Perioperative Management of Patients with Pediatric Sickle Cell Disease

Background

Beyond the first 6 months of life, hemoglobin A, a tetramer composed of 2 α- and 2 β-globin chains, is the predominant form of human hemoglobin. A single nucleotide substitution in the β-globin gene results in the replacement of glutamic acid with valine at the sixth amino acid position of the β-chain and imparts significant functional impairment and clinical sequelae in those who inherit the mutation.

Patients who are homozygous for the mutant sickle gene (β^S) and those heterozygous for the β^S gene who co-inherit a β⁰ thalassemia deletion suffer a similarly severe phenotype and are classified as having sickle cell anemia (SCA). In contrast, most other compound heterozygotes, such as hemoglobin SC disease and sickle β⁺ thalassemia, exhibit a mild to moderate clinical phenotype. Individuals with sickle cell trait are heterozygous for the mutant β^S gene at only one β-chain loci and typically have a benign clinical course in childhood.

Sickle cell disease (SCD) encompasses all sickle genotypes (except sickle trait) and is characterized by varying degrees of intracellular erythrocyte dehydration, irreversible polymerization of hemoglobin, and systemic oxidant stress. The resulting damage to red blood rheology and endothelial cell activation impairs blood flow through the microvasculature, resulting in ischemic tissue injury. Pediatric patients with SCD are at markedly increased risk for serious perioperative complications ranging from vaso-occlusive crisis (VOC) to acute chest syndrome (ACS) and stroke, among others. For this reason, pediatric patients with SCD are of great concern to pediatric anesthesiologists. VOC or acute pain crisis is the most common complication of SCD, characterized by recurrent episodes of severe pain that are usually triggered by infection, dehydration, or hypoxemia. ACS is characterized by fever, respiratory symptoms, and pulmonary infiltrates on chest x-ray, that typically presents following infection, VOC, or after major surgeries.

Image: Comparison of Sickled Red Blood Cells and Normal Red Blood Cells

Fig 1: A figure of photomicrograph results for blood obtained from a person without and with sickle cell trait. (a) Sickled red blood cells (black arrowed) from a person with sickle cell trait under low oxygen tension. (b) Normal red blood cells (red arrowed) from a person with no sickle cells trait
Images obtained from: https://openi.nlm.nih.gov/detailedresult?img=PMC4617725_13104_2015_1583_Fig1_HTML&query=sickle%20cell&it=xg&req=4&npos=2. (a) Reprinted by CC0 1.0; (b) Reprinted by CC BY 4.0.

Preoperative Considerations

• Identify and confirm hemoglobinopathies in pediatric patients with SCD via universal newborn screening, clinical history, hemoglobin electrophoresis, or genetic testing. In developed countries, many will already be known from their hematology clinic affiliations where they receive longitudinal care.
• Evaluate for history of VOC, ACS, or stroke and resulting comorbidities such as cardiac disease, pulmonary disease, and pulmonary artery hypertension. Patients with frequent VOC or stroke, ACS, and advancing end-organ disease related to the hemoglobinopathy are considered high-risk patients.
• Common pediatric conditions such as upper respiratory tract infection, asthma, and obstructive sleep apnea have greater significance in children with SCA, and the presence of these conditions should be sought out.
• Review clinical history with pediatric hematology providers, along with results from any echocardiography, spirometry, central nervous system imaging and transcranial Doppler flow studies, hepatic and renal function tests, most recent complete blood count, and hemoglobin electrophoresis.
• Stratify patients as high-, medium-, or low-risk patients by virtue of their genotype, prior clinical trajectory, and nature of the planned surgical procedure.
• Evaluate use of disease-modifying therapies such as hydroxyurea therapy or chronic transfusion therapy. Be cognizant that children on chronic transfusion therapy are high risk and usually demonstrate frequent debilitating VOC, life-threatening stroke, or ACS.
• Review the proposed surgical procedure for which the patient is presenting. Surgical procedures can be classified as high-, medium-, or low-risk procedures, which we define in the table below. Surgical and procedural risk stratification is further delineated in the TAPS Trial (Howard et al., 2013) and the Cooperative Study of SCD (Koshy et al., 1995).

