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Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery
Accepted Manuscript
Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery Mark M. Smith MD , J. Ross Renew MD , James A. Nelson MBBS , David W. Barbara MD PII: DOI: Reference:
S1053-0770(18)30606-2 https://doi.org/10.1053/j.jvca.2018.08.001 YJCAN 4834
To appear in:
Journal of Cardiothoracic and Vascular Anesthesia
Received date:
26 April 2018
Please cite this article as: Mark M. Smith MD , J. Ross Renew MD , James A. Nelson MBBS , David W. Barbara MD , Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery, Journal of Cardiothoracic and Vascular Anesthesia (2018), doi: https://doi.org/10.1053/j.jvca.2018.08.001
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Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery
J. Ross Renew, M.D. 2 James A. Nelson, M.B.B.S 1
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David W. Barbara, M.D. 1
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Mark M. Smith, M.D.1
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Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and
Science, Rochester, Minnesota, USA 2
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Word Count: 10,040
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Science, Jacksonville, Florida, USA
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Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and
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Corresponding author: Dr. Mark M. Smith
Department of Anesthesiology and Perioperative Medicine Mayo Clinic College of Medicine and Science 200 First Street SW, Rochester, MN 55905 USA
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Declarations of interest: none
Abstract
Disorders affecting red blood cells (RBC) are uncommon yet have many important physiologic
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considerations for patients undergoing cardiac surgery. RBC disorders can be categorized by those which are congenital or acquired, and further by disorders affecting the red blood cell membrane, hemoglobin, intracellular enzymes, or excessive RBC production. A foundational understanding of the physiologic derangement for these disorders is critical when considering perioperative implications and
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optimization, strategies for cardiopulmonary bypass, and the rapid recognition and treatment if complications occur. This review systematically outlines the RBC disorders of frequency and relevance
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with an emphasis on how the disorder impacts normal physiologic processes, a review of the literature
surgery.
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Word Count: 120
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related to the disorder, and the implications and recommendations for patients undergoing cardiac
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Keywords: RBC disorder, RBC dyscrasia, Cardiac Surgery, Cardiopulmonary Bypass
ACCEPTED MANUSCRIPT Page 3 Introduction Disorders affecting red blood cells (RBCs) are uncommon yet confer important perioperative implications for patient undergoing cardiac surgery. The RBC disorders can be categorized by those which are congenital or acquired, and further by disorders affecting the red blood cell membrane,
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hemoglobin, intracellular enzymes, or excessive RBC production (Table 1). Cardiac surgery presents physiologic stressors uncommon to other surgical specialties such as use of hypothermia and extracorporeal circulation which can have a profound impact in this patient population. An
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understanding of the physiologic derangement for these disorders is critical when considering
perioperative implications and optimization, strategies for cardiopulmonary bypass (CPB), and the rapid recognition and treatment should complications occur. While some disorders require minimal deviation from standard care, others necessitate precise changes in perioperative strategy to avoid or limit related
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complications. This review systematically outlines the RBC disorders of frequency and relevance with an emphasis on how the disorder impacts normal physiologic processes, a review of the literature related
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to the disorder, and the implications and recommendations for patients undergoing cardiac surgery.
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RBC overview
Erythrocytes or as they are commonly referred red blood cells (RBCs), are cellular components of blood
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produced within the bone marrow that function to deliver oxygen and buffer carbon dioxide throughout
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the body, and have a circulating life span of approximately 120 days. Congenital and acquired disorders that effect RBCs are not common; however, the frequencies are such that perioperative providers must be familiar with the physiologic implications. RBC cell membrane: Passage of RBCs through the microvasculature requires flexibility and reversible deformability which is a function of the interaction between the intracellular skeletal proteins (e.g. α/βspectrin) membrane proteins (e.g. ankyrin, protein 4.2, band 3), and the cell membrane lipid bilayer.1
ACCEPTED MANUSCRIPT Page 4 The result is an elastic biconcave disc-like RBC which maximizes surface area and has the flexibility to endure the necessary deformation and shear stress within the vascular tree. Hemoglobin: Hemoglobin is a metalloprotein within RBCs which functions to transport oxygen throughout the body. In addition, this iron-containing protein plays important roles in the removal of
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carbon dioxide and regulating homeostasis. The hemoglobin tetramer is composed of four globin chains attached to a heme moiety. During human development and continuing after birth there is a transition of hemoglobin chain types. From birth-6 months of age, fetal hemoglobin (α2γ2) predominates.
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Subsequently, adult hemoglobin (HbA) becomes the primary type (α2β2), with a smaller percentage (~2.5%) consisting of HbA2 (α2δ2). Each hemoglobin molecule can bind up to four oxygen molecules with increasing affinity, a property termed cooperative binding which is the result of a conformational changes. Factors which influence oxygen binding to hemoglobin include temperature, pH, 2,3-
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bisphosphoglycerate (2,3-BPG), and the partial pressure of carbon dioxide. An appreciation for the role of hemoglobin within the RBC is critical to understanding various pathologic states.
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RBC intracellular metabolism/enzymes: RBC metabolism is entirely dependent on anaerobic metabolism
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via glycolysis and the pentose phosphate pathway to produce adenosine triphosphate (ATP) for cellular processes, and reduced glutathione for oxidative free radical scavenging. Defects within the glycolytic or
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pentose phosphate pathway can lead to cellular damage and hemolysis.
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Disorders of Hemoglobin
Hereditary Disorders of Hemoglobin Sickle cell disease Sickle cell disease (SCD) is an autosomal recessive disorder that results from a mutation of the
globin
portion of hemoglobin. Patients with a single allele mutation (heterozygous genotype) possess sickle cell
ACCEPTED MANUSCRIPT Page 5 trait (SCT), affecting 1:13 African Americans without significantly altering life expectancy.2,3 The homozygous genotype (SCD) has an incidence of 1:365 African Americans, and results in a higher burden of sickle cell hemoglobin (HbS) than SCT (~80% vs ~40%, respectively) with a reduced life expectancy.2-4 While most common in African Americans, sickle cell disease can also be seen among Arabic
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populations, which may have a milder phenotype. In contrast to normal RBCs having a flexible biconcave disc structure, RBCs rich with HbS become rigid/sickle-shaped leading to microvascular occlusions and inflammation of the vascular endothelium. Such “sickling crises” are triggered by changes in
temperature, stress, hypovolemia, infection, hypoxia, vasoconstrictors, and acidosis.5 Sickling crises can
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manifest as acute chest syndrome, a complex pathophysiologic state with components of infection, infarction, and embolic events. Such crises may also manifest with painful vaso-occlusive events resulting in tissue ischemia. Acute chest syndrome may be difficult to discern from acute coronary syndrome as symptoms may be similar.6 While SCD itself is not known increase risk of early coronary
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artery disease, acute coronary syndrome should remain in the chest pain differential diagnosis for this
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population. Other complications include splenic sequestration and subsequent infarction, hemolytic anemia, gallstones, pulmonary hypertension, priapism, early arthritis, and a variety of neurologic
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deficits. Patients with functional asplenia are at risk for infection and should receive proper
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perioperative antibiotic prophylaxis. As mentioned previously, patients with SCD have shortened life expectancies. As such, when
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they present for cardiac surgery, it is often for correction of coexisting congenital cardiac conditions, valve replacements related to endocarditis, or rheumatic lesions. In contrast, patients with SCT have a normal life expectancy and thus their surgical history often mirrors that of the general population. Patients with SCD presenting for cardiac surgery may be at a slightly higher risk of perioperative complications with prior studies citing an incidence of postoperative hemorrhage ~6%, stroke ~4%, and postoperative renal failure ~4%.7
ACCEPTED MANUSCRIPT Page 6 While considering the known triggers of sickling crises, cardiac surgery can be problematic for patients with SCD. The literature describing the perioperative care of this population undergoing cardiac surgery consists of case reports 8-10, case series 11,12, and small retrospective studies. 7,13 A focal point in avoiding morbidity in patients with SCD undergoing cardiac surgery relates to proper
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blood management. Historically, efforts were made to reduce HbS to <30% or perhaps even as low as <10% prior to cardiac surgery.14,15 This is accomplished by red blood cell administration that raises the amount of HbA and decreases the proportion of HbS, or via exchange transfusion (i.e. replacing the patients’ blood with allogenic blood). During exchange transfusions, some clinicians have also
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performed platelet and plasma apheresis on the removed autologous blood and returned the non-RBC blood fraction back to the patient.16 Modifications to cardiopulmonary bypass circuits can be made to facilitate intraoperative exchange transfusion.17,18 When performing an intraoperative exchange transfusion, the CPB circuit should be primed with allogeneic RBCs and plasma. The volume of RBCs
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necessary can be determined by estimating the patient’s blood volume and calculating the proportion of
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patient’s circulating volume that clinicians wish to replace. The proportion of the patient’s blood volume that is exchanged varies based on the HbS burden. Isotonic crystalloid and colloid can also be
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added to adjust the hematocrit of this volume. After cannulation, a Y-connector is added to the venous line to enable the perfusionist to drain and sequester the desired volume of the patient’s whole
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blood. The hyperoxygenated prime volume comprised of allogeneic blood products is then transfused through the arterial cannula while the patient’s blood is drained into a reservoir. After the venous
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cannula has drained the desired volume of the patient’s blood, the venous cannula draining into the collection reservoir is clamped at the Y-connection and the bypass circuit resumes its traditional configuration. This sequestered blood can be separated into components via intraoperative autotransfusion techniques. After the RBCs have been separated and discarded, the remaining plasma and platelet rich solution can be returned to the patient after cessation of cardiopulmonary bypass.18
ACCEPTED MANUSCRIPT Page 7 Recent data suggests that avoiding anemia and transfusing allogenic RBCs to a target hemoglobin > than 10 g/dL without consideration for the proportion of circulating HbS may be equally efficacious in avoiding complications from SCD during major surgery .19,20 Both preoperative exchange transfusion and allogenic transfusion to a hemoglobin > than 10 g/dL are superior to no preoperative transfusion in
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reducing the risk of perioperative SCD complications in non-cardiac surgery.21,22 Compared to patients undergoing preoperative exchange transfusion, those targeted to a preoperative hemoglobin > 10 g/dL receive fewer transfusions and experience fewer transfusion reactions.20,22 There are no societal
transfusion guidelines for SCD patients undergoing cardiac surgery. Exchange transfusion remains the
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more commonly employed strategy in this population (targeting HbS <30% or perhaps <10%), yet quality prospective research supporting this practice over more conservative RBC transfusion targets (Hb >10 g/dL) in cardiac surgery is lacking.15 Ultimately, these patients warrant early, individualized, and
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multidisciplinary planning prior to cardiac surgery.
In contrast to patients with SCD, patients with SCT may not require exchange transfusion. Djaiani et
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al reported successful management of patients with sickle cell trait undergoing coronary artery bypass grafting without exchange transfusion. This review of 10 patients revealed successful application of ‘fast
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track’ anesthesia techniques, although there was one death in this small sample.13 Prior studies have
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used a hemoglobin trigger as low as 7.5 g/dL, in this population without complications; however, a slightly more liberal target may be reasonable, yet, evidence supporting a specific target is
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lacking.13,23 Some experts suggest that sickle cell hemoglobinopathy should be approached as a spectrum disease with SCT and SCD serving as the two extremes.24 Indeed, autopsy studies have revealed similar pathologic characteristics in both sickle cell disease and trait.25 Similarly, patients with sickle cell trait have laboratory values suggestive of hypercoagulable states including elevated D-dimers, thrombin-antithrombin complexes, and prothrombin fragments.26
ACCEPTED MANUSCRIPT Page 8 The use of CPB routinely involves controlled hypothermia. Such temperatures can cause vasoconstriction and potentially trigger sickling crises. Core temperatures as low as 18°C have been reported in 2 SCD patients undergoing pulmonary artery thromboendarterectomy via deep hypothermic circulatory arrest. 27 The authors utilized complete exchange transfusion and avoided other potential
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triggers to obtain a successful result. There are no cases detailing the use of deep hypothermic
circulatory arrest in SCT patients, thus evidence to support or contradict exchange transfusion as was performed in the SCD patients is lacking and must be considered on a case by case basis. Experienced centers report successful results while utilizing mild hypothermia (>32°C) in patients with both
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SCT/SCD.7,13,19 While varying degrees of hypothermia on CPB have been successfully described in these populations, efforts to maintain normothermia should be made when feasible. Several cardioplegia solutions have also been used with success, such as tepid blood cardioplegia16as well as cold crystalloid
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based solutions.7,13
Additional strategies to mitigate risk of sickling include hyperoxygenating pump prime solution in an
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effort to ensure the transition to CPB avoids transient hypoxia. Sickling can occur at arterial oxygen saturations < 85%, thus careful attention should be paid to the oxygenator FiO2 with aggressive
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correction of hypoxia if present.28 The utilization of clinical markers such as mixed venous saturation
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can help providers ensure adequate tissue perfusion. In contrast to SCD, SCT cells do not, in the absence of stasis, begin to sickle until saturations are 40%. Pain management can be challenging as patients with
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SCD and a history of painful occlusive events can present on chronic opioid medications with opioid tolerance, complicating perioperative analgesia. Pain and anxiety are known triggers sickling crises, thus an adequate perioperative analgesic strategy is important. The use of multimodal analgesia pathways and the anticipation and preparation for opioid tolerance in chronic pain patients is critical toward blunting the physiologic stress response to pain that can cause vasoconstriction and subsequent sickling crises. The use of cell-salvage systems in SCD patients is not recommended as the negative pressure
ACCEPTED MANUSCRIPT Page 9 suction in addition to the washing and re-transfusion process may risk sickling/hemolysis.15,28 Table 2 summarizes the perioperative management for patients with SCT and SCD undergoing cardiac surgery.
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Thalassemia The thalassemias are a group of disorders characterized by a defect in one or more of the genes
encoded to produce globin proteins leading to a change in the ratio of α to β globin production. This leads to the precipitation of abnormal globin tetramers within RBCs, and destruction of red cell
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precursors leading to extramedullary hematopoiesis and resulting manifestations.
Thalassemia can be defined by phenotype (thalassemia major, intermedia, or minor), transfusion dependence, or by the underlying genetic mutation. Phenotypic severity is related to the number and type of α or β globin gene disorders present. Transfusion dependence leads to secondary
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complications related to frequent transfusions and iron overload. Like SCD, thalassemia is more
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common in patients of Asian and African descent and from the Mediterranean Region 29 Clinical manifestations present across a spectrum from hydrops fetalis and intrauterine death in
and -thalassemia .30 Frequency and severity of clinical manifestations are related to anemia
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both
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the case of the most severe form of -thalassemia, to asymptomatic carrier states in minor forms of
with subsequent extramedullary hematopoiesis and iron overload. Table 3 classifies
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thalassemias in descending order of severity. Survival in this population has improved with the adoption of revised transfusion goals,
combined with oral and parenteral iron chelation therapy. 31-34 In select patients, bone marrow transplant is a viable therapeutic and potentially curative option. 35 In spite of these advances, cardiovascular disease is common and the leading cause of mortality.32 Cardiomyopathy (CM) is the
ACCEPTED MANUSCRIPT Page 10 most common cardiac manifestation and is either a dilated CM with resulting systolic dysfunction, or a restrictive CM with diastolic dysfunction, pulmonary hypertension, and subsequent right heart failure.36 Pulmonary arterial hypertension can occur independently in moderate to severe forms of thalassemia with several series indicating a rate of 60-75% in patients with thalassemia intermedia and major.37
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Valvular heart disease is being recognized with increased frequency in thalassemia patients. Additionally, early onset coronary artery disease, peripheral vascular disease and stroke can all occur with acquired elastic tissue deficiency and endothelial dysfunction playing a role. 38,39 Atrial fibrillation and other conduction abnormalities can result from cardiac iron infiltration due to repeated transfusions
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in addition to the usual causes.40,41 Crainofacial deformities, endocrinopathies, renal tubular dysfunction, and thrombotic complications are also seen in thalassemia patients along with other less common manifestations.
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Management of thalassemia patients undergoing non-cardiac surgery has been detailed in other reviews, emphasizing the importance of a thorough airway exam, optimization of systemic co-
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morbidities, hemodynamic stability, and maintaining adequate hemoglobin levels.42 Drugs known to risk
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hemolysis via increases in oxidative stress in patients with thalassemia include aspirin, penicillin, prilocaine, sodium nitroprusside, sulfonamides, and vitamin K.15
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The literature describing patients with significant thalassemia undergoing cardiac surgery is
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limited.43-46 Perioperative concerns in this population, aside from the cardiac pathology for which they present, include anemia, susceptibility of thalassemia RBCs to hemolysis during CPB, and balancing the risks of bleeding and thrombotic complications. Studies evaluating the ideal preoperative hemoglobin or the extent of hemolysis in patients with significant thalassemia undergoing cardiac surgery are lacking. It is accepted that in patients with thalassemia hemoglobin, oxygen carrying capacity is decreased and risk for hemolysis increased, highlighting the importance of adequate hemoglobin concentration and
ACCEPTED MANUSCRIPT Page 11 oxygen saturation . Prior case reports in cardiac surgery have described transfusion to a hemoglobin concentration between 9 -9.5 g/dL preoperatively, which was near patients’ baseline. 39,43 A study by Cokkinou et al. showed increased hemolysis in patients with thalassemia trait (beta thalassemia minor) after CPB but concluded the level of hemolysis may not be clinically significant. 47 The extent of
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hemolysis in more severe forms of thalassemia is unclear; however, with a larger amount of thalassemia hemoglobin, a greater level of hemolysis is expected. A perioperative strategy for patients at risk for significant hemolysis is detailed later in this review (hereditary spherocytosis section). In scenarios of significant acute hemolysis and also less severe chronic hemolysis, haptoglobin levels may become
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depleted. Intravenous haptoglobin administration has been described in a patient undergoing cardiac surgery with a history of beta-thalassemia.48 Additionaly, Tanaka et al. describe haptoglobin administration in patients without RBC disorders who had a free haptoglobin level of 0 mg/dl and a plasma free hemoglobin (PfHb) > 30mg/dl.49 N-Acetyl-Dpglucosainidase index was used as a marker of
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renal tubular injury which improved after haptoglobin administration in association with a decreased
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PfHb. In spite of these potential benefits, no study has shown an improvement in usual clinical outcomes with the use of haptoglobin or defined the appropriate PfHb threshold in which haptoglobin
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should be administered in patients with RBC disorders undergoing CPB. Therefore, use of haptoglobin in this population remains experimental. Prior authors anticipating significant hemolysis in patients with
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thalassemia have also described continuous ultrafiltration through a hemoconcentrator (sieving
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diameter 65,000 Dalton) to assist in the removal of PfHb (32,000 Daltons). 50 Thalassemia intermedia and major have both been associated with anti-thrombin III (AT III)
deficiency.51,52 This likely occurs through a consumptive process as a result of a chronic hypercoagulable state, and may be more common in patients with prior splenectomy and those who are transfusion dependent.52 Providers should anticipate heparin resistance in this population, and replace AT III when indicated .51 In the immediate postoperative period, bleeding complications are likely more common
ACCEPTED MANUSCRIPT Page 12 than thrombosis, particularly in patients with advanced liver disease and portal hypertension/ venous congestion. The benefit of antifibrinolytic therapy must be weighed against the risk of thrombosis on a case by case basis. There have been no reports of early postoperative thrombosis, although to date no trials have addressed this question. Late thrombosis has been reported of bioprosthetic and mechanical
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valves despite therapeutic anticoagulation. 44-46 The risk of hemolysis and thrombotic complications may be higher in patients receiving mechanical valves, yet data supporting valve replacement type is sparse.39
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Hemoglobin C
Hemoglobin C (HbC) is a variant of normal HbA in which lysine and glutamic acid are substituted within -globin chain. Patients heterozygous for the hemoglobin C mutation, (hemoglobin C trait) have no clinical manifestations. HbC predominates in homozygous patients leading to rigid RBCs, mild hemolytic
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anemia and splenomegaly. Clinical symptoms are mild unless the HbC mutation is coupled with a HbS mutation resulting in HbSC. 53 To date no clinical studies have been published to suggest alterations in
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perioperative management. Patients with HbSC should be treated similar to SCD.
