Hydroxyurea For Sickle Cell Disease Indications, Dosing and Monitoring Guideline

Cincinnati Children’s Hospital Medical Center
Sickle Cell Clinical Practice Guidelines

Hydroxyurea Guideline
Updated: August 18, 2016
HYDROXYUREA FOR SICKLE CELL DISEASE: INDICATIONS, DOSING AND MONITORING GUIDELINE
PURPOSE
To provide guidelines for the indications, dosing, and monitoring of hydroxyurea therapy for patients with sickle
cell disease.
BACKGROUND
All patients with sickle cell anemia (Hb SS) and Sβ0-thalassemia (Hb Sβ0) can benefit from hydroxyurea.
Hydroxyurea has been shown to significantly decrease the number of vaso-occlusive episodes and episodes of
acute chest syndrome, while also reducing the number of transfusions and hospitalizations. Newer studies
suggest it may also provide some protection against overt stroke as well as other end organ damage. Recent
studies have suggested that it lowers overall mortality as well. Therefore, all patients (and/or parents and
guardians) with Hb SS or Hb Sβ0 should be given information about hydroxyurea. If interested, patients should
be started on hydroxyurea. It should not be limited to only the most overtly severe patients. Patients are
monitored as outlined below. We typically use either the liquid hydroxyurea which our pharmacy dispenses at
100 mg/mL or 500 mg capsules.
Hydroxyurea should not be prescribed as initial therapy for patients with overt stroke or abnormal transcranial
Doppler ultrasonography results (TCD), because transfusion therapy is the gold standard for these
complications. Hydroxyurea may be prescribed in these situations if the patient (and/or family) refuses
transfusion therapy or has a contraindication to transfusion therapy such as alloimmunization that precludes
regular transfusions. Transitioning from chronic transfusion therapy to hydroxyurea therapy under defined
circumstances (and covered in a separate guideline: Switching from Transfusions to Hydroxyurea).
The first objective finding in an adherent patient is an increase in the MCV followed by a decrease in absolute
neutrophil count (ANC) and absolute reticulocyte count (ARC). The increase in MCV is seen quickly (within days
of beginning the drug), and MCV increases further as the dose is increased. This is followed by an increase in
the fetal hemoglobin (Hb F) level and then an increase in the hemoglobin concentration. The amount of increase
is patient-specific, but if the patient is on a dose of more than 30mg/kg/day and does not have any increase in
MCV or decrease in ANC, then the patient is almost assuredly non-adherent. The Hb F levels seem to peak
somewhere around 3-6 months after beginning hydroxyurea.
INDICATIONS FOR BEGINNING HYDROXYUREA

1. Diagnosis of Hb SS or Hb Sβ0 regardless of clinical severity (offered as early as 9 months of age as per
NHLBI Guidelines).
2. Patients with a diagnosis of sickle-hemoglobin C disease (Hb SC), Sβ +-thalassemia (Hb Sβ+), or other
symptomatic sickle hemoglobinopathies who are clinically severe may warrant a trial of hydroxyurea at
the physician’s discretion.
RELATIVE CONTRAINDICATIONS (WHEN NOT TO START HYDROYXUREA)

1. Abnormal transcranial Doppler ultrasonography (TCD) or history of overt stroke (transfusion therapy is
the gold standard for these complications) unless there is refusal or contraindication for transfusion
therapy (e.g. severe alloimmunization, religious objection)
2. Diagnosis of compound heterozygosity for Hb S and gene-deletion HPFH (hereditary persistence of
fetal hemoglobin)–HbS/HPFH. Hb SS or Hb Sβ0 with co-inherited non-gene-deletion forms of HPFH are
not excluded.
3. Pregnancy or breast feeding
4. Stated unwillingness to comply with dosing schedule and monitoring requirements
5. Significant impairment in renal or liver function (see toxicity section for details)
Developed by the Pediatric Sickle Cell Program, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center. These
practice guidelines are intended for use by professional healthcare providers. These guidelines do not constitute advice conc erning an
individual patient’s medical care and treatment.
1
© 2017 Cincinnati Children’s Hospital Medical Center
WHEN TO DISCONTINUE HYDROXYUREA

1. Pregnancy
2. Persistent non-adherence with medication
3. Persistent non-adherence with the required monitoring (laboratory tests, clinical visits)
4. Start of chronic transfusion therapy in case of overt stroke or abnormal TCD (uncommon exception:
hydroxyurea may be used as an adjunct to chronic transfusions to suppress erythropoiesis)
DOSING
The starting dose of hydroxyurea is typically 20-25 mg/kg daily by mouth. The dose is increased as tolerated to
reach a target absolute neutrophil count (ANC) of between 1.5-3.0 x 109/L (obtained during “well” or steady state
visits). The increase in hydroxyurea is usually done in increments of 3-5 mg/kg/day, adjusting the dose every 4-
6 weeks as tolerated. The usual effective dose in pediatrics is 26-28 mg/kg/day but can range from 20-30
mg/kg/day. A complete blood count (CBC) is monitored every 4-6 weeks during the period of dose escalation
(usually the first 3 months), then every 3 months when on a stable dose.
Alternatively, the starting dose can be individualized if the patient enrolls in the Therapeutic Response
Evaluation and Adherence Trial (TREAT, NCT NCT02286154). TREAT study participants will swallow a single
20 mg/kg dose in the outpatient clinic, followed by 3 blood samples collected at 15-20 minutes, 60 minutes, and
180 minutes later. The hydroxyurea concentrations at each time point are used to generate a pharmacokinetics
dosing curve for the child, which can then be used to calculate the optimal daily dose at the time of initiation.
Although the ANC is the most common value used to make decisions about dosing and to determine maximum
tolerated dose (MTD), reticulocytopenia or thrombocytopenia can at times be the dose-limiting laboratory value.
Decisions regarding dose escalation and determination of the MTD should always take into account the ANC,
ARC, hemoglobin concentration, and platelet count.
Based on published experiences with hydroxyurea in children, persistent or severe myelosuppression is

extremely rare. MTD is established when there has been a stable dose for at least 8 weeks and the
hematological values are within the target range, usually defined by an ANC of 1.5-3.0 x 109/L.
MONITORING
1. Baseline: before starting the medication:
 CBC with differential
 Reticulocyte count
 Hb F level
 Peripheral blood smear
 Hepatic and renal tests (at least: fractionated bilirubin, ALT, and creatinine)
 History and physical examination
 Medication counseling (method of action, risks/benefits, administration, adherence, safe sex
practices, avoidance of pregnancy)
2. During dose escalation to MTD: every 4-6 weeks:
 Hb F level
 Every 3 months during dose escalation: Hepatic and renal tests (at least: fractionated bilirubin,
ALT, and creatinine)
3. After MTD is reached: every 3 months (may consider longer intervals, e.g. 6 months for select patients):
 Hb F level
2

