MNGHA NEOMEDBOOK (December 2021)

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Amikacin CNS Infection • Draw peak 30 minutes after (cont’d) Meningitis: 30-minute infusion has been Infants: IV: completed or 1 hour following IM Amoxicillin <7 days of age: 15 – 20 mg/kg/day divided injection or beginning of infusion; Amoxicillin- q12hr Draw trough immediately before Clavulanic Acid >7 days of age: 30 mg/kg/ day divided q8h (Augmentin) next dose For <2kg, use a smaller dose and consult the Do peak and trough serum Clinical Pharmacist amikacin levels around the 3rd consecutive dose. VP-shunt infection, ventriculitis:: Intraven- Therapeutic levels for less severe tricular/intrathecal (use a preservative-free infections: preparation): Peak: 21 – 28 mcmol/L 5 to 50 mg/day; usual dose: 30 mg/day Trough: < 10 mcmol/L Therapeutic levels for life-threat- ening infections: Peak: 43 – 60 mcmol/L Trough: < 10 mcmol/L Susceptible infection: Oral: No adjustments needed for 20 to 30 mg/kg/day divided every 12 hours Neonates UTI, prophylaxis Less GI effects than ampicillin. May (hydronephrosis, vesicoureteral reflux): cause rash and diarrhea. Oral: 10 to 15 mg/kg once daily Otitis media, acute (AOM), Group A or B strep- tococcus: 40mg/kg/dose q12h for 7-10 days Oral stepdown therapy after IV/IM penicillin or GFR >30 mL/minute/1.73 m2: ampicillin: No adjustment required. Oral: GFR 10 to 29 mL/minute/1.73 m2: 30 to 40 mg/kg/day in divided doses Q8 hrs 8 to 20 mg amoxicillin/kg/dose Oral: every 12 hours. GFR <10 mL/min- 30 mg amoxicillin/kg/day divided every 12 ute/1.73 m2: 8 to 20 mg amoxicil- hours; recommend using either lin/kg/dose every 24 hours. > 400 mg amoxicillin/57 mg clavulanate/5mL 4:1 formulations: suspension, or (amoxicillin 400 mg/clavulanate > 600 mg amoxicillin/42.9 mg clavula- 57 mg susp; amoxicillin 600 mg/ nate/5mL suspension clavulanate 42.9 mg susp; IV dosing: infants < 4kg 30mg/kg* AUGMENTIN every 12 hours infants >4kg 30mg/kg* AUGMENTIN every 8 hours 50 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Amphotericin B Candidiasis: Invasive, CNS infection: If renal dysfunction is due to drug, IV: 1 – 1.5 mg/kg/dose once daily decrease dose by 50% or give the dose every other day Dilute each dose in 5% dextrose in water to a final concentration of 0.1 mg/mL (peripheral There is no need for a test dose. administration) or 0.25 mg/mL (Central line only) and infuse over 4 - 6 hours. Side effects include hypokalemia, thrombocytopenia, hypercalciuria, hypomagnesemia, and nephro- toxicity. Amphotericin B Lipid Candidiasis, invasive: Monitor serum electrolytes (po- Complex (Abelcet) IV: 3 to 5 mg/kg/dose once daily tassium, creatinine) and complete Amphotericin B, blood count Liposomal Dilute with D5%W to final concentration of 1 No adjustments needed (Ambisome) mg/mL or 2 mg/mL for fluid-restricted patients. Infusion rate: 2.5 mg/kg/hr; if total infusion Side effects: thrombocytopenia, time exceeds 2 hours shake infusion bag every anemia, leucopenia, hypokalemia, 2 hours. hypomagnesemia, Candidiasis, invasive: diarrhea, respiratory failure, skin IV: 3 to 7 mg/kg/dose once daily rash and increases in liver enzymes and bilirubin. 3 – 5 mg/kg/day IV once daily. Dilute with No adjustments needed D5%W to final concentration of 0.2 – 0.5 mg/ Adverse effects include thrombo- mL and infuse over 2 hours. cytopenia, hypokalemia, hypo- mg/m2/day IV over at least 1 hour. magnesemia, hypocalcemia, hyperglycemia, diarrhea, tachycar- dia, skin rash and increases in liver enzymes and bilirubin. General Dosing, susceptible infection: When administering ampicillin with parenteral nutrition, it is GA Post Dose Interval probably safest to temporarily dis- (weeks) Natal mg/kg (hours) continue the parenteral nutrition, (days) and administer the ampicillin by IV push over three to five minutes. <7 50 12 • No adjustments needed in neo- ≤34 75 12 natal period • GFR 30 to 50 mL/minute/1.73 8-28 m2: 35 • to 50 mg/kg/dose every 6 hrs >34 <28 50 8 • GFR 10 to 29 mL/minute/1.73 m2: 35 Ampicillin GBS meningitis: • to 50 mg/kg/dose every 8 to 12 PNA ≤7 days: 200 to 300 mg/kg/day divided hours every 8 hours • GFR <10 mL/minute/1.73 m2: 35 PNA >7 days: 300 mg/kg/day divided every 6 to 50 mg/kg/dose every 12 hours hours Surgical prophylaxis: IV: 50 mg/kg as a single dose within 60 minutes prior to surgical incision UTI Prophylaxis: IV: 10-20 mg/kg/dose once daily or Q12 h Antimicrobial Therapy Drug Dosage Guidelines | 51

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Azithromycin General dosing, susceptible infection: Dilute with either D5%W or normal Oral: 10 mg/kg once daily ; IV: 10 mg/kg once saline to give final concentration of Aztreonam daily 1 mg/mL and infuse over 3 hours or 2 mg/mL and infuse over 1 hour. Chlamydial conjunctivitis or chlamydial Side effects: Increase in liver pneumonia: enzymes, cholestatic jaundice, GI Oral: 20 mg/kg once daily for 3 days discomfort and pain at injection site. CNS penetration is poor. Pertussis, treatment and postexposure pro- phylaxis: Provides coverage for gram-neg- Oral, IV: 10 mg/kg once daily for 5 days ative micro- organisms including Pseudomonas species. Not active Body Post Dose Interval against gram-positive microor- weight Natal mg/kg (hours) ganisms. <1 kg (days) 1-2 kg <14 30 12 >2 kg 15-28 30 8-12 30 12 <7 8-12 8-28 <7 8 8-28 6 BSA-directed dosing: 25 mg/m2/dose once Monitor IV site frequently for signs daily of irritations. Weight-directed dosing: 2 mg/kg/dose once Side effects include thrombophle- daily bitis, hypercalcemia, hypokalemia, elevated liver enzymes, and isolat- Caspofungin For infants with refractory Candida infection, ed direct hyperbilirubinemia. Cefazolin intra-abdominal abscesses, peritonitis, pleural Dilute in normal saline to space infections and in patients who are 0.1—0.5mg/mL intolerant of Amphotericin B or have invasive Aspergillosis refractory to or intolerant of other For surgical prophylaxis against therapies: bacterial organisms such as Staph. 1 – 2 mg/kg/dose Q24H IV infusion over at aureus, and limited gram negative least 1 hr. coverage (E. coli, Klebsiella and Maximum dose: Infants < 3 months: 3 mg/kg/ Proteus mirabilis). day or 25 mg/m2/day IV over at least 1 hour. Adjust dose in renal impairment **The duration of treatment based General Dosing, susceptible infection: on the surgery consultant recom- mendation. GA Post Dose Interval (weeks) Natal mg/kg (hours) (days) <2 kg <7 50 12 8-28 75 8 29-60 100-150 8 <2 kg <7 100 12 8-28 150 8 29-60 100-150 6-8 52 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Cefotaxime • Renally-adjusted dose recom- General Dosing, susceptible infection: mendations are based on doses Cefprozil of 100 to 200 mg/kg/day divided Ceftazidime GA Post Dose Interval every 8 hours. (weeks) Natal mg/kg (hours) • GFR 30 to 50 mL/minute/1.73 m2: (days) 35 to 70 mg/kg/dose every 8 to 12 hours <32 <14 50 12 • GFR 10 to 29 mL/minute/1.73 14-28 8 m2: 35 to 70 mg/kg/dose every 12 hours <32 <7 50 12 • GFR <10 mL/minute/1.73 m2: 35 8-28 8 to 70 mg/kg/dose every 24 hours Gonococcal infections, IM, IV: 25 mg/kg/dose every 12 hours for 7 days; Therapy should be extended to 10 to 14 days if meningitis is documented Meningitis IV: Oral suspension contains aspar- Use smaller doses and longer intervals for tame and phenylalanine and neonates <2 kg. should not be used by phenylke- PNA ≤7 days and <2 kg: tonurics. May cause nausea, vom- 100 kg/day divided every 12 hours iting, diarrhea and liver enzyme PNA >7 days and <2 kg: elevations. 150 mg/kg/day divided every 8 hours Adjust dose in renal failure. PNA ≤7 days and ≥2 kg: 100 to 150 mg/kg/day divided every 8 to 12 hours PNA >7 days and ≥2 kg: 150 to 200 mg/kg/day divided every 6 to 8 hours Mild to moderate infection: Oral: 7.5 to 15 mg/kg/dose twice daily; Maximum single dose: 500 mg/dose. Oral second generation cephalosporin for the treatment of otitis media, pharyngitis/ tonsillitis, acute sinusitis, uncomplicated skin infection and other infections. 15-30mg/kg/day PO ÷ Q12H General Dosing, susceptible infection: • Renally adjusted dose recom- mendations are based on a usual Body Post IV Dose Interval dose of 25 to 50 mg/kg/dose every Wt Natal mg/kg (hours) 8 hours: (days) • GFR >50 mL/minute: No adjust- ment required <1 kg 0 to 14 50 12 • GFR 30 to 50 mL/minute: 50 mg/ 15 to 60 8 kg/dose q 12 hrs • GFR 10 to 29 mL/minute: 50 mg/ 1 to 2 kg 0 to 7 50 12 kg/dose q 24 hrs 8 to 60 8 • GFR ≤10 mL/minute: 50 mg/kg/ dose every 48 hrs >2 kg 0 to 7 50 12 8 to 60 8 Antimicrobial Therapy Drug Dosage Guidelines | 53

