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Hematologic disorders
Disease states related to erythrocytes include anemia and polycythemia. Anemia is characterized by a decrease in the red cell mass, with the main adverse effect being a decrease in the oxygen-carrying capacity of blood. Polycythemia (erythrocytosis) represents an increase in hematocrit (Hct). Its consequences are primarily related to an expanded red cell mass and a resulting increase in blood viscosity.
Physiology of anemia
Anemia is a disease sign manifesting clinically as a reduced absolute number of circulating red blood cells (RBCs). Although a decrease in Hct is used most often as an indicator, anemia has been defined as a reduction in one or more of the major RBC indices: hemoglobin (Hb) concentration, Hct, and RBC count. In adults, the World Health Organization (WHO) defines anemia as Hb concentration less than 12 g/dL for women and less than 13 g/dL for men. In pregnancy, a decreased Hct reflects the increase in plasma volume in relationship to the RBC mass (physiologic anemia). However, Hb less than 11 g/dL in a pregnant patient is considered truly anemic. In acute blood loss the Hct may initially be unchanged. Decreases in Hct that exceed 1% every 24 hours can only be explained by acute blood loss or intravascular hemolysis.
The most important adverse effect of anemia is the reduction in arterial oxygen concentration and the potential for decreased tissue oxygen delivery. For example, a decrease in Hb concentration from 15 g/dL to 10 g/dL results in a 33% decrease in arterial oxygen content. The initial compensation for this decrease in oxygen content is an increase in cardiac output. This occurs via enhanced sympathetic nervous system activity and the decrease in blood viscosity that accompanies anemia. There is also a rightward shift of the oxyhemoglobin dissociation curve, which facilitates release of oxygen from Hb to tissues. This is followed by redistribution of blood flow to the myocardium, lungs, and brain. Muscle and skin blood flow decrease (which results in pallor), as does blood flow to the kidneys (which stimulates erythroid precursors in bone marrow to produce additional RBCs). Fatigue and low exercise tolerance indicate the inability of cardiac output to increase further to maintain tissue oxygenation. This is most notable in anemic patients who are physically active or in patients with coronary artery disease. Orthopnea and dyspnea on exertion, cardiomegaly, pulmonary congestion, ascites, and edema can occur as a consequence of high-output heart failure in chronic severe anemia.
There are many causes and forms of anemia. The most common causes of chronic anemia are iron deficiency, anemia of chronic disease (ACD), thalassemia, and ongoing blood loss.
The transfusion trigger
Preoperative transfusion for the sole purpose of facilitating elective surgery is rarely justified in an asymptomatic anemic patient. During the perioperative period, transfusion should be considered based on the lost circulating blood volume, Hb level, ongoing bleeding, and the risk of end-organ dysfunction due to inadequate oxygenation.
The most appropriate Hb level to serve as the trigger for perioperative blood transfusion is uncertain. The 10/30 rule (transfuse if the Hb level is <10 g/dL or the Hct is <30%) was once a commonly cited reference point. However, there is no evidence that Hb values below this level mandate the need for perioperative RBC transfusion, but there is clear evidence that patients with Hb levels of 6 g/dL benefit from red cell transfusion. Patients with compensated chronic anemia with Hb values between 6 and 10 g/dL can tolerate these levels without evidence of end-organ ischemia.
The strongest evidence regarding perioperative transfusion comes from the Transfusion Requirements in Critical Care (TRICC) trial, which found no significant difference in 30-day mortality rates between a group managed using a “restrictive” transfusion strategy (transfusions were administered as necessary to keep Hb values between 7 and 8 g/dL) and a group treated using a “liberal” strategy (Hb was kept between 10 and 12 g/dL). The restrictive regime did not cause a significant increase in mortality, cardiac morbidity, or duration of hospitalization. Other studies also show no short- or long-term mortality benefit when a liberal transfusion strategy (transfusion when Hb was <10 g/dL) is used in patients with underlying coronary artery disease undergoing hip surgery (vs a more restrictive strategy [i.e., transfusion when Hb <8 g/dL]). Recent data confirm noninferiority of a restrictive transfusion strategy (when Hb <7.5 g/dL) versus a liberal one (transfusion when Hb <9.5 g/dL) in regard to outcomes.
RBC transfusions have been associated with direct transmission of infectious diseases such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection. In critically ill and trauma patients, transfusions are independently associated with longer intensive care unit and hospital lengths of stay, higher mortality rates, an increased incidence of ventilator-associated pneumonia, and increased mortality. The immunomodulatory effects of RBC transfusion can lead to cancer recurrence, postoperative bacterial infection, transfusion-related acute lung injury, and hemolytic transfusion reactions.
An expected blood loss of 15% or less of total blood volume usually requires no blood replacement during surgery. A loss of up to 30% can be replaced exclusively with crystalloid solutions. A loss of more than 30% to 40% generally requires RBC transfusion to restore oxygen-carrying capacity. The transfusion is given with crystalloid or colloid solutions to restore intravascular volume and maintain tissue perfusion. In cases of massive transfusion (>50% of blood volume replaced within 24 hours), RBC transfusion may need to be accompanied by administration of fresh frozen plasma and platelets at a ratio of 1:1:1.
Patients with active coronary artery disease (unstable angina or acute myocardial infarction) merit special consideration. The literature suggests that Hct of 28% to 30% may be an appropriate transfusion trigger in patients with unstable coronary syndromes.
