Availability of Safe and Effective Therapeutic Options to Pregnant and Lactating Individuals Following the United States Food and Drug Administration Pregnancy and Lactation Labeling Rule.

OBJECTIVE: To explore the extent and type of pregnancy and lactation data of newly approved prescription drugs and assess whether the presented recommendations are data-driven, as required by the US Food and Drug Administration Pregnancy and Lactation Labeling Rule implemented in 2015. STUDY DESIGN: In this descriptive analysis, we reviewed pregnancy and lactation data of all new molecular entities approved between 2001 and 2020 in their most updated labeling. Information was collected regarding the pregnancy and lactation risk statements, the source of pregnancy and lactation data, and the design and methods of pregnancy and lactation studies in the labeling. RESULTS: Of the 422 new molecular entities, the key advisory statement for use of 133 (32%) drugs in pregnancy and 194 (46%) drugs in lactation were classified as "against use." Less than 2% of all drugs had a key advisory statement that supported their use during pregnancy or lactation. The sources of data regarding use in pregnancy were studies in human and animals in 46 (11%) and 348 (82%) drugs, respectively. For use during lactation, data included studies in human and animals in 23 (5%) and 251 (59%) drugs, respectively. The key advisory recommendation was consistent with the available human information in 4 (8%) drugs in pregnancy and 3 (13%) drugs in lactation. Prescription drug labeling contains limited data to support informed decision-making for the use of prescription drugs during pregnancy/lactation. Close collaboration among stakeholders is required to enhance the availability of data in this population.

Early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol: a retrospective cohort study.

BACKGROUND: Paracetamol is commonly used for analgesia and patent ductus arteriosus (PDA) treatment in preterm infants. We aimed to evaluate early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol during their neonatal admission. METHODS: This retrospective cohort study included surviving infants born at <29 weeks gestation, or with a birth weight of <1000 grams. Neurodevelopmental outcomes studied were early cerebral palsy (CP) or high risk of CP diagnosis, Hammersmith Infant Neurological Examination (HINE) score and Prechtl General Movement Assessment (GMA) at 3-4 months corrected age. RESULTS: Two hundred and forty-two infants were included, of which 123 were exposed to paracetamol. After adjusting for birth weight, sex and chronic lung disease, there were no significant associations between paracetamol exposure and early CP or high risk of CP diagnosis (aOR 1.46, 95% CI 0.61, 3.5), abnormal or absent GMA (aOR 0.82, 95% CI 0.37, 1.79) or HINE score (adjusted ß -0.19, 95% CI -2.39, 2.01). Subgroup analysis stratifying paracetamol exposure into <180 mg/kg or ≥180 mg/kg cumulative dose found that neither had significant effects on outcomes. CONCLUSIONS: In this cohort of extreme preterm infants, no significant association was found between exposure to paracetamol during the neonatal admission and adverse early neurodevelopment. IMPACT: Paracetamol is commonly used in the neonatal period for analgesia and patent ductus arteriosus treatment in preterm infants, although prenatal paracetamol use has been associated with adverse neurodevelopmental outcomes. Exposure to paracetamol during the neonatal admission was not associated with adverse early neurodevelopment at 3-4 months corrected age in this cohort of extreme preterm infants. The findings from this observational study is consistent with the small body of literature supporting the lack of association between neonatal paracetamol exposure and adverse neurodevelopmental outcomes in preterm infants.

Methadone dosing strategies in preterm neonates can be simplified.

AIMS: A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we investigated developmental PK of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population. METHODS: A single-centre open-label prospective study was performed to collect PK data after a single oral dose of methadone in preterm neonates. A population PK model was built to characterize developmental PK of (R)- and (S)-methadone. Model-based simulations were performed to identify a simplified dosing strategy to reach and maintain target methadone exposure. RESULTS: A total of 121 methadone concentrations were collected from 31 preterm neonates. A one-compartment model with first order absorption and elimination kinetics best described PK data for (R)- and (S)-methadone. Clearance increases with advancing gestational age and differs between R- and S-enantiomer, being slightly higher for the former (0.244 vs 0.167 L/h). Preterm neonates reached target exposure after 48 hours with currently used dosing schedules. Output from simulations revealed that target exposures can be achieved with a simplified dosing strategy during the first 4 days of treatment. CONCLUSION: Methadone clearance in preterm neonates increases with advancing gestational age and its disposition is influenced by its chirality. Simulations that account for developmental PK changes indicate a shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms.

Introduction of microsystems in a level 3 neonatal intensive care unit-an interprofessional approach.

