Int J Clin Pharm DOI 10.1007/s11096-015-0109-0

RESEARCH ARTICLE

Drug utilisation profile in the neonatal unit of a university hospital: a prospective observational study in Brazil Adriana Cristina de Souza Gonc¸alves1 • Adriano Max Moreira Reis2 Ana Carolina Marc¸al Gusma˜o2 • Maria Caˆndida Ferrarez Bouzada3

•

Received: 28 September 2014 / Accepted: 20 March 2015  Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Abstract Background Advances in neonatology have contributed to changes in the drug utilisation profile in neonates, both in the number of drugs and the pharmacotherapeutic groups. Objective To analyse drug use in the neonatal care unit of a teaching hospital in Brazil and to evaluate the associations among perinatal, clinical care and drug use data. Setting The neonatal care unit of a teaching hospital in Brazil. Methods A prospective observational study was conducted. Perinatal, clinical care and pharmacotherapy data were collected from the patients’ medical records. Labelling information regarding neonatal use was analysed for prescribed drugs. The data were analysed using univariate descriptive statistics and quasi-Poisson regression. Main outcome measure Frequency of drug use by gestational age. Results The study included 187 patients; 157 (84.0 %) received drugs. The mean gestational age was 35.8 weeks. The mean number of drugs prescribed per patient was 6.4. The number of drugs used was inversely correlated to gestational age and birth weight. The most commonly prescribed drugs belonged to the following anatomical therapeutic chemical groups: nervous system drugs, anti-infectives for systemic use, and alimentary tract & Adriano Max Moreira Reis [email protected]

and metabolism drugs. Information regarding neonatal use was given in the labelling of only 20.5 % of the prescribed drugs. Of these, only 9.5 % had information specific for preterm infants. Conclusions Drug administration to neonates is frequently and inversely correlated to gestational age and birth weight. Neonates are exposed to different therapeutic classes, reflecting scientific advances in neonatology. In Brazil, the percentage of drugs with neonate-specific labelling information is low. Consequently, there is an evident need for efforts to guarantee effective and safe pharmacotherapy for neonates. Keywords Brazil
Drug utilisation
Infant
Intensive care units
Neonatal
Neonatology
Newborn
Pharmacoepidemiology

Impact of findings on practice statements •

•

1

Unidade Funcional Farma´cia, Hospital das Clı´nicas, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 110, Belo Horizonte, MG CEP 30130-100, Brazil

2

Faculdade de Farma´cia, Universidade Federal de Minas Gerais, Av. Antoˆnio Carlos, 6627, Belo Horizonte, MG CEP 31270-901, Brazil

•

3

Departamento de Pediatria, Faculdade de Medicina, Hospital das Clı´nicas, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 190, Belo Horizonte, MG CEP 30130-100, Brazil

•

The utilisation of lung surfactant, sildenafil, caffeine, fentanyl and antimicrobial drugs in neonatal pharmacotherapy is compatible with current standards of care in international neonatology practice. Drugs of specific interest in neonatology such as ampicillin, aminophylline, azithromycin, caffeine, cefotaxime, hydrochlorothiazide, meropenem, methadone, metronidazole, morphine, theophylline and vancomycin should be included in lists of prioritised medicines for paediatric research. The development of formulations suitable for newborns that contain drugs such as sildenafil, lorazepam, pyrimethamine and sulfadiazine is essential. Drug labelling with information specific to neonates is essential for a safe and effective drug therapy in this population.

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Int J Clin Pharm

Introduction The recent decades have brought many advances in the field of neonatology, with expansion of the diagnostic methods, therapeutic resources and medical technology used in neonatal care. There have been significant improvements in the survival rates of infants born at term and preterm, including those with low birth weight or born at an extremely early gestational age [1]. The availability of these new features has contributed to changes in the drug utilisation profile in neonatology, both in the number of drugs and in the pharmacotherapeutic groups used [2–6]. Newborns, especially extremely preterm and very preterm infants, are more vulnerable due to physiological immaturity, metabolic changes and associated diseases. Consequently, exposure to drugs is high among neonates, as described in published studies from several countries [4, 7–9]. However, investigations on drug use in neonatal intensive care units in Brazil are scarce [10]. Pharmacoepidemiology studies with appropriate methodologies can improve the effectiveness and efficiency of healthcare interventions. Improvements may be of particular importance in the child population because there is limited information on the safety and efficacy of drugs used to treat this age group. Drug utilisation studies, a type of pharmacoepidemiological investigation, are important for evaluating drug prescription patterns, and their outcomes provide useful information that is reflective of the quality of health care offered [2, 5, 11]. Drug utilisation studies in newborns may be used to identify the major therapeutic problems in this population. Moreover, although rational drug therapy is important for all individuals being treated with drugs, it is of paramount importance for neonates [2, 5, 11]. Therefore, it is necessary to analyse the pattern of drug use in neonatal units and to identify therapeutic classes that should be prioritised for future research. The aim of this study was to investigate the profile of drug use in a neonatal care unit (NCU) and to analyse the associations among perinatal variables, clinical care and medications.