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Hemoglobin Zurich
Hemoglobin Zurich (HbZ) is an unstable hemoglobin variant due to a mutation
-globin chain.
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The unstable hemoglobin becomes denatured and precipitates due to an expedited auto-oxidation of
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heme iron, creating methemoglobin, upon exposure to eliciting factors (e.g. oxidant drugs).54 Minimizing hemolysis by avoidance of oxidant drugs, and use drugs with anti-oxidant properties has been advocated in the single case report describing a patient with HbZ undergoing cardiac surgery.54 Drugs with oxidant properties that should be avoided in patients with unstable hemoglobins include: aspirin, prilocaine, penicillin, sodium nitroprusside, sulfonamides, and vitamin K.54 Some drugs with anti-oxidant properties commonly used in cardiac surgical patients include: dopamine, dobutamine, epinephrine,
ACCEPTED MANUSCRIPT Page 13 isoproterenol, norepinephrine, and propofol, among others with slightly less antioxidant properties.54Avoidance of oxidant drugs, use of anti-oxidant drugs (when clinically warranted), and minimizing extremes of pH (slight acidosis preferred over alkalosis) and elevations of temperature will help minimize hemolytic complications in this population. Bernard et al. also describe the preoperative
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use of the antioxidant α-tocopherol (vitamin E) , however, the benefit of this therapy is unknown.54 The diagnosis and treatment of significant hemolysis are covered elsewhere within this review. Acquired Disorders of Hemoglobin
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Carbon monoxide poisoning
Hemoglobinopathy resulting from carbon monoxide (CO) poisoning has been extensively described. 55 CO is a colorless, tasteless, and odorless gas that binds hemoglobin with much greater affinity than oxygen to form carboxyhemoglobin (COHb), thereby inhibiting oxygen binding and transport. Symptoms
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include malaise, vertigo, headache, nausea, and vomiting. In severe cases (CO levels typically >20-25%)
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coma, seizures, lactic acidosis, myocardial ischemia, cardiac dysrhythmias, and death may ensue. The clinical diagnosis of CO poisoning is confirmed with multi-wavelength pulse co-oximetry or arterial blood
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gas COHb measurement. The mainstay of treatment following removal of the CO source is 100% oxygen administration, which decreases the half-life of COHb 3-4 fold. Hyperbaric oxygen is typically reserved
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for more severe cases and can further shorten the half-life of COHb 10-20 fold. Both venoarterial and venovenous extracorporeal membrane oxygenation (ECMO) has been used in cases of severe
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cardiopulmonary instability. 56 Use of ECMO in this patient population is limited to case reports and rigorous data on long term outcomes is hence lacking. Interestingly, cardiopulmonary bypass has been shown to be associated with increased endogenous CO production resulting from heme degradation via oxidase enzymes, although the resultant CO increase remains well below toxic levels. 57 While toxic levels of COHb during CPB are rare,
ACCEPTED MANUSCRIPT Page 14 should CO toxicity occur while on CPB (or ECMO), treatment with 100% oxygen via both extracorporeal circulation and the ventilator (if in use) is warranted. Methemoglobinemia
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Methemoglobinemia can be congenital or, more commonly, acquired and results from oxidation of heme’s normal ferrous (Fe2+) state to the ferric (Fe3+) state.58 This results in an inability of ferric heme to bind oxygen, causing an increased affinity of remaining normal ferrous heme for oxygen. The resultant left-shifted oxygen-hemoglobin dissociation curve impairs oxygen delivery. Methemoglobinemia has
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been previously reviewed in detail, and only a brief overview of acquired methemoglobinemia will follow.58 Normal methemoglobin levels are < 1-2% and can be measured with multi-wavelength pulse co-oximetry or arterial blood gas testing. The presence of methemoglobin interferes with standard pulse oximetry and thus monitoring arterial blood gas sampling with co-oximetry may be necessary to obtain
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accurate gas measurements. Acquired methemoglobinemia most commonly results from various drugs (e.g. local anesthetics, nitroglycerin, inhaled nitric oxide, dapsone, sulfonamides, and quinolones) or
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other ingested substances. With severe methemoglobinemia, the mechanism for reducing
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methemoglobin to hemoglobin via the nicotine adenine dinucleotide (NADH) methemoglobin reductase is overwhelmed and toxic levels of methemoglobin result. Methemoglobinemia (typically >20%) can
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cause cyanosis, dark discoloration of the blood, headache, fatigue, vertigo, dyspnea, altered mental status, coma, dysrhythmias, seizures, or death. Following discontinuation of the causative agent,
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treatment consists of oxygen and methylene blue administration (typically 1 mg/kg). Methylene blue functions by reducing methemoglobin to normal hemoglobin. If the response to a single dose of methylene blue is not adequate, repeat dosing may be required. Additionally, transfusions, exchange transfusions, sodium ascorbate, and hyperbaric oxygen therapy may be used in severe
ACCEPTED MANUSCRIPT Page 15 methemoglobinemia cases or if methylene blue is contraindicated (glucose-6-phosphate dehydrogenase deficiency). Reports of methemoglobinemia diagnosed during CPB are rare.59,60 If present, improvement or
satisfactory hemodynamics and end-organ perfusion is prudent.
Hemolytic Anemias
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Acquired Hemolytic Anemias
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resolution of severe methemoglobinemia prior to weaning CPB to ensure the patient is able to maintain
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) has an incidence of 1-3:100,000 and results from the reaction of antibodies with antigens on RBC and can be divided into two types: warm and cold AIHA. 61 Warm AIHA
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involves the presence of IgG warm agglutinins (i.e. autoantibodies) that are active at normal body
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temperature and develop from a variety of causes including autoimmune, idiopathic, medications, malignancies, post-infection , post-transplantation, or following allogeneic blood transfusion. 61,62 IgG-
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bound RBCs are destroyed by hemolysis or phagocytosis. Signs and symptoms depend on the degree of anemia and include pallor, jaundice, splenomegaly, fatigability, tachycardia, narrow pulse pressure,
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tachypnea, lethargy, confusion, dysrhythmias, and death. Diagnostic testing may include complete blood count, direct antiglobulin test (typically positive), indirect antiglobulin test (typically negative),
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peripheral blood smear (spherocytes can be seen), bilirubin, haptoglobin, and lactate dehydrogenase to assess the degree of hemolysis. Treatment of warm AIHA aims to decrease both antibody titers and activity. 62 Antibody production is most commonly mitigated with glucocorticoids and secondarily with drugs such as rituximab, danzol, or immunosuppressants. Intravenous immunoglobulin and splenectomy are other
ACCEPTED MANUSCRIPT Page 16 therapies that can diminish hemolysis. 61,62 In patients with symptomatic anemia requiring transfusions, compatibility testing of allogeneic RBCs can be confounded by the reactive warm autoantibody. 63 Blood bank techniques such as adsorption testing and extended RBC phenotyping may improve the ability to
perform and may not be possible in emergent settings.
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select appropriate allogeneic RBCs for transfusion; however, these tests require additional time to
The literature detailing cardiac surgery with CPB in patients with warm AIHA is limited to a single case report. In this report, the patient was treated with corticosteroids for > 2 months, and underwent autologous blood donation prior to an uncomplicated CABG operation.64 In a survey of cardiac
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anesthesiologists, warm AIHA was less commonly encountered than cold AIHA during cardiac surgery. 65 Shah et al. conclude “there is therefore no benefit in altering the conduct of cardiopulmonary bypass;” however, the authors recommend preoperative hematology consultation.65 In addition to ensuring
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preoperative optimization of warm AIHA antibody titer and activity with hematology consultation, anesthesiologists should seek early involvement of the blood bank to allow for testing and selection of
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Cold agglutinin disease
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suitable allogeneic RBC units.
Although cold agglutinins (i.e. cold autoantibodies) are less common than warm autoantibodies, much
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more has been published on this disease in the context of cardiac surgery and CPB. Cold agglutinins are IgM autoantibodies that are normally present in nearly all patients but are rarely clinically significant
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because they do not react at normal blood temperatures. 66 It follows that “benign” cold agglutinins must be differentiated from cold agglutinin disease and resulting cold AIHA from the latter. Patients with benign cold agglutinins do not experience hemolytic anemia or other symptoms related to the presence of these autoantibodies, while patients with cold agglutinin disease have autoantibodies that are active at cooler temperatures achieved in the peripheral circulation. On exposure to cold
ACCEPTED MANUSCRIPT Page 17 temperatures, cold agglutinins bind the patient’s RBC causing RBC agglutination and fixation of complement. This manifests clinically at colder temperatures as hemolysis, anemia, acrocyanosis, Raynaud’s phenomenon, or livedo reticularis. Even after rewarming, complement remains fixed on the RBC and hemolysis may continue. These pathologic cold autoantibodies are typically not active at
66,67
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temperatures exceeding 30°C, but cases describing activity at higher temperatures have been reported. Cold agglutinin disease (i.e. cold AIHA) represents 15-30% of all hemolytic anemias and has a
prevalence of 10-15 per million people. 67 The cold agglutinins causing this disease state may be primary in nature or secondary to other conditions such as malignancy (e.g. lymphoma), infection, or
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autoimmune disease.
The diagnosis is confirmed with laboratory testing that includes cold agglutinin antibody titer (which confirms the presence of and quantifies the amount of autoantibodies present), thermal
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amplitude (which quantifies the highest temperature at which agglutination is observed in vitro), and
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hemolysis testing (hemoglobin, direct antibody testing, lactate dehydrogenase, haptoglobin, free plasma hemoglobin, bilirubin, etc.). 66 Treatment is typically aimed at reduction or elimination of cold
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agglutinins and consists of medical treatments such as glucocorticoids, intravenous immunoglobulin, chemotherapy (e.g. rituximab, cyclophosphamide), treating the underlying cause (e.g. infection), and
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plasma exchange.
CPB and cardioplegia commonly result in temperatures at which cold agglutinin-related
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hemolysis or agglutination may occur, with hemolysis and myocardial dysfunction having been reported perioperatively. 66-69 In patients without known cold agglutinin disease prior to cardiac surgery, preoperative RBC type and screening may incidentally demonstrate the presence of cold agglutinins. Additionally, case reports exist of cold agglutination occurring in the CPB machine after initiation of cooling in a patient without known prior cold agglutinins.69 Various reports of patients with both benign
ACCEPTED MANUSCRIPT Page 18 agglutinins and cold agglutinin disease undergoing cardiac surgery with CPB exist, with varying management strategies related to the cold agglutinins. 66-69 We recommend approaching the patient with cold agglutinins requiring cardiac surgery in a systematic fashion based on their cold agglutininrelated symptomatology and the type of cardiac surgery planned (Figure 1). Should cold agglutinin
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disease be diagnosed or suspected without time for the aforementioned preoperative testing and
treatment, normothermic CPB at 37°C and either avoidance of cardioplegia or use of tepid cardioplegia to mitigate further sequelae of the cold agglutinins should be utilized. 66-68
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Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease affecting 1-10 per million people.70 PNH results from a hematopoietic stem cell mutation on the X chromosome that ultimately affects the glycosylphosphatidylinositol RBC surface anchor resulting in complement-mediated hemolysis and
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venous thrombosis, the latter of which is poorly understood. Clinical findings include anemia, fatigue, jaundice, headache, hemoglobinuria, thrombosis, dyspnea, abdominal pain, erectile dysfunction, acute
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or chronic kidney injury, chest pain, esophageal spasm, and cytopenias from bone marrow suppression.
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The “nocturnal” nomenclature of PNH is derived from the predominance of hemoglobinuria with concentrated urine such as occurs with micturition during or immediately following the night; however,
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hemolysis, hemoglobinuria, etc. are not temporarily limited to nocturnal hours. Laboratory studies to confirm the diagnosis include complete blood count, peripheral blood smear, haptoglobin, lactate
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dehydrogenase, bilirubin, plasma free hemoglobin, direct antiglobulin test, urinalysis, bone marrow biopsy, and flow cytometry. In addition to RBC transfusion if required, mainstays of PNH treatment include anticoagulation in cases of thrombosis, eculizumab, and allogeneic stem cell transplantation in severe cases.
ACCEPTED MANUSCRIPT Page 19 Patients with PNH undergoing CPB may experience complement activation and associated hemolysis, and literature on this patient population in the context of CPB is limited to case reports.71,72 The evidence is hence very restricted regarding optimal perioperative management. When feasible, preoperative hematology consultation is indicated to optimally treat PNH prior to cardiac surgery.
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Transfusion with leukocyte-reduced group-specific RBC is recommended, given the potential for allogeneic leukocytes to trigger hemolysis in patients with PNH.71,73 Some authors recommend
prophylactic RBC transfusions to decrease the fraction of abnormal RBCs predisposed to hemolysis. 71,72 Finally, perioperative avoidance of hypoxemia, hypercarbia, acidosis, and infections may help mitigate
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precipitants for thromboses in patients with PNH. Paroxysmal cold hemoglobinuria
While similar to the other cold hemolytic anemias, paroxysmal cold hemoglobinuria (PCH) is distinct in
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that patients have presence of the potent hemolysin Donath-Landsteiner antibodys.74 Patients with PCH can experience massive hemolysis and hence hemoglobinuria upon exposure to cold temperatures. In
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contrast to cold agglutinin disease which is an IgM autoantibody mediated process, PCH is due to an Ig-G
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autoantibody (Donath-Landsteiner antibody) which is a hemolysin rather than a RBC agglutinin.74 With the prevalence of PCH (1.7% of all adult AIHA) being much lower than both cold agglutinin disease and
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paroxysmal nocturnal hemoglobinuria, the literature detailing management of this population undergoing cardiac surgery is limited to a single case report.74 In this report of a patient requiring mitral
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valve replacement, the authors describe a technique of warm (37oC) CPB, and avoidance of topical cardiac cooling, however, did use cold cardioplegia. The authors do mention that the use of fibrillatory arrest in lieu of cardioplegia can be considered. The case and postoperative period were uneventful for hemolysis or related complications.74
ACCEPTED MANUSCRIPT Page 20 Preoperative hemolysis testing (hemoglobin, direct antibody testing, lactate dehydrogenase, haptoglobin, free plasma hemoglobin, bilirubin, etc.) mirrors that of other hemolytic anemias and gauges the level of chronic hemolysis in this population. Similar to cold agglutinin disease, thermal amplitude testing can be performed to quantify the highest temperature at which hemolysis is observed
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in vitro. While the evidence related to the perioperative management for cardiac surgery in this population is lacking, a strategy similar to that advocated for cold agglutinin disease with early
preoperative testing, hematology consultation, treatment (if necessary), operative technique planning,
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and avoidance of hypothermia whenever feasible is warranted. Hereditary Hemolytic Anemia: RBC membrane disorders Hereditary Spherocytosis
Hereditary spherocytosis (HS) is a red blood cell disorder which results in spheroid shaped erythrocytes
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with abnormally rigid cell membranes. With an incidence of around 1:2000 amongst those of northern
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European ancestry, HS is the most common chronic hemolytic anemia.75 Inheritance of HS is autosomal dominant for two-thirds of patients and autosomal recessive or de novo in remaining patients. 75
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Deficiencies in RBC membrane proteins such spectrin, ankyrin, band 3 protein, protein 4.2, or Rhcomplexes, lead to rigid-spherical shaped erythrocytes with impaired deformability and loss of surface
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area. The dysfunctional “spherocytes” become trapped and destroyed within the spleen. Clinical
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severity varies from mild to severe, with the latter possibly requiring splenectomy to reduce or eliminate hemolysis. Patients who have undergone splenectomy are at risk for ischemic/thrombotic complications as the dysfunctional spherocytes are no longer removed and can lead to microvascular occlusions in addition to the infectious complications associated with asplenia.75,76 The literature describing HS and cardiac surgery is sparse. A recent case report and literature review by Hargrave et al. describes in depth the important perioperative considerations for patients
ACCEPTED MANUSCRIPT Page 21 with HS undergoing cardiac surgery.76 Preoperative assessment of patients with HS includes a detailed history of clinical severity, along with current and/or prior therapy and transfusion requirements. A baseline laboratory evaluation to serve as reference for when evaluating for hemolysis should be performed (Table 4).
