Pain, Fever, and ACS in Sickle Cell Disease Sirish Palle, M.D. July 26, 2011

Adenine to thymidine at codon 6 in beta Hb on Chromosome 11 leads to substitution of glutamic acid by valine

Identification Alabama newborn screen tests for sickle cell disease  If a screen is positive, order Hb electrophoresis for verification  If a child has trait, counsel the family regarding risk in future children  Check Hb electrophoresis at one year old

Newborns If diagnosed with sickle cell disease:  Start prophylactic PCN VK at 125 mg PO BID before 2 months old to decrease risk of death from pneumococcal infection  Refer to Hematology, refer family to Genetics for counseling  Give Prevnar (pneumococcal conjugate vaccine) at 2, 4 and 6 mos old  Give influenza vaccine at starting at 6 mos

Infants and Toddlers Start Folic Acid 1 mg PO daily by one year old Give Prevnar (conjugate) at 15 mos Give Pneumovax (polysaccharide) at 2 yo & 5 yo Those that have already received their 4 doses of Prevnar 7, get additional dose of Prevnar 13 Continue to vaccinate yearly against influenza At 3 yo, change to PCN VK 250 mg PO BID May stop PCN VK at 5 yo ≤16yo need TCD to assess for risk of CVA and need for chronic transfusion to prevent

Outcomes Severity is generally based on Hb variant:  SS > S-beta o thalassemia > S-beta + thalassemia > SC Median life expectancy for HbSS is 45 years, for HbSC is 65 years High WBC, low Hb (<7), and VOC crisis in the first year of life are the known risk factors for severe morbidity

Vaso-Occlusive Crises AKA Pain Crisis

VOC (Vaso-Occlusive Crisis) Triggers:  Infection  Temperature extremes  Dehydration  Stress  Idiopathic

History to obtain Location of pain, severity on 0/10 scale Is this their typical pain or is it different? Do they have significant headache (worry about stroke)? Do they have SOB, chest pain, cough (worry about ACS)? If they are male, do they have priapism? Do they have a fever (worry about ACS, sepsis, osteomyelitis)?

Labs to order CBC with differential  Don’t be surprised if the WBC count is elevated due to stress response Reticulocyte count  Expect it to be elevated Chem 14

Therapies Hydration: D5 ½ NS with 20 meq KCl/L to run at 150% maintenance  (unless concerns for ACS or for long periods of time) Heating packs PT consult for ROM, TENS unit, whirlpool Encourage OOB, incentive spirometry

Oral Pain Medications Acetaminophen with Codeine: 120 mg/12 mg/5 mL; 0.5 mg/kg/dose of codeine PO Q 4-6 hours; max dose 60 mg codeine per dose; watch acetaminophen component Acetaminophen/Hydrocodone (Lortab): 500 mg/7.5 mg/15 mL; dose depends on weight, from 3.75 mL to 15 mL PO Q 4-6 hours; watch acetaminophen component

Parenteral Pain Medications Ketorolac (Toradol): NSAID  0.5mg/kg IV/IM Q6 hours, max dose 30 mg IM, 15 mg IV for pediatrics  Don’t use if concerns for bleeding  Don’t use with other NSAIDS  Caution if renal impairment  Watch for gastric irritation  Use for 5 days only

Parenteral Pain Medications Nalbuphine (Nubain): opioid agonist/antagonist  mg/kg/dose IV Q 2-4 hours  Max dose 20 mg  Monitor for respiratory depression  Good for patients who have pruritis with morphine

Morphine Parenteral  mg/kg/dose SC/IM/IV Q2-4 hours  Max dose 15 mg  Can give via PCA if 5 years or older, depends on child’s maturity Counsel family that they cannot push the button! This counteracts the built in safety of a PCA.

