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Drug utilization in a newborn intensive care unit
August 1976
315
The Journal o f P E D I A T R I C S
D r u g utilization in a newborn intensive care unit Jacob V. Aranda, M.D., Ph.D.,* Sylvia Cohen, B.A., and Allen H. Neims, M.D., Ph.D., M o n t r e a l , P. Q., C a n a d a
STUDIES conducted in Edinburgh, 1 Houston, ~ and Oakland :~ have revealed that most pregnant women consume three different drugs during the course of a pregnancy. Although some information is available on the extent of drug exposure during childhood, ~-~ only sparse data have been reported with regard to the newborn infant. ~ We have surveyed the patterns of drug utilization in a referral neonatal intensive care unit in order to (I) provide data for educationaland surveillance programs locally; (2) gain insight into the feasibility of various research protocols; and (3) provide background information for design of a subsequent study of adverse drug reactions. The data are timely because the continued regionalization of high-risk obstetrics and neonatology fosters emergence of an attitude of aggressive therapeutic and diagnostic intervention. Moreover, insufficient prescribing information is available for many of the agents, ~ and therapeutic mishaps have occurred all too frequently in such patients."-1,, METHODS Drug utilization in the 331 newborn infants admitted to the Montreal Children's Hospital NICU from July, 1974, through February, 1975, was assessed by review of charts immediately following discharge. Eleven charts (3.3%) were lost to survey. Recorded information included gestational and postnatal age, dates 6( admission and discharge, birth weight, sex, diagnoses, outcome, and laboratory data such as values of serum bilirubin, glucose, and oxygen tension. Drug utilization data were obtained From The Roche Development Pharmacology Unit, Departments of Pharmacology and Therapeutics, and Pediatrics, McGill University; Department of Newborn Medicine, McGill University-Montreal Children's Hospital Research Institute. *Reprint address: Montreal Children's Hospital, 2300 Tupper St. Montreal, P. Q. H3H 1P3 Canada.
directly from medication records and were confirmed with use of the NICU dru B order sheets, doctors' order sheets, nurses' notes, and progress notes. Careful records were kept of drugs used, dose per administration, number of doses, and timing and route of administration. All drugs were included in the survey except (1) vitamin K and prophylactic ophthalmic ointment except when these compounds were used for nonroutine purposes; (2) fluid and electrolyte solutions; (3) intravenous amino acids, intralipids, and/or glucose, except when glucose was given for the treatment of neonatal hypoglycemia; and (4) phototherapy and oxygen. Data have been entered into a computer for subsequent detailed analyses. Abbreviation used NICU: neonatal intensive care unit
]
RESULTS Characteristics (mean + SEM) of the patient population of 320 infants include: birth weight, 2,612 • 51 gm; gestational age, 36.9 • 0.2 weeks; age on admission, 2.6 ___0.4 days; duration of hospitalization, 14.0 • 1,1 days. The 320 infants were exposed to 71 different drugs. The average number of different drugs used per infant was 3.4 • 0.2 despite the fact that 23.4% of the patients received no agents other than the exceptions denoted above. The most commonly used drugs in this NICU are presented in Fig. 1, Antibiotics were administered to 61.9% of all infants. Penicillin and kanamycin were used most frequently with >40% of infants exposed to each; gentamicin and ampicillin were utilized in 28.8% and 27.5%, respectively, of the infants. About one-fourth of the population was exposed to cMcium gluconate, and a similar portion to sodium bicarbonate; furosemide was given to 10.6% of the infants. Chloramphenicol was used systemically and topically (ophthalmic drops) in three and
VoL 89, No. 2, pp. 315-317
3 16
Aranda, Cohen, and Neims
The Journal of Pediatrics August t 976
Penicillin
!t ~
Kanamytin Gentamicin Ampicillin
Ca G l u t .
.
NaHCO 3 Furosemide
4
Chloramphenical Phenobarbital Digoxin
Cloxadl|in
Methiciln~
Mycastatin
o
Oiazepam
t n f a n t o l (R)
Fet-|n-Sol CR)
1499
MCT-oil 0
20
40
60
i
i
1
80
100
120
2499
BIRTH W E I G H T
1
140
1999
2 5 2999
~ 3499
- 3 5 0 0 - " >4000 3999
GROUP
Fig. 2. Extent of drug exposure and birth weight. *Only four infants had birth weights less than 1,000 gin.
