fragile hemoglobinopathies

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1 Fragile Hemoglobinopathies: Sickle Cell Anemia & Thalassemia and Hereditary Spherocytosis Saturday, February 25, 2012 James J. Fehr, MD Associate Professor Anesthesiology & Pediatrics Washington University in St. Louis Director, Saigh Pediatric Simulation Center St. Louis Children’s Hospital [email protected] Disclosure: The speaker receives no support from any vendor and has no conflicts of interest

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Page 1: Fragile Hemoglobinopathies

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Fragile Hemoglobinopathies: Sickle Cell Anemia & Thalassemia and Hereditary Spherocytosis

Saturday, February 25, 2012

James J. Fehr, MD Associate Professor Anesthesiology & Pediatrics Washington University in St. Louis Director, Saigh Pediatric Simulation Center St. Louis Children’s Hospital [email protected] Disclosure: The speaker receives no support from any vendor and has no conflicts of interest

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Session Objectives: At the end of the lecture, the participants should:

1) Develop an understanding of the various types of hemoglobinopathies and their implications for anesthetic management

2) Consider the perioperative management of patients with sickle cell disease and the indication for transfusion.

3) Contemplate the various ways one can make their team ready to manage patients with sickle cell disease or other hemoglobinopathy.

Introduction:

Normal hemoglobin has an iron-containing heme ring and four globin chains, as seen on the previous page. The globin chains determine the type of hemoglobin: 2 alpha- and 2 beta-chains constitute hemoglobin A, 2 alpha- and 2 gamma-chains are hemoglobin F. Hemoglobin F is 80% of the hemoglobin at birth, the remainder being hemoglobin A. There is also a few percent of hemoglobin A2 consisting of 2 alpha- and 2 delta-chains. Hemoglobinopathies challenge the pediatric anesthesiologist with increased risks for perioperative morbidity. Abnormal hemoglobin molecules can become distorted in the presence of hypoxia or other triggers and result in a chronic hemolysis. The primary hemoglobinopathy encountered by pediatric anesthesiologists is sickle cell anemia. Others hemoglobinopathies such as thalassemia and sickle-thalassemia combinations similarly result in hemolytic anemia. Hereditary Spherocytosis is a red blood cell membrane disorder, not a hemoglobinopathy, but also causes a chronic hemolytic anemia. The lecture will review the presentation and perioperative management of these conditions, focusing on sickle cell anemia as the prototypic hemoglobinopathy.

Sickle Cell Disease:

Sickle cell disease [SCD] is one of the most common genetic diseases in childhood, affecting approximately 1 in 2500 births in the US [Therrell]. It is an autosomal recessively inherited disorder of the β-hemoglobin chain which results in hemoglobin S in place of hemoglobin A [Marchant]. Two variants of the beta-chain, hemoglobin C and hemoglobin E, produce a mild hemolytic anemia. Patients who are heterozygous for SCD have one normal and one abnormal gene; this results in sickle cell trait which confers some protection against malaria. Homozygous patients have both hemoglobin S genes and suffer the widespread and potentially devastating effects of SCD. The disease is characterized by hemolytic anemia, intermittent vaso-occlusive crises and variable phenotypic expression. It occurs predominantly in people of African heritage, with disease occurring in 1 out of 400 and the trait occurring in 1 of 12

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African-Americans. Herrick described the clinical symptoms in 1910: jaundice, dyspnea, dark urine, epigastric pain and anemia associated with sickle-shaped erythrocytes [Herrick]. The first reported surgery for a patient with SCD was a cholecystectomy performed in 1911 [Firth 2005].

Evidence of erythrocyte destruction is a common feature of hemolytic anemias. One can encounter Target Cells as on the peripheral smear on the left and Howell-Jolly bodies as on the peripheral smear to the right. The Howell-Jolly bodies are condensed fragments of DNA normally removed by the spleen.

Target Cells Howell Jolly Bodies [www.wadsworth.org]

The hemoglobin of the patient with SCD aggregates in the presence of hypoxia and results in crescent shaped, fragile erythrocytes. These sickle cells readily hemolyze and their abnormal shape results in increased blood viscosity, sludging and numerous severe and potentially life threatening sequelae including acute chest syndrome, pain crises, hemolytic crises and cerebrovascular accidents.

