Non‐opioid analgesics for procedural pain in neonates

Abstract

Background

Neonates are an extremely vulnerable patient population, with 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU will undergo multiple painful procedures per day throughout their stay. There is increasing evidence that frequent and repetitive exposure to painful stimuli is associated with poorer outcomes later in life.

To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. This review focused on non‐opioid analgesics, specifically non‐steroidal anti‐inflammatory drugs (NSAIDs) and N‐methyl‐D‐aspartate (NMDA) receptor antagonists, which alleviate pain through inhibiting cellular pathways to achieve analgesia. 

The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. We therefore sought to summarize the evidence on the level of pain experienced by neonates both during and following procedures; relevant drug‐related adverse events, namely episodes of apnea, desaturation, bradycardia, and hypotension; and the effects of combinations of drugs. 

As the field of neonatal procedural pain management is constantly evolving, this review aimed to ascertain the scope of non‐opioid analgesics for neonatal procedural pain to provide an overview of the options available to better inform evidence‐based clinical practice. 

Objectives

To determine the effects of non‐opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non‐pharmacological intervention, other analgesics, or different routes of administration.

Search methods

We searched the Cochrane Library (CENTRAL), PubMed, Embase, and two trial registries in June 2022. We screened the reference lists of included studies for studies not identified by the database searches.

Selection criteria

We included all randomized controlled trials (RCTs), quasi‐RCTs, and cluster‐RCTs in neonates (term or preterm) undergoing painful procedures comparing NSAIDs and NMDA receptor antagonists to placebo or no drug, non‐pharmacological intervention, other analgesics, or different routes of administration. 

Data collection and analysis

We used standard Cochrane methods. Our main outcomes were pain assessed during the procedure and up to 10 minutes after the procedure with a validated scale; episodes of bradycardia; episodes of apnea; and hypotension requiring medical therapy.

Main results

We included two RCTs involving a total of 269 neonates conducted in Nigeria and India. 

NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention

One RCT evaluated using oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision. 

The evidence is very uncertain about the effect of ketamine on pain score during the procedure, assessed with the Neonatal Infant Pain Scale (NIPS), compared with placebo (mean difference (MD) −0.95, 95% confidence interval (CI) −1.32 to −0.58; 1 RCT; 145 participants; very low‐certainty evidence). No other outcomes of interest were reported on.

Head‐to‐head comparison of different analgesics

One RCT evaluated using intravenous fentanyl versus intravenous ketamine during laser photocoagulation for retinopathy of prematurity. Neonates receiving ketamine followed an initial regimen (0.5 mg/kg bolus 1 minute before procedure) or a revised regimen (additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg), while those receiving fentanyl followed either an initial regimen (2 μg/kg over 5 minutes, 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion) or a revised regimen (titration of 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour). The evidence is very uncertain about the effect of ketamine compared with fentanyl on pain score assessed with the Premature Infant Pain Profile‐Revised (PIPP‐R) scores during the procedure (MD 0.98, 95% CI 0.75 to 1.20; 1 RCT; 124 participants; very low‐certainty evidence); on episodes of apnea occurring during the procedure (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) −0.09, 95% CI −0.19 to 0.00; 1 study; 124 infants; very low‐certainty evidence); and on hypotension requiring medical therapy occurring during the procedure (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI −0.03 to 0.10; 1 study; 124 infants; very low‐certainty evidence). The included study did not report pain score assessed up to 10 minutes after the procedure or episodes of bradycardia occurring during the procedure.

We did not identify any studies comparing NSAIDs versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention or different routes of administration of the same analgesics. We identified three studies awaiting classification. 

Authors' conclusions

The two small included studies comparing ketamine versus either placebo or fentanyl, with very low‐certainty evidence, rendered us unable to draw meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on NSAIDs or studies comparing different routes of administration.

Future research should prioritize large studies evaluating non‐opioid analgesics in this population. As the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as we identified no studies on NSAIDs, which are widely used in older infants, or comparing different routes of administration, such studies should be a priority going forward. 

Plain language summary

Painkillers other than opioids to treat pain in babies undergoing painful procedures

Key messages 

• We did not find enough evidence on painkillers that are not opioids to manage pain in babies undergoing painful procedures. We found only two small studies that compared a painkiller (ketamine) with either another painkiller (an opioid) or sweet solution to manage different procedures. 

• Larger studies on a variety of painkillers are needed to provide a better understanding of the benefits and harms of the different painkillers and the best way to give them. 

What did we want to find out? 

Babies, particularly those born too early or sickest, may undergo many painful procedures during their hospital stay. It is still unclear which painkillers are best for adequate and safe pain relief. We specifically focused on studies evaluating non‐steroidal anti‐inflammatory drugs (NSAIDs), such as ibuprofen, and N‐methyl‐D‐aspartate (NMDA) receptor antagonists, such as ketamine, for babies during painful procedures. We wanted to find out how they affected pain intensity in babies during the procedures and any side effects the painkillers caused. 

What did we do? 

We searched for studies that compared: 

• NMDA receptor antagonists (e.g. ketamine) or NSAIDs (e.g. ibuprofen) versus no treatment, placebo (dummy treatment), oral sweet solution, or non‐painkiller intervention;

• one painkiller versus another painkiller; or 

• different ways of giving the same painkillers (e.g. through the mouth or vein). 

We evaluated the studies and rated our confidence in the evidence based on study methods. 

What did we find? 

We found two studies involving a total of 269 babies undergoing painful procedures. One study conducted in Nigeria compared giving ketamine versus sugar syrup through the mouth for circumcision. The other study, conducted in India, compared fentanyl and ketamine given through the vein during laser treatment for an eye disease. In both studies, the babies who received ketamine had lower pain scores; however, the studies used different methods and evaluated different procedures, making it difficult to draw any conclusions. The latter study also provided unclear evidence on the effect of the treatments on breathing and blood pressure problems. 

What are the limitations of the evidence? 

We are not confident in the evidence and are very uncertain about the results due to the limited studies included, their small size, and their use of methods likely to produce errors. 

How up‐to‐date is this evidence? 

The evidence is current to June 2022. 

Summary of findings

Summary of findings 1. NMDA receptor antagonists compared to no treatment, placebo, oral sweet solution, or non‐pharmacological intervention for procedural pain in neonates.

NMDA receptor antagonists compared to no treatment, placebo, oral sweet solution, or non‐pharmacological intervention for procedural pain in neonates
Patient or population: Procedural pain in neonates  Setting: Neonatal unit Intervention: NMDA receptor antagonists  Comparison: No treatment, placebo, oral sweet solution, or non‐pharmacological intervention
Outcomes	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)			Certainty of the evidence (GRADE)	What happens
		Without NMDA receptor antagonists	With NMDA receptor antagonists	Difference
Pain score during the procedure, assessed with NIPS (scale 0 to 7, worse) No. of participants: 145 (1 RCT)	‐	The mean pain score during the procedure without NMDA receptor antagonists, assessed with NIPS, was 4.9.	The mean pain score during the procedure with NMDA receptor antagonists, assessed with NIPS, was 3.9.	MD 0.95 lower (1.32 lower to 0.58 lower)	⊕⊝⊝⊝ Very low 1	The evidence is very uncertain about the effect of NMDA receptor antagonists on pain score during the procedure, assessed with NIPS.
Pain score assessed up to 10 minutes after the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
Episodes of bradycardia, defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer, occurring during the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
Episodes of apnea (mean rates of apnea), occurring during the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
Hypotension requiring medical therapy (vasopressors or fluid boluses), occurring during the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; NIPS: Neonatal Infant Pain Scale;NMDA: N‐methyl‐D‐aspartate;RCT: randomized controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded one level for risk of bias (unclear risk in several domains), and two levels for imprecision (one small study; minimally important difference not relevant [less than 1 point between intervention and control group]).