NO. OF PATIENTS
Fig. 1. The most commonly used drugs in the Neonatal Intensive Care Unit. Numbers inside bars indicate percentage of the total NICU population who received the drug. *Chloramphenicol was used systemically in three patients and topically in 27 patients. **Medium-chain triglyceride,
27 infants, respectively. Digoxin, phenobarbital, and diazepam were prescribed not infrequently. Iron and multivitamin preparations are illustrated separately in Fig. 1. Only 8.1% of infants received one drug, whereas 68.1% received two or more agents. Twenty-two percent of infants received five to nine drugs, 6.0% received 10 to 14 drugs, and 1.6% received more than 15 drugs. Low-birthweight infants were exposed to almost twice as many different drugs as were term newborn infants. Infants born prematurely at < 3 7 weeks' gestation were exposed to an average of 4.7 drugs compared to the use of 2.7 drugs per infant born at > 3 7 weeks' gestation. A n inverse relationship between birth weight and the number of drugs used per infant is depicted in Fig. 2. COMMENTS It can be estimated that a 1,500-gm premature infant born in North America is exposed to about 20 prescribed drugs between conception and discharge from the nursery. On the average, as many as ten medications '-' are given to mother and reach the fetus or infant transplacentally or through breast milk; after birth the infant is usually exposed to numerous agents by nursery routine (e.g., vitamin K, triple dye, antibiotic ophthalmic ointment, phenylephrine, and cyclopentolate) and six or seven
drugs prescribed specifically. Total'xenobiotic exposure is substantially greater since over-the-counter medications, alcohol, nicotine, caffeine, and environmental chemicals such as heavy metals and polycyclic hydrocarbons cannot be ignored. The extent of this unapparent exposure has been emphasized by the presence of hexachlorophene H and caffeine"-' in most random cord plasma samples. The earlier in gestation a harmful drug is encountered, the more likely is the potential adverse effect to be unpredictable from an adult data base. By the perinatal period, documented adverse drug reactions tend to reIate to known pharmacologic or toxic actions of the agent. Factors, such as unexpected portals of entry (placenta, skin, conjunctiva, and breast milk) and inappropriate dosing because of decreased clearance, have played important provocative roles in toxicity at this time of life, especially in premature infants. An awareness of these factors and of the agents being used in neonates could serve to decrease the likelihood of future mishaps. There can be little doubt that the pattern of drug utilization will yary substantially from nursery to nursery. Moreover, appreciable fluctuation with time can be expected. Finally, it must be emphasized that the infants included in this study had required referral to an intensive care unit and that the results reflect drug use in a high-risk population of newborn infants. REFERENCES 1. Forfar JO, and Nelson N: Epidemiology of drugs taken by pregnant women. Drugs that may affect the fetus adversely, Clin Pharmacol Ther 14:632, I973.
Volume 89 Number 2
2. Hill RM: Drugs ingested by pregnant women, Clin Pharmacol Ther 14:654, I973. 3. Peckham CH, and King RW: A study of intercurrent conditions observed during pregnancy, Am J Obstet Gynecol 87:609, 1963. 4. Haggerty RJ, and Roghmann K J: Non-compliance and self-medication--tWO neglected aspects Of pediatric pharmacology. Pediatr Clin North Am 19:101, 1972. 5. McKenzie MW, Stewart RM, Weiss CF, et al: A pharmacist:based study of the epidemiology of adverse drug reactions in pediatric medicine patients, Am J Hosp Pharm 30:898, 1974. 6. Boston Collaborative Drug Surveillance Program: Drug surveillance-problems and challenges, Pediatr Clin North Am 19:117, 1972. 7. Sice J: Major drug-prescribing patterns in general hospital, Clin Pharmacol Ther 18:133, 1975. 8. Wilson JT: Pragmatic assessment of medicines available for
Drug utilization in N I C U
3 17
young children and pregnant or breast feeding women, in Morselli PL, Garattini S, and Sereni F, editors: Basic and therapeutic aspects of perinatal pharmacology, New York, 1975, Raven Press, p 411. 9. Burns LE, Hodgman JE, and Cass AB: Fatal circulatory collapse in premature infants receiving chloramphenicol, N Engl J Med 261:1318, 1959. 10. Silverman WA, Anderson DH, Blanc WA, et al: A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibiotic regimes, pediatrics 18:614, 1956. ll. Curley A, Hawk RE, Kimbrough RD, et al: Dermal absorption of hexachlorophene in infants, Lancet 2:296, 1971. 12. Parsons WD, Aranda JV, and Neims AH: Elimination of transplacentally acquired caffeine in full-term neonates, Pediatr Res (abst) 10:333, 1976.
