Sickle Cell Disease

Kevin J. Sullivan

Erin Coletti

Salvatore R. Goodwin

Cynthia Gauger

Niranjan “Tex” Kissoon

KEY POINTS

Normal Hemoglobin Structure and Function

The presence of fetal hemoglobin offers protection from sickle cell disease (SCD) from birth to 6 months of age. After 6 months of age, sickle hemoglobin increases in the circulation and complications of SCD may appear.

SCD represents a variety of genotypes expressing a phenotype that is characterized by hemoglobin deformation in the deoxygenated state and which results in a chronic hemolytic anemia and capillary occlusion by deformed erythrocytes.

Relevance to Pediatric Critical Care

The life-threatening end-organ effects of SCD include acute chest syndrome (ACS), aplastic crisis, splenic sequestration crisis, stroke, and an increased risk of infectious complications.

Pediatric intensivists need to be familiar with the management of acute life-threatening SCD complications, perioperative management, and chronic sequelae such as stroke, cardiovascular dysfunction, and pulmonary artery hypertension.

The erythrocyte cell membrane becomes irreversibly injured when hemoglobin is in a deoxygenated state unless prompt reversal occurs in the pulmonary vasculature.

Biologic Precipitants of Sickle Cell Complications

SCD is a prototypical model of the complex interplay of a genetic defect of hemoglobin structure and function with disordered vascular biology.

Abnormalities of hemoglobin structure and function, endothelial cells, leukocytes, platelets, the coagulation cascade, and systemic inflammation are intricately related in SCD.

Abnormalities of nitric oxide metabolism and oxidantmediated injury are responsible for many of the complications of the disease.

Physiologic precipitants of SCD include dehydration, acid-base imbalance, hyper- and hypothermia, hypoxemia, and vasoconstriction.

Sickle Cell Complications

Vaso-occlusive crisis (VOC) may mimic other severe medical conditions and often precedes some of the severe complications of SCD.

If osteomyelitis cannot be differentiated from VOC, then antimicrobial coverage for Staphylococcus aureus and Salmonella species should be administered.

Simple or exchange transfusions are effective for many complications of SCD, but hematocrit elevations above 33% are associated with increased viscosity and the potential for central nervous system (CNS) thrombotic injury. Repeated transfusions may lead to transfusion-related complications.

ACS may progress quickly to life-threatening respiratory failure and multiple organ system failure.

Stroke is a common source of morbidity and may be recurrent. Focal seizures may be the presenting symptom of acute cerebral ischemia. The differential diagnosis of stroke in SCD includes meningitis and toxic ingestions.

Acute treatment of stroke includes exchange transfusion. Chronic transfusion may attenuate stroke risk, but its discontinuation is associated with increased risk of stroke recurrence.

Chronic Injury of the Cardiovascular System

Children with SCD are surviving further into adulthood, but chronic circulatory and respiratory dysfunction may predispose to premature mortality.

Common chronic hemodynamic disturbances include ventricular diastolic dysfunction and increased pulmonary vascular resistance. Common chronic pulmonary issues include restrictive lung disease and reactive airway disease. These conditions add to SCD-related morbidity.

Pulmonary hypertension is the most important predictor of early mortality and should always be suspected in the acutely ill patient.

Sudden death is common among SCD patients.

Perioperative Management of SCD Patients

The perioperative mortality is greatly increased for patients with SCD.

Simple transfusion is as effective as exchange transfusion in the prevention of perioperative SCD-related complications and is associated with fewer transfusion-related complications.

Important perioperative factors to optimize include hydration, vital organ function, analgesia, and pulmonary toilet.

The risk of perioperative SCD complications varies with the operative procedure and the severity of the patient’s clinical course.

New Concepts in Understanding SCD/Future Directions

The variable expression of SCD can be explained by the interplay of chronic hemolysis/endothelial dysfunction and viscosity/vaso-occlusion.

Hemolysis and endothelial dysfunction are associated with pulmonary hypertension and stroke, while viscosity and vaso-occlusion are associated with ACS, VOC, and osteonecrosis of the bone.

Sickle cell disease (SCD) refers to a clinical phenotype that is expressed as chronic hemolysis, vascular occlusion, painful crises, ischemic end-organ injury, acute life-threatening manifestations of the disease, and development of chronic organ dysfunction. A variety of hemoglobin genotypes that cause hemoglobin deformation in the deoxygenated state can express the SCD phenotype. The most common genetic disorder causing SCD is sickle cell anemia (SCA), in which patients possess two genes for abnormal β chains of the hemoglobin molecule. Other genotypes expressing variations of the SCD phenotype include sickle β⁰ thalassemia, sickle β⁺ thalassemia, and hemoglobin SC disease (HbSC). Patients with homozygous sickle hemoglobin (HbS) or sickle β⁰ thalassemia usually have the most severe manifestations of SCD, whereas patients with HbSC or sickle β⁺ thalassemia usually have a milder course.

The management of patients with SCD phenotypes is relevant to the practice of pediatric critical care medicine because SCD is a multi-organ system disease in which life-threatening acute complications occur commonly. Pediatric intensive care physicians are frequently required to comanage these patients with subspecialists, including hematologists, surgeons, anesthesiologists, cardiologists, and pulmonologists. Finally, SCD is of great interest as few other diseases in medicine better illustrate the interactions in vascular biology that occur between hemoglobin, erythrocytes, endothelial cells, platelets, coagulation cascade, nitric oxide (NO), and injurious oxidant compounds.