Management of anesthesia: General concepts for anemia
If elective surgery is performed in the presence of chronic anemia, it is prudent to minimize the likelihood of significant changes that could further interfere with oxygen delivery to tissues. For example, drug-induced decreases in cardiac output or a leftward shift of the oxyhemoglobin dissociation curve due to respiratory alkalosis from iatrogenic hyperventilation could interfere with tissue oxygen delivery. Decreased body temperature also shifts the oxyhemoglobin dissociation curve to the left (i.e., there is less oxygen release to tissues). Decreased tissue oxygen requirements may accompany the myocardial depressant effects of anesthetic drugs and hypothermia. These offset the decrease in tissue oxygen delivery associated with anemia but to an unpredictable degree. Signs and symptoms of inadequate tissue oxygen delivery due to anemia may be difficult to appreciate during general anesthesia. Effects of anesthesia on the sympathetic nervous system and cardiovascular responses may blunt the usual increase in cardiac output associated with acute normovolemic anemia. Efforts to offset the impact of surgical blood loss by measures such as normovolemic hemodilution and intraoperative blood salvage can be considered in selected patients.
Volatile anesthetics may be less soluble in the plasma of anemic patients because of the decrease in concentration of lipid-rich RBCs. As a result, uptake of volatile anesthetics might be accelerated. However, the effect of this decreased solubility is likely offset by an increased cardiac output. Therefore it seems unlikely that clinically detectable differences in the rate of induction of inhalation anesthetics or vulnerability to an anesthetic overdose would be present in anemic patients compared to patients without anemia.
Evaluation and classification of anemia
Anemia can be classified based on erythrokinetic mechanisms—that is, anemia due to ineffective erythropoiesis, anemia due to increased destruction of RBCs, and anemia due to blood loss. Anemia can also be classified based on morphologic characteristics—that is, microcytic, normocytic, or macrocytic based on mean corpuscular volume.
Initial evaluation of an anemic patient should include a complete blood cell count (CBC) with RBC count and standard indices, white blood cell (WBC) count, and platelet count. In addition, special indices such as RBC distribution width (RDW), which represents a measure of variation in red cell size (>14 is abnormal) and a reticulocyte count (>2% is abnormal) can indicate increased RBC destruction. Analysis of the peripheral blood smear is essential to evaluate RBC morphology.
Microcytic anemias
Microcytic anemias are those with a mean corpuscular volume less than 80 fL. The most common causes of microcytic anemia are iron deficiency and the thalassemias. Sideroblastic anemia and (rarely) anemia of chronic disease can also present as microcytic anemias.
Iron-deficiency anemia
Nutritional deficiency of iron as a cause of anemia is found only in infants and small children. In adults, iron-deficiency anemia (IDA) reflects depletion of iron stores caused by chronic blood loss. Typically these losses are from the gastrointestinal (GI) tract or from the female genital tract (menstruation). Pregnant women are susceptible to development of IDA because of the increased RBC mass required during gestation and the needs of the fetus for iron.
Diagnosis.
Patients experiencing chronic blood loss may not be able to absorb sufficient iron from the diet to form Hb as rapidly as RBCs are lost. As a result, RBCs are produced with too little Hb. Most cases of IDA in the United States are mild, with Hb concentrations of 9 to 12 g/dL. There is a concomitant decrease in serum ferritin concentration (<41 ng/mL), a low reticulocyte count, a decreased serum iron level, and a reduced transferrin saturation (<20%). The absence of stainable iron in a bone marrow aspirate is confirmatory evidence for IDA.
Treatment.
Ideally IDA should be treated with ferrous iron salts administered orally and the iron stores replenished slowly. Oral iron should be considered if elective surgery can be postponed for 2 to 4 months to allow correction of the iron deficiency. Evidence of a favorable response to iron therapy is an increase in Hb concentration of approximately 2 g/dL in about 3 weeks and a return of Hb concentration to normal in about 6 weeks. Continued bleeding is indicated by reticulocytosis and failure of the Hb concentration to increase in response to iron therapy. Oral iron therapy should be continued for at least 1 year after the source of blood loss that caused the iron deficiency has been corrected.
If surgery is scheduled within just a few weeks, intravenous (IV) iron preparations can be used for correction of anemia. The efficacy of IV iron is superior to that of oral preparations, and newer preparations have less risk of anaphylactic reactions. A total dose of 1000 to 1500 mg iron is usually adequate to replenish stores preoperatively and decrease the need for perioperative transfusion.
In addition, while erythropoietin is not generally recommended for treatment of IDA, it is recommended and US Food and Drug Administration (FDA) approved for use for treatment of preoperative IDA, in conjunction with IV iron preparations. Anemic patients (Hb >10 g/dL and <13 g/dL) benefit from erythropoietin preparations prior to elective procedures, including cardiac surgery.
Thalassemia
Globin chains are assembled in the final globin molecule, which is a tetramer of two α-globin and two non–α-globin chains. In the adult, almost all Hb is made up of two α-globin and two β-globin chains (HbA), with minor components of HbF and HbA 2 .
An inherited defect in globin chain synthesis known as thalassemia is one of the leading causes of microcytic anemia in children and adults. This disorder shows a strong geographic influence, with β thalassemia predominating in Africa and the Mediterranean area, and α thalassemia and HbE in Southeast Asia.
Thalassemia differs from IDA in several ways: presence of a family history of thalassemia, iron stores and ferritin are normal or increased, and RBC production is maintained or even disproportionately high. The diagnosis is confirmed by Hb electrophoresis, which determines the types of globin chains present.