Participants and methods Study design This observational prospective study was conducted in the NCU of a teaching hospital in Brazil from January to June 2012. The NCU is located in a teaching hospital that specialises in treating newborns of high-risk pregnancies. The inclusion criteria were all NCU patients hospitalised for more than 24 h whose parents signed a consent form for

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their children to participate in this study. This study was approved by the University Ethics Research Committee with the approval number CAAE-0292.0.203.000-11. Data collection Consecutive eligible patients were prospectively identified during daily review by two investigators (ACSG and ACMG). The following perinatal and demographic data were prospectively collected from the clinical histories in the medical records: gestational age; birth weight; sex; date of birth; date of discharge; clinical outcome; mode of delivery; APGAR score at the 1st min; APGAR score at the 5th min; time on mechanical ventilation; and clinical diagnostics. The patients’ diagnoses according to the international classification of diseases (ICD-10) were identified from the patient records. The newborns were categorised based on their gestational age (GA) as preterm (\37 weeks) or term (C37 weeks). The preterm group was subdivided into extremely preterm (gestational age \28 weeks), very preterm (gestational age 28–30 weeks), late preterm (gestational age 31–33 weeks) and preterm (GA 34–36 weeks) infants [8]. The patients were categorised as non-low birth weight (C2500 g) or underweight (B2499 g). The underweight group was subdivided into low birth weight (2499–1500 g), very low birth weight (1499–1000 g) and extremely low birth weight (\1000 g) groups [12]. All prescription drug-related data such as presentation, dose, dosage and route of administration were collected from patient charts during their length of stay in the NCU. The following prescription items were excluded: 0.9 % sodium chloride, 5 % glucose, blood products (except albumin), heparin for venous access permeabilisation, vaccines, phytomenadione, 1 % silver nitrate eye drops (prescribed at birth for prophylaxis), parenteral nutrition, oxygen, and electrolytes (calcium gluconate, potassium chloride, magnesium sulphate and sodium bicarbonate). The drugs were classified according to first level (anatomical group) and the third level (pharmacological subgroup) based on the anatomical therapeutic chemical (ATC) system [13]. The drugs were also classified according to the information provided in the package insert, which is registered with Brazil’s regulatory agency for drugs (Ageˆncia Nacional de Vigilaˆncia Sanita´ria; ANVISA), as follows: paediatric use; paediatric use, specifically newborns; paediatric use, specifically preterm infants; or adult use. We also identified drugs whose dosage form was converted for administration to neonatal patients, drugs produced from raw materials and imported drugs.

Int J Clin Pharm

Prescription in this study refers to each drug prescribed along with its respective daily dose, number of doses per day, and route of administration; these data were collected from prescriptions charts. Statistical analyses A descriptive analysis was performed by determining the frequencies and percentages of categorical variables as well as measures of central tendency (means and medians) and dispersion (standard deviations and interquartile ranges) for quantitative variables. Numerical variables were tested for normal distribution using Kolmogorov–Smirnov and Shapiro–Wilk tests. The non-parametric Mann–Whitney U test was used for comparisons when the t test did not meet the usual criteria (normality and homoscedasticity); it was used to compare ordinal or continuous variables with categorical variables. The Chi-square test and Fisher’s exact test were used to compare categorical variables. Odds ratios were also calculated. To verify the associations between perinatal and clinical-demographic variables and the number of medications prescribed to newborns, a univariate Poisson regression analysis was performed with a quasi-likelihood approach. A p value\0.05 was considered significant. All statistical analyses were performed using R software, version 2.15.1.

