Medication use in the neonatal intensive care unit in a tertiary hospital in China from 2020 to 2023

Abstract

Background

The use of medication in the neonatal intensive care unit (NICU) is a complex field that requires special attention, as neonatal patients may have different sensitivities and responses to drugs than adults and older children. The administration of medication in the NICU must consider various factors, including the dosage of the medication, the route of administration, monitoring, and potential drug interactions.

Methods

In this study, we conducted a retrospective analysis of medication use in the neonatal intensive care unit of 122 preterm infants treated in our hospital from 2020 to 2023.

Results

Correlation analysis revealed that among perinatal clinical characteristics, birth weight was moderately positively correlated with gestational age, with a correlation coefficient greater than that of birth weight with the Apgar score. The top 3 medication types in the NICU were “vitamins, nutritional drugs, enzyme preparations and drugs that regulate water, electrolytes, and acid-base balance”, “blood hematopoietic system medications”, and “antimicrobial medications”. From 2020 to 2023, the most commonly used drugs in the NICU were vitamin AD (vitamin A and vitamin D) drops and calcium gluconate injections. In addition, we demonstrated that the most commonly prescribed off-label drugs were vitamins, water and electrolyte balance nutrition drugs, and blood circulation system drugs.

Conclusions

Our retrospective study will not only help identify and evaluate interventions to reduce medication errors but also aid healthcare systems and providers in understanding, implementing, and enhancing these interventions to improve the safety and quality of care for newborns. Nonetheless, further research is needed to assess the relative cost-effectiveness of various medication safety interventions to facilitate their adoption and implementation in the decision-making process.

Introduction

The neonatal intensive care unit (NICU) is a specialized unit for unwell and preterm newborns [1]. In the NICU, the use of medication requires special attention and precise management [2]. Currently, many unresolved issues concerning pediatric medication use exist worldwide. In China, pediatric medication also faces several challenges, including a lack of drug varieties, low enthusiasm for research and development by companies, and insufficient guidance and encouragement from the government. There is a severe shortage of pediatric-specific drugs in our country, with fewer than 60 out of more than 3,500 chemical drug preparations accounting for less than 2% of all drugs. Infants in the NICU are exposed to a large number of medications; because of the lack of clinical trials for the safety, dosing, and efficacy of drugs in this population, most of these medications are not labeled for use in infants [3,4,5]. Owing to ethical concerns, difficulties with recruitment and financial expenses, pharmacokinetic studies are difficult to perform in infants [2, 3, 6].

High-risk situations are more often associated with significant harm due to unsafe medication practices or medication errors. The three factors that determine high-risk situations are the use of high-risk (high-alert) medications (such as aminoglycosides, potassium replacement or opioids), patient-related factors such as increased vulnerability at the extremes of life, and systems factors (work environment). On the basis of the former three factors, interventions in NICUs should be considered one of the highest-risk situations for medication errors in inpatient care [7]. In summary, the use of medication in the NICU must be carried out according to professional guidelines and a consensus to ensure the safety and efficacy of the drugs used. Moreover, the field of pediatric medication requires more attention and policy support to promote the research, development, and market supply of pediatric-specific drugs.

Some studies have estimated that 5–27% of medication orders for children contain an error somewhere at any instance, such as prescribing, dispensing, or administering [8,9,10,11]. Previous studies have demonstrated trends in medication use in the NICU [2, 6]. However, there have been no reports on the analysis of drug use in Chinese NICUs to date. This study aimed to identify the drugs used most commonly for NICU infants receiving care at the seventh center of the Chinese PLA General in China and to evaluate medication changes between 2020 and 2023. Our study will assist neonatologists in the use of medication and offer a basis for the formulation of health policies.

Methods

This study was approved by the Ethics Committee of the Seventh Medical Center of PLA General Hospital (S2024-046-01) and consisted of the Declaration of Helsinki. The studies were conducted in accordance with local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because of the retrospective design of the study.

The clinical data of these neonates were recorded during their hospitalization in the NICU. The pharmacy database was used to collect data on all drugs dispensed by the pharmacy. Over 3 years, from September 2000 to October 2023, all neonates were admitted to tertiary academic NICUs at the Seventh Medical Center of the PLA General Hospital, Beijing.