BACKGROUND: Growth of neonatal intensive care units in number and size has raised questions towards ability to maintain continuity and quality of care. Structural organization of intensive care units is known as a key element for maintaining the quality of care of these fragile patients. The reconstruction of megaunits of intensive care to smaller care units within a single operational service might help with provision of safe and effective care. METHODS/DESIGN: The clinical team and patient distribution lay out, admission and discharge criteria and interdisciplinary round model was reorganized to follow the microstructure philosophy. A working group met weekly to formulate the implementation planning, to review the adaptation and adjustment process and to ascertain the quality of implementation following the initiation of the microsystem model. DISCUSSION: In depth examination of microsystem model of care in this study, provides systematic evaluation of this model on variable aspects of health care. The individual projects of this trial can be source of solid evidence for guidance of future decisions on optimized model of care for the critically ill newborns. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02912780 . Retrospectively registered on 22 September 2016.

Trends in pregnancy labeling and data quality for US-approved pharmaceuticals.

OBJECTIVE: Over the past decades, there have been significant efforts in the United States to improve pharmaceutical labeling pertaining to pregnancy. The goal of this study was to describe trends in pregnancy labeling at the time of drug approval and over time. STUDY DESIGN: The labeling data of 213 new pharmaceutical approvals between January 2003 and December 2012 were systematically reviewed. Initial approval data and subsequent labeling revisions were evaluated for pregnancy category, source of pregnancy and breast-feeding data, data in labor and delivery, presence of a registry, black-box warnings, and utilization of the new labeling format. RESULTS: The most commonly approved pregnancy category was C (51.6%). Most pharmaceuticals (92.9%) had pregnancy data based on animal studies and 5.2% had human pregnancy data. For breast-feeding, there were no data in 47.9% of labels, animal data in 42.7%, and human data in 4.7%. There were no labor and delivery data in 85.9% of labels. Only 2.8% of medications had human data, with the remainder having animal data. The majority of medications (85%) did not have a pregnancy registry. Of those that had a registry, 68.7% were by therapeutic category, not agent specific. Seven medications had black-box warnings related to teratogenicity. Since the new labeling recommendations, 4.7% of medications incorporated the new format into the labeling, primarily approvals that occurred in 2012. CONCLUSION: Despite significant efforts to improve drug labeling for pregnancy and lactation, there remains a paucity of human data in this understudied population.

Safety of sildenafil in infants*.

OBJECTIVE: In view of the recent U.S. Food and Drug Administration's warning against the use of sildenafil in pediatric patients, we aimed to provide an updated overview of the dosing and safety of sildenafil in infants and to explore the relevance of the present safety concerns to the infant population. DATA SOURCE: The National Library of Medicine PubMed and Cochrane Database of Systematic Reviews were searched using the following terms: Sildenafil AND (infant OR infants OR newborn OR newborns OR child OR children OR childhood OR pediatric OR pediatrics OR paediatric OR paediatrics). STUDY SELECTION: Studies presenting original clinical data regarding the dosing, use, or safety of sildenafil in infants with pulmonary hypertension would be included. DATA EXTRACTION: Of the 49 included studies, case reports and case series were the most common type of publications (n = 25). The identified trials included 625 children, with more than 140 infants. Persistent pulmonary hypertension of the newborn and pulmonary hypertension associated with other conditions were the most common underlying diagnoses. CONCLUSION: There is currently no evidence of serious adverse event in infants exposed to sildenafil. Present safety concerns regarding the use of sildenafil in pediatric patients should be further explored before being applied to infant population. Sildenafil remains a valuable option for the treatment of pulmonary hypertension in young infants. Prospective studies should be designed in such a way that they include a safety assessment to evaluate potential adverse outcomes of sildenafil therapy in this population.

Topical nitroglycerin in neonates with tissue injury: A case report and review of the literature.

Peripheral tissue injury is one of the well-described morbidities associated with stays in the neonatal intensive care unit. Despite the potential long-term disability associated with this event, the current available therapeutic options remain very limited. Topical nitroglycerin has emerged as a promising agent for the treatment of tissue injury in infants. The present article includes a review of the currently available evidence on the use of topical nitroglycerin in the neonatal population, and describes a unique case involving successful use of 2% nitroglycerin in the late treatment of prolonged tissue ischemia in a newborn infant.

