MNGHA NEOMEDBOOK (December 2021)

2021 NEOMED BOOK I. DEFINITION: Hyperkalemia: Potassium level >6.4 mmol/L II. TREATMENT: In general, serum K+ up to 6.4 mmol/L is well tolerated in preterm infants. Hyperkalaemia should be treated when: 2.1 K+ >6.4 mmol/L and any ECG changes (Peaked/tented T waves; flat/loss of P waves; increase PR interval; wide QRS; VF/Asystole) 2.2 K+ > 7.5 mmol/L (with or without ECG changes) III. RECOMMENDED TREATMENT: 3.1 If there are no ECG abnormalities, confirm Hyperkalaemia on non-haemolysed arterial or venous specimen 3.2 Discontinue any IV fluids or Oral containing Potassium • If peaked T wave or arrhythmia on ECG, give Calcium gluconate 10% 50-100 mg/kg (0.5 -1ml/kg= 4.5 -9 mg Elemental Ca/kg) to be given IV over 15-20 minutes and should be diluted in 5-10ml of D5% (don’t flush it) and • Sodium bicarbonate 4.2% (2 Meq/kg) over 10-20 minutes (not simultaneously via the same line with Calcium gluconate) and • Insulin (regular) give 0.1 u/kg of regular insulin IV with glucose as 0.5 g/kg (5 mL/kg of D10W) over 30 minutes. May repeat this dose in 30 – 60 minutes, if needed. • Salbutamol  IV: 4mcg/kg to be diluted in 5 mL of sterile water or D5% and infuse over 20 minutes and can be repeated in 2-4 hours,  Or Inhaled Salbutamol 0.4 mg in 2 mL normal saline (if no IV access) • Furosemide (Lasix) IV or orally 1-2 mg /kg/ dose once or twice per day • Give Sodium Polystyrene Sulfonate (Kayexalate) 0.5- 1gm/kg/dose Q8-6H PO or PR to be diluted in sterile water or NS 3ml for each 1 gram of Kayexalate (Note: not recommended for infants < 1500 g). • If the potassium is still persistently high, consider:  Exchange transfusion as a last resort where all other therapeutic options have failed. How ever, a long preparation time is required to use the recommended saline washed RBC.  Peritoneal dialysis may also be considered as a last resort. ***References: 1. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 10, 2020 2. DPP 7610-018 Management of Neonatal Non-Oliguric Hyperkalaemia, : 2018 100 | Management of Hyperkalemia

Chapter 14 CALCIUM DOSING IN NEONATES 101

2021 NEOMED BOOK Dilute infusion solution to < 2 mg/mL of elemental calcium with Dextrose and/or saline. - Compatible with KCl. - For peripheral line: The concentration for infusion not to exceed 20mg of elemental calcium in 100 mL. - For central line: The concentration of infusion should not exceed 80mg/kg/day of elemental calcium. I. Background: • Always use adjusted calcium level when interpreting calcium results • Hypocalcemia definition: o Preterm infant: Ca < 1.75 mmol/L o Term infant: Ca < 2 mmol/L • For Symptomatic hypocalcemia (seizure, tetany, stridor): Give IV Calcium • For Asymptomatic Hypocalcemia: Give oral Calcium II. Intravenous calcium supplements for Symptomatic Hypocalcemia: Calcium gluconate: • 100 mg of calcium gluconate in 1ml = 9.3 mg or 0.46 mEq (0.23 mmol) elemental calcium* • Usually dose expressed in milligram of calcium gluconate (salt). • Considered as first line for routine calcium repletion. • All patients receiving calcium infusion should be on a cardiac monitor. • May be administered centrally or peripherally. • Do not administer IM or SQ, or IV via small scalp, hand, or foot veins since severe necrosis and sloughing can occur. • Patients with hypomagnesemia may not respond to calcium repletion until magnesium disorder is corrected. III. Usual dose and route: a. Severe or symptomatic hypocalcemia (Adjusted serum calcium less than 1.8 mmol/L): o Dose expressed in milligram of calcium gluconate (salt). o Neonates and infants: IV Calcium Gluconate (100-200 mg/kg/dose): 9.3 - 18.6 mg/kg of elemental calcium over 10-20 minutes every 6 to 12 hours, then 200 - 400 mg/kg/day (18 – 37 mg of elemental calcium/kg/day) as a continuous infusion. b. Cardiac arrest in the presence of hyperkalemia or hypocalcemia, magnesium toxicity, or calcium antagonist toxicity: o Neonates and Infants: I.V, I.O 60-100 mg/kg/dose (5 – 9.3 mg/kg of elemental calcium); May repeat in 10 minutes if necessary; if effective, consider I.V. infusion c. Tetany, seizures: Neonate: IV: 100-200 mg /kg/dose (9.3 - 18.6 mg/kg of elemental calcium) over 5-10 minutes; may repeat after 6 hours or follow with an infusion with a maximum dose of 400- 800 mg/kg/day (40 - 80 mg/kg of elemental calcium) via central line. d. Daily Maintenance Dose: I.V Dose expressed as elemental calcium IV  Neonates and infants: 40 – 80 mg/kg/day of elemental calcium) 102 | Calcium Dosing in Neonates

Standard Concentration: - Compatible with KCl. - For peripheral line: The concentration for infusion not to exceed 20mg of elemental calcium in 100 mL. - For central line: The concentration of infusion should not exceed 80mg/kg/day of elemental calcium. IV. Maintenance Dose a. For the symptomatic hypocalcemic infant give 1-2 mg of elemental calcium/kg/hour as continuous infusion. b. Alteration of infusion rate should be based on the results of serum calcium. c. For the asymptomatic hypocalcemic infant administer 1 mg of elemental calcium/kg/hour as continuous infusion. V. Oral calcium supplements for Asymptomatic moderate Hypocalcemia (Adjusted serum calcium of 1.80-1.99 mmol/L): Hypocalcemia: Oral calcium can be used as: • CALCIUM GLUBIONATE = 15mg/mL of elemental calcium • CALCIUM GLUCONATE = 9.3mg/mL of elemental calcium • CALCIUM CARBONATE = 100mg/mL of elemental calcium All oral calcium should be given with meals for better calcium absorption, especially in patients with hypoparathyroidism. Neonate: Oral Supplements: 50-150mg/kg/day of elemental calcium divided in 4-6 doses (Maximum of 1000mg/ day elemental calcium) VI. Monitoring Parameters o Serum Calcium Monitor serum calcium level Q8-12H in the hypocalcemic infant. If serum calcium is increasing, maintain same infusion rate and check serum calcium Q12-24H. Once normal serum calcium has been achieved, the infusion rate can be gradually tapered. o Serum Magnesium • Check and correct serum magnesium if hypomagnesemia exists. • Normal serum magnesium level in newborns 0.6-1.15 mmol/L. • If serum magnesium is low, correct with 0.2 mL/kg/dose intramuscular of 50% MgS04 injectable solution. o Heart Rate : Continuous monitoring of EKG in mandatory. o Site of Intravenous Injection Intravenous site should be carefully inspected periodically since Extravasation of the intravenous solution can occur. Calcium Dosing in Neonates | 103

2021 NEOMED BOOK VII. Precautions and Contraindications o All patients receiving calcium infusion should be on a cardiac monitor. o Caution is to be exercised if calcium salts are to be given to patients with sarcoidosis, renal or cardiac disease and in patients receiving cardiac glycosides. o The acidifying nature of calcium chloride means that it should be used with caution in patients with corpulmonale, respiratory acidosis, renal disease or respiratory failure. o Calcium salts are contraindicated in patients with ventricular fibrillation or hypercalcemia or infants less than 28 days old and receiving ceftriaxone. o Incompatible with sodium bicarbonate, inorganic potassium phosphate, and dobutamine. o Compatible with sodium glycerophosphate (organic). VIII. Adverse Reactions o Intravenous administration of calcium salts may cause bradycardia, cardiac arrest, and venous irritation. o Consequently, to avoid too rapid an increase in serum calcium and extravasation of calcium solution into the surrounding tissue with resultant necrosis, calcium salts should be given by slow intravenous injection through a small needle into a large vein. ***References: 1. Micromedex Healthcare Series Inc.; 1974 – 2009 Thomson Reuters 2. J Pediatr Gastroenterol Nutr. 1991 Aug;13(2):134-8. 3. 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 4. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 10, 2020 104 | Calcium Dosing in Neonates

Chapter 15 GUIDELINES FOR THE ADMINISTRATION OF MAGNESIUM IN NEONATES 105

2021 NEOMED BOOK I. GENERAL INFORMATION a. One millimole of magnesium (Mg) = 250 mg salt Mg sulfate = 25 mg elemental Mg b. 1mmol of Mg = 2 Meq Mg c. 1 Meq = 12.5 mg of elemental Mg d. Dilute in a compatible solution (D5, NS,) to a usual concentration : - <60mg/mL of magnesium sulfate for peripheral line - Maximum 200 mg/mL of magnesium sulfate for central line II. HYPOMAGNESEMIA – Serum Magnesium Level < 0.5 mmol/L Signs of hypomagnesemia include: Electrocardiographic changes – increases in PR and QT intervals, flattened T-waves, hypotension, premature ventricular contractions and ventricular fibrillation. III. TREATMENT OF HYPOMAGNESEMIA • Dose is expressed in mg of Magnesium Sulfate: Magnesium sulfate 50% Solution= 500mg of magnesium sulfate/mL = 50 mg elemental Magnesium/mL = 4 meq/mL= 2mmol/mL • Dose depend on clinical condition and serum magnesium concentration • Doses given below are for normal renal function • Dose expressed below as magnesium sulfate (salt) a. Hypomagnesemia (<0.7 mmol/L): o Magnesium sulfate IV: 25-50 mg/kg/dose (2.5–5 mg /kg/dose as elemental Magnesium Sulfate) over 3-4 hours Q8-12 H for 2-3 doses IM: Standard Concentration: 20% Magnesium Sulfate 25-50 mg/kg/dose (2.5–5 mg/kg/dose as elemental Magnesium Sulfate) = (0.125 – 0.25 mL/kg) Doses may be repeated as necessary based on serum magnesium concentrations. Note: IM administration of drugs in neonates, particularly very low birth weight premature neo nates, is not practical due to small muscle mass. Daily Maintenance Dose of magnesium sulfate IV: Neonates, Infants and Children < 50 kg: 30-60 mg/kg/day b. Severe Hypomagnesemia (<0.5 mmol/L): Magnesium Sulfate IV 50-100 mg/kg/dose over 3-4 hours. May repeat dose in 12 hours if necessary. c. Seizures: o In case of seizures secondary to hypomagnesemia, Administer: Magnesium Sulfate 20 – 100 mg/kg/dose IV over 1-2 hours. May repeat dose in 12 hours if necessary. Maximum doses used have ranged up to 200 mg/kg/dose o Magnesium sulfate 25 – 50 mg/kg/dose = 0.1 – 0.25 mL/kg/dose IM of a 20% solution Q12H has been used to treat HYPOCALCEMIC CONVULSIONS in Neonates. 106 | Guidelines for the Administration of Magnesium in Neonates