315
The Journal o f P E D I A T R I C S
D r u g utilization in a newborn intensive care unit Jacob V. Aranda, M.D., Ph.D.,* Sylvia Cohen, B.A., and Allen H. Neims, M.D., Ph.D., M o n t r e a l , P. Q., C a n a d a
STUDIES conducted in Edinburgh, 1 Houston, ~ and Oakland :~ have revealed that most pregnant women consume three different drugs during the course of a pregnancy. Although some information is available on the extent of drug exposure during childhood, ~-~ only sparse data have been reported with regard to the newborn infant. ~ We have surveyed the patterns of drug utilization in a referral neonatal intensive care unit in order to (I) provide data for educationaland surveillance programs locally; (2) gain insight into the feasibility of various research protocols; and (3) provide background information for design of a subsequent study of adverse drug reactions. The data are timely because the continued regionalization of high-risk obstetrics and neonatology fosters emergence of an attitude of aggressive therapeutic and diagnostic intervention. Moreover, insufficient prescribing information is available for many of the agents, ~ and therapeutic mishaps have occurred all too frequently in such patients."-1,, METHODS Drug utilization in the 331 newborn infants admitted to the Montreal Children's Hospital NICU from July, 1974, through February, 1975, was assessed by review of charts immediately following discharge. Eleven charts (3.3%) were lost to survey. Recorded information included gestational and postnatal age, dates 6( admission and discharge, birth weight, sex, diagnoses, outcome, and laboratory data such as values of serum bilirubin, glucose, and oxygen tension. Drug utilization data were obtained From The Roche Development Pharmacology Unit, Departments of Pharmacology and Therapeutics, and Pediatrics, McGill University; Department of Newborn Medicine, McGill University-Montreal Children's Hospital Research Institute. *Reprint address: Montreal Children's Hospital, 2300 Tupper St. Montreal, P. Q. H3H 1P3 Canada.
directly from medication records and were confirmed with use of the NICU dru B order sheets, doctors' order sheets, nurses' notes, and progress notes. Careful records were kept of drugs used, dose per administration, number of doses, and timing and route of administration. All drugs were included in the survey except (1) vitamin K and prophylactic ophthalmic ointment except when these compounds were used for nonroutine purposes; (2) fluid and electrolyte solutions; (3) intravenous amino acids, intralipids, and/or glucose, except when glucose was given for the treatment of neonatal hypoglycemia; and (4) phototherapy and oxygen. Data have been entered into a computer for subsequent detailed analyses. Abbreviation used NICU: neonatal intensive care unit
]
RESULTS Characteristics (mean + SEM) of the patient population of 320 infants include: birth weight, 2,612 • 51 gm; gestational age, 36.9 • 0.2 weeks; age on admission, 2.6 ___0.4 days; duration of hospitalization, 14.0 • 1,1 days. The 320 infants were exposed to 71 different drugs. The average number of different drugs used per infant was 3.4 • 0.2 despite the fact that 23.4% of the patients received no agents other than the exceptions denoted above. The most commonly used drugs in this NICU are presented in Fig. 1, Antibiotics were administered to 61.9% of all infants. Penicillin and kanamycin were used most frequently with >40% of infants exposed to each; gentamicin and ampicillin were utilized in 28.8% and 27.5%, respectively, of the infants. About one-fourth of the population was exposed to cMcium gluconate, and a similar portion to sodium bicarbonate; furosemide was given to 10.6% of the infants. Chloramphenicol was used systemically and topically (ophthalmic drops) in three and
VoL 89, No. 2, pp. 315-317
3 16
Aranda, Cohen, and Neims
The Journal of Pediatrics August t 976
Penicillin
!t ~
Kanamytin Gentamicin Ampicillin
Ca G l u t .
.
NaHCO 3 Furosemide
4
Chloramphenical Phenobarbital Digoxin
Cloxadl|in
Methiciln~
Mycastatin
o
Oiazepam
t n f a n t o l (R)
Fet-|n-Sol CR)
1499
MCT-oil 0
20
40
60
i
i
1
80
100
120
2499
BIRTH W E I G H T
1
140
1999
2 5 2999
~ 3499
- 3 5 0 0 - " >4000 3999
GROUP
Fig. 2. Extent of drug exposure and birth weight. *Only four infants had birth weights less than 1,000 gin.
