Sickle Cell Disease in Vaso-Occlusive Crisis Evidence-Based Guideline

DATE: July 2017 TEXAS CHILDREN’S HOSPITAL EVIDENCE-BASED OUTCOMES CENTER Sickle Cell Disease in Vaso-Occlusive Crisis Evidence-Based Guideline

Definition: Sickle cell disease is an inherited red blood cell Diagnostic Evaluation disorder that can cause both acute and chronic complications History: Assess for and is used to refer to the many genotypes that cause the  Lower respiratory symptoms (cough, wheezing, tachypnea, characteristic clinical syndrome. (1) chest pain) and/or  Previous history of acute chest syndrome episode, asthma, Pathophysiology: Sickle cell anemia (otherwise known as or stroke/transient ischemic attack s HbSS, or homozygous β allele) is the most common form, with  Vaccination status the second most prevalent type being HbSC, or HbS/β- thalassemia. (1) The genetic mutation that causes sickle cell Physical Examination disease creates an HbS polymerization that can disrupt  Assessment for the possibility of other serious hemoglobin architecture and flexibility and oxidative cellular complications concurrently with the treatment of pain (1) stress. The mutation can result in the processes of vaso-  Assess for abnormal vital signs, particularly changes in occlusion with ischemia and reperfusion injury and hemolytic respiratory rate (RR), use of accessory muscles, color (1) anemia.  Auscultate lungs  Assess for pain associated with abdominal distension for Epidemiology: It is estimated that sickle cell disease affects hepatic or splenic sequestration or acute cholecystitis, approximately 100,000 Americans in the United States, and jaundice, or hematuria, occurs in 1 of every 365 Black or African American births, and 1 of every 16,300 Hispanic-American births. Approximately 1 in  Obtain pulse oximetry; detect new onset hypoxemia 13 African-American babies is born with sickle-cell trait. With  Rate severity of SCD according to Clinical Respiratory Score (CRS) the utilization of pneumococcal vaccines and hydroxyurea (See Table 1) therapy, the mortality rate for sickle cell disease has been  Evaluate for signs and symptoms of shock (See Table 2 and 3) dramatically reduced. (2) Table 1. Clinical Respiratory Score Etiology: Vaso-occlusion crises (VOCs) are thought to be Clinical Respiratory Score (CRS) caused by microvascular obstruction and tissue ischemia Assess Score 0 Score 1 Score 2 (1) (ischemia-reperfusion injury) and hemolytic anemia. <2 mos: <50 <2 mos: 50-60 <2 mos: >60 Although VOCs commonly occur in the extremities, when they Respiratory 2-12 mos: <40 2-12 mos: 40-50 2-12 mos: >50 occur in other sites they may be confused with, or can be in the Rate 1-5 yrs: <30 >1-5 yrs: 30-40 >1-5 yrs: >40 early stages of, other acute complications, and etiology of the >5 yrs: <20 >5 yrs: 20-30 >5 yrs: >30 Diminished or pain must be determined in order to rule out potential causes Good air (3) Depressed air absent breath other than uncomplicated VOC. Other acute complications movement, movement, sounds, severe that can manifest in acute vaso-occlusive pain include stroke, scattered inspiratory and wheezing, or acute chest syndrome, renal infarction, myocardial infarction, Auscultation expiratory expiratory rales/crackles, (3) wheezing, priapism, splenic or hepatic sequestration. wheezes or or marked loose rales/crackles prolonged rales/crackles Acute chest syndrome (ACS) is both a common and serious expiration complication of sickle cell disease. Symptoms of lower Mild to no use Moderate respiratory tract disease can present suddenly and be of accessory intercostal Severe accompanied by a new pulmonary infiltrate on chest x-ray, Use of muscles, mild retractions, mild intercostal and although these changes may be subtle in the early stages. (3) Accessory to no to moderate use substernal The most common well-defined etiology is viral or bacterial Muscles retractions, no of accessory retractions, infection (particularly Mycoplasma pneumoniae), but the nasal flaring on muscles, nasal nasal flaring complication may also result from bone marrow fat embolism, inspiration flaring Normal to Irritable, agitated, Mental Status Lethargic intrapulmonary aggregates of sickled cells, atelectasis, or mildly irritable restless. pulmonary edema. (3) Room Air SpO2 >95% 90-95% <90% Cyanotic, Color Normal Pale to normal Inclusion Criteria dusky  Patients 1-21 years with sickle cell disease (Add score from all rows to calculate total CRS score) Exclusion Criteria  Children <1 year  Patients without sickle cell disease  Patients who exhibit signs of stroke