1: Normal Cells, 2: Sickle Cells [www.unm.edu] Sickle Cells [www.wadsworth.org]

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A: Normal Cells, B: Sickle Cells [http://www.nhlbi.nih.gov/health/health-topics/topics/sca/]

Patients with sickle cell are frequently identified on the newborn screen, but the timing of the newborn screen and a mechanism for follow up of the results is variable amongst the states. Pediatric anesthesiologist might therefore anesthetize newborn babies with undiagnosed sickle cell disease. The presence of a high level of HbF in newborns confers some degree of protection against sickle crises [Buchanan] and most children don’t develop symptoms until after 4 or 6 months of age. In addition to the newborn screen, patients with sickle cell disease may be diagnosed early in life presenting with dactylitis, pain crises, hemolysis or stroke. Symptoms of SCD include chest pain, abdominal pain, bone pain, fatigue, dyspnea, jaundice, strokes, pubertal delay, growth delay, blindness, and priapism. The inflammatory response has also been implicated as a causative agent with sickle cell crises. Pain crises can be unpredictable, occurring in some children once every few years while in others they occur frequently within a year. Common childhood conditions such as asthma and upper respiratory infections hold the potential for far greater morbidity in patients with SCD. Children with SCD are at risk of school absence and potential academic underachievement.

 

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Management of SCD focuses on controlling symptoms and minimizing crises. These patients are frequently on folic acid supplements, and are encouraged to follow good general health maintenance including eating a healthy diet, getting plenty of exercise and adequate rest, and keeping well hydrated. Blood transfusions are given as needed although patients who have suffered strokes or severe recurrent pain crises may receive more frequent scheduled transfusions. Antibiotics are used to prevent infection, particularly with pneumococcus. Some patients may be on hydroxyurea which may reduce the frequency and severity of pain crises, but has not been shown to reduce the end organ damage from SCD. In the past, the life expectancy for people with SCD was in the 20s to 40s; with improvements in knowledge and care, patients can currently live into their 50s and beyond.

Anesthetizing children with SCD for major surgery remains a significant challenge for anesthesiologists and surgeons and represent a distinct patient population at increased risk for perioperative morbidity. Children with SCD present for routine surgeries, such as myringotomy tubes, hernia repairs and adenoidectomies. Patients with SCD often require cholecystectomy and may also have other major surgeries, including splenectomy and surgery for trauma. SCD patients often have poor intravascular access due to frequent blood draws and transfusions. They may have alloantigens from previous transfusions and thus be challenging to type and crossmatch. SCD patients must remain well hydrated, and precipitants of sickling such as hypoxia, hypotension, cold temperature and inadequate analgesia administration, must be avoided. They may have been receiving opiates over an extended period and be at risk for inadequate pain relief. Children with SCD require larger doses of opiates in the perioperative period compared to kids without sickle cell [Crawford].

Firth and colleagues recently published a survey of members of the Society of Pediatric Anesthesia to better define current perioperative management of SCD patients. The 510 respondents (25% respondents of the 2006 surveyed) demonstrated a wide variation of transfusion and fluid management. Practice common to most of the respondents included targeted preoperative evaluation and consultation; preoperative fluid administration and transfusion for patients with severe SCD undergoing invasive procedures but oral hydration and avoidance of blood transfusion for mildly affected patients undergoing minor procedures; and careful intraoperative fluid and ventilation management. Of the pediatric anesthesiologists who responded, 13-18% would give preoperative transfusion and intravenous hydration even with mild SCD and a low-risk procedure such as myringotomy tubes [Firth 2011].

The Cooperative Study of Sickle Cell Disease [1978-1988] noted that 24% of the patients requiring surgery underwent cholecystectomy or splenectomy and that 93% of these patients received a blood transfusion. Of the 1,079 surgeries performed on 717 patients, there were 12 deaths, none of which were in patients <14 years old [Koshy]. Many children with SCD have hemoglobin in the range of 5-10 g/dl and typical preoperative practice or major surgery is to transfuse with blood that has thoroughly crossmatched for minor blood groups. Transfusion to dilute the hemoglobin S fraction to less than 30% has not been shown to prevent pain crises or

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sickle cell exacerbations in the perioperative period and remains controversial [Firth 2009, Vichinsky].

