2514/23, 19:39 Management of Acute Events of Sickle Cell Disease Management of Acute Events of Sickle Cell Disease Overview and Recommendations Management of Acute Vaso-occlusive Crisis « An acute vaso-occlusive crisis typically manifesting as sudden new onset of intense pain lasting > 4 hours requiring treatment, is the most frequent acute complication of sickle cell disease (SCD) and the most common reason for visit to emergency department and admission to hospital « The painful crisis results from vaso-occlusion of small blood vessels, which leads to ischemia-reperfusion injury involving interactions with vascular endothelium, as well as contributions from hemolysis, inflammation, and coagulation. It may herald the onset of other complications of SCD such as acute chest syndrome and acute multiorgan failure. + Treat an acute painful sickle cell episode as a medical emergency. + Assess pain intensity using available pain scales (such as visual analog scale), perform a thorough review of signs and symptoms to identify potential triggers (including infection, cold exposure, fever, physical and/or emotional stress, and dehydration), obtain vitals including blood pressure, heart rate, respiratory rate, temperature and oxygen saturation on room air, and examine for findings suggestive of infection, acute chest syndrome, or other organ damage. + Other work up includes complete blood count, including platelet count, reticulocyte count, metabolic panel, and where appropriate, chest-x ray. « Rule out other causes of pain, including pneumonia, acute chest syndrome, papillary necrosis, hepatic or splenic sequestration, septic arthritis, trauma, and other comorbidities. * Supportive care for an acute vaso-occlusive crisis typically includes administration of oxygen, especially if oxygen saturation is < 95%, hydration, use of incentive spirometry, and encouraging patient ambulation and activity. « Transfusion is not recommended in uncomplicated vaso-occlusive crisis but should be considered if there is worsening anemia (for example, decrease of hemoglobin by 2 2 g/dL [20 g/L]) compared to steady state values or hemoglobin <5 g/dl. [50 g/L), hemodynamic compromise, or concern about impending critical organ complications (Strong recommendation). + Pain management: © Choice of a primary analgesic depends on pain severity: - For mild-to-moderate pain, consider treatment with oral nonsteroidal anti- inflammatory drugs (NSAIDs) unless NSAIDs are contraindicated (Weak recommendation), NSAIDs are not suggested if serum creatinine is above the upper limit of normal for age, especially in the presence of albuminuria. https:siwww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-cel-c ase 11592514/23, 19:39 Management of Acute Events of Sickle Cell Disease - For severe pain, rapidly initiate parenteral opioids (Strong recommendation). Adjunctive treatments to consider include: ~ Medications to increase analgesic effect of opioids or reduce side effects of primary medications, for example antihistamines (to offset histamine release by mast cells due to opioids, especially morphine), antiemetics, laxatives, antidepressants, and gabapentinoids. - Nonpharmacologic approaches to treat pain, for example, local heat application and distraction (Weak recommendation). Also consider other approaches such as massage, yoga, transcutaneous electrical nerve stimulation, virtual reality, and guided (audio-visual) relaxation (Weak recommendation). Management of Other Acute Complications « Acute anemia o Defined as a reduction in hemoglobin 2 2 g/dL (20 g/L) below baseline. « May occur as the result of acute chest syndrome, acute splenic sequestration, acute hepatic sequestration, aplastic crisis, hyperhemolysis (from red blood cell transfusion, infection or pain crisis), or acute blood loss. © Obtain a complete blood count, platelet count, and reticulocyte count in all patients with SCD and acute illness (Strong recommendation). Additional evaluation may include: - parvovirus B19 serology for suspected aplastic crisis = direct and indirect antiglobulin test (Coombs test) for suspected transfusion associated hyperhemolysis - blood and urine cultures for suspected infection - chest x-ray for acute chest syndrome - liver function tests for suspected hepatic sequestration = renal function tests for suspected renal failure — unconjugated serum bilirubin, and urine urobilinogen and hemoglobin for hyperhemolysis = tests to diagnose other causes of anemia such as serum vitamin B12, folate levels and glucose-6-phosphate dehydrogenase deficiency if needed. © Aplastic crisis - Typically caused by parvovirus B19-mediated suppression of red blood cell production. ~ Suspected in patient with history of preceding febrile illness. ~ Patient may present with nonspecific symptoms of headache, fever, and shortness of breath, signs of lethargy, and tachycardia and complete blood count showing hemoglobin far below baseline (3-6 g/dL [30-60 g/L]) and severe reticulocytopenia. - Spontaneous resumption of erythropoiesis typically occurs within 7-10 days of aplasia, restoring the hemoglobin to steady state level. - Administer immediate red blood cell transfusion to restore hemoglobin to safe (though not necessarily baseline) level.