 Hepatic and renal tests (at least: fractionated bilirubin, ALT, and creatinine)
TOXICITY
Toxicity from hydroxyurea is defined as any of the following:
1. Absolute neutrophil count <1.0 x 109/L
2. Platelet count <80 x 109/L
3. Absolute reticulocyte count <80 x 109/L if hemoglobin is <9.0g/dL
4. Hemoglobin <5g/dL or >20% below baseline, regardless of the ARC
5. Serum creatinine >1.0 mg/dL (or significant increase from baseline)
6. ALT 2x the patient’s baseline or 3x the ULN, although other etiologies should be pursued
If toxicity occurs, consider stopping hydroxyurea for 4-7 days or until toxicity resolves. Then resume
hydroxyurea at the same dose or a dose decreased by 2.5-5 mg/kg/day. If toxicity does not recur after 12 weeks
on the lower dose, increase the dose by 2.5-5 mg/kg/day. If toxicity recurs on the higher dose, then stop or
adjust hydroxyurea again as above. The goal is to reach an optimal daily dose that is well-tolerated, meaning
the dose provides modest myelosuppression while not causing toxic blood counts.
Efforts to improve adherence might include:

 Monthly clinic visits
 Adjusting the dosing to better fit the patient’s or parent’s schedule, e.g. 5 days a week to be given at
school (if this is used, calculate the average weekly dose to determine the daily dose)
 Involvement of psychology (BMCP) or the adherence center
 Adherence apps for mobile devices
REFERENCES
 McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf.
2015;14(11):1749-58.
 Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010 Jul
1;115(26):5300-11.
 Evidence-Based Management of Sickle Cell Disease. http://www.nhlbi.nih.gov/health-
pro/guidelines/sickle-cell-disease-guidelines/[nhlbi.nih.gov and JAMA 2014;312(10):1033-1048.
3
Acute Stroke
Updated: February 4, 2017
ACUTE STROKE GUIDELINE
PURPOSE: To provide the clinician concise guidelines for the focused evaluation and rapid treatment of
patients with sickle cell disease (SCD) who have signs and symptoms suspicious for acute stroke.
PRESENTATION1
Highly suspicious for stroke:

Weakness of arm or leg2
Hemiparesis
Aphasia or dysphasia
Cranial nerve deficits
Seizure, stupor or coma
Footnotes and Guidance
1. Stroke may be an isolated event or

happen in conjunction with other
STABILIZATION complications of sickle cell disease, such
Rapid Triage
as acute chest syndrome, aplastic crisis,
ABCs or priapism.
Supplemental Oxygen
Place 2 large-bore IVs
iStat (rapid Hgb/Hct, lytes) 2. Children with pain may refuse to use or
Hydration3 protect a painful limb. It is important to
differentiate this from painless weakness,
that is, an inability to move an extremity.
PREPARE TO TRANSFUSE4 NOTIFICATION 3. Avoid over-hydration. Correct any

dehydration and maintain hydration with
1. Hematology (by ED)
CBC, retics
Hb S level (call lab) 2. Neuroradiology (by ED) 3/4 to 1 times maintenance (IV +PO).
Type & cross: sickle-negative PRBCs 3. PICU (by ED) Suggest D5-3/4-NS initially. Avoid
4. Erythrocytapheresis (by Hem)
Place apheresis catheter5
5. Neurology (by Hem) hypotonic fluids.
4. If patient already receives chronic

transfusions or has received recent
Hgb <9 g/dL
transfusions, then the need for further
≥9 g/dL acute transfusions (if any) must be
assessed on a case-by-case basis.
ERYTHROCYTAPHERSIS SIMPLE TRANSFUSION
5. The patient will need at least two sites of
Post-Exchange Goals:
then
While awaiting erythrocytapheresis: venous access for erythrocytapheresis.
Hb S <30% ~10 mL/kg PRBCs
FCR <30% One should be an apheresis catheter
Hct 28-30% Do not exceed a post-transfusion Hgb (draw) but the second can be a large-bore
verify by post-exchange labs of 11 g/dL because of hyperviscosity
peripheral IV or a port or central catheter
(return).
6. Unlike other causes of acute stroke, CT

IMAGING6 angiography is almost never needed,
especially upon initial presentation, in
MRI/MRA
patients with SCD.
CT without contrast if
MRI/MRA unavailable
7. Unlike other causes of acute stroke,
thrombolysis (tPA) is essentially never
used in in SCD. The mainstay of acute
and preventive therapy is transfusion.
ADDITIONAL CARE7
All patients: ICU management
Hemorrhage: consult Neurosurgery
Consider other causes of stroke (e.g.,