d. Oral Magnesium: o Consider oral repletion in mild to moderate deficiency (Asymptomatic). o Solution: Magnesium sulfate mixture: Dose: 50-100 mg (5-10 mg elemental magnesium) /kg/dose orally from one to four times daily (about 30% of dose absorbed by gut) for 5 days. IV. INTRAVENOUS ADMINISTRATION • It is recommended that in infants and children magnesium sulfate be given intravenously in a final solution concentration of <60 mg/mL for peripheral line over at least ONE hour (preferably between 1-6 hours). • In severe conditions, half the magnesium sulfate dose can be given over 30 minutes. • For post cardiac surgery patients, fluid-restricted patients and patients with severe conditions, a final solution concentration of 20% (i.e. 200 mg/mL central line) can be infused over 3 to 6 hours. • Maximum central line concentration: 200 mg/mL • Administer slowly via central line or a large peripheral vein • Serum electrolyte levels should be obtained prior to initiating therapy and monitored during magne sium repletion • Recheck level no sooner than two hours post-infusion I. MONITORING PARAMETERS: • ECG monitoring is required and monitor continuously during magnesium sulfate administration • Monitor vital signs, deep tendon reflexes, • Magnesium level, calcium and potassium level. • Renal function and urine output to avoid risk of hypomagnesemia • Hypomagnesaemia co-existing with drug-induced QT prolongation OR digoxin toxicity • Check any drug interaction with magnesium II. COMPATIBILITY • Magnesium sulfate is compatible with Dextrose 5% in water (D5W) or Sodium Chloride 0.9% (NS). III. RENAL FAILURE • Infants and children who have both magnesium deficiency and impaired renal function should have their magnesium doses decreased by at least 50% and serum concentrations monitored after each dose. IV. PRECAUTION AND ADVERSE EFFECT: • Hypotension – this may be worsened, especially with faster rates of administration • Severe flushing, sweating, heat sensation • Myasthenia gravis – magnesium interferes with neuromuscular transmission and may increase in muscle weakness (especially respiratory), monitor closely. • Renal impairment – increased risk of hypermagnesaemia, dose reduction may be required • Cardiac depression, negative inotropy • Hypocalcemia Guidelines for the Administration of Magnesium in Neonates | 107

2021 NEOMED BOOK • May enhance the effects of CNS depressants • Monitor for signs of hypermagnesaemia – common signs are flushing, nausea and vomiting. Other signs and symptoms include thirst, hypotension, muscle weakness or paralysis, renal failure, blurred vision, drowsiness, bradycardia, coma and cardiac arrest. May occur at serum magnesium levels above 2 mmol/L • Oral formula may cause Diarrhea ***References: 1. Micromedex, Inc. 1974 – 1999; vol. 101 Exp 9/30/1999. 2. Montgomery, P. Treatment of magnesium deficiency. Clin Pharm. 1987; 6:834-5. 3. 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 4. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 10, 2020 108 | Guidelines for the Administration of Magnesium in Neonates

Chapter 16 GUIDELINES FOR THE ADMINISTRATION OF PHOSPHORUS IN NEONATES 109

2021 NEOMED BOOK I. GENERAL INFORMATION a. Phosphorus - atomic mass unit (amu) = 31 b. One millimole of phosphorus (P) = 31 mg c. Order phosphorus (P) in millimoles or milligrams and indicate if sodium phosphate or potassium phos phate is required d. Potassium Phosphate (inorganic phosphate): o Each 1 mL contains 3 mmol of phosphate provides ~ 4.4 mEq of potassium. o Verify infusion time does not exceed acceptable potassium infusion rate e. Sodium Phosphate (inorganic phosphate) o Each 1ml contains 3 mmol of phosphate provides ~ 4 mEq of sodium f. Sodium Glycerophosphate (organic) o Each 1mmol of phosphate provides 2 meq of sodium II. CAUSES OF HYPOPHOSPHATEMIA: a. Starvation b. Protein-energy malnutrition c. Malabsorption syndromes d. Intracellular shiftsassociated with respiratory metabolic alkalosis e. Treatment of diabetic ketoacidosis f. Corticosteroid administration g. Increased renal losses (e.g., renal tubular defects, diuretic use) h. Vitamin D–deficient and vitamin D–resistant rickets III. HYPOPHOSPHATEMIA - Serum phosphorus (P) level < 1.45 mmol/L o Signs and symptoms of hypophosphatemia include: o Anorexia, dysphagia, tachypnea, muscle weakness, confusion, parasthesias, seizures, coma, reduced cardiac contractility, hypotension, respiratory failure, decreased mentation and altered renal function. IV. TREATMENT OF HYPOPHOSPHATEMIA a. Potassium phosphate / sodium phosphate / sodium glycerophosphate* Low dose: if phosphorus level between 0.75 to 0.9 mmol/L (2.3 to 2.7 mg/dL ): 0.08 to 0.16 mmol/kg IV over 4 to 6 hours . Intermediate dose: if phosphorus level between 0.5 to 0.74 mmol/L (1.5 to 2.2 mg/dL): 0.16 to 0.32 mmol/kg IV over 4 to 6 hours. High dose: if phosphorus level <0.5 mmol/L (<1.5 mg/dL): 0.32 to 0.64 mmol/kg IV over 4 to 6 hours. • *If sodium glycerophosphate used , use the lower limit of each group • Repeat doses as required to maintain serum phosphate level greater than 0.7 mmol/L. b. Dilute sodium or potassium phosphate in intravenous fluids and infuse at a rate not exceeding 0.2 mmol/kg/hr. c. Recommended maintenance intravenous dose: 0.5 - 1.5 mmol/kg/day divided Q6H o neonate:1- 2 mmol/kg/day o Infants and children less than 5 kg: 0.5-2 mmol/kg/day Q12 – 6 hrs d. Oral maintenance dose: 1 - 3 mmol/kg/day divided Q8 - 6H 110 | Guidelines for the Administration of Phosphorus in Neonates

V. INTRAVENOUS ADMINISTRATION Dilute phosphate in intravenous fluids to give a final solution concentration of <0.05 mmol/mL or 1.5 mg/mL and infuse at a rate not greater than 0.2 mmol/kg/hr (6.2 mg/kg/hr) via peripheral line, and 0.12mmol/mL through central IV line. VI. COMPATIBILITY Potassium and sodium phosphates are compatible with Dextrose 5% in water (D5W) or sodium chloride 0.9% (NS) VII. SPECIAL CONSIDERATIONS/MONITORING REQUIREMENTS: a. Do not co-infuse phosphate with calcium containing products due to risk of precipitation b. Check serum potassium, calcium and phosphate levels before administering then repeat it within 1-2 hours after dose administration c. Need cardiac monitoring o if intermittent infusion or potassium infusion rates > 0.5 mEq/kg/hr or > 10 mEq/hr, o Risk of cardiac arrhythmia includes cardiac conditions or QT prolonging medications d. Administration of large amounts of phosphate may cause hypocalcemia VIII. RENAL FAILURE Do not administer phosphate salts to patients with markedly impaired renal function. In patients with mild-to-moderate renal insufficiency, judicious monitoring of phosphate and other electrolytes is MANDATORY. ***References: 1. 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 2. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; Septemeber 10, 2020 3. Micromedex Inc. 1974 - 1999; vol. 101: Exp. 9/30/1999. 4. Trissel, LA. Handbook on Injectable Drugs. ASHP, Inc. 1996: 917-922. 5. Tsang, I, Lau, AH. Fluid and Electrolyte Disorders. In: Young, LY, Koda-Kimble, MA (eds) Applied Therapeutics: The Clinical use of Drugs 6th ed. Applied Therapeutics, Inc. 1995: 28-1-28-33. Guidelines for the Administration of Phosphorus in Neonates | 111

2021 NEOMED BOOK Chapter 17 PARENTERAL NUTRITION IN NEONATES (Initiate within 24 hours if clinically indicated) 112 | Parenteral Nutrition in Neonates

I. Indication - malabsorption - necrotizing enterocolitis (NEC) - hypoxic ischemic encephalopathy (HIE) - intestinal obstruction - gastrointestinal surgery - pre-term or term infant unlikely to receive full enteral feeds within 5 to 7 days II. Fluid – To be determined as follows Total daily fluid requirement = Normal maintenance fluids + Deficit + ongoing abnormal losses. Range: 60 – 150 mL/kg/day generally, except in special clinical conditions. Monitoring parameters: weight, serum sodium III. Carbohydrates • 50-60% of the total calories coming from carbohydrates • Dextrose - Start with D10%W; may consider D5% in the ELBW (<1000 g) infant Recommendations: a. Preterm infants - Initial: (6 – 9 g/kg/day) = 4 – 6 mg/kg/minute - Increase gradually to 9 -16 g/kg/day = 7 – 11 mg/kg/minute - Advance by: 0.5 – 1 mg/kg/min per day or increase % dextrose between 1% and 2.5% as tolerated. b. Term and older infants: 1. Initial: (8 – 12 g/kg/day) = 6 – 8 mg/kg/minute 2. Increase gradually to 9 -16 g/kg/day = 7 – 11 mg/kg/minute 3. Advance by: 2 – 4 mg/kg/minute per day or increase % dextrose between 1% and 2.5% as tolerated. 4. Maximal oxidative glucose capacity in neonates: 12 mg/kg/minute (15mg/kg/min can be used in selected cases) - Glucose (mg/kg/minute) = (% dextrose x 10) x (rate of infusion in mL/hr) ÷ wt (kg) ÷ 60 - Monitoring parameters: blood glucose and urine dipsticks - Caloric content: 3.4 kilocalories per gram III. Protein – amino acids • Preterm Neonates: Start with 2 g/kg/day Advance daily by: 1-2 g/kg/day as tolerated Maximum: 3.5 g/kg/day for preterm infants (<33 weeks) and can be 4g/kg/day for preterm infants <28 weeks • Term infants: Start with 1-2 g/kg/day Advance by: 1 g/kg/day as tolerated Maximum: 3 g/kg/day Parenteral Nutrition In Neonates | 113