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Ceftazidime Meningitis: Adverse Effects PNA ≤7 days: • Pruritus, skin rash, Diarrhea, (cont’d) 100 to 150 mg/kg/day divided every 8 to 12 neutropenia thrombocythemia, Ceftriaxone hours thrombocytopenia, Inflammation at injection site, injection site phle- Cefuroxime PNA >7 days: bitis Increased BUN, SCr & LFTs 150 mg/kg/day divided every 8 hours • IVP: Administer over 3 to 5 Cephalexin minutes • Intermittent IV infusion: Adminis- ter over 15 to 30 minutes Gonococcal infection: ** **Do not use in hyperbilirubine- Prophylaxis, asymptomatic neonates born to mic neonates, particularly those mothers with gonococcal infection: IM, IV: 25 who are premature since ceftri- to 50 mg/kg as a single dose; max dose: 125 axone is reported to displace mg/dose bilirubin from albumin binding Disseminated infection (including sepsis, sites; arthritis, and meningitis): Use Cefotaxime May cause reversible cholelithia- Ophthalmia neonatorum: sis, sludging in gall bladder and IM, IV: 25 to 50 mg/kg as a single dose; max- jaundice. imum dose: 125 mg/dose; Note: May also be Side effects include gastrointesti- used for prophylaxis if erythromycin ointment nal discomfort and thrombophle- is not available bitis at the infusion site. General Dosing, susceptible infection: Cefuroxime is not recommended for the treatment of meningitis Body Post Dose Interval Renal Adjustments: IV: Wt Natal mg/kg (hours) • GFR ≥30 mL/minute/1.73 m2: No <1 kg (days) adjustment required 0 to 14 50 12 • GFR 10 to 29mL/minute/1.73 m2: 15 to 28 8 Administer 15mg/kg/dose q12h • GFR <10 mL/minute/1.73 m2: 1 to 2 kg 0 to 7 50 12 Administer 15 mg/kg/dose q24h 8 to 28 8 • CrCl >50 mL/min/1.73 m2: No adjustment. >2 kg 0 to 7 50 12 • CrCl 30 to 50 mL/min/1.73 m2: 5 8 to 28 8 to 10 mg/kg/dose q8h (max. dose: 500 mg/dose). General Dosing, susceptible infection: • CrCl 10 to 29 mL/min/1.73 m2: 5 0 to 7 days: to 10 mg/kg/dose q12h (max dose: 25 mg/kg twice daily (max. per dose 125 mg). 500 mg/dose). 7 days to 20 days: 25 mg/kg q8h (max. per dose 125 mg). 21 days to 28 days: 25 mg/kg q6h (max.per dose 125 mg). 54 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Cephalexin • CrCl <10 mL/min/1.73 m2: 5 to 10 mg/kg/dose q24h (max dose: 500 (cont’d) mg/dose). • Use with caution in renal insuf- ficiency. Side effects include GI discomfort, rash, neutropenia, thrombocytopenia esonophilia and cross sensitivity reaction. Severe infection: •Use with caution in children IV: 10-15 mg/kg/dose every 12 hours <18yrs old. May cause gastroin- testinal upset, headache, renal Ciprofloxacin failure, seizures, restlessness and Clarithromycin rash. Can increase effects and/or toxicity of theophylline, warfarin Clindamycin and cyclosporine. Cloxacillin General dosing, susceptible infection: Adverse effects include nausea, Oral: 15 mg/kg/day divided every 12 hours; diarrhea, dyspepsia, abnormal Maximum single dose: 500 mg taste, abdominal discomfort and headache. May cause cardiac arrhythmias, and may increase serum levels of carbamazepine, theophyllime, cyclosporine and tacrolimus General dosing, susceptible infection: • Endocarditis, culture negative, empiric therapy: AHA Guidelines Body Post Dose Interval (Baltimore 2015): Wt Natal mg/kg (hours) • Administer in combination with (days) other antibiotics for 4-6 weeks • May be used in aspiration pneu- <1 kg 0 to 14 5 12 monia. 15 to 28 8 • Side effects: Diarrhea, rash, Stevens-Johnson syndrome, granu- 1 to 2 kg 0 to 7 5 12 locytopenia, thrombocytopenia or 8 to 28 8 sterile abscess at injection site • Pseudomembranous colitis is >2 kg 0 to 7 5 8 rare in pediatric patients, but may 8 to 28 6 occur up to several weeks after stopping therapy. Usual dosage: IM injection not recommended – 25 mg/kg/dose IV over at least 10 minutes very painful. Severe Infections and Meningitis: 50 mg/kg/dose IV over at least 10 minutes. Antimicrobial Therapy Drug Dosage Guidelines | 55

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Cloxacillin PMA PostNatal Interval (cont’d) (weeks) (days) (hours) 0 to 28 Colistin ≤29 >28 12 Co-Trimoxazole 0 to 14 8 30 to 36 >14 12 (Tmp/Smx) 0 to 7 8 37 to 44 >7 12 ≥45 ALL 8 6 Infants and Children: Mild to moderate infection: IM, IV: 100 to 150 mg/kg/day in divided q6h; max daily dose: 4g/day Severe infection: IM, IV: 150 to 200 mg/kg/day in divided q4-6 h; max daily dose: 12 g/day General dosing, susceptible infection all ages: Each mg of colistin base has a 2.5 to 5 mg/kg/day of colistin base IV or IM potency of 30,000 international divided q6-12h, depending on severity of units. Infusion rate in patients with infection. normal renal function is 5-6 mg/ Maximum: 5 mg/kg/day in patients with nor- hour. Reduce rate in patients with mal renal function. renal impairment. Pulmonary infection: Intraventricular administration: Neonates Inhalation: 4 mg/kg/dose q12h for 10 mg of colistimethate sodium VAP diluted in 1 to 2 mL of preserva- CNS infection (VP-shunt infection, ventriculitis, tive –free normal saline and given meningitis), MDR: through the external ventricular Infants: Intraventricular/Intrathecal: device ONCE DAILY. 2 to 4.2 mg CBA/dose once daily in combina- tion with systemic antibiotics General dosing, susceptible infection: Infants • Not recommended for use in ≥2 months: infants < 2 months. Oral, IV: 6 to 12 mg TMP/kg/day in divided • May cause kernicterus in doses every 12 hours newborns; may also cause blood Maximum single dose: 160 mg TMP/dose dyscrasias, crystalluria, renal or Meningitis, Severe infections and Pneumocystis hepatic injury and hemilysis in carinii pneumonitis: patients with G6PD deficiency. IV: 10 to 20 mg TMP/kg/day divided every 6 to • Renal adjustment: 12 hours for 7 to 21 days • Infants ≥2 months • CrCl >30 mL/min: No adjustment 56 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Co-Trimoxazole UTI prophylaxis for infants > 2 months of age: • CrCl 15 to 30 mL/min: 50% of 2mg of TMP/kg/dose single bed time (h.s.) dose (Tmp/Smx) dose orally. • CrCl <15 mL/min: Use is not (cont’d) recommended Pneumocystis prophylaxis: Not recommended for use in Erythromycin PO or IV: infants < 2 months. May cause 5 mg TMP/kg/day HS daily OR 150mg TMP/m2/ kernicterus in newborns; may also Fluconazole day ÷ 12 hr for 3 consecutive days per week cause blood dyscrasias, crystal- luria, renal or hepatic injury and hemilysis in patients with G6PD deficiency. General dosing: Oral (ethylsuccinate); IV Reduce dose in patients with renal (lactobionate): impairment. • Common side effects include Body Post Dose Interval abdominal cramping, nausea and Wt Natal mg/kg (hours) vomiting. (days) • Although rare, erythromycin may cause hypertrophic pyloric stenosis <1 kg 0 to 14 10 12 and pseudomembranous colitis. 15 to 28 8 • Reduce dose in patients with renal impairment. >1 kg 0 to 7 10 12 • Exposure to these doses in 8 to 28 8 neonates with PNA (postnatal age) <14 days has been associated Chlamydial conjunctivitis or chlamydial with a 10-fold increase in the risk pneumonia: of hypertrophic pyloric stenosis Oral: Full-term neonates: 50 mg/kg/day divid- (Chicella, 2005) ed q6h for 14 days. Pertussis; treatment or postexposure prophy- laxis: Oral: 10 mg/kg/dose 4 times daily for 14 days For Infants and Children General dosing, susceptible infection 15-20 mg/kg/day divided every 6 hours; Maximum daily dose: 4000 mg/day Prokinetic: • Adverse effects include nausea, 10 -12 mg/kg/dose PO every 6-8 hours for 10 vomiting, hypokalemia, elevations days. in liver function Invasive Candidiasis: tests, nephrotoxicity. 12 to 25 mg/kg loading dose, then 6 to 12 mg/ kg per dose IV Note: If the liver enzymes abnor- mal or creatinine is above 70 and rising, please hold fluconazole until resolved. Antimicrobial Therapy Drug Dosage Guidelines | 57

