Drugs to manage pain and sedation during cooling in newborns following poor brain oxygenation at birth (hypoxic-ischaemic encephalopathy)

Review question

Do drugs save lives, or improve pain and sedation, in newborns who have poor brain oxygenation at birth ('hypoxic-ischaemic encephalopathy') and who are undergoing cooling?

Background

Lack of oxygen at birth may damage the brain of the newborn. Babies with less severe brain damage may make a full recovery or only have mild problems. For other babies with more serious damage, this may lead to death or to problems later in life. For instance, some of these babies develop cerebral palsy, intellectual disabilities, or other problems. We currently only have cooling as an approach to treat this condition. Cooling is achieved by the use of special helmets or, more frequently, of thermal mattresses. Cooling may cause pain, which can also have a long-term negative impact on development and quality of life. The aim of this review was to assess if drugs can reduce pain, discomfort and mortality.

Key results

We have not identified any studies that addressed the review question. We identified four potential studies, but we excluded them due to the type of drug or study design. One study is ongoing. 

How up to date is this review?

We searched for studies that were available up to August 2021.

Authors' conclusions: 

We found no studies that met our inclusion criteria and hence there is no evidence to recommend or refute the use of pharmacological interventions for pain and sedation management in newborn infants undergoing therapeutic hypothermia.

Read the full abstract...
Background: 

Newborn infants affected by hypoxic-ischemic encephalopathy (HIE) undergo therapeutic hypothermia. As this treatment seems to be associated with pain, and intensive and invasive care is needed, pharmacological interventions are often used. Moreover, painful procedures in the newborn period can affect pain responses later in life, impair brain development, and possibly have a long-term negative impact on neurodevelopment and quality of life.

Objectives: 

To determine the effects of pharmacological interventions for pain and sedation management in newborn infants undergoing therapeutic hypothermia. Primary outcomes were analgesia and sedation, and all-cause mortality to discharge.

Search strategy: 

We searched CENTRAL, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the trial register ISRCTN in August 2021. We also checked the reference lists of relevant articles to identify additional studies.

Selection criteria: 

We included randomized controlled trials (RCT), quasi-RCTs and cluster-randomized trials comparing drugs used for the management of pain or sedation, or both, during therapeutic hypothermia: any opioids (e.g. morphine, fentanyl), alpha-2 agonists (e.g. clonidine, dexmedetomidine), N-Methyl-D-aspartate (NMDA) receptor antagonist (e.g. ketamine), other analgesics (e.g. paracetamol), and sedatives (e.g. benzodiazepines such as midazolam) versus another drug, placebo, no intervention, or non-pharmacological interventions. 

Primary outcomes were analgesia and sedation, and all-cause mortality to discharge.

Data collection and analysis: 

Two review authors independently assessed studies identified by the search strategy for inclusion. We planned to use the GRADE approach to assess the certainty of evidence. We planned to assess the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomization, blinding, loss to follow-up, and handling of outcome data). We planned to evaluate treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. 

Main results: 

We did not find any completed studies for inclusion. Amongst the four excluded studies, topiramate and atropine were used in two and one trial, respectively; one study used dexmedetomidine and was initially reported in 2019 to be a randomized trial. However, it was an observational study (correction in 2021). We identified one ongoing study comparing dexmedetomidine to morphine.