Thalassemia minor.
Most individuals with thalassemia have thalassemia minor and are heterozygous for either an α-globin (α-thalassemia trait) or β-globin (β-thalassemia trait) gene mutation. Although the mutations may decrease synthesis of the affected globin chain by up to 50%, producing hypochromic and microcytic RBCs, the anemia is usually modest with relatively little accumulation of the unaffected globin. Therefore morbidity associated with chronic hemolysis and ineffective erythropoiesis is rarely encountered.
Thalassemia intermedia.
Patients with thalassemia intermedia show more severe anemia and prominent microcytosis and hypochromia. These individuals may have a mild form of homozygous β thalassemia, a combined α- and β-thalassemia defect, or β thalassemia with high levels of HbF. They can present with symptoms attributable to both anemia and iron overload from repeated transfusions, such as hepatosplenomegaly, cardiomegaly, pulmonary hypertension, and skeletal changes.
Additionally, patients with thalassemia intermedia can present with a hypercoagulable state. The etiology is multifactorial and is thought to include exposure of phosphatidylserine on the surface of the RBC, the increased fragility of phosphatidylserine-positive red cells, and the absence of the spleen.
For thalassemia intermedia, conventional therapy includes splenectomy, transfusion, iron chelation, and HbF modulation (hydroxyurea). New therapies are being evaluated such as JAK2 inhibition, hepcidin modulation, and gene therapy; however, stem cell transplantation remains the only curative treatment so far.
Thalassemia major.
Patients with thalassemia major develop severe life-threatening anemia during the first few years of life. To survive childhood, they require repeated transfusion therapy to correct anemia and suppress the high level of ineffective erythropoiesis. The severity of this form of thalassemia is remarkably variable, even among patients with seemingly identical genetic mutations. In the most severe forms, patients exhibit three defects that markedly depress their oxygen-carrying capacity: (1) ineffective erythropoiesis, (2) hemolytic anemia, and (3) hypochromia with microcytosis. The deficit in oxygen-carrying capacity produces maximum erythropoietin release, and marrow erythroblasts respond by increasing their unbalanced globin synthesis. The accumulating unpaired globin chains aggregate and precipitate, forming inclusion bodies that cause membrane damage to the RBCs. Some of these defective red cells are destroyed within the marrow, which results in ineffective erythropoiesis. Some abnormal erythrocytes escape into the circulation, where their altered morphology causes accelerated clearance (hemolytic anemia) or, at best, reduced oxygen-carrying capacity resulting from the lower Hb content (hypochromia with microcytosis). Other features of severe thalassemia include those attributable to bone marrow hyperplasia, such as frontal bossing, maxillary overgrowth, overall stunted growth, osteoporosis, and extramedullary hematopoiesis (hepatomegaly). Chronic hemolytic anemia leads to splenomegaly with dyspnea and orthopnea. Patients with thalassemia major also present with heart failure due to biventricular dilation and/or pulmonary hypertension and restrictive lung disease. Transfusion therapy will ameliorate many of these changes, but complications resulting from iron overload (e.g., cirrhosis, right-sided heart failure, endocrinopathy) frequently require zinc or chelation therapy (desferrioxamine). Splenectomy should be reserved for patients with hypersplenism or increasing transfusion demand, since it results in an increased infectious and thromboembolic risk. The risk of postsplenectomy sepsis in very young patients argues for deferring this surgery until after age 5 if possible. Bone marrow transplantation is a therapeutic option for young patients with a human leukocyte antigen (HLA)–identical sibling.
Management of anesthesia.
The severity of thalassemia is the critical determinant of the amount of end-organ damage and anesthetic risk. In its mildest forms a chronic compensated anemia is a concern. With more severe forms the anemia is much more significant, as are the associated features of splenomegaly and hepatomegaly, skeletal malformations, congestive heart failure, pulmonary hypertension, intellectual disability, and complications of iron overload such as cirrhosis, right-sided heart failure, and endocrinopathies. Skeletal malformations can make tracheal intubation and regional anesthesia difficult; however, all anesthesia techniques (general and regional) can be safely used in these patients.
In thalassemic patients undergoing splenectomy, a hypertensive response can be seen due to autotransfusion, requiring aggressive treatment to prevent neurologic complications.
A hemoglobin level of 10 g/dL is desirable and accepted as a safe threshold for proceeding with a surgical procedure. As mentioned, patients with thalassemia intermedia and those postsplenectomy have an increased thromboembolic risk, requiring appropriated perioperative surgical prophylactic measures.
Normocytic anemias
Normocytic anemias have a mean corpuscular volume of 80 to 100 fL. Evaluation of normocytic anemia includes examination of the peripheral blood smear (for the presence of abnormally shaped RBCs), measuring the reticulocyte count (which will be low in cases of bone marrow suppression but high with a hemolytic anemia), and measuring other indices of hemolysis such as increased lactate dehydrogenase (LDH), haptoglobin, and indirect bilirubin levels. Creatinine levels will be elevated with the anemia of kidney disease. A search for a source of acute blood loss should also be undertaken.
The most common normocytic anemias are hemolytic anemias, anemia of chronic disease, anemia of kidney disease, aplastic anemia, and acute blood loss.