2021 NEOMED BOOK • Monitoring : Blood urea nitrogen (BUN) : Serum ammonia level : Metabolic acidosis • Caloric content : 4 kilocalories per gram IV. Fats – SMOF Lipids (20%) • 30-40% of the total calories coming from lipids (30% Soybean Oil, 30% MCT, 25% Olive Oil, 15% Fish Oil) - Start with 1 - 2 g/kg/day on day 1 - Advance by: 0.5 – 1 g/kg/day as tolerated - Maximum: 3 g/kg/day - Duration of infusion: 18 – 24 hrs (preferably 24 hours) - Monitoring parameters: serum triglycerides - Optimal Level: 1.7 to 2.7 mmol/L - >2.8 mmol/L, to wean down to not exceed 1g/kg/day - >3.3 mmol/L, to stop the lipid for 24 hours, and consult the Clinical Pharmacist. - If no clinical pharmacist available, do the level every other day, but do not exceed 72 hours without lipids. V. Electrolytes: Maintenance requirements VI. Caloric requirements: 90 – 120 non-protein kilocalories/kg/day  If starting parenteral nutrition in the first 4 days after birth: • Give a starting range of 40 – 60 kcal/kg/day • Gradually increase over 4 days to a maintenance range of 75 – 120 kcal/kg/day.  If starting parenteral nutrition more than 4 days after birth: • Give a range of 75 – 120 kcal/kg/day VII. Add complete multivitamins (water soluble plus fat soluble vitamins) VIII. Add trace element mixture (TE-4): Cu, Zn, Cr, Mn IX. Overall Monitoring: 1.) Do baseline TPN profile, then once per week. 2.) Obtain daily serum electrolytes for first few days until stable, then every other day or twice per week as indicated. X. Complications associated with parenteral nutrition 1. Infectious: sepsis, bacteremia, fungemia and catheter-site infection. 2. Mechanical: venous thrombosis, superior vena cava syndrome, catheter occlusion secondary to Ca-P crystals, embolism, air embolism extravasation of solution, catheter dislodgement, pneumothorax. 114 | Parenteral Nutrition in Neonates

1. Infectious: sepsis, bacteremia, fungemia and catheter-site infection. 2. Mechanical: venous thrombosis, superior vena cava syndrome, catheter occlusion secondary to Ca-P crystals, embolism, air embolism extravasation of solution, catheter dislodgement, pneumothorax. 3. Metabolic: fluid overload, dehydration, electrolyte and mineral abnormalities, acidosis, vitamin or trace element deficiency, essential fatty acid deficiency, fat overload syndrome, amino acid imbalance and hyperlipidemia. 4. Other: Bone demineralization – osteopenia of prematurity, Hepatobiliary dysfunction – cholestasis, cholelithiasis Total Parenteral Nutrition (TPN): Peripheral VS. Central Parenteral Nutrition Peripheral Parenteral Nutrition Central Parenteral Nutrition DURATION Short – term PN ( < 2 week) Long-term PN (> 2 week) OSMOLALITY Up to 900 mOsmol/L Can be > 1000 mOsmol/L DEXTROSE Max: 12.5% > 12.5% as required POTASSIUM Conc: Max: 40 meq/L Conc: Max: 80 meq/L Maximum dose of calcium = 80 mg/kg/day (to be discussed with Pediatric Endocrinologist and Clinical Pharmacist as more than this dose can be used safely and may be required to normalize significant demineralization of the bone. Avoid exceeding 20 mg/100 mL of Calcium concentration peripherally To calculate the maximum calcium dose that can be given peripherally in TPN: Example: Total volume of TPN 300 mL x 0.2 / working weight 2 kg = 30 mg/kg/day Total volume of TPN x 0.2 / working weight = mg/kg/day Solubility: calcium + organic: Trophamine ≤ 45 meq/L (Ca: PO4 Curve) 20 mg of elemental calcium = 1 meq = 0.5 mmol of elemental calcium Try to maximize calcium intake for preterm less than 28 weeks in the first week and adjust if the level of adjusted calcium exceeds 2.7 mmol/L ※ Phosphate: Neonates/infants: 1-1.5 mmol/kg/day (31 – 46.5 mg/kg/day) Maximum dose of phosphate = 2 mmol/kg/day Adjust the dose if the level of phosphate exceeds 2.6 mmol/L Organic Phosphate (Na Glycerophosphate) Inorganic Phosphate (NaPO4 / KPO4 ) 1 mL of Sodium Glycerophosphate = 1 mmol 1 mL of Sodium Phosphate = 0.75 mmol phosphate and 1 (31 mg) of phosphate and 2 mmol sodium mmol sodium No Organic Potassium Phosphate available 1 mL of Potassium Phosphate = 0.68 mmol phosphate and 1 meq Potassium • Preferred to be use in Parenteral Nutrition • Avoid to use, only if Organic Phosphate not available • Less precipitation • Higher risk of precipitation Parenteral Nutrition In Neonates | 115

2021 NEOMED BOOK The recommended range of calcium delivered by PN in preterm infants is wide, 40–80 mg/kg/day for calcium (do not exceed 20 mg/100ml of calcium concentration in peripheral line). But in pathological cases, higher doses will be required after referral to Pediatric Endocrinology. The recommended range of phosphorus delivered by PN in preterm infants is 31–62 mg/kg/day. ※ Calcium/phosphate ratio: Molar Ratio: 2-2.5 mEq calcium: 1 mmol phosphate 1-1.3 mmol calcium (40-50 mg): 1 mmol phosphate (31 mg) Weight Ratio: 1.3 – 1.7 mg calcium: 1 mg phosphate Optimal Ca to P ratio in mg = (1.3 – 1.7 Ca) : 1 P in mg and should not be less than 1.3:1 Calcium: phosphate ratio less than 2 mEq calcium: 1mmol phosphate OR, 1.3 mg calcium : 1mg phosphate or reversed Ratio can cause mineral renal wasting of Calcium, which may lead to bone demineralization and possibility of Nephrocalcinosis Maintain calcium and phosphorus ratio in TPN and oral supplements in VLBW should not be less than the ratio below: Calcium mg Phosphorus mmol (mg) Ratio Ca:P mg: mg 20 0.5 (16) 1.3:1 30 0.7 (22) 1.3:1 40 1 (31) 1.3:1 50 1.2 (37) 1.3:1 60 1.5 (47) 1.3:1 80 2 (62) 1:3:1 ※ Trace Elements and Requirements: a. For short-term parenteral nutrition, a trace element mixture containing copper, zinc, chromium and manganese is recommended. Follow manufacturer’s product information regarding dosage. b. If parenteral nutrition is to be given for an extended period (months) then additional trace elements such as selenium, molybdenum and iodide should be considered. c. In diarrhea states or excess GI fistula losses, extra zinc may be needed. d. In cholestasis (obstructive jaundice), copper and manganese may be eliminated from parenteral nutrition solution e. In renal failure, eliminate chromium and selenium from parenteral nutrition solution; also eliminate or decrease the daily amount of zinc. f. The active ingredients in 1ml of PEDITRACE correspond to: • Zinc: 250 mcg • Copper: 20 mcg • Selenium: 2 mcg • Iodine: I mcg • Fluorine: 57 mcg • Manganese: I mcg The recommended dose is 1 mL PEDITRACE/kg body weight/day for infants and children with a weight of up to 15 kg. Patient with Cholestasis can use 0.5 mL/kg/day to decrease copper dose to 10mcg/kg. 116 | Parenteral Nutrition in Neonates

※ Electrolytes: a. Calcium Gluconate: 1. If the infant have central line in optimal position : - Term Neonates: 40-50 mg/kg/day - Neonates less than 36 weeks GA: 50-60 mg/kg/day - Maximum dose of calcium = 80 mg/kg/day (to be discussed with Pediatric Endocrinologist as more than this dose can be used safely and may be required to normalize significant demineralization of the bone 2. If the infant have peripheral iv line only: - Avoid exceeding 20 mg/100 mL of Calcium concentration peripherally - To calculate the maximum calcium dose that can be given peripherally in TPN: Total volume of TPN x 0.2 / working weight = mg/kg/day Example: total volume of TPN 300 mL x 0.2 / working weight 2 kg = 30 mg/kg/day - Solubility: calcium + organic: Trophamine ≤ 45 meq/L (Ca:PO4 Curve) - 20 mg of elemental calcium = 1 meq = 0.5 mmol of elemental calcium - Try to maximize calcium intake for preterm less than 28 weeks in the first week and adjust if the level of adjusted calcium exceeds 2.7 mmol/L b. Phosphate - Neonates/infants: 1-1.5 mmol/kg/day (31 – 46.5 mg/kg/day) - Maximum dose of phosphate = 2 mmol/kg/day (62 mg/kg/day) - Adjust the dose if the level of phosphate exceeds 2.6 mmol/L The recommended range of calcium delivered by PN in preterm infants is wide, 40–80 mg/kg/day for calcium (do not exceed 20 mg/100ml of calcium concentration in peripheral line). But in pathological cases, higher doses will be required after referral to Pediatric Endocrinology. The recommended range of phosphorus delivered by PN in preterm infants is 31–62 mg/kg/day. The available data suggest that PN does predispose the infant to metabolic bone disease and that PN formula- tion with high-dose calcium and phosphorus content should be used. • Vitamin Requirements A vitamin preparation containing both water-soluble vitamins and fat-soluble vitamins should be used in parenteral nutrition solutions. The specific manufacturer’s product information regarding dosage should be followed. Preterm infants: 2 mL/kg, maximum total dose per day 5 mL MVI-Pediatric (depends on the brand recommendation*) • “Pediavite” where the physician is expected to write the volume based on the infant’s body weight) - babies less than 1.5kg = 1.5ml per day - babies 1.5kg and <3kg = 3.25ml per day - babies equal or more than 3kg = 5ml per day Parenteral Nutrition In Neonates | 117