Summary of findings 2. Head‐to‐head comparison of different analgesics for procedural pain in neonates.

Head‐to‐head comparison of different analgesics for procedural pain in neonates
Patient or population: Procedural pain in neonates  Setting: Neonatal unit Intervention: Ketamine Comparison: Fentanyl
Outcomes	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)			Certainty of the evidence (GRADE)	What happens
		With fentanyl	With ketamine	Difference
Pain score assessed with PIPP‐R during the procedure (scale 0 to 21, worse) No. of participants: 124 (1 RCT)	‐	The mean pain score (PIPP‐R) with fentanyl was 2.8.	The mean pain score (PIPP‐R) with ketamine was 3.4.	MD 0.98 higher (0.75 higher to 1.20 higher)	⊕⊝⊝⊝ Very low 1	The evidence is very uncertain about the effect of head‐to‐head comparison of different analgesics on pain score (PIPP‐R) during the procedure.
Pain score assessed up to 10 minutes after the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
Episodes of bradycardia, defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer, occurring during the procedure	‐	‐	‐	‐	‐	No studies reported this outcome.
Episodes of apnea (mean rates of apnea), occurring during the procedure. No. of participants: 124 (1 RCT)	RR 0.31 (0.08 to 1.18)	Study population			⊕⊝⊝⊝ Very low 1	The evidence is very uncertain about the effect of head‐to‐head comparison of different analgesics on episodes of apnea (mean rates of apnea), occurring during the procedure.
		12.5%	3.9% (1 to 14.8)	8.6% fewer (11.5 fewer to 2.2 more)
Hypotension requiring medical therapy (vasopressors or fluid boluses), occurring during the procedure No. of participants: 124 (1 RCT)	RR 5.53 (0.27 to 112.30)	Study population			⊕⊝⊝⊝ Very low 1	The evidence is very uncertain about the effect of head‐to‐head comparison of different analgesics on hypotension requiring medical therapy (vasopressors or fluid boluses), occurring during the procedure.
		0/64	2/60	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; PIPP‐R: Premature Infant Pain Profile‐Revised; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded two levels for risk of bias (several domains with either high or unclear risk of bias), and one level for imprecision (one small study).

Background

Description of the condition

Neonates, comprising newborn infants fewer than four weeks old, are an extremely vulnerable patient population, with approximately 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU may undergo up to 16 painful procedures per day for diagnostic, therapeutic, or supportive purposes throughout their stay (Courtois 2016).

There is an increasing awareness that frequent and repetitive exposure to painful stimuli (as measured by validated pain rating scales discussed in the How the intervention might work section) is associated with poor neurodevelopmental outcomes later in life (Bouza 2009; Vinall 2014). In extremely preterm infants, acute pain may lead to cerebral blood flow increase, which is one of the main causes of intraventricular hemorrhage (IVH), thus potentially leading to neurodevelopmental impairment. Despite the negative effects of pain exposure and the standardized practice of routinely performed procedures, such as venipunctures, lumbar punctures, intubation and extubation, and invasive ventilation, a limited consensus has been reached on the provision of medication for adequate pain relief.

To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. Such techniques can be non‐pharmacological, such as music, hypnosis, acupuncture, and cognitive‐behavioral approaches that distract from or reduce the perception of the procedure being undergone; pharmacological techniques, which include topical local anesthetics, local infiltration, systemic analgesics, and inhalation techniques (Mangat 2018); or non‐pharmacological treatments, such as sucrose, breastfeeding, and non‐nutritive sucking (Johnston 2017; Pillai Riddell 2015). Combinations of methods are often applied in children and neonates. Due to the immaturity of their bodily systems, neonates are typically more sensitive to the effects of medication and are at a higher risk of the ensuing side effects. This highlights the importance of proper administration and precise observation during the course of treatment (AAP 2016).

The intricacies of neonatal pain management and potential adverse effects further underscore the need to summarize and better understand all available methods to improve treatment and outcomes in this population. Evidence on paracetamol, clonidine, and non‐pharmacological techniques has been previously investigated (Ohlsson 2020a; Pillai Riddell 2015; Romantsik 2020). The Cochrane Review therefore specifically focused on non‐opioid analgesics, in particular non‐steroidal anti‐inflammatory drugs (NSAIDs) and N‐methyl‐D‐aspartate (NMDA) receptor antagonists, for procedural pain in neonates. 

Description of the intervention

Analgesics are a class of medication that specifically alleviates pain. They are distinct from anesthetics, in that they do not block nerve conduction, alter sensory perception, or affect consciousness. Instead, they specifically inhibit cellular pathways to achieve analgesia and are classified according to their mechanism of action (Cregg 2013). 

NMDA receptor antagonists provide a sedative, analgesic, and amnesic effect. Of these, ketamine is the most widely used, with its rapid onset and short duration of action. Similar to benzodiazepines, research on NMDA receptor antagonists is lacking due to concern over side effects, limiting their clinical application. Despite potential harms, administration is beneficial for hypotensive neonates, and cerebral blood flow is not significantly affected (Hall 2014; McPherson 2021). Furthermore, less respiratory depression is seen with ketamine when compared to opioids, and lower pain scores have been reported in an observational study (Wilson‐Smith 2011). Methadone is another NMDA receptor antagonist with considerable potential in neonates. However, it has only been investigated in rat models to date. Further research is needed on recommended dosing range to investigate the long‐term effects of NMDA receptor antagonist administration. 

NSAIDs, which notably include ibuprofen, ketorolac, ketoprofen, and indomethacin, have strong implications for use in neonatal procedural pain as there is no risk associated with respiratory depression or opioid‐linked sedation adverse effects (Hall 2014; Peng 2021; Whittaker 2013). These sedation adverse effects include oxygen desaturation, apnea, or systemic hypotension. To date, NSAIDs have mainly been for the closure of patent ductus arteriosus (PDA) (Squillaro 2019). Furthermore, NSAIDs offer an opioid‐sparing effect, meaning opioids can be coupled alongside in lower dosages than usual (Parry 2014). For example, although this review does not focus on postoperative pain management, ketorolac, the most commonly used intravenous NSAID in neonates, has been shown to decrease postoperative morphine administration and has shown promising pain control when administered as a single postoperative dose, without systemic complications (Burd 2002; Papacci 2004). Although people undergoing high‐dose and long‐term NSAID treatment are more likely to experience renal injury, necrotizing enterocolitis (NEC), and gastrointestinal bleeding, ibuprofen has been found to have fewer adverse effects compared to indomethacin and is a common choice for the prevention or treatment of pain in newborns (Ohlsson 2020a; Ohlsson 2020c). Of note, 10% of newborn infants with acute kidney injury might develop chronic kidney disease (Mammen 2012).

This review thus aimed to summarize the effect of NMDA and NSAID administration for procedural pain and potential adverse effects limiting clinical application. 

How the intervention might work

NMDA receptor antagonists work to antagonize the NMDA receptor, to which excitatory neurotransmitter glutamate binds following noxious peripheral stimuli (Kreutzwiser 2019). This results in a state of dissociation, providing analgesic and amnesic effects. 

NSAIDs target the cyclooxygenase (COX) enzymes, COX‐1 and COX‐2, in the arachidonic acid cascade. Both enzymes aid in the production of prostaglandins. However, COX‐1 is particularly responsible for prostaglandins that activate blood clotting and protect the stomach mucous lining, while COX‐2 prostaglandins promote pain, inflammation, and fever. For this reason, pain relief is attributed to the blocking of the COX‐2 enzyme, and recent NSAIDs have been developed to selectively only block COX‐2. Notably, the most common NSAIDs in use today block both COX enzymes, and close monitoring is required to avoid any bleeding or renal side effects (Cregg 2013). 