(Strong recommendation). https:siwww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-cel-c ase 2592514/23, 19:39 Management of Acute Events of Sickle Col Disease ~ Isolate hospitalized patients to prevent spread of parvovirus B19 to pregnant women, other patients with SCD, or patients with compromised immunity (Strong recommendation), © Splenic sequestration - Caused by trapping of red blood cells in the splenic sinuses which leads to a sudden rapid enlargement of the spleen — Usually occurs in children aged <5 years before the spleen has spontaneously infarcted. - Suspect in young patient with sudden enlargement of spleen, causing severe abdominal pain and distension, signs of hypovolemia, hemoglobin decrease 22 g/dL from baseline with elevated reticulocyte count, and circulating nucleated red blood cells. = Suspect in adults with hemoglobin SC disease or sickle beta-thalassemia* with milder symptoms, or with severe pain from splenic infarction, - In cases of hypovolemia from severe acute splenic sequestration, provide immediate IV fluids (Strong recommendation) - Incases of severe anemia, perform a transfusion in consultation with a SCD expert to increase hemoglobin to a stable level (Strong recommendation) - Consider splenectomy in patients with recurrent acute splenic sequestration or symptomatic hypersplenism (Weak recommendation). Hyperhemolytic crisis - Acute anemia with the evidence of accelerated hemolysis may result from acute vaso-occlusive painful crises, acute or delayed hemolytic reaction following a transfusion of red blood cells, infection, or drug exposure. - Suspect transfusion-associated hyperhemolytic crisis in patients with SCD with recent red blood cell transfusion who present with drop in hemoglobin below pretransfusion levels, paradoxical reticulocytopenia, increased unconjugated serum bilirubin, positive direct antiglobulin test (Coombs test) (though may be negative), and hemoglobinuria. - Transfusion-associated hyperhemolytic crisis is characterized by hemolysis of both donor and autologous red blood cells (bystander hemolysis). Additional transfusions may cause further hemolysis, leading to life-threatening anemia. - in patients with delayed hemolytic reaction and continuing hyperhemolysis, consider immunosuppressive therapy with IV immunoglobulin, corticosteroids, rituximab, and/or eculizumab (Weak recommendation). * Acute chest syndrome o Usually develops during a painful crisis or after surgery. o Reported causes include acute infection, bone marrow fat embolism from necrotic bone marrow during pain crisis, and microvascular pulmonary infarction from intravascular sickling. ° Suspect acute chest syndrome in patients presenting with fever and/or respiratory symptoms, together with clinical signs of new pulmonary infiltrate and low oxygen https:siwww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-cel-c ase 31592514/23, 19:39 Management of Acute Events of Sickle Cell Disease saturation. e Evaluation includes: = chest x-ray = complete blood count, including platelet count = renal and liver function tests = blood cultures = oxygen saturation (SpO,) measurement by pulse oximetry - arterial blood gas on room air in adults (if Sp) < 94% on room air) - serology for atypical respiratory organisms and urine for Pneumococcal and Legionella antigen = sputum for bacterial culture and sputum and nasopharyngeal aspirate for immunofluorescence or polymerase chain reaction (PCR) for viruses in patients with coryzal symptoms - determination of the presence of fat bodies causing pulmonary fat embolism in bronchoalveolar fluid and in induced sputum « Diagnosis supported by low oxygen saturation or hypoxemia and new pulmonary infiltrate on chest x-ray. o Consider presence of triggering factors including pulmonary embolism, fluid overload, and opiate overdose. © Initiate treatment with 2 broad-spectrum antibiotics and supplemental oxygen as needed, and monitor for bronchospasm, acute anemia, and hypoxemia (Strong recommendation). Recommendations for transfusion - For patients with mild acute chest syndrome and decrease in hemoglobin > 1 g/dL. (10 g/L) below baseline: + Consider simple blood transfusion (10 mL/kg red blood cells in children) to improve oxygen carrying capacity. In adults, amount of red blood transfusion is determined by degree of anemia and reasons for transfusion. + If hemoglobin concentration is = 9 g/dL (90 g/L), simple transfusion may not be necessary (Weak recommendation), - For patients with severe or rapidly progressing acute chest syndrome: « urgent exchange transfusion with consultation from hematology, critical care, and/or apheresis specialists is indicated «Signs of rapid progression include oxygen saturation < 90% on supplemental oxygen, increasing respiratory distress, progressive pulmonary infiltrates and decreased hemoglobin despite simple transfusion (Strong recommendation). + Consider exchange transfusion aiming for a %HDS target of < 30% o Start hydroxyurea in adults with sickle cell anemia with a history of severe or recurrent acute chest syndrome (Strong recommendation). Priapism o Typically defined as unwanted painful erection lasting 2 4 hours. https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 41592514/23, 19:39 Management of Acute Events of Sickle Col Disease o Characterized by pain in the penis and/or scrotum, a fully erect penis and a soft glans. o Goals of treatment are pain relief and prevention of impotence. o Initiate vigorous oral or IV hydration and oral or IV analgesia (Strong recommendation). o Consult with a urologist for further evaluation and intervention for symptoms which do not resolve with initial conservative management (Strong recommendation). o Transfusion therapy for immediate treatment of priapism is not recommended, but may be indicated in preparation for surgery. * Acute renal failure o Defined as rapid reduction in renal function manifested by increased serum creatinine and reduced glomerular filtration rate, with or without decreased urine output. o Causes include pre-renal causes, such as dehydration, intrinsic renal disease, including glomerular injury, and post-renal causes such as obstruction. o Assess for predisposing factors including volume depletion, hypethemolysis, and use of non-steroidal anti-inflammatory drugs © Patients with SCD have increased renal