2021 NEOMED BOOK • Vitamins: each 5 mL of vitamin contain: Vitamins 5mL (>3kg) 3.25mL (1.5 – <3kg) 1.5mL (<1.5kg) Vitamin D 400 IU 260 IU 120 IU Vitamin E 7 IU 4.55 IU 2.1 IU Vitamin A 2300 IU 1495 IU 690 IU Folic Acid 140 mcg 91 mcg 42 mcg Cyanocobalamin (B12) 1 mcg 0.65 mcg 0.3 mcg Biotin 20 mcg 13 mcg 6 mcg * All TPN requirements and adjustments is daily revised and approved by the Clinical Pharmacist. ※ Vanilla TPN (Starter TPN): Vanilla TPN is a standardized preparation supplied in premixed bags containing 4% amino acids and 10% dextrose. This is usually prescribed if the baby is born after the allotted time for TPN orders has passed (at 13:00 hrs). For convenience, it is mixed in advance and remains stable in unit refrigerators for 1 week after compounding; Thus, it is immediately available when a very-low-birth weight infant is admitted to the unit. Vanilla TPN is used for infants weighing less than 1250 g birth weight or less than 29 weeks gestation for the first 24 hours of life until individualized TPN orders can be written and filled. Early infusion of amino acids decreases fluctuations of serum glucose, minimizes nutrient deficits, reduces the catabolism of lean body mass, and is, in general, more physiologic. So Neonatology Department Requesting To Provide Us With 3 Syringes of This Vanilla TPN Formula , and To Replace any Used One In a Daily Bases TPN Formula: 60 mL syringe contains: 3 grams protein 6 grams Glucose 9 milligram elemental calcium 0.25 units per milliliter of heparin The volume will depend on the baby’s birth weight. For example: If the birth weight is 600 g, and the Total Fluid Intake (TFI) is 80 mL/kg/day, so the Vanilla TPN rate will be 2ml/hr (birth weight X 80ml ÷ 24). The baby will receive a total of 48ml per 24 hours. ***References: 1. ASPEN Parenteral Nutrition Handbook, 3rd Edition 2020 2. Lewis ST. Nutritional management of the very low birthweight infant. Program and abstracts of the National Association of Neonatal Nurses 20th Annual Conference; October 13-16, 2004; Orlando, Florida. 3. Laura A Stokowski, RN, MS . Nutritional Management of the Very- Low-Birthweight Infant .Medescape -2005 118 | Parenteral Nutrition in Neonates

Frequently-asked Questions about TPN Management 1.) What is the maximum TPN osmolality in peripheral and central line? Answer: Peripheral Parenteral Nutrition Central Parenteral Nutrition OSMOLALITY Up to 900 mOsmol/L Can be > 1000 mOsmol/L 2.) How do we improve the calorie intake for a patient on TPN? Answer: a.) By increasing total fluid intake (TFI). b.) By increasing the glucose infusion rate to maximum of 17 g/kg/day. c.) By increasing lipid infusion to maximum of 3 g/kg/day. d.) By ensuring that the actual TPN rate is not less than 50-75% of the total TPN rate. 3.) What is the recommended daily intake calorie from the TPN? Answer: Daily intakes (kcal/kg) of energy recommended by parenteral nutrition Postnatal Days D1 D2 – D6 >D7 Term Infants 40 60-80 90-100 Preterm Infants 45-55 60-80 90-120 4.) How do we manage Hypercalcemia for patients on TPN? Answer: If the phosphorus serum level is <1.5 mmol/L: - increase the phosphorus infusion rate and make the calcium-phosphorus ratio 1:1 or reverse ratio 0.8 : 1 for 1-2 days - keep the calcium infusion rate the same If the phosphorus serum level is >2 mmol/L: - decrease the calcium infusion rate 5.) How do we manage TPN of patients with cholestasis? Answer: a.) Try to start enteral feeding b.) Decrease the lipid infusion rate to 1-2 g/kg/day c.) Start Ursodeoxycholic acid 6.) What is the maximum Glucose Infusion Rate (GIR) per kg per min? Answer: In the first Four (4) Days of life After Four (4) Days of life 6-9 g/kg/day (4-6 mg/kg/min) 9-16 g/kg/day (6-12 mg/kg/min) Parenteral Nutrition In Neonates | 119

2021 NEOMED BOOK Chapter 18 GENERAL INFORMATION ABOUT IMMUNIZATION All recommended dosing are verified to ensure consistency with MNGHA’s Medical Record System (BestCare) and the BBraun Drug Library. 120

General Information about Immunization Q: How should I manage children who have fallen behind on their vaccinations? A: Infants or children who are more than one month or one dose behind schedule should be accel erated, which means the intervals between doses should be reduced to the minimum allowable. Q: How long can the interval between doses of a vaccine be without having to restart the vaccine series over? A: Every effort should be made to adhere to the recommended vaccine schedule, including the spacing between doses. However, if the interval between doses is prolonged, there is no need to restart the series of any vaccine. Q: What childhood vaccines may be given simultaneously? A: All vaccines used for routine childhood vaccination in the United States may be given simultaneously. There is no evidence that simultaneous administration of vaccines either reduces vaccine effectiveness or increases the risk of adverse events. The only vaccines which should NOT be given simultaneously are cholera and yellow fever vaccines. Q: Is it true that MMR and OPV no longer have to be separated by a month if not given together? A: The 1994 General Recommendations state that no waiting period is required if OPV and MMR are not administered simultaneously. All vaccines may be administered simultaneously. If vaccines are not administered simultaneously, there are a few situations when a waiting interval is recommended. These include the non-simultaneous administration of MMR and yellow fever vaccines, and when individual antigens of MMR are administered separately. In these situations, doses of vaccine should be separated by 30 days. No data are available for the non-simultaneous administration of varicella vaccine and other live vaccines. Until additional information is obtained, it is reasonable to separate MMR, yellow fever, varicella vaccine by 30 days if not administered simultaneously. Q: If an infant needs 3 injections (for example, DTP, Hib, and hepatitis B vaccine), which ones should be given in the same leg? A: There is no absolute rule for placement of multiple intramuscular vaccines in a single limb. However, a reasonable approach would be to place the vaccine most likely to cause a local adverse event in one leg (DTP in this instance in one leg, and the two less reactive vaccines in the other leg). Q: After a blood transfusion, which vaccines are contraindicated, and for how long? A: Any vaccine containing live measles virus (e.g. MMR, MR, single antigen measles), and varicella vaccine should not be given for 6 months following a transfusion of whole blood. Inactivated vaccines may be given at any time before or after receipt of blood product. Q: If a child has recently received a dose of immune globulin, should I withhold any vaccines” If so, which ones, and for how long? A: Inactivated vaccines (DTP, DTaP, Hib, hepatitis B, inactivated polio) and oral polio vaccine may be given any time before or after a dose of immune globulin. Measles, mumps, rubella, and varicella vaccine viruses may be inactivated by passive antibodies in the immune globulin, so vaccination should be delayed. The length of the delay depends on the dose and route of administration of the immune globulin, and may range from 3 months to as long as 11 months. General Information about Immunization | 121

2021 NEOMED BOOK Q: What vaccines are contraindicated if a child’s mother or other household contact is pregnant? A: An attempt should be made to locate the missing record, or to verify what vaccines have been received. Ask the child’s mother to recheck at home. You can also try to locate a record by contacting the child’s previous doctor or clinic. If a record cannot be located after a reasonable search, the child should be considered unimmunized, and revaccinated as appropriate for the child’s age. Q: What vaccines may be given if the patient is taking steroid drug such as prednisone or hydrocortisone? A: If the patient is receiving immunosuppressive doses of steroids (i.e., more than 2 mg/kg/day or more than 20 mg of prednisone per day), live vaccines (MMR, OPV, varicella) should not be given. All vaccines may be administered if lower doses are being taken. Examples of non-immunosuppressive doses of steroids include inhalers, topical preparations, short rapidly-tapering courses, and alternate day schedules. Q: Are any vaccines contraindicated if a household contact is immunosuppressed from cancer treatment? A: Oral polio vaccine should not be given if a household contact is immunosuppressed. Other live ` vaccines (MMR and varicella) may be given as usual. Q: What vaccines are recommended for children infected with human immunosufficiency virus (HIV)? Are there different recommendations for symptomatic and asymptomatic patients? A: All routine inactivated vaccines are recommended for children with either symptomatic or asymptomatic HIV infection. These include diphtheria and tetanus toxoids, whole cell or acellular pertussis vaccine, Haemophilus influenzae type b conjugate vaccine, and hepatitis B vaccine. Children 6 months of age and older should receive influenza vaccine, and children 2 years of age and older should receive pneumococcal vaccine. Measles- mumps-rubella (MMR) vaccine is recommended for children with asymptomatic infection, and should be considered for chil dren with symptomatic infection. Oral polio vaccine is contraindicated in children with either symptomatic or HIV asymptomatic infection; inactivated polio vaccine should be used. Varicella vaccine is contraindicated in children with either symptomatic or asymptomatic infection. More information on the use of vaccines in persons with immunodeficiency, including HIV, can be found in the ACIP statement (MMWR 1993; 42 (RR 4): 1-18). Q: What vaccines can a child with severe combined immunodeficiency syndrome (SCIDS) receive? A: Children with SCIDS may be given inactivated vaccines (i.e. DTP, Hib, Hepatitis B). They should not be given live vaccines (MMR, oral polio, and varicella). Inactivated polio vaccine should be substituted for oral polio vaccine. Q: Some doctors do not vaccinate children with colds, ear infections and other minorillnesses. Are minor illnesses a contraindication to vaccination? A: The ACIP and the American Academy of Pediatrics recommend that children with minor illnesses, with or without low-grade fever should be vaccinated. Minor illness would include upper respiratory infections, most cases of otitis media, colds and diarrhea. There is no consistent evidence that these minor illnesses interfere with response to the vaccine, or increase adverse events. Children with more serious illness should be vaccinated as soon as the concur- rent illness resolves. 122 | General Information about Immunization

Q: Some doctors administer half doses of vaccine. How should I count these partial doses? A. Only full doses of vaccine should ever be administered. Any vaccination using less than the full dose recommended by the manufacturer should not be counted, and the person should be re-vaccinated according to age. Q: What length of needle is recommended for subcutaneous and intramuscular vaccines given to children and adults? A: In both children and adults, subcutaneous injections (MMR, varicella, IPV) should be given with a 5/8 to ¾ inch, 23 to 25 gauge needle. For intramuscular injections in infants and children, a minimum needle length of 7/8-inch should be used for anterolateral thigh injections, and a minimum of 5/8 inch for deltoid intramuscular injections is recommended. For adults, a 1 to 1-1/2 inch needle is recommended. General Information about Immunization | 123

2021 NEOMED BOOK Chapter 19 MINISTRY OF HEALTH (KINGDOM OF SAUDI ARABIA) RECOMMENDED SCHEDULE FOR IMMUNIZATION OF INFANTS AND CHILDREN 124