Hemolytic anemias
Hemolytic anemia represents accelerated destruction (hemolysis) of erythrocytes, caused most often by hemoglobinopathies and immune disorders. In hemolytic anemias, either RBCs are removed from the circulation by the reticuloendothelial system (extravascular hemolysis) or the cells are lysed within the circulation (intravascular hemolysis). Therefore RBC life span is shorter than the normal 120 days.
Hemolytic anemia is characterized by reticulocytosis, an increased mean corpuscular volume (reflecting the presence of immature erythrocytes), unconjugated hyperbilirubinemia, increased LDH levels, and decreased serum levels of haptoglobin. Confirmation of a hemolytic anemia should be followed by examination of a peripheral blood smear and a direct antiglobulin test (DAT; also known as the Coombs test) to rule out an immunologic cause.
Disorders of red cell structure.
The mature RBC has the shape of a biconcave disk. It lacks a nucleus and mitochondria, and one-third of its mass is made up of a single protein, Hb. Intracellular energy requirements are supplied by glucose metabolism, which is targeted at maintaining Hb in a soluble reduced state, providing appropriate amounts of 2,3-diphosphoglycerate (2,3-DPG) and generating adenosine triphosphate (ATP) to support membrane function. Without a nucleus or protein metabolic pathway, the cell has a limited life span of about 120 days. However, the unique structure of the adult RBC provides maximum flexibility as the cell travels throughout the microvasculature.
Hereditary spherocytosis.
Abnormalities in membrane protein composition can result in lifelong hemolytic anemia. Hereditary spherocytosis is inherited in an autosomal dominant pattern. It is the most common inherited hemolytic anemia in patients of Northern European ancestry, with a frequency of 1 in 2000 individuals. The principal defect is a deficiency in membrane skeletal proteins spectrin, ankyrin, band 3, and band 4.2. Affected cells show abnormal osmotic fragility and a shortened circulation half-life. Hereditary spherocytosis can be clinically silent, and about one-third of patients have only a very mild hemolytic anemia and spherocytes rarely visible on peripheral blood smear. Some patients, however, have a more severe degree of hemolysis and anemia, but fewer than 5% of patients with spherocytosis develop life-threatening anemia. Patients with hereditary spherocytosis often have splenomegaly and experience easy fatigability that is out of proportion to the degree of anemia. These patients are at risk for episodes of hemolytic crisis, often precipitated by viral or bacterial infection. These crises worsen the chronic anemia and may be associated with jaundice. Infection with parvovirus B19 can produce a transient (10–14 days) but profound aplastic crisis. The risk of pigment gallstones is high in patients with hereditary spherocytosis and should be considered in patients complaining of biliary colic.
Management of anesthesia.
Anesthetic risk in these patients is dictated by the severity of the anemia and whether the hemolysis is stable or in a period of exacerbation due to concurrent infection.
Episodic anemia, often triggered by viral or bacterial infection and cholelithiasis, must be considered in the preoperative evaluation. Patients undergoing cardiac surgery merit special consideration. Mechanical heart valves should be avoided as they may lead to excessive hemolysis because spherocytes are more susceptible to mechanical and shear stress than normal erythrocytes. Similarly, the use of cardiopulmonary bypass accelerates hemolysis; this process should be closely monitored, as both anemia and occlusion of small vasculature by plasma-free hemoglobin may cause end-organ damage. Moreover, free hemoglobin within the plasma is a potent nitric oxide scavenger, leading to increased systemic and pulmonary vascular resistances. In addition, patients with spherocytosis who have undergone splenectomy are at increased risk of arterial and venous thromboembolism, requiring appropriate prophylaxis.
Hereditary elliptocytosis.
Hereditary elliptocytosis is caused by an abnormality in one of the membrane proteins, spectrin or glycophorin, which makes the erythrocyte less pliable. Hereditary elliptocytosis is inherited as an autosomal dominant disorder and is prevalent in regions where malaria is endemic. In those areas the incidence may reach 3 in 100 people. Hereditary elliptocytosis is most often diagnosed as an incidental finding. The majority of RBCs demonstrate an elliptical or even rodlike appearance. Most patients with hereditary elliptocytosis are heterozygous and only rarely experience hemolysis. In contrast, those with homozygous or compound heterozygous defects may demonstrate greater degrees of hemolysis and more severe anemia.
Acanthocytosis.
Acanthocytosis is another defect in membrane structure found in patients with a congenital lack of β lipoprotein (abetalipoproteinemia) and infrequently in patients with cirrhosis or severe pancreatitis. It results from cholesterol or sphingomyelin accumulation on the outer membrane of the erythrocyte. This accretion gives the membrane a spiculated appearance and signals the splenic macrophages of the reticuloendothelial system to remove the red cell from the circulation, which produces hemolysis.
Paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is a stem cell disorder that may arise in hematopoietic cells any time from the second to the eighth decade of life, with a median onset in the third decade of life. Classically, hemolysis is suspected when patients pass dark-colored urine in the morning due to the presence of hemosiderin. PNH causes complement-activated hemolysis in RBCs deficient in surface-bound complement-regulating proteins such as CD55 and CD59. Hemolytic anemia can be either intravascular (mediated by reduced CD59) or extravascular (mediated by reduced CD55). This is caused by a mutation in the PICA gene located on the X chromosome, thus affecting both males and females equally. Besides hemolytic anemia, patients are at risk for other complications of Hb release such as smooth muscle dystonia, pulmonary hypertension, renal insufficiency, and hypercoagulability. Thromboses occur in approximately 40% of patients and can involve the hepatic and portal veins as well as other veins. The basis of the tendency to develop thromboses is unclear. In the absence of protectin, a critical glycosylphosphatidyl inositol–linked protein, patients can develop a dysplastic or aplastic bone marrow suggestive of damage to all hematopoietic precursor cells, manifesting as aplastic anemia or thrombocytopenia.