tubular secretion of creatinine, which may mask early renal insufficiency. o For patients with an acute increase in serum creatinine 2 0.3 mg/dL (26.5 mcmol/L), monitor renal function daily, avoid potential nephrotoxic drugs and imaging agents, and investigate all potential etiologies in consultation with a nephrologist (Strong recommendation). « Fever and infection © Treat fever as a medical emergency due to risk of overwhelming bacterial infection as a result of reduced or absent splenic function. o Causes include: = septicemia and meningitis (most common causative organism Streptococcus pneumoniae) - acute chest syndrome associated with diverse organisms (including mycoplasma) ~ gram-negative enteric infections involving the urinary tract or hepatobiliary system - osteomyelitis caused by Staphylococcus aureus, salmonella, or other enteric pathogen o For patients with a temperature 2 101.3 degrees F (38.5 degrees C), workup includes history and physical, complete blood count with differential, platelet count, reticulocyte count, blood culture, sputum culture/gram stain as needed, and urine culture if urinary tract infection is suspected. o If febrile illness occurs with: - shortness of breath, tachypnea, cough, and/or rales, obtain chest x-ray immediately to assess for acute chest syndrome (Strong recommendation). - localized or multifocal bone tenderness, especially with erythema and swelling, consider bacterial osteomyelitis in differential diagnosis and manage patient accordingly (Strong recommendation) https:siwww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-cel-c ase 5592514/23, 19:39 Management of Acute Events of Sickle Cell Disease o In children with a temperature 2 101.3 degrees F (38.5 degrees (), start empiric treatment with parenteral antibiotics which cover Streptococcus pneumoniae and gram-negative enteric organisms (Strong recommendation). Inpatients with temperature 2 103.1 degrees F (39.5 degrees C) who appear ill, admit to hospital for close observation and IV antibiotic treatment (Strong recommendation). Stroke More common in patients with sickle cell anemia than in patients with hemoglobin SC disease or hemoglobin S-beta®-thalassemia. «Patients with overt ischemic stroke may be preceded by a transient ischemic attack and present with sudden weakness, aphasia, seizures, or coma Patients with hemorrhagic stroke may present with severe headache or loss of consciousness without hemiparesis. o For patients with SCD and suspected stroke (Strong recommendation): - seek consultation with a SCD expert and/or neurologic consultation. - perform an urgent head computerized tomography (CT) scan followed by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) if available e Perform an exchange transfusion in patients who develop acute stroke confirmed by neuroimaging, in consultation with a SCD expert (Strong recommendation), o Consider hydroxyurea therapy if a transfusion program is not possible (Weak recommendation). Hepatobiliary complications @ Acute complications include acute cholecystitis, acute choledocholithiasis acute hepatic sequestration [AHS] and acute intrahepatic cholestasis [AIC]) « Patients with acute cholecystitis may present with severe colicky pain in the right upper quadrant, nausea and vomiting, fever, abdominal tenderness and leukocytosis. o Patients with acute choledocholithiasis typically present with dull pain in the right upper quadrant, tender hepatomegaly and rapidly increasing jaundice. «Patients with AHS present with hepatic enlargement without other explanation, > 2 g/dL decrease in hemoglobin from baseline and rise in the reticulocyte count. o Patients with AIC present sudden onset of right upper quadrant pain, increasing jaundice, light-colored stool, thrombocytopenia and coagulation abnormalities, and progressively enlarging and tender liver may be present. Abdominal ultrasound and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) studies can help diagnose acute cholecystitis and maybe useful for investigation of common bile duct gallstones. « For patients with suspected AHS or AIC, provide hydration, rest, and close observation and consult with a SCD expert to confirm diagnosis and to determine further management (Strong recommendation). o For patients with confirmed AHS or severe AIC, perform a simple or exchange transfusion (Strong recommendation). Ocular complications https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 61592514/23, 19:39 Management of Acute Events of Sickle Col Disease « Acute ocular complications include hyphema, central retinal artery occlusion and orbital infarct. Hyphema defined by presence of blood in ocular anterior chamber is usually caused by trauma and may present with visual abnormalities (floaters and flashers, light sensitivity, and/or blurry vision). It may result in increased intraocular pressure, which may in turn lead to central retinal artery occlusion and infarction of the optic nerve. » Orbital infarct results from infarction of the orbital bone, typically during a vaso- occlusive crisis and presents with eye protrusion, eye pain, and lid and/or orbital edema Arrange immediate consultation with an ophthalmologist for patients presenting with hyphema (Strong recommendation). o Promptly refer any patient with signs and symptoms of eye trauma including protrusion of the eye, changes in visual acuity (floaters or flashers), and unilateral or bilateral vision loss to an eye specialist for a dilated eye exam to assess visual acuity, intraocular pressure, and the peripheral retina (Strong recommendation) * Multisystem organ failure o Asevere, life-threatening complication typically associated with a vaso-occlusive crisis and characterized by the failure of the lungs, liver, and/or kidneys. o Immediately start transfusion