Adjepong

Perioperative Management of Sickle Cell Disease

Kwame Ofori Adjepong1, Folashade Otegbeye2 and Yaw Amoateng Adjepong3

1 Warren Alpert Medical School, Brown University, United States.
2 Case Western Reserve University, University Hospitals Cleveland Medical Center, United States.
3 Yale University School of Medicine, Yale New Haven Health, Bridgeport Hospital, United States.

Corresponding author: Yaw Amoateng Adjepong, MD MPH Ph.D. FACP. Assistant Clinical Professor, Yale University School of Medicine. Senior Attending, Yale New Haven Health, Bridgeport Hospital. 267 Grant Street, Bridgeport, CT 06610, USA. Tel: 203.374.4716, Fax: 203.384.3949. E-mail: pyamoa@bpthosp.org 

Published: May 1, 2018
Received: December 4, 2017
Accepted: April 19, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018032 DOI 10.4084/MJHID.2018.032
This article is available on PDF format at: 

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
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Abstract

Over 30 million people worldwide have sickle cell disease (SCD).  Emergent and non-emergent surgical procedures in SCD have been associated with relatively increased risks of peri-operative mortality, vaso-occlusive (painful) crisis, acute chest syndrome, post-operative infections, congestive heart failure, cerebrovascular accident and acute kidney injury.  Pre-operative assessment must include a careful review of the patient's known crisis triggers, baseline hematologic profile, usual transfusion requirements, pre-existing organ dysfunction and opioid use. Use of preoperative blood transfusions should be selective and decisions individualized based on the baseline hemoglobin, surgical procedure and anticipated volume of blood loss. Intra- and post-operative management should focus on minimizing hypoxia, hypothermia, acidosis, and intravascular volume depletion. Pre- and post-operative incentive spirometry use should be encouraged.  



Introduction

Over 30 million people worldwide, from 163 countries, have sickle cell disease (SCD), with the highest concentration of the disease among persons of African, Middle Eastern, and Central Indian ancestry.[1-3] SCD patients undergo emergent and elective surgical procedures for SCD complications and for surgical indications common to the general population. Table 1 lists the most common surgical procedures carried out in SCD patients. Surgeries in the SCD population are associated with higher peri-operative complication rates. We briefly review the epidemiology and pathophysiology of SCD and discuss the major issues in the peri-operative management of SCD patients.

Table 1 Table 1. Common surgical procedures in sickle cell disease.

Ideally, peri-operative care of the SCD patient must be a collaborative effort between the surgeon, anesthetist, recovery room staff, primary care physician, and a consulting hematologist experienced in the management of SCD. Unfortunately, in many areas of the world, services from such expert hematologists are not available. It is essential therefore for all physicians who care for SCD patients to become familiar with the perioperative management of SCD patients. This review is therefore directed towards the global audience of generalist physicians, surgeons, anesthetists, nurses, and intensivists involved in the peri-operative management of SCD patients.

Genetics of Sickle Cell Disease

The normal adult hemoglobin, Hemoglobin A (HbA), is formed by two α and two β globin chains (α2β2), clustered on chromosomes 16 and 11. The sickle hemoglobin mutation (Hb S) results from a single amino acid substitution of valine for glutamic acid in the 6th position of the β globin chain.[4] The sickle cell gene evolved independently in sub-Saharan Africa, the Arabian Peninsula and Central India.[2] Several other hemoglobin gene variants have emerged in different populations from spontaneous mutations. These are either structural variants resulting from changes in the amino acid sequence or thalassemias that lower or abolish globin chain production. Homozygous inheritance of the sickle cell gene (Hb SS) or co-inheritance of the sickle cell gene with another mutated hemoglobin gene variant results in SCD.[1-7] The compound heterozygotes include a combination of HbS with hemoglobin gene variants such as Hemoglobin C (Hb SC), Hemoglobin D (Hb SD), Hemoglobin E (Hb SE), Hemoglobin O Arab (Hb SO Arab) or with beta thalassemia (Hb Sβa thal). A combination of HbS with the normal hemoglobin A results in the carrier state (Sickle Cell trait), Hb AS, which is not considered sickle cell disease.[2] Globally the homozygous Hb SS, also called Sickle Cell Anemia, is the most common sickle cell genotype.[1,3-6]
The various sickle cell disease states differ in the percent HbS concentration (Table 2).[8] This results in considerable heterogeneity in the phenotypic manifestations of sickle cell disease, including the baseline hemoglobin level. Overall, the most severe manifestations are seen in the homozygous Hb SS and Hb Sβ0 thal genotypes.