RECOMMENDED AGE VACCINE At 1 month (post-natal and medi- Hep B cally or clinically stable otherwise IPV, DTaP, Hep B, Hib, PCV (Prevenar), *Rota wait until stable) IPV, DTaP, Hep B, Hib,PCV (Prevenar, 2 months from first dose), *Rota 2 months (1 month from 1st Hep B dose) 4 months (2 months from second Hep B dose) 6 months BCG , IPV, DTaP, Hep B, Hib, PCV (Prevenar, 2 months from second dose) 9 months Measles (monovalent), MCV4 12 months) 18 months MMR, MCV4, PCV (Prevenar, 6 months from 3rd dose), OPV 24 months OPV, DTaP, Hib, Hep A, MMR, Varicella 4 – 6 years Hep A 11 years OPV, DTaP, MMR, Varicella 12 years Tdap, HPV (females only) 18 years HPV (females only) MCV4 • BCG - Bacillus Calmette Guerin vaccine • Hib - Haemophilus influenzae type b conjugate • Hep B - Hepatitis B vaccine vaccine • OPV - Oral Polio vaccine • IPV - Inactivated Polio vaccine • MMR - Measles, mumps and rubella vaccine • DTaP - Diphtheria and tetanus toxoids and acellular • Hep A - Hepatitis A vaccine • *Rota - Oral rotavirus vaccine pertussis vaccine • TdaP – Tetanus toxoids and diphtheria and acellular (Rotarix=2 doses, RotaTeq=3 doses) (Not to be given to inpatients). Should not be Initi pertussis vaccine ated for infants age 15 weeks or older. • MCV4 - Quadrivalent meningococcal conjugate vaccine • PCV - Pneumococcal polysaccharide conjugate vaccine Note: MMR, Measles, and Varicella are SubQ. Polio and Rota are Oral. The rest are IM. Ministry of Health’s Recommended Schedule for Immunization of Infants & Children | 125

2021 NEOMED BOOK Chapter 20 GUIDELINES FOR IMMUNIZATION OF PRETERM INFANTS AT KAMC-RIYADH 126

1. If mother is Hepatitis B surface antigen negative, then give Hepatitis B vaccine at chronological or post-natal age of 30 days provided that the infant is medically or clinically stable. Subsequent doses can be given at 4 to 8 weeks from the first dose and 6 months from the first dose. 2. If mother is Hepatitis B surface antigen positive (HbsAg+ve), administer Hepatitis B immuno globulin immediately after birth, irrespective of the baby’s weight. In addition, give Hepatitis B vaccine as soon as possible, preferably within 12 hours after birth. Administer the second and third doses of Hepatitis B vaccine at 4 weeks and 6 months IMMUNIZATION SCHEDULE FOR PRE-TERM INFANTS AT KAMC-R RECOMMENDED AGE VACCINE At 1 month (post-natal and medi- cally or clinically stable otherwise Hep B wait until stable) IPV, DTaP, Hep B, Hib, PCV (Prevenar), *Rota 2 months IPV, DTaP, Hep B, Hib,PCV (Prevenar, 2 months from first dose), *Rota (1 month from 1st Hep B dose) 4 months BCG , IPV, DTaP, Hep B, Hib, PCV (Prevenar, 2 months from second dose) Measles (monovalent), MCV4 (2 months from second Hep B dose) 6 months MMR, MCV4, PCV (Prevenar, 6 months from 3rd dose), OPV 9 months OPV, DTaP, Hib, Hep A, MMR, Varicella 12 months) Hep A 18 months OPV, DTaP, MMR, Varicella 24 months Tdap, HPV (females only) 4 – 6 years HPV (females only) 11 years MCV4 12 years 18 years • BCG - Bacillus Calmette Guerin vaccine • Hib - Haemophilus influenzae type b conjugate • Hep B - Hepatitis B vaccine vaccine • OPV - Oral Polio vaccine • IPV - Inactivated Polio vaccine • MMR - Measles, mumps and rubella vaccine • DTaP - Diphtheria and tetanus toxoids and acellular • Hep A - Hepatitis A vaccine • *Rota - Oral rotavirus vaccine pertussis vaccine • TdaP – Tetanus toxoids and diphtheria and acellular (Rotarix=2 doses, RotaTeq=3 doses) (Not to be given to inpatients). Should not be Initi pertussis vaccine ated for infants age 15 weeks or older. • MCV4 - Quadrivalent meningococcal conjugate vaccine • PCV - Pneumococcal polysaccharide conjugate vaccine Note: MMR, Measles, and Varicella are SubQ. Polio and Rota are Oral. The rest are IM. Guidelines for Immunization of Preterm Infants at KAMC-Riyadh, MNGHA | 127

2021 NEOMED BOOK Chapter 21 GUIDELINES IN TREATING NEONATES WITH HEPATITIS B MOTHERS (Positive/Unknown/Negative) 128

MOTHER STATUS DESCRIPTION NEONATAL MANAGEMENT Maternal HBsAg-positive HepB vaccine and HBIG within 12 hours of birth, administered at different injection sites (e.g, separate limbs) HBsAg-positive • Infants with birth weights (≥2000 g) should receive the first dose of: - HepB vaccine + HBIG within 12 hours of birth - HepB vaccine continue vaccine series as per schedule, (3 vaccine doses) don’t count birth dose. • Infants with birth weights (<2000 g) should receive both HepB vaccine and HBIG, within 12 hours of birth (administered at different injection sites (e.g., separate limbs). - HepB vaccine again at one month of age. THEN, continue with vaccine doses series as per schedule (4 vaccine doses) don’t count birth dose. Unknown Infants born to If the mother’s HBsAg status cannot be determined: (HBsAg test result women for whom • Infants with birth weights (≥2000 g) should receive the first during pregnancy is dose of: HBsAg testing unavailable) results during - HepB vaccine within 12 hours of birth pregnancy are not - HBIG as soon as possible but no later than age seven days available but other - HepB vaccine continue vaccine series as per schedule, (3 evidence sugges- tive of maternal vaccine doses) don’t count birth dose. HBV infection If the mother’s HBsAg status cannot be determined within 12 exists (e.g., pres- hours of birth: ence of HBV DNA, • Infants (<2000 g) should receive both HepB vaccine and HBIG, HBeAg-positive. within 12 hours of birth (administered at different injection sites (e.g., separate limbs). - HepB vaccine again at one month of age. THEN continue with vaccine doses series as per schedule (4 vaccine doses) don’t count birth dose. HBsAg-Negative HBsAg-Negative • Infants with birth weights (≥2000 g) - HepB vaccine at birth, - HepB vaccine continue vaccine series as per schedule, (3 vaccine doses, don’t count birth dose) • Infants with birth weights (<2000 g) - HepB vaccine at one month of age - HepB vaccine continue vaccine series as per schedule, (3 vaccine doses) don’t count one month dose. When an HBsAg positive mother arrives in our lab or for caesarean section, labour ward must inform the on-call neonatal team Guidelines in Treating Neonates with Hepatitis B Mothers | 129

2021 NEOMED BOOK Doses of HBIG: • The acceptable dose to protect the babies as prophylaxis is 100 IU / dose • Caution: brands have different doses and may be subjected to change based on availability: HepaGam B Fovepta 200 IU P Behring Each vial contain >312 IU/mL of Contain 200 IU / 0.4 mL of An- Each vial contain at least 200 IU Anti-HBs. ti-HBs. / 1mL Dose: 0.5 mL (156 IU) Dose: 0.4 mL (200 IU) Dose: 0.5 mL (100 IU) Intramuscular (IM) Subcutaneous or IM Intramuscular (IM) • Monitor infants born <28 weeks’ gestation for 72 hrs after HBIG How Use 2 separate injection sites for hepatitis B vaccine and HBIG, in anterolateral thighs • (not buttocks) • Give hepatitis B vaccine IM, except in bleeding disorder where it may be given deep subcutaneously 130 | Guidelines in Treating Neonates with Hepatitis B Mothers

Chapter 22 USE OF IMMUNOGLOBULIN (IVIG) AND HBIG IN NEONATES 131

2021 NEOMED BOOK I. Alert - If the patient has ANY adverse reaction, stop infusion and call the Physician IMMEDIATELY. - Privigen 10% are available for Pediatric/ Neonatal use. Other preparations such as Intratect 5% for adult and can be used in Pediatric if Privigen 10% is not available. II. Indication a. Indication can be prescribed by Neonatologist: • Hemolytic disease of the newborn (HDN) (Isoimmunization or ABO Incompatibility) (Immunoglobulins seem to block Fc receptors on macrophages, which reduces the breakdown of antibody coated erythrocytes and lowers the circulating unconjugated bilirubin levels) b. Other Indications need Approval of Hematologist or Immunologist before use as below list: - Neonatal Alloimmune Thrombocytopenia (NAIT) - Immune thrombocytopenic purpura - Primary immunodeficiency diseases - Secondary hypogammaglobulinaemia - Gestational Alloimmune liver disease (GALD) - Severe neonatal enterovirus infection including myocarditis or hepatitis - Neonatal myasthenia gravis III. Trade Name - Privigen 10% Contains 5 g of immunoglobulin G in 50 mL (for pediatrics and neonates) - Intratect 5% Contains 2.5 g of immunoglobulin G in 50 mL (only for adults, or when Privigen is unavailable) IV. Method of administration • Privigen 10% Infuse at: _______ mL/hr for 30 min (0.6 mL/kg/hr; maximum 15 mL/hr); if tolerated _______ mL/hr for 30 min (1.2 mL/kg/hr; maximum 24 mL/hr); if tolerated _______ mL/hr for 30 min (2.4 mL/kg/hr; maximum 42 mL/hr); if tolerated _______ mL/hr for 30 min till finished (4.8 mL/kg/hr; maximum 90 mL/hr); • Intratect 5% an initial rate 1.4 mL/kg/h for 30 minutes must not be exceeded. If well tolerated, the rate of administration may gradually be increased to a maximum of 1.9 mL/kg/h for the remainder of the infusion (over 8 -10 hours). V. Ordering - To order in the BestCare System, the physician must write “Privigen® 10%”, not immunoglobulin. To be checked by two Registered Nurses. • Requires a surgically (medical aseptic) clean procedure. • Given via intravenous cannula, central line, long line or port. • Administered by infusion pump. • A blood filter is not required, but may be used. • Sodium chloride 0.9% may be used as a flush at the end of the infusion 132 | Use of Immunoglubulin and HBIG in Neonates