© Evidence-Based Outcomes Center 1 Texas Children’s Hospital DATE: July 2017 Table 2. PALS Adjusted Vital Signs for Septic Shock  Consider obtaining blood cultures if concerned for Age Heart Rate Resp Rate Systolic BP Temp (°C) infectious pathology. 0d-1m >205 >60 <60 <36or>38  Consider obtaining type and screen if concerned for need >1m-3m >205 >60 <70 <36or>38 for transfusion. >3m-1y >190 >60 <70 <36or>38.5 Diagnostic Imaging Studies: >1y-2y >190 >40 <70+(ageinyrx2) <36or>38.5  Obtain a chest radiograph if patient has respiratory >2y-4y >140 >40 <70+(ageinyrx2) <36or>38.5 symptoms at presentation to the hospital or during >4y-6y >140 >34 <70+(ageinyrx2) <36or>38.5 admission. Fever in the absence of these symptoms does >6y-10y >140 >30 <70+(ageinyrx2) <36or>38.5 not necessitate evaluation with a chest radiograph. >10y-13y >100 >30 <90 <36or>38.5 >13y >100 >16 <90 <36or>38.5

Table 3. Signs and Symptoms of Shock Exam Abnormalities Cold Shock Warm Shock Non-Specific Peripheral Decreased Bounding Pulses or weak Capillary Refill (central ≥3 sec Flash (<1 sec) vs. peripheral) Flushed, ruddy, Petechiae below the Skin Mottled, cool erythroderma nipple, any purpura (other than face) Decreased, irritability, confusion, inappropriate crying or drowsiness, Mental poor interaction with Status parents, lethargy, diminished arousability, obtunded

Laboratory Tests:  Obtain a complete blood count with reticulocyte count and note changes in baseline CBC or reticulocyte count or any laboratory abnormalities (such as increasing creatinine, liver function tests, coagulation abnormalities, etc.).

Critical Points of Evidence* Evidence Supports  Collect complete blood count with differential, platelet count, reticulocyte count initially and daily for the patient with acute chest syndrome until the patient is improving. Results should be compared to the patient’s baseline values. (4-7) – Strong recommendation, low quality evidence  Collect secretory phospholipase A2 (sPLA2) levels for the suspicion of acute chest syndrome when the lab becomes available at Texas Children’s Hospital. (7) – Strong recommendation, low quality evidence  Obtain a chest radiograph if patient has cough, chest pain, hypoxemia, or lower respiratory symptoms at presentation to the hospital or during admission. Fever in the absence of these symptoms does not necessitate evaluation with a chest radiograph. (8-12) – Strong recommendation, very low quality evidence  Encourage oral fluid intake and to administer total fluid intake (intravenous plus oral) at maintenance rate to encourage that the patient remains euvolemic. (13) – Strong recommendation, very low quality evidence  Transfuse the patient with acute chest syndrome with PRBCs to a hemoglobin goal of 9-10 g/dL. (14,15) – Strong recommendation, very low quality evidence  Use continuous pulse oximetry monitoring in patients with sickle cell disease who experiencing vaso-occlusive crisis who are being treated in the emergency center. (16-22) – Strong recommendation, very low quality evidence  Encourage incentive spirometry in patients with sickle cell disease at risk for or with acute chest syndrome who are admitted to the hospital. (23-26) – Strong recommendation, low quality evidence  Administer inhaled bronchodilators every 6 six to eight hours with acute illness if patient has a history of asthma or presents with wheezing. (23-26) – Strong recommendation, very low quality evidence  Administer a one week course of prednisolone or three days of dexamethasone to patients who have clinical wheezing with or without a known history of asthma who are being treated in the inpatient setting. (27-31) – Strong recommendation, very low quality evidence  Administer ketorolac in patients with mild to moderate pain. (32-34) – Strong recommendation, very low quality evidence  Administer ketorolac as adjuvant therapy while initiating morphine via patient controlled analgesia for patients with severe pain (pain scores greater than seven). (32-34) – Strong recommendation, very low quality evidence