therapy (preferably exchange) in consultation with a SCD expert or hematologist (Strong recommendation). « Venous thromboembolism (VTE) Patients with SCD have increased risk of VTE. Recommendations for VTE treatment or prophylaxis are based on individual assessment for the risk of thrombosis and bleeding. © Anticoagulation for first time VTE: ~ First VTE: « If unprovoked, consider indefinite anticoagulant therapy rather than shorter duration of therapy (Weak recommendation). « If provoked (by surgery or nonsurgery-related), consider anticoagulation for 3-6 months rather than indefinite duration of therapy (Weak recommendation). « Indefinite anticoagulation is not suggested for first VTE provoked by factors such as central venous line. However anticoagulation should be continued as long as provoking risk is present (including central venous line). - For recurrent provoked VTE, consider indefinite duration of anticoagulation rather than defined duration of therapy (Weak recommendation). « See Chronic Management of Sickle Cell Disease for information on strategies to prevent acute complications of SCD. Acute Vaso-occlusive Crisis (VOC) General Considerations https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 71592514/23, 19:39 Management of Acute Events of Sickle Cell Disease = voc!:23 2 most frequent acute complication of sickle cell disease (SCD) = most common cause of emergency department visits and hospitalization for patients with SCD; reported to account for 95% of all admissions = occurs in nearly all patients with SCD = more frequent in hemoglobin (Hb) SS or HbS beta®-thalassemia compared to other types of SCD - often occurs prior to onset of other complications of the disease such as acute chest syndrome and acute multiorgan failure = should be treated as an acute medical emergency (NICE 2012 Jun:CG143 por @) e typical presentation includes = dactylitis (also known as hand foot syndrome) with associated pain and swelling in hands and feet in children - sudden new onset of intense pain (though some present with gradual onset), that has no cause other than SCD lasting > 4 hours requiring treatment with opioids or other analgesics (N Eng] | Med 1995 May 18;332(20):1317 full-text B), commentary can be found in N Engl J Med 1995 Oct 12;333(15):1008 J = pain occurs most commonly in the extremities, chest, and back in adults Image 1 of 4 Dactylitis "Sausage-shaped' third and fourth digits of the left foot and fourth digit of the right foot caused by dactylitis. Used with permission from the American College of Physicians. Image 2 of 4 Dactylitis Dactylitis manifests as swelling of the entire digit and arises from inflammation of the flexor tendon and adjacent soft tissue. Used with permission from the American College of Physicians. https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease ais2514/23, 19:39 Management of Acute Events of Sickle Col Disease o results from vaso-occlusion of small blood vessels, which leads to ischemia- reperfusion injury involving interactions with vascular endothelium, as well as contributions from hemolysis, inflammation, and coagulation o factors associated with increased frequency of episodes include — higher Hb levels = environmental factors, including + hot and cold weather (though inconsistent results reported across studies) « higher wind speeds + high and low humidity * exposure to firsthand or secondhand tobacco smoke « Reference - N EnglJ Med 2017 Jul 20;377(3):305 e factors associated with decreased frequency of episodes include - high levels of fetal hemoglobin (HbF) - coinheritance of alpha-thalassemia, beta*- thalassemia, or HbSC e ina minority of cases, VOC is preceded by obvious precipitating factor; such factors include - dehydration = stress (physical or emotional) ~ infection - asthma = acidosis ~ sleep apnea = climate (especially sudden changes in temperature) = pregnancy = menstruation (| Womens Health (Larchmt) 2019 Feb;28(2):162 B) © patients with > 3 hospitalizations for VOC in 1 year are at increased risk of early death © evaluation = no specific tests for diagnosis of VOC — consider assessing intensity of pain by several methods such as visual analog scale, verbal scale, numerical scale, or Wong-Baker faces scale for childre! should be chosen and used routinely = may present with low-grade fever, mild decrease in Hb, increased leukocyte count, decreased platelet count, increased lactate dehydrogenase, and increased reticulocyte count, but may also present with normal vital signs and hematologic parameters unchanged frorn baseline scale o rule out other causes of pain, including — pneumonia = acute chest syndrome - acute stroke ~ papillary necrosis - hepatic or splenic sequestration, or other hepatobiliary complications https:siwww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-cel-d ase 91s2514/23, 19:39 Management of Acute Events of Sickle Col Disease - trauma = causes not related to SCD such as migraine headache, menstruation, or comorbidities © perform thorough review of systems since minor infections including dental decay, gingivitis, urinary tract infections, and minor upper respiratory infection may trigger crisis (Emerg Med Pract 2011 Aug;13(8):1 @, J Interdiscip] Med Dent Sci 2014, 2:6 B) o observe for sudden clinical changes during episodes of severe pain since they may indicate impending life-threatening complications; key clinical changes include 4 ~ increasing oxygen requirement - decreasing Hb or platelet level - altered mental status = sudden change in renal function e Reference - Annu Rev Genomics Hum Genet 2018 Aug 31;19;113 B Treatment Setting « general considerations » acute care for patients with sickle cell disease (SCD) is most often provided in the emergency department which is associated with several barriers to optimal