates hypoxemia with a widened alveolar _ arterial oxygen gradient.23 Echocardiography may show right ventricular dysfunction, septal bowing to the left, and tricuspid regurgitation as a result of elevated pulmonary arterial pressure, as well as a hyperkinetic, dilated left ventricle.24-25

Treatment

Treatment for the acute chest syndrome includes nonspecific supportive measures, as well as strategies specifically designed to attenuate intra-vascular sickling and endothelial cell damage.

Respiratory Support

Supplemental oxygen is administered to treat hypoxemia and prevent further sickling. If frank respiratory failure is present, mechanical ventilation is instituted taking measures to minimize barotrauma as lung compliance may be markedly diminished. Such measures include ventilation with smaller tidal volumes and more rapid rate to maintain minute ventilation. Positive end-expiratory pressure is incrementally added to recruit collapsed and infiltrated alveoli. Inspiratory time can be progressively prolonged until the normal physiologic I:E ratio is inverted. High frequency oscillating ventilation can also be used for refractory hypoxemia.

Circulatory Support

Crystalloid is administered as a bolus to correct any overt fluid deficits, and maintenance fluid is administered at a rate equal to one and a half times the expected maintenance requirements to ensure adequate intravascular hydration status. It is exceedingly common for patients with sickle cell anemia to have a dilated, hyperkinetic left ventricle as a result of chronic anemia and the need to meet the body's demand for oxygen.25 What is less commonly appreciated is that there is a significant incidence of right ventricular dysfunction and pulmonary hypertension in asymptomatic patients with sickle cell anemia.24 In the setting of severe, acute lung disease, this quiescent pulmonary hypertension can cause right ventricular dysfunction that is severe enough to cause circulatory compromise. Hypotension therefore, in this setting mandates invasive hemodynamic monitoring to determine which ventricle is responsible for circulatory compromise and to optimize hemodynamics. Finally, blood products will be necessary to optimize intravascular volume, and to restore oxygen carrying capacity in the severely anemic patient with cardiopulmonary compromise.

Treatment Of Presumed Infection

Functionally asplenic sickle cell patients are predisposed to serious bacterial infection. Hypotension and poor perfusion may be a manifestation of compensated or decompensated septic shock with low systemic vascular resistance. Until sputum and blood cultures are known, we feel it is prudent to initiate broad-spectrum antibiotics to all febrile, critically ill patients with sickle cell anemia. As soon as the trachea is intubated, tracheobronchial secretions are cultured for bacteria and other less common or opportunistic pathogens as dictated by the clinical suspicion of the physician. Empiric antibiotic therapy is initiated to cover encapsulated organisms including S. Pneumoniae. Such coverage usually includes high dose third generation cephalosporins plus a macrolide antibiotic to cover atypical community acquired pneumonia. Although it is generally thought that high dose cephalosporins can overcome intermediate cephalosporin resistance seen frequently in pneumococcal isolates, vancomycin can be considered if the probability of resistance is high and the patient is unstable.

Transfusion Therapy

Transfusion is the cornerstone of therapy for the acute chest syndrome.23 The rationale is that the cycle of hypoxemia and sickling can be broken through the elimination of sickle hemoglobin from the circulation. Transfusion therapy may be administered as a simple transfusion. The purpose of this is to increase the oxygen carrying capacity of the blood. This is especially important in patients who have refractory hypoxemia. In addition to improving oxygen carrying capacity, simple transfusion had an additional effect of decreasing the alveolar - arterial gradient.23 Simple transfusion had a salutory effect on V/Q mismatch or intrapulmonary shunt through unclear mechanisms possibly related to improved pulmonary microvascular blood flow.23 The target hemoglobin concentration for sickle cell patients is generally between 9 and 10.5 g/dl in order to optimize oxygen carrying capacity without impeding microvascular flow due to increased viscosity and sludging.

While simple transfusion may have some beneficial effects, exchange transfusion is much more efficacious in rapidly lowering the hemoglobin S concentration. Exchange transfusion is routinely used as a first line treatment for the more seriously ill sickle cell patient, or if the patient deteriorates after simple transfusion. Sufficient blood is exchanged to reduce the hemoglobin S concentration to less than 30% of the total while maintaining the total hemoglobin concentration near 10 g/dl. Subsequently, simple transfusion is performed whenever the hemoglobin concentration falls to a level that will allow the post transfusion hemoglobin concentration to fall within the target range of 9 - 10.5 g/dl. Such an approach suppresses endogenous marrow production of sickle hemoglobin while maximizing oxygen carrying capacity without impairing microvascular flow with excessive viscosity.

