Adverse Drug Reactions in the Newborn

SAVITRI P. KUMAR, M.D.

Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

ABSTRACT Adverse drug reactions have been noted to occur in one of three new borns admitted to intensive care units. The factors associated with adverse drug reactions and the adverse reactions to commonly used medications in neonatal intensive care units are discussed. Methods of preventing or reducing these undesired effects are suggested.

Introduction Factors Implicated in Adverse Drug Reactions in Newborn Infants Adverse drug reactions (ADR) occur more frequently in sick neonates than in The vulnerability of the neonate to adult patients . 1 These undesirable and adverse drug reactions results from sev unintended effects of drugs administered eral factors: for therapeutic or diagnostic purposes have been noted to occur in 10 to 30 per (1) Increased Drug Exposure: The cent of infants in intensive care units , 3,25 neonate is exposed postnatally to a with 7.5 percent experiencing life-threat large number of drugs in addition ening reactions. 3 Studies of drug utiliza to those acquired transplacentally tion in an intensive care unit have shown and from the breast milk. that three-fourths of all infants admitted (2) Immaturity of Systems: The imma received between one to 26 drugs, with turity of the drug metabolizing and the average number of drugs used being eliminating systems, and the added six per baby. 2 strain of disease, can adversely Infants with ADR were noted to have affect pharmacokinetics, leading to significantly lower births weights and accumulation of drugs to toxic con gestational ages, with marked reductions centrations. 9 in such reactions observed in babies (3) Paucity of Pharmacologic Data: greater than 33 weeks. 3 Cardiovascular Many potent drugs are used in neo drugs, diuretics, antibiotics, and com nates, in spite of inadequacy of ponents of parenteral nutrition solutions pharmacologic data, leading to were the most commonly suspected adverse effects. a g e n ts . 1 The increased frequency and (4) Practice of Polypharmacy: The high fatality rate associated with ADR presence of multiple disorders make it a major health care problem in (e.g., RDS, PDA, apnea) in a single the neonatal period. infant, leading to the practice of 195 0091-7370/85/0500-0195 $01.50 © Institute for Clinical Science, Inc. 196 KUMAR

polypharmacy, increases the risk of commonly used compounds, kanamycin drug interactions. 3 and amikacin are the most cochleotoxic, (5) Medication Errors: Errors in drug followed by gentamicin and tobramycin. computation increase the risk of Vestibular toxicity follows a different medication errors in newborns, order: streptomycin is most toxic, fol leading to overdosage and ADR . 30 lowed by gentamicin, tobramycin, and amikacin. 4 Although several studies exist Adverse drug reactions may be classi evaluating the ototoxicity of aminogly fied as resulting from (a) overdosage or coside antibiotics, in the neonate, it is exaggeration of the desired pharmaco difficult to estimate accurately the true logic effect of the drug; (b) side effect or incidence of drug-induced ototoxicity undesired but known pharmacologic from various reports available. Estimates effect of the drug; (c) cytotoxic effect, derived from audiometric measurements e.g., liver necrosis or abnormal blood of cochlear function show extreme vari morphology, from the drug causing ability ranging from four to 15 percent. 13 unwanted morphologic changes in tis Eviatar and Eviatar demonstrated labo sues. These reactions may be severe or ratory evidence of vestibular dysfunction life-threatening, moderate requiring and delays of head and postural control therapy or prolonged hospitalization, or in eight of 43 infants tested between two mild with spontaneous resolution. The and five years. 12 Aminoglycoside neph purpose of this paper is to review the rotoxicity results from tubular damage adverse reactions to the commonly used and measurements of proteins or en drugs in neonatal intensive care units. zymes of tubular origin have been used This review will not include adverse as indicators of tubular toxicity. It is sug reactions to oxygen, parenteral fluids, or gested that urinary elimination of lyso- components of intravenous nutrition zomal enzyme N acetyl glucosaminidase solutions. (NAG) may be a more sensitive indicator of tubular damage than serum creati- OQ Adverse Reactions to Drugs Commonly nine. Used in Neonatal Intensive Care Units Aminoglycoside antibiotics potentiate or prolong muscle weakness in patients