care; these include - lack of continuity and communication with patient's SCD care team ~ delays in initial administration of analgesia, re-evaluation, and repeat dosing = stigma and discrimination and negative provider attitudes towards patients who may be labeled as drug-seeking, especially during the present opioid epidemic - increased burden on the health care system o Reference - Blood Adv 2020 Jun 23;4(12):2656 Bfull-text B + American Society of Hematology (ASH) recommendations in patients who develop SCD-related acute pain episode requiring hospital care, consider admission to hospital-based acute care facilities such as day hospitals and infusion centers with experience in evaluating, diagnosing and treating pain and other SCD-related complications over typical emergency department-based care (ASH Conditional recommendation, Low-certainty of effects) o these acute care settings include, but are not limited to, day hospital, observation unit, acute pain center, infusion center, or inpatient unit o care at SCD-specific hospital-based acute care facilities allows direct access to pain management and continuity of care with primary SCD health care team; benefits include - improved pain control - shorter time to administration of analgesics - shore length of hospital stay and decreased frequency of hospitalization - reduced need for emergency department care after facility discharge e Reference - Blood Adv 2020 Jun 23;4(12):2656 Bfull-text B https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 10/592514/23, 19:39 Management of Acute Events of Sickle Cell Disease STUDY SUMMARY treatment in infusion center associated with shorter time to first dose of parenteral pain medication and higher rate of pain reassessment and discharge to home compared to treatment in emergency department in adults with sickle cell disease having uncomplicated VOC (pynamted Level 2 COHORT STUDY: Ann Intern Med 2021 Jul 6 early online Details ¥ © based on prospective cohort study © 483 adults (mean age 34 years, 61% women) with sickle cell disease living within 60 miles of infusion centers in 4 study sites who had acute care visits within previous 2 years were enrolled and followed for 18 months © 269 patients (mean age 33 years, 61% women) who completed follow-up and had 2 1 acute care visit to infusion center or emergency department on weekdays were included in analysis e 1,441 acute care visits for uncomplicated VOC (defined as acute episode of pain with no other known cause that required parenteral therapy) occurred including = 1,200 infusion center visits - 241 emergency department visits © propensity score for likelihood of visiting infusion center or emergency department was calculated for each acute care visit based on clinical, demographic, and healthcare use factors © comparing infusion center visits vs. emergency department visits in propensity- matched analysis = mean time to first dose of parenteral pain medication 62 minutes vs. 132 minutes (p < 0.001) - rate of completed pain reassessment within 30 minutes of first dose of parenteral pain medication 38% vs. 10% (p < 0.001) infusion center visits associated with increased likelihood of discharge to home compared to emergency department visits (p < 0.001) Reference - Ann Intern Med 2021 Jul 6 early online @, editorial can be found in Ann Intern Med 2021 Jul 6 early online B Supportive Care « administer oxygen if patient has oxygen saturation < 95% on room air (NHLBI Consensus-Panel Expertise) ' « hydration « avoid overhydration by checking daily intake/output in hospitalized patient, daily weight, and presence of edema (Paediatr Drugs 2018 Feb;20(1):29 B) « guideline recommendations on IV fluid administration https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 111592514/23, 19:39 Management of Acute Events of Sickle Cell Disease - National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) recommendation - in euvolemic patients unable to drink fluids, provide IV hydration, but do not exceed maintenance rate (NHLBI Consensus-Adapted) ! - American Society of Hematology (ASH) guidance + no recommendation offered for or against IV fluids in addition to standard pharmacologic therapy for treatment of acute pain + in this nonrecommendation, IV fluid administration refers to bolus infusions and infusions to maintain adequate fluid balance as well as type of fluids administered in these infusions (for example, normal [0.9%] saline, half-normal [0.45%] saline) + this guidance does not apply to administration of IV fluids to patients with significant dehydration to re-establish euvolemia « risks associated with administration of IV fluids may be greater in adults compared to children because adults have more cardiopulmonary dysfunction and other comorbid conditions « Reference - Blood Adv 2020 Jun 23;4(12):2656 Bfull-text Z STUDY SUMMARY no randomized trials found evaluating fluid replacement therapy for acute painful episode in patients with sickle cell disease COCHRANE REVIEW: Cochrane Database Syst Rev 2017 Jul 31;7:cD005406 Details ¥ ~ based on Cochrane review = systematic review of randomized or quasi-randomized trials evaluating supplemental fluids by any route in addition to analgesics for acute painful episode in patients with sickle cell disease (SCD) - 16 studies were identified but were not eligible for inclusion ~ Reference - Cochrane Database Syst Rev 2017 Jul 31;7:cD005406 * to reduce the risk of acute chest syndrome in patients hospitalized for VOC ' encourage use of incentive spirometry while awake (NHLBI Strong Recommendation, Moderate-quality Evidence) encourage ambulation and activity as soon as possible (NHLBI Consensus-Panel Expertise) STUDY SUMMARY incentive spirometry associated with reduced rate of pulmonary complications of acute chest syndrome