© Evidence-Based Outcomes Center 2 Texas Children’s Hospital DATE: July 2017  Administer intranasal fentanyl or oral morphine for pain control in patients when there is a delay in IV placement. (35-38) – Strong recommendation, low quality evidence  Try any non-pharmacologic intervention to help control pain. (39-44) – Strong recommendation, low quality evidence  Use a high basal dose with a low on demand (intermittent opioid infusion) morphine via patient controlled analgesia in patients who present with pain crisis. Titrate depending on patient’s pain control as determined by patient self-report of pain score. Once patient has achieved good control, wean until patients intravenous opioid dose can be transitioned to an oral dose. (45-49) – Strong recommendation, low quality evidence

Evidence Against  Avoid corticosteroids unless indicated. (27-31) – Strong recommendation, very low quality evidence

Evidence Lacking/Inconclusive  Progress to intrapulmonary percussive ventilation (IPV) or vest therapy if patient appears to be worsening. – Strong consensus recommendation  Use of a risk score to predict health care utilization – Unable to make a recommendation  Using functional pain scales as compared to traditional pain scales to assess pain in children – Unable to make a recommendation  Administer antibiotics of symptoms suggest acute chest or if the patient has worsening respiratory distress. – Strong consensus recommendation

*NOTE: The references cited represent the entire body of evidence reviewed to make each recommendation.

Condition-Specific Elements of Clinical Management

Consults/Referrals: Measures  Consult Pulmonary Service prior to discharge for CRS ≥5 Structure  Consult Critical Care Medicine for CRS ≥4  Availability of sPLA2 laboratory testing  Consider Pain Service consult for: child hospitalized ≥3 days with no clinical improvement, avascular necrosis, Process unmanageable side effects from PCA, failure to control  Order set utilization in the EC and inpatient units pain after titrating up and trying other agents, or  Documentation of CRS scores every 4 hours complicated pain history  Incidence of pulmonary treatments  Consider Child Life request to see for coping concerns  Length of time on oxygen and/or procedural preparations  Frequency of ambulation  Time to PCA initiation Discharge Criteria:  Percentage of patients with CRS ≥5 referred to pulmonary  Improved pulmonary symptoms and documentation of clinic adequate oxygenation on room air  Percentage of patients/caregivers who received IS and IS  Afebrile ≥24 hours and negative cultures for ≥24-48 hours, education if applicable  CRS score of patients transferred to PCU/PICU  Stable hemoglobin/hematocrit  Percentage of patients with documented RT consult upon  Taking adequate oral fluids and able to take PO arrival to unit medications, if applicable Outcome  Adequate pain relief with oral analgesics, if applicable  Number of patients who develop ACS  Slow wean from steroids (over 7-10 days), if applicable  Number of simple blood transfusions  Home care agencies notified as needed  Number of exchange transfusions  Number of patients transferred to the PCU or PICU Caregiver understands:  ED and IP LOS  Discharge care, including steroid wean, if applicable  Time on opioid  When Hematology Clinic and Pulmonary SCD Clinic  Total PCA morphine dose follow-ups scheduled  Number of patients with ACS with identified pathogen  How and when to use IS  Number of patients with unscheduled return visit to the  Medications and how to obtain them ED/triage and/or admission for the same diagnosis within 14 days of discharge

Texas Children’s Hospital Evidence-Based Outcomes Center Sickle Cell Disease Respiratory Management Algorithm

Pt 1-21 years with SCD Begin presenting with pain and fever and/or ACS

- Assess CRS q 4 h - If actively wheezing, place on RAMP protocol - If rales/crackles AND history of asthma, place on RAMP protocol - IS in pts ≥ 5 years as follows: 10 breaths IS and 10 breaths PEP alternating q 2 h between 8a and 10p; in pts < 5 years, PEP and/or IS can be introduced, but lack of cooperation should lead to earlier consideration of vest therapy *Acute Chest Syndrome (ACS) Criteria - CXR if cough, chest pain, hypoxemia, or any lower Acute illness associated with lower respiratory symptoms present or develop respiratory symptoms, new or worsening hypoxemia, or new infiltrate on CXR