2021 NEOMED BOOK DRUG PMA DOSAGE Interval SIDE EFFECTS/COMMENTS Fluconazole (weeks) (hours) • Monitor liver and kidney function PostNatal tests weekly. (cont’d) ≤29 (days) 48 0 to 14 24 Ganciclovir 30 and older >14 48 Gentamicin 0 to 7 24 >7 Candidiasis; Prophylaxis (birth weight <1Kg): Initiate within 48-72 hours from birth 3 to 6 mg/kg/dose IV or orally twice weekly for 6 weeks Meningitis or Serious Infections: 6mg/kg/dose IV Q12h Thrush: • Use with extreme caution in chil- 6 mg/kg once daily on Day 1, then 3 mg/kg per dren less than 12 years old. Reduce dose every 24 hours orally. dose in renal failure. Congenital CMV (symptomatic; CNS-disease); • Oral absorption is poor. IV: 6 mg/kg/dose every 12 hours for 6 weeks; • Side effects: neutropenia, throm- bocytopenia, retinal detachment Infants ≥3 months and Children and confusion. CMV infection: CNS infection, treatment • Minimum dilution 10mg/mL to (HIV-exposed/-positive): be infused over > 1 hour. 5 mg/kg/dose every 12 hours plus foscarnet;, • if neonate diagnosed as HIV-pos- followed by chronic suppression itive, a longer duration of therapy may be considered Disseminated disease and retinitis, treatment: Induction: 5 -7.5 mg/kg/dose every 12 hours for 14-21 days; Maintenance: 5 mg/kg/dose as a single daily dose for 5-7 days/week Secondary prevention in HIV-exposed/-infected patients: 5 mg/kg/dose once daily Other CMV infections: Timing of serum samples for Con- Initial: 5 mg/kg/dose every 12 hours for 14-21 ventional dosing: days; maintenance therapy: 5 mg/kg/dose (See Chap. 5, pg. 77-79) once daily Trough: Immediately before next There are two regimes in using Gentamicin dose. dosing; Extended Interval Dosing (which is Peak: 30 minutes after the 30 preferred) and Conventional Dosing. minutes drug infusion. For a Q12H schedule, do peak and Neonatal Conventional Dosing of Gentamicin trough levels around the 5th dose <7 days: <28 wks at birth: 2.5 mg/kg/dose Q30H IV or IM 29-32 wks at birth: 2.5 mg/kg/dose Q24h IV/IM 33-36 wks at birth: 2.5 mg/kg/dose Q18H IV/IM Term: 2.5 mg mg/kg/dose Q12H IV or IM 58 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Gentamicin >7 days up to 1 month: For a Q8H, Q18H or Q24H sched- <28 weeks: 2.5 mg/kg/dose Q30H IV or IM ule, do peak and trough levels (cont’d) 29-32 weeks: 2.5 mg/kg/dose Q24H IV or IM around the 3rd dose; 33-36 weeks: 2.5 mg/kg/dose Q18H IV OR IM For a Q30H do peak and trough Term: 2.5 mg/kg/dose Q8H IV or IM levels around the 2nd dose. Peak: 10.5-21 mcmol//L After 1 month: Trough: <4.2 mcmol//L <31 weeks: 2.5 mg/kg/dose Q18H IV or IM 31-36 weeks: 2.5 mg/kg/dose Q12H IV or IM Therapeutic Concentrations: Term: 2.5 mg/kg/dose Q8H IV or IM Peak In patients with normal renal function: Life-threaten- 17-21 IM/IV: 2.5mg/kg/dose Q8H ing infection mcmol/L In patients with cystic fibrosis: IM/IV: 2.5-3.5 mg/kg/dose Q8H Serious Infec- 12 to 17 tions mcmol/L For Infants and Children: UTI 8 to 13 Conventional dosing: mcmol/L IM, IV: 2 to 2.5 mg/kg/dose every 8 hours Synergy G+ve 6 to 10 Neonatal Extended Interval Dosing of Genta- organisms mcmol/L micin Trough GA PNA Dose Interval Serious / 1-2 (weeks) (days) mg/kg (hours) Life-threaten- mcmol/L ing infection 0 to 7 5 48 ≤29* 8 to 28 4 36 Timing of serum samples for Extended Interval dosing: ≥29 4 24 (See Chap. 5, pg. 77-79) • Trough before 2nd dose and Peak 30 to 34 0 to 7 4.5 36 after 2nd dose. ≥8 4 24 • Draw peak 30 minutes after 30-minute infusion has been ≥35 ALL 4 24 completed or 1 hour following IM injection or beginning of infusion; Extended-interval dosing: Notes: IV: 4.5 to 7.5 mg/kg/dose every 24 hours in • Use with caution in patients patients with normal renal function with neuromuscular disorders or receiving neuromuscular blocking Cystic fibrosis, pulmonary infection: agents. Extended-interval dosing: IV: • May cause ototoxicity and neph- 10 to 12 mg/kg/dose every 24 hours rotoxicity. • Loop diuretics may potentiate Note: The CF Foundation recommends extend- ototoxicity. ed-interval dosing as preferred over conven- • Measure serum concentrations tional dosing. when treating for more than 48 hours For intrathecal/intraventricular administration (use preservative- free product only): >3months: 1-2mg/day. For asphyxiated newborns or newborns with suspected renal anomalies, use cefotaxime instead of gentamicin if empiric antibiotics are indicated Antimicrobial Therapy Drug Dosage Guidelines | 59

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Isoniazid (INH) Prophylaxis against Tuberculosis: • INH should not be used alone for 10 mg/kg/dose (maximum dose 300 mg) PO treatment. Common side effects Linezolid once daily include peripheral neuropathy Meropenem optic neuritis, seizures, encepha- Congenital tuberculosis: lopathy and hepatic effects. 10 – 15 mg/kg/dose (max. dose 300 mg) PO • Follow LFT’s monthly. Supple- once daily mental Pyridoxine (1 – 2 mg/kg/ day) is recommended. Treatment of tuberculosis: • For congenital tuberculosis, if 10-15 mg/kg/dose PO Q24H (maximum dose: resistance rate to INH is < 4% a 300mg) 3-drug regimen is acceptable thus: • Rifampicin 10 – 20 mg/kg/dose (Maximum dose 600 mg) PO once daily PLUS • Pyrazinamide 15 – 30 mg/kg/ dose (maximum dose 2g) PO once daily. • Give 3-drug regimen for first 2 months, then INH + Rifampicin for 4 to 10 months depending on severity of disease. Indications: Most common side effects include • Pneumonia, bacteremia, nausea, diarrhea, anemia, leucope- • complicated skin/skin structure infections nia, pancytopenia, and thrombo- • Vancomycin-resistant E. faecium (VRE): cytopenia. Pseudomembranous IV/PO: colitis and neuropathy have also been reported. PMA Post Dose Interval Note: Higher dose 12-15 mg/kg/ (weeks) Natal mg/kg (hours) dose every 8 hours to treat VRE (days) endocarditis and meningitis/ven- triculitis 0 to 7 10 12 <34 8 Infuse each dose over 30 minutes. May cause thrombocytopenia. >7 Adjust dose in renal impairment >34 all 10 8 PMA Post Dose Interval (weeks) Natal mg/kg (hours) (days) <32 <14 20 mg 12 >32 ≥14 20 mg 8 <14 20 mg 8 ≥14 30 mg 8 Meningitis and severe infections caused by Pseudomonas sp: 40 mg/kg/dose IV Q8H Infants > 3 months and children: Mild to moderate infection: 20mg/kg/dose IV Q8H 60 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Metroni Dazole • For infants with bowel perfora- General dosing, susceptible infection tion, a loading dose of 15 mg/kg Moxifloxacin Loading dose: 15 mg/kg orally or IV infusion by IV may be used. Then in pre- term Nitrofuran- syringe pump followed by below maintenance and term infants start maintenance (after 12 hours from the loading dose): dose after 12 hrs. toin Nystatin PMA Dose Interval • The duration of maintenance (weeks) mg/kg/dose (hours) dose based on Infectious Diseases’ recommendation. <34 7.5 12 • Breastfeeding is permissible if >35 7.5 8 the mother is taking regular or maintenance dose. However, it is Clostridioides difficile infection: not recommended to breastfeed Oral, IV: 7.5 mg/kg/dose Q6h for 10 days; for at least 24 hours from receiving a single high dose (2 grams). Maximum dose: 500 mg/dose Severe/infection IV: 10 mg/kg/dose Q8h for 10 days; Maximum dose: 500 mg/dose Surgical prophylaxis: Weight Dose <1.2kg 7.5mg/kg as a single dose 30- 60 minutes prior to procedure and two more doses 12 hours after procedure (7.5 mg/kg/ dose q12h) >1.2kg 15mg/kg as a single dose 30- 60 minutes prior to procedure and two more doses 12 hours after procedure (7.5 mg/kg/ dose q8h) General dosing, susceptible infection May cause QT prolongation. GA 32 to 37 weeks, PNA ≤28 days: IV: 5 mg/kg/dose every 24 hours GA >37 weeks, PNA ≤28 days: • May cause nausea, vomiting, IV: 10 mg/kg/dose every 24 hours cholestatic jaundice, hepato- Infants > 1 month toxicity, hemolytic anemia and hypersensitivity reactions. UTI, prophylaxis: • Contraindicated in severe renal Oral: 1 to 2 mg/kg/day in a single dose (at disease, G6PD deficiency and in bedtime) infants < 1 month of age. UTI, treatment: 5 – 7 mg/kg/day Q6H PO Maximum Dose: 400 mg/day • Side effects: Nausea, vomiting, Prophylaxis: 1 mL (100,000 units)/dose PO Q6H diarrhea. Treatment: 100,000 - 400,000 units/dose PO Q6H Antimicrobial Therapy Drug Dosage Guidelines | 61

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Oseltamivir Neonates Influenza, treatment: • Prophylaxis is Not recommended PMA <38 weeks: Oral: 1 mg/kg/dose twice for infants 3 months old because of (Tamiflu) daily; limited safety and efficacy data in (15mg/Ml) PMA 38 to 40 weeks: Oral: 1.5 mg/kg/dose this age group twice daily. PMA >40 weeks: Oral: 3 mg/kg/dose twice • The usual duration of therapy is daily. 5 days; a longer duration may be necessary in severely ill or immu- Treatment: nocompromised patients Infants ≤8 months: Oral: 3 mg/kg/dose twice daily • Prophylaxis Duration: 10 days Infants ≥9 months: Oral: 3.5 mg/kg/dose twice daily Penicillin G Prophylaxis: • May cause anaphylaxis, urticaria, Parenteral/Aqueous Infants 3 to 8 months: Oral: 3 mg/kg/dose once interstitial nephritis, and hemolytic daily anemia. (Iv Or Im) Infants ≥9 months: Oral: 3.5 mg/kg/dose once • For meningitis, use higher daily daily dose at shorter dosing intervals. Group B Streptococcal meningitis: Adjust dose in renal impairment. < 7 days: 250,000-450,000 u/kg/day IV ÷ Q8H > 7 days: 450,000 u/kg/day IV ÷ Q6H Syphilis, congenital (with or without CNS involvement): PNA ≤7 days: IV: 50,000 units/kg/dose q12h; at PNA 8 days increase to 50,000 units/kg/dose • If >1 day of therapy is missed, the q8h for total 10 days. entire course needs to be restarted PNA ≥8 days: IV: 50,000 units/kg/dose q8h for 10 days. For Infants: General dosing, susceptible infection (non- CNS) IV: 100,000-400,000 u/kg/day ÷ Q4-6H Max. dose: 24 million u/day General dosing, susceptible infection May be used in infants with Pseu- domonas infections. May cause PMA Post Dose Interval bone marrow suppression. (weeks) Natal mg/kg (hours) Adjust dose in renal impairment (days) Piperacillin/ Tazo- 0 to 28 12 bactam (Tazocin) ≤29 100 8 >28 30 to 36 0 to 14 100 12 >14 8 37 to 44 0 to 7 100 12 >7 8 ≥45 ALL 100 6 62 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Piperacillin/ Tazo- Nosocomial pneumonia: May cause GI irritation, fever, hep- bactam (Tazocin) Infants 2 to 9 months: IV: 80 mg/kg/dose q6h atitis, blood dyscrasias, interstitial nephritis, elevated BUN and uric (cont’d) H. Influenzae Prophylaxis: acid. Causes red discoloration of IV, Oral: 10 mg/kg/day once daily for 4 days body secretions (urine, saliva and Rifampin Meningococcal prophylaxis: tears). IV, Oral: 0-1 month: 10 mg/kg/day divided q12h for 2 days > 1 month: 20 mg/kg/day ÷ Q12H PO x 2 days Persistent Staphylococcus aureus, synergy for infections: IV, Oral: 5 to 20 mg/kg/day in divided doses every 12 hours with other antibiotics Tobramycin <30 weeks: For a Q12H schedule, do peak and (<14 days): trough levels around the 5th dose; 5mg/kg/dose every 48 hours for a Q8H, Q18H or Q24H schedule, >15 days: do peak and trough levels around 5mg/kg/dose every 36 hours the 3rd dose; for a Q30H do peak 30-34 weeks and trough levels around the 2nd 4.5mg/kg/dose every 36 hours dose. >35 weeks Trough: Immediately before the 5mg/kg/dose every 24 hours next dose. Peak: 30 minutes after the 30 minutes drug infusion. Serum therapeutic levels: same as gentamicin Trimethoprim UTI, prophylaxis (hydronephrosis, VUR): 2mg/kg/dose oral once daily Valgancilovir Congenital CMV infection; treatment: GA ≥32 weeks and ≥1.8 kg : Oral: 16 mg/kg/dose every 12 hours for 6 months Congenital CMV infection; treatment: Infants 1 to 6 months: Oral: 16 mg/kg/dose every 12 hours for 6 months Antimicrobial Therapy Drug Dosage Guidelines | 63