A minoglycosides with postsynaptic defects of cholinergic function or presynaptic defects resulting These antibiotics are widely used in from decreased acetylcholine release . 23 the treatment of neonatal sepsis and are The decreased acetylcholine release that potentially ototoxic and nephrotoxic. occurs in magnesium intoxication in Aminoglycoside ototoxicity can be ex infants results in a clinical syndrome plained by progressive accumulation of characterized by poor feeding, weak cry, the drug that occurs in the inner ear muscle weakness, and respiratory fail upon repetitive administration or contin ure, a syndrome that appears similar to uous infusion. Risk factors associated infant botulism. When these infants with aminoglycoside ototoxicity include require antimicrobial therapy, alternate high daily and total dosage, elevated drugs should be used, or if aminoglyco peak and trough concentrations, pre side antibiotics are administered, the vious aminoglycoside treatment, con infants should be closely monitored for comitant diuretic administration, and possible development of respiratory fail familial predisposition to aminoglycoside ure. As the difference between effective ototoxicity. Hypoxia increases the risk of and toxic doses of aminglycosides is nar aminoglycoside ototoxicity. Among the row, infants being treated with these ADVERSE DRUG REACTIONS IN THE NEWBORN 197

drugs should have peak and trough blood been shown to be prevented by clysis of levels measured . 9 hyaluronidase at the site of infiltration . 34

C hloramphenicol F u r o s e m i d e

Despite well-known toxic effects of Furosemide, a potent diuretic, is chloramphenicol, especially the Gray extensively used in low birth weight Baby Syndrome, errors in prescription (LBW) neonates in the treatment of and administration of the drug still occur, congestive heart failure associated with leading to fatal reactions. No infant patent ductus arteriosus and in broncho should be treated with chloramphenicol pulmonary dysplasia (BPD). Prolonged without monitoring serum concentra use of furosemide leads to hypokalemia tions. Immaturity of hepatic and renal and metabolic alkalosis. Furosemide functions can result in toxic concentra markedly increases calcium excretion in tions with circulatory collapse and the urine and renal calculi are frequently d e a th . 24 Charcoal hemoperfusion has seen with prolonged use of this drug in been shown to be effective in reducing LBW infants. Autopsies of infants have toxic blood levels. 21 shown that parenchymal calcium depos its are mainly in the interstitial areas of the renal papillae rather than in the V a n c o m y c in tubules. Calculi are frequently composed The increased incidence of coagulase of calcium oxalate and calcium phos negative staphylococcal infections in sick p hate . 20 Secondary hyperparathyroidism neonates has led to the increased use of and bone disease have also been re this drug. This drug is potentially oto ported to complicate long-term furosem toxic and nephrotoxic, especially with ide therapy . 36 Furosemide-related renal concurrent administration of aminoglyco calcification can be reversed by concur sides. Recent studies suggest that the rent administration of chlorothiazide, a liver may be involved in metabolism of diuretic which promotes tubular reab vancomycin. In very low birth weight sorption of calcium. It has been sug infants, hepatic immaturity, in addition gested that prophylactic use of chloro to renal immaturity, may lead to drug thiazide can prevent renal calcification in accumulation. Monitoring of blood levels infants with chronic lung disease who is mandatory to ensure therapeutic effi require long-term diuretic therapy . 20 cacy without toxicity. Although furosemide has been used in A high incidence of histamine-like skin the management of hemodynamically eruptions has been noted to occur during patent ductus arteriosus, Green et al15 infusion of the drug, accompanied by suggest that furosemide can interfere hypotension in an occasional infant. 5 with ductal closure by stimulating the renal release of prostaglandin E2, a potent dilator of immature ductus arte

N a f c i l l i n riosus and by causing hypocalcemia, which can inhibit ductal closure. Subcutaneous extravasation of paren Cholelithiasis has been seen in some teral nafcillin sodium can cause deep tis infants receiving total parenteral nutri sue necrosis, sometimes necessitating tion. It has been suggested that furose multiple debridements and skin grafting. mide may predispose to biliary litho- This nafcillin extravasation injury has genesis by increasing biliary calcium 198 KUMAR

excretion . 20 Furosemide potentiates oto diuresis and dehydration, as well as elec toxicity of aminoglycoside antibiotics. 4 trolyte abnormalities have been noted in infants overdosed with aminophylline. 17