Les lésions des tissus périphériques font partie des morbidités bien décrites associées à des séjours à l'unité de soins intensifs néonatals. Malgré les invalidités potentielles à long terme qui y sont liées, les possibilités thérapeutiques demeurent très limitées. La nitroglycérine topique a émergé comme un agent prometteur dans le traitement des lésions tissulaires chez les nourrissons. Le présent article contient une analyse des données probantes sur l'utilisation de la nitroglycérine topique dans la population néonatale, ainsi que la description d'un cas unique portant sur l'utilisation réussie de nitroglycérine 2 % dans le traitement tardif d'une ischémie tissulaire prolongée chez un nouveau-né.

Drug related adverse event assessment in neonates in clinical trials and clinical care.

INTRODUCTION: Assessment of drug-related adverse events is essential to fully understand the benefit-risk balance of any drug exposure, weighing efficacy versus safety. This is needed for both drug labeling and clinical decision-making. Assessment is based on seriousness, severity and causality, be it more difficult to apply in neonates. Adverse event detection or prevention in the neonatal clinical setting is also more complicated because of polypharmacy, and off-label or unlicensed pharmacotherapy. AREAS COVERED: Tools became available to assess severity and causality of adverse events in neonates recruited in clinical trials. The first version of the Neonatal Adverse Event severity score (NAESS) reduced the inter-observer variability. Causality tools like the Naranjo score were also tailored to neonates. These tools are also instrumental to support proactive pharmacovigilance in clinical care, while multidisciplinary care teams and computerized pharmacovigilance using advanced data analysis, like machine learning are emerging approaches to develop effective decision strategies. EXPERT OPINION: All stakeholders involved in development of medicines or its clinical use should be aware of the limitations of the currently available assessment tools. Extension and optimization of these tools, advanced data analysis approaches, and capturing the variability in time-dependent physiology are warranted to improve pharmacovigilance in neonates.

Intravenous acetaminophen for postoperative pain in the neonatal intensive care unit: A protocol for a pilot randomized controlled trial (IVA POP).

BACKGROUND: In neonates, uncontrolled pain and opioid exposure are both correlated with short- and long-term adverse events. Therefore, managing pain using opioid-sparing approaches is critical in neonatal populations. Multimodal pain control offers the opportunity to manage pain while reducing short- and long-term opioid-related adverse events. Intravenous (IV) acetaminophen may represent an appropriate adjunct to opioid-based postoperative pain control regimes. However, no trials assess this drug in patients less than 36 weeks post-conceptual age or weighing less than 1500 g. OBJECTIVE: The proposed study aims to determine the feasibility of conducting a randomized control trial to compare IV acetaminophen and fentanyl to a saline placebo and fentanyl for patients admitted to the neonatal intensive care unit (NICU) undergoing major abdominal or thoracic surgery. METHODS AND DESIGN: This protocol is for a single-centre, external pilot randomized controlled trial (RCT). Infants in the NICU who have undergone major thoracic or abdominal surgery will be enrolled. Sixty participants will undergo 1:1 randomization to receive intravenous acetaminophen and fentanyl or saline placebo and fentanyl. After surgery, IV acetaminophen or placebo will be given routinely for eight days (192 hours). Appropriate dosing will be determined based on the participant's gestational age. Patients will be followed for eight days after surgery and will undergo a chart review at 90 days. Primarily feasibility outcomes include recruitment rate, follow-up rate, compliance, and blinding index. Secondary clinical outcomes will be collected as well. CONCLUSION: This external pilot RCT will assess the feasibility of performing a multicenter RCT comparing IV acetaminophen and fentanyl to a saline placebo and fentanyl in NICU patients following major abdominal and thoracic surgery. The results will inform the design of a multicenter RCT, which will have the appropriate power to determine the efficacy of this treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05678244, Registered December 6, 2022.

Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

INTRODUCTION: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. METHODS: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. RESULTS: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to S-conversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25-32% increase in S-ibuprofen exposure following oral administration with AUC72h values varying between 700-2,213 mg*h/L (oral) and 531-1,762 (IV) for the standard or 1,704-2,893 (oral) and 1,295-2,271 mg*h/L (IV) for PNA-based dosing. DISCUSSION: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing.

Long-Term Safety of Prenatal and Neonatal Exposure to Paracetamol: A Systematic Review.

