INTRODUCTION
Anesthesiologists are frequently called upon to care for patients with hemoglobinopathies. As in this case, the complications of the disease often occur in the postoperative period. Adequate preoperative preparation, intraoperative and postoperative management may prevent many of the complications associated with this disease.
What Is the Genetic Cause of Sickle Cell Disease?
Hb consists of two α chains and two non-α chains. In the case of normal adult Hb, these non-α chains are β chains. The α chain production is coded by two alleles located in the chromosome 11, whereas the β chain production is controlled by four alleles paired on chromosome 16. Abnormal Hb states can result from underproduction of a globin chain or production of an abnormal amino acid sequence within a chain.
Underproduction of a given chain results in the group of disorders known as thalassemia. α-Thalassemia is the underproduction of the α chain. There are four types of α-thalassemia, ranging in severity from mild to severe, depending on how many of the four α-globulin chains are underproduced. β-Thalassemia is commonly seen in people from the Mediterranean Sea region. It results from an underproduction of β chains. Heterozygotes have a mild anemia known as thalassemia minor. Homozygotes are known as thalassemia major, or Cooley’s anemia, and are usually transfusion-dependent. Patients may be genetically coded to have both a sickling disorder and one of the thalassemias.
SCD is the most common of all hereditary disorders, affecting up to 0.2% of the adult African American population with SCD, 8% with sickle cell trait,
1 and approximately 50,000 children in the United States with SCD.
2,
3 A single amino acid substitution at position 6 on the β chain is responsible for the condition. SCD is inherited as an autosomal recessive disorder following a predictable Mendelian pattern. Therefore, heterozygote (HbAS) parents will have a 25% chance of producing either a normal (HbAA) or SCD (HbSS) and a 50% chance of producing another heterozygote (HbSA, trait) child.
Normal adult red blood cells contain three types of Hb, HbA (α
2,β
2) and small quantities of HbA
2 (α
2,δ
2) and
HbF (α
2γ
2). Patients with SCD have >50% HbS, with the remainder being HbF or HbA
2 (see
Table 37.1). They contain no HbA unless they have a double heterozygous condition such as both SCD and β-thalassemia. However, they will always have more than 50% HbS. Individuals with a combination of normal HbA and <50% HbS have sickle cell trait. Infants may have >70% HbF, which persists for up to 4 months of age when the fetal red cells are replaced by hematopoiesis of adult red cells as β chain production replaces γ chain production. When fetal Hb is present and persists into adulthood, it can provide protection against sickling. HbC and thalassemia β
+ also provide some protection against sickling, and these patients usually have a milder clinical course.
What Background Knowledge Is Relevant for Sickle Cell Disease?
In SCD, there is a glutamic acid to valine substitution at position 6 on the 146 amino acid β chain. This substitution creates a structural abnormality of the Hb molecule, rendering it unstable, as well as less soluble when deoxygenated. The former causes accelerated breakdown and hemolytic anemia, whereas the latter permits Hb tetramers to form polymers.
4 These Hb polymers form long helical bands, causing distorted red cells.
5 As the cells sickle and reform, the intricate balance of iron metabolism and cellular hydration is disturbed, which alters the red cell membrane, thereby making them sticky. Historically, it was felt that this red cell abnormality was solely responsible for SCD-related problems. However, the interactions between red cells, platelets, leukocytes, thrombin, and endothelial cells, along with disturbances of nitric oxide (NO) biology, are now known to be at least equally important. Recent evidence shows that there is decreased production and increased scavenging of NO in patients with SCD. Through different mediators, this leads to a complex pathophysiology, including endothelial dysfunction, enhanced platelet aggregation and coagulation, increased leukocyte endothelial adhesion, susceptibility to oxidantmediated injuries, and both acute and chronic pulmonary hypertension. In fact, the administration of inhaled NO has been shown to be beneficial in some patients suffering a vaso-occlusive crisis, including stroke and ACS.
With time, these complex interactions between the deformed and sticky red cells and the endothelium results in widespread chronic endothelial inflammation, injury, and organ dysfunction.
The HbS red cell is unstable and insoluble, resulting in early red cell destruction, sickling, and endothelial damage. Red blood cells with HbSS begin sickling when the oxygen saturation falls below 85% (PaO
2 of approximately 40 to 50 mmHg). Acidosis, hypoxia, intracellular dehydration, and vascular stasis increase the sickling process (see
Table 37.2). Decreased cardiac output and hypovolemia lead to increased transit time through the hypoxic environment of the capillary bed, also increasing the sickling process. The consequence of sickling is endothelial adhesion and occlusion of the microvasculature. Erythrocytes, leukocytes, platelets, vascular endothelium, NO, and the coagulation cascade are involved in the vascular injury that results from the sickled red blood cell. In fact, SCD should be considered as much a vascular endothelial disease as a red blood cell disease.
What Are the Clinical Manifestations of Sickle Cell Disease?
Sickle cell problems begin in infancy and culminate in multiorgan damage in adulthood after years of endothelial damage, microinfarcts and ischemic damage to end organs (see
Table 37.3). Because of immunologic deficits and splenic dysfunction, these patients are at very high risk for overwhelming sepsis. One of the main reasons for widespread postnatal screening for this disease is so children can be placed on penicillin until the age of 6 to assure appropriate immunoprophylaxis. The clinical manifestations of SCD can be grouped into acute and chronic. Typically, the acute problems have been grouped as various crises: Splenic sequestration, hyperhemolytic, aplastic, and vaso-occlusive. The vaso-occlusive crisis can be further broken down into: Painful, priapism, ACS, and stroke. It is these vaso-occlusive events that are of the most concern during the perioperative period.
ACS and stroke are the most concerning perioperative complications. ACS may result from pneumonia, fat emboli, pulmonary vaso-occlusion, and sequestration. It occurs in 10% to 20% of postoperative patients,
6,
7,
8 and may rapidly progress to respiratory failure. The mortality rate from ACS is 2% to 12%. This, more than anything else, accounts for the very high perioperative mortality rate of 1% in these patients. Treatment for ACS includes supplemental oxygen, exchange transfusion, hydration, aggressive respiratory support, and antibiotics (see
Table 37.4). Inhaled NO may also have a unique role in treating ACS.
8
Cerebral vascular accidents occur in approximately 5% of subjects with SCD.
9 Most CVAs in children are due to ischemic infarcts, whereas adults may also be hemorrhagic. It has recently been recognized that as many as 15% to 25% of asymptomatic children have radiographic evidence of silent cerebral infarcts. In many centers, patients with SCD are screened with transcranial Doppler, and those with elevated flow velocities in the middle cerebral and terminal internal carotid arteries are placed on hypertransfusion regimens. Individuals with a previously documented CVA are placed on transfusion regimens, usually for a period of 10 years. It is only recently that we are noting that patients coming off these regimens are experiencing recurrence.
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