M e t h y l X a n t h i n e s Hyperglycemia may result from ami nophylline overdosage. Mechanisms pro The adverse reactions of these drugs posed are stimulation of glycogenolysis in are principally the exaggeration of their muscle and liver, and stimulation of glu- pharmacologic actions. 17 Although the coneogenesis. Theophylline stimulates ophylline and caffeine are primarily used glucagon release. Methyl xanthines may in the management of apnea of prema also induce insulin release in the pre turity, caffeine continues to be used mature infant. Stimulation of lipolysis, infrequently as a respiratory stimulant in with increases in free fatty acids (FFA), the asphyxiated infant, where it is not triglycerides, and glycerol have also been only ineffective but also may lead to noted. worsening of hypotension. As the neo Theophylline and caffeine inhibit the nate can metabolize theophylline to caf synthesis of cholesterol in cultured glial feine, unlike the adult, possible additive cells, implying a possible impairment of or potentiating effects should be taken neuronal developm ent. However, a fol- into consideration. lowup study by Nelson et al28 failed to Excessive doses and high plasma con show any difference in growth or de centrations of these drugs have led to velopment between the theophylline overt central nervous system (CNS) exci treated infants and matched controls. tation. Opisthotonus, fine tremors, and The adverse effects of methyl xanthines clonic and tonic movements with exag could be avoided by monitoring plasma geration of reflexes have been described concentrations. Owing to the long half- in newborn infants with overdoses of caf life and narrow serum fluctuations of caf feine sodium benzoate. Sinus bradycar feine in infants, weekly monitoring of caf dia has also been observed during con feine is usually satisfactory, while the current therapy with digitalis, suggesting ophylline with a much shorter half-life an additive effect of the two vagotonic should be monitored more often . 17 drugs.

Tachycardia is a well-known side effect P rostaglandin E of theophylline which has been noted even at therapeutic serum levels. Sud Currently, prostaglandin E is being den death from bolus injections of the widely used in ductal-dependent cya ophylline, presumably from cardiogenic notic heart disease to maintain ductal origin, has also been noted. Administra patency. Well-documented side effects tion of theophylline should be over 15 encountered with this drug infusion to 20 minute periods. Gastrointestinal include hyperthermia, hypotension, skin symptoms with vomiting, increased gas flushing and edema, diarrhea, apnea, tric acid secretion, is seen with serum and bradycardia. Prostaglandins are rap theophylline concentrations greater than idly inactivated by tissues, especially 20 jjug per ml. A possible relationship of with passage through the lungs. These theophylline usage and necrotizing side effects are often noted at the onset enterocolitis (NEC) has been raised . 1117 of treatment and are reversible with A decrease in lower esophageal sphincter reduction or discontinuation of infusion. pressure has been noted with large doses Damage to the wall of the ductus with of theophylline. Although methylated aneurysm formation has resulted from a xanthines act as mild diuretics, marked three to six day infusion of the drug. Pro ADVERSE DRUG REACTIONS IN THE NEWBORN 199 longed infusions of prostaglandin Ex and inations of the extremities throughout E 2 have been associated with widespread the period of infusion. Meticulous atten cortical hyperostosis resembling Caffey’s tion must be paid to the calculation of disease. 35 Serum calcium has been noted the dose, dilution, and infusion rates to to be normal. The etiology of these skel avoid these side effects. etal changes remains unknown.