2021 NEOMED BOOK DRUG DOSAGE SIDE EFFECTS/COMMENTS Vancomycin General dosing, susceptible infection IV infusion over 90 to 120 minutes Voriconazole 10 to 15 mg/kg/dose IV Trough PMA Postnatal Interval (weeks) Age (days) (hours) MRSA Bacteremia, <29 0 to 14 18 Endocarditi- 10.3 – 13.8 > 14 12 sOsteomyeliti, mcmol/L MRSA, Pneu- 30 to 36 0 to 14 12 monia, > 14 8 Meningitis 37 to 44 0 to 7 12 other infec- 6.9-13.8 mc- >7 8 tions mol/L >45 ALL 6 Dosing Adjustments • GFR 30-50 mL/min/1.73 m²: Infection Dose (mg/ Interval 10mg/kg q 12hours kg) Hours • GFR 10-29 mL/min/1.73 m²: Skin (Non-necro- 10 10mg/kg q 18-24 hours. tizing) 6 10 • Therapeutic serum trough level: Intra-abdominal 10 - 15 6 > Mild infection: 6-10 mcmol/L. infection 12.5 - 15 8-6 > Moderate to Severe infection: 10-13.8 mcmol/L. Pneumonia 15 6 > For a Q6H,Q8H or Q12H sched- Endocarditis ule, do trough levels 30 minutes Bacteremia, 6 before the 5th dose Meningitis & > For a Q18H or Q24H schedule, Osteomyelitis and do trough levels 30 minutes before Skin (Necrotizing) the 3rd dose. > If the trough level is out of range and the dose needs to be adjusted the time for the next trough level, call the Clinical Phar- macist for consultation. Fungal infection, severe; treatment • “Red Man Syndrome” associated 12 to 20 mg/kg/day divided every 8 to 12 with rapid IV infusion may occur. hours; (Max: 24 mg/kg/day) Infuse over 60-120 minutes. Oto- General dosing, susceptible infection toxicity and nephrotoxicity may Infants <2 years: occur and may be exacerbated IV, Oral (Oral suspension): with concurrent aminoglycoside Initial: 9 mg/kg/dose every 12 hours administration. (range: 12 to 71 mg/kg/day) divided every 12 •Note: Doses >40 mg/kg/day were hours administered in 3 divided doses; •Note: Monitor serum concentra- tions to maintain trough concen- trations of 4.1 to 12.5 mcmol/L (Red Book [AAP 2018]). Common side effects include GI disturbances, fever, hepatic abnor- malities, photosensitivity, and rash. Liver and renal failure are rare side effects. 64 | Antimicrobial Therapy Drug Dosage Guidelines

DRUG DOSAGE SIDE EFFECTS/COMMENTS Zidovudine HIV-1 perinatal transmission, prevention • The shorter 4-week course is rec- Zidovudine dosing should begin as soon as ommended if the mother received possible after birth (within 6 to 12 hours after standard combination antiretro- delivery). viral therapy during pregnancy, viral suppression was sustained, Oral: and maternal adherence is not a GA <30 weeks: 2 mg/kg/dose q12h; at 4 weeks concern of age, increase dose to 3 mg/kg/dose q12h for 2 weeks for a total of 6 weeks • If oral medication is not available, you can use IV medication, which GA ≥30 weeks and <35 weeks: is 75% of the oral dose. 2 mg/kg/dose q12h; at PNA 15 days, increase to 3 mg/kg/dose q12h for 4 weeks for a total of 6 weeks GA ≥35 weeks: 4 mg/kg/dose q12h duration is 4 to 6 weeks. ***References: 1. Ped. Pharmacotherapy Vol. 11, No. 4: April 2005 2. Pediatrics, April 1999; Vol. 103, No. 4: 843-852 3. Pediatrics International 2008; 50: 124 – 126 4. J of Ped Gastroenterology and Nutrition, Jan. 2002; 34:1:pp 13-15 5. NEJM Vol. 330; No. 15, April 1994; 1051 – 1054 6. The Harriet Lane Handbook 17th ed Mosby – Year Book Inc; 2005. 7. Starke JR, Mason Jr. EO, et al. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis 1987; 155: 766-74. 8. Nelson, JD. Pocketbook of Pediatric Antimicrobial Therapy 14th ed. Williams & Wilkins 2000-2001. 9. Nahata, MC. Clinical use of amphotericin B and flucytosine in pediatric systemic fungal infections. J Pharm. Tech 1986; 257-60. 10. Red Book (AAP 2018) 11. Hospital Pharmacy Vol. 44; No. 5, May 2009; 423-428. 12. Cont Edu Anaesth Crit Care & Pain. 2007 ;7(5):143-147 13. Pediatrics. 1998; 101(6): 1079-1088 14. Arch Dis Child 2009; 94: 165-167 15. Eur J Pediatr 2010; 169: 867-874. 16. South Australian Neonatal Medication Guidelines Workgroup at:[email protected] 17. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; October, 2020 18. Neofax.micromedexsolutions.com. 2020. Neofax. [online] Available at: <http://neofax.micromedexsolutions.com/neofax/neofax.php> [Ac- cessed 1 October 2020]. 19. Bradley JS and Nelson JD, eds. Nelson’s Pediatric Antimicrobial Therapy. 25th ed. Itasca, IL: American Academy of Pediatrics; 2019. 20. American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018. 21. Bnfc.nice.org.uk. 2020. BNF For Children British National Formulary - NICE. [online] Available at: <https://bnfc.nice.org.uk/> [Accessed 1 October 2020]. 22. Schenarts PJ, Sagraves SG, Bard MR, Toschlog EA, Goettler CE, Newell MA, Rotondo MF. Low-dose dopamine: a physiologically based review. Curr Surg. 2006 May-Jun;63(3):219-25. doi: 10.1016/j.cursur.2005.08.008. PMID: 16757377. 23. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e44S-e88S. doi:10.1378/chest.11-2292 24. Saito M, Kamoda T, Kajikawa D, Miyazono Y, Kanai Y, et al. (2016) High Dose Octreotide for the Treatment of Chylothorax in Three Neonates. J Neonatal Biol 5: 218. doi:10.4172/2167-0897.1000218 25. Alhasoon MA. Use of high‑dose octreotide in the treatment of congenital chylothorax. J Clin Neonatol 2020;9:289-91. Antimicrobial Therapy Drug Dosage Guidelines | 65

2021 NEOMED BOOK Chapter 3 GUIDELINES FOR THE CONTINUOUS INFUSION OF CRITICAL CARE DRUGS IN NEONATES All recommended dosing are verified to ensure consistency with MNGHA’s Medical Record System (BestCare) and the BBraun Drug Library. 66

DRUG DRUG DOSING RANGE MAXIMUM COMPA- EXPIRA- CONCENTRATION TIBILITY TION* Alprostadil 0.01 – 0.05 mcg/kg/min (Prostaglandin) Maximum Dose: 0.4mcg/ Peripheral Central D5W, D10W, NS 24 hrs kg/min IV Line IV Line Amiodarone Loading dose: D5W 24 hrs 5 mg/kg IV over 1 hr 5mcg/mL 20 mcg/mL D5W, NS 24 hrs Bumetanide Then maintenance infusion: 5 D5W, NS 24 hrs Cisatracurium to 15 mcg/kg/min 2mg/mL 4 mg/mL 24 hrs (Initial 5mcg/kg/min and 24 hrs Dexmede increase as clinically needed) 25 mcg/mL 250 mcg/mL 24 hrs tomidine 2-5 mcg/kg/hr 0.1 mg/mL 0.4 mg/mL 24 hrs (Precedex) Maximum dose: 10 mcg/kg/hr 24 hrs Dobutamine 0.5 – 4 mcg/kg/min 48 hrs Dopamine Maximum dose: 10 mcg/kg/ 24 hrs Epinephrine min 24 hrs Esmolol 0.05 -0.75 mcg/kg/hr 2 mcg/mL 4 mcg/mL NS, D5W Fentanyl 24 hrs Furosemide 2 – 20 mcg/kg/min 500 mcg/mL 5000 mcg/ D5W, D10W, NS Maximum Dose: 25mcg/kg/ 800 mcg/mL mL D5W, NS, D10W Heparin min 1600 mcg/mL D5W, D10W, NS 2 - 20 mcg/kg/min 3200 mcg/ Maximum: 30 mcg/kg/min 10 mg/mL mL D5W, NS, ½ NS 0.05 – 2 mcg/kg/min D5W, NS Maximum: 2.6 mcg/kg/min 10 mcg/mL 64 mcg/mL D5W, NS 50 –300 mcg/kg/min 1 mg/mL Loading dose: 500 mcg/kg IV 20 mg/mL D5W, NS, ½ NS over 4 mins. Then continuous infusion: 20 mcg/mL 50 – 600 mcg/kg/min 2 mg/mL 1 – 5 mcg/kg/hr 0.1 – 0.4 mg/kg/hr Loading Dose: 75 units/kg IV over 10 minutes , followed by Maintenance dose of 28 units/ 40 units/mL 40 units/mL kg/hr. Adjust per protocol Maximum: 35 units/kg/hr (as per Drug Libraby) Insulin 0.01- 0.5 unit/kg/hr 0.1 unit/mL 1 unit/mL NS, ½ NS Maximum: 0.6 unit/kg/hr If more is needed, consultant must approve. Guidelines for Continuous Infusion of Critical Care Drugs in Neonates | 67