The neonates’ gestational age, birth weight, sex, date of birth, admission and discharge dates, clinical outcomes, Apgar scores, duration of mechanical ventilation, and clinical diagnoses were collected from medical records. The infants were divided into preterm infants (less than 37 weeks) and full-term infants (37 weeks or more). Preterm infants were further divided into three subgroups based on gestational age: the 24- to 30-week group, the 31- to 33-week group, and the 34- to 36-week group. The infants were divided into normal birth weight infants (2500 g or more) and low birth weight infants (less than 2500 g). Low birth weight infants were further divided into two subgroups: very low birth weight infants (1000 to 1499 g) and low birth weight infants (1500 to 2499 g).

All the medications were assigned to a drug category, such as antibiotics or analgesics, based on the most frequent indications and physiological effects. The number of medications refers to the total variety of drugs prescribed to all pediatric patients. If multiple medication orders contain the same type of drug, the number of medications is combined and counted as one. The cumulative number of medications is the sum of the medications used by all patients.

Statistical analysis

Statistical analysis was performed via SPSS 20.0 software. The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to assess the normality of the quantitative data. Data that were normally distributed are expressed as the mean ± standard deviation, whereas nonnormally distributed quantitative data are represented as M(Q25, Q75). The relationships between perinatal and clinical demographic characteristics and the number of medications used in neonatal patients were analyzed via the Mann-Whitney U test, the Kruskal-Wallis H test, and Spearman’s rank correlation analysis. A difference was considered statistically significant at P < 0.05.

Results

Demographic data

A total of 122 patients were enrolled, including 66 males and 56 females (Fig. 1A). Among the 122 patients, 75 (61.5%) were from urban areas, and 47 (38.5%) were from rural areas, indicating that hospital admissions from urban areas are far greater than those from rural areas (Fig. 1B). Figure 1C shows the patient count each year from 2020 to 2023.

Fig. 1

NICU infants at the Seventh Medical Center of the PLA General Hospital (2020–2023). (A) Gender distributions for inpatients. (B) Location distributions for inpatients. (C) Inpatient admissions by year

In this study, among the 122 severe neonatal cases included, 42 were preterm infants (35%), and 78 were full-term infants (65%). In addition, there were 2 infants whose babies were abandoned, and personal information had not obtained. All 122 neonates were exposed to drug treatment, with 116 different types of drugs used, and the total number of drugs used by the patients was 2,926. The sex of the infant and the mode of delivery had no significant impact on the number of drugs used in neonates. Correlation analysis revealed that among perinatal clinical characteristics, birth weight was moderately positively correlated with gestational age. Specifically, the correlation coefficient between birth weight and gestational age was greater than that between birth weight and the Apgar score. There was a weak negative correlation between hospital stay and the Apgar score, as shown in Fig. 2. The gestational age at birth, mode of delivery, birth weight, Apgar score, and clinical treatment outcomes of the neonates were negatively correlated with the number of drugs used by the neonates; hospital stay was positively correlated with the number of drugs used by the neonates. In terms of the magnitude of the correlation coefficients, gestational age, birth weight, hospital stay, and the Apgar score were strongly correlated with the number of drugs used by the neonates, as shown in Table 1.

Table 1 Clinical and demographic characteristics of the 122 infants

Fig. 2

Analysis of the correlation between clinical characteristics and the number of medications

Medication changes in the neonatal intensive care unit from 2020 to 2023

From 2020 to 2023, the drugs were classified, the percentage was determined, and the dosage was calculated according to the minimum package of each drug (tablets and packages were calculated to the minimum unit). The top 3 medication types in the NICU of our hospital were vitamins, nutritional drugs, enzyme preparations and drugs that regulate water, electrolyte, and acid-base balance (26, 22.41%), blood hematopoietic system medications (23, 19.83%), and anti-infective medications (17, 14.66%) (Table 2).

Table 2 Distributions of medications used in the NICU

The number of drugs used in the NICU tended to decrease, and the total amount of drugs used decreased slightly (Table 3). Taking the total dosage in 2020 as a reference (set at 100%), the dosages in 2021, 2022 and 2023 were 91.34%, 97.86% and 89.25%, respectively. The increase in total drug dosage from 2020 to 2023 compared with that in the previous year was − 8.52%, -8.62% and − 13.77%, respectively. From 2020 to 2023, the total amount of nutritional drugs, hematological and hematopoietic drugs, and antiinfective drugs increased by -8.08%, 101.79%, and − 6.16%, respectively, compared with the total amount in the previous year.