Although there is a range of opinion about the particulars of perioperative management of children with SCD, there are some components of management that are noncontroversial. The general principal is to absolutely avoid conditions that induce sickling: cold, hypovolemia, acidosis, hypotension, inadequate analgesia and hypoxemia [Kim]. Oxygen should be administered to maintain adequate oxygen saturation. The operating room environment should be maintained at a level to minimize heat loss by the patient. Fluid warmers and active patient warmers can aid in maintaining normothermia. Padding should be generous, and use of tourniquets minimized. Intravenous fluid management should be determined by the needs of the patient and the surgery with the goal to avoid dehydration. Laparoscopic cholecystectomy results in shorter hospital stay with a comparable complication rate to open surgery and may be considered [Goers]. Patients with SCD should not be added onto the schedule in a haphazard fashion. Ideally, scheduled elective surgeries would be done during the day so that the patient is in the postoperative care unit with fewer care providers available. The overarching theme should be to keep clear channels of communication between surgeon, anesthesiologist, hematologist and the family. The perioperative management of these patients is a significant challenge for the anesthesiologist as untoward outcomes can occur even with optimal control of the patient’s physiologic parameters and the ambient environment.

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Thalassemias:

Thalassemia is another autosomal recessive disorder of hemoglobin that results in hemolytic anemia. It is frequently encountered in people of Mediterranean or South Asian ancestry and occurs because of a disruption of the normal 1:1 ratio of α– and β-chains [Firth 2009]. There are multiple forms of thalassemias. Imbalance of α– and β–chains results in rapid erythrocyte destruction and turnover with a chronic hemolytic anemia. Inheritance of thalassemia mutations with hemoglobin S will produce a sickle-thal disease very similar to sickle cell anemia.

Thalassemia [www.unm.edu] Thalassemia [www.meddean.luc.edu]

Alpha globin chain production occurs on chromosome 16. Alpha thalassemia is characterized by the deficiency or deletion of alpha–chains and beta thalassemia is caused by reduced or absent synthesis of beta-chains. Alpha thalassemia major, also called hemoglobin Bart’s, occurs when 4 alpha–chains are replaced by gamma-chains; this results in hydrops fetalis syndrome. The absence of 3 alpha–chains results in alpha-thalassemia intermedia which has four beta-chains and hemolytic anemia. These excess beta-chains form unstable tetramers called hemoglobin H with abnormal oxygen dissociation curves. When 2 alpha–chains are involved, the patients have alpha thalassemia minor and a mild anemia; a single alpha–chain involvement results in the alpha thalassemia carrier state [Muncie].

Beta globin chain production is controlled by chromosome 11. The single gene defect results in beta thalassemia minor. Patients are asymptomatic and have mild anemia. Beta thalassemia intermedia is intermediate between minor and major; patients require only occasionally require transfusions. Beta-thalassemia major is also known as Cooley’s anemia and involves the absence of 4 beta–chain production. This results in severe hemolytic anemia, poor growth, skeletal abnormalities, hepatosplenomegaly, jaundice and vascular damage. These children require lifelong transfusion and the life may be foreshortened by the cardiac complications of iron overload.

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Hereditary Spherocytosis:

Hereditary Spherocytosis [HS] is an inherited disorder of the erythrocyte membrane and the most common disorder of the red blood cell membrane (1 in 5,000 of Northern European ancestry). The symptoms of patients with HS are often attributable to the anemia and include fatigue, weakness and dyspnea. The often have splenomegaly and spherocytes, sphere-shaped erythrocytes, are seen on peripheral smear. These patients may undergo splenectomy as it can result in normal erythrocyte lifespan with resolution of the anemia despite continuing to have spherocytes on peripheral smear. This may be delayed when they are young, as to reduce their infectious risk of encapsulated organisms; it may become unnecessary as they get older and become functionally asplenic. As with any patient with chronic hemolysis, they have an increased risk of cholelithiasis; they are also at risk for aplastic crisis from parvovirus B19 [Kellermayer, Lackner]. These patients also require pneumococcal vaccine following splenectomy [Golan].