I ndomethacin

T o l a z o l i n e This drug is a prostaglandin synthatase This pulmonary vasodilator drug is inhibitor frequently used in the phar used frequently in the syndrome of “per macologic closure of patent ductus arte sistent pulmonary hypertension” of the riosus in preterm infants. Indomethacin newborn. In addition to blocking alpha causes platelet dysfunction and increases adrenergic receptors, it has sympathetic the risk of intracranial and gastrointes and cholinergic activity and is a hista tinal hemorrhage. Necrotizing enteroco mine agonist. Although 30 to 62 percent litis with gastrointestinal perforation of infants with “pulmonary vasospasm” has been noted to occur following indo treated with tolazoline have responded methacin therapy in low birth weight with transient and sometimes marked infants. 27 Transient renal dysfunction is increases in Pa02, the rate of complica usually seen, although acute renal failure tions has been unfortunately very high. may occur on occasion. The drug is con Serious complications of this drug have traindicated if serum creatine is greater included pulmonary and gastrointesti than 1.6 mg per dl. Acute hyponatre nal hemorrhage, systemic hypotension, mia, with rise in urinary osmolality and renal dysfunction, and thrombocyto body weight, secondary to transient penia. 10 Although tolazoline can increase increase in antidiuretic hormone, has PaOa in some patients, and especially also been reported. The use of furose- when used with drugs that augment sys mide together with indomethacin ther temic hypertension, such as dopamine, apy has been advocated to reduce this its therapeutic inconsistency and high effect. 38 Elevation of serum digitalis lev complication rate make this an ineffec els to toxic ranges, with prolongation of tive agent in the newborn. half-life, has been noted in infants treated with indomethacin, following

D o p a m i n e medical therapy for congestive heart fail u r e . 32 Blindness secondary to intense Dopamine has been used extensively vasoconstriction and obliteration of in pediatric intensive care units because ophthalmic vessels has been reported . 20 of its ability to raise blood pressure and increase urine output in patients with D i g o x i n shock. Increase in heart rate, myocardial contractility, coronary and renal blood Although the newborn appears to be flow, and cardiac output are the major less sensitive to digoxin than the adult, cardiovascular effects. However, over toxicity and fatal adverse reactions do dosage with this medication has led to occur in the neonatal period. High serum intense peripheral vasoconstriction, met levels of digoxin are associated with poor abolic acidosis, dry gangrene of the feeding, persistent vomiting, and elec extremities and midgut infarction . 18 26 trocardiographic abnormalities, mostly Any infant receiving peripheral infusion atrial in origin with or without atrioven of the drug should have frequent exam tricular nodal block. Ventricular arrhyth 200 KUMAR mias are rarely noted. Assay of serum and is associated with the risk of necro digoxin levels, if obtained after a week or tizing enterocolitis. 11 more of administration and five to eight hours after the dose, may be of assistance S o d i u m B i c a r b o n a t e in diagnosing toxicity. Levels less than two ng per ml exclude digoxin toxicity. 33 This commonly used drug has an Computation errors frequently lead to osmolality of 1555 mOsm per kg of water overdosage, which may be life-threat in the concentration of one mEq per ml. ening. Liberal use of this drug has been asso ciated with intraventicular hemorrhage

P h e n y t o i n in low birth weight infants. 12

Dilantin* is added to the anticonvul V i t a m i n E sant therapy in the newborn infant when seizure activity is not controlled by phé Low birth weight infants frequently nobarbital alone. In this age group, the receive vitamin E for the treatment of pharmacokinetics of dilantin are unpre vitamin E deficient hemolytic anemia, dictable because of delays in absorption and to reduce the incidence of the seri when administered by mouth and delays ous sequelae of retinopathy of prematur in elimination in both term and preterm ity. Increased incidence of sepsis and infants. Cardiovascular toxicity with necrotizing enterocolitis has been re atrial fibrillation, hypotension, sinus bra ported in low birth weight infants re dycardia, sinus arrhythmia, and incom ceiving large oral doses of Aquasol E,± plete bundle branch block has been the currently available oral prepara noted in adults and older children. tion . 14 Aquasol E is hyperosmolar (15 IU Recently, persisent bradycardia and leth per 0.3 ml, 3990 mOsm per kg H 20 ), and argy has been reported in a preterm the hyperosmolality is related in large infant with toxic levels (60 |xg per ml) of part to the propylene glycol contained in dilantin . 37 the preparation. Consideration should be given to the use of a parenteral form of