Table 3 Medication use in the neonatal intensive care unit

Analysis of the defined daily dose (DDD) of medications in the NICU

Drug consumption can be expressed in terms of cost, number of units, number of prescriptions or the physical quantity of drugs. However, these variables can vary between regions and countries over time, which limits comparisons of drug consumption at an international level. To address this, a technical unit of measurement, the defined daily dose (DDD), was created.

The DDD, established by the World Health Organization (WHO) as the average standard daily dose of a medicine DDD, is very important in drug utilization research (DUR), as it can help researchers assess trends in medication use and differences in drug utilization among various populations or at different points in time [12, 13]. Table 4 shows the top 15 drugs ranked by DDDs in the NICU from 2020 to 2023 in our hospital. Among them, calcium gluconate injection had the highest DDDs, ranking first for three consecutive years. From 2020 to 2023, the top three most commonly used drugs in the NICU were vitamin AD drops and calcium gluconate injection, which are the preparations for vitamin AD and calcium supplementation for neonates. The therapeutic drugs mainly include fructose sodium diphosphate oral solution, vitamin K1 injection, imipenem and cilastatin sodium, water-soluble and fat-soluble vitamins and furosemide injection. During this periods, the top 15 drugs associated with DDDs did not change significantly; these drugs included vitamins, water and electrolyte balance nutrition drugs, anti-infective drugs and hematological system drugs.

Table 4 The top 10 drugs ranked by DDDs in the NICU of our hospital from 2020–2023

Use of off-label medicines in neonatal intensive care

Preterm newborns received more off-label drugs than full-term newborns [14]. During this period, 20 kinds of drugs were not mentioned in the instructions for neonates, accounting for 17.24% (20/116) of all kinds. The most commonly prescribed off-label drugs were vitamins, water and electrolyte balance nutrition drugs, and blood circulation system drugs (Table 5).

Table 5 Most commonly prescribed off-label drugs

Discussion

With the development of perinatal neonatal medicine, the survival rate of newborns has significantly increased, and the incidence and mortality rates of various diseases have decreased, with improvements in the cure and improvement rates, indicating that there may be more newborns in urban areas who are sent to the NICU because they can receive better treatment [15,16,17].

The drugs used in the NICU from 2020 to 2023 were collected in this study. A total of 122 severe neonates were enrolled, including 43 preterm infants (35.54%) and 78 full-term infants (64.46%). The number of drug varieties used in this study was 116, and the cumulative number of drugs used was 2,926. The gestational age at birth, mode of delivery, birth weight, Apgar score, and clinical treatment outcomes of the neonates were negatively correlated with the number of drugs used by the neonates.

The top 3 medication types used in our NICU were “vitamins, nutritional drugs, enzyme preparations and drugs that regulate water, electrolyte, and acid-base balance”, “blood hematopoietic system medications”, and “antimicrobial medications”. Our study demonstrated that the number and total amount of drugs used in our NICU tended to decrease. From 2020 to 2023, the top 15 drugs affected by DDDs did not change significantly.

The medications used in the NICU change frequently over time, and medication use trends usually follow trends in diseases of the neonate [6]. The disease spectrum observed among neonates has changed markedly in recent years [18]. In the NICU, primary prevention strategies such as vaccines or immunoglobulins (e.g., against RSV), antifungal prophylaxis, and careful antibiotic use and other antimicrobial stewardship actions can help reduce drug use, disease incidence, and complications [19,20,21,22]. The neonatal period is defined as the first 4 weeks of life, and it is the time during which children are most vulnerable, with an estimated 2.3 million newborns dying during this period in 2022, according to the WHO. With the increase in facility births (almost 80% globally), there is a great opportunity for providing essential newborn care and identifying and managing high-risk newborns. Hsieh et al. reported that the medications administered from 2005 to 2010 in the United States were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant [2]. The medications with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Those associated with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram. Notably, only 35% of the most commonly prescribed medications are FDA-approved for infants [2].