Steroids

Administration of exogenous steroids is beneficial in mild to moderate ACS.12 Dexamethasone administration to a group of patients with ACS resulted in shorter hospitalization, shorter duration of fever, less transfusion requirement, less analgesic use, and less oxygen requirement.12 The authors hypothesized that dexamethasone may have attenuated the release of inflammatory mediators (i.e., phospholipase A2) associated with inflammation, ischemia and infarction.12 There may be a return of symptoms after steroid treatment. This "rebound" effect correlated with the time required for the half-life of the drug to pass and may represent some recrudescence of the intravascular inflammatory process that had been suppressed by the glucocorticoid.12

Inhaled Nitric Oxide

Nitric oxide (NO) is administered as an inhaled gas for a variety of medical conditions associated with severe lung
disease and pulmonary hypertension in neonates, children and adults.26-28 While the specific role of NO in many disease processes is still being elucidated, we, along with others, believe NO possesses several properties that may make it an ideal medication for the treatment of acute chest syndrome and other complications of sickle cell anemia.29 It is directly absorbed from the alveolus into the pulmonary vasculature where it diffuses into the abluminal smooth muscle and mediates smooth muscle relaxation and blood vessel dilation.26-32 As a consequence, more blood is diverted from poorly ventilated alveoli to the well-ventilated alveoli that entrained the NO. It is an ideal inhaled pulmonary vasodilator as it augments favorable V/Q matching.26-28 Additionally, it's smooth muscle relaxant properties effectively lower the pulmonary arterial hypertension26-30 associated with severe lung disease and may in and of itself improve right ventricular performance, pulmonary vascular resistance, and cardiac output. Because it is rapidly inactivated by the erythrocytes in the pulmonary circulation it has the additional benefit of not causing systemic arterial vasodilatation and hypotension. This is a property unique to NO and is not shared by any of the parenteral vasodilators. In addition to the favorable effects of NO on V/Q matching and pulmonary hemodynamics, NO possesses several properties that makes it ideal for the management of acute chest syndrome. Such properties relate to the ability of NO to modulate oxygen unloading from the erythrocyte, an inhibitory effect on platelets, and potential local regulation of vasomotor tone.

Sickle hemoglobin binds oxygen more avidly in the presence of nitric oxide.33 Increased oxygen avidity prevents the hemoglobin molecule from assuming the deoxygenated state, a state associated with "sickling" and microvascular occlusion. Additionally, inhaled nitric oxide has a potent and reversible anti-platelet effect that is likely to be beneficial in acute chest syndrome.34 The effect is mediated by intracellular increases in platelet cGMP that result in inhibition of fibrinogen binding to the glycoprotein IIb/IIIa receptor.35 Additionally, the family of nitrovasodilators prolongs the activity of tissue plasminogen activator, which results in increased thrombolytic activity.36 Such effects might indeed be beneficial in a disease characterized by heightened endothelial and platelet interactions.

Finally, it is believed that nitric oxide may have some influence on vascular tone, and as a result, on distribution of blood flow to various tissue beds. Nitric oxide is rapidly bound by hemoglobin in the pulmonary circulation. It is believed to bind to the cysteine 93 residue on the beta chain.37 From there, it is carried to the tissues where it is released as a result of allosteric changes associated with oxygen unloading. It diffuses into the abluminal arteriolar smooth muscle where it mediates vasodilatation of the tissue bed. In this manner, nitric oxide may also work in the periphery to prevent microvascular occlusion and tissue injury. Others and we have had considerable success in managing critically ill children with severe ACS with inhaled nitric oxide.38-39

Prevention And Outcome

While many of the patients presenting with medical illness have already begun the intravascular cascade that will ultimately lead to ACS, elective surgical patients are a high-risk group for whom appropriate preventive steps may be taken to decrease the likelihood of ACS. Simple transfusion to hemoglobin of 10 g/dl is as effective in avoiding post-operative complications as is exchange transfusion.40 As such, sickle cell patients who present for any surgical procedure other than the most minor peripheral procedure are electively transfused to a hemoglobin concentration of 10 g/dl. Pre-operative exchange transfusion should be considered if the patient has a history of particularly aggressive sickle cell disease or a predilection towards major sickle cell complications such as ACS or stroke. This would be particularly true for major abdominal or thoracic cavity procedures associated with post-operative pulmonary dysfunction. It would also be true for peripheral extremity procedures where a tourniquet is used intra-operatively. Other anesthetic goals should include meticulous attention to temperature preservation, maintaining euvolemia, and avoiding hypoxemia. Post-operative care should emphasize vigorous pulmonary toilet, and an analgesic regimen that can encourage deep breathing maneuvers without causing excessive sedation or hypoxemia. Regional anesthetic techniques, including major neuraxial blockade (epidural anesthesia) is ideally suited for this as it provides dense analgesia without suppressing respiratory drive. Additionally, it inhibits sympathetic tone and vasoconstriction that can result in microvascular sludging.

ACS can cause disability and death. The risk of death differs according to age and is about 2% in children and 4.3% in adults.2 Survivors of ACS may be left with debilitating chronic lung injury, pulmonary fibrosis, intimal hyperplasia, pulmonary hypertension, and cor pulmonale.5-7,24-25 Thus aggressive and timely intervention from a multidisciplinary team of physicians is required to minimize the morbidity, and mortality associated with this devastating complication of sickle cell disease. Currently, research at Wolfson Children's Hospital is being directed at determining the state of endogenous nitric oxide production in children with SCD and a history of ACS, as well as evaluating the efficacy and safety of inhaled nitric oxide in the early treatment of acute chest syndrome of sickle cell disease.

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Jacksonville Medicine / June, 2000

 

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