in children and adolescents with sickle cell disease hospitalized with acute chest pain (_bynaMed Level 3 RANDOMIZED TRIAL: N Engl J Med 1995 Sep 14;333(11):699 Details ¥ https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 121592514/23, 19:39 Management of Acute Events of Sickle Col Disease - based on small randomized trial without clinical outcomes - 29 patients aged 8-21 years with SCD who were hospitalized for 38 episodes of acute chest or back pain above diaphragm and had unchanged or normal chest x- rays were randomized to incentive spirometry vs. control - incentive spirometry group took 10 maximal inspirations with incentive spirometer every 2 hours between 8 AM and 10 PM and while awake at night until chest pain subsided - thoracic bone infarction occurred in 39.5% - comparing incentive spirometry vs. control, pulmonary complications (atelectasis or infiltrates) in = 5% vs. 42% overall (p = 0.019, NNT 3) ‘* 0% vs. 63% in patients with thoracic bone infarction (p = 0.025, NNT 2) - Reference - N Engl | Med 1995 Sep 14;333(11):699 Z Pain Management General Considerations + National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) recommendations for acute pain management! © pain management should be guided by patient-reported pain severity, using analgesia (typically opioids) for treatment in adults and children with sickle cell disease (SCD) and pain, evaluate for causes of pain other than VOC while starting treatment for painful episode (NHLBI Consensus- Adapted) © determine characteristics, symptoms, location, and intensity of pain based on patient self-report and observation; if VOC pain atypical, investigate for other possible causes of pain (NHLBI Consensus-Adapted) © assess patient's recent use of analgesia (opioid and nonopioid) (NHLBI Consensus- Adapted) e initiate analgesic therapy within 30 minutes of triage, or within 60 minutes of registration (NHLBI Consensus-Panel Expertise) © analgesia should be selected based on pain assessment, associated symptoms, outpatient analgesic use, patient's knowledge of effective agents and doses, and past experience with side effects (NHLBI Consensus-Adapted) © use an individualized prescribing and monitoring protocol or a SCD specific protocol whenever possible (NHLBI Consensus-Panel Expertise) « American Society of Hematology (ASH) recommendations for acute pain management ° assess patient and administer analgesia immediately (within 1 hour of emergency department arrival), with frequent assessment (every 30-60 minutes) to ensure optimal pain control (ASH Strong recommendation, Low-certainty of effects); for rapid analgesic treatment, consider non-IV route of analgesic administration (for example, subcutaneous or intranasal) © benefits of rapid assessment and administration of analgesia include https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 19/592514/23, 19:39 Management of Acute Events of Sickle Cell Disease ~ avoiding hospital admission ~ earlier detection of other underlying serious condition that may be present in patient with acute pain o Reference - Blood Adv 2020 Jun 23;4(12):2656 B full-text Nonopioid Analgesics « general considerations e while opioids are standard and effective treatment for SCD-related acute pain, some patients do not respond to opioids alone 2 minimizing opioid exposure is suggested due to short- and long-term risks e while opioids are not used as chronic pain management in most patients, administration of nonopioid analgesics for acute pain may help reduce total dose and duration of exposure to opioids while maintaining or improving pain control o Reference - Blood Adv 2020 Jun 23;4(12):2656 B full-text B * guideline recommendations NHLBI recommendation - consider nonsteroidal anti-inflammatory drugs (NSAIDs) for management of mild-to-moderate pain (NHLBI Moderate recommendation, Low- quality evidence), and offer oral NSAIDs as adjuvant analgesic unless contraindicated (NHLBI Consensus-Adapted)! ° ASH recommendations for patients with SCD-related acute pain = consider short course (5-7 days) of NSAID) in addition to opioids (ASH Conditional recommendation, Very low-certainty of effects) ~ NSAIDS include selective and nonselective COX inhibitors ~ factors to consider when evaluating patient for treatment with NSAIDs include, but not limited to « renal, vascular, and gastrointestinal toxicity © Patient at risk of renal toxicity is especially important to identify o in patients with comorbidities with significant risk such as peptic ulcer disease and renal dysfunction, potential benefits of NSAIDs may not outweigh the harms * anticoagulation requirements; in patients on full-dose anticoagulation, potential benefits of NSAIDs may not outweigh the harms + presence of cardiovascular disease ~ Reference - Blood Adv 2020 Jun 23;4(12):2656 B full-text B « if serum creatinine is above the upper limit of normal for age, consider holding NSAIDs, especially in the presence of albuminuria? STUDY SUMMARY continuous infusion of ketorolac might reduce acute VOC pain at 24 hours in adults with SCD (_bynamed Level 2 COCHRANE REVIEW: Cochrane Database Syst Rev 2019 Nov 14;2019(11):CD012187 & https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 141592514/23, 19:39 Management of Acute Events of Sickle Cell Disease Details v e based on Cochrane review with limited evidence e systematic review of 9 randomized trials evaluating pharmacological treatments of acute, painful VOC in 594 adults with SCD © 3 small trials (sample size range 21-54 patients) compared NSAIDs to placebo o heterogeneity in methodology and outcomes precluded meta-analysis © comparing ketorolac 30 mg (loading dose) followed by continuous IV infusion ketorolac 120 mg on day 1 and maximum 120 mg up to 5 days compared to placebo in 1 trial with 21 adults, continuous