APLA, PFO)
Developed by the Cincinnati Comprehensive Sickle Cell Program, Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center. These practice guidelines are intended for use by professional healthcare providers. These
guidelines do not constitute advice concerning an individual patient’s medical care and treatment.
1
Acute Stroke
REFERENCES:
1. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple
transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective
cohort study of 137 children with sickle cell anemia. Journal of Pediatrics 2006; 149(5):710–2.
2. Oyesiku NM, Barrow DL, Eckman JR, et al. Intracranial aneurysms in sickle-cell anemia: clinical
features and pathogenesis. Neurosurgery 1991; 75(3):356–63.
3. Strouse JJ, Lanzkron S, Urrutia V. The epidemiology, evaluation and treatment of stroke in adults with
sickle cell disease. Expert Review of Hematology. 2011; 4(6):597–606.
4. U.S. Department of Health and Human Services. National Institutes of Health. NationaI Heart, Lung and
Blood Institute. (2014). Evidenced based management of sickle cell disease: Expert panel report 2014.
http:www.nih.nhlbi.gov/guidelines.
Developed by the Cincinnati Comprehensive Sickle Cell Program, Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center. These practice guidelines are intended for use by professional healthcare providers. These
guidelines do not constitute advice concerning an individual patient’s medical care and treatment.
2
Decision Tree for Screening TCDs
Page 1
Applies to:
Order
Genotypes: HbSS, HbSβº
Screening TCD
Ages: 2 - 18 years
repeat within
4-6 months
Study adequate?
No 2
Yes
TAMMV 1,2
highest mean velocity
< 155 155 - 184 185 - 204 ≥ 205

cm/s cm/s cm/s cm/s
Discuss intermediate
Discuss high risk of
Discuss low risk of risk of stroke.
stroke and chronic
stroke. Repeat TCD in Discuss intensifica-
transfusions.
1 year. tion of SCD therapy.
Repeat TCD 1 mos.
Repeat in 3-6 mos.
Discuss very high

Page Page Page risk of stroke. Offer
1 2 3 chronic transfusion.
We use imaging TCD (TCDi) at CCHMC, by which flow velocities average 15 cm/s lower than non-imaging
TCD (standard STOP imaging values that you see in the literature). Pay attention to the TCDi adjusted cut-
off values for TAMMV (time-averaged maximal mean velocity), also referred to as “mean velocity,” shown in
the table above. All decisions apply to TAMMVs (mean velocities) in the distal ICA, bifurcation (BIF), and/or
MCA. For bilateral or multifocal TAMMVs ≥ 155 cm/s, choose the highest single value for the decision tree.
You may use PSV (peak systolic velocity), also referred to a “max velocity” to supplement your interpretation
and modify your actions, but the predictive ability is best established for TAMMV. The CCHMC report
considers both TAMMV and PSV to arrive at a classification.
You may also use ACA velocities to supplement your interpretation and modify your actions, but the
predictive ability
© 2017 is best
Cincinnati established
Children’s Hospitalfor the other
Medical Centervessels (dICA, BIF, MCA). Recurrent difficulty obtaining an
adequate study or “low” velocities may indicate severe stenosis. Consider MRA.
Page 2 — Conditional Velocities (TAMMV 155 - 184 cm/s)
Applies to:
Ages: 2 - 18 years
Order
TCD
repeat within
3-4 months
Study adequate?
No 2
Yes
TAMMV 1,2
< 155 155 - 184 185 - 204 ≥ 205

cm/s cm/s cm/s cm/s
Discuss high risk of
Discuss low risk of risk of stroke.
stroke and chronic
stroke. Repeat TCD Discuss intensifica-
transfusions. Repeat
in 6 mos. tion of SCD therapy.
TCD 1 month.
Repeat TCD in 6 mos.
Discuss very high

Page Page Page risk of stroke. Offer
2 2 3 chronic transfusion.
* **
*If a previously conditional TCD converts to normal on 2 consecutive studies, consider decreasing
the frequency of TCDs to yearly (then start from the top of page 1).
**If a conditional TCD remains conditional on 4 consecutive studies, consider decreasing the
frequency of TCDs to yearly (then start from the top of page 1).
Page 3 — Abnormal Velocities (TAMMV ≥ 185 cm/s)
Applies to:
Ages: 2 - 18 years
Order
TCD
repeat within
2 weeks
Study adequate?
No 2
Yes
TAMMV
< 155 155 - 184

≥185 cm/s
cm/s cm/s
Discuss low risk of risk of stroke. Discuss high risk of
stroke. Repeat TCD in Discuss intensifica- stroke. Offer chronic
6 mos. tion of SCD therapy. transfusions.
Repeat TCD in 6 mos.
Page Page
3 3
* **
*If a previously abnormal TCD converts to normal on 2 consecutive studies, consider decreasing
the frequency of TCDs to yearly (then start from the top of page 1).
**If a previously abnormal TCD converts to conditional on 4 consecutive studies, consider

decreasing the frequency of TCDs to yearly (then start from the top of page 1).
Fever Management
SICKLE CELL FEVER MANAGEMENT GUIDELINE
PURPOSE
To provide guidelines about prompt evaluation and early, empiric intervention to prevent bacteremia/sepsis in
children with sickle cell disease and fever.
BACKGROUND
Children with sickle cell disease (all genotypes) are at increased risk for invasive infections with encapsulated
bacteria. All children with sickle cell disease should be considered functionally asplenic (even if they have not
had a surgical splenectomy and even if the spleen is palpable). Pneumococcal sepsis was once the leading
cause of mortality in children with sickle cell disease before these universal guidelines for evaluation and
management were implemented. Rapid triage, assessment and empiric antibiotic treatment are critical for
reducing sepsis.
Fever is defined as a temperature of 38.3° C (101° F) or greater, whether measured by medical personnel OR
reported by the patient or caregivers.
EVALUATION
Rapid triage, aggressive evaluation and treatment are required, including:
1. Physical examination, vital signs, oxygen saturation, evaluation of spleen size, neurologic exam, and
assessment of cardiorespiratory status.
2. Laboratory evaluation: Do not wait on results of labs to give empiric IV antibiotic.
 CBC/differential and reticulocyte count
 Blood culture (from central line if present)
 The following labs can be considered on a case-by-case basis
i. Consider type and screen for symptomatic anemia or concern for sepsis
ii. Renal and liver function studies if there is concern for sepsis
iii. Urinalysis if indicated for urinary symptoms of no apparent focus of infection
iv. Respiratory viral panel for respiratory signs or symptoms
v. Consider parvovirus PCR for worsened anemia with relative reticulocytopenia
3. Chest X-ray (CXR) if indicated (consider for chest pain, tachypnea, dyspnea, or hypoxemia in
combination with fever). Fever by itself is not an indication for CXR. Do not wait on results of CXR to
give empiric IV antibiotic.
TREATMENT
1. Ceftriaxone 50 mg/kg (max 2 grams) IV once. Patient should receive antibiotic within one hour of
presentation and evaluated for evidence of sepsis (irrespective of a documented source of fever)
 Penicillin/cephalosporin allergic patients should receive clindamycin 10-15 mg/kg (max 600 mg)
2. Acetaminophen 15mg/kg or ibuprofen 10mg/kg may be given by mouth (check when last dose was
given by parents)
3. Normal saline bolus only if indicated base on perfusion. NS bolus is not automatically indicated for
children with sickle cell disease and fever, only if there is evidence of dehydration or sepsis.
HOSPITALIZATION
1. In consultation with Hematologist, hospitalization is necessary for:

 Toxic appearance*
 Worsening clinical status on reassessment (critically important)*
 Oxygen requirement
*consider adding vancomycin until negative cultures by 48 hours

Developed by the Cincinnati Comprehensive Sickle Cell Program, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital
Medical Center. These practice guidelines are intended for use by professional healthcare providers. These guidelines do not constitute
advice concerning an individual patient’s medical care and treatment.
1

Fever Management
2. Other high-risk features to consider when making the decision to admit or not:
 Patient age less than 6 months
 History of pneumococcal sepsis*
 History of surgical splenectomy
 Temperature greater than 40° C
 New significant infiltrate on chest x-ray
 Dehydration
 Hemoglobin less than 5g/dl
 White blood count (WBC) greater than 30* or less than 5.0K/mcl (absolute neutrophil count less
than 1000)
 Platelet count less than 100,000
 Reticulocyte count less than 2% (possible aplastic crisis)
 Concurrent severe pain
*consider adding vancomycin until negative cultures by 48 hours
3. Additional criteria to consider when making the decision to admit or not:

 History of non-adherence to medical plan
 Likely to have difficulty with outpatient follow-up
 Allergy to penicillin/cephalosporin requiring shorter duration antibiotic
DISCHARGE FROM ED/CLINIC

All patients must be reviewed with Hematology MD/NP prior to discharge.
1. Observation: all patients must be observed for at least one hour after the completion of the IV
antibiotic.
2. If patient does not meet the criteria for admission, discharge with instructions to return/seek medical
attention for:
 Fever 101°F or higher after 24 hours
 Worsening respiratory symptoms, difficulty breathing
 Chest pain
 Not taking oral fluids, persistent vomiting and/or diarrhea
 Lethargy
3. Remind family to call the sickle cell team the next business day for follow-up
REFERENCES
1. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G et al. Prophylaxis with oral penicillin in
children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593-9.
2. Halasa, NB, Shankar SM, Talbot TR, Arbogast PG, Mitchel, EF, Wang WC, et al. Incidence of invasive
pneumococcal disease among individuals with sickle cell disease before and after the introduction of the
pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44:1428-33
3. Rogovik AL, Friedman JN, Persaud J, Goldman RD. Bacterial blood cultures in children with sickle cell
disease. The Am J Emerg Med 2010;28:511-514
4. McCavit, TL, Quinn, CT, Techasaensiri C, Rogers, ZR. Increase in invasive streptococcus pneumoniae
infections in children with sickle cell disease since pneumococcal conjugate vaccine licensure. J Pediatr
2011;158:505-7.
2

Immunizations
Updated: September 16, 2016
SICKLE CELL DISEASE IMMUNIZATION GUIDELINE
PURPOSE: to educate clinicians about functional hyposplenism in sickle cell disease (SCD) and the importance
of timely and complete immunizations to prevent overwhelming, life-threatening infections. To alert clinicians of
the need for the pneumococcal polysaccharide (23-valent) vaccine and the different schedule for meningococcal
vaccination in SCD, which differ from the general pediatric population.
BACKGROUND
Individuals with SCD have functional hyposplenism, which greatly increases their risk of invasive bacterial
infections throughout their life, beginning as early as 2-3 month of age. The greatest risk is for the
pneumococcus and other encapsulated organisms. Antibiotic prophylaxis up to five years of age and timely,
complete immunizations can prevent overwhelming sepsis and death from pneumococci, meningococci, and
Haemophilus influenzae type b infections.
Evidenced Based Management of Sickle Cell Disease: Expert Panel Report 2014 recommendations:
1. All individuals with SCD should receive immunizations according to the ACIP harmonized immunization
schedule unless they have a personal contraindication as noted in the ACIP schedule. (Consensus-
Adapted)
2. Because of their increased susceptibility to invasive pneumococcal disease, all infants with SCD should
receive the complete series of the 13-valent conjugate pneumococcal vaccine series beginning shortly after
birth and the 23-valent pneumococcal polysaccharide vaccine at age 2 years, with a second dose at age 5
years. (Consensus –Adapted)
IMMUNIZATION SCHEDULE FOR SICKLE CELL DISEASE AT CINCINNATI CHILDRENS HOSPITAL

All patients with SCD should receive immunizations according to the Advisory Committee on Immunization
Practice (ACIP) and per the Expert Panel Report (2014).
At CCHMC:
1. Haemophilus influenzae type b (Hib): one dose of Hib vaccine for those greater than 5 years who have
not previously received Hib vaccine
2. Pneumococcal vaccination
• Ensure complete childhood series of PCV13 (or administer catch-up doses, if applicable)
• Pneumovax 23® (pneumococcal polysaccharide vaccine polyvalent, Merck) at 2 years of age, 5
years of age, and just before transition to adult care (approximately 20 years of age)
3. Meningococcal ACWY vaccination:

• Menactra® (MenACWY-D, Sanofi) at 2 years of age, then 3 years after primary series (5 years
of age), and booster every 5 years thereafter
• Always give a 2-dose primary series at any age (given 8-12 weeks apart), but if ≥ 7 years of age
at time of primary series, give booster every 5 years after primary series.
•
4. Meningococcal Group B Series:
nd rd
• Trumenba® (MenB-FHbp, Wyeth) 3-dose series (with 2 and 3 doses given 2 and 6 months
after the first dose) at ≥ 10 years of age
• Can be given concomitantly with MenACWY-D (Menactra)
Age: 2 years 5 years 10 years 15 years 20 years (adult

transition)
Pneumovax 23 Pneumovax 23 Trumenba (3-dose series) Pneumovax 23
Vaccine: Menactra (2-dose series) Menactra Menactra Menactra Menactra
1
Immunizations
Updated: September 16, 2016
5. Influenza:
• Trivalent inactivated influenza vaccine (Fluzone® or similiar) injection is preferred
REFERENCES
1. CDC. (2013). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal
polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions:
Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease
Control and Prevention: Morbidity and Mortality Weekly Report. June 28, 2013. Vol. 62 (No 25).
2. Cohn, AC, et al. (2013). Prevention and control of meningococcal disease: Recommendations of the
Advisory Committee on Immunization Practice (ACIP). Centers for Disease Control and Prevention:
Morbidity and Mortality Weekly Report. March 22, 2013. Vol. 62(No. 2).
3. Folaranmi, T, et al. (2015). Use of serogroup B meningococcal vaccines in persons aged > 10 years at
increased risk for serogroup B meningococcal disease: Recommendations of the Advisory Committee
on Immunizations Practices (ACIP). Centers for Disease Control and Prevention: Morbidity and Mortality
Weekly Report. June 12, 2015. Vol. 64( No. 22).
4. Kobayashi, M et al. (2015). Intervals between PCV13 and PPSV23 vaccines: Recommendations of the
Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention:
Morbidity and Mortality Weekly Report. September 4, 2015. Vol 64 (No 34).
5. MacNeil, JR, et al. (2014). Use of MenACWY-CRM vaccine in children aged 2 through 23 months at
increased risk for meningococcal disease: Recommendations of the Advisory Committee on
Immunization Practices (ACIP), 2013. Centers for Disease Control and Prevention: Morbidity and
Mortality Weekly Report. June 20, 2014. Vol.63 (No. 24).
6. Nuorti, JP, Whitney, CG. (2010). Prevention of pneumococcal disease among infants and children-Use
of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine:
Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease
Control and Prevention: Morbidity and Mortality Weekly Report. December 10, 2010. Vol. 59 (No.RR-
11).
7. U.S. Department of Health and Human Services. National Institutes of Health. NationaI Heart, Lung and
Blood Institute. (2014). Evidenced based management of sickle cell disease: Expert panel report 2014.
http:www.nih.nhlbi.gov/guidelines.
2
Priapism
PRIAPISM IN SICKLE CELL DISEASE

PURPOSE
To educate clinicians and standardize the management of patients with sickle cell disease (SCD) who have
priapism.
BACKGROUND
Priapism is an unintended, painful erection of the penis. It is a common complication in males with SCD. The
probability of experiencing priapism is 13% by 10 years of age, 50% by 15 years of age, and 89% by 20 years of
age. Priapism has been reported to occur as young as 3 years of age, and one series found that 16% of patients
had their first episode of priapism before 5 years of age. Patients may be reluctant to mention this problem to
physicians, so it is important to ask about its occurrence and provide anticipatory guidance.
Priapism occurs in two general patterns: (1) stuttering—brief episodes that resolve spontaneously, often occur
in clusters, and may herald a prolonged event; and (2) prolonged—episodes that last ≥4 hours and may cause
permanent vascular damage and impotence. Delayed diagnosis and treatment of priapism may eventually result
in impotence.
HOME MANAGEMENT
First steps:
Upon onset, instruct the patient/family:
• Take oral ibuprofen or other oral analgesic
• Increase fluid intake (drink water)
• Try to urinate
• Take a warm bath or shower
• For patients who have had priapism before, take a dose of oral pseudoephedrine (30 mg < 10 years; 60
mg ≥ 10 years).
Next steps:
• If full detumescence occurs in <4 hours, no further intervention is needed. Arrange phone follow-up with
the SCD team the next morning.
• Any episode that lasts ≥4 hours should be considered an emergency that requires prompt medical
intervention (referral to E.D with consultation by Urology).
E.D. EVALUATION
• History and physical to determine duration and type of priapism (prolonged vs. stuttering) and time of
last urination
• CBC, reticulocyte count, type and screen (in case anesthesia is necessary)
• Urinalysis and culture (if unable to void, perform a straight catheterization which may potentially cause
detumescence)
• Make patient NPO (in case anesthesia is necessary)
• Notify Hematology
• If priapism is prolonged (≥4 hours) upon presentation, consult Urology immediately for evaluation for
potential direct aspiration and irrigation
• If the patient appears comfortable and the penis is not fully erect and swollen, consider the possibility of
stuttering priapism.
E.D. TREATMENT
• Do NOT use ice, ice packs, ice bath, or ice water enemas
• 10 mL/kg normal saline bolus over 1 hour, then continue D5-1/2-NS fluids at maintenance rate
1
Priapism
• Acute transfusion is not effective for priapism. There is old, anecdotal evidence that acute exchange
transfusion may be cause neurologic events (e.g., stroke).
• Provide aggressive analgesia with parenteral opiates per the E.D. protocol for sickle cell pain with
frequent reassessments every 15-30 minutes. The patient may require repeated, frequent doses to
achieve adequate pain relief.
If full detumescence occurs with supportive therapy:

• No further specific intervention is required, and the patient may be discharged.
• Upon discharge from the E.D. or hospital, consider prophylaxis with pseudoephedrine 30 mg by mouth
nightly (<10 years) or 60 mg by mouth nightly (>10 years).
If the patient has no or incomplete detumescence ≥4 hours after onset:

• Consult Urology for evaluation for penile aspiration and irrigation.
• Aspiration and irrigation can be performed at the bedside in the E.D.
• In the unlikely event that general anesthesia is required for aspiration and irrigation, consider simple
transfusion with packed red blood cells to increase the hemoglobin concentration to 10-11 g/dL for
prevention of post-operative acute chest syndrome.
• The pH of aspirated penile fluid does not guide the need for transfusion.
• If full detumescence occurs after aspiration and irrigation, the patient may be discharged from the E.D.
• Upon discharge from the E.D. or hospital, consider prophylaxis with pseudoephedrine 30 mg by mouth
nightly (<10 years) or 60 mg by mouth nightly (>10 years).
NEED FOR HOSPITALIZATION
Many individuals do not need to be hospitalized after E.D. management. Consider hospitalization for poorly
controlled pain or observation post-sedation or post-anesthesia observation.
DISCHARGE FROM THE HOSPITAL
Discharge Criteria:
1. Resolved or ongoing resolution of priapism (complete detumescence and resolution of edema after
discharge may take 3-4 weeks
2. Taking adequate oral fluids and able to take PO medications
3. Adequate pain relief with oral analgesics
Discharge and Follow-up Plan:

1. Consider starting pseudoephedrine upon discharge for priapism prophylaxis:
a. Age <10 years: 30 mg by mouth nightly
b. Age>10 years: 60 mg by mouth nightly
2. Arrange follow-up with sickle cell team within 1-2 weeks of discharge
PREVENTION
• Patients who have frequent episodes (≥2 within one month or ≥4 within one year), additional treatments
may be indicated and should be discussed with the primary sickle cell team.
• For such patients, prophylaxis with pseudoephedrine 30 mg by mouth nightly (<10 years) or 60 mg by
mouth nightly (>10 years) the be prescribed.
• Other preventive therapies include Lupron and Casodex can be considered.
• Maximize (or prescribe) disease-modifying therapy (e.g., hydroxyurea).
• Generally, shunt procedures are avoided.
REFERENCES
Rogers, Z. R. (2005). Priapism in sickle cell disease. Hematol Oncol Clin N Am, 19(5), 917–28– viii.
2
Switching from Transfusions to Hydroxyurea
Updated: January 19, 2017
SWITCHING FROM TRANSFUSIONS TO HYDROXYUREA
PURPOSE: To describe a careful transition process that allows hydroxyurea therapy to replace
chronic erythrocyte transfusions, usually in the setting of stroke prevention or other organ damage.
BACKGROUND:
For patients with sickle cell anemia (SCA) who receive chronic transfusions for primary or secondary
stroke prophylaxis, an important therapeutic goal is to maintain the total hemoglobin concentration
high enough to suppress endogenous sickle erythropoiesis; operationally this means maintaining
≤30% HbS, which is typically measured just before each transfusion. Although this 30% HbS target
has never been tested formally in a randomized clinical trial, it has both a physiological basis and
many years of clinical effectiveness. In actual practice for stroke prevention, most academic practices
can achieve values close to this goal; trough HbS levels in children transfused either for primary or
secondary stroke prevention average about 35%. [1,2] Since transfusions are effective, the decision
to pursue a “therapeutic switch” from a familiar transfusion regimen to a less familiar hydroxyurea
protocol must be carefully considered, especially when the patient has an increased risk of stroke.
In designing a switch from transfusions to hydroxyurea, three key principles should be recognized: (1)
an overlap period of dual therapy is desirable, since the benefits of transfusions are immediate while
those of hydroxyurea have a slower onset; (2) transfusions should be weaned gradually to allow
endogenous erythropoiesis to occur under the influence of hydroxyurea treatment; and (3)
hydroxyurea should reach a stable MTD with documented hematological benefits before transfusions
are discontinued. To accomplish this switch efficiently and safely, we have developed a procedure
that simultaneously weans transfusions while escalating hydroxyurea to MTD, based on experience
with over 150 children who have undergone this therapeutic transition. The most critical feature is
weaning the transfusions with stepwise lowering of hemoglobin targets, while increasing the
hydroxyurea dose progressively to a stable MTD; [3] in children with SCA who are adherent and
achieve a stable MTD, the transition can be safely accomplished in approximately 6-8 months. [4,5]
With proper planning and an established process, outpatient phlebotomy can commence soon after
transfusions have been discontinued.
Hydroxyurea should be gradually escalated per this protocol. Starting at a pharmocokinetically-
determined dose (predicted MTD) of hydroxyurea is not recommended.
Patients receiving chronic transfusions for a non-neurological indication (e.g., frequent pain or acute
chest syndrome) do not necessarily require a gradual transition to hydroxyurea as outlined in this
protocol. However, this protocol can be followed for such patients at the discretion of the provider.
PROCEDURES:
Eligibility criteria for switching:
1. Currently receiving chronic transfusions for primary stroke prevention (abnormal TCD
velocities);
2. Has received at least 12 months of chronic transfusions; and
3. No history or evidence of overt clinical stroke, transient ischemic attack, or severe
vasculopathy.
advice concerning
© 2017 an individual
Cincinnati Children’spatient’s
Hospitalmedical
Medicalcare and treatment.
Center
1
Baseline (pre-switch) testing:
1. MRI/MRA of brain
2. TCD
Transfusion weaning process:
This section details the overlap of hydroxyurea and transfusion therapy in a procedure that features
simultaneous weaning of transfusions while escalating hydroxyurea to a stable MTD, aiming for a
robust hydroxyurea treatment effect (usually indicated by a corrected HbF ≥20%) before discontinuing
transfusions (adapted from references 3 and 5). These steps are also summarized in the Table of
Recommendations at the end of this section.
1. At a scheduled transfusion visit, obtain baseline laboratory studies that are appropriate to initiate
hydroxyurea at 15-20 mg/kg/day, as outlined for hydroxyurea dose escalation to MTD (see
separate hydroxyurea treatment guidelines).
2. On the day hydroxyurea treatment starts, give a simple packed RBC transfusion with a target
hemoglobin concentration of ~11.5 g/dL.
For all transfusions in this protocol, use the following formula to calculate the volume of PRBCs to
be administered (where Hb is expressed in g/dL; weight is expressed in kg; 75 mL/kg is the blood
volume; and 20 g/dL is the average Hb concentration of PRBCs):
𝑑𝑒𝑠𝑖𝑟𝑒𝑑 𝐻𝑏 − 𝑐𝑢𝑟𝑟𝑒𝑛𝑡 𝐻𝑏 × 75 × 𝑤𝑒𝑖𝑔ℎ𝑡
𝑉𝑜𝑙𝑢𝑚𝑒 𝑚𝐿 =
20
Example:
Current Hb = 9.5 g/dL, desired Hb = 11.5 g/dL, and weight = 30 kg.
11.5 − 9.5 × 75 × 25
𝑉𝑜𝑙𝑢𝑚𝑒 𝑚𝐿 = = 225
20
3. After one month of hydroxyurea therapy, assess for evidence of hydroxyurea adherence and
effect. Early laboratory changes will include a higher MCV and RDW, along with a lower ANC and
ARC.
4. If no laboratory toxicities are identified, continue hydroxyurea at 15-20 mg/kg/day and transfuse to
the same hemoglobin target of ~11.5 g/dL (use the transfusion formula).
5. After two months of hydroxyurea therapy, increase the hydroxyurea dose as tolerated to 20-25
mg/kg/day. Perform hemoglobin electrophoresis and assess HbF induction by calculating HbF /
(HbF + HbS). Note that the HbS will begin to rise above the typical target of 30%.
Example Corrected HbF Calculation:
Hb electrophoresis results: HbA = 55%, HbS = 35%, HbF = 10%
𝐻𝑏𝐹 10
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝐻𝑏𝐹 = = = 22%
(𝐻𝑏𝐹 + 𝐻𝑏𝑆) (10 + 35)
Note: the total HbF value (10%) underestimates true HbF induction (22%) because HbF is diluted
by transfused HbA.
advice concerning
Hospitalmedical
Center
2
6. Continue to wean transfusions by providing a simple PRBC transfusion with a slightly lower
hemoglobin target of ~11.0 g/dL (use the transfusion formula).
7. At three months of hydroxyurea therapy, assess for evidence of hydroxyurea adherence and
effect, especially an increased MCV and RDW as well as lower ANC and ARC. Continue
hydroxyurea at 20-25 mg/kg/day and transfuse to the same hemoglobin target of ~11.0 g/dL (use
the transfusion formula).
8. After four months of hydroxyurea therapy, increase hydroxyurea dose as tolerated to 25-30
mg/kg/day. Perform hemoglobin electrophoresis and assess HbF induction by calculating HbF /
(HbF + HbS). Note the HbS may exceed 50% at this point, as the HbA declines.
9. Continue transfusion weaning by providing a simple PRBC transfusion with a lower target
hemoglobin concentration of ~10.5 g/dL (use the transfusion formula).
10. Assess monthly to document the hydroxyurea effect and to establish the MTD. Continue
transfusions using a target hemoglobin concentration of ~10.5 g/dL (use the transfusion formula)
until a stable MTD has been reached with a robust HbF response, which is usually
indicated by HbF / (HbF + HbS) ≥ 20%.
11. Certain scenarios warrant special consideration and modification of the overlap procedure, such
as a brisk hydroxyurea response, high baseline hemoglobin concentration, and poor medication
adherence.
12. Once transfusions have been discontinued, commence phlebotomy if there is documented
evidence of transfusion-acquired iron overload.
13. Consider TCD 6 months after cessation of transfusions.
Table of Recommendations
Month HU dose Transfusion Goal3 Labs
0 Start at 11.5 g/dL CBC, differential and reticulocytes
15-20 mg/kg Peripheral smear, Hb electrophoresis
Hepatic and renal profiles
1 15-20 mg/kg1 11.5 g/dL CBC, differential and reticulocytes
Peripheral smear, Hb electrophoresis
Hepatic and renal profiles
May stop transfusions when HbF / (HbF + HbS) ≥ 20%
1
Continue this HU dose unless ANC is < 1,000
2
Escalate HU dose if ANC is > 3,000
3
Use transfusion formula in this protocol
advice concerning
Hospitalmedical
Center
3
Roadmap for the Medical Record
(cut and paste into Epic)