Results Of the 187 patients included in the study, 100 (53.5 %) were preterm, and 87 (46.5 %) were full-term. Among the preterm infants, 4 (2.1 %) were extremely premature. The mean hospital stay was 20.6 days [standard deviation (SD), 22.3; range 1–128 days]. The most common admission diagnoses, grouped according to the three characteristic categories of the ICD-10, were disorders related to the length of gestation and foetal growth (32.1 %), respiratory and cardiovascular disorders (25.1 %) and congenital malformations (21.9 %). Moreover, 102 different drugs were used; these and other perinatal, pharmacotherapeutic, clinical and demographic characteristics of the 187 studied patients are presented in Table 1. Table 2 shows that the extremely preterm patients remained hospitalised for longer periods (mean 56 days) than newborns at [28 weeks, and the mean length of stay decreased with increasing gestational age. Of all patients in the study, 14 (7.4 %) died. The death rate was higher in the group of infants of a younger gestational age. Additionally, all of the full-term patients who died were diagnosed with malformations. Among the patients who died, 57.1 % were diagnosed with malformations.

Pharmacotherapeutic aspects Pharmacotherapeutic profile The records revealed a total of 1187 prescriptions that involved 102 different active ingredients from 127 medicines because some medicines were prescribed in more than one drug dosage form. The mean number of drugs prescribed per patient was 6.4 (range 0–40; Table 1). The medications were primarily administered intravenously (57.7 %), followed by oral (23.4 %) and topical (7.5 %) administration. With respect to the information provided in the package insert of the 127 medicines concerning dosing and indications for paediatric patients, 63 (49.6 %) pharmaceutical products contained drug information for paediatric use (without specifying neonates or premature infants). Only 26 (20.5 %) had drug package insert information for use in neonates; among these, 12 (9.5 %) had information for use in preterm neonates. There were 19 (14.9 %) medicines with information for adult use only; these included carvedilol, captopril, clonidine, lorazepam, milrinone, sildenafil and pamidronate. Regarding the therapeutic groups of the ATC classification, 356 (30.0 %) of the prescriptions belonged to group N (nervous system). Among these, the most prescribed therapeutic subgroups were general anaesthetics subgroup and the hypnotics and sedatives subgroup. The second most-prescribed group was group J (anti-infectives for systemic use); the most common subgroups were aminoglycoside antibacterials, beta-lactam antibacterials, penicillins, and other beta-lactam antibacterials, which accounted for 292 (24.6 %) of the prescriptions. Group A (alimentary tract and metabolism) accounted for 147 (12.4 %) of the prescriptions, and the most frequent subgroup was multivitamins. The most frequent subgroups of group C (cardiovascular system drugs) were cardiac stimulants, excluding cardiac glycosides and high-ceiling diuretics. Among group R (respiratory system), more than half (57.1 %) of the prescriptions belonged to the other subgroup of respiratory system products, which includes lung surfactants. Considering level 5 of the ATC classification, the drug with the highest absolute frequency of prescription for all of the patients was fentanyl (110), followed by multivitamins (100) and gentamicin (94). Analysis of the exposure to drugs by gestational age (Table 3) showed that fentanyl, midazolam and multivitamins were among the most frequently prescribed medications in all age groups. Lung surfactants were prescribed for all (100.0 %) of the extremely preterm (\27 weeks) patients and for almost half (42.9 %) of the very preterm infants (28–30 weeks).

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Int J Clin Pharm Table 1 Perinatal characteristics and demographic, clinical and pharmacotherapeutic data of the 187 studied neonates

Demographic and clinical

Values

Route of childbirth [n (%)] Vaginal

73 (39.0)

Caesarean section

106 (56.7)

Forceps

8 (4.3)

Gestational age in weeks (median interquartile range)

36.6 (33.9–38.3)

24–27 (extreme prematurity) [n (%)]

4 (2.1)

28–30 (very preterm) [n (%)]

14 (7.5)

31–33 (late preterm) [n (%)]

30 (16.0)

34–36 (late preterm) [n (%)]

52 (27.8)

[37 (full term) [n (%)]

87 (46.5)

APGAR score (median interquartile range) 1 min

8.0 (6.0–9.0)

5 min

9.0 (8.0–9.0)

Gender [male (%)]

108 (57.8)

Birth weight (median interquartile range) C2500 g [n (%)]

2410 (1870–3105) 85 (45.5)

2499–1500 g [n (%)]

79 (42.2)

1499–1000 g [n (%)]

17 (9.1)

\1000 g [n (%)]

6 (3.2)

Duration of mechanical ventilation (days) (median interquartile range)

3.9 (0.0–2.0)

Length of stay (days) [mean (SD)]

20.6 (22.3)

Evolution [death (%)]

14 (7.5)

Diagnosis [n (%)] Disorders related to length of gestation and growth

60 (32.1)

Respiratory and cardiovascular disorders in the perinatal period

47 (25.1)