There are no pharmacokinetic data on the use of these drugs for procedural pain. However, data on ibuprofen are available for treating PDA, with a recommended administration of a single dose of ibuprofen 10 mg/kg followed by two additional dosages of 5 mg/kg every 24 hours (Ohlsson 2020b). Indomethacin is dosed at a recommended 0.1 mg/kg/day for three to four days for treating PDA and for preventing intravascular hemorrhage (Morris 2003). Ketorolac has been applied intravenously at 0.5 mg/kg/dose every six hours for postoperative pain control in previous studies (Aldrink 2011). 

Through the use of pain assessments employing validated pain scales, the level of pain experienced by neonates both during and following procedures can be evaluated and used to inform clinical practice. Furthermore, drug‐related adverse events following administration and potential correlations to dosage can be explored, alongside requirements for adding additional pharmacological interventions to provide adequate pain relief. Specific to adverse events, episodes of apnea, desaturation, bradycardia, and hypotension are of interest due to the subsequent clinical interventions required. 

The potential association of pain exposure and inadequate pain relief with serious and life‐threatening adverse events, namely mortality, IVH, and poor neuro‐ and cognitive developmental outcomes, is also of clinical relevance and was explored in this review. 

Why it is important to do this review

Neonates in the NICU are a vulnerable patient population repeatedly exposed to painful procedures daily. Such exposure is associated with long‐term consequences and restricted growth and neurodevelopment, which can be avoided with adequate pain management (Vinall 2014). Despite the advances made in the field of procedural pain management in neonates, much of the medication used today lacks clear guidelines and is associated with various adverse effects. The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. This review aimed to ascertain the scope of analgesics for neonatal procedural pain in order to deliver higher‐quality, evidence‐based medical care to this population. 

Previous Cochrane Reviews have focused on procedural pain management through the administration of opioids, dexmedetomidine, paracetamol (acetaminophen), and clonidine (Ohlsson 2020a; Pillai Riddell 2015; Romantsik 2020). An ongoing Cochrane Review is assessing the effects of opioids on procedural pain in neonates (Kinoshita 2021). Of note, opioids are thought to be associated with a higher risk of harms compared to non‐opioid analgesics. However, little work has been done to summarize the benefits and harms of the administration of analgesics in neonates. As the field of neonatal procedural pain management is constantly evolving, a better understanding of the evidence‐based options available is warranted to inform clinical practice. 

Objectives

To determine the effects of non‐opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non‐pharmacological intervention, other analgesics, or different routes of administration.

Methods

Criteria for considering studies for this review

Types of studies

We included prospective randomized controlled trials (RCTs), quasi‐RCTs, cluster‐RCTs, and cross‐over RCTs.

Types of participants

We included preterm and term infants of postmenstrual age (PMA) up to 46 weeks and 0 days, irrespective of their gestational age at birth, receiving non‐opioid analgesics for procedural pain related to blood sampling or intravenous access (placement of Broviac catheter, venipuncture, arterial line placement, insertion of central line, heel‐lance) as well as certain other painful procedures, including chest tube placement, examination for retinopathy of prematurity, and lumbar puncture. Though not listed in the protocol, we included studies on neonatal circumcision, as we considered it a procedure rather than a surgery.

We excluded the use of analgesics in certain other situations, as they are the topic of other published or planned Cochrane Reviews:

• infants receiving analgesics pre‐intubation (assessed in a separate Cochrane Review, Ayed 2017);

• infants undergoing endotracheal suctioning (assessed in a separate Cochrane Review, Pirlotte 2019);

• infants undergoing therapeutic hypothermia (assessed in a separate Cochrane Review, Bäcke 2022);

• infants receiving analgesics for postoperative pain (assessed in a planned, unpublished Cochrane Review). 

We also planned to include studies that reported on a subset of the aforementioned population, provided results were available for this subset alone. 

Types of interventions

We included studies on non‐opioid analgesics, specifically NMDA receptor antagonists (such as ketamine) and NSAIDs (such as ibuprofen), for procedural pain.

We excluded studies on dexmedetomidine, opioids, paracetamol (acetaminophen), and clonidine, as these are included in separate Cochrane Reviews (Ibrahim 2022; Kinoshita 2021; Ohlsson 2020a; Romantsik 2020). 

We included the following comparisons: 

• comparison 1: NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.);

• comparison 2: NSAIDs versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.);

• comparison 3: a head‐to‐head comparison of different analgesics (e.g. ibuprofen versus ketamine);

• comparison 4: different routes of administration of the same analgesics (e.g. enteral ibuprofen versus intravenous ibuprofen).

We included any systemic route of administration, dose, or frequency. However, we excluded topical administration for needle‐related pain (assessed in a separate Cochrane Review, Foster 2017).

Types of outcome measures

Outcome measures did not form part of the eligibility criteria.

Primary outcomes

• Pain assessed with the following scales: ABC scale (Bellieni 2005); Bernese Pain Scale for Neonates (Cignacco 2004); Behavioral Indicators of Infant Pain (BIIP) (Holsti 2008); Douleur Aiguë du Nouveau‐né (DAN) (Acute Pain in Newborn infants, APN, English version) (Carbajal 1997); Neonatal Infant Pain Scale (NIPS) (Lawrence 1993); Neonatal Pain, Agitation, and Sedation Scale (N‐PASS) (Hummel 2008); Premature Infant Pain Profile (PIPP)/PIPP‐Revised (PIPP‐R) (Gibbins 2014; Stevens 1996). If a study reported more than one pain scale among those specified above, we reported them separately. We planned to report the mean values of each pain scale assessed:

  • during the procedure;

  • up to 10 minutes after the procedure;

  • between 11 and 59 minutes after the procedure; and

  • at one to two hours after the procedure.

If a study reported more than one time point among those specified above, we reported them all. We reported the worst score within each timeframe.

Secondary outcomes

• Episodes of bradycardia, defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer.

• Episodes of desaturation, defined as a decrease of arterial oxygen saturation SpO₂ < 80%, with no minimum duration specified.

• Episodes of apnea (mean rates of apnea).

• Hypotension requiring medical therapy (vasopressors or fluid boluses).

• Use of additional pharmacological intervention for the relief of procedural pain.

• Parent satisfaction with care provided in the NICU (as measured by a validated instrument/tool) (Butt 2013).

• IVH; all (grade 1 or 2) or severe (grade 3 or greater) on cranial ultrasound, as per Papile classification (Papile 1978).

• Chronic kidney disease, defined as abnormalities of kidney structure or function, present for more than three months, with implications for health (Stevens 2013).

• NEC (modified Bell stage 2/3; Walsh 1986).

• Major neurodevelopmental disability: cerebral palsy, developmental delay (Bayley Scales of Infant Development ‐ Mental Development Index Edition II (BSID‐MDI‐II; Bayley 1993), Bayley Scales of Infant and Toddler Development ‐ Edition III Cognitive Scale (BSITD‐III) (Bayley 2005)), or Griffiths Mental Development Scale ‐ General Cognitive Index (GCI) (Griffiths 1954; Griffiths 1970), assessment greater than 2 standard deviations (SDs) below the mean, intellectual impairment (intelligence quotient (IQ) greater than 2 SDs below the mean), blindness (vision less than 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013). We planned to separately assess data on children aged 18 to 24 months and those aged 3 to 5 years.

• Cognitive and educational outcomes in children aged more than five years old.