Morphine Oral  MS Contin (extended release) mg/kg PO Q 12 hours Don’t chew Comes as 15,30,60 mg  MSIR (immediate release) mg/kg PO Q 4-6 hours PRN severe pain Comes as 15 mg, 30 mg pills, or as 10 mg/5mL, 20 mg/10 mL solution

Transition from IV to PO Morphine Oral dose is 3x the IV dose  If a patient is comfortable on Morphine 3 mg IV Q 3 hours, total daily dose is 24 mg/day  Oral dose = 3 x 24 = 72 mg/day  Can give MS Contin 30 mg PO Q12 hours  Can give MSIR for breakthrough pain; 3-5 mg PO Q 4-6 hours PRN severe pain

Other Medications If patient is on hydroxyurea at home, continue it at the same dose Folate 1 mg PO daily Consider transfusion in the case of severe anemia; typically not done in VOC unless acute chest, risk of stroke, acute multi-organ failure, heart failure, reticulocytopenia (eg ParvoB19), hepatic/splenic sequestration or preoperative

Fever

Functional asplenia from sickling in the microcirculation in 90% of patients by age 6 years  unless chronic transfusions which may prolong the function of the spleen Increased risk of infection with encapsulated organisms Haemophilus influenzae type b Streptococcus pneumoniae Salmonella typhi Neisseria meningitides Group B streptococcus Klebsiella pneumoniae

Bottom Line Any patient with sickle cell disease and T>101 F (38.4 C) gets parenteral antibiotics, even if you have a source!

Labs that you must have CBC with differential Reticulocyte count CRP Blood culture Chest X-ray

Labs that you might want CP14 UA, urine culture Parvovirus B19 titers if a drop in Hb and inappropriately low reticulocyte count  Look for elevated IgM, if +, needs isolation from pregnant women If swollen painful limb, consider osteomyelitis (MRI)

Medications Ceftriaxone (Rocephin):  mg/kg/day IV divided Q12-24 hours  mg/kg/day IV divided Q12-24 hours if cephalosporin resistant S pneumo suspected/prevalent in area Vancomycin:  Consider adding if clinically ill  Commonly used vancomycin doses outside of the neonatal period range from 40 to 60 mg/kg/d divided every 6 to 8 hours  The exact dose will depend on the clinical presentation and may need to be altered based on the results of therapeutic monitoring  Level prior to 5 th dose – trough  Some evidence suggests that keeping vancomycin trough levels >10 μg/mL may help prevent the development of heteroresistance in MRSA, level closer to in CNS, bone/joint infections and/or suspected MRSA pulmonary infections   Pediatric Infectious Disease Journal: May Volume 29 - Issue 5 - pp

Adjusting Vancomycin Overall, nephrotoxicity in adult patients is estimated to be <5% However, there are reports of an increased risk of nephrotoxicity when vancomycin is combined with an aminoglycoside Use with caution in renal insufficiency (BUN/Creat) & GFR Although initially reported to be associated with ototoxicity, this association has been called into question Many initial reports of ototoxicity occurred in patients with potential confounding factors (eg, concurrent meningitis and aminoglycoside use) Red Man's Syndrome an association of erythema and flushing of the face, neck, and torso occurs in a significant number of patients (up to 50% in some series) and is believed to be secondary to histamine release  stop/slow infusion rate and administer Benadryl

Other Medications Hydroxyurea:  Continue at the patient’s home dose  Hold if leukopenia, neutropenia, or thrombocytopenia is noted Folate 1 mg PO daily

Acute Chest Syndrome AKA new infiltrate on CXR and a fever

Acute Chest Syndrome Definition is debated…  New infiltrate on CXR (the best film is an old film) AND one or more of the following:  Fever (>38.5)  Chest pain  Tachypnea, wheezing, cough or appearance of increased work of breathing (retractions)  Hypoxemia relative to baseline measurements Bottom Line: keep ACS forefront in your mind if your patient has any pulmonary complaints: cough, SOB, chest pain, chest wall pain, hypoxia on exam  Febrile pt with SCD need xray up to 61% not clinically suspected prior to radiograph evidence of infiltrate  Repeat CXR on kids in VOC pain crisis if resp symptoms

Treatment Incentive spirometry with older patients (10 breaths per hour while awake) or have younger children blow bubbles Albuterol nebulizer/MDI Q 4 hours ATC Chest PT, Mucomyst nebs Ceftriaxone IV or other 3 rd generation Cephalosporin (consider S pneumo resistance) Azithromycin  10mg/kg PO/IV day one, then 5 mg/kg daily for days 2-5 Continue Folate and Hydroxyurea