Congenital malformations, deformations and chromosomal abnormalities

41 (21.9)

Other disorders originating in the perinatal period

12 (6.4)

Certain infectious and parasitic diseases

6 (3.2)

Other \6 %

21 (11.3)

Pharmacotherapy Number of prescriptions Number of drugs

1187 127

Number of medications per patient [mean (SD)]

6.35 (7.7)

Among the anti-infectives for systemic use, gentamicin and ampicillin were the most frequently prescribed drugs. Among the preterm infants of 24–27 weeks of gestation, 75.0 % were treated with these drugs. Patients with a GA of 28–30 weeks constituted the group that received the most antimicrobials during hospitalisation. Determinants of drug use Among the 187 newborns, 157 (83.9 %) received drugs during hospitalisation; among those with gestational ages of 24–30 weeks, 100.0 % received drugs. In the group with gestational ages of 31–33 weeks, 93.3 % received drugs; this decreased to 74.7 % among those with gestational ages [37 weeks. The lower the gestational age, the higher the mean use of drugs (Table 2).

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There was a significant difference (p \ 0.001) between the preterm and term patients in the use of medication. There were also significant differences based on birth weight. Among the newborns with low birth weight (\2500 g), 91 (89.0 %) received drugs, whereas among those who weighed 2500 g or more, this number was 66 (78.0 %). All of the patients who died had been administered medicines; however, mortality was not significantly associated with drug use (Table 4). According to the Mann–Whitney U test, the duration of mechanical ventilation was significantly higher for the group of patients who received medications than for those who received no medications (p \ 0.001). There was a similar finding for the length of stay; among the group that received medication, the hospitalisation time was significantly longer (p \ 0.001). The APGAR scores did not significantly differ between the groups.

Int J Clin Pharm Table 2 Clinical variables and perinatal and pharmacotherapeutic factors according to the gestational age of the 187 studied neonates Variable

Gestational age (weeks) 24–27 semanas

28–30 semanas

31–33 semanas

34–36 semanas

C37 semanas

Total

4

14

30

52

87

187

788.8 66.5

1271.4 326.5

1818.8 339.1

2345.6 554.2

3046.4 632.3

2473.4 831.6

Mean

56.0

48.3

20.6

18.9

15.4

20.6

SD

51.7

18.9

10.4

21.7

19.9

22.3

Mean number of drugs per patient

18.5

13.3

4.7

6.9

4.9

6.4

Percentage of newborns who received medications

100.0

100.0

93.3

80.0

74.7

83.9

Percentage of deaths

50.0

14.0

7.0

12.0

2.0

7.5

Number of newborns Birth weight Mean SD Length of hospital stay (days)

The quasi-Poisson regression analysis identified perinatal, clinical and demographic variables that were significantly associated with the number of drugs prescribed. According to Table 5, an analysis of the beta coefficients of the quasi-Poisson regression indicated that a gestational age of 28–30 weeks was associated with a 28.2 % reduction in the mean number of prescription drugs compared with a gestational age of 24–27 weeks (intercept). For a GA of 31–33 weeks, the reduction was 74.4 %; for a GA [ 37 weeks, the reduction was 73.4 %. For newborns weighing less than 1000 g, the mean number of prescribed drugs increased by approximately three times compared with patients weighing 2500 g or more. An increase of one day in the duration of hospitalisation increased the mean number of drugs prescribed by 2.5 %; however, the time on mechanical ventilation increased by 4.0 % per day of hospitalisation.

Discussion The present study showed that newborns, particularly extremely preterm and very preterm infants, are exposed to a high number of drugs. The number of patients administered drugs during hospitalisation was 157 (83.9 %). Drug use was related to the patient’s gestational age, birth weight and delivery route (vaginal or Caesarean section). The drugs most commonly prescribed belonged to the following ATC groups: nervous system drugs, anti-infectives for systemic use, and alimentary tract and metabolism drugs. The use of medications throughout the life cycle shows a J-shaped distribution, with a high prevalence during childhood, a gradual decrease in adolescence, an increase in adulthood and a further increase among the elderly [14].