V. Ordering - To order in the BestCare System, the physician must write “Privigen® 10%”, not immunoglobulin. To be checked by two Registered Nurses. • Requires a surgically (medical aseptic) clean procedure. • Given via intravenous cannula, central line, long line or port. • Administered by infusion pump. • A blood filter is not required, but may be used. • Sodium chloride 0.9% may be used as a flush at the end of the infusion VI. Dosage / Interval - Hemolytic disease of the newborn (HDN) (Isoimmunisation or ABO Incompatiblilty) 1 g/kg (range 0.5-1 g/kg) IV. Dose may be repeated in 12-24 hours if required. - Neonatal alloimmune thrombocytopenia (NAIT), Immune thrombocytopenic purpura (ITP): 1 g/kg IV. Repeat if required. - Immunodeficiency: 0.4 g/kg IV (dose should be based on number of infections and trough serum IgG - Neonatal myasthenia gravis: 1g/kg IV daily for 2 days (total dose: 2 g/kg). - Severe enterovirus infection/myocarditis or hepatitis: 1g/kg IV (up to 2.5 g/kg) as a single dose within 3 days of onset. - Sepsis/infection (prevention or treatment) - not recommended - Neonatal haemochromatosis: 1-2 g/kg/day IV following exchange transfusion in the first 7 days and then 1 g/kg weekly, as required - Enterovirus infection: 2.5 g/kg/day VII. Monitoring • Vital sign monitoring of temperature, heart rate, respiratory rate and blood pressure to be recorded before commencement of infusion. - If the patient is unwell or there are any concerns particularly regarding the baseline observations, the Physician should be contacted before the infusion commences. • Vital signs (temperature, heart rate, respiratory rate, blood pressure, etc.) should then be checked and recorded: - Within 15 minutes after the start of the infusion; - Hourly during the infusion; At the end of the infusion. VIII. Drug Interactions Concurrent use of immunoglobulin and live virus vaccines may result in interference with the immune response to the live vaccine. - Rotavirus vaccine may be administered at any time before, after or concurrently with any blood product, including antibody-containing products. - BCG vaccine can be given at any time before or after administration of immunoglobulin or any anti body-containing blood product. - Following the receipt of IVIG, an interval of 8-10 months should elapse before vaccination with an MMR, MMRV or Varicella vaccine. Use of Immunoglubulin and HBIG in Neonates | 133

2021 NEOMED BOOK IX. Adverse Reactions If adverse reactions occur, the first response should be to stop the infusion, then notify Physician. • Severe reactions are uncommon especially in neonates. In older patients are most likely to occur during the first infusion, but may occur subsequently. More common reactions are: flushing, fever, headache, pallor, shivering and tachycardia. HBIG USE IN NEONATE USES: FOR TERM OR PRETERM INFANTS OF A MOTHER with HBsAg-positive or unknown. When: should be given within 12 hours for - Preterm infant if the mother have HBsAg-positive; or Unknown. and - For Term infant if the mother HBsAg-Unknown and HBsAg status cannot be determined within 12 hours HBIG can be delayed but should be given not later than 7 days. Doses of HBIG: • The acceptable dose to protect the babies as prophylaxis is 100 IU / dose • Caution: brands have different doses and may be subjected to change based on availability: HepaGam B Fovepta 200 IU P Behring Each vial contain >312 IU/mL of Contain 200 IU / 0.4 mL of An- Each vial contain at least 200 IU Anti-HBs. ti-HBs. / 1mL Dose: 0.5 mL (156 IU) Dose: 0.4 mL (200 IU) Dose: 0.5 mL (100 IU) Intramuscular (IM) Subcutaneous or IM Intramuscular (IM) • Monitor infants born <28 weeks’ gestation for 72 hrs after HBIG How • Use 2 separate injection sites for hepatitis B vaccine and HBIG, in anterolateral thighs (not buttocks) • Give hepatitis B vaccine IM, except in bleeding disorder where it may be given deep subcutaneously ***References: 1. Louis D et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2014;99:F325-31. 2. Zwiers C et al. Immunoglobulin for alloimmune hemolytic disease in neonates. Cochrane Database Syst Rev. 2018 Mar 3. immunoglobulins in the management of neonatal hyperbilirubinemia due to ABO incompatibility: a meta-analysis]. Arch Pediatr. 2014;21:976- 83. 4. AAP Subcommittee on H. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297- 316. 5. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2015 6. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2013 7. O’Carroll P, Bertorini TE, Jacob G, Mitchell CW, Graff J. Transient neonatal myasthenia gravis in a baby born to a mother with new-onset an- ti-MuSK-mediated myasthenia gravis. J. 2009;11:69-71. 8. Bassan H, et al. High-dose intravenous immunoglobulin in transient neonatal myasthenia gravis. Pediatr Neurol. 1998;18:181-3. 9. Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. J Clin Virol. 2015;64:92-6. 10. Baruteau J et al. Transient neonatal liver disease after maternal antenatal intravenous IG infusions in gestational alloimmune liver disease associ- ated with neonatal haemochromatosis. Journal of Pediatric Gastroenterology and Nutrition. 2014;59:629-35. 11. Taylor SA et al. The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality. Journal of Pediatrics. 2018;196:123-8. 12. RedBOOK, 2018 13. IVIG Pediatric Taskforce Meeting, 24 April 2017, King Abdullah Specialized Children’s Hospital, MNGHA, Riyadh, K.S.A 134 | Use of Immunoglubulin and HBIG in Neonates

Chapter 23 ROTAVIRUS 135

2021 NEOMED BOOK General Information about Immunization • Why is it important to vaccinate against rotavirus? Isn’t the disease benign? Before rotavirus vaccines were available, rotavirus was the most common cause of severe gas troenteritis in infants and young children in the United States and worldwide. Almost all children were infected by age 5 years. Before vaccine was introduced in the United States, rotavirus was responsible each year for about 3 million episodes of gastroenteritis, 410,000 physician visits, 205,000–272,000 emergency department visits, 55,000–70,000 hospitalizations, and between 20 and 60 deaths among children younger than age 5 years. • Is it possible for adults to contract rotavirus? What are the symptoms in adults? Yes. Rotavirus infection of adults is usually asymptomatic but may cause diarrheal illness. Outbreaks of diarrheal illness caused by rotavirus have been reported, especially among elderly persons living in retirement communities. For more information on this issue see MMWR 2011; 60:1456. • What are the recommendations for use of rotavirus vaccines? Two rotavirus vaccines are available in the United States. RotaTeq (Merck) is recommended for rou tine oral administration for all infants as a 3-dose series. The usual schedule is at ages 2, 4, and 6 months. Rotarix (GlaxoSmithKline) is recommended as a 2-dose series at ages 2 and 4 months. ACIP recommendations for use of rotavirus vaccines are available at www.cdc.gov/mmwr/preview/ mmwrhtml/rr5802a1.htm. The minimum age for the first dose is 6 weeks and the maximum age for dose #1 is 14 weeks 6 days. Vaccination should not be initiated for infants age 15 weeks 0 days or older because there are insuf ficient data on the safety of dose #1 in older infants. The minimum interval between doses of rotavi rus vaccine is 4 weeks. The maximum age for the last dose of rotavirus vaccine is 8 months and 0 days. • How do the two rotavirus vaccines differ? The two rotavirus vaccine products differ in composition and schedule of administration. RotaTeq (RV5) contains five reassortant rotaviruses developed from human and bovine parent rotavirus strains; 3 doses are given in the series. Rotarix (RV1) contains an attenuated human rotavirus strain; 2 doses are given in the series. • Can RotaTeq (RV5; Merck) and Rotarix (RV1; GlaxoSmithKline) vaccines be used interchange ably? If so, what schedule should we follow? ACIP recommends that the rotavirus vaccine series be completed with the same product whenever possible. However, vaccination should not be deferred because the product used for a previous dose is not available or is unknown. In these situations, the provider should continue or complete the series with the product available. If any dose in the series was RV5, or the vaccine product is unknown for any dose in the series, a total of 3 doses of rotavirus vaccine should be administered. The minimum interval between doses of rotavirus vaccine is 4 weeks. All doses should be adminis tered by age 8 months and 0 days. • If we don’t know which rotavirus vaccine an infant previously received, how should we com plete the schedule? If the product used for a previous dose is unknown, and the infant is at an age when the vaccine can still be given, give a total of 3 doses of rotavirus vaccine. All doses should be administered by age 8 months and 0 days. 136

• If the first dose of rotavirus vaccine is inadvertently given to a child age 15 weeks 0 days or older, should the series be continued? Infants for whom the first dose of rotavirus vaccine was inadvertently administered at age 15 weeks or older should receive the remaining doses of the series at the routinely recommended intervals. Timing of the first dose should not affect the safety and efficacy of the remaining doses. Rotavirus vaccine should not be given after age 8 months 0 days even if the series is incomplete. • Our experience has been that many babies who receive the oral rotavirus vaccine spit a lot of it out. We know not to give them more. But how can we be sure that the little they ingest is enough? Try to follow general guidelines for oral administration of liquid vaccines. First, give this vaccine at the beginning of the office visit, while the baby is still happy, and before you administer injections or perform other procedures. Second, make every effort to aim the dropper containing the vaccine down one side and toward the back of the child’s mouth. Don’t put the dropper so far back that you gag the child. You may find the following information from the RotaTeq manufacturer helpful: www. merckvaccines.com/Products/RotaTeq/Pages/dosageandadministration. You can also find a pictorial description of both reconstitution and administration of Rotarix in the package insert at http:// us.gsk.com/products/assets/us_rotarix.pdf. • Can rotavirus vaccine be given via G-Tube? If so, is it okay to flush with normal saline or sterile water? The manufacturer has not addressed this issue but CDC considers administration of rotavirus vac cine via gastrostomy tube to be acceptable practice. There should be no problem flushing the tube after vaccine has been administered. • A child received the first rotavirus vaccine and after a while he got the disease (laboratory confirmed). Should we continue the vaccine? ACIP recommends that infants who have had rotavirus gastroenteritis before receiving the full series of rotavirus vaccination should still start or complete the schedule according to the age and interval recommendations because the initial rotavirus infection might provide only partial protection against subsequent rotavirus disease. • Should we warn parents/guardians to wash their hands after diaper changes, which they should be doing anyway, after the baby has received rotavirus vaccine? Yes. Rotavirus vaccine virus is shed during the first weeks after administration of rotavirus vaccine. Handwashing after diaper changing is always recommended. • Which infants should not receive rotavirus vaccine? Do not give rotavirus vaccine to an infant who has a history of a severe allergic reaction (for exam ple, anaphylaxis) after a previous dose of rotavirus vaccine or to a vaccine component. The oral applicator for Rotarix contains latex rubber so infants with a severe (anaphylactic) allergy to latex should not be given Rotarix; the RotaTeq dosing tube is latex-free. Rotavirus vaccine is contraindi cated in infants diagnosed with the rare disorder, severe combined immunodeficiency (SCID) and infants with a history of intussusception. Rotavirus | 137