Table 2 Table 2. Percent Hb S concentration in selected major Sickle Cell genotypes.

Pathophysiology

The hallmark of sickle cell disease is recurrent vaso-occlusion. It is now apparent that complex and dynamic mechanisms underlie the vaso-occlusive process, of which Hb S polymerization plays an essential role.[9-15] Hemoglobin deoxygenation in SCD leads to sickling of the RBCs as a result of Hb S polymerization. The process of polymerization is triggered and/or enhanced by hypoxia, vascular stasis, infection, inflammation, increased blood viscosity, vasoconstriction, dehydration, hypotension, stress, cold temperature, acidosis, and decreased flow.[9,10] There is RBC clumping, endothelial damage, and inflammatory response with release of mediators that up-regulate cell adhesion molecules on the endothelial cells. These lead to adhesion of sickled cells to the vascular endothelium, fibrin deposition and microvascular occlusion. Neutrophils, monocytes, invariant natural killer T (iNKT) cells, other leukocytes, and platelets are activated and participate in the vascular occlusion. The vascular occlusion delays flow, further enhancing deoxygenation of the affected red blood cells, leading to worsening polymerization. The resulting ischemia creates a feedback loop of deteriorating endothelial activation. These changes occur in multiple vascular beds resulting in multisystem involvement. The half-life of the sickled red cells is markedly reduced from the normal 120 days to 10 to 12 days, resulting in a chronic hemolytic anemia, with its attendant hyper-proliferative bone marrow and hyperdynamic circulation, even at baseline.[4,16,17]

Surgical Complications

Historically, surgical procedures in sickle cell patients have been associated with relatively increased risks of peri-operative mortality, vaso-occlusive (painful) crisis, acute chest syndrome, post-operative infections, and congestive heart failure.[18-29] Careful pre-operative assessment and judicious peri-operative management are critical in mitigating these risks. 

Pre-Operative Assessment and Interventions

The goals of pre-operative assessment are to ensure that the patient is medically optimized for the intended surgical procedure, estimate the risk of peri-operative complications, and plan for the optimal management of anticipated peri-operative complications. Sickle cell disease must be appreciated as a multisystem disease that affects almost all organs.[30]
Currently, none of the generally available surgical risk calculators have been validated for patients with sickle cell disease.[31-33] Risk estimates obtained using these surgical risk calculators, while helpful, must be presumed to underestimate the overall peri-operative risk in SCD patients.
During the pre-operative assessment one must ascertain the sickle cell genotype, frequency of crisis and the date of patient's last crisis, average length of hospital stay during painful crisis, known triggers for crisis, baseline level of activity, baseline opioid use, steady-state hemoglobin and hematocrit, reticulocyte count, and WBC count, as well as history of blood transfusions. A sample pre-operative data abstraction form is attached as Supplementary Appendix 1. The severity of pre-existing cardiac and pulmonary complications of SCD need to be ascertained in the pre-operative assessment. Table 3 lists selected known cardiac and pulmonary complications in SCD patients. Routine pre-operative cardiac echography in all SCD undergoing general anesthesia is unnecessary and will likely not impact the peri-operative management in most patients. Nonetheless, given the relatively large amounts of fluids administered to SCD patients, cardiac echo may be useful to ascertain the extent of cardiac dysfunction in patients with prior history of heart failure, poor functional status or with dyspnea at baseline. In resource-poor countries (where obtaining cardiac echography may not be readily accessible), patients who develop breathlessness, fatigue or palpitations and have to stop when walking at their own pace on a level ground or when climbing a flight of stairs must be presumed to have significant cardiac or pulmonary dysfunction. Inability to perform these tasks will correspond to class III or higher on the New York Heart Association heart failure classification,[35] or less than 4 metabolic equivalents functional activity level.[34] Extreme caution must be used in decisions about the volume of fluid administration in such patients.