In this chapter, we review (a) the basic biochemical abnormalities of the hemoglobin molecule in SCD, (b) the comprehensive vascular biology that underlies the clinical manifestations of the disease, (c) the acute and chronic clinical complications of SCD and clinical management strategies, (d) anesthetic and surgical considerations relevant to the patient with SCD, and (e) outcomes and prognosis for patients with SCD.

NORMAL HEMOGLOBIN STRUCTURE AND FUNCTION

Normal human hemoglobin is a tetrameric protein composed of two α and two β chains. Each chain consists of an ironcontaining protoheme moiety, which binds oxygen, as well as a globin chain of amino acids arranged in a specific sequential and spatial pattern. While the iron-containing heme group in each chain is identical, the amino acid sequences of the globin chains differ and impart unique chemical and functional characteristics, including oxygen affinity.

With the exception of hemoglobin expressed early in embryologic development, hemoglobin consists of two α and two non-α chains attached to four iron-containing heme complexes. Hemoglobin A comprises the majority (95%) of normal adult hemoglobin and contains two α and two β chains (HbA: α₂, β₂). Hemoglobin A₂ is also a component (1%-4%) of normal adult hemoglobin and is composed of two α and two δ chains (HbA₂, α₂, d₂). Fetal hemoglobin, which is the predominant hemoglobin in fetal development, gradually declines during the first 6 months of life and is composed of two α and two γchains (HbF: α₂, γ₂). At birth, human erythrocytes contain 70%-90% HbF, which normally predominates until 2-4 months of age. The persistence of HbF production exists in many conditions and offers a protective effect when present

in patients with certain hemoglobinopathies.

SCD refers to a variety of genotypes that all result in the production of sickled erythrocytes upon hemoglobin deoxygenation, eventually leading to chronic hemolysis, recurrent vaso-occlusion, and ischemic end-organ injury to every organ

system. All patients with an SCD phenotype inherit a mutant β-globin allele in which the sixth codon is altered, resulting in the substitution of valine for glutamine at the sixth amino acid position of the β-globin chain. Hemoglobin that incorporates this mutant β^S-globin chain is referred to as HbS, and homozygotes for the β^S allele are said to have SCA (HbSS), while heterozygotes for the β^S allele are said to have sickle cell trait (SCT, HbAS). Patients with SCT do not express the SCD phenotype because of the protective effects of HbA.

Heterozygous genotypes coding for HbS, together with other alterations in β-chain production (non-HbA), can also result in the expression of the SCD phenotype. The most common heterozygous SCD genotypes are HbSC and the sickle β thalassemias. Approximately 70% of the SCD patients in the United States are homozygous for β^S (SCA), while HbSC (˜20%) and sickle β thalassemias (10%) comprise the remainder (1). Patients with HbSC or HbS-β⁺ thalassemia demonstrate less severe symptoms than patients with HbSS because of the protective effects of HbF (in patients with HbSC) or hemoglobins A and F (patients with HbS-β⁺ thalassemia produce some, but a reduced amount of, β chains of HbA). Patients with HbS-β⁰ thalassemia produce no β chains of HbA and exhibit a clinical course similar in severity to that of patients with HbSS (Table 119.1)(2).

As a result of global migration, SCD now has worldwide distribution and is one of the most common monogenetic disorders in the world. SCT is estimated to be present in 8%-9% of African Americans (3,4). SCA affects nearly 1 in 600 African Americans (5) and an estimated 1%-4% of all infants born in sub-Saharan Africa (6). SCD is inherited in an autosomal recessive fashion with standard Mendelian inheritance.

RELEVANCE TO PEDIATRIC CRITICAL CARE

The common, acute complications of SCD that require the attention of the pediatric intensive care physician include splenic sequestration, aplastic crisis, sepsis, acute chest syndrome

(ACS), and stroke. Additionally, the intensive care physician may be called upon to assist in the management of SCD patients with refractory vaso-occlusive crisis (VOC), priapism, or orbital infarction. Finally, intensive care physicians
and anesthesiologists are often involved in the perioperative

management of patients with SCD.

TABLE 119.1 SEVERITY AND DIAGNOSTIC TESTING FOR RELEVANT SICKLE CELL SYNDROMES

				Hemoglobin Electrophoresis in Older Children (%)
▪ SYNDROME	▪ GENOTYPE	▪ SEVERITY	▪ NEONATAL SCREENING^a	▪ HBA	▪ HBS	▪ HBF	▪ HBA₂	▪ HBC
Sickle cell anemia	S-S	++++	FS	0	80-95	2-20	<3.5	0
Sickle β⁰ thalassemia^b	S-β⁰	+++	FS	0	80-92	2-15	3.5-7	0
Hemoglobin	SC disease S-C	++	FSC	0	45-50	1-5	NA^c	45-50
Sickle β⁺ thalassemia^b	S-β⁺	+	FSA or FS^d	5-30	65-90	2-10	3.5-6	0
Sickle cell trait	A-S	0	FAS	50-60	35-45	<2	<3.5	0
^aHemoglobins reported in order of decreasing quantity (e.g., FS = F > S); F, fetal hemoglobin; S, sickle hemoglobin; C, hemoglobin C; A, hemoglobin A. ^bβ⁰ indicates thalassemia mutation with absent production of β-globin; β⁺ indicates thalassemia mutation with reduced production of β-globin. ^cQuantity of HbA₂ cannot be measured in the presence of HbC. ^dQuantity of HbA at birth sometimes insufficient for detection.
Adapted from Lane PA. Sickle cell disease. Pediatr Clin N Am 1996;43:639-64, table 1 on page 642, with permission.

The severity of SCD varies widely but leads to repetitive injuries to every organ system. Therefore, chronic injury to the circulatory, respiratory, nervous, renal, and immune systems may already be present in children with SCD who present to the PICU

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