The results of this study also reveal a J-shaped curve for the use of medicines stratified by gestational age. Recently, Ellsbury and Ursprung highlighted the importance of critically analysing which drugs are used and how they are used, with the aim of minimising the damage caused by drug use and maximising the clinical and therapeutic benefits of drugs. These authors emphasised that such an analysis allows the identification of gaps in knowledge regarding the process of medication use. Integrating this knowledge with methods of analysing roots causes of illness contributes to the optimisation of drug use in neonates [15]. Data concerning the epidemiological determinants of medicine utilisation in children are scarce; however, the few available studies show differences between adults and children younger than 2 years of age. In adults, medication use is associated with female gender, which is not the case in children. In a study of children younger than 2 years old, gender was not associated with medication use [14]. Among studies of drug use in neonatology, the relationship between gender and drug administration was investigated in only one study, which was conducted in Detroit, MI, USA and found an association with male gender [2, 3, 5, 16]. No association between drug use and gender was identified in the present study. The inverse relationships between the number of medications used and gestational age and low birth weight are in agreement with previous studies [3, 8, 16, 17]. Very preterm infants have a higher rate of medical complications and require longer periods of hospitalisation, resulting in a higher rate of drug administration and a larger number of medications used. The high number of different medications used per patient, especially among neonates at high risk, is consistent

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123

1

1

1

1

1

1

1

1

1

1

1

1

Amikacin

Amphotericin B

Atropine

Cefadroxil

Cefazolin

Cefepime

Cefotaxime

Dipyrone

Glycerol

Chloral hydrate

Hydrochlorothiazide

Hydrocortisone

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

50.0

50.0

50.0

50.0

50.0

50.0

50.0

75.0

75.0

75.0

75.0

75.0

75.0

100.0

100.0

Zinc oxide and vitamins A ? D

2

Vancomycin

a

2

Ferrous sulphate

2

Caffeine anhydrous

2

3

Multivitamin

Furosemide

3

Midazolam

2

3

Gentamicin

Dopamine

3

Phytomenadione

2

3

Phenobarbital

2

3

Ampicillin

Dobutamine

4

Surfactant

Dexamethasone

4

Fentanyl

1 1

Captopril

1

2

2

2

2

2

3

3

3

3

3

4

4

Benzylpenicillin Potassium

Albumin

Methadone

Glycerol

Dopamine

Clindamycin

Amikacin

Paracetamol

Meropenem

Dobutamine

Cefepime

Amphotericin B

Furosemide

Dimethicone

4

5

Zinc oxide A and Da Cefotaxime

6

6

6

6

7

7

10

11

12

12

13

13

N

Surfactant

Phytomenadione

Dipyrone

Caffeine anhydrous

Vancomycin

Aminophylline

Ampicillin

Midazolam

Ferrous sulphate

Gentamicin

Multivitamin

Fentanyl

4

Epinephrine

100.0

n = 14

N

n=4

Incidence

Drugs for gestational age = 28–30 weeks

Drugs for gestational age = 24–27 weeks

7.1

7.1

7.1

14.3

14.3

14.3

14.3

14.3

21.4

21.4

21.4

21.4

21.4

28.6

28.6

28.6

35.7

42.9

42.9

42.9

42.9

50.0

50.0

71.4

78.6

85.7

85.7

92.9

92.9

Incidence

Tropicamide

Rocuronium

Paracetamol

Oxacillin

Methadone

Lidocaine

Indomethacin oral solution

Hypromellose ? dextran

Furosemide

Phenylephrine

Epinephrine

Cefotaxime

Amikacin

Nystatin

Dimethicone

Vancomycin

Phytomenadione

Dipyrone

Aminophylline

Surfactant

1

1

1

1

1

1

1

1

1

1

1

1

1

2

2

3

3

3

6

8

9 8

Zinc oxide A and Da

10

10

10

11

12

26

N

Ferrous sulphate

Midazolam

Caffeine anhydrous

Ampicillin

Gentamicin

Fentanyl

Multivitamin

n = 30

Drugs for gestational age = 31–33 weeks

Table 3 Exposure rates (%) for the most frequently prescribed drugs according to gestational age