Treatment of PNH.
Mildly symptomatic patients can be managed with surveillance only, whereas those who are transfusion dependent or with disabling symptoms such as fatigue, smooth muscle dystonia, thrombosis, and significant renal insufficiency benefit from eculizumab. Eculizumab is a monoclonal antibody against complement factor C5, which is essential for the complement system to develop membrane attack complexes. In addition, iron therapy should be supplemented and patients with thromboses should be anticoagulated. Patients with severe aplastic anemia, with bone marrow failure, and patients unresponsive to eculizumab are candidates for allogeneic bone marrow transplantation as a definitive treatment.
Management of anesthesia.
The nocturnal manifestation of hemolysis is thought to result from carbon dioxide retention and the subsequent respiratory acidosis. Therefore during anesthesia, predisposing factors such as hypoxemia, hypoperfusion, and hypercarbia that can lead to acidosis and complement activation must be avoided. Inhalational agents and propofol may have a theoretical advantage over thiopental, which can be associated with complement-activated anaphylactoid reactions. Prophylaxis against venous thrombosis should be administered perioperatively. If perioperative transfusion is deemed necessary, washed RBCs should be administered to decrease the risk of complement activation. Use of salvaged autologous RBCs in patients with PNH should be limited to critical situations, such as massive bleeding, as a hemolytic reaction may be present inside the transfer bag even after the wash process.
Disorders of red cell metabolism.
Lacking a nucleus and having a limited life expectancy, the erythrocyte maintains only the very narrow spectrum of activities necessary to carry out its oxygen transport function. The stability of the RBC membrane and the solubility of intracellular Hb depend on four glucose-supported metabolic pathways. These four pathways are illustrated in Fig. 23.1 . The most clinically relevant pathways are described in the following sections.
Embden-Meyerhof pathway.
The Embden-Meyerhof pathway (nonoxidative or anaerobic pathway) is responsible for generation of the ATP necessary for membrane function and the maintenance of cell shape and pliability. Defects in anaerobic glycolysis are associated with increased red cell rigidity and decreased survival, which produces a hemolytic anemia. Deficiencies of the glycolytic pathway are not associated with any typical morphologic red cell changes, nor do they lead to hemolytic crisis after exposure to oxidants. The severity of hemolysis is highly variable and largely unpredictable.
Phosphogluconate pathway.
The phosphogluconate pathway couples oxidative metabolism with nicotinamide adenine dinucleotide phosphate (NADP) and glutathione reduction. It counteracts environmental oxidants and prevents globin denaturation. When patients lack either glucose-6-phosphate dehydrogenase (G6PD) or glutathione reductase, denatured Hb precipitates on the inner surface of the RBC membrane. This is visible on the peripheral blood smear as Heinz bodies and results in membrane damage and hemolysis.
Glucose-6-phosphate dehydrogenase deficiency.
G6PD deficiency is an X-linked genetic disease and is the most common enzymatic disorder of RBCs, with more than 400 million people affected worldwide. G6PD activity is normally highest in young red cells and declines with the age of these cells. The half-life of erythrocytes in G6PD deficiency is approximately 60 days. Clinical manifestations depend on the amount of the enzyme present, with five classes described by the WHO. Patients can have chronic hemolytic anemia (class I, <10% G6PD activity), intermittent hemolysis (class II, 10% G6PD activity), and hemolysis only with stressors (class III, 10–60% G6PD activity). Classes IV and V have increased G6PD activity. There is no hemolysis in class IV or V.
Hemolysis is the result of the inability of a G6PD-deficient RBC to protect itself from oxidative damage. Events that can precipitate new or aggravate preexisting hemolysis include infection, certain metabolic conditions such as diabetic ketoacidosis, certain drugs, and ingestion of fava beans.
Anesthetic risk is largely a function of the severity and acuity of this anemia. The goal is to avoid the risk of hemolysis by not exposing the patient to oxidative drugs. Benzodiazepines (except for diazepam) are safe and beneficial preoperatively, to decrease the anxiety and risk of hemolysis. Codeine, propofol, fentanyl, and ketamine have been proven safe, but it might be wise to avoid isoflurane, sevoflurane, metoclopramide, and penicillin, all of which depress G6PD activity in vitro. Methylene blue is a particular concern. If a patient with methemoglobinemia (with already compromised oxygen delivery) is also G6PD deficient, methylene blue administration may be life threatening. Drugs that can induce methemoglobinemia (e.g., lidocaine, prilocaine, silver nitrate) should be avoided. Many antibiotics and vitamin K should also be avoided. Hypothermia, acidosis, hyperglycemia, and infection can precipitate hemolysis in the G6PD-deficient patient, and these conditions need to be aggressively treated in the perioperative period.
Pyruvate kinase deficiency.
Pyruvate kinase deficiency, an autosomal recessive disorder, is the most common erythrocyte enzyme defect causing congenital hemolytic anemia. Pyruvate kinase deficiency is found worldwide but shows a higher prevalence among people of Northern European extraction and individuals from some regions of China. Although less prevalent than G6PD deficiency, pyruvate kinase deficiency is much more likely to produce a chronic hemolytic anemia. The severity of the clinical presentation ranges from a mild fully compensated process without anemia to life-threatening, transfusion-requiring hemolytic anemia at birth. Severely affected individuals may have chronic jaundice, develop pigmented gallstones, and manifest splenomegaly. Splenectomy does not totally prevent hemolysis but does decrease the rate of RBC destruction and may even eliminate the need for transfusion.
