Phenobarbital is Associated with Cholestasis in Preterm Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

doi:10.21203/rs.3.rs-1599063/v1

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Phenobarbital is Associated with Cholestasis in Preterm Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

https://doi.org/10.21203/rs.3.rs-1599063/v1

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Objectives: This retrospective study aimed to assess whether phenobarbital was associated with cholestasis in preterm infants with hemo-dynamically significant patent ductus arteriosus (hsPDA).

Methods: This study included 151 preterm infants (24~34 weeks, birth weight<2000 g) diagnosed with hsPDA, admitted to a level III neonatal intensive care unit (NICU) from September 2016 to September 2019. Of the 151 infants, twenty-seven infants were diagnosed with cholestasis. To assess the independent association of phenobarbital with cholestasis, binary logistic regression was done, adjusting for major confounders (birth weight, gestational age, critical risk index for babies and etc).

Result: To explore whether the risk of cholestasis was independently increased by duration of phenobarbital, binary logistic regression analysis was done adjusting for significant confounders (p<0.05). After adjustment with confounders “critical risk index for babies”, “invasive mechanical ventilation”, “any sepsis onset in 28 days” and “duration of cimetidine”, cholestasis was still associated with “duration of phenobarbital” (OR: 1.350; 95% CI: 1.064, 1.714; P = 0.014) and “CMV infection” (OR: 10.818; 95% CI: 0.915, 127.914; P = 0.059). Furthermore, “duration of phenobarbital” might independently delay the time to reach full enteral feeding (OR: 1.479; 95% CI: 1.088, 2.011; P = 0.013), causing parenteral nutrition associated cholestasis.

Conclusion: This study found that duration of phenobarbital was associated with neonatal cholestasis in premature infants with hsPDA. Phenobarbital should be used cautiously in preterm infants with hsPDA or cholestasis.

neonatal cholestasis

phenobarbital

patent ductus arteriosus

premature infants

What is known?

Case reports indicated that phenobarbital might cause cholestasis in children and adults.

Controversy of phenobarbital in treatment of cholestasis in NICU.

What is new?

The duration of phenobarbital increased the risk of cholestasis in premature infants with hsPDA.

Phenobarbital has been extensively used in neonates for treatment of seizure, hypoxic ischaemic encephalopathy (HIE), or for prophylaxis of intraventricular hemorrhage (IVH). Phenobarbital is still the first-line choice for neonatal seizures, because of extensive clinical experience, despite limited clinical effectiveness and potential neurotoxicity [1–3]. Furthermore, phenobarbital is used in combination with therapeutic hypothermia for seizure control and neuroprotection in neonates with HIE. The neuroprotective benefits of phenobarbital have been described in animal [4] and clinical studies of HIE [5]. Postnatal administration of phenobarbital is also used to prevent IVH in preterm infants, whereas is associated with an increased need for mechanical ventilation [6].

Notably, phenobarbital is also used in treatment of hyperbilirubinemia, cholestasis and its complication, pruritus in neonates. Phenobarbital regulates constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR), which further regulates hepatocellular metabolism enzymes and transporters, including UDP-glucuronosyltransferase (UGT1A1) and multidrug-resistance-associated protein 2 (MRP2) [7–9], responsible for the detoxification of bilirubin. Phenobarbital is reported to reduce the serum bile acid in cholestasis [10]. Furthermore, phenobarbital improves neonatal unconjugated hyperbilirubinemia in the liver [11]. Phenobarbital also increases the accuracy of hepatobiliary scintigraphy by enhancing bile isotope excretion [12]. Case reports indicated that phenobarbital is useful for treatment of Dubin-Johnson syndrome with conjugated hyperbilirubinemia [13, 14], which is caused by deficit of MRP2 [15]. Additionally, phenobarbital is useful in controlling pruritus, a complication of cholestasis, in children [16].

Controversially, growing evidences suggest that phenobarbital may aggravate neonatal cholestasis. A study found that 60% of phenobarbital-treated infants developed parenteral nutrition (PN) associated cholestasis, as compared to 33% of the untreated patients[17]. A retrospective cohort study suggested that phenobarbital has limited efficacy for the reduction of direct bilirubin in neonates and young infants with cholestasis in the neonatal intensive care unit (NICU), and advocated to avoid phenobarbital in the treatment of neonatal cholestasis [18]. Additionally, case reports indicated phenobarbital can aggravate the cholestatic bile acid pattern in infants with cholestasis [19].