No Does the patient meet Yes ACS Criteria*? - If febrile, give ceftriaxone injection: 50 - Initiate ceftriaxone injection: 50 mg/kg IV for 30 min mg/kg IV for 30 min (MAX: 2 g/day) (MAX: 2 g day) in the ED/Outpatient Hematology Center - If signs of fluid overload, consider furosemide and continue q 24 hours 0.5 mg/kg IV X 1 dose (MAX: 40 mg/dose) NOTE: if pt is allergic to penicillin/cephalosporin, NOTE: If pt is allergic to penicillin/ substitute clindamycin: 10 mg/kg/dose IV q 6-8 h (MAX: cephalosporin, substitute clindamycin: 10 mg/ 900 mg/dose) kg/dose IV q 6-8 h (MAX: 900 mg/dose) - Administer azithromycin: 10 mg/kg PO on day 1 (MAX: 500 mg/dose), then 5 mg/kg PO once daily (MAX: 250 mg/dose) for 4 days (erythromycin may be substituted) - For severe illness, consider adding vancomycin: for children < 70 kg: 15 mg/kg/dose IV q 8 h; for children ≥ 70 kg: 1 gram IV q 12 h (MAX: 1 gram/ dose) - If signs of fluid overload, consider furosemide 0.5 mg/kg IV X 1 dose (MAX: 40 mg/dose) - IV fluids should be given at no more than maintenance - Repeat CXR if signs and symptoms are worsening

Assess CRS and manage patient based on score

CRS <2 CRS 2-3 CRS 4 CRS 5 CRS ≥ 6

- Vital signs q 4 h - Consider transfer to - Transfer to PCU or PICU - Manage in PICU - Assess CRS every - Continuous pulse PCU w/ CCM consult (consider management in - Continuous pulse oximetry four hours oximetry (goal SpO2 of - Vital signs q 2 h PICU if history of previous (goal SpO2, unless ACS is 92% unless ACS is - Continuous pulse ACS episode w/ exchange suspected) suspected) oximetry (goal SpO2, transfusion) - Consult Pulmonary - Transfuse to Hb goal unless ACS is - Consult Pulmonary Service Service of 9-10 g/dL suspected) prior to discharge prior to DC - Transfuse to Hb goal - Vital signs every 2 hours - Perform exchange If pt < 5 years: of 9-10 g/dL - Continuous pulse oximetry transfusion (NOTE: - Vest TID if ≥ 10 kg - IPV or vest therapy (goal SpO2 , unless ACS is Remove venous catheters If pt ≥ 5 years: every 4 hours (vest suspected) as soon as possible after - Vest or IPV TID (vest preferred if wheezing) - Transfuse to Hb goal of exchange transfusion) preferred if wheezing) - Consider BiPAP 9-10 g/dL - BiPAP + IPV q 4 h (may - Consider exchange use vest instead of IPV, if If wheezing: If wheezing: transfusion to 10 g/dL wheezing) - Methylprednisolone: - Methylprednisolone: - BiPAP + IPV q 4 h (may use 1mg/kg/ dose IV q 12 h 1 mg/kg/dose IV q 6 h vest instead of IPV, if If wheezing or rales (MAX: 80 mg/DAY) (MAX: 80 mg/DAY) wheezing) crackles: - Methylprednisolone: Clinical Respiratory Score (CRS) If wheezing or rales/crackles: 1 mg/kg/dose IV q 6 h Assess Score 0 Score 1 Score 2 - Methylprednisolone: (MAX: 80 mg/DAY) < 2 mos: < 50 < 2 mos: 50-60 < 2 mos: > 60 1 mg/kg/dose IV q 6 h Respiratory 2-12 mos: < 40 2-12 mos: 40-50 2-12 mos: > 50 (MAX: 80 mg/DAY) Rate 1-5 yrs: < 30 > 1-5 yrs: 30-40 > 1-5 yrs: > 40 > 5 yrs: < 20 > 5 yrs: 20-30 > 5 yrs: > 30 Diminished or Good air Depressed air absent breath movement, movement, sounds, severe scattered inspiratory and wheezing, or Auscultation expiratory expiratory rales/crackles, wheezing, wheezes or or marked loose rales/crackles prolonged rales/crackles expiration Follow-up considerations Mild to no use Moderate of accessory intercostal Severe For more severe cases of Acute Chest Use of muscles, mild retractions, mild intercostal and Syndrome, make follow up appointment Accessory to no to moderate use substernal in joint Heme/Pulm clinic. Muscles retractions, no of accessory retractions, nasal flaring on muscles, nasal nasal flaring inspiration flaring Normal to Irritable, agitated, Mental Status Lethargic mildly irritable restless. Room Air SpO2 > 95% 90-95% < 90% Cyanotic, Color Normal Pale to normal dusky July 2017 (Add score from all rows to calculate total CRS score) © Evidence-Based Outcomes Center 4 Texas Children’s Hospital DATE: July 2017