Methemoglobin reductase pathway.
The methemoglobin reductase pathway uses the pyridine nucleotide–reduced NADP generated from anaerobic glycolysis to maintain heme iron in its ferrous state. An inherited mutation of the methemoglobin reductase enzyme results in an inability to counteract oxidation of Hb to methemoglobin. The ferric form of Hb does not transport oxygen. Patients with type I enzyme deficiency accumulate small amounts of methemoglobin in circulating red cells, whereas patients with type II disease have severe cyanosis and intellectual disability.
Luebering-Rapoport pathway.
The Luebering-Rapoport pathway is responsible for production of 2,3-DPG. A single enzyme—2,3-bisphosphoglycerate mutase—mediates both the synthesis of 2,3-DPG and the phosphatase activity that then converts 2,3-DPG to 3-phosphoglycerate, returning it to the glycolytic pathway. The balance of formation versus metabolism of 2,3-DPG is pH sensitive, with alkalosis favoring synthetic activity and acidosis favoring metabolic breakdown. The 2,3-DPG response is also influenced by the supply of phosphate. Severe phosphate depletion in patients with diabetic ketoacidosis or nutritional deficiency can result in reduced 2,3-DPG production.
Disorders of hemoglobin.
Inherited defects in Hb structure can interfere with its affinity for oxygen and the process of binding/unloading oxygen. Most defects are substitutions of a single amino acid in either the α- or β-globin chains. Some interfere with molecular movement, restricting the molecule to either a low- or high-affinity state, whereas others change the valency of heme iron from ferrous to ferric or reduce the solubility of the Hb molecule. HbS (the abnormal Hb in sickle cell disease) is an example of an Hb with a single amino acid substitution that results in reduced solubility, which causes precipitation of the abnormal Hb.
Sickle S hemoglobin.
Sickle cell disease is a disorder caused by the substitution of valine for glutamic acid in the β-globin subunit. In the deoxygenated state, HbS undergoes conformational changes that expose a hydrophobic region of the molecule. In states of severe deoxygenation the hydrophobic regions aggregate, and this results in distortion of the erythrocyte membrane, oxidative damage to the membrane, impaired deformability, and a shortened life span of only 10 to 20 days.
Sickle cell anemia, the homozygous form of HbS disease, presents early in life with severe hemolytic anemia and progresses to significant end-organ damage involving the bone marrow, spleen, kidneys, and central nervous system. Patients experience episodic painful crises (vasoocclusive crises) characterized by bone and joint pain that may or may not be associated with concurrent illness, stress, or dehydration. The severity and progression of the disease can vary remarkably. Organ damage can start early in childhood, with recurrent splenic infarction culminating in loss of splenic function in the first decade of life. The kidney can demonstrate painless hematuria and loss of concentrating ability as an early feature and then progress to chronic renal failure in the third or fourth decade of life. Pulmonary and neurologic complications are the major causes of morbidity and mortality. Lung damage results from chronic persistent inflammation. Acute chest syndrome, a pneumonia-like complication, is characterized by the presence of a new pulmonary infiltrate involving at least one entire lung segment plus at least one of the following: chest pain, fever, tachypnea, wheezing, or cough. Neurologic complications include stroke, usually as a result of arterial disease rather than sickling. Adolescents present with cerebral infarction, whereas adults typically develop hemorrhagic strokes.
Chronic medical management of sickle cell disease relies on administration of hydroxyurea. Through stimulation of HgbF and release of endogenous nitric oxide, it decreases the incidence of acute chest syndrome and vasooclusive crisis. Symptomatic treatment for vasooclusive crises includes rehydration, supplemental oxygen therapy, aggressive analgesia, and incentive spirometry. Similar principles apply to the treatment of acute chest syndrome with the addition of blood exchange transfusion. Hematopoietic stem cell transplantation remains an option for young patients with serious complications such as stroke, acute chest syndrome, or refractory pain.
Management of anesthesia.
Sickle cell trait does not cause an increase in perioperative morbidity or mortality. However, sickle cell disease is associated with a high incidence of perioperative complications. Risk factors include advanced age, frequent and severe recent episodes of sickling, evidence of end-organ damage (e.g., low baseline oxygen saturation, elevated creatinine level, cardiac dysfunction, history of stroke), and concurrent infection. Risks intrinsic to the type of surgery are also important considerations, with minor procedures considered to be low risk, intraabdominal operations categorized as intermediate risk, and intracranial and intrathoracic procedures classified as high risk. Among orthopedic procedures, hip surgery and hip replacement in particular are associated with a high risk of complications, including excessive blood loss and sickling events.
The goals of preoperative management in patients with sickle cell disease have changed in recent years. Studies examining the effects of aggressive transfusion strategies aimed at increasing the ratio of normal Hb to sickle Hb appear to show no benefit compared with the more conservative goal of achieving an overall preoperative Hct of 30% (HbS combined with HbA or HbF). The aggressive strategy had necessitated significantly more transfusions, and complications from these transfusions have been significant.