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Cardiac surgery particularly with the use of CPB in patients with HS risks hemolysis and
associated complications, as the rigid yet fragile erythrocytes are susceptible to the physiologic
derangements common during these procedures. Shear stress, turbulence, alterations in oncotic
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pressure, and hypothermia are all known to risk hemolysis in HS, therefore, proper actions to limit or avoid erythrocyte trauma should be taken. Reducing alterations in the oncotic pressure balance on the erythrocyte can be achieved by limiting the hemodilution that occurs with CPB crystalloid pump prime. The use of retrograde autologous priming should be considered whenever possible, and the addition of
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albumin to the pump prime solution may help assimilate the osmotic balance.76 The shear stress and turbulence within the CPB circuit can be reduced with the use of large
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diameter, reduced length, straight tip cannulas and tubing. Pressure gradients between the aortic inflow
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cannula and systemic pressure should be kept ideally <100 mmHg. There is insufficient evidence to suggest use of non-occlussive roller pumps vs. centrifugal pumps. The use of vacuum-assisted venous
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drainage can increase shear stress and turbulence, thus if use is necessary, negative pressures should be kept to a minimum with an absolute cutoff of -80mmHg.76 Minimizing suction cannula negative
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pressures and avoiding small tip suction orifices can also reduce the risk of hemolysis. The use of intraoperative autologous transfusion (i.e. cell-saver) appears safe for patients with HS. If hemolysis is suspected, the cell saver suction should be used in favor of the cardiotomy suction as the former allows removal of the plasma free hemoglobin (PfHb) and intracellular components. While mild hypothermia and cold solution cardioplegia are commonly used in cardiac surgery, both are known to increase the
ACCEPTED MANUSCRIPT Page 22 risk for hemolysis in patients with HS. Use of normothermic CPB, and tepid cardioplegia should be considered and used whenever possible in this population.76 Prior authors comment that in patients with HS requiring valve replacement, valve type (biologic vs. mechanical) should be taken into consideration as the mechanical valves may risk hemolysis,
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however, there is insufficient data to make firm recommendations.76,77 A single case report exists of a patient with HS undergoing successful LVAD insertion (HeartWare) as a bridge to cardiac transplantation without clinically relevant hemolysis.78
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Despite proper precautions, patients with HS are still at risk for perioperative hemolysis. Prompt diagnosis and treatment are vitally important to limit associated complications. With progressive hemolysis and the resultant anemia, tissue oxygen delivery can become critically impaired. Hemolysis leads to the release of PfHb into the circulation which under normal circumstances is scavenged without
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incident. However, in massive hemolysis these scavenging mechanisms (e.g. haptoglobin) become overwhelmed which can lead to PfHb associated microvascular occlusions. This PfHb is a nitric oxide
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scavenger which can increase systemic and pulmonary vascular resistance and alter platelet function.
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Treatment with sodium nitroprusside and/or inhaled nitric oxide to combat increases in vascular resistances may help reduce further hemolysis/PfHb release.79 Laboratory findings consistent with
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hemolysis include anemia, elevations of PfHb, lactate dehydrogenase, bilirubin, and decreased levels of
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haptoglobin.
The management of hemolysis includes identification and reversal of causative insults.
Transfusion is indicated if anemia risks inadequate oxygen carrying capacity. With large amounts of PfHb, pigment deposits within the renal tubules risk acute renal failure. Assuring adequate volume resuscitation, renal perfusion, and urine output is critical. Use of sodium bicarbonate infusions are common in this scenario, however, evidence to support this practice in lieu of isotonic crystalloids such
ACCEPTED MANUSCRIPT Page 23 as normal saline is lacking.80 Mannitol is also described in this setting and may act as a free radical scavenger; however, avoidance of diuresis induced hypovolemia is important. Loop-diuretics should be reserved for patients who have failed the aforementioned therapies, have adequate circulating volume and perfusion indices, yet remain oliguric or anuric with concern for volume overload. As previously
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mentioned, prior authors anticipating significant hemolysis in a thalassemia patient described
ultrafiltration through a hemoconcentrator (sieving diameter 65,000 Dalton) to assist with removal of PfHb (32,000 Daltons). 50 The efficacy of this technique is unknown.
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Patients remain at risk for hemolysis into the postoperative period, and should be monitored with serial laboratory analyses to assess for hemolysis and end organ function (Table 4.) Hereditary Elliptocytosis
Hereditary elliptocytosis (HE) is an autosomal dominant disorder most common in malaria endemic
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areas with a regional prevalence of 2%.1 The spectrum of clinical severity ranges from asymptomatic
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carriers to severe anemia, with 10% of patients suffering from the later.1 In HE, alterations in spectrin and less commonly protein 4.1 are responsible for the defects in skeletal membrane
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stability.1 The result is the formation of elliptocytes, which have reduced surface area and increased susceptibility to fragmentation with eventual sequestration and destruction within the spleen.1 The
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literature detailing patients with HE undergoing cardiac surgery is limited to 2 patients, for which
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perioperative details were lacking.44 These patients are still at risk for hemolysis due to defective RBCs that lack elasticity and deformability. Avoidance of factors known to increase risk of shear stress and turbulence as was detailed in the management of hereditary spherocytosis seems reasonable (Table 4). Hereditary Hemolytic Anemia: RBC enzyme disorders Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
ACCEPTED MANUSCRIPT Page 24 In healthy patients, the enzyme glucose-6-phosphate dehydrogenase (G6PD) functions within the pentose phosphate pathway to convert glucose-6-phospate into 6-phosphogluconate, reducing nicotinamide adenine dinucleotide phosphate (NADPH) and replenishing glutathione, a reactive oxidative species scavenger.81 As the most common RBC enzymopathy (affecting 400 million people
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worldwide), G6PD-deficiency, known as “favism”, has a higher prevalence within malarial endemic regions as it is protective against severe infection. 82 The gene for G6PD is located on the X-
chromosome, thus G6PD is more common among males, particularly those of African descent.81 In patients with G6PD deficiency, NAPDH and glutathione become depleted allowing oxidative damage to
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hemoglobin and the RBC membrane risking hemolysis.82
Disease severity is classified (Class I-V) via the World Health Organization by percent of enzyme activity ranging from severe disease (Class I) with activity <10% to a non-deficient variant with normal or
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increased enzyme activity (Class V).23,82 Patients with G6PD deficiency are usually asymptomatic at baseline and only experience hemolysis and jaundice with triggered oxidative stressors or exposures
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(e.g. fava bean ingestion, infection, medication).
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Diagnostic findings on peripheral smear may include anisocytosis, poikilocytosis, bite cells, and Heinz bodies. During a hemolytic event, reticulocyte G6PD content may falsely elevate the G6PD activity
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level, confusing the diagnosis.82 The most common cause of acute hemolysis in G6PD-deficient patients is systemic infection (e.g. hepatitis A or B, cytomegalovirus, pneumonia).81 Medication ingestion is also a
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common cause of acute hemolysis (24-72 hours after ingestion).81 Drugs commonly used in cardiac surgery that should be avoided when feasible in G6PD deficient patients are listed in Table 5.83 A complete list of drugs that should be avoided in this population can be found online at www.g6pd.org. The literature detailing the perioperative management of patients with G6PD-deficieincy undergoing cardiac surgery is limited, but highlights the risk for hemolysis and perioperative
ACCEPTED MANUSCRIPT Page 25 complications in this population.84 The physiologic stressors of cardiac surgery such as pain, anxiety, ischemia, reperfusion, hypothermia, acidosis, and flow through the CPB circuit risk oxidative free radical production and hemolysis as antioxidant production (i.e. glutathione) may be inadequate .23 Cardiopulmonary bypass is known to cause an inflammatory response with free radical production, thus
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when feasible “off pump” operations should be considered.23 Avoidance of medications known to risk hemolysis in this population is critical. As found in Table 5, several drugs commonly used during
anesthesia and cardiac surgery risk hemolysis in G6PD-deficient patients and should be avoided.83 The use of volatile anesthetics (isoflurane and sevoflurane) and benzodiazepines (diazepam and midazolam)
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have been linked to hemolysis from in vitro data, yet subsequent authors have described successful use of these medications in this population.85,86 Nonetheless it is probably reasonable to avoid these controversial drugs given that other non-triggering intravenous options exist. The use of cardioplegia solutions that contain local anesthetics such as del Nido (lidocaine) should be avoided. Prior authors
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have discussed strategies to limit mechanical damage from RBC shear stress and turbulence, thereby
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reducing or limiting hemolysis.86 These preventative strategies include the use of non-occlusive roller pumps, large diameter/short length tubing and cannulas, limiting suction and vacuum pressures, etc.,
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and are outlined in prior sections of this review. While off pump cardiac surgery is preferred, the successful management of patients requiring cardiac surgery with CPB and even deep hypothermic
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circulatory arrest has been reported.87
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Avoidance of medications known to risk methemoglobinemia (e.g. sodium nitroprusside) is important as this population is unresponsive to therapy with methylene blue, which may itself risk hemolysis.87
The use of mannitol as a free radical scavenger in patients undergoing cardiac surgery is common and a reasonable option in patients with G6PD-deficiency.88 Previous authors have also
ACCEPTED MANUSCRIPT Page 26 described the use of ascorbic acid as an antioxidant to help limit oxidative damages and hemolysis in G6PD deficient patients, however, supra-physiologic doses have been linked to hemolysis.87,89 There is insufficient data to make recommendations on the use of ascorbic acid in this population. In the event of a hemolytic crisis, attempts to abate triggering factors should be made. In cases
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of severe hemolysis and anemia, RBC transfusion is warranted. As with any hemolytic crisis, ensuring adequate volume resuscitation, perfusion pressure, and urine output are essential. Additional management strategies for severe hemolysis have been described elsewhere in this review.
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Pyruvate kinase deficiency
Pyruvate kinase (PK) is an important enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate thereby generating ATP. Pyruvate kinase deficiency is an autosomal recessive defect and the second most common RBC enzyme deficiency. With an incidence in the United
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States of 1:20,000 this rare disorder is seen most frequently in those of northern European decent and
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Pennsylvania Amish.82,90 Patients with PK deficiency lack the ability to appropriately generate ATP within RBCs which disrupts the cationic cellular gradient and ultimately leads to a rigid cellular structure that is
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susceptible to splenic destruction. The exact mechanism by which PK deficiency leads to hemolysis is poorly understood. Clinical manifestations present only in homozygotes or compound heterozygotes. PK
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levels in symptomatic patients are usually between 5-40% normal.82 Clinical severity ranges from mild anemia to lifelong transfusion dependence, but is fairly constant for most patients with occasional
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hemolytic crises during physiologic stressors (e.g. infection).82 Chronic therapy is largely supportive with splenectomy reserved for severe disease. The literature detailing perioperative management of patients PK deficiency undergoing cardiac surgery is limited to a single case report.90 Assessment of baseline laboratory parameters (hemoglobin, bilirubin, pyruvate kinase levels, etc.) can serve as a reference for the perioperative period. Prior authors
ACCEPTED MANUSCRIPT Page 27 discuss avoidance of factors known to further increase RBC shear stress and risk hemolysis, and also avoiding hypothermia when appropriate.90 Outside of minimizing the physiologic stressors of cardiac surgery and CPB, there is insufficient data to make further recommendations. Diagnostic and therapeutic goals should a hemolytic crisis occur are detailed previously.
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Chronic Myeloproliferative Neoplasm Polycythemia vera
Chronic myeloproliferative neoplasms (CPNs) encompass a group of blood related disorders including
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polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. Polycythemia vera is the most common of the CPNs with an incidence of 2.5-10:100,000 and is associated most commonly with JAK2 gene mutations.91 Commonly, PV presents with erythrocytosis, thrombocytosis, and leukocytosis, but patients can have isolated erythrocytosis.91 Patients with PV are at an elevated risk for
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thromboembolic complications which may be the first sign of the disease process.91 The pathologic basis
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of the disease is overactive hematoposesis leading to quantitative overproduction of qualitatively normal erythrocytes. Of note, PV is the only one of the CPNs that displays erythrocytosis. A detailed
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overview of the diagnostic and therapeutic guidelines for PV is beyond the scope of this review, but is extensively reviewed elsewhere.91 The mainstay of therapy in PV is phlebotomy which often is used to
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target normal hematocrit values (<45% male, <42% female), reducing thromboembolic risk.91 Treatment
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of patients with PV is based on risk-stratification criteria taking into account age and history of prior thrombotic complications. Higher risk patients are commonly treated with cytoreductive therapies (i.e. hydroxyurea) and possibly antiplatelet or anticoagulant medications. Thrombocytosis is a common feature of PV (50% of PV patients), and the primary derangement in patients with ET. Excessive thrombocytosis in these populations risks arterial and venous thrombosis with 20-50% of patients suffering thrombotic complications.92 Excessive thrombocytosis (>800 x 109/L) in
ACCEPTED MANUSCRIPT Page 28 patients with ET undergoing cardiac surgery has been associated with major perioperative thrombotic complications.93 Less commonly, bleeding diathesis can be seen and thought to be secondary to qualitative platelet dysfunction. Additionally, patients with PV and ET with elevated platelet counts are at risk for the development of acquired von Willebrand syndrome (AvWS).91 One recent study cited the
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incidence of AvWS of 55% and 49% respectively among ET and PV patients. The mechanism for the development of AvWS in these populations is not entirely clear but may be partially the result of
alterations in vWF proteolysis, which in PV may be resultant of the higher viscosity and shear stress within the blood leading to a conformational change in the vWF molecule.94
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The literature describing patients with PV undergoing cardiac surgery is limited.92,95 Osada et al. discuss a patient undergoing bilateral internal mammary CABG for which intraoperative phlebotomy to reduce the hematocrit <45% was performed, however, the patient suffered from left internal mammary
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thrombosis intraoperatively and acute right internal mammary occlusion on POD 1 necessitating angiography and stenting.95 The authors note that phlebotomy and optimization prior to the surgical
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procedure (not intraoperatively), and also full heparin dosing prior to IMA takedown should be considered for future cases.95 Reducing hematocrit values into the normal range (<45% male, <42%
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female), prior to cardiac surgery is warranted as this is a common therapeutic target for this population
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in general. Further reductions in hematocrit for patients undergoing cardiac surgery with moderate or deep hypothermia may be necessary but exact targets are unknown.
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In the limited reports, postoperative anticoagulation for PV patients having undergone CABG
included aspirin, clopidiogrel, and warfarin.92,95 Additionally, appropriate preoperative platelet reduction/optimization strategies are important in avoiding thrombotic and less commonly hemorrhagic complications in patients with ET, however, such practices have not been described in PV .93 While it is likely that PV directed therapy with phlebotomy and/or cytoreductive therapies will simultaneously
ACCEPTED MANUSCRIPT Page 29 reduce platelet counts, if excessive thrombocytosis persists (>800 x 109/L) therapeutic platelet reduction strategies (e.g. plateletpheresis) may be reasonable and would warrant preoperative hematology consultation.
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Summary In conclusion, RBC disorders are rare but can have profound implications for patients undergoing cardiac surgery. Understanding the physiologic derangements and implications is critical for those caring for this patient population. While some disorders require minimal deviation from standard perioperative care,
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others necessitate precise changes in perioperative strategy to avoid or limit complications. An early preoperative multidisciplinary team approach to these patients is important toward establishing the best individualized perioperative care plan. Additionally, a prior transfusion history may complicate RBC crossmatch compatibility, thus should be anticipated and planned for well in advance to the surgical
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date. This review is not an exhaustive resource, but references current available literature and gives
Narla J, Mohandas N. Red cell membrane disorders. Int J Lab Hematol 2017;39 Suppl 1:47-52.
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1.
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References
PT
ED
providers reasonable recommendations when encountering patients with such disorders.
2.
Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk
factors for early death. N Engl J Med 1994;330:1639-44. 3.
. (Accessed June 27, 2018, at https://www.cdc.gov/ncbddd/sicklecell/data.html.)
4.
Koshy M, Weiner SJ, Miller ST, et al. Surgery and anesthesia in sickle cell disease. Cooperative
Study of Sickle Cell Diseases. Blood 1995;86:3676-84.
ACCEPTED MANUSCRIPT Page 30 5.
Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med
2013;3:a011783. 6.
Pannu R, Zhang J, Andraws R, Armani A, Patel P, Mancusi-Ungaro P. Acute myocardial infarction
in sickle cell disease: a systematic review. Crit Pathw Cardiol 2008;7:133-8. Yousafzai SM, Ugurlucan M, Al Radhwan OA, Al Otaibi AL, Canver CC. Open heart surgery in
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7.
patients with sickle cell hemoglobinopathy. Circulation 2010;121:14-9. 8.
Lazopoulos G, Kantartzis MM, Kantartzis M. Mitral valve replacement and tricuspid valve repair
in a patient with sickle cell disease. Thorac Cardiovasc Surg 2008;56:56-7.
Sachithanandan A, Nanjaiah P, Wright CJ, Rooney SJ. Mitral and tricuspid valve surgery in
AN US
9.
homozygous sickle cell disease: perioperative considerations for a successful outcome. J Card Surg 2008;23:167-8. 10.
Frimpong-Boateng K, Amoah AG, Barwasser HM, Kallen C. Cardiopulmonary bypass in sickle cell
Balasundaram S, Duran CG, al-Halees Z, Kassay M. Cardiopulmonary bypass in sickle cell
ED
11.
M
anaemia without exchange transfusion. Eur J Cardiothorac Surg 1998;14:527-9.
anaemia. Report of five cases. J Cardiovasc Surg (Torino) 1991;32:271-4. Harban FM, Connor P, Crook R, Bingham R. Cardiopulmonary bypass for surgical correction of
PT
12.
congenital heart disease in children with sickle cell disease: a case series. Anaesthesia 2008;63:648-51. Djaiani GN, Cheng DC, Carroll JA, Yudin M, Karski JM. Fast-track cardiac anesthesia in patients
CE
13.
with sickle cell abnormalities. Anesth Analg 1999;89:598-603. Esseltine DW, Baxter MR, Bevan JC. Sickle cell states and the anaesthetist. Can J Anaesth
AC
14.
1988;35:385-403. 15.
Farooqui F, Chaney MA, Staikou C, Cole SP. CASE 10-2016: Hemoglobinopathies and Cardiac
Surgery. J Cardiothorac Vasc Anesth 2016;30:1409-18.
ACCEPTED MANUSCRIPT Page 31 16.
Sanders DB, Smith BP, Sowell SR, et al. Sickle cell disease and complex congenital cardiac
surgery: a case report and review of the pathophysiology and perioperative management. Perfusion 2014;29:153-8. 17.
Raut MS, Khanuja JS, Srivastava S. Perioperative considerations in a sickle cell patient
18.
Bocchieri KA, Scheinerman SJ, Graver LM. Exchange transfusion before cardiopulmonary bypass
in sickle cell disease. Ann Thorac Surg 2010;90:323-4. 19.
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undergoing cardiopulmonary bypass. Indian J Anaesth 2014;58:319-22.
Edwin F, Aniteye E, Tettey M, et al. Hypothermic cardiopulmonary bypass without exchange
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transfusion in sickle-cell patients: a matched-pair analysis. Interact Cardiovasc Thorac Surg 2014;19:7716. 20.
Alotaibi GS, Alsaleh K, Bolster L, McMurtry MS, Wu C. Preoperative transfusion in patients with
Hematology 2014;19:463-71.
Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell
ED
21.
M
sickle cell disease to prevent perioperative complications: a systematic review and meta-analysis.
Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013;381:930-8. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive
PT
22.
transfusion regimens in the perioperative management of sickle cell disease. The Preoperative
23.
CE
Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995;333:206-13. Dogra N, Puri GD, Rana SS. Glucose-6-phosphate dehydrogenase deficiency and cardiac surgery.