Search methods for identification of studies

The Cochrane Sweden Information Specialist and the Cochrane Neonatal Group Information Specialist developed a draft search strategy for Ovid Medline in consultation with the review authors. An Information Specialist peer reviewed this strategy using the Peer Review of Electronic Search Strategies (PRESS) Checklist (McGowan 2016a; McGowan 2016b). We translated the MEDLINE strategy using appropriate syntax for other databases. Methodological filters were used to limit retrieval to RCT and quasi‐RCTs; and systematic reviews. We performed the searches without language, publication year, publication type, or publication status restrictions. We conducted the searches on 1 and 2 June 2022. 

Electronic searches

We searched the following databases: 

• Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library (Issue 5, 2022), search date 2 June 2022;

• PubMed (pubmed.ncbi.nlm.nih.gov) to 1 June 2022;

• Embase via Elsevier, 1974 to 2 June 2022.

Search strategies are available in Appendix 1.

Searching other resources

We identified trial registration records by independent searches of the US National Library of Medicine ClinicalTrials.gov (clinicaltrials.gov/) (2 June 2022) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (who.int/clinical-trials-registry-platform/the-ictrp-search-portal) (2 June 2022).

We screened the reference lists of included studies for studies not identified by the database searches.

We searched for errata or retractions for included studies published on PubMed (ncbi.nlm.nih.gov/pubmed).

We conducted a grey literature search to identify reports of trials conducted by or referenced in research by CORDIS EU (cordis.europa.eu/); National Institute for Health and Care Excellence (NICE); NHSGGC Paediatrics for Health Professionals (clinicalguidelines.scot.nhs.uk/nhsggc-guidelines/). Sources were identified by consulting the Technical Supplement of Lefebvre 2021 (training.cochrane.org/handbook/current/chapter-04-appendix-resources).

Data collection and analysis

For each included trial, we collected information regarding the method of randomization, blinding, intervention, stratification, and whether the trial was single or multicenter. We noted information regarding trial participants including birthweight, gestational age, number of participants, type of procedural pain, modality of administration, and dose of analgesics. We analyzed the clinical outcomes noted above in Types of outcome measures.

Selection of studies

We used Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components: known assessments—a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labeled as an RCT or as Not an RCT; the RCT classifier—a machine learning model that distinguishes RCTs from non‐RCTs; and, if appropriate, Cochrane Crowd—Cochrane’s citizen science platform where the Crowd help to identify and describe health evidence. For more information about Screen4Me and the evaluations that have been done, please visit the Screen4Me web page on the Cochrane Information Specialist’s portal. In addition, more detailed information regarding evaluations of the Screen4Me components can be found in the following publications: Marshall 2018; Noel‐Storr 2020; Noel‐Storr 2021; Thomas 2020.

We included all RCTs, quasi‐RCTs, and cluster‐RCTs that fulfilled our inclusion criteria. Two review authors (EP, ABP) assessed the search results and independently selected studies for inclusion in the review. Any disagreements were resolved by discussion.

We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and a Characteristics of excluded studies table (Moher 2009).

Data extraction and management

Two review authors (EP, ABP) independently extracted data using a data extraction form integrated with a modified version of the Cochrane Effective Practice and Organisation of Care (EPOC) Group data collection checklist (Cochrane EPOC Group 2017). We piloted the form within the review team.

We extracted the following characteristics from each included study:

• administrative details: study author(s); published or unpublished; year of publication; year in which study was conducted; presence of vested interest; details of other relevant papers cited;

• study: study design; type, duration, and completeness of follow‐up (e.g. greater than 80%); country and location of study; informed consent; ethics approval;

• participants: sex, birthweight, gestational age, number of participants;

• interventions: initiation, dose, and duration of analgesics administration;

• outcomes as mentioned above in Types of outcome measures.

Any disagreements were resolved by discussion. We described any studies awaiting classification identified by our search, detailing the primary author, research question(s), methods, and outcome measures, together with an estimate of the reporting date, and reported them in the Characteristics of studies awaiting classification table.

In cases where additional data were required, we contacted study investigators/authors for clarification. This was the case for Madathil 2021.

Two review authors (EP, ABP) used Cochrane Review Manager 5 software for data entry (Review Manager 2020). We replaced any standard error of the mean (SEM) with the corresponding SD value.

Assessment of risk of bias in included studies

Two review authors (EP, ABP) independently assessed the risk of bias (low, high, or unclear) of all included trials using the Cochrane risk of bias tool for the following domains (Higgins 2011).

• Sequence generation (selection bias)

• Allocation concealment (selection bias)

• Blinding of participants and personnel (performance bias)

• Blinding of outcome assessment (detection bias)

• Incomplete outcome data (attrition bias)

• Selective reporting (reporting bias)

• Any other bias

Any disagreements were resolved by discussion. See Appendix 2 for a more detailed description of the risk of bias for each domain.

We assessed the overall risk of bias as one of three categories, as follows.

• Low risk of bias: we classified the outcome result of a trial as overall low risk of bias only if all domains were classified as at low risk of bias.

• Unclear risk of bias: we classified the outcome result of a trial as overall unclear risk of bias if one or more domains were classified as unclear, and no domain was at high risk of bias.

• High risk of bias: we classified the outcome result of a trial as overall high risk of bias if at least one domain was classified as high risk of bias.

Measures of treatment effect

We performed statistical analyses using Review Manager 5 (Review Manager 2020). We summarized the data in a meta‐analysis if they were sufficiently homogeneous, both clinically and statistically.

Dichotomous data

For dichotomous data, we presented results using risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CIs). We calculated the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) with 95% CIs if there was a statistically significant reduction (or increase) in RD.

Continuous data

For continuous data, we used the mean difference (MD) when outcomes were measured in the same way between trials. We used the standardized mean difference (SMD) to combine trials that measured the same outcome but employed different methods. However, we planned not to pool pain scores assessed with different scales in the same analysis. Where trials reported continuous data as the median and interquartile range (IQR) and data passed the test of skewness, we would convert median mean to median estimate the SD as IQR/1.35.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomized trials, and an infant was considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital was the unit of analysis in cluster‐RCTs. We analyzed cluster‐RCTs using an estimate of the intracluster correlation coefficient (ICC) derived from the trial if possible, or from a similar trial or from a study with a similar population as described in Section 16.3.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). If we used ICCs from a similar trial or from a study with a similar population, we would report this and conduct a sensitivity analysis to investigate the effect of variation in the ICC.

If any trials had multiple arms that were compared against the same control condition that was included in the same meta‐analysis, we would either combine groups to create a single pair‐wise comparison, or select one pair of interventions and exclude the others.

If we identified both cluster‐RCTs and individual RCTs, we would only combine the results from both if there was little heterogeneity between the study designs and interaction between the effect of the intervention and the choice of randomization unit was considered to be unlikely.

In the event that we identified cross‐over trials, in which the reporting of continuous outcome data precluded paired analysis, we would not include these data in a meta‐analysis in order to avoid unit of analysis error. Where carry‐over effects were thought to exist, and where sufficient data were available, we would only include data from the first period in the analysis (Higgins 2021).

We acknowledged any possible heterogeneity in the randomization unit and performed a sensitivity analysis to investigate the possible effects of the randomization unit.