NO. OF PATIENTS
Fig. 1. The most commonly used drugs in the Neonatal Intensive Care Unit. Numbers inside bars indicate percentage of the total NICU population who received the drug. *Chloramphenicol was used systemically in three patients and topically in 27 patients. **Medium-chain triglyceride,
27 infants, respectively. Digoxin, phenobarbital, and diazepam were prescribed not infrequently. Iron and multivitamin preparations are illustrated separately in Fig. 1. Only 8.1% of infants received one drug, whereas 68.1% received two or more agents. Twenty-two percent of infants received five to nine drugs, 6.0% received 10 to 14 drugs, and 1.6% received more than 15 drugs. Low-birthweight infants were exposed to almost twice as many different drugs as were term newborn infants. Infants born prematurely at < 3 7 weeks' gestation were exposed to an average of 4.7 drugs compared to the use of 2.7 drugs per infant born at > 3 7 weeks' gestation. A n inverse relationship between birth weight and the number of drugs used per infant is depicted in Fig. 2. COMMENTS It can be estimated that a 1,500-gm premature infant born in North America is exposed to about 20 prescribed drugs between conception and discharge from the nursery. On the average, as many as ten medications '-' are given to mother and reach the fetus or infant transplacentally or through breast milk; after birth the infant is usually exposed to numerous agents by nursery routine (e.g., vitamin K, triple dye, antibiotic ophthalmic ointment, phenylephrine, and cyclopentolate) and six or seven
drugs prescribed specifically. Total'xenobiotic exposure is substantially greater since over-the-counter medications, alcohol, nicotine, caffeine, and environmental chemicals such as heavy metals and polycyclic hydrocarbons cannot be ignored. The extent of this unapparent exposure has been emphasized by the presence of hexachlorophene H and caffeine"-' in most random cord plasma samples. The earlier in gestation a harmful drug is encountered, the more likely is the potential adverse effect to be unpredictable from an adult data base. By the perinatal period, documented adverse drug reactions tend to reIate to known pharmacologic or toxic actions of the agent. Factors, such as unexpected portals of entry (placenta, skin, conjunctiva, and breast milk) and inappropriate dosing because of decreased clearance, have played important provocative roles in toxicity at this time of life, especially in premature infants. An awareness of these factors and of the agents being used in neonates could serve to decrease the likelihood of future mishaps. There can be little doubt that the pattern of drug utilization will yary substantially from nursery to nursery. Moreover, appreciable fluctuation with time can be expected. Finally, it must be emphasized that the infants included in this study had required referral to an intensive care unit and that the results reflect drug use in a high-risk population of newborn infants. REFERENCES 1. Forfar JO, and Nelson N: Epidemiology of drugs taken by pregnant women. Drugs that may affect the fetus adversely, Clin Pharmacol Ther 14:632, I973.
Volume 89 Number 2
2. Hill RM: Drugs ingested by pregnant women, Clin Pharmacol Ther 14:654, I973. 3. Peckham CH, and King RW: A study of intercurrent conditions observed during pregnancy, Am J Obstet Gynecol 87:609, 1963. 4. Haggerty RJ, and Roghmann K J: Non-compliance and self-medication--tWO neglected aspects Of pediatric pharmacology. Pediatr Clin North Am 19:101, 1972. 5. McKenzie MW, Stewart RM, Weiss CF, et al: A pharmacist:based study of the epidemiology of adverse drug reactions in pediatric medicine patients, Am J Hosp Pharm 30:898, 1974. 6. Boston Collaborative Drug Surveillance Program: Drug surveillance-problems and challenges, Pediatr Clin North Am 19:117, 1972. 7. Sice J: Major drug-prescribing patterns in general hospital, Clin Pharmacol Ther 18:133, 1975. 8. Wilson JT: Pragmatic assessment of medicines available for
Drug utilization in N I C U
3 17
young children and pregnant or breast feeding women, in Morselli PL, Garattini S, and Sereni F, editors: Basic and therapeutic aspects of perinatal pharmacology, New York, 1975, Raven Press, p 411. 9. Burns LE, Hodgman JE, and Cass AB: Fatal circulatory collapse in premature infants receiving chloramphenicol, N Engl J Med 261:1318, 1959. 10. Silverman WA, Anderson DH, Blanc WA, et al: A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibiotic regimes, pediatrics 18:614, 1956. ll. Curley A, Hawk RE, Kimbrough RD, et al: Dermal absorption of hexachlorophene in infants, Lancet 2:296, 1971. 12. Parsons WD, Aranda JV, and Neims AH: Elimination of transplacentally acquired caffeine in full-term neonates, Pediatr Res (abst) 10:333, 1976.