INTRODUCTION: Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the frequent use of paracetamol, concerns have been raised regarding the high variability in neonatal dosing regimens and the long-term safety of early life exposure. OBJECTIVE: To investigate the available evidence on the long-term safety of prenatal and neonatal paracetamol exposure. METHODS: We conducted a systematic search of the electronic databases Ovid Medline, Ovid Embase and Web of Science from inception to August 2021 for original research studies of any design that described the use of paracetamol in the prenatal or neonatal (within the first four weeks of life) periods and examined the occurrence of neurodevelopmental, atopic or reproductive adverse outcomes at or beyond birth. RESULTS: We identified 1313 unique articles and included 30 studies in the final review. Of all studies, 27 (90%), two (7%) and one (3%) were on the long-term safety of prenatal, neonatal and both prenatal and neonatal exposure, respectively. Thirteen (46%), 11 (39%) and four (15%) studies examined neurodevelopmental, atopic and reproductive outcomes. Eleven (100%), 11 (100%), and three (27%) studies on prenatal exposure reported adverse neurodevelopmental, atopic and reproductive outcomes. Only one study found a possible correlation between neonatal paracetamol exposure and long-term adverse outcomes. CONCLUSIONS: The available evidence, although limited, suggests a possible association between prenatal paracetamol exposure and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes. There is an immediate need for robust data on the long-term safety of paracetamol exposure in the prenatal and neonatal periods.

Efficacy and Safety of Vasopressin and Terlipressin in Preterm Neonates: A Systematic Review.

INTRODUCTION: The use of arginine vasopressin (AVP) and terlipressin to treat hypotension in preterm neonates is increasing. Our aim was to review the available evidence on the efficacy and safety of AVP and terlipressin for use in preterm neonates. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar from inception to September 2021 were searched for studies of AVP and terlipressin in the treatment of hypotension of any cause in preterm neonates. Primary outcomes were improvement in end-organ perfusion and mortality. The risk of bias assessment and certainty of the evidence were performed using appropriate tools. RESULTS: Fifteen studies describing the use of AVP (n = 12) or terlipressin (n = 3) among 148 preterm neonates were included. Certainly, the available evidence for the primary outcome of end-organ perfusion rated as very low. AVP or terlipressin were used to treat 144 and 4 neonates, respectively. Improvement in markers of end-organ perfusion was reported in 143 (99%) neonates treated with AVP and 3 (75%) treated with terlipressin. The mortality rate was 41% (n = 59) and 50% (n = 2) for neonates who received AVP and terlipressin, respectively. Hyponatremia was the most frequently reported adverse event (n = 37, 25%). CONCLUSION: AVP and terlipressin may improve measured blood pressure values and possibly end-organ perfusion among neonates with refractory hypotension. However, the efficacy-safety balance of these drugs should be assessed on an individual basis and as per the underlying cause. Studies on the optimal dosing, efficacy, and safety of AVP and terlipressin in preterm neonates with variable underlying conditions are critically needed.

US drug shortages compared to the World Health Organization's Model List of Essential Medicines for Children: A cross-sectional study.

PURPOSE: To describe US drug shortages affecting medications on the 2019 World Health Organization (WHO) Model List of Essential Medicines for Children (EMLc). METHODS: Drug shortage data from January 2014 to December 2019 were obtained from the University of Utah Drug Information Service. Shortage data for drugs on the EMLc were analyzed for the type of drug, American Hospital Formulary Service category, reason for the shortage, duration of the shortage, marketing status (generic vs brand name), and whether the agent was a single- or multisource drug. RESULTS: From 2014 to 2019, a total of 209 drug shortages impacted medications on the EMLc, of which 77 (36.8%) remained unresolved by 2019. Of all active shortages, 13 (6.2%) began before 2014. Resolved shortages had a median duration of 5.9 months (interquartile range [IQR], 3.6-13.2 months) while active shortages had a median duration of 18.3 months (IQR, 10.9-33.5 months; P ≤ 0.0001). The therapeutic categories most impacted by drug shortages were anti-infective agents (27.3%), central nervous system agents (12.9%), and antineoplastic agents (11.0%). The reason for the shortage was not reported in 46.4% of cases. When a reason was provided, the most common reason was manufacturing problems (29.2%) followed by supply/demand mismatch (15.8%). CONCLUSION: US drug shortages affected many medications on the WHO EMLc. Future studies should examine the global shortage climate and implications for patient care.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

OBJECTIVE: Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. SETTING: Neonatal intensive care unit at McMaster Children's Hospital. PATIENTS: Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA. METHODS: Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. MAIN OUTCOME MEASURE: Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0-72h >900 mg·hour/L). RESULTS: Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. CONCLUSION: We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0-72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates.

In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure-response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of ≤60 ng/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.

Efficacy and safety of low-dose versus high-dose hydrocortisone to treat hypotension in neonates: a protocol for a systematic review and meta-analysis.