Interestingly, some evidences indicate hemo-dynamically significant patent ductus arteriosus (hsPDA) is associated with increased risk of cholestasis in preterm infants. An epidemiological study with multiple logistic regression analysis identifies that patent ductus arteriosus (PDA) is an independent risk factor for PN associated cholestasis in infants [20]. Neonates with cholestasis is associated with hsPDA (76.9% vs 42.4%, P = 0.04) than neonates without cholestasis [21]. Our previous study found that preterm neonates with hsPDA is associated with increased risk of cholestasis than neonates without significant PDA (19.0% vs 3.4%, P = 0.007), this result is still significant even after adjustment with multiple logistic regression (OR: 6.730; 95% CI: 1.279, 35.410; P = 0.024) [22]. Therefore, this retrospective study aimed to further explore whether phenobarbital is associated with cholestasis in preterm infants with hsPDA.

Study design

In this study, preterm infants (24~34 weeks, birth weight<2000 g) diagnosed with hsPDA, admitted to the NICU of our hospital in 48 hours after birth between September 2016 to September 2019, were included. Clinical and demographic data were collected from medical records of the included patients until discharge. Exclusion criteria were as follows: malformations, genetic defects, severe asphyxia (defined as a blood pH<6.8), admitted to NICU at ≥48 hours of postnatal age, hospital stay <28 days, and death or giving up treatment in postnatal 28 days. Finally, a total of 151 preterm infants were included in the analysis (Fig. 1).

If there were any signs of cardiomegaly or pulmonary edema on chest radiograph, respiratory difficulty, hypotension, decreased urine output or metabolic acidosis suggesting hsPDA, we checked the echocardiography for the confirmation of hsPDA, which was defined as a PDA with a transductal diameter ≥1.4 mm/kg with significant left to right shunt[23, 24].

Feeding protocol

Enteral feeding was started mostly on the first day of life at 10-20 ml/kg/day divided into 8 meals with own mother’s milk or donor milk. Human milk fortifier was added when enteral feeding reached 80-100 ml/kg. Aspirate residual from an orogastric tube and abdominal aspect were checked before each meal. In the absence of signs of feeding intolerance for 24 hours, enteral feeding was increased daily by 10~20 ml/kg. Enteral nutrition was discontinued in the case of erythematic abdominal wall, absence of bowel sounds, blood in the stools, or bile or blood in aspirates associated with a radiologic marker of NEC-Bell stage II. PN was maintained through a central line in all infants to ensure adequate intake of fluids, electrolytes, and nutrients until full enteral feeding was reached. Iron was supplemented orally according to recommendations.

PN solutions

Common PN solutions for VLBW infants were composed of Sodium Glycerophosphate Injection (Glycophos, Fresenius kabi sspc), 10% and 50% glucose injection, 10% sodium chloride injection, 10% potassium chloride injection, Multi-trace Elements Injection (II) (Addamel, Fresenius kabi sspc.), Pediatric Compound Amino Acid Injection (19AA-I) (taurine included, China Resources Double-Crane Pharma.), Magnesium Sulfate Injection, Calcium Gluconate Injection, and 20% Soybean Oil, Fat Emulsions (Intralipid, Fresenius Kabi).

Once neonatal cholestasis diagnosed, fat emulsion were replaced immediately with 20% Multi-oil Fat Emulsion Injection (SMOFlipid, Fresenius Kabi Austria GmbH) to protect the infants from cholestasis[25]. There was no change during the period of retrospective study in terms of new generation lipid emulsion, carnitine, taurine, etc. No cyclic PN had been adopted in included cases [25].

Outcome measures

The main outcomes were the incidence rate of adverse outcomes of gastrointestinal tract, such as neonatal cholestasis (conjugated hyperbilirubinemia, duration of hospital stay > 21 days, and conjugated bilirubin ≥ 2 mg/dL, without other causes of hepatic dysfunction) and NEC (≥ Bell stage 2), during the hospitalization period. Secondary outcomes were time to reach full enteral feeding and hospital stay.