• Restore and preserve normal intravascular volume, adequate oxygen-carrying capacity (as indicated by hemoglobin and hematocrit counts), and optimization of any SCD-related organ system dysfunction. Determine with the patient’s hematologist, surgeon, and family whether the patient should be admitted the night before surgery for intravenous hydration, prophylactic red cell transfusion, and/or optimization of any recognized SCD-related organ system dysfunction.
• Assure preoperative hydration with intravenous fluids in the inpatient setting or through the administration of clear fluids by mouth until 2 hours before surgery. If possible, these patients should be scheduled for surgeries and procedures early in the day to minimize NPO times and avoid dehydration. In general, inpatient intravenous preoperative hydration should be used in medium- and high-risk patients undergoing medium- and high-risk procedures. Low-risk patients undergoing low-risk procedures can be hydrated preoperatively at home. Parents must be made aware of the importance of active oral hydration before procedures.
• Transfusion therapy can be administered as a simple transfusion (goal of hemoglobin 10 g/dL) or an exchange transfusion (goal of hemoglobin 10 g/dL and HbS% < 30).
• Prophylactic transfusion for pediatric patients with HbSS and HbSβ⁰ undergoing low- and medium-risk procedures with a hemoglobin target of 10 g/dL% is a safe and efficacious standard of care. Preoperative prophylactic transfusion should be administered within 1 week of surgery with the simple transfusion goals outlined above. Simple transfusion therapy is as effective as exchange transfusion for preventing SCA-related complications and is less likely than exchange transfusion to cause transfusion-related complications (especially alloimmunization and iron overload). Prophylactic transfusion of other sickle hemoglobin genotypes undergoing low-risk procedures is controversial and should be discussed on a case-by-case basis with the patient’s hematology providers.
• Preoperative exchange transfusions are administered on a case-by-case basis but are generally reserved for patients undergoing high-risk neurosurgical and cardiothoracic procedures or high-risk patients undergoing moderate- and other high-risk procedures.

Intraoperative Considerations

• Minimize risk of hypoxemia and maintain oxygen saturation above 95%.
• Maintain hydration and volume status by estimating and replacing ongoing losses using isotonic solutions and colloid to maintain intravascular volume and a hematocrit of 27% to 30%. Note that excessive volume loading may exacerbate lung disease in general and ACS in particular.
• Arterial catheter insertion for longer and more invasive cases allows for serial measurement of hemoglobin and hematocrit concentration, acid-base balance, and serum lactate concentration in accordance with basic anesthesia practice.
• Estimate maximum allowable blood loss and transfuse to maintain a hemoglobin concentration between 9 and 10 g/dL in this population, as the propensity for stroke increases above hemoglobin concentrations of 11 g/dL in the acute setting.
• Monitor core body temperatures carefully as children with SCA are at increased risk for hypothermia, which can contribute to VOC.
• Use multi-modal analgesia with regional anesthetic blocks, acetaminophen, non-steroidal anti-inflammatory drugs, and titrate small doses of opioids.
• If a tourniquet is used as part of an orthopedic procedure, the limb should be completely exsanguinated before tourniquet inflation, and tourniquet use should be limited to the shortest feasible duration (preferably less than 1 hour).

Postoperative Considerations

• Collaborate with hematology providers, surgeons, and parents as to whether the patient is a candidate for outpatient surgery. Patients who are not should be admitted for hydration, pulmonary toilet, and postoperative analgesia.
• Be mindful that an uneventful intraoperative course does not guarantee a benign postoperative course. For practical purposes only, low-risk patients undergoing low-risk procedures are considered candidates for surgery on an outpatient basis, and there should be a low threshold for postoperative admission whenever there is a concern about outpatient management and/or follow-up.
• Consider pulmonary hygiene and pulmonary toilet with incentive spirometry in older children.
• Use analgesia with non-steroidal anti-inflammatory drugs, patient-controlled opioids, or peripheral nerve blocks.
• Monitor for hydration status, check for insensible losses, and maintain input versus output balance.
• The most common significant perioperative complication is VOC, which can progress rapidly to ACS or stroke.
• Use transfusion therapy either as simple transfusion or exchange transfusion to treat perioperative SCA complications. Other therapeutic considerations are listed in the table below:

References

1. Firth, P. G., Head, C. A., & Warltier, D. C. (2004). Sickle cell disease and anesthesia. Anesthesiology, 101(3), 766-785.
2. Howard, J., Malfroy, M., Llewelyn, C., Choo, L., Hodge, R., Johnson, T., … & Fijnvandraat, K. (2013). The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial.  Lancet, 381(9870), 930-938.
3. Koshy, M., Weiner, S. J., Miller, S. T., Sleeper, L. A., Vichinsky, E., Brown, A. K., … & Kinney, T. R. (1995). Surgery and anesthesia in sickle cell disease. Cooperative Study of Sickle Cell Diseases.
4. Marchant, W. A., & Walker, I. (2003). Anaesthetic management of the child with sickle cell disease. Pediatric Anesthesia, 13(6), 473-489.
5. Sullivan, K. J., Dayan, J., Reichenbach, M., Irwin, M., Pitkin, A., Gauger, C., … & Kissoon, N. (2017). Perioperative Management of Paediatric Patients with Sickle Cell Disease. West Indian Medical Journal, 66(4).
6. Vichinsky, E. P., Haberkern, C. M., Neumayr, L., Earles, A. N., Black, D., Koshy, M., … & Preoperative Transfusion in Sickle Cell Disease Study Group. (1995). A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. New England Journal of Medicine, 333(4), 206-214.

Article Authors:

Sayoni Saha, Kevin Sullivan, Vandy Black, Timothy Martin, and Nikolaus Gravenstein of the University of Florida