2021 NEOMED BOOK • Can rotavirus vaccine be given to an infant who has an immunosuppressed household contact? Having an immunocompromised household contact is not usually a reason for delaying routine vaccination for others in the household. Rotavirus vaccine should be administered to susceptible household contacts and other close contacts of immunocompromised patients when indicated. All members of the household should wash their hands after changing the diaper of an infant. This minimizes rotavirus transmission from an infant who received rotavirus vaccine. Additional informa tion on this topic can be found in the ACIP General Recommendations on Immunization, available at www.cdc.gov/mmwr/pdf/rr/rr6002.pdf. • Can preterm infants receive rotavirus vaccine? ACIP supports vaccination of preterm infants according to the same schedule and precautions as full-term infants and under the following conditions: if the infant’s chronological age meets the age requirements for rotavirus vaccine (for example, age 6 weeks to 14 weeks 6 days for dose #1), the infant is clinically stable, and the vaccine is administered at the time of discharge from the hospital or after discharge from the hospital. • Have these vaccines (RotaTeq or Rotarix) been associated with intussusception? Large prelicensure clinical trials of both RotaTeq and Rotarix did not find an increased risk for intussusception among vaccine recipients. A large postlicensure study of more than 1.2 million rotavirus vaccine recipients found a very small increased risk of intussusception (1 to 1.5 additional cases of intussusception per 100,000 vaccinated infants) in the 7 to 21 days following the first dose. No increased risk of intussusception was found after the second or third doses. CDC and the Food and Drug Administration (FDA) continue to believe that the benefits of rotavirus vacci nation outweigh the risks associated with vaccination and that routine vaccination of infants should continue. Additional information on this topic can be found on the FDA website at www.fda.gov/ BiologicsBloodVaccines/SafetyAvailability/ucm356758.htm. • According to the package inserts the maximum age for a dose of RotaTeq is 32 weeks and the maximum age for Rotarix is 24 weeks. According to ACIP recommendations the maximum age for a dose of rotavirus vaccine is 8 months 0 days. Eight months 0 days is older than age 24 weeks and may be older than age 32 weeks. Should I follow the package labels or the ACIP recommendation? ACIP recommendations and package inserts do not always match. Occasionally, ACIP may use different data to formulate its recommendations, or try to add flexibility to its recommendations (as was the case in this situation), which results in a recommendation different than the package insert. Published recommendations of national advisory groups (such as ACIP or AAP’s Committee on Infectious Diseases) should be considered equally as authoritative as those on the package insert. You should consider 8 months 0 days as the maximum age for a dose of rotavirus vaccine. • What are the storage and handling guidelines for rotavirus vaccine (RotaTeq and Rotarix)? Both vaccines should be stored at refrigerator temperature and protected from light. Do not administer the vaccine if it has been frozen or exposed to freezing temperatures. Reviewed and revised August 2013 138

Chapter 24 TREATMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN CHILDHOOD 139

2021 NEOMED BOOK A. Definition of Pneumonia An acute illness that is associated with fever (temperature greater than 380C) and cough and evidence of lower respiratory tract symptoms and signs like nasal flaring, tachypnea, grunting, retractions, crackles, decreased breath sounds and/or evidence of pulmonary infiltrate on chest radiograph. B. Common Microbial Causes of Community-Acquired Pneumonia in Childhood Based on Age AGE GROUPING PREVALENT PATHOGENS Birth to 20 days Group B streptococci Gram-negative enteric bacteria Cytomegalovirus Listeria monocytogenes 3 weeks to 3 months Chlamydia trachomatis Respiratory syncytial virus (RSV) Parainfluenza virus 3 Streptococcus pneumoniae Bordetella pertussis Staphylococcus aureus C. Suggested Antimicrobial Treatments for Community-Acquired Pneumonia in Infants and Children Age Grouping Outpatient Inpatient, without Lo- Inpatient, with signs bar or lobular infiltrate, of sepsis, alveolar pleural effusion or both infiltrate, large pleural effusion, or all three Birth to 20 days Admit patient Administer ampicillin Administer intravenous and gentamicin, OR ampicillin and gentamicin, cefotaxime OR cefotaxime.* 3 weeks to If patient is afebrile, give If patient is afebrile, Administer intravenous 3 months oral erythromycin 30 – 40 administer intravenous Cefotaxime 200mg/kg/ erythromycin 40mg/kg/ mg/kg/day Q6H or oral day Q6H. In infants < 6 day azithromycin 1 dose of weeks of age, consider Q8H*. 10mg/kg on day 1, then treatment with intrave- 5mg/kg/day on days 2-5. nous azithromycin 5mg/ Admit patient if fever or kg/day Q12H (because of reports of hypertrophic hypoxia is present. pyloric stenosis in infants who received erythromy- cin). If patient is febrile, add Cefotaxime 200mg/ kg/day IV Q8H. * Staphylococcal pneumonia is unusual, however, if cultures of blood or pleural fluid grow Staphylococcus aureus or, in other exceptional circumstances, cloxacillin, or in areas where methicillin resistant Staph. Aureus (MRSA) is a reasonable possibility, vancomycin should be added. In general, duration of treatment should be 10 to 14 days. ***References: 1. N Engl J Med 2002, Vol. 346 No. 6: 429 – 437. 140 | Treatment of Community - Acquired Pneumonia in Childhood

Chapter 25 GUIDELINES FOR THE TREATMENT OF BRUCELLOSIS 141

2021 NEOMED BOOK A. For Children less than 8 years of age TYPE OF BRUCELLOSIS ANTIMICROBIAL AGENT DURATION Uncomplicated: Rifampicin + TMP/SMX 6 weeks OR 6 weeks acute brucellosis, brucella bactere- mia, brucella arthritis, or brucella Rifampicin + Gentamycin* *Gentamicin for 7 days osteomyelitis. 3 to 12 months Complicated: Rifampicin + TMP/SMX + Cipro- Neurobrucellosis, or Brucella floxacin endocarditis. Gentamicin for the initial 2 weeks For Neurobrucellosis: Ceftriaxone has shown some efficacy and it is usually used in the initial therapy for 2-4 weeks B. Recommendations for the treatment of brucellosis in special group of patients: 1. Patients with spondylitis should be treated with doxycycline plus rifampicin plus gentamicin for the initial 2 – 3 weeks followed by 6 weeks of rifampicin and doxycycline (doses same as recommended above). 2. Patients with meningoencephalitis may need doxycycline plus either rifampicin alone or rifampicin and co-trimoxazole (doses same as recommended above). To control the inflammatory process, a brief course of adjunctive corticosteroid therapy has been used, however, studies are limited. 3. Patients with endocarditis require aggressive therapy with gentamicin plus doxycycline plus rifampicin plus cotrimoxazole for at least 4 weeks, followed by at least 2 to 3 active agents (without aminoglyco sides) for another 8 – 12 weeks. Drug Dosage Rifampicin 10 - 20 mg/kg /day divided into two doses (Max. 600mg/day) PO TMP/SMX 10 mg/kg per day TMP (Max. 480 mg/day) and 50 mg/kg per day SMX (Max. 2.4 g/day) divided into two doses PO Gentamicin 5-7.5 mg/kg/day single dose or divided to three doses IV or IM (Please refer to gentamicin dosing for neonates) Doxycycline 5 mg/kg/day in two divided doses (Max. 200 mg/day) PO Only for children more than 8 years of age Streptomycin 15 mg/kg once daily (Max. 1 g/day) IV or IM Ciprofloxacin 30 mg/kg/day in two divided doses (Max. 1.5 g) ***References: 1. HPA Centre for Infections. Version 1.6 18 September, 2009 2. http://emedicine .medscape.com/article/213430-print. Accessed: 8 December 2009. 3. A. Alshaalan, M., 2014. Brucellosis In Children: Prevention, Diagnosis And Management Guidelines For General Pediatricians Endorsed By The Saudi Pediatric Infectious Diseases Society (SPIDS). [online] Spids.org.sa. 142 | Guideline for the Treatment of Brucellosis

Chapter 26 GLUCOCORTICOIDS 143

2021 NEOMED BOOK INDICATIONS FOR WITHDRAWING GLUCOCORTICOIDS: It is helpful to briefly review the indications for glucocorticoid withdrawal before discussing the different glucocorticoids withdrawal regimens. These indications include the following: • When the maximum desired therapeutic benefit has been obtained • When inadequate therapeutic benefit has been obtained after an adequate trial • When side effects, such as lumbar spine osteoporosis or hypertension, become serious or uncontrollable with medication In addition, there are two complications that require immediate cessation, or reduction to a physiological dose, of glucocorticoids not tapering: • Steroid-induced acute psychosis, which is often unresponsive to antipsychotic medications • Herpes virus-induced corneal ulceration, which can rapidly lead to perforation of the cornea and possibly permanent blindness. If immediate cessation is not possible, discontinuing steroids as soon as possible is strongly advised. Com parison of commonly used glucocorticoid preparations Drug Approximate Anti- Sodium retaining Biologic equivalent dose inflammatory potency half-life (hours) (mg) potency Hydrocortisone 20 1 1 8 – 12 (cortisol) Cortisone 25 0.8 0.8 8 – 12 Prednisone 5 4 0.8 18 – 36 Prednisolone 5 4 0.8 18 – 36 Methylprednisolone 4 5 0 18 – 36 Betamethasone 0.6 – 0.75 25 0 36 – 54 Dexamethasone 0.75 25 0 36 – 54 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SUPPRESSION Administration of exogenous glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis (HPA). Abrupt cessation, or too rapid withdrawal, or glucocorticoids in such patients may cause symptoms of adrenal insufficiency. Patients exposed to glucocorticoids can be classified and managed as follows: • Patients suspected of having HPA suppression who are otherwise candidates for glucocorticoid with drawal can be cautiously weaned. • Patients determined to have a low risk of clinically significant HPA suppression may have glucocorticoids weaned as dictated by control of disease activity rather than by concern for adrenal insufficiency. • Patients for whom the likelihood of HPA suppression is uncertain, but for whom the consequences of developing acute adrenal insufficiency are serious (e.g. the patient who is about to undergo major surgery), may benefit from testing of the HPA functional reserve to guide further therapy. 144