2021 NEOMED BOOK DRUG DRUG DOSING MAXIMUM COMPA- EXPIRA- Isoproterenol RANGE CONCENTRATION TIBILITY TION* # Ketamine 0.05 – 0.2 mcg/kg/min Peripheral Central D5W, D10W, NS 24 hrs Labetalol IV Line IV Line Midazolam D5W, NS 24 hrs Milrinone Maximum dose: 1 mcg/kg/ D5W, D5NS, NS 24 hrs min 48 hrs D5W, NS 48 hrs Correct acidosis before 10 mcg/mL 10 mcg/mL D5W, NS, ½ NS infusion. Start at minimum dose and increase every 5 – 10 minutes by 0.1 mcg/kg/min until desired effect or onset of toxicity. Sedation/analgesia: 5-20 mcg/kg/min Mechanically-ventilated 1mg/mL 2 mg/mL children with severe bron- chospasm: Start with 8 mcg/ kg/min and titrate to desired clinical effect. Maximum dose: 32 mcg/ 100 mcg/mL 100 mcg/mL kg/min Start with 0.4 mg/kg/hr and titrate to desired clinical response up to maximum of 3 mg/kg/hr. May initiate with a 0.2 – 1 mg/kg bolus; Maximum bolus: 20 mg. Sedation with mechanical ventilation: 0.25 – 2mcg/kg/min Status epilepticus: 250 mcg/mL 500 mcg/mL 1-6 mcg/kg/min. If higher dose is needed, then must be approved by Consultant and Clinical Pharmacist. Loading dose: 50 mcg/kg over 15 minutes (Reduce loading dose to 25 100 mcg/mL 200 mcg/mL mcg/kg or omit in patients at risk for hypotension.) Continuous Infusion: To start immediately after loading dose: 0.375 – 0.75 mcg/kg/min 68 | Guidelines for Continuous Infusion of Critical Care Drugs in Neonates

DRUG DRUG DOSING MAXIMUM COMPA- EXPIRA- Morphine RANGE CONCENTRATION TIBILITY TION* Nitroglycerin Non-ventilated patient: Peripheral Central D5W, D10W, NS 24 hrs 10-30 mcg/kg/hr IV Line IV Line 24 hrs Ventilated patient: 10-50 mcg/kg/hr 40 mcg/mL 100mcg/mL Maximum Dose: 100 mcg/ (0.04 mg/mL) (0.1mg/mL) kg/hr Maximum 0.25 – 10 mcg/kg/min conc. (500 mcg/ mL) (0.5 mg.mL) 100 mcg/mL 200 mcg/mL D5W, NS Or 400 mcg/ mL Nitroprusside 0.5 – 10 mcg/kg/min 200 mcg/mL 800 mcg/mL D5W, NS 24 hrs Norepine-phrine 0.05 – 2 mcg/kg/min 8 mcg/mL 50 mcg/mL D5W 24 hrs 1 -12 mcg/kg/hr 24 hrs Octreotide Maximum Dose: 20 mcg/ 4 mcg/mL 8 mcg/mL NS, D5W 24 hrs Phentolamine kg/hr 24 hrs Phenylephrine 2.5 – 50 mcg/kg/min 1.6 mg/mL 1.6 mg/mL NS 24 hrs *Salbutamol 0.1 – 0.5 mcg/kg/min 60 mcg/mL 80 mcg/mL D5W 24 hrs 0.2 – 5 mcg/kg/min D5W Terbutaline Hyperkalemia: 4 mcg/kg 10 mcg/mL 10 mcg/mL Sterile water, D5W 8 hours Loading dose: 10 mcg/kg IV 24 hrs over 10 minutes followed by 0.25 mg/mL 0.5 mg/mL D5W, NS Continuous infusion: 0.2 – 6 mcg/kg/mi 0.2-0.5 mg/kg/hr For upper extremity occlusion microvascular thrombosis aortic thrombo- sis, lysis thrombus, renal vein thrombosis, thrombosis in SVC, aorta, femoral artery. Tissue Plasminogen Loading dose: 0.5 mg/mL 0.5 mg/mL D5W Activator 0.1 – 0.5 mg/kg IV over 20 Dilute in D5%W (t-PA) mins, Followed by: 0.1 – 0.5 mg/kg/ hr for 6 hours Catheter occlusion: 1mg/ mL diluted to volume of catheter; leave for one hour, then aspirate. If unsuccessful, attempt second dose 1mg/ mL diluted to volume of catheter; leave for 2 hours then aspirate Guidelines for Continuous Infusion of Critical Care Drugs in Neonates | 69

2021 NEOMED BOOK DRUG DRUG DOSING MAXIMUM COMPA- EXPIRA- Vasopressin RANGE CONCENTRATION TIBILITY TION* Persistent Pulmonary hyper- Peripheral Central D5W, NS 24 hrs tension: IV Line IV Line 0.3-1.2 mIU /kg/minutes Cardiac surgery: 0.3 to 0.5 mIU /kg/minute Hypotension (initial therapy): 0.1 unit/mL 0.5 unit/mL (GA ≤30 wks): 1 unit/mL 0.17 to 0.67 mIU/kg/minute Hypotension unresponsive to fluid resuscitation and exogenous catecholamines (regardless of gestational age): Shock: refractory Intractable hypotension: 2 – 4 mIU/kg/min Abbreviations: DL, Drug Library; BUD Beyond use date Note: # not recommended in infants < 3 months of age. Note: VOLUME TO BE SUPPLIED DEPENDS ON THE RATE OF INFUSION. 70 | Guidelines for Continuous Infusion of Critical Care Drugs in Neonates

***References: 1. Neonatal Drug Formulary 5th edition, edited by Bhatt DR, Bragman DS, Thayer-Thomas J et al. Wirtschafter NDF, Los Angeles, 2002. 2.) The Harriet Lane Handbook 15th ed. Mosby – Year Book Inc., 2000. 2. www.musc.edu/pedres/pharmacy/nicu-infusion.htm 3. Buck LM Amiodarone use in children. Monthly Newsletter from the Children’s Medical Center at the University of Virginia 2001; 7: 1-6. 4. Octreotide product information. Norvatis 5. Trissel L A. Handbook on injectable drugs 10th edition. ASHP Inc; 1998 6. Neofax 2004: A Manual of Drugs used in Neonatal Care, ed. 17. Raleigh, North Carolina: Acorn Publishing, USA, 2004. 8.) The Journal of Thoracic and Cardiovascular Surgery, Feb. 2005 Vol. 129, No 2; 464 – 6. 7. Ped Pharmacotherapy vol. 5; No. 8 Aug 1999 10.) J Pediatr 2008 (Article in press). 8. J Pediatr Pharmacol Ther 2010; 15:17 – 29 9. Pharmacological Treatment for Neonatal Seizure (Systematic Review), JChild Neurol.2013 (28)351-364 10. Mohamed A, Nasef N., Shah V. et al, Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series. Pediatr Crit Care Med 2014; 15(2):148-154 11. Malikiwi A, Saso A, Tan K, et al. Vasopression as an adjunct therapy for pulmonary hypertension: a case report. Eur J Pediatr 2014;173(12):1651- 1654 12. Acker SN, Kinsella JP, Abman SH et al. Vasopressin improves hemodynamic status in infants with congenital diaphragmatic hernia. J Pediatr. 2014; 165(1):53-58 13. Rios DR, Kaiser JR. Vasopressin versus dopamine for treatment of Hypotension in extremely low birth weight infants: a randomized, blinded pilot study. J pediatric. 2015; 166(4):850-855 14. Saito M, Kamoda T, Kajikawa D, Miyazono Y, Kanai Y, et al. (2016) High Dose Octreotide for the Treatment of Chylothorax in Three Neonates. J Neonatal Biol 5: 218. doi:10.4172/2167-0897.1000218 15. Alhasoon MA. Use of high‑dose octreotide in the treatment of congenital chylothorax. J Clin Neonatol 2020;9:289-91 Example: A 2-kg infant to receive dopamine 5 mcg/kg/min. First, calculate dopamine requirement for 24 hrs. Thus: 5 mcg/kg/min x 2 kg x 60 min/hr x 24 hr/1 day = 14400 mcg 1. Then, for central line administration, volume for dilution is given by: 14400 mcg/3200 mcg/mL = 4.5 mL. The value of 4.5 mL can be rounded up to 5 mL or 10 mL such that the order will read: Dopamine 14.4 mg in 10 mL D5W at rate of 0.4 mL/hr. (Note that rate is given by 10 mL/24 hrs = 0.4 mL/hr). 2. For peripheral line administration, volume for dilution is given by: 14400 mcg/800 mcg = 18 mL. The value of 18 mL can be rounded up to 20 mL so that the order will read: Dopamine 14.4 mg in 20 mL D5W at rate of 0.8 mL/hr (Again, note that rate is given by 20 mL/24 hrs = 0.8 mL/hr). Guidelines for Continuous Infusion of Critical Care Drugs in Neonates | 71

2021 NEOMED BOOK Chapter 4 VANCOMYCIN MONITORING GUIDELINES 72

1. Dose and dosing interval: • The initial dose of vancomycin and dosing schedule is determined on the basis of the patient weight and estimated creatinine clearance. Neonatal General dosing, susceptible infection: 10 to 15 mg/kg/ dose Neonatal General dosing, susceptible infection: 10 to 15 mg/kg/dose IV PMA Postnatal Age(days) Interval (hours) (weeks) 0 to 14 18 <29 > 14 12 12 30 to 36 0 to 14 8 > 14 12 37 to 44 0 to 7 8 > 45 >7 6 ALL Infants and children: General dosing, susceptible infection: 10 to 15 mg/kg/dose IV every 8 to 6 hours Infection Dose (mg/kg) Interval (Hours) Bacteremia Meningitis 15 6 Osteomyelitis Skin (Necrotizing) 15 6 Skin ( Non-necrotizing) 10 6 Intra-abdominal 10 6 infection Pneumonia 10 - 15 8-6 Endocarditis 12.5 - 15 6 2. Infusion Rate: • The most common hypersensitivity reaction associated with vancomycin is red man syndrome (RMS), typi- cally presenting as pruritus and erythematous rash over the face, neck and upper torso. • Patients may complain of diffuse burning and itching and of generalized discomfort or become dizzy and agitated. RMS usually occurs within ten minutes or starting vancomycin infusion and is associated with rapid infusion (<1h). • The whole vancomycin dose should be given as intravenous infusion over a minimum of one hour, at a maximum infusion rate of 15 mg/min. • The infusion rate should be reduced (ie; infusion time increased) if the patient experiences red man syn- drome reaction. Vancomycin Monitoring Guidelines | 73