C a l c i u m S a l t s vitamin E in the first few days of life, until oral adminstration may be safely The majority of premature infants rou instituted. tinely receive parenteral calcium infu A recently available intravenous vita sion to prevent early onset hypocalcium. min E preparation (E-Ferol aqueous A rapid bolus adminstration of calcium solution) § containing 25 mg per ml vita gluconate is associated with severe bra min E, has been associated with an dycardia and extravasation of calcium unusual syndrome of hepatomegaly, containing fluids cause necrosis and cal splenomegaly, cholestatic jaundice, azo cification of soft tissues. Recently, calci temia, thrombocytopenia, and fatalities fication of the brain has been reported at in over half the infants less than 1500 autopsy in severely stressed newborns grams receiving this preparation. The following parenteral calcium therapy . 7 reported outbreaks from the two hospi Calcium glubionate (Neo-calglucon)t tals ceased shortly after discontinuation administered orally, has a high osmolality of E-Ferol. 6

* Parke Davis, Morris Plains, NJ 07950. i Armour Pharmaceutical, Tarrytown, NY 10591. t Dorsey Pharmaceuticals, Lincoln, NE 68501. § O’Neal, Jones & Feldman, St. Louis, MO. ADVERSE DRUG REACTIONS IN THE NEWBORN 201

Additives and Preservatives in used in intensive care units have osmo Parenteral Preparations lalities in excess of 1000 mOsm per kg of water, and often several-fold greater than B e n z y l A l c o h o l parenteral preparations when corrected Benzyl alcohol, used as a preservative for the same concentrations, such as mul in a wide variety of parenteral medica tivitamins, vitamin E, theophylline, cal tions and fluids, has been associated with cium glubionate, furosemide, and phé a syndrome of severe metabolic acidosis, nobarbital. The high osmolalities found encephalopathy, respiratory depression in some preparations are not due to with gasping, leading to death in several drugs themselves but secondary agents infants receiving large volumes of fluids such as propylene glycol, ethanol, sor- containing 0.9 percent benzyl alcohol. bital, and other pharmaceutical addi Metabolically, benzyl alcohol is oxidized tives. Necrotizing enterocolitis has been to benzoic acid, conjugated with glycine associated with hyperosmolar feedings. in the liver and excreted as hippuric acid. The fact that several hyperosmolar med This metabolic pathway may not be func ications, such as vitamin E, theophylline, tional in premature infants, leading to multivitamins, are given together with accumulation of benzoic acid with result formula fluids may be responsible for ing metabolic acidosis and toxicity. It has necrotizing enterocolitis frequently seen been recommended that flush solution in low birth weight infants. 11 containing 0.9 percent benzyl alcohol not be used in infants and parenteral M e d i c a t i o n B e z o a r s medications be reviewed for the quantity of benzyl alcohol contained. Infants who Bezoar formations in the stomach, died of this suspected iatrogenic syn small intestine, and colon has been asso drome received 99 to 234 |xg per kg per ciated with cholestyramine, polystyrene day. Since the minimum toxic level is (Kayexalate)* and Amphojel.f Bezoar still unknown, awareness of this potential formation and fecal impaction occurs problem in infants receiving multiple when intestinal motility is reduced, as drugs containing benzyl alcohol is seen in premature infants. Medication essential8 bezoars are often asymptomatic although intestinal obstruction or hemorrhage