TCH Evidence-Based Outcomes Center Emergency Department/Outpatient Hematology Center Pain Management Algorithm for Patients With Sickle Cell Disease in Vaso-Occlusive Crisis

Child with sickle cell disease presents with persistent pain^ Begin * NOTE: (Notify Hematology Clinic or Hematology Fellow on call after initial assessment) - If pt asleep after administering pain meds, wake patient up to reassess pain as directed. (e.g., q 10 min x 3) - If patient is unable to tolerate morphine, Patient pain Mild pain Moderate/Severe pain use dilaudid IV/ PCA at standard 1:10 No moderate to Yes (score 1-3) (score 4-10) conversion) severe?

- NS bolus followed by 1 ½ x maintenance, unless ACS is suspected - Apply warm packs to painful areas - Depending on severity of pain, if patient on home NOTE: If pain ≥ 4 opioids, escalate 15-25% of home medication and unable to access equivalent IV within 15 minutes, Narcotic given at - Morphine 0.1 – 0.2 mg/kg/dose (MAX: 8 mg) IV Yes consider home within last 12 h? - Ketorolac 1 mg/kg for first dose, then 0.5 mg/kg administering oral every 6 h not to exceed 5 days (MAX: 30 mg/dose) morphine or (NOTE: avoid use of ketorolac in pts w/ renal intranasal fentanyl dysfunction, ARF, ESRD, or SCr > 2 x baseline, or No active bleeding) - Assess pain 30 min after administration of - Oral fluids ketorolac - Apply warm packs to painful areas - Give oral morphine (0.2-0.5 mg/kg; MAX: 30 MG Q4 hours) Pain well Yes No - Give ibuprofen (if none within last 6 controlled hours)

No Patient received total of 3 Yes doses morphine?

Pain well No Repeat morphine 0.1 – controlled? 0.2 mg/kg/dose IV q 10 min (MAX: 8 mg)* Yes

Observe for Pain remains - Initiate morphine PCA: Yes No Observe for 1 h in ED 20 min - 1 h in ED well controlled? Loading dose 0.1 mg/kg (MAX: 8 mg) Basal rate 0.02 mg/kg/hour Intermittent dose 0.035 mg/kg Yes (MAX: 8 mg) Pain remains No well controlled? Lockout interval 10 min 4-hour limit 0.5-0.75 mg/kg - IV fluids 1 ½ x maintenance, unless ACS is suspected Pain remains No Yes well controlled? - Initiate bowel regimen

Give dose of oral morphine (0.2-0.5 mg/ kg) and observe for at least 30 min in ED

Yes Pain remains No well controlled?

Yes ^Administer IV antibiotics if the patient is ill-appearing, toxic-appearing, - Discharge on oral - Discharge on oral - Admit bacteremic, or has a morphine (0.2-0.5 mg/kg) morphine (0.2-0.5 mg/kg) - Notify PCP significantly elevated white (alternate w/ ibuprofen) (alternate w/ ibuprofen) count. Refer to the septic - Emphasize fluid intake - Emphasize fluid intake shock guideline if suspicion - Give SCD discharge - Give SCD discharge of shock. Be cautious with instruction sheet instruction sheet fluid management if - Instruct patient to follow up - Instruct patient to follow up concern for acute chest in clinic in 3-5 days in clinic in 3-5 days syndrome. July 2017

TCH Evidence-Based Outcomes Center Sickle Cell Disease in Vaso-Occlusive Crisis Inpatient Pain Management Algorithm