AC
Perfusion 2010;25:417-21. 24.
Hemming AE. Pro: Exchange transfusion is required for sickle cell trait patients undergoing
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2004;18:663-5. 25.
Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension
in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002;33:1037-43.
ACCEPTED MANUSCRIPT Page 32 26.
Westerman MP, Green D, Gilman-Sachs A, et al. Coagulation changes in individuals with sickle
cell trait. Am J Hematol 2002;69:89-94. 27.
Yung GL, Channick RN, Fedullo PF, et al. Successful pulmonary thromboendarterectomy in two
patients with sickle cell disease. Am J Respir Crit Care Med 1998;157:1690-3. Crawford TC, Carter MV, Patel RK, et al. Management of sickle cell disease in patients
undergoing cardiac surgery. J Card Surg 2017;32:80-4. 29.
Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia.
Blood Rev 2012;26 Suppl 1:S3-6.
Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden.
AN US
30.
CR IP T
28.
Blood 2010;115:4331-6. 31.
Borgna-Pignatti C. The life of patients with thalassemia major. Haematologica 2010;95:345-8.
32.
Lai ME, Grady RW, Vacquer S, et al. Increased survival and reversion of iron-induced cardiac
M
disease in patients with thalassemia major receiving intensive combined chelation therapy as compared
33.
ED
to desferoxamine alone. Blood Cells Mol Dis 2010;45:136-9. Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ. Improved survival of
Reson 2008;10:42.
Olivieri NF, Liu PP, Sher GD, et al. Brief report: combined liver and heart transplantation for end-
CE
34.
PT
thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn
stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med
AC
1994;330:1125-7. 35.
Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in
thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 2014;99:811-20.
ACCEPTED MANUSCRIPT Page 33 36.
Kremastinos DT, Farmakis D, Aessopos A, et al. Beta-thalassemia cardiomyopathy: history,
present considerations, and future perspectives. Circ Heart Fail 2010;3:451-8. 37.
Morris CR, Vichinsky EP. Pulmonary hypertension in thalassemia. Ann N Y Acad Sci
2010;1202:205-13. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling
CR IP T
38.
pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. Blood 2002;99:30-5. 39.
Raffa GM, Mularoni A, Di Gesaro G, Vizzini G, Cipolla T, Pilato M. Thalassemia and heart surgery:
aortic valve repair after endocarditis. Ann Thorac Surg 2015;99:e1-2.
Wood JC. Cardiac complications in thalassemia major. Hemoglobin 2009;33 Suppl 1:S81-6.
41.
Detterich J, Noetzli L, Dorey F, et al. Electrocardiographic consequences of cardiac iron overload
AN US
40.
in thalassemia major. Am J Hematol 2012;87:139-44. 42.
Staikou C, Stavroulakis E, Karmaniolou I. A narrative review of peri-operative management of
Botta L, Savini C, Martin-Suarez S, et al. Successful mitral valve replacement in a patient with a
ED
43.
M
patients with thalassaemia. Anaesthesia 2014;69:494-510.
severe form of beta-thalassaemia. Heart Lung Circ 2008;17:77-9. deLeval MR, Taswell HF, Bowie EJ, Danielson GK. Open heart surgery in patients with inherited
PT
44.
hemoglobinopathies, red cell dyscrasias, and coagulopathies. Arch Surg 1974;109:618-22. Farmakis D, Polonifi A, Deftereos S, Tsironi M, Papaioannou I, Aessopos A. Aortic valve
CE
45.
replacement in a patient with thalassemia intermedia. Ann Thorac Surg 2006;81:737-9. Omoto T, Tedoriya T, Kondo Y, et al. Aortic valve replacement in a patient with alpha-
AC
46.
thalassemia. Ann Thorac Cardiovasc Surg 2010;16:365-6. 47.
Cokkinou V, Katsiyanni A, Orkopoulou M, Michalis A, Tolis G, Cokkinos DV. Evidence of increased
hemolysis after open heart surgery in patients heterozygous for Beta-thalassemia. Tex Heart Inst J 1988;15:35-8.
ACCEPTED MANUSCRIPT Page 34 48.
Horai T, Tanaka K, Takeda M. Coronary artery bypass grafting under cardiopulmonary bypass in
a patient with beta-thalassemia: report of a case. Surg Today 2006;36:538-40. 49.
Tanaka K, Kanamori Y, Sato T, et al. Administration of haptoglobin during cardiopulmonary
bypass surgery. ASAIO transactions / American Society for Artificial Internal Organs 1991;37:M482-3. Richardson R, Issitt R, Crook R. Beta-thalassemia in the paediatric cardiac surgery setting - a case
report and literature review. Perfusion 2018;33:232-4. 51.
Abosdera MM, Almasry AE, Abdel-Moneim ES. Coagulation defects in thalassemic patients.
Pediatr Neonatol 2017;58:421-4.
Fayed MA, Abdel-Hady HE, Hafez MM, Salama OS, Al-Tonbary YA. Study of platelet activation,
AN US
52.
CR IP T
50.
hypercoagulable state, and the association with pulmonary hypertension in children with betathalassemia. Hematol Oncol Stem Cell Ther 2018;11:65-74. 53.
Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev
Bernard E, Schmid ER, Schmidlin D, Schaffner A, Germann R. Hemoglobin Zurich and
ED
54.
M
2003;17:167-78.
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14:705-6. Rose JJ, Wang L, Xu Q, et al. Carbon Monoxide Poisoning: Pathogenesis, Management, and
PT
55.
Future Directions of Therapy. Am J Respir Crit Care Med 2017;195:596-606. McCunn M, Reynolds HN, Cottingham CA, Scalea TM, Habashi NM. Extracorporeal support in an
CE
56.
adult with severe carbon monoxide poisoning and shock following smoke inhalation: a case report.
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Perfusion 2000;15:169-73. 57.
Schober P, Kalmanowicz M, Schwarte LA, Loer SA. Cardiopulmonary bypass increases
endogenous carbon monoxide production. J Cardiothorac Vasc Anesth 2009;23:802-6. 58.
Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for
management. J Cardiothorac Vasc Anesth 2014;28:1043-7.
ACCEPTED MANUSCRIPT Page 35 59.
Champigneulle B, Lecorre M, Bouzguenda H, et al. Late diagnosis of congenital
methemoglobinemia in an elderly patient during cardiac surgery. J Cardiothorac Vasc Anesth 2014;28:730-2. 60.
McRobb CM, Holt DW. Methylene blue-induced methemoglobinemia during cardiopulmonary
61.
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bypass? A case report and literature review. J Extra Corpor Technol 2008;40:206-14.
Barros MM, Blajchman MA, Bordin JO. Warm autoimmune hemolytic anemia: recent progress in
understanding the immunobiology and the treatment. Transfus Med Rev 2010;24:195-210.
King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Semin Hematol 2005;42:131-6.
63.
Petz LD. A physician's guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol
AN US
62.
2004;124:712-6. 64.
Onoe M, Magara T, Yamamoto Y. Cardiac operation for a patient with autoimmune hemolytic
anemia with warm-reactive antibodies. Ann Thorac Surg 2001;71:351-2.
Shah S, Gilliland H, Benson G. Agglutinins and cardiac surgery: a web based survey of cardiac
M
65.
66.
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anaesthetic practice; questions raised and possible solutions. Heart Lung Vessel 2014;6:187-96. Barbara DW, Mauermann WJ, Neal JR, Abel MD, Schaff HV, Winters JL. Cold agglutinins in
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patients undergoing cardiac surgery requiring cardiopulmonary bypass. The Journal of thoracic and cardiovascular surgery 2013;146:668-80. Patel PA, Ghadimi K, Coetzee E, et al. Incidental Cold Agglutinins in Cardiac Surgery:
CE
67.
Intraoperative Surprises and Team-Based Problem-Solving Strategies During Cardiopulmonary Bypass. J
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Cardiothorac Vasc Anesth 2017;31:1109-18. 68.
Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg
1995;60:1143-50. 69.
Bracken CA, Gurkowski MA, Naples JJ, et al. Case 6--1993. Cardiopulmonary bypass in two
patients with previously undetected cold agglutinins. J Cardiothorac Vasc Anesth 1993;7:743-9.
ACCEPTED MANUSCRIPT Page 36 70.
Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804-11.
71.
Ghoreishi M, Baer MR, Bhargava R, Stauffer CE, Griffith BP, Gammie JS. Aortic valve bypass for
aortic stenosis in a patient with paroxysmal nocturnal hemoglobinuria. Ann Thorac Surg 2010;90:279-81. 72.
Knobloch K, Lichtenberg A, Leyh RG, Schubert J. Aortic valve replacement and coronary
9. 73.
Dinesh D, Baker B, Carter JM. Cardiopulmonary bypass surgery in a patient with paroxysmal
nocturnal haemoglobinuria. Transfus Med 2006;16:206-8.
Kypson AP, Warner JJ, Telen MJ, Milano CA. Paroxysmal cold hemoglobinuria and
AN US
74.
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revascularization in paroxysmal nocturnal hemoglobinuria. Interact Cardiovasc Thorac Surg 2003;2:647-
cardiopulmonary bypass. Ann Thorac Surg 2003;75:579-81. 75.
Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008;372:1411-26.
76.
Hargrave JM, Capdeville MJ, Duncan AE, Smith MM, Mauermann WJ, Gallagher PG. CASE 5-
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2016Complex Congenital Cardiac Surgery in an Adult Patient With Hereditary Spherocytosis: Avoidance
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of Massive Hemolysis Associated With Extracorporeal Circulation in the Presence of Red Blood Cell Fragility. J Cardiothorac Vasc Anesth 2016;30:800-8. Matsuzaki Y, Tomioka H, Saso M, et al. Open-heart surgery using a centrifugal pump: a case of
PT
77.
hereditary spherocytosis. J Cardiothorac Surg 2016;11:138. Huenges K, Panholzer B, Cremer J, Haneya A. Ventricular assist device implantation in a young
CE
78.
patient with non-compaction cardiomyopathy and hereditary spherocytosis. Eur J Cardiothorac Surg
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2017. 79.
Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a
review in search of a treatment algorithm. The Journal of extra-corporeal technology 2008;40:257-67. 80.
Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview
for clinicians. Critical care 2005;9:158-69.
ACCEPTED MANUSCRIPT Page 37 81.
Belfield KD, Tichy EM. Review and drug therapy implications of glucose-6-phosphate
dehydrogenase deficiency. Am J Health Syst Pharm 2018;75:97-104. 82.
Haley K. Congenital Hemolytic Anemia. Med Clin North Am 2017;101:361-74.
83.
(Accessed April 24, 2018, at
84.
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https://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.)
Gerrah R, Shargal Y, Elami A. Impaired oxygenation and increased hemolysis after
cardiopulmonary bypass in patients with glucose-6-phosphate dehydrogenase deficiency. Ann Thorac Surg 2003;76:523-7.
Altikat S, Ciftci M, Buyukokuroglu ME. In vitro effects of some anesthetic drugs on enzymatic
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85.
activity of human red blood cell glucose 6-phosphate dehydrogenase. Pol J Pharmacol 2002;54:67-71. 86.
Kumar R. Precautionary Measures for Successful Open Heart Surgery in G6PD Deficient Patient-
A Case Report. J Clin Diagn Res 2016;10:PD11-PD2.
Staudt GE, Qu JZ. Deep Hypothermic Circulatory Arrest in a Patient With Severe G6PD
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87.
88.
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Deficiency. J Cardiothorac Vasc Anesth 2017.
Larsen M, Webb G, Kennington S, et al. Mannitol in cardioplegia as an oxygen free radical
89.
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scavenger measured by malondialdehyde. Perfusion 2002;17:51-5. Quinn J, Gerber B, Fouche R, Kenyon K, Blom Z, Muthukanagaraj P. Effect of High-Dose Vitamin C
90.
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Infusion in a Glucose-6-Phosphate Dehydrogenase-Deficient Patient. Case Rep Med 2017;2017:5202606. Basantwani S, Govardhane B, Shinde S, Tendolkar B. Mitral Valve Replacement With
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Cardiopulmonary Bypass in a Patient With Pyruvate Kinase Deficiency. J Cardiothorac Vasc Anesth 2017;31:262-5. 91.
Spivak JL. Polycythemia Vera. Curr Treat Options Oncol 2018;19:12.
92.
Oz BS, Asgun F, Akay HT, Kaya E, Kuralay E, Tatar H. Anticoagulation after coronary artery
surgery in patients with polycythemia vera: report of two cases. J Card Surg 2007;22:420-2.
ACCEPTED MANUSCRIPT Page 38 93.
Smith BB, Nuttall GA, Pruthi RK, Joyce DL, Schuldes MS, Smith MM. A Novel Approach to
Essential Thrombocythemia and Cardiac Surgery. Ann Thorac Surg 2017;103:e249-e50. 94.
Rottenstreich A, Kleinstern G, Krichevsky S, Varon D, Lavie D, Kalish Y. Factors related to the
polycythemia vera. Eur J Intern Med 2017;41:49-54. 95.
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development of acquired von Willebrand syndrome in patients with essential thrombocythemia and
Osada H, Nakajima H, Meshii K, Ohnaka M. Acute coronary artery bypass graft failure in a
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patient with polycythemia vera. Asian Cardiovasc Thorac Ann 2016;24:175-7.
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Figure 1 – Perioperative management of the patients with cold agglutinins
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Disorders of Hemoglobin Hereditary Disorders of Hemoglobin Sickle cell disease Thalassemias Hemoglobin C Hemoglobin Zurich Acquired Disorders of Hemoglobin Carbon monoxide poisoning Methemoglobinemia
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Hereditary Hemolytic Anemias RBC membrane disorders Hereditary Spherocytosis Hereditary Elliptocytosis
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Hemolytic Anemias Acquired Hemolytic Anemias Autoimmune hemolytic anemia Cold agglutinin disease Paroxysmal nocturnal hemoglobinuria Paroxysmal cold hemoglobinuria
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RBC enzyme disorders Glucose-6-phosphate dehydrogenase deficiency Pyruvate Kinase deficiency
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Chronic Myeloproliferative Neoplasms: Polycythemia vera
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Table 1. Red blood cell disorders
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Table 2. Perioperative management of patients with sickle cell hemoglobinopathy
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Preoperative: Early, individualized, and multidisciplinary planning prior to cardiac surgery to determine need for transfusion or exchange transfusion Detailed history relating to hemolysis, transfusions, chronic pain, opioid tolerance Baseline laboratory analysis: blood type and antibody screen, hemoglobin level, hemoglobin electrophoresis to quantify Hgb S % Minimize NPO duration to ensure adequate hydration Continue preoperative hydroxyurea therapy (if currently taking)
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Intraoperative: Sickle Cell Trait Rarely requires special precautions Consider a similar strategy to sickle cell disease in patients with a higher HbS %, or those with a history of clinical manifestations related to sickle cell Sickle Cell Disease If not preformed preoperative, consider allogenic RBC transfusion vs. exchange transfusion via the CPB circuit, depending on HbS % Avoidance of hypoxia (hyperoxygenate pump prime) and acidosis Avoidance of hypothermia and cold cardioplegia whenever feasible Avoidance vasoconstrictors unless absolutely necessary Avoidance of cell-salvage systems Minimize CPB and aortic cross clamp times Ensure adequate multimodal analgesia
If significant hemolysis occurs: Mitigate causes for hemolysis Consider exchange transfusion Ensure adequate circulating volume and urine output Consider systemic or inhaled vasodilators if elevations in systemic or pulmonary vascular resistances (e.g. inhaled nitric oxide)
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Postoperative: Serial laboratory monitoring for hemolysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin, urinalysis (hemoglobinuria) Avoidance of hypoxia via necessary supplementation, and early/aggressive correction of acidosis Ensure adequate multimodal analgesia Abbreviations: HbS -- hemoglobin S, CPB -- cardiopulmonary bypass
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Table 3. Thalassemia severity & classification Severity
Genetic Disorder
RBC Analysis
Other findings
Inactivity of all α globin genes
Severe microcytic anemia
Hb Barts (Hb γ tetramer) Intrauterine death common
Severe microcytic anemia (Hb 3-4g/dL if untreated)
Begins after neonatal period Severe clinical manifestations
Hydrops Fetalis
β-Thalassemia Major Inactivity of both β (TD) globin genes
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Severe
Inactivity of 3 of 4 α globin genes
β-Thalassemia Intermedia (Often NTD)
Reduced activity of both β globin genes
Variable presentation Moderate microcytic anemia (Hb 8-11g/dL)
HbH (β globin tetramer) present
Variable presentation Moderate microcytic anemia (Hb 8-11g/dL)
HbF (2 α and 2 γ subunits) 50%
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HbH Disease (Variable TD)
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Moderate
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Mild
50% inactivity of α globin genes
Mild microcytic anemia
Hb Barts (3 to 8%)
Silent α Carrier
25% genetic inactivity α globin genes
Normal
None
Reduced or no activity of 1 of 2 β globin genes
Mild microcytic anemia
Increased HbF Limited clinical manifestations
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β-Thalassemia Minor (Trait)
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α-Thalassemia Minor
Abbreviations: Hb-hemoglobin, NTD – Non transfusion dependent, RBC—Red blood cell, TD – Transfusion dependent
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Table 4. Perioperative management of patients with hereditary spherocytosis
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Preoperative: Detailed history relating to hemolysis, transfusions, and prior treatments Baseline laboratory analysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin/hemopexin
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Intraoperative: Avoidance of hypothermia and cold cardioplegia Use of large diameter, short length, straight cannulas and tubing Avoid or minimize vacuum pressures in venous and suction cannulas If significant hemolysis: Mitigate causes for hemolysis Transition to autologous transfusion suction (cell saver) to allow removal of plasma free hemoglobin and intracellular components Assure adequate circulating volume, perfusion pressure, and urine output Consider vasodilators if elevations in systemic or pulmonary vascular resistances Consider continuous ultrafiltration through CPB hemoconcentrator “washing”
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Postoperative: Serial laboratory monitoring for hemolysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin, urinalysis (hemoglobinuria), and markers for renal and hepatic function
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*In vitro study only74
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Acetazolamide Ascorbic Acid Aspirin Bezodiazepines (diazepam, midazolam)* Amide local anesthetics (lidocaine, prilocaine) Fluroquinolones Gentamicin Diphendyramine Dopamine Metaclopramide Methylene Blue Nitric Oxide Nitrofurantoin Nitroglycerin Penicillin Sulfonamide antibiotics Vitamin K Volatile Anesthetics (isoflurane, sevoflurane)*
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Table 5. Drugs commonly used in cardiac surgery patients that risk hemolysis in G6PD deficiency72
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Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery Mark M. Smith MD , J. Ross Renew MD , James A. Nelson MBBS , David W. Barbara MD PII: DOI: Reference:
S1053-0770(18)30606-2 https://doi.org/10.1053/j.jvca.2018.08.001 YJCAN 4834
To appear in:
Journal of Cardiothoracic and Vascular Anesthesia
Received date:
26 April 2018
Please cite this article as: Mark M. Smith MD , J. Ross Renew MD , James A. Nelson MBBS , David W. Barbara MD , Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery, Journal of Cardiothoracic and Vascular Anesthesia (2018), doi: https://doi.org/10.1053/j.jvca.2018.08.001
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Red Blood Cell Disorders: Perioperative Considerations for Patients Undergoing Cardiac Surgery
J. Ross Renew, M.D. 2 James A. Nelson, M.B.B.S 1
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David W. Barbara, M.D. 1
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Mark M. Smith, M.D.1
1
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and
Science, Rochester, Minnesota, USA 2
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Word Count: 10,040
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Science, Jacksonville, Florida, USA
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Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and
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Corresponding author: Dr. Mark M. Smith
Department of Anesthesiology and Perioperative Medicine Mayo Clinic College of Medicine and Science 200 First Street SW, Rochester, MN 55905 USA
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Declarations of interest: none
Abstract
Disorders affecting red blood cells (RBC) are uncommon yet have many important physiologic
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considerations for patients undergoing cardiac surgery. RBC disorders can be categorized by those which are congenital or acquired, and further by disorders affecting the red blood cell membrane, hemoglobin, intracellular enzymes, or excessive RBC production. A foundational understanding of the physiologic derangement for these disorders is critical when considering perioperative implications and
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optimization, strategies for cardiopulmonary bypass, and the rapid recognition and treatment if complications occur. This review systematically outlines the RBC disorders of frequency and relevance
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with an emphasis on how the disorder impacts normal physiologic processes, a review of the literature
surgery.