BACKGROUND: Impaired adrenal function is a well-described entity in critically ill term and preterm neonates with systemic hypotension. The standard treatment for neonatal hypotension includes volume expanders and vasopressors. Recent evidence supports the use of glucocorticoids for the primary or rescue treatment of neonatal hypotension associated with impaired adrenal function. However, inconsistency regarding the prescribed dosing regimen to provide the best balance between efficacy and safety in this vulnerable population remains an area of concern. METHODS: We will conduct a systematic review and meta-analysis to evaluate low-dosing compared with high-dosing regimens of hydrocortisone for the treatment of hypotension in critically ill term, preterm and very low birth weight neonates. Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Web of Science will be searched from inception to November 2021. Study screening and selection will be completed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Our primary outcomes will be (1) an improvement in end-organ perfusion, defined as an increase in blood pressure along with an increase in urine output or a reduction in serum lactate and (2) mortality prior to discharge. Our secondary outcomes will be the development of (1) major neurosensory abnormality, (2) bronchopulmonary dysplasia and (3) the occurrence of adverse events. DISCUSSION: Hydrocortisone may be beneficial in the treatment of hypotension associated with impaired adrenal function among critically ill neonates. However, its optimal dosing to balance desired efficacy with the risk of adverse events is yet to be determined. Our systematic review and meta-analysis aims to address this evidence gap, providing valuable knowledge for a large audience, including guideline developers, policy-makers and clinicians. PROSPERO REGISTRATION NUMBER: This protocol is submitted for registration to the international database of prospectively registered systematic reviews (PROSPERO, awaiting registration number).

Efficacy and safety of vasopressin and terlipressin in preterm neonates: a protocol for a systematic review.

Background: The use of vasoactive agents like arginine vasopressin (AVP) and terlipressin to treat hypotension or persistent pulmonary hypertension in critically ill preterm neonates is increasing. Therefore, a systematic review of the available data on dosing, efficacy and safety of AVP and terlipressin in this patient population appears beneficial. Methods: We will conduct a systematic review of the available evidence on the use of AVP and terlipressin for the treatment of hypotension or persistent pulmonary hypertension in preterm neonates. We will search Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and Google Scholar from inception to March 2021. Two reviewers will independently screen titles and abstracts, review the full text of eligible studies, extract data, assess the risk of bias and judge the certainty of the evidence. Our primary outcome will be an (1) improvement of end-organ perfusion after initiation of AVP or terlipressin and (2) mortality prior to discharge. Our secondary outcomes will include (1) major neurosensory abnormality and (2) the occurrence of adverse events. Discussion: The currently available evidence on the efficacy and safety of AVP and terlipressin in preterm neonates is limited. Yet, evidence on the pharmacology of these drugs and the pathophysiology of vasoplegic shock support the biological plausibility for their clinical effectiveness in this population. Therefore, we aim to address this gap concerning the use of vasopressin and terlipressin among critically ill preterm neonates. Trial registration: This protocol has been submitted for registration to the international database of prospectively registered systematic reviews (PROSPERO, awaiting registration number).

Topical nitroglycerin ointment as salvage therapy for peripheral tissue ischemia in newborns: a systematic review.

BACKGROUND: Topical nitroglycerin (TNG) ointment has been used for almost 3 decades to treat neonatal peripheral tissue ischemia, but this product is now no longer being produced by its Canadian manufacturer. Our aim was to investigate the efficacy and safety of TNG products in newborns in neonatal intensive care units. METHODS: In this systematic review we searched Embase, CINAHL, MEDLINE, PubMed and Web of Science from inception to April 2020 for studies on the use of TNG products (TNG ointment, TNG spray, glyceryl trinitrate [GTN] patch) for the treatment of neonatal tissue ischemia. We did not apply language or study design limitations. Animal studies and duplicate records were excluded. Two reviewers screened and extracted data. The Tool for Evaluating the Methodological Quality of Case Reports and Case Series was used to assess the risk of bias of individual studies. RESULTS: We included 23 articles (20 case reports, 2 case series and 1 retrospective audit) describing the use of TNG ointment, TNG spray or GTN patch in the treatment of 39 tissue ischemia events in 37 newborns. Twenty-three (62.2%), 12 (32.4%), 1 (2.7%) and 1 (2.7%) infants received TNG ointment, GTN patch, both TNG ointment and GTN patch, and TNG spray, respectively. Nineteen (76.0%) and 7 (53.8%) injuries treated with TNG ointment and GTN patch showed complete recovery, respectively. Two (16.7%) infants treated with GTN patch experienced adverse events (i.e., methemoglobinemia) requiring treatment discontinuation. INTERPRETATION: TNG ointment presents a safe therapeutic modality for salvage therapy of neonatal tissue ischemia. Engagement of stakeholders is essential to address its recent commercial inaccessibility in Canada.