P r o p y l e n e G l y c o l may occur. Presence of bezoar should be suspected if large “fecal” masses are Although thought to have low toxicity noted in radiographs of the small bowel and used in many drug preparations, or colon in low birth weight infants propylene glycol has been associated receiving these medications. 20 with central nervous system depression and is one-third as intoxicating as Topical Agents ethanol. As propylene glycol is metabo lized to lactate, metabolic acidosis may M y d r ia t ic s occur iii susceptible individuals. Iatro genic hyperosmolality has been noted in Ophthalmologic examination of low very small infants receiving medications birth weight infants is a routine proce containing propylene glycol. 16 dure in intensive care units. Phenyleph rine 1 0 percent ophthalmic solution has Oral Medications * Breon Labs, New York, The majority of oral drug preparations t Wyeth Labs, Philadelphia, PA 19101. 202 KUMAR caused adverse reactions in adults and used with extreme caution in very low children with blood pressure elevation, birth weight infants. and blanching of the skin, particularly the lower eyelid. Currently, medications Sum m ary used most frequently for dilating the pupils are phenylephrine, 2.5 percent Adverse drug reactions can be pre solution, and Mydriacyl 0.5 to one per vented or reduced by increasing the cent solution. The known metabolic awareness of the problem in neonates, pathways for phenylephrine inactivation especially premature infants, cautious include hepatic conjugation and mono use of drugs, with avoidance of therapeu amine oxidase and tyrosinase degrada tic agents whose pharmacologic data is tion. These pathways are not yet mature inadequately known, monitoring of ther in early infancy, leading to prolonged apeutic drug concentrations where fea blood levels. sible, and the institution of a unit-dose In a study evaluating the systemic system of drug dispensing to reduce effect of mydriatic eye drops, phenyleph medication errors. rine 2.5 percent solution and Mydriacyl 0.5 percent solution, although achieving R eferences the maximum mydriasis, was noted to consistently increase mean blood pres 1. A ran da , J. V., P o r t u c e z-M alavasi, A ., C o l - l in g e , J. M ., G erm anson, T., and O uterbridge, sure by 20 percent and by 50 percent in E. : Epidemiology of adverse drug reaction in the one fourth of the group. The combination newborn. Dev. Pharmacol. Ther. 7:173-184, of eyedrops of one percent phenyleph 1982. 2. A randa, J. V., C o l l in g e , J. M., and C larkson, rine and 0 . 2 percent cyclopentolate has S.: Epidemiologic aspects of drug utilization in been suggested as the agent of choice for a newborn intensive care unit. Semin. Perinatol. mydriasis in low birth weight infants. 19 6:148-154, 1982. 3. A randa, J. V.: Factors associated with adverse drug reactions in the newborn. Pediatr. Phar macol. 3:245-249, 1983. P o v i d o n e I o d i n e 4. A ssael, B. M., P arini, R., and R usconi, F.: Oto toxicity of aminoglycoside antiobiotics in infants Perinatal iodine exposure causes tran and children. Pediatr. Inf. Dis. 1:357-365, 1983. sient hypothyroidism in a significant 5. B a n er, W., Jr . and R ay, G . C.: Vancomycin in number of newborns. Although hypothy perspective. Am. J. Dis. Child. 138:14—16, 1984. roidism is transient and lasts less than 6. Center for Disease Control: Unusual syndrome two weeks, careful monitoring of these with fatalities among premature infants: Associ infants and followup of thyroid function ation with a new intravenous vitamin E product. Morbidity and Mortality Weekly Report. is necessary. 22 33:198-199, 1984. 7. C hangaris, D . G ., P uro hit, D . M., B alen tin e , J. D ., L e v k o f f , A. M ., H o l d e n , A. E. C., I s o p r o p y l A l c o h o l D ea n , D . L . , J r., and B riggs, P. J.: Brain cal cification in severely stressed newborns receiv Isopropyl alcohol is a commonly used ing parenteral calcium. J. Pediatr. 204:941-946, 1984. disinfectant. Alcohol pledgets have occa 8. Committee on Drugs: American Academy of sionally been used as substitutes for con Pediatrics: Benzyl alcohol: Toxic agent in neo ducting electrode paste beneath limb natal units. Pediatrics 72:356-357, 1983. 9. C ra ft , J. C .: Monitoring antibiotic therapy in electrodes. Second and third degree the newborn infant. Clin. Perinatol. 8:263-272, burns with fatal outcomes have been 1981. reported in premature infants. 31 As kera- 10. D r u m m o n d , W. H . and L o c k , J. E.: Neonatal “pulmonary vasodilator” drugs: Current status. tinization of the skin is incomplete until Dev. Pharmacol. Ther. 7:1-20, 1984. 25 weeks, isopropyl alcohol should be 11. E r n s t , J. A., W illia m s, J. M ., G l ic k , M. R., ADVERSE DRUG REACTIONS IN THE NEWBORN 203

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