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Word Count: 120
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related to the disorder, and the implications and recommendations for patients undergoing cardiac
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Keywords: RBC disorder, RBC dyscrasia, Cardiac Surgery, Cardiopulmonary Bypass
ACCEPTED MANUSCRIPT Page 3 Introduction Disorders affecting red blood cells (RBCs) are uncommon yet confer important perioperative implications for patient undergoing cardiac surgery. The RBC disorders can be categorized by those which are congenital or acquired, and further by disorders affecting the red blood cell membrane,
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hemoglobin, intracellular enzymes, or excessive RBC production (Table 1). Cardiac surgery presents physiologic stressors uncommon to other surgical specialties such as use of hypothermia and extracorporeal circulation which can have a profound impact in this patient population. An
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understanding of the physiologic derangement for these disorders is critical when considering
perioperative implications and optimization, strategies for cardiopulmonary bypass (CPB), and the rapid recognition and treatment should complications occur. While some disorders require minimal deviation from standard care, others necessitate precise changes in perioperative strategy to avoid or limit related
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complications. This review systematically outlines the RBC disorders of frequency and relevance with an emphasis on how the disorder impacts normal physiologic processes, a review of the literature related
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to the disorder, and the implications and recommendations for patients undergoing cardiac surgery.
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RBC overview
Erythrocytes or as they are commonly referred red blood cells (RBCs), are cellular components of blood
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produced within the bone marrow that function to deliver oxygen and buffer carbon dioxide throughout
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the body, and have a circulating life span of approximately 120 days. Congenital and acquired disorders that effect RBCs are not common; however, the frequencies are such that perioperative providers must be familiar with the physiologic implications. RBC cell membrane: Passage of RBCs through the microvasculature requires flexibility and reversible deformability which is a function of the interaction between the intracellular skeletal proteins (e.g. α/βspectrin) membrane proteins (e.g. ankyrin, protein 4.2, band 3), and the cell membrane lipid bilayer.1
ACCEPTED MANUSCRIPT Page 4 The result is an elastic biconcave disc-like RBC which maximizes surface area and has the flexibility to endure the necessary deformation and shear stress within the vascular tree. Hemoglobin: Hemoglobin is a metalloprotein within RBCs which functions to transport oxygen throughout the body. In addition, this iron-containing protein plays important roles in the removal of
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carbon dioxide and regulating homeostasis. The hemoglobin tetramer is composed of four globin chains attached to a heme moiety. During human development and continuing after birth there is a transition of hemoglobin chain types. From birth-6 months of age, fetal hemoglobin (α2γ2) predominates.
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Subsequently, adult hemoglobin (HbA) becomes the primary type (α2β2), with a smaller percentage (~2.5%) consisting of HbA2 (α2δ2). Each hemoglobin molecule can bind up to four oxygen molecules with increasing affinity, a property termed cooperative binding which is the result of a conformational changes. Factors which influence oxygen binding to hemoglobin include temperature, pH, 2,3-
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bisphosphoglycerate (2,3-BPG), and the partial pressure of carbon dioxide. An appreciation for the role of hemoglobin within the RBC is critical to understanding various pathologic states.
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RBC intracellular metabolism/enzymes: RBC metabolism is entirely dependent on anaerobic metabolism
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via glycolysis and the pentose phosphate pathway to produce adenosine triphosphate (ATP) for cellular processes, and reduced glutathione for oxidative free radical scavenging. Defects within the glycolytic or
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pentose phosphate pathway can lead to cellular damage and hemolysis.
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Disorders of Hemoglobin
Hereditary Disorders of Hemoglobin Sickle cell disease Sickle cell disease (SCD) is an autosomal recessive disorder that results from a mutation of the
globin
portion of hemoglobin. Patients with a single allele mutation (heterozygous genotype) possess sickle cell
ACCEPTED MANUSCRIPT Page 5 trait (SCT), affecting 1:13 African Americans without significantly altering life expectancy.2,3 The homozygous genotype (SCD) has an incidence of 1:365 African Americans, and results in a higher burden of sickle cell hemoglobin (HbS) than SCT (~80% vs ~40%, respectively) with a reduced life expectancy.2-4 While most common in African Americans, sickle cell disease can also be seen among Arabic
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populations, which may have a milder phenotype. In contrast to normal RBCs having a flexible biconcave disc structure, RBCs rich with HbS become rigid/sickle-shaped leading to microvascular occlusions and inflammation of the vascular endothelium. Such “sickling crises” are triggered by changes in
temperature, stress, hypovolemia, infection, hypoxia, vasoconstrictors, and acidosis.5 Sickling crises can
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manifest as acute chest syndrome, a complex pathophysiologic state with components of infection, infarction, and embolic events. Such crises may also manifest with painful vaso-occlusive events resulting in tissue ischemia. Acute chest syndrome may be difficult to discern from acute coronary syndrome as symptoms may be similar.6 While SCD itself is not known increase risk of early coronary
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artery disease, acute coronary syndrome should remain in the chest pain differential diagnosis for this
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population. Other complications include splenic sequestration and subsequent infarction, hemolytic anemia, gallstones, pulmonary hypertension, priapism, early arthritis, and a variety of neurologic
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deficits. Patients with functional asplenia are at risk for infection and should receive proper
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perioperative antibiotic prophylaxis. As mentioned previously, patients with SCD have shortened life expectancies. As such, when
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they present for cardiac surgery, it is often for correction of coexisting congenital cardiac conditions, valve replacements related to endocarditis, or rheumatic lesions. In contrast, patients with SCT have a normal life expectancy and thus their surgical history often mirrors that of the general population. Patients with SCD presenting for cardiac surgery may be at a slightly higher risk of perioperative complications with prior studies citing an incidence of postoperative hemorrhage ~6%, stroke ~4%, and postoperative renal failure ~4%.7
ACCEPTED MANUSCRIPT Page 6 While considering the known triggers of sickling crises, cardiac surgery can be problematic for patients with SCD. The literature describing the perioperative care of this population undergoing cardiac surgery consists of case reports 8-10, case series 11,12, and small retrospective studies. 7,13 A focal point in avoiding morbidity in patients with SCD undergoing cardiac surgery relates to proper
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blood management. Historically, efforts were made to reduce HbS to <30% or perhaps even as low as <10% prior to cardiac surgery.14,15 This is accomplished by red blood cell administration that raises the amount of HbA and decreases the proportion of HbS, or via exchange transfusion (i.e. replacing the patients’ blood with allogenic blood). During exchange transfusions, some clinicians have also
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performed platelet and plasma apheresis on the removed autologous blood and returned the non-RBC blood fraction back to the patient.16 Modifications to cardiopulmonary bypass circuits can be made to facilitate intraoperative exchange transfusion.17,18 When performing an intraoperative exchange transfusion, the CPB circuit should be primed with allogeneic RBCs and plasma. The volume of RBCs
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necessary can be determined by estimating the patient’s blood volume and calculating the proportion of
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patient’s circulating volume that clinicians wish to replace. The proportion of the patient’s blood volume that is exchanged varies based on the HbS burden. Isotonic crystalloid and colloid can also be
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added to adjust the hematocrit of this volume. After cannulation, a Y-connector is added to the venous line to enable the perfusionist to drain and sequester the desired volume of the patient’s whole
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blood. The hyperoxygenated prime volume comprised of allogeneic blood products is then transfused through the arterial cannula while the patient’s blood is drained into a reservoir. After the venous
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cannula has drained the desired volume of the patient’s blood, the venous cannula draining into the collection reservoir is clamped at the Y-connection and the bypass circuit resumes its traditional configuration. This sequestered blood can be separated into components via intraoperative autotransfusion techniques. After the RBCs have been separated and discarded, the remaining plasma and platelet rich solution can be returned to the patient after cessation of cardiopulmonary bypass.18
ACCEPTED MANUSCRIPT Page 7 Recent data suggests that avoiding anemia and transfusing allogenic RBCs to a target hemoglobin > than 10 g/dL without consideration for the proportion of circulating HbS may be equally efficacious in avoiding complications from SCD during major surgery .19,20 Both preoperative exchange transfusion and allogenic transfusion to a hemoglobin > than 10 g/dL are superior to no preoperative transfusion in
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reducing the risk of perioperative SCD complications in non-cardiac surgery.21,22 Compared to patients undergoing preoperative exchange transfusion, those targeted to a preoperative hemoglobin > 10 g/dL receive fewer transfusions and experience fewer transfusion reactions.20,22 There are no societal
transfusion guidelines for SCD patients undergoing cardiac surgery. Exchange transfusion remains the
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more commonly employed strategy in this population (targeting HbS <30% or perhaps <10%), yet quality prospective research supporting this practice over more conservative RBC transfusion targets (Hb >10 g/dL) in cardiac surgery is lacking.15 Ultimately, these patients warrant early, individualized, and
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multidisciplinary planning prior to cardiac surgery.
In contrast to patients with SCD, patients with SCT may not require exchange transfusion. Djaiani et
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al reported successful management of patients with sickle cell trait undergoing coronary artery bypass grafting without exchange transfusion. This review of 10 patients revealed successful application of ‘fast
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track’ anesthesia techniques, although there was one death in this small sample.13 Prior studies have
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used a hemoglobin trigger as low as 7.5 g/dL, in this population without complications; however, a slightly more liberal target may be reasonable, yet, evidence supporting a specific target is
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lacking.13,23 Some experts suggest that sickle cell hemoglobinopathy should be approached as a spectrum disease with SCT and SCD serving as the two extremes.24 Indeed, autopsy studies have revealed similar pathologic characteristics in both sickle cell disease and trait.25 Similarly, patients with sickle cell trait have laboratory values suggestive of hypercoagulable states including elevated D-dimers, thrombin-antithrombin complexes, and prothrombin fragments.26
ACCEPTED MANUSCRIPT Page 8 The use of CPB routinely involves controlled hypothermia. Such temperatures can cause vasoconstriction and potentially trigger sickling crises. Core temperatures as low as 18°C have been reported in 2 SCD patients undergoing pulmonary artery thromboendarterectomy via deep hypothermic circulatory arrest. 27 The authors utilized complete exchange transfusion and avoided other potential
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triggers to obtain a successful result. There are no cases detailing the use of deep hypothermic
circulatory arrest in SCT patients, thus evidence to support or contradict exchange transfusion as was performed in the SCD patients is lacking and must be considered on a case by case basis. Experienced centers report successful results while utilizing mild hypothermia (>32°C) in patients with both
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SCT/SCD.7,13,19 While varying degrees of hypothermia on CPB have been successfully described in these populations, efforts to maintain normothermia should be made when feasible. Several cardioplegia solutions have also been used with success, such as tepid blood cardioplegia16as well as cold crystalloid
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based solutions.7,13
Additional strategies to mitigate risk of sickling include hyperoxygenating pump prime solution in an
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effort to ensure the transition to CPB avoids transient hypoxia. Sickling can occur at arterial oxygen saturations < 85%, thus careful attention should be paid to the oxygenator FiO2 with aggressive
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correction of hypoxia if present.28 The utilization of clinical markers such as mixed venous saturation
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can help providers ensure adequate tissue perfusion. In contrast to SCD, SCT cells do not, in the absence of stasis, begin to sickle until saturations are 40%. Pain management can be challenging as patients with
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SCD and a history of painful occlusive events can present on chronic opioid medications with opioid tolerance, complicating perioperative analgesia. Pain and anxiety are known triggers sickling crises, thus an adequate perioperative analgesic strategy is important. The use of multimodal analgesia pathways and the anticipation and preparation for opioid tolerance in chronic pain patients is critical toward blunting the physiologic stress response to pain that can cause vasoconstriction and subsequent sickling crises. The use of cell-salvage systems in SCD patients is not recommended as the negative pressure
ACCEPTED MANUSCRIPT Page 9 suction in addition to the washing and re-transfusion process may risk sickling/hemolysis.15,28 Table 2 summarizes the perioperative management for patients with SCT and SCD undergoing cardiac surgery.
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Thalassemia The thalassemias are a group of disorders characterized by a defect in one or more of the genes
encoded to produce globin proteins leading to a change in the ratio of α to β globin production. This leads to the precipitation of abnormal globin tetramers within RBCs, and destruction of red cell
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precursors leading to extramedullary hematopoiesis and resulting manifestations.
Thalassemia can be defined by phenotype (thalassemia major, intermedia, or minor), transfusion dependence, or by the underlying genetic mutation. Phenotypic severity is related to the number and type of α or β globin gene disorders present. Transfusion dependence leads to secondary
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complications related to frequent transfusions and iron overload. Like SCD, thalassemia is more
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common in patients of Asian and African descent and from the Mediterranean Region 29 Clinical manifestations present across a spectrum from hydrops fetalis and intrauterine death in
and -thalassemia .30 Frequency and severity of clinical manifestations are related to anemia
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both
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the case of the most severe form of -thalassemia, to asymptomatic carrier states in minor forms of
with subsequent extramedullary hematopoiesis and iron overload. Table 3 classifies
-
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thalassemias in descending order of severity. Survival in this population has improved with the adoption of revised transfusion goals,
combined with oral and parenteral iron chelation therapy. 31-34 In select patients, bone marrow transplant is a viable therapeutic and potentially curative option. 35 In spite of these advances, cardiovascular disease is common and the leading cause of mortality.32 Cardiomyopathy (CM) is the
ACCEPTED MANUSCRIPT Page 10 most common cardiac manifestation and is either a dilated CM with resulting systolic dysfunction, or a restrictive CM with diastolic dysfunction, pulmonary hypertension, and subsequent right heart failure.36 Pulmonary arterial hypertension can occur independently in moderate to severe forms of thalassemia with several series indicating a rate of 60-75% in patients with thalassemia intermedia and major.37
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Valvular heart disease is being recognized with increased frequency in thalassemia patients. Additionally, early onset coronary artery disease, peripheral vascular disease and stroke can all occur with acquired elastic tissue deficiency and endothelial dysfunction playing a role. 38,39 Atrial fibrillation and other conduction abnormalities can result from cardiac iron infiltration due to repeated transfusions
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in addition to the usual causes.40,41 Crainofacial deformities, endocrinopathies, renal tubular dysfunction, and thrombotic complications are also seen in thalassemia patients along with other less common manifestations.
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Management of thalassemia patients undergoing non-cardiac surgery has been detailed in other reviews, emphasizing the importance of a thorough airway exam, optimization of systemic co-
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morbidities, hemodynamic stability, and maintaining adequate hemoglobin levels.42 Drugs known to risk
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hemolysis via increases in oxidative stress in patients with thalassemia include aspirin, penicillin, prilocaine, sodium nitroprusside, sulfonamides, and vitamin K.15
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The literature describing patients with significant thalassemia undergoing cardiac surgery is
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limited.43-46 Perioperative concerns in this population, aside from the cardiac pathology for which they present, include anemia, susceptibility of thalassemia RBCs to hemolysis during CPB, and balancing the risks of bleeding and thrombotic complications. Studies evaluating the ideal preoperative hemoglobin or the extent of hemolysis in patients with significant thalassemia undergoing cardiac surgery are lacking. It is accepted that in patients with thalassemia hemoglobin, oxygen carrying capacity is decreased and risk for hemolysis increased, highlighting the importance of adequate hemoglobin concentration and
ACCEPTED MANUSCRIPT Page 11 oxygen saturation . Prior case reports in cardiac surgery have described transfusion to a hemoglobin concentration between 9 -9.5 g/dL preoperatively, which was near patients’ baseline. 39,43 A study by Cokkinou et al. showed increased hemolysis in patients with thalassemia trait (beta thalassemia minor) after CPB but concluded the level of hemolysis may not be clinically significant. 47 The extent of
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hemolysis in more severe forms of thalassemia is unclear; however, with a larger amount of thalassemia hemoglobin, a greater level of hemolysis is expected. A perioperative strategy for patients at risk for significant hemolysis is detailed later in this review (hereditary spherocytosis section). In scenarios of significant acute hemolysis and also less severe chronic hemolysis, haptoglobin levels may become
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depleted. Intravenous haptoglobin administration has been described in a patient undergoing cardiac surgery with a history of beta-thalassemia.48 Additionaly, Tanaka et al. describe haptoglobin administration in patients without RBC disorders who had a free haptoglobin level of 0 mg/dl and a plasma free hemoglobin (PfHb) > 30mg/dl.49 N-Acetyl-Dpglucosainidase index was used as a marker of
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renal tubular injury which improved after haptoglobin administration in association with a decreased
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PfHb. In spite of these potential benefits, no study has shown an improvement in usual clinical outcomes with the use of haptoglobin or defined the appropriate PfHb threshold in which haptoglobin
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should be administered in patients with RBC disorders undergoing CPB. Therefore, use of haptoglobin in this population remains experimental. Prior authors anticipating significant hemolysis in patients with
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thalassemia have also described continuous ultrafiltration through a hemoconcentrator (sieving
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diameter 65,000 Dalton) to assist in the removal of PfHb (32,000 Daltons). 50 Thalassemia intermedia and major have both been associated with anti-thrombin III (AT III)
deficiency.51,52 This likely occurs through a consumptive process as a result of a chronic hypercoagulable state, and may be more common in patients with prior splenectomy and those who are transfusion dependent.52 Providers should anticipate heparin resistance in this population, and replace AT III when indicated .51 In the immediate postoperative period, bleeding complications are likely more common
ACCEPTED MANUSCRIPT Page 12 than thrombosis, particularly in patients with advanced liver disease and portal hypertension/ venous congestion. The benefit of antifibrinolytic therapy must be weighed against the risk of thrombosis on a case by case basis. There have been no reports of early postoperative thrombosis, although to date no trials have addressed this question. Late thrombosis has been reported of bioprosthetic and mechanical
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valves despite therapeutic anticoagulation. 44-46 The risk of hemolysis and thrombotic complications may be higher in patients receiving mechanical valves, yet data supporting valve replacement type is sparse.39
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Hemoglobin C
Hemoglobin C (HbC) is a variant of normal HbA in which lysine and glutamic acid are substituted within -globin chain. Patients heterozygous for the hemoglobin C mutation, (hemoglobin C trait) have no clinical manifestations. HbC predominates in homozygous patients leading to rigid RBCs, mild hemolytic
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anemia and splenomegaly. Clinical symptoms are mild unless the HbC mutation is coupled with a HbS mutation resulting in HbSC. 53 To date no clinical studies have been published to suggest alterations in
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perioperative management. Patients with HbSC should be treated similar to SCD.