Table 3 Table 3. Cardiac and Pulmonary Complications in Sickle Cell disease.

Special steps should be taken during the peri-operative process to avoid triggering a sickle cell crisis. Common triggers of the acute crisis include anxiety, emotional stress, infection, dehydration, acidosis, hypoxia, vascular stasis and increased blood viscosity.[9,11] Adequate counseling, including education of patient about the procedure and awareness of patient’s special considerations, can significantly assuage the emotional stress and anxiety about the surgical procedure. If needed, anxiolytics can be used cautiously.
Intracellular dehydration is a known trigger for Hb S polymerization.[9-11] Whenever possible, prolonged pre-operative fasting must be avoided. Patients should be encouraged to drink clear fluids up until 2-4 hours before surgery. For patients undergoing moderate or major procedures, intravenous hydration must be used. Supplement 2 lists the composition, osmolarity and pH of commonly used solutions. Normal saline (9 g/dl of sodium chloride contains 154 milliequivalents of sodium, pH of 5.5, osmolarity of 308 milliosmoles per liter) is acidic and increases the viscosity of the blood.[36] Hypotonic fluids, in theory, decrease RBC sickling and are preferred.[37-39] Excessive fluid loading is associated with pulmonary edema and can precipitate acute chest syndrome and thus needs to be avoided.[40,41] Exactly how much fluid should be given is unknown.[42] Standard maintenance amounts may be used in most patients and the intravenous infusion rate must be significantly reduced once the patient resumes oral intake. Changes in daily weights and input/output data may help guide the fluid management decisions.
Hypoxia is the most important trigger of sickle cell crisis and needs to be avoided.[9-14,43] However, routine use of oxygen supplementation is not advisable as its potential harm far exceeds its benefits.[44-46] To identify those in need of supplemental oxygen, oxygen monitoring in the perioperative period must be considered mandatory in all patients. Pulse oximetry does not correlate well with arterial oxygen tension in some SCD patients.[47] It is therefore important that arterial blood gas confirmation is obtained in hypoxic patients.
The use of incentive spirometry has been shown to decrease the incidence of atelectasis and acute chest syndrome in hospitalized patients.[40,48,49] Accordingly, use of incentive spirometry before and after the procedure needs to be strongly encouraged. Given the relatively high frequency of acute chest syndrome following high risk (intracranial, cardiovascular, and intrathoracic) procedures and the need to monitor arterial blood gases during its management, establishing baseline blood gas values in such patients is advised. Routine assessment of baseline pulmonary function tests is not needed.[50,51]
The role of routine pre-operative blood transfusions, either simple RBC transfusion or exchange transfusion, remains controversial.[27-29,52-68] Theoretically, transfusion will reduce the percent HbS concentration and improve tissue oxygen delivery. However, transfusion increases the blood viscosity and thereby increases the risk of Hb polymerization.[55,56] There is a net benefit of increased tissue oxygen delivery over increased viscosity when the transfused hemoglobin level is kept at or just below 10 g/dl.[55,56] However, no increase in perioperative complications has been observed in centers that do not routinely offer preoperative transfusion, or in countries with low availability of blood for routine preoperative transfusion.[54] Also, transfusion is associated with increased risks of alloimmunization, iron overload and may be associated with increased risk of infections.
The largest cohort study of surgery in SCD patients, the Cooperative Study of Sickle Cell Disease, found beneficial effects of preoperative transfusion in Hb SC patients for all surgical procedures.[27] For Hb SS patients, peri-operative transfusion was associated with a lower rate of SCD-related postoperative complications in patients undergoing low-risk procedures (such as inguinal hernia repair, myringotomy, dilatation and curettage, and surgeries on eyes, skin, and nose). However, there was no association between transfusion and sickle-related postoperative complications among patients who had moderate risk procedures (throat, neck, spine, proximal extremities, hip replacement, genitourinary system, and intra-abdominal).[27]
Using a target hemoglobin level of 10 g/dl, the Preoperative Transfusion in Sickle Cell Disease study Group performed a multicenter, randomized controlled trial and found conservative, simple RBC transfusion was equally effective as exchange transfusion (maintaining hemoglobin at 10g/dl and HbS level of 30% or less) in preventing peri-operative complications.[58] However, the study did not have a comparable group without blood transfusion. Also, transfusion was associated with increased rates of allo-immunization.
Recently, the Transfusion Alternatives Preoperatively In Sickle Cell Disease (TAPS) study,[53] a multicenter randomized trial of 67 Hb SS and Hb Sβ0 thal patients, found a reduction in clinically important complications in the transfused patients undergoing medium risk procedures (15% vs. 39%, p=0.02). In contrast, preoperative transfusion was associated with a higher rate of post-operative complications in a matched prospective study of 40 patients undergoing laparoscopic cholecystectomy for cholelithiasis in Saudi Arabia (25% vs. 0%, p=0.007).[59]
Tables 4 and 5 summarize the findings of published original studies on pre-operative transfusions.[27-29,53,57-68] A systematic review and meta-analysis of the randomized and observational studies found no difference in perioperative mortality, vascular, or non-vascular perioperative complications between those treated with preoperative transfusion versus no transfusion strategy.[52] This review notwithstanding, the current consensus in the United States is “to bring the hemoglobin level to 10 g/dl prior to undergoing a surgical procedure involving general anesthesia” in patients with Hb SS or Sβ0 thal.[56]