Data collection

Data regarding gestational age, weight at birth, mode of delivery, multiple birth, sex, Apgar score, presence of respiratory distress syndrome, presence of mechanical ventilation, start of enteral feeding, time to reach full enteral feeding, time-to-discharge, occurrence of late-onset sepsis, NEC≥stage 2, were collected by researchers not in charge of the clinical management of the participants. Discharge was decided with criteria indicated by the American Academy of Pediatrics.

Cholestasis associated risk factors were also recorded, including course of ibuprofen, type and duration of antibiotics, cytomegalovirus (CMV) infection during hospital stay. The drugs associated with cholestatic injury were scrutinized thoroughly in included cases, the usage of potential hepatotoxic antibiotics (such as ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) and other potential hepatotoxic agents (phenobarbital and cimetidine)[26] were recorded as confounders. The presence of any sepsis onset (early or late onset sepsis clinically diagnosed or cuture-proven) in 28 days of hospital stay may affect the onset of cholestasis, therefore were recorded as confounders.

Statistical analysis

The Kolmogorov-Smirnov test was used to determine whether variables were normally distributed. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test. For continuous variables of normal distribution, groups were compared with the independent-sample t-test. The chi-square test and Fisher’s exact test were used for categorical variables. To assess the independent association of treatment or duration of ibuprofen with the main outcomes and the secondary outcomes, binary logistic regression analysis was done, adjusting for indicated major confounders. The statistical analysis was done with IBM SPSS Statistics version 19.0 (IBM Corp., Amarok, NY, USA). P values less than 0.05 (2-sided) were considered statistically significant.

Ethics statement

This study was approved by the Institutional Review Board of Shenzhen Baoan women’s and Children’s Hospital (LLSCHY-2019-10-32). The need for informed consent was not required because of the retrospective nature of this study. All methods were performed in accordance with the relevant guidelines and regulations.

1. Main demographic and clinical characteristics of the study population

Among 151 preterm infants (<34 weeks, birth weight<2000 g) with hsPDA, 27 infants were diagnosed with cholestasis, with an estimated prevalence rate at 17.88% in this population (see Table1). Infant with cholestasis had more severe conditions, such as higher score of critical risk index for babies (p=0.034), been more often exposed to invasive mechanical ventilation (p=0.018), compared to infants without cholestasis.

Table 1

Main demographic and clinical characteristics of the study population

Characteristics	No cholestasis (n=124)	Cholestasis (n=27)	P
birth weight（g, mean±sd）†	1199.03±310.45	1088.70 ±279.75	0.091
gestational age（wk, mean±sd）†	29.09±2.09	28.45 ±2.03	0.149
twins [n(%)]‡	49 (39.5%)	12 (44.4%)	0.636
male [n(%)]‡	71 (57.3%)	17 (63.0%)	0.586
antenatal dexamethasone [n (%)]‡	97 (78.2%)	20 (74.1%)	0.640
cesarean delivery [n(%)]‡	79 (60.5%)	12 (44.4%)	0.126
small for gestational age [n(%)]‡	13(10.5%)	5 (18.5%)	0.401
Apgar score at 1 min [M (P25, P75)]§	8(7, 10)	9(7, 10)	0.672
Apgar score at 5 min [M (P25, P75)]§	10(9, 10)	10(9, 10)	0.786
critical risk index for babies [M (P25, P75)]§	7(4.25, 9)	8(6, 10)	0.034
start of enteral nutrition [days, M (P25, P75)]§	2(1, 3)	1(1, 3)	0.761
time to reach full enteral feeding [days, M (P25, P75)]§	19.5(14, 27)	29(24, 43)	0.002
NRDS [n (%)]‡	84 (67.7%)	14 (51.9%)	0.117
invasive mechanical ventilation [n (%)]‡	76 (61.3%)	23 (85.2%)	0.018
hospital stay (day, mean±sd) †	64.73±23.54	74.04±18.52	0.056

†. For continuous variables of normal distribution, groups were compared with the independent-sample t-test.

‡ . The chi-square test and Fisher’s exact test were used for categorical variables.

§ . For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test.

PLT, platelet; NRDS, neonatal respiratory distress syndrome.

2. Possible cholestasis associated risk factors in this study.

CMV infection and necrotising enterocolitis during hospital stay were included as confounders. The drugs associated with cholestatic injury were scrutinized thoroughly, the usage of risk drugs (phenobarbital, ibuprofen and cimetidine) and whether use the risk antibiotics (ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) were recorded as confounders. All possible cholestasis associated risk factors are listed in table 2.