2021 NEOMED BOOK 3. Vancomycin Monitoring: • Peak levels should NOT be routinely obtained. • Trough levels are most accurate and practical method monitoring Vancomycin effectiveness and toxicity. 3.1 Measuring serum Vancomycin levels: o Samples for trough (pre-dose) levels should be obtained 30-60 minutes before the next dose is due. o The first sample for vancomycin trough levels should be obtained just prior to the next dose at steady state conditions, usually just before the 4th dose. o It is not necessary to wait for the results of the level before giving a single further dose, unless renal function is abnormal or previous levels have been high. 3.2 Trough levels should be monitored regularly in patients with any the following circumstances: o Deteriorating/unstable renal function (e.g. high Scr >25% above baseline) or dialysis (consult pharmacist regarding monitoring in dialysis patients). o Concurrent therapy with nephrotoxic agents (e.g. aminoglycosides, Colistin, Amphotericin B) o Infants & children with serious infections such as meningitis, endocarditis, osteomyelitis or MRSA pneumonia, MRSA bacteraemia, necrotizing fasciitis and when treating infections caused by organism with high vancomycin minimum inhibitory concentrations (MIC). 3.3 Prolonged courses (>7 days) of therapy o Vancomycin trough levels should be monitored every 3-4 days in pediatric patients with stable renal function who have achieved desired trough levels. o More frequent Vancomycin trough levels monitoring is required for pediatric patient who are hemodynamically unstable and/or with changing renal function 3.4 Target Vancomycin Trough Levels: Diagnosis/Indication Target Vancomycin Trough Levels Traditional recommendation for indications 6.9-10.3 mcmol/L including neutropaenic fever, skin and soft tissue infections. 10.3-13.8 mcmol/L For serious infection such as pneumonia, osteo- myelitis, endocarditis, MRSA bacteremia, Necrotizing Fasciitis and CNS Infections. 3.5 Interpretation and dose adjustments: The Vancomycin trough (pre-dose) level will indicate further action(s) to be taken, depending on the target trough level: 74 | Vancomycin Monitoring Guidelines

Trough (pre-dose) level Target Level Interpretation Action(s)required <3.45 mcmol/L 3.45-6.9 mcmol/L Too low Half the dosage interval to next frequency AND increase daily Vancomycin by 10% of the dose 3.45-6.9 mcmol/L 6.9–10.35 mcmol/L Half the dosage interval to next frequency OR increase Low daily Vancomycin by 10% of the dose 6.9–10.35 mcmol /L 6.9–10.35 mcmol/L Good NO change in dosing regimen. 6.9–10.35 mcmol /L 10.35-13.8 mcmol/L Low Half the dosing interval to next High frequency OR Increase the 10.35-13.8 mcmol /L 6.9–10.35 mcmol/L dose by 10%. Omit the next dose and double the dosage interval OR decrease daily Vancomycin dose by 10% and re-check trough level 24 hours later. >13.8 mcmol/L 10.35-13.8 mcmol/L Good NO change. 10.35-13.8 mcmol/L High Decrease dose by 10% OR double the dosing interval to the next frequency and resume therapy once level is within target range. 4. Monitoring for Toxicity: • Serum creatinine should be measured at least every other day initially, then weekly if patient’s renal func- tion remains stable. • Check full blood count twice weekly. • Routine formal audiology testing is not recommended for patients receiving vancomycin, unless signs and symptoms of ototoxicity became apparent. ***References: 1. Vancomycin Therapeutic Guidelines: A Summary of cons Recommendations from IDSA, ASHP and SIDP. linical Infectious 49:325-7. 2. The Hospital for Sick Children, Handbook of pediatrics, 2009. 3. Vancomycin Therapeutic Monitoring: Review and Recommendations from the ASHP, IDSA and SIDP Task Force. American Journal of Healthcare System Pharmacists. 2009; 66:82-98. 4. Antibiotic Guidelines treatment recommendation for adult inpatient (Johns Hopkins); 2010-2011 Guidelines Vancomycin Monitoring Guidelines | 75

2021 NEOMED BOOK Chapter 5 AMINOGLYCOSIDE MONITORING GUIDELINES 76

I. General Rules • Avoid aminoglycosides in children with impaired renal function or those on multiple concomitant nephro- toxins if possible • Conventional dosing (q8 hours) is more commonly used in pediatrics patients (>30 days old) than extended interval (q 24 hour dosing) o Doses can be given over 30 minutes o Peak serum concentrations are important for bacterial killing o Trough serum concentration monitoring is recommended as a safety marker. Should be checked at least once weekly for pediatric patients on aminoglycoside therapy of 30 minutes prior to a dose II. Therapeutic Drug Monitoring • Aminoglycoside serum concentrations should NOT be drawn from same intravenous line through which drug is infusing. Drug may adhere to the lumen of the line even if the line is flushed. • Conventional dosing (q 8 hours) o Peaks: 10-17 mcmol/L (depends on the severity of the disease, see page 60) > Should be drawn 30 minutes following (after) the infusion of the 3rd dose > Peaks not necessary for treatment of urinary tract infections o Troughs: <4.2 mcmol/L > Drawn before 3rd dose • Extended interval dosing, (q24, q36, q48 hours) o Do trough level before the 2nd dose - If <4 mcmol/L, continue the same regimen - If >4 mcmol/L; • In 24-hrs, 36-hrs regimen - Hold the next dose and take random level after 12 hrs of holding the dose • In 48-hrs regime - Hold the next dose and take random level after 24 hrs of holding the dose. • If the random level is <4 mcmol/L, continue on the new frequency. • If the random level is still >4 mcmol/L, repeat the above process and inform the MRP and Clinical Pharmacist III. Following the initial dose, do not administer further doses of gentamicin if urine output is less than 1 mL/kg/hr. IV. Recommendations for abnormal aminoglycoside serum levels: A. Therapeutic peak and high trough. 1. Hold further doses and do a random serum level as follows: a. If the dosing frequency is Q8H, draw a random level 12 hours after the last dose. b. If the dosing frequency is Q12H, draw a random level 18 hours after the last dose. c. If the dosing frequency is Q18H, draw a random level 24 hours after the last dose. d. If the dosing frequency is Q24H, draw a random level 30 hours after the last dose. o Note that it may be necessary, in some instances, to wait longer than 6 hours beyond the current dosing frequency if the trough level is significantly elevated. AminoglycosideMonitoring Guidelines | 77

2021 NEOMED BOOK 2. If the random serum level is less than 4.2 mcmol/L, restart the same dose with the corrected increased dosing interval. (e.g. patient on 3 mg IV Q12H, trough level found to be high therefore an 18-hour random level is drawn; this is found to be 3.0 mcmol/L. New dose should be changed to 3 mg IV Q18H). 3. If the random serum level is still greater than 4.2 mcmol/L, continue to hold further doses and re peat the random level 6 hours later. If the repeated random level is less than 4.2 mcmol/L then refer to # 2 above; otherwise continue to hold further doses and repeat random level after another 6 hours. B. High peak and therapeutic trough o When the serum peak level is high and the trough level is therapeutic (eg, Gentamicin< 4.2 mcmol/L; Amikacin ≤10mcmol/L, etc.), reduce the dose by 10-20%. C. High peak and high trough o Hold further doses and refer to procedure in A until random serum level is less than 4.2 mcmol/L. Physician will then adjust both the dose and dosing frequency. D. Low peak and low trough o Physician to adjust dosage regimen The above guidelines are applicable to amikacin and tobramycin, with the following exceptions: 1. To restart therapy, ensure that the random amikacin serum level is less than 10 mcmol/L. 2. To restart therapy, ensure that the random tobramycin serum level is less than 4.2 mcmol/L. In General: 1. When the serum peak level is therapeutic and the trough level is high, reduce the dosing frequency (e.g., from Q8H to Q12H or Q12H to Q18H, etc.) but ONLY AFTER holding the next dose and doing a random level, as described above, which shows gentamicin to be less than 4.2mcmol/L and amikacin to be ≤10mcmol/L. 2. If there are no changes made in the dose or dosing frequency, then monitoring the serum peak and trough levels ONCE every 7 days is adequate. 78 | Aminoglycoside Monitoring Guidelines

Chapter 6 RETINOPATHY OF PREMATURITY (ROP) MEDICATIONS 79

2021 NEOMED BOOK 1. Ophthalmic Solution Administration (Medications for eye examination): 1.1 One hour prior to examination, instill eye drops as follows: a. Phenylphrine Hcl 2.5% (ophthalmic) – 1 drop each eye every 15 minutes 2x b. Tropicamide 0.5% or 1% (ophthalmic) – 1 drop each eye every 15 minutes 4x c. Tetracaine 1% (ophthalmic) – 1 drop each eye will be instilled by the Ophthalmologist just before the eye examination to minimize the baby’s discomfort. 1.2 To administer the drops, open the baby’s eyelids, drop the medication under the lower lid and hold the eyelids. Open for a few seconds to allow the medication to spread. 1.3 After administering the last dose of Tropicamide, wait for 15 minutes and check whether the pupils are dilated with a pupil torch. 1.4 If the pupils are not dilated, then add an extra drop of Phenylphrine HCL 2.5%. This additional drop of Phenylphrine needs to be documented in the MAR. 1.5 The Tetracaine 1% will be administered by the Ophthalmologist and it will take a few seconds to work. 2. Intravitreal Eye Injection 2.1 Ranibizumab for the treatment of Retinopathy of Prematurity (ROP) Ranibizumab: 0.25 mg/ 0.025 mL ***References: 1. Br J Ophthalmol. 2013;97(7):816-819. 2. PP 7610-031 Screening and Treatment of Retinopathy of Prematurity 80 | Retinopathy of Prematurity (ROP) Medications

Chapter 7 EMERGENCY MANAGEMENT OF ACUTE HYPERAMMONEMIA All recommended dosing are verified to ensure consistency with MNGHA’s Medical Record System (BestCare) and the BBraun Drug Library. 81

2021 NEOMED BOOK Emergency Management of Acute Hyperammonemia • Start 1.5 to double maintenance I.V.F as D10% 0.45NS + KCL 30meq/l until the serum K result is available and then adjust accordingly. • Call the pharmacy to prepare the medications and Intralipid. • Call the Biochemical Geneticist (metabolic) on call. • If ammonia >100mcmol/l in infants, children and adults; and >150mcmol/l in neonates (start loading dose of combined sodium benzoate and sodium phenylacetate (AMMONUL®) and Arginine (see page #) • Start IV Intralipid/SMOF Lipid 20% 2-3gram/kg/day to give additional calories (if fatty acid oxidation defects are excluded). • If the patient is on combined sodium benzoate and phenylacetate (AMMONUL®) or arginine, give KCl 40 meq/l because it causes hyperchloremic hypokalemic metabolic acidosis. KCl can be given through peripheral line up to 60 meq/l; rate must not exceed 0.125meq/kg/hour. • Start dialysis if ammonia > 500mcmol/l in neonates and children and there is no response to the medical treatment within 4 hrs. Consult ICU and Nephrology team if you anticipate starting dialysis in the next few hours. • In an undiagnosed acute hyperammonemia case, also start N-carbamylglutamate (Carbaglu®). It only exists as an enteral form, so it is generally given by nasogastric (NG) tube. Give 100 mg/kg once followed by 50 mg/kg q 6 hrs. • In an undiagnosed acute case, start L-carnitine IV 100 mg/kg/day divided q 6hr, hydroxycobalamin 1mg IM/IV, and biotin 10mg IV/PO. • DO NOT decrease dextrose rate or amount, and DO NOT STOP calorie delivery in the acute stage for any reason (e.g. medications, fluid bolus, or hyperglycemia) as this can precipitate hypoglycemia and catabolism which will further worsen the patient’s condition. • Antibiotics may be started if there is any evidence of sepsis. • Protein should be reintroduced within 24‐48 hours of initiation of therapy even if the patient is on dialysis. ***References: 1. Al Fadhl M., Alsaif S., Al Zaben A., Manual of Establishing a Newborn Screening Program (2016) 82 | Emergency Management of Acute Hyperammonemia