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Hemoglobin Zurich
Hemoglobin Zurich (HbZ) is an unstable hemoglobin variant due to a mutation
-globin chain.
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The unstable hemoglobin becomes denatured and precipitates due to an expedited auto-oxidation of
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heme iron, creating methemoglobin, upon exposure to eliciting factors (e.g. oxidant drugs).54 Minimizing hemolysis by avoidance of oxidant drugs, and use drugs with anti-oxidant properties has been advocated in the single case report describing a patient with HbZ undergoing cardiac surgery.54 Drugs with oxidant properties that should be avoided in patients with unstable hemoglobins include: aspirin, prilocaine, penicillin, sodium nitroprusside, sulfonamides, and vitamin K.54 Some drugs with anti-oxidant properties commonly used in cardiac surgical patients include: dopamine, dobutamine, epinephrine,
ACCEPTED MANUSCRIPT Page 13 isoproterenol, norepinephrine, and propofol, among others with slightly less antioxidant properties.54Avoidance of oxidant drugs, use of anti-oxidant drugs (when clinically warranted), and minimizing extremes of pH (slight acidosis preferred over alkalosis) and elevations of temperature will help minimize hemolytic complications in this population. Bernard et al. also describe the preoperative
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use of the antioxidant α-tocopherol (vitamin E) , however, the benefit of this therapy is unknown.54 The diagnosis and treatment of significant hemolysis are covered elsewhere within this review. Acquired Disorders of Hemoglobin
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Carbon monoxide poisoning
Hemoglobinopathy resulting from carbon monoxide (CO) poisoning has been extensively described. 55 CO is a colorless, tasteless, and odorless gas that binds hemoglobin with much greater affinity than oxygen to form carboxyhemoglobin (COHb), thereby inhibiting oxygen binding and transport. Symptoms
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include malaise, vertigo, headache, nausea, and vomiting. In severe cases (CO levels typically >20-25%)
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coma, seizures, lactic acidosis, myocardial ischemia, cardiac dysrhythmias, and death may ensue. The clinical diagnosis of CO poisoning is confirmed with multi-wavelength pulse co-oximetry or arterial blood
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gas COHb measurement. The mainstay of treatment following removal of the CO source is 100% oxygen administration, which decreases the half-life of COHb 3-4 fold. Hyperbaric oxygen is typically reserved
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for more severe cases and can further shorten the half-life of COHb 10-20 fold. Both venoarterial and venovenous extracorporeal membrane oxygenation (ECMO) has been used in cases of severe
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cardiopulmonary instability. 56 Use of ECMO in this patient population is limited to case reports and rigorous data on long term outcomes is hence lacking. Interestingly, cardiopulmonary bypass has been shown to be associated with increased endogenous CO production resulting from heme degradation via oxidase enzymes, although the resultant CO increase remains well below toxic levels. 57 While toxic levels of COHb during CPB are rare,
ACCEPTED MANUSCRIPT Page 14 should CO toxicity occur while on CPB (or ECMO), treatment with 100% oxygen via both extracorporeal circulation and the ventilator (if in use) is warranted. Methemoglobinemia
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Methemoglobinemia can be congenital or, more commonly, acquired and results from oxidation of heme’s normal ferrous (Fe2+) state to the ferric (Fe3+) state.58 This results in an inability of ferric heme to bind oxygen, causing an increased affinity of remaining normal ferrous heme for oxygen. The resultant left-shifted oxygen-hemoglobin dissociation curve impairs oxygen delivery. Methemoglobinemia has
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been previously reviewed in detail, and only a brief overview of acquired methemoglobinemia will follow.58 Normal methemoglobin levels are < 1-2% and can be measured with multi-wavelength pulse co-oximetry or arterial blood gas testing. The presence of methemoglobin interferes with standard pulse oximetry and thus monitoring arterial blood gas sampling with co-oximetry may be necessary to obtain
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accurate gas measurements. Acquired methemoglobinemia most commonly results from various drugs (e.g. local anesthetics, nitroglycerin, inhaled nitric oxide, dapsone, sulfonamides, and quinolones) or
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other ingested substances. With severe methemoglobinemia, the mechanism for reducing
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methemoglobin to hemoglobin via the nicotine adenine dinucleotide (NADH) methemoglobin reductase is overwhelmed and toxic levels of methemoglobin result. Methemoglobinemia (typically >20%) can
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cause cyanosis, dark discoloration of the blood, headache, fatigue, vertigo, dyspnea, altered mental status, coma, dysrhythmias, seizures, or death. Following discontinuation of the causative agent,
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treatment consists of oxygen and methylene blue administration (typically 1 mg/kg). Methylene blue functions by reducing methemoglobin to normal hemoglobin. If the response to a single dose of methylene blue is not adequate, repeat dosing may be required. Additionally, transfusions, exchange transfusions, sodium ascorbate, and hyperbaric oxygen therapy may be used in severe
ACCEPTED MANUSCRIPT Page 15 methemoglobinemia cases or if methylene blue is contraindicated (glucose-6-phosphate dehydrogenase deficiency). Reports of methemoglobinemia diagnosed during CPB are rare.59,60 If present, improvement or
satisfactory hemodynamics and end-organ perfusion is prudent.
Hemolytic Anemias
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Acquired Hemolytic Anemias
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resolution of severe methemoglobinemia prior to weaning CPB to ensure the patient is able to maintain
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) has an incidence of 1-3:100,000 and results from the reaction of antibodies with antigens on RBC and can be divided into two types: warm and cold AIHA. 61 Warm AIHA
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involves the presence of IgG warm agglutinins (i.e. autoantibodies) that are active at normal body
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temperature and develop from a variety of causes including autoimmune, idiopathic, medications, malignancies, post-infection , post-transplantation, or following allogeneic blood transfusion. 61,62 IgG-
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bound RBCs are destroyed by hemolysis or phagocytosis. Signs and symptoms depend on the degree of anemia and include pallor, jaundice, splenomegaly, fatigability, tachycardia, narrow pulse pressure,
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tachypnea, lethargy, confusion, dysrhythmias, and death. Diagnostic testing may include complete blood count, direct antiglobulin test (typically positive), indirect antiglobulin test (typically negative),
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peripheral blood smear (spherocytes can be seen), bilirubin, haptoglobin, and lactate dehydrogenase to assess the degree of hemolysis. Treatment of warm AIHA aims to decrease both antibody titers and activity. 62 Antibody production is most commonly mitigated with glucocorticoids and secondarily with drugs such as rituximab, danzol, or immunosuppressants. Intravenous immunoglobulin and splenectomy are other
ACCEPTED MANUSCRIPT Page 16 therapies that can diminish hemolysis. 61,62 In patients with symptomatic anemia requiring transfusions, compatibility testing of allogeneic RBCs can be confounded by the reactive warm autoantibody. 63 Blood bank techniques such as adsorption testing and extended RBC phenotyping may improve the ability to
perform and may not be possible in emergent settings.
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select appropriate allogeneic RBCs for transfusion; however, these tests require additional time to
The literature detailing cardiac surgery with CPB in patients with warm AIHA is limited to a single case report. In this report, the patient was treated with corticosteroids for > 2 months, and underwent autologous blood donation prior to an uncomplicated CABG operation.64 In a survey of cardiac
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anesthesiologists, warm AIHA was less commonly encountered than cold AIHA during cardiac surgery. 65 Shah et al. conclude “there is therefore no benefit in altering the conduct of cardiopulmonary bypass;” however, the authors recommend preoperative hematology consultation.65 In addition to ensuring
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preoperative optimization of warm AIHA antibody titer and activity with hematology consultation, anesthesiologists should seek early involvement of the blood bank to allow for testing and selection of
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Cold agglutinin disease
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suitable allogeneic RBC units.
Although cold agglutinins (i.e. cold autoantibodies) are less common than warm autoantibodies, much
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more has been published on this disease in the context of cardiac surgery and CPB. Cold agglutinins are IgM autoantibodies that are normally present in nearly all patients but are rarely clinically significant
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because they do not react at normal blood temperatures. 66 It follows that “benign” cold agglutinins must be differentiated from cold agglutinin disease and resulting cold AIHA from the latter. Patients with benign cold agglutinins do not experience hemolytic anemia or other symptoms related to the presence of these autoantibodies, while patients with cold agglutinin disease have autoantibodies that are active at cooler temperatures achieved in the peripheral circulation. On exposure to cold
ACCEPTED MANUSCRIPT Page 17 temperatures, cold agglutinins bind the patient’s RBC causing RBC agglutination and fixation of complement. This manifests clinically at colder temperatures as hemolysis, anemia, acrocyanosis, Raynaud’s phenomenon, or livedo reticularis. Even after rewarming, complement remains fixed on the RBC and hemolysis may continue. These pathologic cold autoantibodies are typically not active at
66,67
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temperatures exceeding 30°C, but cases describing activity at higher temperatures have been reported. Cold agglutinin disease (i.e. cold AIHA) represents 15-30% of all hemolytic anemias and has a
prevalence of 10-15 per million people. 67 The cold agglutinins causing this disease state may be primary in nature or secondary to other conditions such as malignancy (e.g. lymphoma), infection, or
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autoimmune disease.
The diagnosis is confirmed with laboratory testing that includes cold agglutinin antibody titer (which confirms the presence of and quantifies the amount of autoantibodies present), thermal
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amplitude (which quantifies the highest temperature at which agglutination is observed in vitro), and
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hemolysis testing (hemoglobin, direct antibody testing, lactate dehydrogenase, haptoglobin, free plasma hemoglobin, bilirubin, etc.). 66 Treatment is typically aimed at reduction or elimination of cold
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agglutinins and consists of medical treatments such as glucocorticoids, intravenous immunoglobulin, chemotherapy (e.g. rituximab, cyclophosphamide), treating the underlying cause (e.g. infection), and
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plasma exchange.
CPB and cardioplegia commonly result in temperatures at which cold agglutinin-related
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hemolysis or agglutination may occur, with hemolysis and myocardial dysfunction having been reported perioperatively. 66-69 In patients without known cold agglutinin disease prior to cardiac surgery, preoperative RBC type and screening may incidentally demonstrate the presence of cold agglutinins. Additionally, case reports exist of cold agglutination occurring in the CPB machine after initiation of cooling in a patient without known prior cold agglutinins.69 Various reports of patients with both benign
ACCEPTED MANUSCRIPT Page 18 agglutinins and cold agglutinin disease undergoing cardiac surgery with CPB exist, with varying management strategies related to the cold agglutinins. 66-69 We recommend approaching the patient with cold agglutinins requiring cardiac surgery in a systematic fashion based on their cold agglutininrelated symptomatology and the type of cardiac surgery planned (Figure 1). Should cold agglutinin
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disease be diagnosed or suspected without time for the aforementioned preoperative testing and
treatment, normothermic CPB at 37°C and either avoidance of cardioplegia or use of tepid cardioplegia to mitigate further sequelae of the cold agglutinins should be utilized. 66-68
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Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease affecting 1-10 per million people.70 PNH results from a hematopoietic stem cell mutation on the X chromosome that ultimately affects the glycosylphosphatidylinositol RBC surface anchor resulting in complement-mediated hemolysis and
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venous thrombosis, the latter of which is poorly understood. Clinical findings include anemia, fatigue, jaundice, headache, hemoglobinuria, thrombosis, dyspnea, abdominal pain, erectile dysfunction, acute
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or chronic kidney injury, chest pain, esophageal spasm, and cytopenias from bone marrow suppression.
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The “nocturnal” nomenclature of PNH is derived from the predominance of hemoglobinuria with concentrated urine such as occurs with micturition during or immediately following the night; however,
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hemolysis, hemoglobinuria, etc. are not temporarily limited to nocturnal hours. Laboratory studies to confirm the diagnosis include complete blood count, peripheral blood smear, haptoglobin, lactate
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dehydrogenase, bilirubin, plasma free hemoglobin, direct antiglobulin test, urinalysis, bone marrow biopsy, and flow cytometry. In addition to RBC transfusion if required, mainstays of PNH treatment include anticoagulation in cases of thrombosis, eculizumab, and allogeneic stem cell transplantation in severe cases.
ACCEPTED MANUSCRIPT Page 19 Patients with PNH undergoing CPB may experience complement activation and associated hemolysis, and literature on this patient population in the context of CPB is limited to case reports.71,72 The evidence is hence very restricted regarding optimal perioperative management. When feasible, preoperative hematology consultation is indicated to optimally treat PNH prior to cardiac surgery.
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Transfusion with leukocyte-reduced group-specific RBC is recommended, given the potential for allogeneic leukocytes to trigger hemolysis in patients with PNH.71,73 Some authors recommend
prophylactic RBC transfusions to decrease the fraction of abnormal RBCs predisposed to hemolysis. 71,72 Finally, perioperative avoidance of hypoxemia, hypercarbia, acidosis, and infections may help mitigate
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precipitants for thromboses in patients with PNH. Paroxysmal cold hemoglobinuria
While similar to the other cold hemolytic anemias, paroxysmal cold hemoglobinuria (PCH) is distinct in
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that patients have presence of the potent hemolysin Donath-Landsteiner antibodys.74 Patients with PCH can experience massive hemolysis and hence hemoglobinuria upon exposure to cold temperatures. In
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contrast to cold agglutinin disease which is an IgM autoantibody mediated process, PCH is due to an Ig-G
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autoantibody (Donath-Landsteiner antibody) which is a hemolysin rather than a RBC agglutinin.74 With the prevalence of PCH (1.7% of all adult AIHA) being much lower than both cold agglutinin disease and
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paroxysmal nocturnal hemoglobinuria, the literature detailing management of this population undergoing cardiac surgery is limited to a single case report.74 In this report of a patient requiring mitral
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valve replacement, the authors describe a technique of warm (37oC) CPB, and avoidance of topical cardiac cooling, however, did use cold cardioplegia. The authors do mention that the use of fibrillatory arrest in lieu of cardioplegia can be considered. The case and postoperative period were uneventful for hemolysis or related complications.74
ACCEPTED MANUSCRIPT Page 20 Preoperative hemolysis testing (hemoglobin, direct antibody testing, lactate dehydrogenase, haptoglobin, free plasma hemoglobin, bilirubin, etc.) mirrors that of other hemolytic anemias and gauges the level of chronic hemolysis in this population. Similar to cold agglutinin disease, thermal amplitude testing can be performed to quantify the highest temperature at which hemolysis is observed
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in vitro. While the evidence related to the perioperative management for cardiac surgery in this population is lacking, a strategy similar to that advocated for cold agglutinin disease with early
preoperative testing, hematology consultation, treatment (if necessary), operative technique planning,
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and avoidance of hypothermia whenever feasible is warranted. Hereditary Hemolytic Anemia: RBC membrane disorders Hereditary Spherocytosis
Hereditary spherocytosis (HS) is a red blood cell disorder which results in spheroid shaped erythrocytes
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with abnormally rigid cell membranes. With an incidence of around 1:2000 amongst those of northern
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European ancestry, HS is the most common chronic hemolytic anemia.75 Inheritance of HS is autosomal dominant for two-thirds of patients and autosomal recessive or de novo in remaining patients. 75
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Deficiencies in RBC membrane proteins such spectrin, ankyrin, band 3 protein, protein 4.2, or Rhcomplexes, lead to rigid-spherical shaped erythrocytes with impaired deformability and loss of surface
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area. The dysfunctional “spherocytes” become trapped and destroyed within the spleen. Clinical
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severity varies from mild to severe, with the latter possibly requiring splenectomy to reduce or eliminate hemolysis. Patients who have undergone splenectomy are at risk for ischemic/thrombotic complications as the dysfunctional spherocytes are no longer removed and can lead to microvascular occlusions in addition to the infectious complications associated with asplenia.75,76 The literature describing HS and cardiac surgery is sparse. A recent case report and literature review by Hargrave et al. describes in depth the important perioperative considerations for patients
ACCEPTED MANUSCRIPT Page 21 with HS undergoing cardiac surgery.76 Preoperative assessment of patients with HS includes a detailed history of clinical severity, along with current and/or prior therapy and transfusion requirements. A baseline laboratory evaluation to serve as reference for when evaluating for hemolysis should be performed (Table 4).