Dealing with missing data

Where feasible, we intended to carry out analysis on an intention‐to‐treat basis for all outcomes. Whenever possible, we analyzed all participants in the treatment group to which they had been randomized, regardless of the actual treatment received. If we identified important missing data (in the outcomes) or unclear data, we requested the missing data by contacting the original trial authors. If a trial contained a mixed population (i.e. postoperative and non‐operative infants grouped together in the report), we would (1) assess whether subgroup results for non‐operative infants were reported. If not, we would contact the trial authors. If results were unavailable, we would (2) include all the trial data if non‐operative infants made up 50% or more of the total trial population. We planned to carry out a sensitivity analysis to assess the impact of including studies with mixed populations if we could not obtain subgroup data from trial authors. We made explicit assumptions of any methods used to deal with missing data. We planned to perform sensitivity analyses to assess how sensitive the results were to reasonable changes in the undertaken assumptions. We planned to address the potential impact of missing data on the findings of the review in the Discussion section.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic value. We graded the degree of heterogeneity as:

• less than 25%: no heterogeneity;

• 25% to 49%: low heterogeneity;

• 50% to 75%: moderate heterogeneity;

• more than 75%: substantial heterogeneity.

If we noted statistical heterogeneity (I² > 50%), we would explore the possible causes (e.g. differences in study quality, participants, intervention regimens, or outcome assessments) and consider conducting sensitivity analysis (see Sensitivity analysis).

Assessment of reporting biases

We planned to create and examine a funnel plot to explore possible small‐study biases. In interpreting funnel plots, we planned to examine the different possible reasons for funnel plot asymmetry as outlined in Section 10.4 of the Cochrane Handbook for Systematic Reviews of Interventions and relate this to the results of the review. If we were able to pool more than 10 trials, we would undertake formal statistical tests to investigate funnel plot asymmetry, following the recommendations in Section 10.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2017).

To assess outcome reporting bias, we checked the trial protocols against the published reports. For studies published after 1 July 2005, we screened the WHO ICTRP for the a priori trial protocol. We evaluated whether the selective reporting of outcomes was present.

Data synthesis

If we identified multiple studies considered to be sufficiently similar, we would perform meta‐analysis using Review Manager 5 (Review Manager 2020). For categorical outcomes, we calculated the typical estimates of RR and RD, each with its 95% CI; for continuous outcomes, we calculated the MD or the SMD, each with its 95% CI. We used a fixed‐effect model to combine data where it was reasonable to assume that studies were estimating the same underlying treatment effect. If we judged meta‐analysis to be inappropriate, we would analyze and interpret the results from individual trials separately. If there was evidence of clinical heterogeneity, we would attempt to explain this based on the different study characteristics and subgroup analyses.

Subgroup analysis and investigation of heterogeneity

We explored high statistical heterogeneity in the outcomes by visually inspecting the forest plots and by removing the outlying studies in the sensitivity analysis (Higgins 2020). We assessed differences between subgroups using the formal test for subgroup differences in Review Manager 5 (Review Manager 2020). Where statistical heterogeneity was significant, we interpreted the results of the meta‐analyses accordingly, downgrading the certainty of evidence in the summary of findings tables according to the GRADE recommendations.

We considered the following groups for subgroup analysis where data were available: 

• gestational age: term infants (37 weeks' gestation or greater); preterm infants (less than 37 weeks' gestation); extreme preterm (fewer than 28 weeks' gestation);

• type of comparator, i.e. studies where the control group was no treatment or placebo; oral sweet solution; non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.), for comparison 1;

• routes for administration (e.g. enteral, intravenous) for comparisons 1, 2, and 3;

• type of administration (with or without loading dose; bolus or continuous infusion);

• with or without other pharmacological sedation/analgesia as co‐interventions;

• specific clinical conditions, e.g. infants undergoing dialysis or extracorporeal membrane oxygenation.

We restricted these analyses to the primary outcomes.

Sensitivity analysis

Where we identified substantial heterogeneity, we conducted sensitivity analysis to determine if the findings were affected by the inclusion of only those trials considered to have used adequate methodology with a low risk of bias (selection, performance, and reporting bias). We reported the results of sensitivity analyses for our primary outcomes only.

Given that there is no formal statistical test that can be used for sensitivity analysis, we provided informal comparisons between the different ways of estimating the effect under different assumptions. We did not use changes in P values to judge whether there was a difference between the main analysis and sensitivity analysis, since statistical significance may be lost with fewer studies included.

We reported sensitivity analysis results in tables rather than forest plots.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of the evidence for the following (clinically relevant) outcomes.

• Pain assessed during the procedure with the following scales: ABC scale (Bellieni 2005); Bernese Pain Scale for Neonates (Cignacco 2004); BIIP (Holsti 2008); DAN (APN, English version) (Carbajal 1997); NIPS (Lawrence 1993); N‐PASS (Hummel 2008); PIPP/PIPP‐R (Gibbins 2014; Stevens 1996).

• Pain assessed up to 10 minutes after the procedure with the following scales: ABC scale (Bellieni 2005); Bernese Pain Scale for Neonates (Cignacco 2004); BIIP (Holsti 2008); DAN (APN, English version) (Carbajal 1997); NIPS (Lawrence 1993); N‐PASS (Hummel 2008); PIPP/PIPP‐R (Gibbins 2014; Stevens 1996).

• Episodes of bradycardia, defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer, occurring during the procedure.

• Episodes of apnea (mean rates of apnea), occurring during the procedure.

• Hypotension requiring medical therapy (vasopressors or fluid boluses), occurring during the procedure.

Two review authors (EP, MB) independently assessed the certainty of the evidence for each of the outcomes above, for the following comparisons:

• comparison 1: NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.);

• comparison 2: NSAIDs versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.);

• comparison 3: a head‐to‐head comparison of different analgesics (e.g. ibuprofen versus ketamine);

• comparison 4: different routes of administration of the same analgesics (e.g. enteral ibuprofen versus intravenous ibuprofen).

We considered evidence from RCTs as high certainty, downgrading the certainty of the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used GRADEpro GDT software to create summary of findings tables to report the certainty of the evidence (see Table 1; Table 2) (GRADEpro GDT).

The GRADE approach results in an assessment of the certainty of a body of evidence as one of four grades, as follows. 

• High: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

• Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Results of the search

The literature searches run in June 2022 retrieved 6581 records overall, which was reduced to 5231 records following deduplication. We utilized Cochrane’s Screen4Me workflow to help identify potential RCTs and screen records. The results of the Screen4Me assessment process are shown in Figure 1. We then screened the titles and abstracts of the remaining 2368 records. We excluded 2357 records, leaving 11 studies for full‐text review. Of these, we excluded six studies, assessed three studies as awaiting classification, and included two studies. For more information, see Figure 2. 

1.

Screen4Me summary diagram.

2.

Study flow diagram.

Included studies

Two RCTs recruiting 269 neonates met our inclusion criteria (Madathil 2021; Modekwe 2021). For details, see Characteristics of included studies. The trials used different routes (oral and intravenous (IV)) for the administration of ketamine.

Madathil 2021 was an RCT conducted between 16 April 2018 and 5 May 2019 in a tertiary care hospital daycare facility in North India using IV fentanyl and IV ketamine for pain relief during laser photocoagulation for retinopathy of prematurity in preterm infants. Neonates with type 1 retinopathy of prematurity who required laser photocoagulation were included if they were hemodynamically stable, not anemic (packed cell volume of more than 30%), had no IVH of grade III to IV, had no PDA or NEC, and the anticipated duration of the procedure was over 30 minutes. Neonates who were sick enough to need continuous positive airway pressure or mechanical ventilation, NICU care, or those with any known congenital malformations were excluded. An independent investigator was used for randomization and allocation concealment. One group received an IV fentanyl bolus, followed by an infusion (2 μg/kg over 5 minutes 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion thereafter until the end of the procedure), and the other received intermittent IV ketamine boluses (bolus dose of 0.5 mg/kg of ketamine 1 minute before procedure). Furthermore, both groups of infants were swaddled and contained during the procedure and received 0.5% ophthalmic paracrine drops as topical anesthesia. After the start of the study, the protocol was adapted from the initial drug phase to a revised regimen with increased drug concentrations. The fentanyl group had their infusion rate titrated by 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour, and the ketamine group received additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg (total of four boluses). 