HU Dose HU dose Hb target
Month Date Hb F/F+S (%) Hb S (%)
(mg) (mg/kg) (g/dL)
0
1
2
3
5
6
Date transfusions stopped:
REFERENCES
1. Aygun B, McMurray MA, Schultz WH, et al for the SWiTCH Investigators. Chronic transfusion
standards for children with sickle cell anemia and stroke. Br J Haematol 2009;145:524-528.
2. Aygun B, Wruck L, Schultz WH, et al for the TWiTCH Trial Investigators. Chronic transfusion
practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD
velocities. Am J Hematol 2012;87(4):428-430.
3. Ware RE, Schultz WH, Yovetich N, et al. Stroke with transfusions changing to hydroxyurea
(SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia,
stroke, and iron overload. Pediatr Blood Cancer 2011;57:1011-1017.
4. Ware RE, Helms RW for the SWiTCH Investigators. Stroke with transfusions changing to
hydroxyurea (SWiTCH). Blood 2012;119:3925-3932.
5. Ware RE, Zimmerman SA, Sylvestre PB, et al. Prevention of secondary stroke and resolution of
transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy.
J Pediatr 2004;145:346-52.
advice concerning
Hospitalmedical
Center
4
Vitamin D Supplementation
Updated: January 2017

VITAMIN D SUPPLEMENATION IN SICKLE CELL DISEASE GUIDELINE
PURPOSE: To educate clinicians about the high incidence and health consequences of vitamin D deficiency in patients with
sickle cell disease. To provide recommendations for evaluation and treatment.