Table 2

Possible cholestasis associated risk factors

Risk factors	No cholestasis (n=124)	Cholestasis (n=27)	P
Phenobarbital [n (%)]‡	58 (46.8%)	20 (74.1%)	0.010
duration of Phenobarbital [days, M (P25, P75)]§	0 (0, 2)	1.5 (0, 4)	0.001
cimetidine [n (%)]‡	8 (6.5%)	5 (18.5%)	0.100
duration of cimetidine [days, M (P25, P75)]§	0 (0, 0)	0 (0, 0)	0.038
duration of ibuprofen [days, M (P25, P75)]§	3 (2, 3)	3 (3, 3)	0.367
whether use the risk antibiotics* [n (%)]‡	25 (20.3%)	8 (29.6%)	0.288
CMV infection [n (%)]‡	1 (0.8%)	3 (11.1%)	0.018
necrotising enterocolitis [n (%)]‡	1 (0.8%)	2 (7.4%)	0.143
any sepsis onset in 28 days [n (%)]‡	37 (29.8%)	14 (51.9%)	0.028

‡ . The chi-square test and Fisher’s exact test were used for categorical variables.

§ .For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test..

* The risk antibiotics included ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin;

^& The other potential risk drugs included Phenobarbital and cimetidine.

nd, not done.

CMV, cytomegalovirus.

3. The risk of cholestasis was associated with “duration of phenobarbital” in preterm infants with hsPDA.

To explore whether the risk of cholestasis was independently increased by “duration of phenobarbital”, binary logistic regression analysis was done adjusting for significant confounders (p<0.05), listed in Table 1 and Table 2 except for outcome variables “time to reach full enteral feeding”.

After adjustment with confounders “critical risk index for babies”, “invasive mechanical ventilation”, “any sepsis onset in 28 days” and “duration of cimetidine”, cholestasis was still associated with “duration of phenobarbital” (OR: 1.350; 95% CI: 1.064, 1.714; P = 0.014) and “CMV infection” (OR: 10.818; 95% CI: 0.915, 127.914; P = 0.059).

4. Delay of full enteral feeding was associated with “duration of phenobarbital” in preterm infants with hsPDA.

The risk of PN associated cholestasis was independently increased by the prolongation of PN, which means the “delay of full enteral feeding”, defined as “reach full enteral feeding at 28 days later” in this study. To explore whether the “delay of full enteral feeding” (41 cases delayed) was independently associated with “duration of phenobarbital”, binary logistic regression analysis was done adjusting for significant confounders, “birth weight”, “gestational age”, “Apgar score at 1 min”, “critical risk index for babies”, “any sepsis onset in 28 days”, “necrotising enterocolitis”, and “small for gestational age”.

After adjustment, the “delay of full enteral feeding” was still associated with “duration of phenobarbital” (OR: 1.479; 95% CI: 1.088, 2.011; P = 0.013), “birth weight” (OR: 0.995; 95% CI: 0.990, 0.999; P = 0.018), “gestational age” (OR: 0.390; 95% CI: 0.185, 0.820; P = 0.013), “any sepsis onset in 28 days” (OR: 3.409; 95% CI: 1.337, 8.693; P = 0.010), and “duration of cimetidine”(OR: 2.276; 95% CI: 1.310, 3.953; P = 0.004).

This study revealed that duration of phenobarbital was associated with cholestasis in preterm infants with hsPDA, even after adjustment for relevant confounders, such as critical risk index for babies, invasive mechanical ventilation, any sepsis in postnatal 28 days, CMV infection and duration of cimetidine. Accordingly, several case reports suggested that phenobarbital caused hepatoxicity and conjugated hyperbilirubinemia in infants and children [27–29]. The most common liver disturbances induced by phenobarbital include elevated aminotransferases, conjugated hyperbilirubinemia, prolonged prothrombin time (leading to significant coagulopathy), decreased vitamin K dependent clotting factors, even fulminant hepatic falure and death[27–29]. Prompt and permanent cessation of phenobarbital results in resolution of symptoms in most patients. [29].