Child w/ SCD presents with persistent pain; consider Begin nonpharmacologic methods to complement medication^ ^Administer IV antibiotics if the patient is ill-appearing, NOTE: If child on toxic-appearing, home opioids, give bacteremic, or has a current home significantly elevated white Patient pain medication No Yes count. Refer to the septic moderate to severe? equivalents; convert shock guideline if suspicion and escalate, or of shock. Be cautious with Moderate to Severe continue Mild Pain fluid management if (score 1-3) Pain concerned for acute chest (score 4-10) If patient is unable syndrome, especially with to tolerate desaturations. morphine, use Assess pain 30 dilaudid IV/ PCA at Continue/Administer oral min after initiation standard 1:10 ibuprofen or IV ketorolac 1 mg/kg of morphine PCA conversion) if first dose, then 0.5 mg/kg every 6 h not to exceed 5 days (MAX: 30 mg/dose) Yes Pain well No NOTE: avoid use in pts w/ renal controlled? dysfunction, ARF, ESRD, or SCr > 2 x baseline, or active bleeding Continue pain assessment every 30 min NOTE: Replace Assess pain 30 min ketorolac w/ oral After 30 min, if pain after administration ibuprofen after 5 uncontrolled, increase of ketorolac Pain well days, if needed No continuous dose by 0.01 controlled? mg/kg/h and reassess every 30 min X 2 Yes Yes Pain well No controlled? Continue pain assessment every 30 min Continue pain Consider Oral or PCA morphine No assessment per standard Oral morphine: 0.2 to 0.5 mg/kg Q 3-4 hours Pain well controlled? Initiate morphine PCA: Loading dose (mg/kg) – 0.1 Yes Pain well Pain well No (MAX: 8 mg) controlled? controlled Basal rate (mg/kg/h) – 0.02 Intermittent dose (mg/kg) – 0.035 (MAX: 8 mg) No Lockout interval (min) – 10 Yes 4-hour limit (mg/kg) – 0.5-0.75 After 30 min, if pain IV fluids 1 ½ x maintenance, uncontrolled, increase unless ACS is suspected Continue pain continuous dose by 0.01 Initiate bowel regimen assessment per mg/kg/h and reassess standard every 30 min X 2 Yes Continue pain assessment per Pain well standard Yes Pain remains well controlled? controlled? No No

Pain remains well Increase intermittent controlled? dose by 20% (MAX: 8 mg if pt < 50 kg; MAX: 10 mg if ≥ 50 kg) and reassess Yes every 15 min X 2

Yes Yes Pain remains well controlled?

Begin DC planning Begin DC planning Begin DC planning *see below for *see below for Consult DC on oral ibuprofen instructions on opioid instructions on opioid Pain Service q6 for 5 days weaning weaning

Instructions for opioid weaning: NOTE: IVFs + PO intake should equal Consider consulting Pain Service for: 1 ½ x maintenance, unless ACS is - If pt’s PCA demands are ½ of actual dose available, consider switching pt to oral meds - child hospitalized ≥ 3 days with no clinical suspected. Wean IVFs according to improvement patient oral intake. (long-acting for basal, short-acting for bolus) - If pt’s condition improving and FLACC score - Avascular Necrosis (AVN) has improved ≥ 2 measurements over 2 shifts, - unmanageable side effects from PCA - failure to control pain after titrating NOTE: Rebalance opioid dose every titrate down from continuous to long-acting up and trying other agents 24 hours. - Assess need for PCA every 24 h - complicated pain history