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

3.3

6.7

6.7

10.0

10.0

10.0

20.0

26.7

26.7

30.0

33.3

33.3

33.3

36.7

40.0

86.7

Incidence

Hydrochlorothiazide

Glycerol

Phenobarbital

Paracetamol

Pancuronium

Dexamethasone

Cefotaxime

Cefazolin

Cefadroxil

Rocuronium

Dextroketamine

Surfactant

Furosemide

Epinephrine

Dopamine

Amikacin

Nystatin

Vancomycin

Ferrous sulphate

Phytomenadione

Dobutamine

Dipyrone

Ampicillin

Gentamicin

Midazolam

Fentanyl

3

3

3

4

4

4

4

4

4

5

5

6

6

6

6

6

7

8

8

8

8

10

15

17

19

20

38 21

Multivitamin

N

Zinc oxide A and Da

n = 52

Drugs for gestational age = 34–36 weeks

5.8

5.8

5.8

7.7

7.7

7.7

7.7

7.7

7.7

9.6

9.6

11.5

11.5

11.5

11.5

11.5

13.5

15.4

15.4

15.4

15.4

19.2

28.8

32.7

36.5

38.5

40.4

73.1

Incidence

Metronidazole

Meropenem

Lidocaine

Glycerol

Furosemide

Dopamine

Dextroketamine

Cefotaxime

Amikacin

Rocuronium

Nystatin

Ferrous sulphate

Phytomenadione

Dexamethasone

Vancomycin

Phenobarbital

Epinephrine

Cefadroxil

Paracetamol

Cefazolin

Midazolam

Fentanyl

Dipyrone

Multivitamin

Zinc oxide A and Da

Ampicillin

Gentamicin

n = 87

3

4

4

4

4

4

4

4

6

7

7

8

8

9

11

11

12

12

14

15

17

17

17

20

26

28

35

N

3.4

4.6

4.6

4.6

4.6

4.6

4.6

4.6

6.9

8.0

8.0

9.2

9.2

10.3

12.6

12.6

13.8

13.8

16.1

17.2

19.5

19.5

19.5

23.0

29.9

32.2

40.2

Incidence

Drugs for gestational age C37 weeks

Int J Clin Pharm

Int J Clin Pharm Table 4 Univariate analysis of clinical, demographic and perinatal variables associated with drug use in the 187 studied neonates Variable

Factor

Gender

Death

Gestational age

Birth weight

Route of Childbirth

a

Odds ratio,

b

Use of medicine

p value

No

Yes

Total

Male

19

89

108

Female

11

68

79

Total

30 (16 %)

157 (84.0 %)

187 (100.0 %)

No

30

143

173

Yes

0

14

14

Total

30 (16 %)

157 (84.0 %)

187 (100.0 %)

[37 weeks \37 weeks

22 8

65 92

87 100

ORa

ICb 95 % LLc

0.63e

1.00 1.32

0.13f

0.001e

ULd

0.59

2.96

1.00 2.91

0.358

106.1

1.00 3.89

1.632

9.28

1.062

5.33

Total

30 (16 %)

157 (84.0 %)

187 (100.0 %)

Without low weight

19

66

85

With low weight

11

91

102

Total

30 (16 %)

157 (84.0 %)

187 (100.0 %)

Vaginal

18

55

73

Caesarean

9

97

106

3.12

1.46

8.00

Forceps

3

5

8

0.40

0.12

2.21

Total

30 (16 %)

157 (84.0 %)

187 (100.0 %)

confidence interval, c lower limit,

d

0.03e

1.00 2.38

0.002g

1.00

upper limit, e Chi-square test with Yates correction, f Fisher’s exact test,

with international studies showing an increase since the 1990s, and reflects advances and changes in neonatal pharmacotherapy. The mean number of different drugs administered per patient in the present study was 6.4, which is consistent with published reports showing variations between 3.6 and 11.1 medications per patient [2, 3, 5, 8, 18–20]. Variables that are directly or indirectly related to the severity of the patient’s condition may be associated with a higher prevalence of drug administration [14]. Therefore, the duration of mechanical ventilation, length of hospital stay, Caesarean section delivery, low birth weight and gestational age may have affected the number amount of drugs administered to the neonates in the NCU investigated in this study. Multiple diagnoses and specific physiological and biochemical changes in newborns are determinants of polypharmacy in this age group. Among the competitors or intercurrent diagnoses common in neonatology, which may predispose clinicians toward prescribing drugs, we highlight respiratory distress syndrome, apnea, patent ductus arteriosus, transient tachypnea, aspiration syndrome and sepsis [6]. Some of these diagnoses were common in the investigated NCU; thus, they contributed as determinants in the drug utilisation profile. A multicentre study conducted in the USA found a profile of antimicrobials such as ampicillin and gentamicin that represented the most prescribed anti-infectives for systemic use [22]. Moreover, those authors found that