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Cardiac surgery particularly with the use of CPB in patients with HS risks hemolysis and
associated complications, as the rigid yet fragile erythrocytes are susceptible to the physiologic
derangements common during these procedures. Shear stress, turbulence, alterations in oncotic
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pressure, and hypothermia are all known to risk hemolysis in HS, therefore, proper actions to limit or avoid erythrocyte trauma should be taken. Reducing alterations in the oncotic pressure balance on the erythrocyte can be achieved by limiting the hemodilution that occurs with CPB crystalloid pump prime. The use of retrograde autologous priming should be considered whenever possible, and the addition of
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albumin to the pump prime solution may help assimilate the osmotic balance.76 The shear stress and turbulence within the CPB circuit can be reduced with the use of large
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diameter, reduced length, straight tip cannulas and tubing. Pressure gradients between the aortic inflow
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cannula and systemic pressure should be kept ideally <100 mmHg. There is insufficient evidence to suggest use of non-occlussive roller pumps vs. centrifugal pumps. The use of vacuum-assisted venous
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drainage can increase shear stress and turbulence, thus if use is necessary, negative pressures should be kept to a minimum with an absolute cutoff of -80mmHg.76 Minimizing suction cannula negative
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pressures and avoiding small tip suction orifices can also reduce the risk of hemolysis. The use of intraoperative autologous transfusion (i.e. cell-saver) appears safe for patients with HS. If hemolysis is suspected, the cell saver suction should be used in favor of the cardiotomy suction as the former allows removal of the plasma free hemoglobin (PfHb) and intracellular components. While mild hypothermia and cold solution cardioplegia are commonly used in cardiac surgery, both are known to increase the
ACCEPTED MANUSCRIPT Page 22 risk for hemolysis in patients with HS. Use of normothermic CPB, and tepid cardioplegia should be considered and used whenever possible in this population.76 Prior authors comment that in patients with HS requiring valve replacement, valve type (biologic vs. mechanical) should be taken into consideration as the mechanical valves may risk hemolysis,
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however, there is insufficient data to make firm recommendations.76,77 A single case report exists of a patient with HS undergoing successful LVAD insertion (HeartWare) as a bridge to cardiac transplantation without clinically relevant hemolysis.78
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Despite proper precautions, patients with HS are still at risk for perioperative hemolysis. Prompt diagnosis and treatment are vitally important to limit associated complications. With progressive hemolysis and the resultant anemia, tissue oxygen delivery can become critically impaired. Hemolysis leads to the release of PfHb into the circulation which under normal circumstances is scavenged without
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incident. However, in massive hemolysis these scavenging mechanisms (e.g. haptoglobin) become overwhelmed which can lead to PfHb associated microvascular occlusions. This PfHb is a nitric oxide
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scavenger which can increase systemic and pulmonary vascular resistance and alter platelet function.
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Treatment with sodium nitroprusside and/or inhaled nitric oxide to combat increases in vascular resistances may help reduce further hemolysis/PfHb release.79 Laboratory findings consistent with
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hemolysis include anemia, elevations of PfHb, lactate dehydrogenase, bilirubin, and decreased levels of
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haptoglobin.
The management of hemolysis includes identification and reversal of causative insults.
Transfusion is indicated if anemia risks inadequate oxygen carrying capacity. With large amounts of PfHb, pigment deposits within the renal tubules risk acute renal failure. Assuring adequate volume resuscitation, renal perfusion, and urine output is critical. Use of sodium bicarbonate infusions are common in this scenario, however, evidence to support this practice in lieu of isotonic crystalloids such
ACCEPTED MANUSCRIPT Page 23 as normal saline is lacking.80 Mannitol is also described in this setting and may act as a free radical scavenger; however, avoidance of diuresis induced hypovolemia is important. Loop-diuretics should be reserved for patients who have failed the aforementioned therapies, have adequate circulating volume and perfusion indices, yet remain oliguric or anuric with concern for volume overload. As previously
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mentioned, prior authors anticipating significant hemolysis in a thalassemia patient described
ultrafiltration through a hemoconcentrator (sieving diameter 65,000 Dalton) to assist with removal of PfHb (32,000 Daltons). 50 The efficacy of this technique is unknown.
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Patients remain at risk for hemolysis into the postoperative period, and should be monitored with serial laboratory analyses to assess for hemolysis and end organ function (Table 4.) Hereditary Elliptocytosis
Hereditary elliptocytosis (HE) is an autosomal dominant disorder most common in malaria endemic
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areas with a regional prevalence of 2%.1 The spectrum of clinical severity ranges from asymptomatic
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carriers to severe anemia, with 10% of patients suffering from the later.1 In HE, alterations in spectrin and less commonly protein 4.1 are responsible for the defects in skeletal membrane
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stability.1 The result is the formation of elliptocytes, which have reduced surface area and increased susceptibility to fragmentation with eventual sequestration and destruction within the spleen.1 The
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literature detailing patients with HE undergoing cardiac surgery is limited to 2 patients, for which
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perioperative details were lacking.44 These patients are still at risk for hemolysis due to defective RBCs that lack elasticity and deformability. Avoidance of factors known to increase risk of shear stress and turbulence as was detailed in the management of hereditary spherocytosis seems reasonable (Table 4). Hereditary Hemolytic Anemia: RBC enzyme disorders Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
ACCEPTED MANUSCRIPT Page 24 In healthy patients, the enzyme glucose-6-phosphate dehydrogenase (G6PD) functions within the pentose phosphate pathway to convert glucose-6-phospate into 6-phosphogluconate, reducing nicotinamide adenine dinucleotide phosphate (NADPH) and replenishing glutathione, a reactive oxidative species scavenger.81 As the most common RBC enzymopathy (affecting 400 million people
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worldwide), G6PD-deficiency, known as “favism”, has a higher prevalence within malarial endemic regions as it is protective against severe infection. 82 The gene for G6PD is located on the X-
chromosome, thus G6PD is more common among males, particularly those of African descent.81 In patients with G6PD deficiency, NAPDH and glutathione become depleted allowing oxidative damage to
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hemoglobin and the RBC membrane risking hemolysis.82
Disease severity is classified (Class I-V) via the World Health Organization by percent of enzyme activity ranging from severe disease (Class I) with activity <10% to a non-deficient variant with normal or
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increased enzyme activity (Class V).23,82 Patients with G6PD deficiency are usually asymptomatic at baseline and only experience hemolysis and jaundice with triggered oxidative stressors or exposures
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(e.g. fava bean ingestion, infection, medication).
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Diagnostic findings on peripheral smear may include anisocytosis, poikilocytosis, bite cells, and Heinz bodies. During a hemolytic event, reticulocyte G6PD content may falsely elevate the G6PD activity
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level, confusing the diagnosis.82 The most common cause of acute hemolysis in G6PD-deficient patients is systemic infection (e.g. hepatitis A or B, cytomegalovirus, pneumonia).81 Medication ingestion is also a
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common cause of acute hemolysis (24-72 hours after ingestion).81 Drugs commonly used in cardiac surgery that should be avoided when feasible in G6PD deficient patients are listed in Table 5.83 A complete list of drugs that should be avoided in this population can be found online at www.g6pd.org. The literature detailing the perioperative management of patients with G6PD-deficieincy undergoing cardiac surgery is limited, but highlights the risk for hemolysis and perioperative
ACCEPTED MANUSCRIPT Page 25 complications in this population.84 The physiologic stressors of cardiac surgery such as pain, anxiety, ischemia, reperfusion, hypothermia, acidosis, and flow through the CPB circuit risk oxidative free radical production and hemolysis as antioxidant production (i.e. glutathione) may be inadequate .23 Cardiopulmonary bypass is known to cause an inflammatory response with free radical production, thus
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when feasible “off pump” operations should be considered.23 Avoidance of medications known to risk hemolysis in this population is critical. As found in Table 5, several drugs commonly used during
anesthesia and cardiac surgery risk hemolysis in G6PD-deficient patients and should be avoided.83 The use of volatile anesthetics (isoflurane and sevoflurane) and benzodiazepines (diazepam and midazolam)
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have been linked to hemolysis from in vitro data, yet subsequent authors have described successful use of these medications in this population.85,86 Nonetheless it is probably reasonable to avoid these controversial drugs given that other non-triggering intravenous options exist. The use of cardioplegia solutions that contain local anesthetics such as del Nido (lidocaine) should be avoided. Prior authors
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have discussed strategies to limit mechanical damage from RBC shear stress and turbulence, thereby
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reducing or limiting hemolysis.86 These preventative strategies include the use of non-occlusive roller pumps, large diameter/short length tubing and cannulas, limiting suction and vacuum pressures, etc.,
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and are outlined in prior sections of this review. While off pump cardiac surgery is preferred, the successful management of patients requiring cardiac surgery with CPB and even deep hypothermic
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circulatory arrest has been reported.87
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Avoidance of medications known to risk methemoglobinemia (e.g. sodium nitroprusside) is important as this population is unresponsive to therapy with methylene blue, which may itself risk hemolysis.87
The use of mannitol as a free radical scavenger in patients undergoing cardiac surgery is common and a reasonable option in patients with G6PD-deficiency.88 Previous authors have also
ACCEPTED MANUSCRIPT Page 26 described the use of ascorbic acid as an antioxidant to help limit oxidative damages and hemolysis in G6PD deficient patients, however, supra-physiologic doses have been linked to hemolysis.87,89 There is insufficient data to make recommendations on the use of ascorbic acid in this population. In the event of a hemolytic crisis, attempts to abate triggering factors should be made. In cases
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of severe hemolysis and anemia, RBC transfusion is warranted. As with any hemolytic crisis, ensuring adequate volume resuscitation, perfusion pressure, and urine output are essential. Additional management strategies for severe hemolysis have been described elsewhere in this review.
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Pyruvate kinase deficiency
Pyruvate kinase (PK) is an important enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate thereby generating ATP. Pyruvate kinase deficiency is an autosomal recessive defect and the second most common RBC enzyme deficiency. With an incidence in the United
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States of 1:20,000 this rare disorder is seen most frequently in those of northern European decent and
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Pennsylvania Amish.82,90 Patients with PK deficiency lack the ability to appropriately generate ATP within RBCs which disrupts the cationic cellular gradient and ultimately leads to a rigid cellular structure that is
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susceptible to splenic destruction. The exact mechanism by which PK deficiency leads to hemolysis is poorly understood. Clinical manifestations present only in homozygotes or compound heterozygotes. PK
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levels in symptomatic patients are usually between 5-40% normal.82 Clinical severity ranges from mild anemia to lifelong transfusion dependence, but is fairly constant for most patients with occasional
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hemolytic crises during physiologic stressors (e.g. infection).82 Chronic therapy is largely supportive with splenectomy reserved for severe disease. The literature detailing perioperative management of patients PK deficiency undergoing cardiac surgery is limited to a single case report.90 Assessment of baseline laboratory parameters (hemoglobin, bilirubin, pyruvate kinase levels, etc.) can serve as a reference for the perioperative period. Prior authors
ACCEPTED MANUSCRIPT Page 27 discuss avoidance of factors known to further increase RBC shear stress and risk hemolysis, and also avoiding hypothermia when appropriate.90 Outside of minimizing the physiologic stressors of cardiac surgery and CPB, there is insufficient data to make further recommendations. Diagnostic and therapeutic goals should a hemolytic crisis occur are detailed previously.
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Chronic Myeloproliferative Neoplasm Polycythemia vera
Chronic myeloproliferative neoplasms (CPNs) encompass a group of blood related disorders including
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polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. Polycythemia vera is the most common of the CPNs with an incidence of 2.5-10:100,000 and is associated most commonly with JAK2 gene mutations.91 Commonly, PV presents with erythrocytosis, thrombocytosis, and leukocytosis, but patients can have isolated erythrocytosis.91 Patients with PV are at an elevated risk for
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thromboembolic complications which may be the first sign of the disease process.91 The pathologic basis
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of the disease is overactive hematoposesis leading to quantitative overproduction of qualitatively normal erythrocytes. Of note, PV is the only one of the CPNs that displays erythrocytosis. A detailed
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overview of the diagnostic and therapeutic guidelines for PV is beyond the scope of this review, but is extensively reviewed elsewhere.91 The mainstay of therapy in PV is phlebotomy which often is used to
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target normal hematocrit values (<45% male, <42% female), reducing thromboembolic risk.91 Treatment
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of patients with PV is based on risk-stratification criteria taking into account age and history of prior thrombotic complications. Higher risk patients are commonly treated with cytoreductive therapies (i.e. hydroxyurea) and possibly antiplatelet or anticoagulant medications. Thrombocytosis is a common feature of PV (50% of PV patients), and the primary derangement in patients with ET. Excessive thrombocytosis in these populations risks arterial and venous thrombosis with 20-50% of patients suffering thrombotic complications.92 Excessive thrombocytosis (>800 x 109/L) in
ACCEPTED MANUSCRIPT Page 28 patients with ET undergoing cardiac surgery has been associated with major perioperative thrombotic complications.93 Less commonly, bleeding diathesis can be seen and thought to be secondary to qualitative platelet dysfunction. Additionally, patients with PV and ET with elevated platelet counts are at risk for the development of acquired von Willebrand syndrome (AvWS).91 One recent study cited the
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incidence of AvWS of 55% and 49% respectively among ET and PV patients. The mechanism for the development of AvWS in these populations is not entirely clear but may be partially the result of
alterations in vWF proteolysis, which in PV may be resultant of the higher viscosity and shear stress within the blood leading to a conformational change in the vWF molecule.94
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The literature describing patients with PV undergoing cardiac surgery is limited.92,95 Osada et al. discuss a patient undergoing bilateral internal mammary CABG for which intraoperative phlebotomy to reduce the hematocrit <45% was performed, however, the patient suffered from left internal mammary
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thrombosis intraoperatively and acute right internal mammary occlusion on POD 1 necessitating angiography and stenting.95 The authors note that phlebotomy and optimization prior to the surgical
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procedure (not intraoperatively), and also full heparin dosing prior to IMA takedown should be considered for future cases.95 Reducing hematocrit values into the normal range (<45% male, <42%
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female), prior to cardiac surgery is warranted as this is a common therapeutic target for this population
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in general. Further reductions in hematocrit for patients undergoing cardiac surgery with moderate or deep hypothermia may be necessary but exact targets are unknown.
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In the limited reports, postoperative anticoagulation for PV patients having undergone CABG
included aspirin, clopidiogrel, and warfarin.92,95 Additionally, appropriate preoperative platelet reduction/optimization strategies are important in avoiding thrombotic and less commonly hemorrhagic complications in patients with ET, however, such practices have not been described in PV .93 While it is likely that PV directed therapy with phlebotomy and/or cytoreductive therapies will simultaneously
ACCEPTED MANUSCRIPT Page 29 reduce platelet counts, if excessive thrombocytosis persists (>800 x 109/L) therapeutic platelet reduction strategies (e.g. plateletpheresis) may be reasonable and would warrant preoperative hematology consultation.
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Summary In conclusion, RBC disorders are rare but can have profound implications for patients undergoing cardiac surgery. Understanding the physiologic derangements and implications is critical for those caring for this patient population. While some disorders require minimal deviation from standard perioperative care,
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others necessitate precise changes in perioperative strategy to avoid or limit complications. An early preoperative multidisciplinary team approach to these patients is important toward establishing the best individualized perioperative care plan. Additionally, a prior transfusion history may complicate RBC crossmatch compatibility, thus should be anticipated and planned for well in advance to the surgical
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date. This review is not an exhaustive resource, but references current available literature and gives
Narla J, Mohandas N. Red cell membrane disorders. Int J Lab Hematol 2017;39 Suppl 1:47-52.
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1.
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References
PT
ED
providers reasonable recommendations when encountering patients with such disorders.
2.
Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk
factors for early death. N Engl J Med 1994;330:1639-44. 3.
. (Accessed June 27, 2018, at https://www.cdc.gov/ncbddd/sicklecell/data.html.)
4.
Koshy M, Weiner SJ, Miller ST, et al. Surgery and anesthesia in sickle cell disease. Cooperative
Study of Sickle Cell Diseases. Blood 1995;86:3676-84.
ACCEPTED MANUSCRIPT Page 30 5.
Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med
2013;3:a011783. 6.
Pannu R, Zhang J, Andraws R, Armani A, Patel P, Mancusi-Ungaro P. Acute myocardial infarction
in sickle cell disease: a systematic review. Crit Pathw Cardiol 2008;7:133-8. Yousafzai SM, Ugurlucan M, Al Radhwan OA, Al Otaibi AL, Canver CC. Open heart surgery in
CR IP T
7.
patients with sickle cell hemoglobinopathy. Circulation 2010;121:14-9. 8.
Lazopoulos G, Kantartzis MM, Kantartzis M. Mitral valve replacement and tricuspid valve repair
in a patient with sickle cell disease. Thorac Cardiovasc Surg 2008;56:56-7.
Sachithanandan A, Nanjaiah P, Wright CJ, Rooney SJ. Mitral and tricuspid valve surgery in
AN US
9.
homozygous sickle cell disease: perioperative considerations for a successful outcome. J Card Surg 2008;23:167-8. 10.
Frimpong-Boateng K, Amoah AG, Barwasser HM, Kallen C. Cardiopulmonary bypass in sickle cell
Balasundaram S, Duran CG, al-Halees Z, Kassay M. Cardiopulmonary bypass in sickle cell
ED
11.
M
anaemia without exchange transfusion. Eur J Cardiothorac Surg 1998;14:527-9.
anaemia. Report of five cases. J Cardiovasc Surg (Torino) 1991;32:271-4. Harban FM, Connor P, Crook R, Bingham R. Cardiopulmonary bypass for surgical correction of
PT
12.
congenital heart disease in children with sickle cell disease: a case series. Anaesthesia 2008;63:648-51. Djaiani GN, Cheng DC, Carroll JA, Yudin M, Karski JM. Fast-track cardiac anesthesia in patients
CE
13.
with sickle cell abnormalities. Anesth Analg 1999;89:598-603. Esseltine DW, Baxter MR, Bevan JC. Sickle cell states and the anaesthetist. Can J Anaesth
AC
14.
1988;35:385-403. 15.
Farooqui F, Chaney MA, Staikou C, Cole SP. CASE 10-2016: Hemoglobinopathies and Cardiac
Surgery. J Cardiothorac Vasc Anesth 2016;30:1409-18.
ACCEPTED MANUSCRIPT Page 31 16.
Sanders DB, Smith BP, Sowell SR, et al. Sickle cell disease and complex congenital cardiac
surgery: a case report and review of the pathophysiology and perioperative management. Perfusion 2014;29:153-8. 17.
Raut MS, Khanuja JS, Srivastava S. Perioperative considerations in a sickle cell patient
18.
Bocchieri KA, Scheinerman SJ, Graver LM. Exchange transfusion before cardiopulmonary bypass
in sickle cell disease. Ann Thorac Surg 2010;90:323-4. 19.
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undergoing cardiopulmonary bypass. Indian J Anaesth 2014;58:319-22.
Edwin F, Aniteye E, Tettey M, et al. Hypothermic cardiopulmonary bypass without exchange
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transfusion in sickle-cell patients: a matched-pair analysis. Interact Cardiovasc Thorac Surg 2014;19:7716. 20.
Alotaibi GS, Alsaleh K, Bolster L, McMurtry MS, Wu C. Preoperative transfusion in patients with
Hematology 2014;19:463-71.
Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell
ED
21.
M
sickle cell disease to prevent perioperative complications: a systematic review and meta-analysis.
Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013;381:930-8. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive
PT
22.
transfusion regimens in the perioperative management of sickle cell disease. The Preoperative
23.
CE
Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995;333:206-13. Dogra N, Puri GD, Rana SS. Glucose-6-phosphate dehydrogenase deficiency and cardiac surgery.