In the NICU, the use of off-label (OL) medications is a common practice. Nearly all newborns in intensive care units, mainly preterm infants, were exposed to at least one off-label (OL) medication during their hospital stay [23]. Among these off-label medications, anti-infective drugs are the most commonly prescribed type. In particular, newborns with respiratory failure and pneumonia use these drugs more frequently, and no association was found between the use of off-label medications and the number of deaths [23]. Although the use of off-label medications is not significantly associated with the occurrence of complications during hospitalization, many of these medications were used in preterm infants with complications such as atelectasis and respiratory failure. Another study enrolled 799,016 infants treated in the NICU from 2010 to 2018 and reported that the most frequently prescribed medications were ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, acetaminophen; however, only 40% of the medications used in infants with extremely low birth weights (ELBWs) were FDA-approved [6].

Our study demonstrated that the dosage of nutritional drugs ranked first for three consecutive years. Nutrition is very important in neonatal monitoring. Nutritional drugs include vitamins, water and electrolyte balance drugs. Recently, adequate nutrition and caloric intake have been shown to be crucial in reducing the risk and severity of BPD. Greater respiratory demands in infants with respiratory distress syndrome. Protein anabolism is also maintained, as amino acids are responsible for the growth and repair of damaged tissues, such as alveoli, and the synthesis of proteins, such as hemoglobin, hormones and enzymes. Among lipid mixtures, long-chain fatty acids are known to have important anti-inflammatory functions and to participate in the lung maturation process [24].

The DDD values of drugs for newborns are not all clear. The World Health Organization has not specified the DDD values of drugs for newborns because of the differences in neonatal weight between countries [25]. Based on “New Pharmacology” and drug instructions, combined with the actual clinical application in our hospital, the DDD value was determined, and the corresponding DDDs were calculated to understand the medication situation in the NICU.

This study revealed that the DDDs of vitamin AD agents and calcium gluconate injections used for the prevention and treatment of vitamin A and D deficiency ranked in the top three for 4 consecutive years. Vitamin A, also known as retinol, retinal, and retinoic acid (RA), was the first fat-soluble vitamin. Retinol is the transported form of vitamin A stored in the liver and is converted to retinyl esters. Moreover, vitamin A is considered a significant hormone and an immune modulator in terms of structure and functionality. Retinoic acid and its cognate retinoic acid receptors (RAR and RXR) are considered pleiotropic modulators of adaptive and innate immune responses [26].

The functions of vitamin D include growth and bone mineralization, regulation of immune function, regulation of insulin secretion, control of cell proliferation, stimulation of cell differentiation, induction of apoptosis, regulation of phosphorus and calcium homeostasis, and regulation of muscle calcium transport [27]. Vitamin B12 (cobalamin) is required for red blood cell (RBC) synthesis, nervous system health, myelin synthesis, production and functioning of the innate and adaptive immune systems, cellular growth, and accelerated DNA synthesis. Active forms of vitamin B12, including adenosyl-hydroxy and methyl-cobalamin, are essential for gut microbiome modulation [28]. B12 deficiency can lead to increased methylmalonic acid and homocysteine levels. This increase could induce intensified inflammation, reactive oxygen species, and oxidative stress, contributing to endothelial dysfunction, platelet activation, and stimulation of the coagulation cascade [29, 30]. The top 15 DDDs were also Zhihuang granules, vitamin K1 injection, fat-soluble vitamins for injection, fat emulsion injection, and amino acid injection, which are in line with the clinical diagnosis and treatment guidelines.

Our study emphasizes the necessity of reviewing drug package inserts to provide more support for professionals who prescribe medications and to offer greater safety for patients who need to use them. Given the ethical difficulties in conducting clinical trials in newborns, retrospective studies on the use of off-label medications in NICUs can be used by regulatory agencies to review drug package inserts.

In this study, we described the medications reported most commonly for neonates admitted to the NICU. We believe these data will be essential in helping focus future research activities. The results of this study confirm that critically ill neonates receive a significant number of drugs during their hospital stay.

Conclusions

In conclusion, the characteristics of the main drugs used in our NICU are clear, but some off-label drugs are used. The frequency of the use of anti-infective drugs in neonates is low. However, owing to the particularity of the use of intensive care, attention still needs to be paid to improving the rationality of medication-related management. The monitoring of adverse drug reactions should be strengthened to improve further the safety, rationality and effectiveness of neonatal drugs in our hospital.