g

Chi-square test

41.0 % of patients in the NCU used at least one antimicrobial. In our study, this rate was 48.7 %; however, there is an apparently wide variation in the most frequently used antibiotics. Amikacin, tobramycin, ampicillin, sulbactam ? ampicillin, piperacillin and cefotaxime were reported in some studies as the most frequently prescribed antibiotics for neonates [3–5, 7, 18, 19, 21, 23], The administration of systemic antifungal drugs such as amphotericin B, deoxycholate and liposomal amphotericin B occurred only in patients with gestational ages \30 weeks in the present study. In a retrospective cohort study of the drugs used in an NCU, amphotericin was primarily administered to extremely premature neonates with a mortality rate greater than 20.0 % [4]. In the present work, the pattern of drugs used according to gestational age was equivalent to the findings of a retrospective cohort study conducted in the USA [4]. In both studies, neonates with gestational ages \32 weeks were administered caffeine citrate, surfactants, vancomycin, furosemide, dopamine and nystatin. Neonates with gestational ages [37 weeks, reflecting less severe clinical conditions, mainly received gentamicin, ampicillin and multivitamins. Chronic lung diseases are more common among premature infants, and their incidence is inversely correlated to birth weight and gestational age [24]. Surfactant therapy has revolutionised neonatal respiratory care in the last two decades [25]. Warrier et al. [3] reported that the majority of patients (81.0 %) who were born at 24–27 weeks received

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Int J Clin Pharm Table 5 Factors influencing the number of drugs used in treating the 187 studied neonates

ba

Variable

SEb

p value

Expc (b)

Gender Intercept = male

1.728

0.122

0.000

5.629

Gender = female

0.264

0.175

0.134

1.302

2.918

0.345

0.000

18.501

Gestational age Intercept = 24–27 weeks Gestational age 28–30 weeks

-0.331

0.408

0.418

0.718

Gestational age 31–33 weeks

-1.363

0.425

0.002

0.256

Gestational age 34–36 weeks

-0.991

0.379

0.010

0.371

Gestational age [37 weeks

-1.325

0.373

0.001

0.266

Birth weight Intercept C2500 g Birth weight 2499–1500 g

1.802

0.132

0.000

6.059

-0.192

0.201

0.341

0.825

Birth weight 1500–1000 g

0.507

0.265

0.058

1.660

Birth weight B1000 g

1.070

0.321

0.001

2.916

1.123

0.086

0.000

3.073

0.024

0.002

0.000

1.025

Intercept = discharge

1.925

0.108

0.000

6.852

Evolution = death

0.900

0.219

0.000

2.460

-0.747

0.228

0.001

0.474

Length of stay Intercept = 0 Length of stay Evolution

Evolution = transfer Route of childbirth Intercept = vaginal

1.544

0.162

0.000

4.685

Route of childbirth, Caesarean

0.495

0.193

0.011

1.641

-0.223

0.569

0.696

0.800

Intercept = 0

1.530

0.076

0.000

4.619

Mechanical ventilation time (days)

0.039

0.003

0.000

1.040

Route of childbirth, Forceps Mechanical ventilation time (days)

a

Coefficient of regression,

b

standard error,

surfactant, whereas Neubert et al. [8] and Lindner et al. [26] found lower percentages (70.0 and 75.0 %, respectively). In our study, surfactants were prescribed to 100.0 % of the neonates in this age group, which reflects the complexity of care for neonates in the investigated NCU. Among the very preterm infants (28–30 weeks), nearly half (42.9 %) received surfactants; this rate was close to that found by Neubert et al. [8]. Methylxanthines have long been used to treat apnea of prematurity and to facilitate the successful extubation of mechanically ventilated patients. Recurrent apnea occurs frequently in preterm children, and its incidence and severity are inversely related to gestational age [27–29]. In the present study, 50.0 and 42.9 % of the patients born at 24–27 weeks and 28–30 weeks of gestation, respectively, received caffeine. Neubert et al. [8] reported similar values (53.8 and 45.4 %, respectively) in a study conducted in Germany. Sildenafil was used for only one patient with pulmonary hypertension in the present work. Despite recent advances,

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c

exponential

the clinical approach to treating persistent pulmonary hypertension of the newborn remains an important challenge for neonatologists [30]. Recent studies have proposed the use of sildenafil, an inhibitor of phosphodiesterase 5, for refractory forms of pulmonary hypertension. However, this drug has not yet been approved for this indication in children and neonates by either the FDA or the ANVISA. However, increased neonatal death related to prolonged use of sildenafil has been reported [31]. Therefore, safety and pharmacokinetic studies with appropriate designs and sufficient statistical power to establish the risk/benefit ratio of this drug are necessary to contribute to the development of utilisation protocols [32, 33]. In the package inserts of the medicines available in Brazil, the availability of information about drug use in specific paediatric age groups is scarce. Specific information on drug use in neonatology, and in particular directed to preterm infants, was less common in Brazilian drug labelling than in labelling in other countries. This finding was also verified by Lass et al. [17] in the Estonian