Patients undergoing low-risk procedures now rarely require any preoperative transfusion, and patients undergoing moderate- to high-risk operations need only have preoperative anemia corrected to a target Hct (all Hb types) of 30%. However, some suggest that HbS levels below 30% are desirable for major noncardiac surgery, and HbS levels below 5% are desirable for cardiac surgery involving cardiopulmonary bypass, which is associated with several factors that can promote sickling and hemolysis. In such patients, exchange transfusion can be used perioperatively in conjunction with hydroxyurea to achieve the desired low concentration of HbS.
Anesthetic technique does not appear to significantly affect the risk of complications stemming from sickle cell disease. Secondary goals such as avoiding anxiety, emotional stress, dehydration, acidosis, and hypothermia do help reduce the risk of perioperative sickling events. Use of occlusive orthopedic tourniquets is not contraindicated, but the incidence of perioperative complications is increased with their use. Postoperative pain requires aggressive, typically multimodal, pain management. Patients often have a degree of tolerance to opioids, and a subset of patients may even have opiate addiction, but these facts must not interfere with appropriate perioperative pain management.
Despite concerns that regional anesthesia might have detrimental effects in sickle cell patients, it is not contraindicated and may offer an advantage in pain control.
Procedures requiring administration of intravenous contrast merit special consideration. Hyperosmolar solution may result in RBC polymerization and sickling, therefore hypo- or isoosmolar products are recommended.
Acute chest syndrome may develop 2 to 3 days postoperatively and requires treatment of hypoxemia, pain, hypovolemia, anemia, likely infection, and possible venous thrombosis. Excessive intravenous volume is a risk factor and should be avoided. Mild cases may respond to simple transfusion. Exchange transfusion may be needed in severely affected patients.
Sickle C hemoglobin.
The prevalence of HbC is about one-fourth that of HbS. HbC causes the erythrocyte to lose water via enhanced activity of the potassium chloride cotransport system. This results in cellular dehydration that in the homozygous state may produce a mild to moderate hemolytic anemia. HbS trait or HbC trait in isolation causes no symptoms. However, when they are present together (HbSC disease) they can produce sickling and complications similar to those of HbSS disease. It appears that the dehydration produced by HbC increases the concentration of HbS within the erythrocyte, exacerbating its insolubility and tendency to polymerize.
Management of anesthesia.
The anesthetic risks of HbSC disease have not been as well studied as those of HbSS disease. However, one investigation suggested that perioperative transfusion may reduce the incidence of sickling complications.
Sickle hemoglobin–β thalassemia.
Among the black population, the frequency of the β thalassemia gene is only one-tenth that of the gene for HbS. The clinical presentation of this compound heterozygous state is largely determined by whether it is associated with reduced amounts of HbA (sickle cell–β + thalassemia) or no HbA whatsoever (sickle cell–β 0 thalassemia). In the absence of any HbA, patients experience acute vasoocclusive crises, acute chest syndrome, and other sickling complications at rates approaching those of patients with HbSS.
Unstable hemoglobins.
Hbs are made unstable by structural changes that reduce their solubility or render them more susceptible to oxidation of amino acids within the globin chains. More than 100 unique unstable Hb variants have been documented, most associated with minimal clinical impact. The mutations typically impair the globin folding or heme-globin binding that stabilizes the heme moiety within the hydrophobic globin pocket. Once freed from its cleft, the heme binds nonspecifically to other regions of the globin chains. This causes formation of precipitates (Heinz bodies) that contain globin chains, chain fragments, and heme. Heinz bodies interact with the red cell membrane, reducing its deformability and favoring its removal by macrophages in the spleen. Unstable Hbs vary in their propensity to form Heinz bodies and in the severity of any associated anemia. Hemolysis may be aggravated by the development of additional oxidative stresses, such as infection or ingestion of oxidizing drugs. Patients with recurring bouts of severe hemolysis or significant morbidity from the chronic anemia should be considered candidates for splenectomy, which is usually effective in reducing or even eliminating symptoms and signs.
Management of anesthesia.
Anesthetic management of patients with unstable Hbs is largely dictated by the degree of hemolysis. Transfusion during bouts of severe hemolysis and avoidance of oxidizing drugs are important. These patients may have severe anemia and Hb-induced renal injury.
Autoimmune hemolytic anemias.
Autoimmune hemolytic anemias result from RBC cell lysis due to warm agglutinins (mostly immunoglobulin G [IgG]–mediated lysis at body temperature) or cold agglutinins (IgM-mediated lysis at lower temperatures). Antibodies against RBCs can be detected by a DAT (Coombs test). Warm autoimmune hemolytic anemia (WAHA) is associated with lupus (10% of lupus patients develop warm agglutinins), hematologic malignancies (non-Hodgkin lymphoma, chronic lymphocytic leukemia), viral infections (HIV), or drugs (penicillins, cephalosporins, quinine, quinidine, nonsteroidal antiinflammatory drugs [NSAIDs]). WAHA episodes are managed supportively and/or with corticosteroids. Patients who are not responsive to steroids are candidates for splenectomy, rituximab, or other cytotoxic drugs.
Cold agglutinin disease manifests as hemolytic episodes that occur at lower temperatures. Pathologic cold agglutinins can be a result of certain infections ( Mycoplasma pneumoniae, infectious mononucleosis) or of neoplastic/paraneoplastic processes. Avoidance of cold temperatures is the mainstay of therapy in such patients. Although the majority of patients do not require treatment, more severe cases may benefit from treatment with rituximab with or without fludarabine. Glucocorticoids and splenectomy have no value in cold agglutinin disease. Plasmapheresis is an attractive option and could be considered in patients about to undergo high-risk surgery (especially surgery involving cardiopulmonary bypass), since it can remove up to 80% of these antibodies. However, plasmapheresis can lead to fluid overload, infection, and altered hemostasis. Intravenous administration of immunoglobulin has also been described as a viable therapeutic option.