AC
Perfusion 2010;25:417-21. 24.
Hemming AE. Pro: Exchange transfusion is required for sickle cell trait patients undergoing
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2004;18:663-5. 25.
Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension
in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002;33:1037-43.
ACCEPTED MANUSCRIPT Page 32 26.
Westerman MP, Green D, Gilman-Sachs A, et al. Coagulation changes in individuals with sickle
cell trait. Am J Hematol 2002;69:89-94. 27.
Yung GL, Channick RN, Fedullo PF, et al. Successful pulmonary thromboendarterectomy in two
patients with sickle cell disease. Am J Respir Crit Care Med 1998;157:1690-3. Crawford TC, Carter MV, Patel RK, et al. Management of sickle cell disease in patients
undergoing cardiac surgery. J Card Surg 2017;32:80-4. 29.
Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia.
Blood Rev 2012;26 Suppl 1:S3-6.
Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden.
AN US
30.
CR IP T
28.
Blood 2010;115:4331-6. 31.
Borgna-Pignatti C. The life of patients with thalassemia major. Haematologica 2010;95:345-8.
32.
Lai ME, Grady RW, Vacquer S, et al. Increased survival and reversion of iron-induced cardiac
M
disease in patients with thalassemia major receiving intensive combined chelation therapy as compared
33.
ED
to desferoxamine alone. Blood Cells Mol Dis 2010;45:136-9. Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ. Improved survival of
Reson 2008;10:42.
Olivieri NF, Liu PP, Sher GD, et al. Brief report: combined liver and heart transplantation for end-
CE
34.
PT
thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn
stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med
AC
1994;330:1125-7. 35.
Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in
thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 2014;99:811-20.
ACCEPTED MANUSCRIPT Page 33 36.
Kremastinos DT, Farmakis D, Aessopos A, et al. Beta-thalassemia cardiomyopathy: history,
present considerations, and future perspectives. Circ Heart Fail 2010;3:451-8. 37.
Morris CR, Vichinsky EP. Pulmonary hypertension in thalassemia. Ann N Y Acad Sci
2010;1202:205-13. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling
CR IP T
38.
pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. Blood 2002;99:30-5. 39.
Raffa GM, Mularoni A, Di Gesaro G, Vizzini G, Cipolla T, Pilato M. Thalassemia and heart surgery:
aortic valve repair after endocarditis. Ann Thorac Surg 2015;99:e1-2.
Wood JC. Cardiac complications in thalassemia major. Hemoglobin 2009;33 Suppl 1:S81-6.
41.
Detterich J, Noetzli L, Dorey F, et al. Electrocardiographic consequences of cardiac iron overload
AN US
40.
in thalassemia major. Am J Hematol 2012;87:139-44. 42.
Staikou C, Stavroulakis E, Karmaniolou I. A narrative review of peri-operative management of
Botta L, Savini C, Martin-Suarez S, et al. Successful mitral valve replacement in a patient with a
ED
43.
M
patients with thalassaemia. Anaesthesia 2014;69:494-510.
severe form of beta-thalassaemia. Heart Lung Circ 2008;17:77-9. deLeval MR, Taswell HF, Bowie EJ, Danielson GK. Open heart surgery in patients with inherited
PT
44.
hemoglobinopathies, red cell dyscrasias, and coagulopathies. Arch Surg 1974;109:618-22. Farmakis D, Polonifi A, Deftereos S, Tsironi M, Papaioannou I, Aessopos A. Aortic valve
CE
45.
replacement in a patient with thalassemia intermedia. Ann Thorac Surg 2006;81:737-9. Omoto T, Tedoriya T, Kondo Y, et al. Aortic valve replacement in a patient with alpha-
AC
46.
thalassemia. Ann Thorac Cardiovasc Surg 2010;16:365-6. 47.
Cokkinou V, Katsiyanni A, Orkopoulou M, Michalis A, Tolis G, Cokkinos DV. Evidence of increased
hemolysis after open heart surgery in patients heterozygous for Beta-thalassemia. Tex Heart Inst J 1988;15:35-8.
ACCEPTED MANUSCRIPT Page 34 48.
Horai T, Tanaka K, Takeda M. Coronary artery bypass grafting under cardiopulmonary bypass in
a patient with beta-thalassemia: report of a case. Surg Today 2006;36:538-40. 49.
Tanaka K, Kanamori Y, Sato T, et al. Administration of haptoglobin during cardiopulmonary
bypass surgery. ASAIO transactions / American Society for Artificial Internal Organs 1991;37:M482-3. Richardson R, Issitt R, Crook R. Beta-thalassemia in the paediatric cardiac surgery setting - a case
report and literature review. Perfusion 2018;33:232-4. 51.
Abosdera MM, Almasry AE, Abdel-Moneim ES. Coagulation defects in thalassemic patients.
Pediatr Neonatol 2017;58:421-4.
Fayed MA, Abdel-Hady HE, Hafez MM, Salama OS, Al-Tonbary YA. Study of platelet activation,
AN US
52.
CR IP T
50.
hypercoagulable state, and the association with pulmonary hypertension in children with betathalassemia. Hematol Oncol Stem Cell Ther 2018;11:65-74. 53.
Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev
Bernard E, Schmid ER, Schmidlin D, Schaffner A, Germann R. Hemoglobin Zurich and
ED
54.
M
2003;17:167-78.
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14:705-6. Rose JJ, Wang L, Xu Q, et al. Carbon Monoxide Poisoning: Pathogenesis, Management, and
PT
55.
Future Directions of Therapy. Am J Respir Crit Care Med 2017;195:596-606. McCunn M, Reynolds HN, Cottingham CA, Scalea TM, Habashi NM. Extracorporeal support in an
CE
56.
adult with severe carbon monoxide poisoning and shock following smoke inhalation: a case report.
AC
Perfusion 2000;15:169-73. 57.
Schober P, Kalmanowicz M, Schwarte LA, Loer SA. Cardiopulmonary bypass increases
endogenous carbon monoxide production. J Cardiothorac Vasc Anesth 2009;23:802-6. 58.
Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for
management. J Cardiothorac Vasc Anesth 2014;28:1043-7.
ACCEPTED MANUSCRIPT Page 35 59.
Champigneulle B, Lecorre M, Bouzguenda H, et al. Late diagnosis of congenital
methemoglobinemia in an elderly patient during cardiac surgery. J Cardiothorac Vasc Anesth 2014;28:730-2. 60.
McRobb CM, Holt DW. Methylene blue-induced methemoglobinemia during cardiopulmonary
61.
CR IP T
bypass? A case report and literature review. J Extra Corpor Technol 2008;40:206-14.
Barros MM, Blajchman MA, Bordin JO. Warm autoimmune hemolytic anemia: recent progress in
understanding the immunobiology and the treatment. Transfus Med Rev 2010;24:195-210.
King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Semin Hematol 2005;42:131-6.
63.
Petz LD. A physician's guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol
AN US
62.
2004;124:712-6. 64.
Onoe M, Magara T, Yamamoto Y. Cardiac operation for a patient with autoimmune hemolytic
anemia with warm-reactive antibodies. Ann Thorac Surg 2001;71:351-2.
Shah S, Gilliland H, Benson G. Agglutinins and cardiac surgery: a web based survey of cardiac
M
65.
66.
ED
anaesthetic practice; questions raised and possible solutions. Heart Lung Vessel 2014;6:187-96. Barbara DW, Mauermann WJ, Neal JR, Abel MD, Schaff HV, Winters JL. Cold agglutinins in
PT
patients undergoing cardiac surgery requiring cardiopulmonary bypass. The Journal of thoracic and cardiovascular surgery 2013;146:668-80. Patel PA, Ghadimi K, Coetzee E, et al. Incidental Cold Agglutinins in Cardiac Surgery:
CE
67.
Intraoperative Surprises and Team-Based Problem-Solving Strategies During Cardiopulmonary Bypass. J
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Cardiothorac Vasc Anesth 2017;31:1109-18. 68.
Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg
1995;60:1143-50. 69.
Bracken CA, Gurkowski MA, Naples JJ, et al. Case 6--1993. Cardiopulmonary bypass in two
patients with previously undetected cold agglutinins. J Cardiothorac Vasc Anesth 1993;7:743-9.
ACCEPTED MANUSCRIPT Page 36 70.
Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804-11.
71.
Ghoreishi M, Baer MR, Bhargava R, Stauffer CE, Griffith BP, Gammie JS. Aortic valve bypass for
aortic stenosis in a patient with paroxysmal nocturnal hemoglobinuria. Ann Thorac Surg 2010;90:279-81. 72.
Knobloch K, Lichtenberg A, Leyh RG, Schubert J. Aortic valve replacement and coronary
9. 73.
Dinesh D, Baker B, Carter JM. Cardiopulmonary bypass surgery in a patient with paroxysmal
nocturnal haemoglobinuria. Transfus Med 2006;16:206-8.
Kypson AP, Warner JJ, Telen MJ, Milano CA. Paroxysmal cold hemoglobinuria and
AN US
74.
CR IP T
revascularization in paroxysmal nocturnal hemoglobinuria. Interact Cardiovasc Thorac Surg 2003;2:647-
cardiopulmonary bypass. Ann Thorac Surg 2003;75:579-81. 75.
Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008;372:1411-26.
76.
Hargrave JM, Capdeville MJ, Duncan AE, Smith MM, Mauermann WJ, Gallagher PG. CASE 5-
M
2016Complex Congenital Cardiac Surgery in an Adult Patient With Hereditary Spherocytosis: Avoidance
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of Massive Hemolysis Associated With Extracorporeal Circulation in the Presence of Red Blood Cell Fragility. J Cardiothorac Vasc Anesth 2016;30:800-8. Matsuzaki Y, Tomioka H, Saso M, et al. Open-heart surgery using a centrifugal pump: a case of
PT
77.
hereditary spherocytosis. J Cardiothorac Surg 2016;11:138. Huenges K, Panholzer B, Cremer J, Haneya A. Ventricular assist device implantation in a young
CE
78.
patient with non-compaction cardiomyopathy and hereditary spherocytosis. Eur J Cardiothorac Surg
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2017. 79.
Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a
review in search of a treatment algorithm. The Journal of extra-corporeal technology 2008;40:257-67. 80.
Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview
for clinicians. Critical care 2005;9:158-69.
ACCEPTED MANUSCRIPT Page 37 81.
Belfield KD, Tichy EM. Review and drug therapy implications of glucose-6-phosphate
dehydrogenase deficiency. Am J Health Syst Pharm 2018;75:97-104. 82.
Haley K. Congenital Hemolytic Anemia. Med Clin North Am 2017;101:361-74.
83.
(Accessed April 24, 2018, at
84.
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https://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.)
Gerrah R, Shargal Y, Elami A. Impaired oxygenation and increased hemolysis after
cardiopulmonary bypass in patients with glucose-6-phosphate dehydrogenase deficiency. Ann Thorac Surg 2003;76:523-7.
Altikat S, Ciftci M, Buyukokuroglu ME. In vitro effects of some anesthetic drugs on enzymatic
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85.
activity of human red blood cell glucose 6-phosphate dehydrogenase. Pol J Pharmacol 2002;54:67-71. 86.
Kumar R. Precautionary Measures for Successful Open Heart Surgery in G6PD Deficient Patient-
A Case Report. J Clin Diagn Res 2016;10:PD11-PD2.
Staudt GE, Qu JZ. Deep Hypothermic Circulatory Arrest in a Patient With Severe G6PD
M
87.
88.
ED
Deficiency. J Cardiothorac Vasc Anesth 2017.
Larsen M, Webb G, Kennington S, et al. Mannitol in cardioplegia as an oxygen free radical
89.
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scavenger measured by malondialdehyde. Perfusion 2002;17:51-5. Quinn J, Gerber B, Fouche R, Kenyon K, Blom Z, Muthukanagaraj P. Effect of High-Dose Vitamin C
90.
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Infusion in a Glucose-6-Phosphate Dehydrogenase-Deficient Patient. Case Rep Med 2017;2017:5202606. Basantwani S, Govardhane B, Shinde S, Tendolkar B. Mitral Valve Replacement With
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Cardiopulmonary Bypass in a Patient With Pyruvate Kinase Deficiency. J Cardiothorac Vasc Anesth 2017;31:262-5. 91.
Spivak JL. Polycythemia Vera. Curr Treat Options Oncol 2018;19:12.
92.
Oz BS, Asgun F, Akay HT, Kaya E, Kuralay E, Tatar H. Anticoagulation after coronary artery
surgery in patients with polycythemia vera: report of two cases. J Card Surg 2007;22:420-2.
ACCEPTED MANUSCRIPT Page 38 93.
Smith BB, Nuttall GA, Pruthi RK, Joyce DL, Schuldes MS, Smith MM. A Novel Approach to
Essential Thrombocythemia and Cardiac Surgery. Ann Thorac Surg 2017;103:e249-e50. 94.
Rottenstreich A, Kleinstern G, Krichevsky S, Varon D, Lavie D, Kalish Y. Factors related to the
polycythemia vera. Eur J Intern Med 2017;41:49-54. 95.
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development of acquired von Willebrand syndrome in patients with essential thrombocythemia and
Osada H, Nakajima H, Meshii K, Ohnaka M. Acute coronary artery bypass graft failure in a
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patient with polycythemia vera. Asian Cardiovasc Thorac Ann 2016;24:175-7.
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Figure 1 – Perioperative management of the patients with cold agglutinins
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Disorders of Hemoglobin Hereditary Disorders of Hemoglobin Sickle cell disease Thalassemias Hemoglobin C Hemoglobin Zurich Acquired Disorders of Hemoglobin Carbon monoxide poisoning Methemoglobinemia
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Hereditary Hemolytic Anemias RBC membrane disorders Hereditary Spherocytosis Hereditary Elliptocytosis
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Hemolytic Anemias Acquired Hemolytic Anemias Autoimmune hemolytic anemia Cold agglutinin disease Paroxysmal nocturnal hemoglobinuria Paroxysmal cold hemoglobinuria
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RBC enzyme disorders Glucose-6-phosphate dehydrogenase deficiency Pyruvate Kinase deficiency
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Chronic Myeloproliferative Neoplasms: Polycythemia vera
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Table 1. Red blood cell disorders
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Table 2. Perioperative management of patients with sickle cell hemoglobinopathy
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Preoperative: Early, individualized, and multidisciplinary planning prior to cardiac surgery to determine need for transfusion or exchange transfusion Detailed history relating to hemolysis, transfusions, chronic pain, opioid tolerance Baseline laboratory analysis: blood type and antibody screen, hemoglobin level, hemoglobin electrophoresis to quantify Hgb S % Minimize NPO duration to ensure adequate hydration Continue preoperative hydroxyurea therapy (if currently taking)
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Intraoperative: Sickle Cell Trait Rarely requires special precautions Consider a similar strategy to sickle cell disease in patients with a higher HbS %, or those with a history of clinical manifestations related to sickle cell Sickle Cell Disease If not preformed preoperative, consider allogenic RBC transfusion vs. exchange transfusion via the CPB circuit, depending on HbS % Avoidance of hypoxia (hyperoxygenate pump prime) and acidosis Avoidance of hypothermia and cold cardioplegia whenever feasible Avoidance vasoconstrictors unless absolutely necessary Avoidance of cell-salvage systems Minimize CPB and aortic cross clamp times Ensure adequate multimodal analgesia
If significant hemolysis occurs: Mitigate causes for hemolysis Consider exchange transfusion Ensure adequate circulating volume and urine output Consider systemic or inhaled vasodilators if elevations in systemic or pulmonary vascular resistances (e.g. inhaled nitric oxide)
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Postoperative: Serial laboratory monitoring for hemolysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin, urinalysis (hemoglobinuria) Avoidance of hypoxia via necessary supplementation, and early/aggressive correction of acidosis Ensure adequate multimodal analgesia Abbreviations: HbS -- hemoglobin S, CPB -- cardiopulmonary bypass
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Table 3. Thalassemia severity & classification Severity
Genetic Disorder
RBC Analysis
Other findings
Inactivity of all α globin genes
Severe microcytic anemia
Hb Barts (Hb γ tetramer) Intrauterine death common
Severe microcytic anemia (Hb 3-4g/dL if untreated)
Begins after neonatal period Severe clinical manifestations
Hydrops Fetalis
β-Thalassemia Major Inactivity of both β (TD) globin genes
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Severe
Inactivity of 3 of 4 α globin genes
β-Thalassemia Intermedia (Often NTD)
Reduced activity of both β globin genes
Variable presentation Moderate microcytic anemia (Hb 8-11g/dL)
HbH (β globin tetramer) present
Variable presentation Moderate microcytic anemia (Hb 8-11g/dL)
HbF (2 α and 2 γ subunits) 50%
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HbH Disease (Variable TD)
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Mild
50% inactivity of α globin genes
Mild microcytic anemia
Hb Barts (3 to 8%)
Silent α Carrier
25% genetic inactivity α globin genes
Normal
None
Reduced or no activity of 1 of 2 β globin genes
Mild microcytic anemia
Increased HbF Limited clinical manifestations
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β-Thalassemia Minor (Trait)
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α-Thalassemia Minor
Abbreviations: Hb-hemoglobin, NTD – Non transfusion dependent, RBC—Red blood cell, TD – Transfusion dependent
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Table 4. Perioperative management of patients with hereditary spherocytosis
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Preoperative: Detailed history relating to hemolysis, transfusions, and prior treatments Baseline laboratory analysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin/hemopexin
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Intraoperative: Avoidance of hypothermia and cold cardioplegia Use of large diameter, short length, straight cannulas and tubing Avoid or minimize vacuum pressures in venous and suction cannulas If significant hemolysis: Mitigate causes for hemolysis Transition to autologous transfusion suction (cell saver) to allow removal of plasma free hemoglobin and intracellular components Assure adequate circulating volume, perfusion pressure, and urine output Consider vasodilators if elevations in systemic or pulmonary vascular resistances Consider continuous ultrafiltration through CPB hemoconcentrator “washing”
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Postoperative: Serial laboratory monitoring for hemolysis: hemoglobin, bilirubin, reticulocyte count, lactate dehydrogenase, haptoglobin, urinalysis (hemoglobinuria), and markers for renal and hepatic function
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*In vitro study only74
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Acetazolamide Ascorbic Acid Aspirin Bezodiazepines (diazepam, midazolam)* Amide local anesthetics (lidocaine, prilocaine) Fluroquinolones Gentamicin Diphendyramine Dopamine Metaclopramide Methylene Blue Nitric Oxide Nitrofurantoin Nitroglycerin Penicillin Sulfonamide antibiotics Vitamin K Volatile Anesthetics (isoflurane, sevoflurane)*
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Table 5. Drugs commonly used in cardiac surgery patients that risk hemolysis in G6PD deficiency72
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