Hereditary Spherocytosis [www.wadsworth.org & www.unm.edu]

Conclusions:

Patients with fragile hemoglobinopathies represent a distinct patient population at increased risk for potentially significant perioperative morbidity. These patients have chronic hemolytic anemia and often have chronic hepatomegaly, functional asplenia, recurrent blood transfusions, and potential poor vascular access. They can be cared for in a safe manner, but recognition of the increased risks is mandated to optimize outcomes. Optimal outcomes can occur when there is clear and consistent communication between the various providers from hematology, surgery, anesthesiology and the sedation team and, most importantly, with the family. Best practices include avoiding prolonged NPO times and subsequent dehydration, not anesthetizing a child with sickle cell disease for elective surgery when their general health is not optimized, and avoiding administering anesthetics to these children for elective surgery late in the day when fewer staff are available postoperatively for monitoring.

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References:

1. Buchanan, GR, Debaun, MR, et al. Sickle Cell Disease. Hematology, 2004; 35-47. 2. Crawford, MW, Galton S et al., Postoperative morphine consumption in children with sickle-cell

disease. Ped Anes Feb 2006, 16(2):152-157. 3. Firth, PG, Head, A., Sickle Cell Disease and Anesthesia. Anesthesiology, Sept 2004; 101:766-785. 4. Firth, PG, Anaesthesia for peculiar cells—a century of sickle cell disease, Br J Anaesth 2005; 95:

287–99 5. Firth, PG, McMillan, KN, et al., A survey of perioperative management of sickle cell disease in North

America. Paediatr Anaesth. 2011 Jan; 21(1):43-9. 6. Firth, PG, Anesthesia and Hemoglobinopathies, Anesthesiology Clin 27 (2009) 321–336 7. Goers, T, Panepinto J, et al., Laparoscopic versus open abdominal surgery in children with sickle cell

disease Is associated with a shorter hospital stay. Pediatr Blood Cancer, 2008, 603-606. 8. Golan DE. Hemolytic anemias: red cell membrane and metabolic disorders. In: Goldman L, Ausiello

D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 165. 9. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.

Arch Intern Med 1910; 6: 517–21 10. http://www.meddean.luc.edu/lumen/meded/mech/cases/case7/image_f.htm, for images of the

peripheral smear of thalassemia 11. http://www.nhlbi.nih.gov/health/health-topics/topics/sca/ for images of the sickle cell vessels 12. http://www.unm.edu/~mpachman/Blood, for images of the peripheral smears 13. http://www.wadsworth.org/chemheme/heme/microscope, for images of the peripheral smears 14. http://en.wikipedia.org/wiki/Hemoglobin for front image of hemoglobin molecule 15. Kellermayer, R, Faden H et al., Clinical presentation of parvovirus B19 infection in children with

aplastic crisis. Ped Infect Dis J, Dec 2003, 22(12):1100-1101. 16. Kim, TW; Perioperative Care of the Patient with Sickle Cell Disease. ASA Refresher Courses in

Anesthesiology. 36(1):61-74, 2008. 17. Koshy, M, Weiner, SJ, et al., Surgery and anesthesia in sickle cell disease. Cooperative study of

Sickle Cell Diseases. Blood, 1995,86:3676-3684. 18. Lackner, H, Sovinz, P et al., The spectrum of Parvoviurs B19 infection in a pediatric chemato-

oncologic ward. Ped Infect Dis J, May 2011, 30(5):440-442. 19. Marchant, WA, Walker, I., Anesthetic management of the child with sickle cell disease. Ped Anes,

2003; 13(6):473-489. 20. Muncie, HL, Campbell, JS, Alpha & Beta Thalassemia, Am Fam Physician. 2009;80(4):339-344. 21. National Institutes of Health, NHLBI, The Management of Sickle Cell Disease, NIH publication # 02-

2117, 4th ed, June 2002. 22. Therrell BL, Hannon WH: National evaluation of US newborn screening system components, Mental

Retardation and Developmental Disabilities Research Reviews 12:236, 2006 23. Vichinsky EP, Haberkern CM, Neumayr L, et al.: A comparison of conservative and aggressive

transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med 1995; 333:206–14.