The hepatoxicity is suggested to be related with defect in phenobarbital detoxification and hypersensitivity[27]. Notably, accumulation of phenobartbital is not uncommon in preterm neonates with immature liver and kidney. The mean half-life of phenobarbital is very long in neonates, about 115 hours after 1 week and about 67 hours after 4 weeks of administration[30]. The main reasons of phenobarbital poisoning in infants and children were therapeutic intoxication when phenobarbital therapy performed according to the recommended dosage in guidelines[27]. Drug accumulation may occur using the recommended maintenance dose during the first 2 weeks of life [31].

Furthermore, increasing evidences indicate that phenobarbital is associated with direct hepatoxicity. By analyzing 2.6 million adverse event reports made from the FDA Adverse Event Reporting System (FAERS) database between July 1, 2018 and March 31, 2020 for drug-induced liver injury (DILI) due to antiseizure medications (ASMs), the reporting odds ratio (ROR) of DILI for phenobarbital versus all non-ASM reports is 2.91 (CI:2.24–3.77, p < 0.0001) [32]. Mitochondrial toxicity and oxidative stress is involved in the hepatotoxicity induced by phenobarbital [33, 34]. Laboratory animal studies have reported the hepatotoxicity of high dose phenobarbital in juvenile male rats [35].

Notably, phenobarbital is used in 51.65% (78/151) of preterm infants in our study, partly for sedation during invasive mechanical ventilation. After the adjustment, duration of phenobarbital is still associated with neonatal cholestasis (OR: 1.350; 95% CI: 1.064, 1.714; P = 0.014), indicating that phenobarbital might increase the risk of cholestasis in preterm infants with hsPDA. Furthermore, “duration of phenobarbital” might independently delay the time to reach full enteral feeding (OR: 1.629; 95% CI: 1.185, 2.240; P = 0.003), causing parenteral nutrition associated cholestasis. In other respects, phenobarbital induces neuronal apoptosis, which involves the cortex, hypothalamus, thalamus, basal ganglia, and developing white matter [1, 36, 37], and causes long-term behavioral toxicity and impaired cognitive development in neonates [38–40]. In order to reduce the risk of neurotoxicity and hepatoxicity in preterm infants, phenobarbital should be cautiously and conservatively used. Furthermore, phenobarbital is reported to has limited efficacy for reduction of direct bilirubin in neonates and young infants with cholestasis[18], therefore phenobarbital is suggested not be used to treat neonatal cholestasis in preterm infants with hsPDA.

To our best knowledge, this study suggested for the first time that phenobarbital duration-dependently increased the risk of cholestasis in preterm infants with hsPDA. The limitation of this retrospective case-control study is obvious that the sample size was as small as 151 cases in total, and the cholestasis group includes only 27 cases. Additionally, the factors associated with cholestatic injury are quite vast. Only several other factors such as CMV infection, invasive mechanical ventilation and duration of cimetidine are found to be possible factors associated with cholestasis. We cannot conclude whether phenobarbital aggravates the established cholestasis in preterm infants due to the background of this study; however, Phenobarbital should be used cautiously in preterm infants with hsPDA or cholestasis.

Acknowledgements

The authors thank professor Lin Hung-Chih from China Medical University Children Hospital, Taichung, Taiwan for providing constructive advice on manuscript writing. This study is supported by Research Foundation of Shenzhen Baoan Women’s and Children’s Hospital, Jinan University (BAFY 2022001)

Data Availability Statement

All data generated or analysed during this study are included in this published article and its supplementary information files.

Declarations of interest

none. All methods were performed in accordance with the relevant guidelines and regulations.

Author contributions

Xintian Shen designed the retrospective study, Xintian Shen supervised this study in pharmacy and medicine fields. Yie Huang analyzed the data and Xintian Shen wrote the manuscript. HaiboPengand Ping Zhou retrieved and checked the data.

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No competing interests reported.

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Phenobarbital is Associated with Cholestasis in Preterm Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

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Abstract

Figures

What Is Known/ What Is New

Introduction

Materials And Methods

Results

1. Main demographic and clinical characteristics of the study population

2. Possible cholestasis associated risk factors in this study.

3. The risk of cholestasis was associated with “duration of phenobarbital” in preterm infants with hsPDA.

4. Delay of full enteral feeding was associated with “duration of phenobarbital” in preterm infants with hsPDA.

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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