BACKGROUND
Low serum vitamin D status is very common in children with sickle cell disease (SCD), with rates reported to be 65-100%.
Vitamin D deficiency in SCD patients may be associated with complications such as musculoskeletal weakness, chronic
bone pain, avascular necrosis, bone fragility and fractures. Some studies suggest that sufficient vitamin D levels are
associated with improvement in pain and quality of life. A vitamin D concentration (serum 25-hydroxy-vitamin D or 25OH
Vitamin D as listed in Epic) of 30 ng/mL is desired to achieve adequate bone mineral density and improve other health
outcomes.

EVALUATION:
1. Vitamin D (25OH-vitamin D) level should be obtained every 6 months to yearly, beginning at 1 year of age.

TREATMENT:
The goal of therapy is to maintain 25OH vitamin D levels between 30-100 ng/mL.

May use vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) for treatment, however it is preferred that vitamin D3
be used (particularly with larger dosing) as there are reports stating that vitamin D3 effectiveness is up to three times that
of vitamin D2.

For patients on chronic transfusion therapy, considering giving 50,000 IU at each transfusion visit. For patients with poor
adherence to home medications, consider supplementing at each outpatient visit

DOSING
1. Infants up to 1 year of age:
• All infants should receive 400 IU vitamin D daily independent of the type of feeding (breast or formula)

2. > 1 year of age and 25OH Vitamin D levels:
• < 20ng/mL:
50,000 IU vitamin D3 weekly for 16 weeks
If level within goal at end of 16 week therapy begin 1,000-2,000 IU daily or 50,000 IU monthly

• 20-30 ng/mL
1,000 – 2,000 IU vitamin D3 once daily or 50,000 IU monthly

• > 30-100 ng/mL
400-1000 IU vitamin D3 daily

Continue vitamin D supplementation as above if 25-OH-vitamin D level is not above 100ng/mL. If 25-OH-
vitamin D level is above 100ng/mL on 2 consecutive monthly levels, consider decreasing the dose to
maintain the level between 30 and 100ng/mL

1

Vitamin D Supplementation
Updated: January 2017

REFERENCES

1. Bischoff-Ferrari HA, Giovannucci E, Willet WC, Dietrich T, & Dawson Hughes B. (2006). Estimation of optimal
serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. American Journal of Clinical
Nutrition 84,18-28.
2. Busion A, Kawchak D, Schall J, Ohene-Frempong K, Stallings V & Zemel B. (2004). Low vitamin D status in children
with sickle cell disease. The Journal of Pediatrics, 145, 622-627.
3. Holick, MF, et al. (2011). Evaluation, treatment and prevention of vitamin D deficiency: An Endocrine Society
clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism, 96(7):1911-1930.
4. Misra M, Pacaud D, Petryk A, Collett-Solberg P, & Kappy M. (2008). Vitamin D deficiency in children and its
management: Review of current knowledge and recommendations. Pediatrics, 122,398-417.
5. Osunkwo I, Zieger TR, Alvarez J, McCracken C, Cherry K, Osunkwo CE, et al. (2012). High dose vitamin D therapy
for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot
study.
6. Wagner C, and Greer F. (2008). Prevention of rickets and vitamin D deficiency in infants, children and
adolescents. Pediatrics, 122, 1142-1152.

2


Hydroxyurea For Sickle Cell Disease Indications, Dosing and Monitoring Guideline

Hochgeladen von

Dokumentinformationen

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Hydroxyurea For Sickle Cell Disease Indications, Dosing and Monitoring Guideline

Hochgeladen von

Copyright:

Verfügbare Formate

Cincinnati Children’s Hospital Medical Center

Sickle Cell Clinical Practice Guidelines

INDICATIONS FOR BEGINNING HYDROXYUREA

RELATIVE CONTRAINDICATIONS (WHEN NOT TO START HYDROYXUREA)

WHEN TO DISCONTINUE HYDROXYUREA

Based on published experiences with hydroxyurea in children, persistent or severe myelosuppression is

 Peripheral blood smear

Efforts to improve adherence might include:

Highly suspicious for stroke:

1. Stroke may be an isolated event or

PREPARE TO TRANSFUSE4 NOTIFICATION 3. Avoid over-hydration. Correct any

4. If patient already receives chronic

6. Unlike other causes of acute stroke, CT

All patients: ICU management

Hemorrhage: consult Neurosurgery

Consider other causes of stroke (e.g.,

< 155 155 - 184 185 - 204 ≥ 205

Discuss very high

< 155 155 - 184 185 - 204 ≥ 205

Discuss very high

< 155 155 - 184

**If a previously abnormal TCD converts to conditional on 4 consecutive studies, consider

SICKLE CELL FEVER MANAGEMENT GUIDELINE

1. In consultation with Hematologist, hospitalization is necessary for:

*consider adding vancomycin until negative cultures by 48 hours

© 2017 Cincinnati Children’s Hospital Medical Center

*consider adding vancomycin until negative cultures by 48 hours

3. Additional criteria to consider when making the decision to admit or not:

DISCHARGE FROM ED/CLINIC

© 2017 Cincinnati Children’s Hospital Medical Center

SICKLE CELL DISEASE IMMUNIZATION GUIDELINE

IMMUNIZATION SCHEDULE FOR SICKLE CELL DISEASE AT CINCINNATI CHILDRENS HOSPITAL

3. Meningococcal ACWY vaccination:

Age: 2 years 5 years 10 years 15 years 20 years (adult

PRIAPISM IN SICKLE CELL DISEASE

If full detumescence occurs with supportive therapy:

If the patient has no or incomplete detumescence ≥4 hours after onset:

NEED FOR HOSPITALIZATION

DISCHARGE FROM THE HOSPITAL

Discharge and Follow-up Plan:

SWITCHING FROM TRANSFUSIONS TO HYDROXYUREA

Baseline (pre-switch) testing:

13. Consider TCD 6 months after cessation of transfusions.

Roadmap for the Medical Record

(cut and paste into Epic)

Date transfusions stopped:

VITAMIN D SUPPLEMENATION IN SICKLE CELL DISEASE GUIDELINE

Das könnte Ihnen auch gefallen