ketorolac IV infusion associated with - reduced pain score at 24 hours on 0-100 visual analog scale (VAS) (mean 58.6 points with ketorolac vs. 72.6 points with placebo, p < 0.05) - shorter duration of hospital stay (median 3.3 days vs. 7.2 days, p < 0.05) © no significant differences in pain scores on 0-100 VAS in 1 trial with 18 patients comparing ketorolac 60 mg intramuscularly to placebo at 4 hours © no significant difference in rescue opioid consumption found in either trial © no trials reported on proportion of patients with 2 50% or 2 30% reduction in pain o Reference - Cochrane Database Syst Rev 2019 Nov 14;2019(11):cb012187 B o IV ketoprofen may not be associated with shortened duration of VOC or improved pain relief in adults with SCD DynaMed Level 2 - based on small randomized trial - 54 patients > 15 years (mean age 27 years) homozygous for SCD with VOC requiring hospital admission (66 episodes evaluated) were randomized to IV ketoprofen vs. placebo + ketoprofen given as 300 mg/day by continuous IV infusion for 2 days, then 100 mg every 8 hours for 3 days « all patients had standard therapy (bed rest, fluid replacement, folic acid, and analgesia) = no significant difference between groups in « duration of VOC morphine consumption + pain relief treatment failure - Reference - Blood 2009 Oct 29;114(18):3742 B STUDY SUMMARY addition of IV acetaminophen may not reduce opioid dose requirement or treatment duration in children with SCD on opioids for VOC (_bynated Level 2 COHORT STUDY: P T 2019 Jan;44(1):5 B | Full Text B Details ¥ https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 15/592514/23, 19:39 Management of Acute Events of Sickle Cell Disease © based on retrospective cohort study @ 46 children with SCD presenting with pain from VOC were administered IV acetaminophen with opioids (39%) or opioids alone were evaluated mean acetaminophen dose ranged from 12.5 mg/kg/dose IV every 4 hours to 15 mg/kg/dose IV every 6 hours; time between administration of opioid and acetaminophen = 45 minutes most common IV opioid administered was morphine, followed by hydromorphone; most common oral opioid administered was oxycodone comparing IV acetaminophen with opioids vs. opioids alone = daily opioid requirement (morphine equivalent) 2.6 mg/kg vs. 3.1 mg/kg (not significant) - duration of opioid treatment duration 3.4 days vs. 3.8 days (not significant) = mean pain score (out of score of 10 with higher score indicating more pain) 4.6 vs. 5.4 (no p value reported) - gastrointestinal and respiratory adverse effects 50% vs. 61% (no p value reported) o Reference - P T 2019 Jan;44(1):5 @full-text B Opioid Analgesics « initiating opioid therapy © NHLBI recommendations for initiation of opioid therapy | - for severe pain, rapidly initiate parenteral opioids (NHLBI Strong Recommendation, High-quality Evidence) ~ calculate parenteral opioid dose (IV or subcutaneous) based on total daily short- acting opioid dose currently used in outpatient setting to manage VOC pain (NHLBI Consensus-Panel Expertise) = use subcutaneous administration if IV access is difficult (NHLBI Consensus-Panel Expertise) = reassess pain and re-administer opioids every 15-30 minutes if necessary for continued severe pain until patient reports adequate relief of pain (NHLBI Consensus-Adapted) = maintain dose, or consider 25% dose escalation until pain is controlled (NHLBI Consensus-Panel Expertise) ~ reassess after each dose for pain relief and side effects (NHLBI Consensus-Panel Expertise) ~ initiate around-the-clock opioid administration by patient-controlled analgesia (PCA) or frequently scheduled doses, instead of as requested (PRN) administration (NHLBI Moderate Recommendation, Low-quality Evidence) ASH recommendations - in patients presenting to acute care setting, if opioid therapy is indicated, consider dosing based on baseline opioid therapy and prior effective treatment (ASH Conditional recommendation, Moderate-certainty of effects for adults; ASH conditional recommendation, Low-certainty of effects in children) https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 16/592514/23, 19:39 Management of Acute Events of Sickle Cell Disease ~ individualized treatment plans should be developed by acute care and SCD specialists and incorporated into electronic medical record to help guide opioid dosing - for minority of patients, frequent treatment for acute pain using individualized opioid dosing may be unhelpful and detrimental to long-term goals for care; chronic care strategy with other approaches may be required ~ acute pain management should take into consideration patient preferences and incorporate patient education on limits and harms of opioid therapy - standard of care for treatment of acute pain at most hospitals is to administer IV opioids by PCA when appropriate; addition of basal opioid infusion (continuous IV opioid infusion) is a common practice despite limited evidence of benefit = no recommendation offered for or against basal opioid dosing in patients requiring treatment for acute pain in the hospital in conjunction with on-demand dosing (opioid given at frequency depending on patient need) or scheduled intermittent dosing (opioids given on set schedule that is not reliant on patient request) - Reference - Blood Adv 2020 Jun 23;4(12):2656 @ full-text B + do not use meperidine unless it is the only effective opioid for an individual patient (NHLBI Consensus-Adapted) due to neurotoxicity! * monitoring and titration for patients receiving opioids ' ° monitor patients receiving opioids for oversedation using objective measurement sedation scale, respiratory rate, and oxygenation levels (NHLBI Consensus-Panel Expertise) gradually titrate down parenteral opioids as VOC resolves (NHLBI Consensus-Panel Expertise) © if using