Anemia of chronic disease
ACD manifests as a normocytic, normochromic, hypoproliferative anemia due to decreased production of RBCs coupled with somewhat shortened RBC survival. ACD is thought to result from several mechanisms: trapping of iron in macrophages (resulting in a lower level of circulating iron available for hematopoiesis), a decrease in erythropoietin concentrations resulting in a decrease in bone marrow red cell production, and shorter RBC life span due to increased macrophage activity.
Patients with ACD present with low iron levels, normal to low transferrin levels, normal to high ferritin levels, but a normal transferrin saturation. This is in particular contrast to IDA, in which there is a low transferrin saturation. Markers of active inflammation may be present, such as an elevated sedimentation rate and C-reactive protein level. The CBC may support a diagnosis of infection with a high WBC count.
The diagnosis of ACD is supported by the clinical picture, with most patients already carrying a diagnosis of a chronic inflammatory or infectious disease or malignancy at the time the anemia is discovered.
Treatment.
The ideal treatment for ACD is cure of the underlying disease, which unfortunately is not often possible. Preoperative treatment of patients with ACD may involve administration of iron with erythropoiesis-stimulating drugs such as darbepoetin and erythropoietin. Iron alone should never be given to patients with ACD due to malignancy and infection, since iron can worsen the underlying disease(s). Erythropoiesis-stimulating drugs should be avoided in patients with ACD due to cancer (especially during active treatment), but they are approved for treatment of significant anemia due to chemotherapy. The minimum effective dose should be administered to avoid thromboembolic complications. These drugs can also be used in patients with rheumatoid arthritis and HIV with low erythropoietin levels.
Anemia of chronic kidney disease
The anemia of chronic kidney disease results from decreased erythropoietin production. Therefore these patients benefit from administration of erythropoiesis-stimulating drugs. The target Hb should be 10 to 12 g/dL, even with patients on hemodialysis, since these patients benefit with a reduction in their symptoms and a better quality of life. Concurrent iron deficiency should be investigated and treated to ensure optimal red cell production.
Aplastic anemia
Congenital aplastic anemia (Fanconi anemia) is an autosomal recessive disorder that presents in the first two decades of life with severe pancytopenia that often progresses to acute leukemia. When the gene is fully expressed (as occurs in 1 per 100,000 live births), this disorder is associated with progressive bone marrow failure, a number of physical defects, chromosomal abnormalities, and a predisposition to cancer. Not all patients have the classic physical defects, so the diagnosis should be considered in all children and young adults with acute myelogenous leukemia.
Acquired aplastic anemia is due to bone marrow toxicity, typically from drugs. Anemia due to bone marrow damage is a predictable side effect of chemotherapy, and this anemia is usually mild unless high-dose multidrug chemotherapy that can cause pancytopenia is used. So long as the drugs do not irreversibly damage the bone marrow, recovery is usually complete. High-energy radiation can also produce anemia from bone marrow damage, the degree of which is predictable from the type of radiation, the dose, and the extent of bone marrow exposure. Long-term exposure to low levels of external radiation or ingested radioisotopes can produce aplastic anemia.
Several drugs have been associated with the development of severe, often irreversible, aplastic anemia. Table 23.1 lists many classes of these drugs. Some (e.g., chloramphenicol) can produce severe irreversible aplastic anemia after only a few doses, but most (e.g., phenylbutazone, propylthiouracil, tricyclic antidepressants) are associated with a more gradual onset of pancytopenia, which is reversible if the offending drug is withdrawn.
TABLE 23.1
Classes of Drugs Associated With Marrow Damage
| Antibiotics (chloramphenicol, penicillin, cephalosporins, sulfonamides, amphotericin B, streptomycin) |
| Antidepressants (lithium, tricyclics) |
| Antiepileptics (phenytoin, carbamazepine, valproic acid, phenobarbital) |
| Antiinflammatory drugs (phenylbutazone, nonsteroidals, salicylates, gold salts) |
| Antidysrhythmics (lidocaine, quinidine, procainamide) |
| Antithyroidal drugs (propylthiouracil) |
| Diuretics (thiazides, pyrimethamine, furosemide) |
| Antihypertensives (captopril) |
| Antiuricemics (allopurinol, colchicine) |
| Antimalarials (quinacrine, chloroquine) |
| Hypoglycemics (tolbutamide) |
| Platelet inhibitors (ticlopidine) |
| Tranquilizers (prochlorperazine, meprobamate) |
Immunosuppression of stem cell growth can also produce anemia, even aplastic anemia. This can be seen following viral illnesses such as viral hepatitis, Epstein-Barr virus infection, HIV infection, and rubella. Parvovirus B19 infection can cause an acute reversible pure red cell aplasia in patients with congenital hemolytic anemia. Although most of these anemias are reversible, some infections can produce fatal aplastic anemia.
Management of anesthesia.
Patients may come for surgery with anemia and thrombocytopenia severe enough that transfusion is necessary preoperatively. The severity of the neutropenia will affect the need for and choice of antibiotic coverage. The use of granulocyte colony-stimulating factor preoperatively to increase neutrophil counts is controversial.
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