The overall PIPP‐R scores measured every 15 minutes were less than seven, and the proportion of the procedure time the infant spent crying was less than five per cent. The authors also provided us with exact PIPP‐R scores following email request: initial phase fentanyl (mean: 2.84 [SD: 0.34]), revised regimen fentanyl (mean: 2.66 [SD: 0.62]), initial phase ketamine (mean: 3.89 [SD: 0.75]), revised regimen ketamine (mean: 2.82 [SD: 1.34]). Secondary outcomes included episodes of apnea, need for supplemental oxygen, and hypotension requiring medical therapy. 

Modekwe 2021 was an RCT on the efficacy and safety of oral ketamine in neonatal circumcision conducted at Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra, Nigeria, including 145 neonates between March 2015 and December 2015. Trial participants were male neonates undergoing circumcision. Exclusion criteria included neonates delivered preterm, those with penile lesions, such as rashes and ulcers, and congenital penile anomalies, such as hypospadias or epispadias. Neonates were randomly divided into two groups by a simple ballot method weekly, picking from a bag containing an equal amount of tags. Two separate assistants were responsible for the balloting and administration. At the end of the procedure, the group and medications were listed on the pro forma. The neonates in group A received 10 mg of oral ketamine per kilogram of body weight. As a placebo, neonates in group B received simple sucrose (66.7% w/w) at 1 mL/kg body weight. A compounding section of the hospital pharmacy prepared the oral ketamine using sucrose as a base and sweetener without a preservative to ensure that neonates of similar weight received the same amount of syrup. 

The hospital anesthesia department provided monitored anesthesia care and observed for life‐threatening adverse effects of ketamine, such as apnea, laryngeal spasm, and aspiration. Continuous pulse oximetry was performed on the neonates before, during, and after the procedure. Restrictions were placed on feeding. The pre‐procedural and intra‐procedural peripheral oxygen saturation (SpO₂) and pulse rate were determined at various stages. NIPS scores were assessed during the procedure. The mean NIPS were significantly higher in the placebo group compared to the oral ketamine group at all stages of the procedure (P < 0.001). 

For further details, see Characteristics of included studies.

Excluded studies

Following full‐text screening, we excluded six studies: two due to no NMDA receptor antagonist or NSAID administration (Choi 1997; Janevski 2010); one for not following an RCT study design (NCT03705468); one for exclusively evaluating infants undergoing surgery (Kamiyama 1980); one focused on anesthesia (Trabold 2002); and one focused on endotracheal suctioning (Saarenmaa 2001). For more information, see Characteristics of excluded studies.

Awaiting classification

We identified three studies awaiting classification (ACTRN1261000025; Meau‐Petit 2005; Pees 2003). We contacted the study authors for further details, but have received no response or co‐operation to date. For more information, see Characteristics of studies awaiting classification.

Risk of bias in included studies

A risk of bias graph and risk of bias summary are shown in Figure 3 and Figure 4. 

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

4.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Outcomes: PIPP‐R score, episodes of apnea, need for supplementary oxygen, hypotension requiring medical therapy (Madathil 2021). 

Random sequence generation: we assessed the risk of bias as unclear, as it was unclear how the random sequence was generated. 

Allocation concealment: we assessed the risk of bias as low; well‐described allocation concealment. 

Outcome: NIPS score (Modekwe 2021). 

Random sequence generation: we assessed the risk of bias as low; infants were randomized using a simple ballot method weekly. 

Allocation concealment: we assessed the risk of bias as unclear; one assistant was responsible for the balloting and another for administering the medications, but insufficient information on concealment was provided to permit a judgement of low or high risk of bias. 

Blinding

Outcomes: PIPP‐R score, episodes of apnea, need for supplementary oxygen, hypotension requiring medical therapy (Madathil 2021). 

Performance bias: we assessed the risk of bias as unclear; blinding was not possible due to the obvious nature of the intervention (infusion versus intermittent boluses). However, knowledge of the kind of anesthesia was likely to have had little impact on the overall results recorded. 

Detection bias: we assessed the risk of bias as low; outcome assessors were blinded. 

Outcome: NIPS score (Modekwe 2021). 

Performance and detection bias: we assessed the risk of bias as low; the surgeon, parent or caregiver, anesthetists, and the assistant that recorded the details were all blinded to the type of oral medication received. 

Incomplete outcome data

Outcomes: PIPP‐R score, episodes of apnea, need for supplementary oxygen, hypotension requiring medical therapy (Madathil 2021). 

We assessed the risk of bias as unclear. The authors reported: "We could not analyze outcome of cry duration/proportion of cry in four infants during the first phase of the study due to inadequate cry recordings" and "small number of infants enrolled in the second phase of the study due to logistical constraints as we had to stop the trial after achieving the target sample size".

Outcome: NIPS score (Modekwe 2021). 

We assessed the risk of bias as unclear; the study authors did not mention incomplete outcome data. 

Selective reporting

Outcomes: PIPP‐R score, episodes of apnea, need for supplementary oxygen, hypotension requiring medical therapy (Madathil 2021). 

We assessed the risk of bias as high. The authors reported: “…intermittent video recording of the infant focusing on the face…prior to the procedure…followed by every 15 minutes until the end... . Each recording was done for a duration of 30 seconds. Two independent assessors…analysed all the recorded videos by comparing the infant’s reaction with that of the ‘reference’... . The discrepancies were resolved through mutual discussions”.

Outcome: NIPS score (Modekwe 2021). 

We assessed the risk of bias as high; 14 infants in group A and 10 infants in group B were excluded for "technical hitches", but no further explanation given.  

Other potential sources of bias

Outcomes: PIPP‐R score, episodes of apnea, need for supplementary oxygen, hypotension requiring medical therapy (Madathil 2021). 

We assessed the risk of bias as low; no other concerns detected. 

Outcome: NIPS score (Modekwe 2021). 

We assessed the risk of bias as low; no other concerns detected. 

Effects of interventions

See: Table 1; Table 2

The two included studies (269 infants) comparing different non‐opioid analgesics are reported in the following comparisons.

• Comparison 1 (NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention): Modekwe 2021, comparing oral ketamine with sucrose administration, see Table 1.

• Comparison 3 (head‐to‐head comparison of different analgesics): Madathil 2021, comparing IV ketamine with fentanyl, see Table 2.

We identified no studies evaluating comparison 2 (NSAIDs versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention) or comparison 4 (different routes for administration of the same analgesics).

Comparison 1. NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention

Primary outcomes

Pain assessed during the procedure

One RCT reported this outcome (Modekwe 2021). We are very uncertain whether ketamine reduces pain during the procedure compared to sweet solution (mean difference (MD) −0.95, 95% confidence interval (CI) −1.32 to −0.58; 1 study; 145 infants; I² not applicable; very low‐certainty evidence; Analysis 1.1). 

1.1. Analysis.

Comparison 1: NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention, Outcome 1: Pain score (NIPS) during the procedure

Pain was not assessed at the other prespecified time points (i.e. up to 10 minutes after the procedure; between 11 and 59 minutes after the procedure; at one to two hours after the procedure).

Secondary outcomes

None of our secondary outcomes were reported for this comparison (i.e. episodes of bradycardia; episodes of desaturation; episodes of apnea; hypotension requiring medical therapy; use of additional pharmacological intervention for the relief of procedural pain; parent satisfaction with care provided in the NICU; IVH all (grade 1 or 2) or severe (grade 3 or greater) on cranial ultrasound; chronic kidney disease; NEC; major neurodevelopmental disability; cognitive and educational outcomes in children over five years old) (Modekwe 2021).