around-the-clock continuous infusion of opioids via PCA, determine whether long-acting oral opioids should be withheld to prevent oversedation (NHLBI Consensus-Panel Expertise) ~ if demand-dosing only ordered via PCA, continue use of long-acting oral opioids (NHLBI Consensus-Panel Expertise) - at discharge, evaluate inpatient analgesic requirements, wean parenteral opioids prior to conversion to oral opioids, and adjust home dosing of long- and short- acting opioid prescriptions to prevent subsequent opioid withdrawal symptoms (NHLBI Consensus-Panel Expertise) « for patients who require antihistamines for itching secondary to opioid administration (NHLBI Consensus-Panel Expertise) ' o prescribe agents orally o re-administer every 4-6 hours as needed STUDY SUMMARY insufficient evidence to evaluate opioids to relieve acute VOC pain in adults with SCD https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 171592514/23, 19:39 Management of Acute Events of Sickle Cell Disease COCHRANE REVIEW: Cochrane Database Syst Rev 2019 Nov 14;2019(11):CD012187 & Details v « based on Cochrane review 2 systematic review of 9 randomized trials evaluating pharmacological treatments of acute, painful VOC in 594 adults with SCD © 2trials compared opioid to active comparator o heterogeneity in methodology and outcomes precluded meta-analysis comparing IV morphine vs. paracetamol in 1 trial with 106 patients (available as abstract only) = mean pain score at 30 minutes on 0-100 VAS 44 mm vs. 41 mm (not significant) - additional rescue morphine at 30 minutes in 50% vs. 46% (no p value reported) comparing intramuscular morphine vs. butorphanol in 1 trial with 18 patients = mean pain score on 0-100 VAS 46 mm vs. 44 mm (no p value reported) ~ patient-reported global impression of improvement as excellent in 33.3% vs. 19.1% (no p value reported) - patient-reported global impression of improvement as good in 38.1% vs. 47.6% (no p value reported) « no serious adverse events reported in any group in both trials e Reference - Cochrane Database Syst Rev 2019 Nov 14;2019(11):cD012187 4 « review of opioids for management of acute painful crisis in adults with SCD can be found in BrJ Haematol 2014 Jul;166(2):157 B Combination Analgesia STUDY SUMMARY addition of fentanyl buccal tablet to continuous infusion of ketorolac plus tramadol plus metoclopramide may reduce VOC pain in adults with SCD (_bynaMed Level 2 RANDOMIZED TRIAL: Pain Pract 2016 Jul;16(6):680 Details ¥ «based on nonrandomized crossover trial (available as abstract only) © 20 adults aged 18-45 years (mean age 22 years) with SCD presenting to emergency department with severe pain (VAS score 2 7) VOC and who had not received opioids in previous 2 weeks were given 1 of 2 combination analgesia regimens during 2 VOC episodes occurring 2 6 months apart - first VOC episode treated with continuous IV infusion of ketorolac 0.86 mg/kg/day plus tramadol 7.2 mg/kg/day plus metoclopramide 0.57 mg/kg/day up to 72 hours (KTM infusion) - second VOC episode treated with KTM infusion plus fentanyl 100 meg buccal tablet + fentanyl tablet given 3 hours after start of KTM infusion « fentanyl could be repeated at 2 30 minutes from first dose (maximurn 24-hour cumulative dose 400 mcg) https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 18/592514/23, 19:39 Management of Acute Events of Sickle Col Disease © comparing fentanyl plus KTM infusion vs. KTM infusion - 50% reduction in pain intensity at 6 hours in 60% vs. 0% (p < 0.0001, NNT 2) - 50% reduction in pain intensity at 12 hours in 90% vs. 0% (p < 0.0001, NNT 2) 2 KTM infusion plus fentanyl associated with reduced anxiety, improved mood, and increased sedation measured with 0-10 VAS at 12 hours compared to KTM infusion alone (p < 0.05), but between-group differences in these outcomes were not significant at 24 hours © no nausea, vomiting, or respiratory depression events occurred in either group o Reference - Pain Pract 2016 Jul;16(6):680 2 No additional trials evaluating addition of fentanyl buccal tablet to continuous infusion of KTM for treatment of acute VOC in adults with SCD found in Cochrane review (Cochrane Database Syst Rev 2019 Nov 14;2019(11):CD012187 @) Adjunctive Therapies « nonpharmacologic approaches to pain management NHLBI recommendation - consider using adjunctive nonpharmacologic approaches to treat pain, including local heat application and distraction (NHLBI Consensus- Adapted)! o ASH recommendations - consider massage, yoga, transcutaneous electrical nerve stimulation (TENS), virtual reality, and guided (audio-visual) AV relaxation in addition to standard pharmacologic treatment (ASH Conditional recommendation, Very low-certainty of effect) + recommendation based on evidence in patients with SCD as well as indirect evidence in postoperative adults + while evidence is based on studies performed in adults, there is low risk of harm in children; age of the child, feasibility, and acceptability should be considered in choosing an appropriate intervention such as yoga and guided AV relaxation - no recommendation offered for or against acupuncture or biofeedback in addition to standard pharmacologic treatment + pharmacologic therapies are the first-line treatment for acute pain, but medications alone may not be effective in adequately alleviating pain or psychosocial consequences of acute pain and they are associated with adverse effects « if biofeedback and acupuncture are being considered as treatment, treatment plan should be individualized, taking into consideration patient experience and preference — other options include mindfulness, spirituality, cognitive behavioral therapy, and meditation = Reference - Blood Adv 2020 Jun 23;4(12):2656 full-text B https:svww.dynamed.comimanagement/management-of-acute-ovents-of-sickle-coll-disease 19159