Figure 1 Table 4. Randomized control trials.

Figure 2 Table 5. Observational studies

Based on the current aggregate data, it is fair to advocate that transfusion decisions need to be selective and individualized based on the type of SCD, the baseline hemoglobin, the baseline cardiopulmonary reserve, and the risk of the surgical procedure. If a decision to transfuse is made, phenotypically matched blood must be used to minimize the risk of alloimmunization. For those with hemoglobin levels less than 9g/dl, simple RBC transfusion is equally efficacious compared to exchange transfusion. For those with high baseline hemoglobin (above 9 g/dl), perhaps exchange (or partial exchange) transfusion, rather than simple transfusion, should be used to avoid raising the hemoglobin level above 10 g/dl.
Cold weather and skin chilling are known precipitants of the crisis in some sickle cell patients.[9,10] It has been hypothesized that hypothermia leads to exaggerated reflex vasoconstriction, increased capillary transit time, red cell sludging, and may lead to shunting of blood from the bone marrow.[15,69,70] Accordingly, thermoregulation has been strongly recommended in the perioperative care of SCD patients. Warm intravenous fluids are advised. Many centers fearfully avoid hypothermia, even in cardiac surgery, in sickle cell patients. To date, there are no known reports of peri-operative hypothermia as a contributory cause of perioperative vaso-occlusive crisis. In vitro, there is delayed RBC sickling and slowing of polymerization with hypothermia. Indeed, hypothermic cardiopulmonary bypass, including cold crystalloid cardioplegia and systemic hypothermia, have been and continue to be successfully used in cardiac surgery in sickle cell patients at one major center without any significant adverse effects.[54,71] This center’s protocol meticulously avoids hypoxia, acidosis, hypotension, and dehydration in these patients. It has been suggested that the level of anesthesia needed for cardiopulmonary bypass impairs thermoregulatory vasoconstriction, the presumed mechanism of hypothermia-induced sickling.[25,54]

Anesthetic Agents

In general, anesthetic techniques used in SCD patients must minimize exposure to hypoxemia, hypercapnia, acidosis, hypothermia, and hypovolemia during surgery. Care with positioning is important to minimize venous stasis. Respiratory depressants are avoided. Intubations are usually performed after paralysis with a short-acting agent. During induction, steps are taken to avoid breath holding, laryngeal spasm and struggling. A variety of anesthetic agents have been used successfully and the choice of a specific study, the use of halothane for anesthesia was associated with the lowest risk of perioperative atelectasis (25%) as compared with isoflurane (83%) or enflurane (59%).[72] The choice of agent used had no effect on SCD-related morbidity.
The relative safety of general anesthesia compared to regional anesthesia in SCD patients is unclear. SCD related complications were more frequent in those who received regional anesthesia compared with those who received general anesthesia in the Cooperative Study of Sickle Cell Disease.[27] However, there was no adjustment for potential confounding by the effect of obstetric procedures, for which regional procedures were more often used. Similarly, regional procedures were often used for sicker patients who were considered too high a risk for general anesthesia. Other studies have failed to confirm such an association between regional anesthesia and increased complications.[73,74] Theoretically, in regional anesthesia there is regional hypoperfusion, venous stasis, and lack of control of ventilation. There is a redistribution of blood flow with increase in capillary and venous oxygen tension in the blocked region, and compensatory vasoconstriction in the non-blocked area with resultant fall in oxygen.