Chapter 8 COMMON INBORN ERRORS OF METABOLISM MEDICATION AND COFACTORS 83

2021 NEOMED BOOK DRUGS INDICATIONS HOW DOSE SUPPLIED Alpha lipoic acid 300mg PO BID (Alpha Lipoic Acid, Mitochondrial disorder Coenzyme Q Creatine 2.5g PO BID Creatine, Coenzyme (hydrochloride Coenzyme Q 10 or 120 or Hydrosoluble form 200mg PO BID Q, Vitamin E) not powder) Vitamin E 400 IU PO BID cocktail AMMONUL1, * Use for Urea cycle disorder to Injectable Loading dose: 250 mg/kg IV in (Benzoate Sodium decrease the nitrogen pool D10%W and Sodium Pheny- over 90 minutes followed by Continuous infusion: 250 mg/kg lacetate), IV in D10%W over 24 hours. 1. DO NOT REPEAT Loading Intravenous Dose 2. DO NOT EXCEED 250mg/kg/ day Arginine Hyperammonemia secondary Powder 250-400 mg/kg/day as loading to urea cycle disorders dose over 90 minutes followed by 250 mg/kg/day Arginine (intrave- Hyperammonemia secondary 10% solution 300 mg/kg IV diluted in D10W as nous) to urea cycle disorders; not (100mg/mL) loading dose over 90 minutes; recommended in patients followed by 300 mg/kg/day with arginase deficiency diluted in D10W infused over 24 hrs. * DO NOT REPEAT LOADING DOSE. Ascorbic Acid Transient tyrosinemia, alkap- 100, 500, 1000 mg 20 – 50 mg/kg/day PO ÷ BID Benzoate Sodium tonuria, and as a cofactor for tablets some cases of primary lactic 250 mg/kg/day PO ÷ QID acidosis and mitochondrial Powder 250 mg/kg/day PO ÷ TID disorders. (on discharge and at home) Non-ketotic hyperglycinemia and in urea cycle disorders Betaine Homocystinuria Powder 100 mg/kg/day PO ÷ QID Maximum dose: 300mg/kg/day Biopterin (BH4 Biopterin-dependent phenyl- Powder PO ÷ TID ketonuria Test dose: 20 – 40 mg/kg/day PO ÷ TID over 2 days Maintenance dose: 10 – 15 mg/ kg/day PO ÷ TID 84 | Common Inborn Errors of Metabolism Medication and Cofactors

DRUGS INDICATIONS HOW DOSE Biotin SUPPLIED Biotinidase deficiency: 10 – 50 Carbaglu® * mg/kg/day PO given OD (carglumic acid) 2 Holocarboxylase and biotin- 10, 50 mg tablets Biotin-responsive BGD: 5 – 10 L-Carnitine idase deficiency, propionic mg/kg/day ÷ BID (Oral) acidemia L-Carnitine Biotin-Responsive Basal Gan- 100mg/kg bolus per NG tube (intravenous) glia Disease (BBGD) Then 25–62.5mg/kg Replace N-acetylglutamate 300 mg/mL oral 100 – 300 mg/kg/day PO ÷ TID (NAG) as an activator of preparation mitochondrial carbamoyl 200 mg/kg/day IV ÷TID phosphate synthetase (CPS1), In metabolic acidosis crisis, give the first enzyme of the urea Loading dose: 250 mg/kg IV cycle over 3 minutes. Carnitine deficiency, various organic acidemia and fatty acid oxidation disorders. Newborns on TPN; patients on hemodialysis. Acute metabolic decompen- 200 mg/mL sation in organic acidemias or 300 mg/mL and fatty acid oxidation disorders. Coenzyme Q10 Some cases of primary lactic 25 mg tablets 10 mg/kg/day PO ÷ BID Folinic Acid acidosis 15 mg/day PO OD; all weights Methionine Preferred over folic acid when 15 mg tablets 150 mg/kg/day PO ÷ TID the disease involves CNS. Available in pow- Sodium Benzoate* Homocystinuria type 3 der, tablet, capsule Weight≤20kg: Sodium or liquid 250mg/kg as loading dose over Conjugation with glycine to 90 minutes followed by 250-500 Phenylacetate* form hippuric acid mg/kg/day (or its precursor, sodium phenylbu- Urea cycle disorder; to de- Powder 250 – 500 mg/kg/day PO ÷ QID crease the nitrogen pool. tyrate) Polycitra Systemic alkanizer, especially 334 mg/5ml 2 – 5 mL/kg/day PO ÷ QID (potassium citrate, for propionic acidemia and solution sodium citrate, citric methylmalonic acidemia; primary lactic acidosis acid) Common Inborn Errors of Metabolism Medication and Cofactors | 85

2021 NEOMED BOOK DRUGS INDICATIONS HOW DOSE Pyridoxal Pyridoxine-dependent SUPPLIED Phosphate neonatal seizures Idiopathic intractable 10mg tablets 10 – 50 mg/kg/day ÷ Q6H epilepsy Pyridoxine Homocystinuria, oxaluria 25, 50 mg tablets 10 – 100 mg/kg/day PO given (Vitamin B6) Pyridoxine-dependent OD seizures Riboflavin Glutaric aciduria type I and II; 100 mg tablets 25 – 100 mg/kg/day given OD (Vitamin B2) some of the oxidative phos- Maximum dose: 300 mg/day phorylation defects (fatty acid oxidation defect) THAM When acute metabolic acido- Intravenous 6 mL/kg/dose intravenous Q4H (Tromethamine) sis cannot be controlled by solution intravenous (0.3M) Sodium bicarbonate or there is hypernatremia Thiamine Pyruvate, alpha ketoglutarate 100 and 300 mg 50 – 100 mg/kg/day PO given (Vitamin B1) deficiencies, thiamine-re- tablets OD sponsive Maple Syrup Urine Maximum dose: 300 mg/day Disease, and some cases of Leigh disease Ammonul or Urea cycle disorder to de- Powder 250 mg/kg/day PO ÷ Q4H Ucephan crease the nitrogen pool 1. Methylmalonic aciduria 1 mg ampules for For Vitamin B12 deficiency: 1 (Sodium benzoate I.M. injection mg I.M. once per month and Sodium Pheny- and homocystinuria secondary to defect of lacetate folate and cobalamin Vitamin B12 metabolism 2. Vitamin B12 deficiency 86 | Common Inborn Errors of Metabolism Medication and Cofactors

BUN, Blood urea nitrogen 1: It is supplied as a vial of 50 mL or 5000mg constitute of concentrated, aqueous 10% sodium benzoate and 10% sodium phenylacetate solution. Thus, each mL provides 100 mg of sodium benzoate and 100 mg of sodium phe- nylacetate in water. According to the prescribing information, AMMONUL must be diluted with sterile Dextrose Injection, 10% (D10W) at ≥ 25 mL/Kg before administration. *: It should be given through a central line; however, it could be given peripherally on limited bases. 2: It is supplied as a 200mg tablet, 5 or 60 tablets in a polypropylene bottle with a polyethylene cap and desiccant unit. Full list of Common Inborn Errors of Metabolism Medication and Cofactors in Appendix II. ***References: 1. Manual of Metabolic disorders, 1st ed. 1998 by Al-Eissa, M and Ozand P. 2. Manual of Establishing a Newborn Screening Program (2016) by Al Fadhl M., Alsaif S., Al Zaben A. 3. J Pediatr 2001; 138: S46 - S55 4. Alfadhel M, Al-Thihli K, Moubayed H, et al. Drug treatment of inborn errors of metabolism: a systematic review Archives of Disease in Childhood 2013;98:454-461. Common Inborn Errors of Metabolism Medication and Cofactors | 87

2021 NEOMED BOOK Chapter 9 INITIAL FLUID REQUIREMENT IN NEONATES All recommended dosing are verified to ensure consistency with MNGHA’s Medical Record System (BestCare) and the BBraun Drug Library. 88

Initial Fluid Requirement in Neonates Practice points • Initial water needs compensate for insensible losses as well as providing a vehicle for nutrition. • Appropriate weight loss for most babies is up to 10% of birth weight over the first 4-5 days. In extremely low birth weight infants, this can be up to 15%. • The best method of assessing hydration status is by measuring the weight of the infant. Serum sodium concentration and urine output may also be useful. Water requirements • Initial water requirement is typically 40-80 mL/kg/day • Consider 40 mL/kg/day for asphyxiated term infants (but ensure acceptable blood glucose level) • Consider 60ml/kg/day for late preterm and term infants with TTN (Transient Tachypnea of New borns) • Consider 80ml/kg/day for premature infants under warmer/phototherapy or extremely prema ture infants with translucent skin. The ELBW baby may have a water requirement of up to 150ml/ kg/day. Initial IV Fluids of choice • Standard IV fluid of choice through UAC or unused lumen of UVC: NS or ½ NS + heparin with the dose of:  0.25 unit/mL for preterm infants less than 1kg.  0.5 unit/mL for term and preterm infants more than 1kg. • D10W (with heparin for UVC) for maintenance, substituting with TPN as soon as feasible. • 0.45% saline with heparin may be used in UAC for infants as needed. • 0.45% or 0.9% saline with heparin may be used for peripheral arterial lines (so better avoided in very low birth weight premature infants). • Maintenance Na and K are not routinely needed until 2-3 days of age. Monitoring • Bedside glucose monitoring as per protocol. Low chemstrips should be confirmed with lab or gas machine specimen. • Initial serum (or gas machine) electrolytes at 12-24 hours age for infants <28 weeks gestation, then daily until stable and/or receiving over half of water requirement enterally. • Electrolytes may need to be done more frequently in very premature infants: Infants 23-25 weeks gestation at birth should have electrolytes checked within the first 6- 12 hours. Glucose Low High Na Increase glucose concentration and/or increase Reduce dextrose, not less than 4-6mg/kg/min K rate of glucose infusion. .Consider sepsis. Insulin therapy should first be discussed with neonatologist Reduce water intake UNLESS there is an exag- Increase water intake. Repeat in 6-12 hours if gerated and inappropriate weight loss, (or-in outside normal older infants-poor weight gain in spite of adequate caloric intake Confirm with venous or arterial sample prior Consider adding or increasing K+ in IV fluids. to taking any action Initial Fluid Requirements in Neonates | 89