July 2017

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© Evidence-Based Outcomes Center 8 Texas Children’s Hospital DATE: July 2017 Clinical Standards Preparation - 3 meta-analyses, 15 randomized controlled trials, and 37 This clinical standard was prepared by the Evidence-Based nonrandomized studies Outcomes Center (EBOC) team in collaboration with content experts at Texas Children’s Hospital. Development of this clinical 5. Summarize the Evidence standard supports the TCH Quality and Patient Safety Program - Materials used in the development of the guideline, evidence initiative to promote clinical standards and outcomes that build a summary, and order sets are maintained in a Vaso-occlusive culture of quality and safety within the organization. Crisis in Sickle Cell Disease evidence-based review manual within EBOC. Sickle Cell in Vaso-occlusive Crisis Content Expert Team Aderonke Adekunle-Ojo, MD, MPH, Emergency Center Evaluating the Quality of the Evidence Angela Baldonado, RN, Nursing, West Campus Published clinical guidelines were evaluated for this review using Rachel Beaty, PharmD, Pharmacy the AGREE II criteria. The summary of these guidelines are Julienne Brackett, MD, Cancer Center included in the literature appraisal. AGREE II criteria evaluate Corrie Chumpitazi, MD, Emergency Center Guideline Scope and Purpose, Stakeholder Involvement, Rigor of Hillary Cloyd, RN, Anesthesiology Development, Clarity and Presentation, Applicability, and Editorial Danielle Coleman, MS, CCLS, Child Life Independence using a 4-point Likert scale. The higher the score, Anna Foy, RN, Cancer Center the more comprehensive the guideline. Alex George MD, PhD, Hematology Center This clinical standard specifically summarizes the evidence in Tara Haworth, PharmD, Pharmacy support of or against specific interventions and identifies where Melody Hellsten, DNP, RN, PPCNP-BC, Cancer Center, Palliative evidence is lacking/inconclusive. The following categories describe Care how research findings provide support for treatment interventions. Joy Hesselgrave, MSN, RN, CNS, Cancer Center “Evidence Supports” provides evidence to support an intervention Suzanne Iniguez, RT, Respiratory Care “Evidence Against” provides evidence against an intervention. Grace Kao, PhD, Psychology, Pain Service “Evidence Lacking/Inconclusive” indicates there is insufficient Julie Katkin, MD, Pulmonology evidence to support or refute an intervention and no conclusion can Sara Liechti, PharmD, Pharmacy be drawn from the evidence. Evelyn Monico, MD, Anesthesiology The GRADE criteria were utilized to evaluate the body of evidence Brady Moffett, PharmD, MPH, Pharmacy used to make practice recommendations. The table below defines Mandy Owens, RN, Cancer Center, West Campus how the quality of the evidence is rated and how a strong versus Satid Thammasitboon, MD, MHPE, Critical Care Medicine weak recommendation is established. The literature appraisal Jennifer Tran, DO, Cancer Center reflects the critical points of evidence. Nidhy Varghese, MD, Pulmonary Recommendation Amber Yates, MD, Hematology Center Desirable effects clearly outweigh undesirable effects or STRONG EBOC Team vice versa Desirable effects closely balanced with undesirable Karen Gibbs, MSN/MPH, RN, APHN-BC, CPN, Research Specialist WEAK Christine Procido, MPH, Research Specialist effects Charles Macias, MD, MPH, Medical Director Quality Type of Evidence High Consistent evidence from well-performed RCTs or Additional EBOC Support exceptionally strong evidence from unbiased Tom Burke, Research Assistant observational studies Sherin Titus, Research Assistant Moderate Evidence from RCTs with important limitations (e.g., Andrea Jackson, MBA, RN, Research Specialist inconsistent results, methodological flaws, indirect Betsy Lewis, MSN, RN, Research Specialist evidence, or imprecise results) or unusually strong Jennifer Loveless, MPH, Research Specialist evidence from unbiased observational studies Sheesha Porter, MS, RN, Research Specialist Low Evidence for at least 1 critical outcome from Ellis Arjmand, MD, MMM, PhD, Associate Director observational studies, RCTs with serious flaws or Christina Davidson, MD, Associate Director indirect evidence Anne Dykes, MSN, RN, Assistant Director Very Low Evidence for at least 1 critical outcome from Kathy Carberry, MPH, RN, Director unsystematic clinical observations or very indirect No relevant financial or intellectual conflicts to report. evidence

Development Process Recommendations This clinical standard was developed using the process outlined in Practice recommendations were directed by the existing evidence the EBOC Manual. The literature appraisal documents the following and consensus amongst the content experts. Patient and family steps: preferences were included when possible. The Content Expert Team and EBOC team remain aware of the controversies in the 1. Review Preparation diagnosis/management of vaso-occlusive crisis in children with - PICO questions established sickle cell disease. When evidence is lacking, options in care are - Evidence search confirmed with content experts provided in the clinical standard and the accompanying order sets (if applicable). 2. Review of Existing External Guidelines - Evidence-Based Management of Sickle Cell Disease Expert Approval Process Panel Report (National Heart, Lung, and Blood Institute) 2014 Clinical standards are reviewed and approved by hospital - Sickle Cell Disease: Managing acute painful episodes in committees as deemed appropriate for its intended use. Clinical hospital (National Institute for Clinical Excellence) 2012 standards are reviewed as necessary within EBOC at Texas 3. Literature Review of Relevant Evidence Children’s Hospital. Content Expert Teams are involved with every - Searched: PubMed, Cochrane Library, CINAHL, Guidelines review and update. Clearinghouse, Google Scholar Disclaimer 4. Critically Analyze the Evidence Practice recommendations are based upon the evidence available at the time the clinical standard was developed. Clinical standards © Evidence-Based Outcomes Center 9 Texas Children’s Hospital DATE: July 2017 (guidelines, summaries, or pathways) do not set out the standard of care, and are not intended to be used to dictate a course of care. Each physician/practitioner must use his or her independent judgment in the management of any specific patient and is responsible, in consultation with the patient and/or the patient family, to make the ultimate judgment regarding care

Version History Date Action Comments Jun 2011 Originally completed Jul 2017 Updated