Int J Clin Pharm

summaries of product characteristics. Thus, an upgrade of the package inserts is required in Brazil, and the dose recommendations and safety information must be available at moment the drug is registered by a regulatory agency. For some drugs, such as ampicillin and gentamicin, information is available in the literature to support a safe and effective prescription in neonates [8]. However, this information is not included in the Brazilian drug labelling. The National Institute of Child Health and Human Development (NICHD) in the USA and the European Medicines Agency have developed a prioritised list of paediatric drugs requiring further research [33, 35]. The medications on the NICHD list that are of specific interest to neonatology include hydrochlorothiazide and betamethasone for treating bronchopulmonary dysplasia, morphine for treating pain, methadone for treating neonates exposed to opioids and antiinfectives (metronidazole, ampicillin, meropenem and azithromycin) for treating neonatal infections [35]). Clark et al. [4] recommended that caffeine, aminophylline, and theophylline for treating apnea and vancomycin and cefotaxime for treating sepsis be included in this list. Our study reinforces that research on these drugs is critical to enhance the safety of neonatal pharmacotherapy because these drugs are commonly available in the therapeutic arsenal of neonatal units in Latin America. With regard to the use of sildenafil in neonatal care, considering the level of current evidence on neonatal and employment criteria, Ward et al. [36] recommended that this drug be included in the lists of drugs to be investigated in neonates when prioritising research on medicines for paediatric patients. The development of formulations suitable for infants that contain drugs such as sildenafil, lorazepam, pyrimethamine and sulfadiazine is also essential. Toxoplasmosis infections are still prevalent in Brazil; thus, identifying the proper formulation to optimise treatment and allow the patient to remain at home, which requires both an accurate dose and ease of administration, is critical. The drugs that are unregistered in Brazil but were used during the study period were modified from the registered dosage form by the nurse staff or pharmacy service to suit the neonate patient (such as crushing tablets to prepare a suspension or powder) or were imported drugs (drugs such as alprostadil that were imported from a country where they are licensed). Compounding was used as a means to facilitate the administration of the following drugs: amiodarone, caffeine, captopril, carvedilol, spironolactone, furosemide, hydrochlorothiazide, indomethacin, lorazepam, methadone, nifedipine, pyrimethamine, sildenafil, sulfadiazine, and methimazole. The lack of drugs with appropriate dosage forms and dosage strengths for neonates compels physicians to prescribe drugs in solid forms marketed for paediatric or adult use [37, 38]. To administer these medicines, hospital

nursing staff must perform unacceptable procedures such as crushing tablets and mixing them with diluents or opening capsules and mixing the powder with diluents or food. The following risks are associated with these adaptations: dose inaccuracy, contamination during handling, incompatibilities, and different interactions [39–41]. The strengths of present study include the follow-up of the newborns’ drug prescriptions during the entire length of stay in the NCU and the investigation of perinatal factors that influence drug usage in neonatology, which is a subject that is still rarely investigated. However, the study does have several limitations. First, the study was conducted at a single teaching hospital and may reflect local practices rather than patterns of drug use at other centres across Brazil. Second, the sampling was consecutive and limited to 187 participants. Nevertheless, the findings relating to the drug pattern were very similar to those obtained at centres in other countries. Importantly, most newborns included in this study had required referral to a tertiary care centre, and the results reflect drug use in a high-risk population of newborns. Third, the population was admitted to the NCU for [24 h. Further studies would be required to describe drug therapy in NCU populations admitted for \24 h. Finally, we used univariate Poisson regression analysis, which differs from multiple regression because it does not permit the identification of many variables that operate independently or in concert with one another to explain variation in the dependent variable. The identification of factors related to drug use in neonatology using multivariate regression analysis should also be addressed in future investigations. In Brazil, more studies must be conducted to verify the therapeutic classes that are priorities for drug research in neonatology and to identify which incentives should be introduced to promote more research in this area.

Conclusions Drug utilisation in neonatology units is common and is inversely correlated with gestational age and birth weight. Newborns are exposed to a variety of therapeutic classes; this exposure reflects the recent scientific advances in neonatology. The drug profile is compatible with current standards of care in international neonatology practice. However, the availability of drug labelling with information specific to neonates is scarce for Brazilian medicines. Funding This research was supported by a grant from Pro´-Reitoria de Pesquisa da Universidade Federal de Minas Gerais for the Qualitative Improvement Program of Scientific Production. Conflicts of interest

The authors declare no conflict of interest.

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Int J Clin Pharm

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