Treatment When should you give oxygen?  When your patient has desaturations <90-92%  Starting oxygen when not needed ( for “comfort”) can decrease reticulocytosis  If you have to start oxygen, get an ABG first unless oxygen need is urgent  Keep O2 Sats <95% once O2 started

Treatment When should you give blood?  Keep H/H around 10/30  Transfuse with leukocyte poor, sickle trait negative PRBCs; consider extended antigen match in chronic transfusion patients to avoid alloimmunization  premedicate with Tylenol and Benadryl  Do not transfuse to >12/36 as this can increase the risk for stroke  Consider exchange transfusion if worsening even with H/H 10/30 Need double lumen central line; Red Cross involved

Consent for Blood

Hydration Status Overhydration can worsen ACS  If dehydrated, correct with isotonic solution  D5 ½ NS with 20 meq KCl/L at 100% maintenance for continued fluid needs  Daily weights Monitor in and outs closely Adjust fluids as needs Furosemide if fluid overload suspected

Remember… Children with sickle cell disease and acute chest syndrome can get ill very quickly and go into respiratory failure When called to evaluate children with sickle cell disease with shortness of breath, ALWAYS go to the bedside to assess them

Case 1 Kevin is a 13 yo AAM with Hb SS disease who is admitted with left leg pain for the last 2 days, unresponsive to Lortab 5mg at home. Pain is 7/10, nonradiating, and is similar to previous pain crises.

History What further questions?  Fever?  SOB? Cough?  Priapism?  HA?  Injury or wounds?

PE Well developed, NAD, mild scleral icterus T=99, HR=80, RR=16, BP 110/70, O2 sats 97% RA 1/6 SEM Leg without erythema or wounds, mild TTP, CR brisk

Labs H/H 10/30 Retic count 5% CP14 with T bili mildly elevated

What medications? He weighs 45 kg and has no allergies What else do you want to order to treat the pt in the hospital?

Hospital course Hospital Day # 2: You are called at 0200; his leg pain is 2/10 but he has abdominal pain.  What do you want to do? Hospital Day # 3: his pain is 2/10 and he is tolerating food well.  What do you want to do?

Hospital Course His leg and abdominal pain resolves and you discharge him home. What advice should you give his parents?  Importance of yearly influenza vaccine  Importance of fever  Folate 1 mg PO daily  Pain management and concerns for addiction

Case 2 Alexis is a 2 yo AAF with HbSS disease who comes to your office as a new patient with T=102. Her parents report that she has had rhinorrhea for 3 days and has been pulling at her left ear. She has been eating and drinking well and has normal UOP. You examine her and diagnose left otitis media.

What do you want to do? Admit her to the hospital Labs? Medications? She weighs 15 kg and has no allergies.

On call You are paged at 0100 on hospital day #2. Alexis has vomited once and her parents say that she is not acting right. The nurse reports that she seems a little sleepy, but it is past her bedtime. What do you do?

In her room… You find Alexis to be sleepy but awakes easily. She is fussy when you awaken her and is somewhat consolable by her mother. T=104.3, BP is 85/50, O2 sats=100% RA, RR=30. PE: CR is 2-3 seconds, lungs are clear. What do you do?

Follow-up A nurse calls you with Alexis’s Vancomycin level of 14 at 2100 the next night. She is worried. What do you do? What if the level was 22? What if the level was 4?

Discharge Advice Yearly influenza vaccine Has she had Pneumovax (due at 2 yo)? PCN VK 125 mg PO BID Folate 1 mg PO daily Follow up in your office

Case 3 Tony is a 16 yo AAM with HbSS disease who comes into the ER with a cough for 24 hours and pain in his left chest. He denies fever at home, denies SOB, denies priapism. He is on hydroxyurea at home. He has received multiple transfusions.

What next? Physical exam Are there crackles? Is he tachypneic? Is he febrile? What is his O2 sat? CXR: left lower lobe infiltrate

What next? Medications? He weighs 70 kg and has no allergies Other therapies?