Comparison 2. NSAIDs versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention

No studies were included for this comparison.

Comparison 3. Head‐to‐head comparison of different analgesics

Primary outcomes

Pain assessed during the procedure

One RCT reported this outcome (Madathil 2021). We are very uncertain whether ketamine reduces pain during the procedure compared to fentanyl (MD 0.98, 95% CI 0.75 to 1.20; 1 study; 124 infants; I² = 78%; very low‐certainty evidence; Analysis 2.1). 

2.1. Analysis.

Comparison 2: Head‐to‐head comparison of different analgesics, Outcome 1: Pain score (PIPP‐R) up to 10 minutes after the procedure

Outcome data were reported for the initial and revised dose regimen separately. We are uncertain whether ketamine reduces pain during the procedure compared to fentanyl.

Pain was not assessed at the other prespecified time points (i.e. up to 10 minutes after the procedure; between 11 and 59 minutes after the procedure; at one to two hours after the procedure).

Secondary outcomes

Episodes of apnea

One RCT reported this outcome (Madathil 2021). We are very uncertain whether ketamine reduces episodes of apnea compared to fentanyl (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) −0.09, 95% CI −0.19 to 0.00; 1 study; 124 infants; I² for RR and RD = 6% and 76%, respectively; very low‐certainty evidence; Analysis 2.2). Outcome data were reported for the initial and revised dose regimen separately. 

2.2. Analysis.

Comparison 2: Head‐to‐head comparison of different analgesics, Outcome 2: Episodes of apnea

Need for supplemental oxygen

One RCT reported this outcome (Madathil 2021). We are very uncertain whether ketamine reduces need for supplemental oxygen compared to fentanyl (RR 0.33, 95% CI 0.12 to 0.89; RD −0.15, 95% CI −0.28 to −0.03; 1 study; 124 infants; I² for RR and RD = 29% and 73%, respectively; very low‐certainty evidence; Analysis 2.3). Outcome data were reported for the initial and revised dose regimen separately. 

2.3. Analysis.

Comparison 2: Head‐to‐head comparison of different analgesics, Outcome 3: Need for supplemental oxygen

Hypotension requiring medical therapy

One RCT reported this outcome (Madathil 2021). We are very uncertain whether ketamine reduces hypotension requiring medical therapy compared to fentanyl (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI −0.03 to 0.10; 1 study; 124 infants; I² for RR and RD = not applicable and 0%, respectively; very low‐certainty evidence; Analysis 2.4). Outcome data were reported for the initial and revised dose regimen separately. 

2.4. Analysis.

Comparison 2: Head‐to‐head comparison of different analgesics, Outcome 4: Hypotension requiring medical therapy

None of the following secondary outcomes were reported for this comparison: episodes of bradycardia; episodes of desaturation; use of additional pharmacological intervention for the relief of procedural pain; parent satisfaction with care provided in the NICU; IVH all (grade 1 or 2) or severe (grade 3 or greater) on cranial ultrasound; chronic kidney disease; NEC; major neurodevelopmental disability; cognitive and educational outcomes in children over five years old (Madathil 2021).

Comparison 4. Different routes for administration of the same analgesics

No studies were included for this comparison.

Subgroup analyses

Subgroup analyses were not conducted due to the paucity of included studies.

Discussion

Summary of main results

We evaluated the benefits and harms of non‐opioid analgesics for procedural pain in neonates. We included two trials (enrolling 269 infants) that could not be pooled because one compared oral ketamine with sucrose administration (Modekwe 2021), and the other compared IV ketamine with fentanyl (Madathil 2021).

The evidence is very uncertain about the effect of NMDA receptor antagonists on pain score during the procedure as assessed with NIPS. No studies reported the other main outcomes of this review, that is pain assessed up to 10 minutes after the procedure, episodes of bradycardia, episodes of apnea, or hypotension requiring medical therapy.

The evidence is very uncertain about the effect of head‐to‐head comparison of different analgesics on the PIPP‐R pain score during the procedure. No studies reported pain assessed up to 10 minutes after the procedure or episodes of bradycardia. The evidence is very uncertain about the effect of head‐to‐head comparison of different analgesics on episodes of apnea, need for supplemental oxygen, or hypotension requiring medical therapy.

Overall completeness and applicability of evidence

To date, there are only two trials comparing non‐opioid analgesics versus placebo or other interventions for procedural pain, enrolling a total of 269 infants. Study authors reported limited data about potential adverse effects of opioids and did not report relevant, long‐term outcomes such as major neurodevelopmental disability and cognitive and educational outcomes. We excluded two studies because they included infants for indications not included in this review (i.e. procedures related to the endotracheal intubation, Saarenmaa 2001, or infants undergoing surgery, Kamiyama 1980), and two other studies that were beyond the scope of this review as they assessed the effects of paracetamol, Janevski 2010, or chloral hydrate, Choi 1997. We could not perform an appropriate a priori subgroup analysis to detect differential effects because of the paucity of included trials.

Quality of the evidence

According to the GRADE approach, the overall certainty of the evidence for the few reported critical outcomes was very low. We downgraded the certainty of the evidence for all outcomes for study limitations (multiple domains with either high or unclear risk of bias) and imprecision of the estimates (only one trial in each comparison, wide confidence intervals).

We did not explore publication bias using funnel plots because fewer than 10 studies met our inclusion criteria.

Potential biases in the review process

Though not listed in the protocol, we included studies on neonatal circumcision, as we considered it to be a procedure rather than surgery.

Agreements and disagreements with other studies or reviews

There is limited evidence on the provision of non‐opioid analgesics in neonates for procedural pain to date, as most studies have focused on other drugs or indications in this population. One review evaluating procedural sedation and analgesia in neonates and children found that ketamine provided adequate anesthesia and was well‐tolerated without serious adverse effects (Poonai 2017). Another review evaluating postoperative neonates also found that ketorolac provision reduced morphine administration and lowered pain scores (Stone 2021). Similarly, the efficacy of NSAIDs for procedural pain in children and immense potential for neonates has not been well‐researched (Ziesenitz 2022). This evidence gap highlights the necessity for further research in neonates. 

Authors' conclusions

Implications for practice.

The inclusion of only two small studies (ketamine versus either placebo or fentanyl) with very low‐certainty evidence precluded any meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on non‐steroidal anti‐inflammatory drugs (NSAIDs) or studies comparing different routes of administration.

Implications for research.

Future research should prioritize large studies evaluating non‐opioid analgesics in this population. Given that the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as no studies were identified on NSAIDs, which are widely used in older infants, or comparing different routes of administration, these should be a priority going forward. 