Surgical Procedures

The uses of laparoscopic procedures have significantly shortened hospital stay. Among SCD patients, laparoscopic cholecystectomy and laparoscopic splenectomy are preferred compared to open cholecystectomy or splenectomy. In many centers, it has been associated with significant reductions in post-operative complications.[75-77] In one center, however, laparoscopic surgery did not decrease the risk of developing ACS.[78]
The use of an arterial tourniquet in SCD patients is controversial. It is dogma that application of arterial tourniquet creates ideal conditions for sickling from the stasis, hypoxia, and acidosis distal to the tourniquet. As such, SCD has long been considered a contraindication to tourniquet use.[79] This dogma is now being questioned.[80-83] Tourniquets have been used successfully in SCD patients with acceptable or no complications, while paying “meticulous attention to preoperative preparation and intraoperative management”.[83] It has been postulated that the acute acidotic environment induced by the tourniquet application alters endothelium-RBC membrane interactions, promote systemic vasodilatation, and “alter a host of other biochemical reactions” that on balance may not promote sickling.[83] No randomized studies have been conducted. A review of the rather limited published reports suggests that tourniquets may be used with relative safety in most patients with sickle cell disease with proper perioperative management.[84]

Radiological Contrast

Contrast imaging studies are often needed in cardiac and neurologic surgeries. Hyperosmolar contrast media can induce RBC dehydration, polymerization and sickling, with a resultant sickle crisis.[85] Isotonic media have no such deleterious effects.[86] Accordingly, it is recommended that low osmolar or isotonic contrast media be used in sickle cell disease patients.[86] Radiologic contrast should be avoided in SCD patients with renal failure.