HPA suppression likely Patients who have received glucocorticoids who meet the following criteria are presumed to have HPA suppression: • Anyone who has received a glucocorticoid dose comparable to more than 20 mg of prednisone a day for more than two weeks. • Anyone who has received an evening/bedtime dose of ≥ 5 prednisone for more than a few weeks. • Any patient who has a Cushingoid appearance HPA suppression unlikely Patients who meet one of the following criteria regarding steroid use are less likely to have a suppressed HPA and therefore may have glucocorticoids weaned as is appropriate for the underlying disease. • A patient who has received any dose of glucocorticoid for less than two weeks • Patients treated with alternative-day glucocorticoid therapy Intermediate/uncertain risk of HPA suppression- Patients who have an intermediate or uncertain risk of HPA suppression include those with the following characteristics: • Those taking 10 to 20 mg of prednisone per day for more than three weeks. • Any patient who has taken less than 10 mg of prednisone or its equivalent per day for more than a few weeks, providing that it is not taken as a single bedtime dose. If withdrawal from glucocorticoids is otherwise indicated, gradual reduction in dose is appropriate for these patients with an intermediate or uncertain risk of HPA suppression. Such patients do not need to be tested for HPA functional reserve unless abrupt discontinuation is being considered or the patient is facing an acute stress such as surgery. In the latter case, one can give stress doses of glucocorticoids as per the guide lines below or, if time permits, test for the responsiveness of the adrenal with an ACTH (cosyntropin) stimu lation test. Pediatric Stress-dose steroid recommendations A. Situations in which it is indicated: B. Stress-dose steroid recommendations: 1. Less than 10 days after a burst (5 days) of steroids • Refer to an endocrinologist. 2. Less than 30 days after completion of the last of • Doses usually ranges from 50 to 100 mg/m2 IV multiple short courses of steroids. hydrocortisone for major surgeries. And up to 50 3. Less than 1 year after completing a prolonged mg/m2 for minor surgeries has been used course for steroids (> 3 months). • In neonates, a bolus of 2mg/kg hydrocortisone 4. Previously treated with fluticasone over 500 mcg/ has shown effectiveness for cardiac operations. day. 5. Daily parenteral or enteral steroids for more than 3 weeks. 6. Impaired response to cosyntropin stimulation test In a suspected patient. RECOMMENDED TAPERING REGIMEN Short-term glucocorticoid therapy (up to three weeks), even if a fairly high dose, can simply be stopped and need not be tapered. HPA suppression due to glucocorticoid use of this duration will not persist and is highly unlikely to have any clinical consequence. However, in a frail or dangerously ill patient, the clinician may elect to proceed more cautiously as noted below. Glucocorticoids | 145

2021 NEOMED BOOK In patients who have taken a glucocorticoid for a longer time, we suggest a regimen which is largely based upon experience and rests upon the following assumptions: • Factors of age, frailty, concomitant illnesses, dangerousness and likelihood of flare of underlying Illness, psychological factors, and duration of previous use of glucocorticoids are taken into account. • The disease is sufficiently stable so that tapering of the dose is appropriate. • The patient has received long-term steroid therapy, not recurrent “pulses” as might be used in asthma. • Most patients on a daily dose of 5 mg/day do not have to be tapered. The recommended regimen also assumes that repeated morning cortisol determinations are too expensive for routine use and that the appropriate end-points are the patient’s signs and symptoms. The goal of tapering is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency due to persistent HPA suppression. In general, the aim is to achieve a relatively stable decrement of 10 to 20 percent, while accommodating convenience and individual patient response The dose is tapered by: • 5-10 mg/day every one to two weeks at an initial dose above 40 mg of prednisone or equivalent per day. • 5 mg/day every one to two weeks to prednisone doses between 40 and 20 mg/day. • 2.5 mg/day every two to three weeks at prednisone does between 20 and 10 mg/day. • 1 mg/day every two to four weeks at prednisone doses between 10 and 5 mg/day. • 0.5 mg/day every two to four weeks at prednisone doses below 5 mg/day. This can be achieved by alternating daily doses, e.g. 5 mg on day one and 4 mg on day two. This regimen will generally prevent symptoms of cortisol deficiency. However, many patients with rheu matic diseases complain of recurrent symptoms of the underlying disease. In this setting it may be difficult to distinguish between mild symptoms of glucocorticoid withdrawal (i.e. arthralgia and myalgia or pseu dorheumatism) or recrudescence of the underlying rheumatic disease. If the symptoms are not major, try to wait 7 to 10 days, and use a non-steroidal anti-inflammatory drug or other analgesic. Resolution of symptoms during this period of time suggests pseudorheumatism. If the symptoms do not subside within this time frame, increase the prednisone dose by to to 15 percent (to the next convenient mg table regimen) and maintain that dose for two to four weeks. If the symptoms resolve, the above tapering regimen can be resumed, using two to four weeks between decrements rather than one to two weeks. Should this modest increase in dose not be sufficient to alleviate symptoms, double the prednisone dose. The disease flare is allowed to subside and the taper is reinstituted at a slower rate (e.g. once monthly) or at smaller decrements (e.g. one half of the original decrement). It should also be appreciated that incremental change is inappropriate if life-threatening flares occur (as in acute recurrence of lupus nephritis, severe hemolysis, acute polymyositis, or vasculltis). In these settings, a return to the original, highest dose of steroids should be instituted. Tapering which is slowed in rate or decrement can be undertaken after the flare subsides, but specific guidelines become both convoluted and impractical in the latter situations. 146

***References: 1. UpToDate. Glucocorticoids Withdrawal (2020). Retrieved 15 August 2020, from https://www.uptodate.com/contents/glucocorticoid- with- drawal?search=corticosteroids&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3 2. Hughes, H., & Kahl, L. (2018). The Harriet Lane handbook (21st ed., p. 271). 3. KIMBALL, C. P. (1971). Psychological Dependency on Steroids? Annals of Internal Medicine, 75(1), 111. doi:10.7326/0003-4819-75-1-111 4. Koch-Weser, J., & Byyny, R. L. (1976). Withdrawal from Glucocorticoid Therapy. New England Journal of Medicine, 295(1), 30– 32. doi:10.1056/ nejm197607012950107 5. Richter, B., Neises, G., & Clar, C. (2002). Glucocorticoid withdrawal schemes in chronic medical disorders. Endocrinology and Metabolism Clinics of North America, 31(3), 751–778. doi:10.1016/s0889-8529(02)00008-7 6. Ueda, N., Chihara, M., Kawaguchi, S., Niinomi, Y., Nonoda, T., Matsumoto, J., … Yasaki, T. (1988). Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome. The Journal of Pediatrics, 112(1), 122–126. doi:10.1016/s0022- 3476(88)80136-7 7. Axelrod, L. (2003). Perioperative management of patients treated with glucocorticoids. Endocrinology and Metabolism Clinics of North America, 32(2), 367–383. doi:10.1016/s0889-8529(03)00008-2 8. Livanou, T., Ferriman, D., & James, V. H. T. (1967). RECOVERY OF HYPOTHALAMO-PITUITARY-ADRENAL FUNCTION AFTER CORTICOSTEROID THER- APY. The Lancet, 290(7521), 856–859. doi:10.1016/s0140-6736(67)92592-5 9. Todd, G. R. G. (2002). Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Archives of Disease in Childhood, 87(6), 457–461. doi:10.1136/adc.87.6.457 10. Zöllner, E. W., Lombard, C., Galal, U., Hough, S., Irusen, E., & Weinberg, E. (2011). Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids – more common than expected? Journal of Pediatric Endocrinology and Metabolism, 24(7-8). doi:10.1515/jpem.2011.198 11. Chilkoti GT, Singh A, Mohta M, Saxena AK. Perioperative “stress dose” of corticosteroid: Pharmacological and clinical perspective. J Anaesthesiol Clin Pharmacol [serial online] 2019 [cited 2020 Aug 17];35:147-52. Available from: http://www.joacp.org/text.asp?2019/35/2/147/261289 12. Suominen, P. K., Keski-Nisula, J., Ojala, T., Rautiainen, P., Jahnukainen, T., Hästbacka, J., … Lapatto, R. (2017). Stress-Dose Corticosteroid Versus Placebo in Neonatal Cardiac Operations: A Randomized Controlled Trial. The Annals of Thoracic Surgery, 104(4), 1378– 1385.doi:10.1016/j. athoracsur.2017.01.111 13. Dixon, R. B., & Christy, N. P. (1980). On the various forms of corticosteroid withdrawal syndrome. The American Journal of Medicine, 68(2), 224– 230.doi:10.1016/0002-9343(80)90358-7 14. Joseph, R. M., Hunter, A. L., Ray, D. W., & Dixon, W. G. (2016). Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Seminars in Arthritis and Rheumatism, 46(1), 133–141.doi:10.1016/j.semarthrit.2016.03.001 Glucocorticoids | 147

2021 NEOMED BOOK Chapter 27 GUIDELINES FOR WARFARIN THERAPY FOR INR OF 2-3 IN PEDIATRICS 148

LOADING DOSE: Day #1: Usual loading dose: 0.2 mg/kg for one day Maximum initial dose limit: 10mg for one dose Consider not giving bolus dose in patients with poor liver function, congenital heart disease with heart failure in some post-operative cardiac patients, etc. NOTE: A loading dose of warfarin is not necessary in most cases, although it has been used in some treatment protocols. Day #2 – 7 Give once daily dose at 1800H, round dose off nearest 0.25 mg. Usual maintenance dose is about 0.1 mg/kg/day. INR STARTING MAINTENANCE DOSE 1.1 – 1.3 0.2 mg/kg 1.4 – 1.9 0.1 mg/kg 0.1 mg/kg 2–3 0.05 mg/kg 3.1 – 3.5 Hold until INR < 4 <3.5 then restart at 25% > 3.5 of loading dose LONG-TERM MAINTENANCE DOSAGE GUIDELINES Keep in mind that INR value reflects dosage given 2 days ago. INR STARTING MAINTENANCE DOSE 1.1 – 1.4 Increase dose by 20 % 1.5 – 1.9 Increase dose by 10% No change 2–3 Decrease dose by 10% 3.1 – 3.5 Hold until INR < 3.5, then restart at 20% less than > 3.5 the previous dose 3.6 – 4 or > 4 Hold until INR < 4, then restart at 20% less than previous dose. ***References: 1. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 10, 2020 Guidelines for Warfarin Therapy for INR of 2-3 in Pediatrics | 149