2021 NEOMED BOOK Increasing fluids Increase according to weight drop and serum [Na]. The water intake of an infant without renal com promise and significant lung disease may usually be increased by 20-30 mL/kg/day. Reducing fluids Anticipate renal compromise from indomethacin or other nephrotoxic drugs by reducing water intake before the weight goes up and the serum [Na] goes down. Electrolyte compositions and suggested replacement of various GI Fluids ***References: 1. Unal S, Ekici F, Cetin İİ, Bilgin L. Heparin infusion to prevent umbilical venous catheter related thrombosis in neonates. 2. Thromb Res. 2012 Nov;130(5):725-8. doi: 10.1016/j.thromres.2012.07.018. Epub 2012 Aug 16. PMID: 22901699. 3. Bradford NK, Edwards RM, Chan RJ. Normal saline (0.9% sodium chloride) versus heparin intermittent flushing for the prevention of occlusion in long-term central venous catheters in infants and children. Cochrane Database of Systematic Reviews 2020, Issue 4. Art. No.: CD010996. DOI: 10.1002/14651858.CD010996.pub3. 4. Leung LCK et al., Initial intravenous fluid prescription in general paediatric in-patients aged >28 days and <18 years: consensus statements, Hong Kong Med J 2021 Aug;27(4):276–86, https://doi.org/10.12809/hkmj209010 90 | Initial Fluid Requirement in Neonates

Chapter 10 WHY IT IS NOT SAFE TO USE ¼ NORMAL SALINE? 91

2021 NEOMED BOOK Osmolality is a measurement of the number of solute in fluid. Serum osmolality ranges 280 – 300 mOsm/kg and is a measurement of the osmolality of the extracellular fluid. Osmolarity, the number of solute in a liter of water (mOsm/L), is used in reference to intravenous fluid or parenteral preparations. A fluid is termed isotonic, hypertonic or hypotonic based on its osmolarity (see table). When administered, an isotonic solution (e.g. NS) has no effect on intracellular fluid volume. On the other hand, the infusion of a hypertonic or hypotonic based on its osmolarity (see table). When administered, an isotonic solution (e.g. NS) has no effect on intracellular fluid vol- ume. On the other hand, the infusion of a hypertonic or hypotonic solution can cause cell shrinkage or swelling, respectively. Solution Osmolarity (mOsm/L) Na+ (meq/L) Tonicity 0.9% saline (NS) 308 154 Isotonic 0.45% saline (1/2 NS) 154 77 Hypotonic 0.25% saline (1/4 NS) 77 38.5 Hypotonic D5W 278 - Isotonic D10W 500 - Hypertonic D5W NS 560 154 Hypertonic D5W ½ NS 406 77 Hypertonic D5W ½ NS + 10meq/L KCL 426 77 Hypertonic D5W ¼ NS 321 38.5 Isotonic Ringer’s lactate 273 130 Isotonic *Tonicity of any fluids containing dextrose will decrease in the body after infusion as glucose is eventually metabolized to water. Hypotonic solutions provide free water and are used to resolve cellular dehydration. However, excessive infusion of hypotonic solutions can reduce cellular tonicity, disturb energy metabolism, and cause hemolysis and water intoxication in severe cases. Such adverse effects are dependent on the degree of tonicity of the fluid, the volume, rate and site of fluid administration. A slow rate of infusion (minimizes rapid cellular fluid shifts) and administration through a central line (where dilution occurs quickly) lower the risk of side effects. One-quarter sodium chloride (0.225%) has an osmolarity of only 77 mOsm/L and is profoundly hypotonic when compared to plasma and other intravenous fluids. Rare cases of using ¼ NS solution for hyperosmolar hypergly- cemic non-ketotic coma have been reported. However, due to the occurrence of hemolysis, other approaches have been utilized such as a ½ NS (0.45% NS) solution or when hypernatremic state persists, D5w (along with insulin infusion) has been used successfully to lower osmolarity after temporary hyperglycemia. Since dextrose 5% is an isotonic solution, it can be safely administered without the risk of hemolysis. However, it becomes hypo- tonic once the body metabolizes the dextrose into free water. An in-vitro study also indicated that ¼ NS solution caused 5.4% hemolysis after brief contact (60 seconds in most cases) with red blood cells from newborn infants, which was significantly higher than all other fluids examined. In view of its limited therapeutic values and concern of reported side effects, use of ¼ NS should be avoided and discouraged. Adding only potassium chloride to a ¼ NS bag usually fails to raise the tonicity adequately (10 meq/L/KCl = 20 mOsm/L). Dextrose should be added to ¼ NS to increase tonicity and reduce the risk of hemoly- sis. 92 | Why it is not Safe to Use ¼ Normal Saline

***References: 1. Gennaro AL. Remington: The Science and Practice of Pharmacy 20thed, Lippincott Williams & Wilkins, 2. Jackson JK, Derleth DP. Effects of various arterial infusion solutions on red blood cells in the newborn; Archives of Disease in Childhood 2000: (83)2:130-134; 3. Stephen DK. Selecting and managing fluid therapy. Critical Care Nursing Clinic of North America 1998:10(4):401-410. 4. Sterns RH. Hypernatremia in the intensive care unit: Instant quality-just add water. Critical Care Medicine 1999:27(6):1041- 42. 5. Knodel LC, Quandt C. Sodium chloride one-quarter percent infusion – indications and adverse effects. Drugdex®. Micromedex®. 6. Tanaka S. Kobayashi T. Kawanami D, et al. Paradoxical glucose infusion for hypernatremia in diabetic hyperglycaemic hyperosmolar syndrome. Journal of Internal Medicine 2000:248(2):166-168. Why it is not Safe to Use ¼ Normal Saline | 93

2021 NEOMED BOOK Chapter 11 SODIUM AND POTASSIUM ACETATE INFUSION 94

Writing orders for acetate (sodium or potassium) in ½ NS, NS or D5%W for central or peripheral intravenous lines BUT NOT for arterial line. ½ NS, NS, D5%W + Sodium or potassium acetate (calculate mmol/kg/day) PLUS or MINUS heparin (0.25 units/mL for <1kg and 0.5 units/mL for >1kg) at rate of 0.5 mL/hr. Dose of acetate: 1 – 2 mmol/kg/day. However, if potassium acetate is used in infants with weight > 1kg do not order mmol/kg/day to prevent potassium concentration in excess of 0.2 mmol/mL which is not recommended even for a central IV line infusion. To be able to safely administer a dose of sodium acetate 2 mmol/kg/day, it may be necessary to increase the volume (12ml) to further dilute the sodium concentration and correspondingly increase the rate (0.5ml/hr) in some instances. Maximum Concentrations: Sodium Acetate in CENTRAL IV LINE: 0.5 mmol or meq/mL Sodium Acetate in PERIPHERAL IV LINE: 0.154 mmol or meq/mL Potassium Acetate in CENTRAL IV LINE: 0.2 mmol or meq/mL Potassium Acetate in PERIPHERAL IV LINE: 0.06 mmol or meq/mL Sodium and Potassium Acetate Infusion | 95

2021 NEOMED BOOK Chapter 12 MANAGEMENT OF HYPOKALEMIA 96

General Information: o Concentration of KCl solution: (2 mmol/mL = 2 meq/mL) o Potassium infusion MUST be diluted before administration o Potassium should be administered through the largest vein available to avoid extravasation o It is recommended that a serum magnesium level be checked and corrected when hypokalemia is present o Do not infuse potassium phosphate with calcium containing IV fluids as precipitation will result o Intermittent IV potassium Administration reserved for severe depletion situation: Neonate: 0.5 to 1 mEq/kg/dose o The maximum infusion rate/dose includes potassium from all sources (i.e. TPN, IV/PO mainte nance). o Patients should be on a cardiac monitoring for all non-maintenance pediatric potassium infu sions. Indication for Intravenous Bolus Infusion: o Severe hypokalemia (serum potassium level <2.5mmol/L) o ECG changes present A. Central Lines o Final concentration of Potassium Bolus Infusion: 0.1-0.2 mmol/mL o Use dextrose 5% in water as diluent for KCl bolus o Rate of infusion not to exceed 0.5 mmol/kg/dose over 1 hr (Can give for 1 or 2 hours) o Check serum potassium 2 hours after completion of infusion. o May need to extend infusion time if infant receiving other infusions to avoid overloading the circulatory system with fluid. o Patients should be on a cardiac monitor B. Peripheral lines o For peripheral lines, potassium concentrations should be 20-40 mmol/L with a maximum of 60 mmol/L in exceptional circumstances. Peripheral lines Recommended 40 mmol/L or Bolus Infusion:0.2mmol/ concentration: 0.04 mmol/mL kg/dose over 1 hr. Can give for 1 or 2 or 3 Maximum rate: 0.3mmol/kg/dose over hours. Maximum 1 hour Bolus infusion: concentration: 60 mmol/L or 0.2mmol/kg/dose over Maximum Rate: 0.06 mmol/mL 1 hour 0.3 mmol/kg/hr Management of Hypokalemia | 97

2021 NEOMED BOOK o Keep in mind that solutions containing high potassium concentrations can cause skin sloughing and tissue necrosis. o The rate of infusion should not exceed 0.3 mmol/kg/hr. o Check serum potassium every 4 hours. o Use dextrose 5% in water as diluent for KCl bolus. o May need to extend infusion time if infant receiving other infusions to avoid overloading the circulatory system with fluid. C. Precautions o “Double bolus” needs a separate physician order. o Administer KCl infusion to maintain serum K+ between 3.5 and 4.5 mmol/L. o After infusion of 1 KCl bolus, check serum K+ level. o Always check and double check infusion rate on syringe pump and monitor KCl bolus during entire infusion. o Use with extreme caution in renal impairment, tumor lysis burns and dehydration. o Caution when used concurrently with ACE inhibitors, cyclosporin and potassium sparing diuretics as can lead to hyperkaliemia ***References: 1. The Harriet Lane Handbook 17th ed. Mosby-Year Book Inc.; 2005 2. Cochran EB, Phelps S J et al. Parenteral nutrition in pediatric patients. Clin Pharm. 1988; 7:351-66 3. Parenteral Nutrition Manual April 2006; Montreal Children’s Hospital 4. Phelps SJ, Hageman TM, Lee KR,Thompson JA. Pediatric Injectable Drugs the Teddy Bear Book. Bethesda, MD: American Society of Health-Sys- tem Pharmacists; 2018 5. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 10, 2020 98 | Management of Hypokalemia

Chapter 13 MANAGEMENT OF HYPERKALEMIA 99