Postoperative Care

Pain control. An important issue in the perioperative management of sickle cell disease patients is adequate pain control. Nonpharmacologic measures, including music, relaxation, heat or ice packs, may be used as adjuncts to pharmacologic pain management.[56] The patient's self-report, in addition to the vital signs, needs to be incorporated in adjusting pain medications. Many adult SCD patients in the US have had multiple exposures to opioids, are often opioid-tolerant, and tend to require large doses of opiates for adequate pain control.[56,87] If known, patients’ opioid doses used for management of their painful crises can serve as a guide to post-operative pain management. A combination of long-acting opioids and a short-acting opioid for breakthrough pain often provides adequate relief. Alternatively, continuous administration of pain medications, through the use of patient-controlled analgesia pumps, may be used. Morphine and hydromorphone are the major opioid agonists used for severe pain management in sickle cell patients in the post-operative period. These drugs have no ceiling effect. However, they can cause severe sedation and respiratory depression. Hence, doses should be discontinued or skipped in patients with a respiratory rate less than 10 and in those with severe sedation.
Acute chest syndrome. Sickle cell patients are at risk for acute chest syndrome in the immediate post-operative period. Excessive administration of IV fluids, as well as respiratory sedation from the use of opioid medications and adjuvants, potentiate this risk.[40] Maintaining adequate ventilation is the best preventive measure. Pre and post-operative use of incentive spirometry is strongly advised. The role of prophylactic CPAP in the immediate post-operative period has yet to be evaluated. Fluid administration should not exceed one and one-half (1.5) times the patient’s maintenance requirements.[40,56]
Prompt recognition of acute chest syndrome is important. By definition, acute chest syndrome is the presence of a new pulmonary infiltrates with chest pain, tachypnea, hypoxia, dyspnea, cough, fever, or leukocytosis.[30,40,56] However, not all the cardinal signs and symptoms may be present initially. The spectrum of presentation may range from mild, where hypoxia is minimal, to severe acute respiratory distress. Management consists of ensuring adequate ventilation, including the use of mechanical ventilation in severe cases, oxygen administration, bronchodilators (even in the absence of wheezing), antibiotics, moderate use of analgesia, and judicious hydration.[56] Simple blood transfusion or exchange transfusion in severe cases can accelerate the resolution. The use of steroids, particularly in adult patients, is controversial.[56] The use of nitric oxide or other vasodilators (calcium channel blockers, prostacyclin), and the nonionic surfactant poloxamer 188, is currently undergoing clinical trials.[56]
Deep vein thrombosis prophylaxis. Sickle cell disease is a hypercoagulable state.[88-90] Current evidence suggests increased platelet and coagulation activation, even at the patient’s basal state. SCD patients have low circulating levels of anticoagulant proteins C and S, moderate thrombocytosis, decreased platelet thrombospondin-1 content, and increased levels of markers of platelet activation.[88-90] Adequate deep vein thrombosis prophylaxis must be instituted after all major surgeries until the patients are sufficiently ambulatory.
Post-operative fever. Post-operative fever is a common complication of many major surgical procedures in the general population, with estimates ranging from 14% to 91% depending on the type of procedure.[91,92] Major traumatic surgeries are associated with higher risks of postoperative fever. Highest fever rates are observed after major orthopedic procedures.[91] Interleukin – 6 is an important driver of this response. Fever tends to be non-infectious in etiology if it occurs within the intra-operative period or in the first 48-hours. Other non-infectious causes include administration of blood products, heparin, and other medications. Infections account for most fevers occurring after the second postoperative day.[91,92]
Reported rates of post-operative fever among SCD patients are comparable to rates for non-SCD patients.[27,93,94] However, because of the higher rates of functional asplenia in SCD patients, they are more susceptible to invasive bacterial infections from encapsulated organisms such as Streptococcus pneumonia and Hemophilus influenza. These infections can be overwhelming if therapy is delayed. Fortunately, immunization with pneumococcal and Hemophilus influenza vaccinations have significantly decreased these risks in many countries. Nonetheless, the occurrence of post-operative fever in SCD requires careful clinical and laboratory evaluation. The extent of diagnostic work-up must be guided by the history and physical examination findings. Fever occurring after 48 hours must be managed as infectious in origin until proven otherwise. Common causes of infection include urinary tract infections, pneumonia, intravascular catheter-related infections, surgical site infections, and/or infected prosthesis. Viral infections from transfused blood products are now rare and tend to occur after 4 weeks.[92]

Conclusions

In conclusion, pre-operative assessment of SCD patients undergoing emergent or non-emergent surgery must include a careful review of the patient's known crisis triggers, baseline hematologic profile, standard transfusion requirements, pre-existing organ dysfunction and opioid use. Use of preoperative blood transfusions should be selective, and decisions must be individualized based on the baseline hemoglobin, surgical procedure and anticipated volume of blood loss. Intra- and post-operative management should focus on minimizing hypoxia, hypothermia, acidosis, and intravascular volume depletion. Excessive administration of IV fluids, as well as respiratory sedation from the use of opioid medications and adjuvants, potentiate the risk of acute chest syndrome. Use of pre- and post-operative incentive spirometry should be strongly encouraged. Arterial tourniquets and hypothermic cardiopulmonary bypass have been safely used in SCD patients at some centers.

Take Home Points

1.Surgical procedures in SCD have been associated with relatively increased risks of peri-operative mortality, vaso-occlusive (painful) crisis, acute chest syndrome, post-operative infections, congestive heart failure and acute kidney injury.
2.Use of preoperative blood transfusions should be selective.
3.Intra- and post-operative management should focus on minimizing hypoxia, hypothermia, acidosis, and intravascular volume depletion.
4.Pre- and post-operative use of incentive spirometry decreases the risk of acute chest syndrome.
5.Use of arterial tourniquets and hypothermic cardiopulmonary bypass in SCD patients, though controversial, have been safely utilized at some centers.

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