History

Protocol first published: Issue 7, 2022

Appendices

Appendix 1. Search strategies

Searches performed by Matthias Bank, Lund University, Faculty of Medicine, Library & ICT

 

Search strategies

The documentation is structured according to PRISMA 2020, international standard for systematic reviews.  See PRISMA 2020 for further information:  http://prisma-statement.org/  and http://prisma-statement.org/Extensions/Searching 

 

PubMed

Date of search: 01 June 2022

#1 general surgery[Mesh:noexp]  40,296

“2 (Surgical procedures, Operative[MeSH Terms]) 3,427,620

#3 ("Perioperative Medicine"[Mesh]) OR "Perioperative Care"[Mesh] OR "Perioperative Period"[Mesh] OR "Perioperative Nursing"[Mesh]  258,304

#4 ((((((("Catheterization"[Mesh]) OR "Catheters"[Mesh:NoExp]) OR "Cannula"[Mesh]) OR "Catheter Obstruction"[Mesh]) OR "Catheters, Indwelling"[Mesh]) OR "Urinary Catheters"[Mesh]) OR "Vascular Access Devices"[Mesh]) OR ("Cardiac Catheters"[Mesh]) OR "Central Venous Catheters"[Mesh] OR "Chest Tubes"[Mesh]  228,120

#5 "Retinopathy of Prematurity"[Mesh] 6,657

#6 "Spinal Puncture"[Mesh] 6,621

#7 catheter*[TIAB] OR cannula*[TIAB] OR surgery[TIAB] OR surgical*[TIAB] OR retinopathy[TIAB] OR puncture[TIAB] OR needle[TIAB] OR needles[TIAB] OR "heel lanc*"[TIAB] OR heellanc*[TIAB] OR "chest tube"[TIAB] OR "chest tubes"[TIAB] 2,488,861

#8 operativ*[TIAB] OR postoperat*[TIAB] OR post‐operat*[TIAB] OR perioperativ*[TIAB] OR peri‐operativ*[TIAB] OR preopera*[TIAB] OR pre‐opera*[TIAB]  1,069,352

#9 "Pain, Postoperative"[Mesh] OR “Pain perception”[Mesh] OR “Stress, psychological”[Mesh]  200,275

#10 presurgi*[TIAB] OR pre‐surgi*[TIAB]  13,188

#11 "procedural pain"[TIAB] OR "pain procedure*"[TIAB] OR “painful procedure*”[TIAB] 3,137

#12 "invasive procedure*"[TIAB] OR "Blood specimen collection"[Mesh] OR "Injections"[Mesh] OR "Phlebotomy"[Mesh] OR "Punctures"[Mesh] OR "Sutures"[Mesh] 447,537   

#13 (injection*[TIAB] OR intravenous*[TIAB] OR "Needles"[Mesh]) OR (((((( "Anesthesia, Intravenous"[Mesh]) OR "Immunoglobulins, Intravenous"[Mesh]) OR "Administration, Intravenous"[Mesh]) OR "Fat Emulsions, Intravenous"[Mesh]) OR "Anesthetics, Intravenous"[Mesh]) OR "Infusions, Intravenous"[Mesh])  1,010,728

#14 drainage[TIAB] OR suction*[TIAB] OR ("Drainage"[Mesh:NoExp]) OR "Suction"[Mesh] 146,100

#15 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14
[SURGICAL PROCEDURES AND PAIN]   5,948,440

#16 ((pain[mh] OR "pain management"[mh] OR pain measurement[mh] OR pain threshold[mh]) OR (Anxiety[mh] or Behavior[mh] or Crying[mh] or Facial expressions[mh] or Fear[mh] or Gestures[mh] or Heart Rate[mh] or Infant Behavior[mh] or Oxygen Consumption[mh] or Panic[mh] or Wakefulness[mh])) OR (anxiet*[TIAB] OR anxious[TIAB] OR behavior*[TIAB] OR behaviour*[TIAB] OR crying[TIAB] OR discomfort*[TIAB] OR distress*[TIAB] OR Douleur Aigue du Nouveau ne[TIAB] OR facial expression*[TIAB] OR fear*[TIAB] OR fright*[TIAB] OR gesture*[TIAB] OR grimac*[TIAB] OR heart rate*[TIAB] OR Median Premature Infant Pain Profile score*[TIAB] OR Neonatal Facial Action*[TIAB] OR Neonatal Facial Activity Coding System[TIAB] OR Neonatal Facial Coding Score*[TIAB] OR NFCS[TIAB] OR neonatal facial coding system[TIAB] OR nociceptive reaction*[TIAB] OR orosensorial antinociceptive effect*[TIAB] OR oxygen consumption[TIAB] OR oxygen saturation*[TIAB] OR pain*[TIAB] OR panic*[TIAB] OR sleep wake state*[TIAB] OR wakefulness[TIAB])   4,482,838
 

#17 #15 OR #16 9,480,568
[SURGICAL PROCEDURES AND BROADER PAIN TERMS]

#18 "Ibuprofen"[Mesh] OR "Fenoprofen"[Mesh] OR "Indoprofen"[Mesh] OR "Ketoprofen"[Mesh] OR "Suprofen"[Mesh] OR Phenylpropionates[Mesh] OR "Diclofenac"[Mesh] 23,875

#19 "Chloral Hydrate"[Mesh] OR "Propofol"[Mesh] OR “ketamine”[Mesh] OR “indomethacin”[Mesh] OR “ketorolac”[Mesh]   63,154

 #20 “Analgesics, non‐narcotic”[Mesh] OR "Cyclooxygenase Inhibitors"[Mesh] OR "Analgesics, Short‐Acting"[Mesh] OR “Anti‐inflammatory agents, non‐steroidal”[Pharmacological action] OR "Receptors, N‐Methyl‐D‐Aspartate"[Mesh]  279,926

#21 ibuprofen[TIAB] OR fenoprofen[TIAB] OR indoprofen[TIAB] OR ketoprofen[TIAB] OR suprofen[TIAB] OR Phenylpropionate*[TIAB] OR diclofenac[TIAB] OR "cyclooxygenase inhibit*"[TIAB] OR chloral hydrate[TIAB] OR propofol[TIAB] OR ketamine[TIAB] OR NMDA[TIAB] OR N‐methylaspartate[TIAB] OR N‐Methyl‐D‐Aspartate[TIAB] OR NSAID*[TIAB] OR nonsteroidal anti‐inflammator*[TIAB] OR nonsteroidal antiinflammator*[TIAB] OR ketorolac[TIAB] OR indomethacin[TIAB] 193,721

#22 #18 OR #19 OR #20 OR #21 [ANALGESICS] 390,993 
#23 ((("infant, newborn"[MeSH Terms]) ) OR (intensive care, neonatal[MeSH Terms])) OR (intensive care unit, neonatal[MeSH Terms])   654,536

#24 baby*[TIAB] OR babies[TIAB] OR infant[TIAB] OR infants[TIAB] OR infant s[TIAB] OR infant's[TIAB] OR infantile[TIAB] OR infancy[TIAB] OR low birth weight[TIAB] OR low birthweight[TIAB] OR neonat*[TIAB] OR newborn*[TIAB] OR new born[TIAB] OR new borns[TIAB] OR newly born[TIAB] OR 
premature[TIAB] OR prematures[TIAB] OR prematurity[TIAB] OR preterm[TIAB] OR preterms[TIAB] OR pre term[TIAB] OR preemie[TIAB] OR preemies[TIAB] OR premies[TIAB] OR premie[TIAB] OR VLBW[TIAB] OR LBW[TIAB] OR ELBW[TIAB] OR NICU[TIAB] 972,584

#25 #23 OR #24 [NEONATES]  1,254,238

#26 (((randomized controlled trial[PT]) OR (controlled clinical trial[PT])) OR (randomized[TIAB] OR placebo[TIAB] OR randomly[TIAB] OR trial[TIAB] OR groups[TIAB] ) OR ("drug therapy"[MeSH Subheading]))  5,441,671

#27 ("Animals"[Mesh]) NOT "Humans"[Mesh]  5,010,889

#28 #26 NOT #27 [RCTs]   4,742,419

#29 #17 AND #22 AND #25 AND #28 1,953
[SURGICAL PROCEDURES/PAIN AND ANALGESICS AND NEONATES AND RCT]

 

CENTRAL via Cochrane Library (Wiley), Issue 5, 2022

Date of search: 02 June 2022

#1 MeSH descriptor: [General Surgery] this term only 366

#2 MeSH descriptor: [Surgical Procedures, Operative] explode all trees 128680

#3 MeSH descriptor: [Perioperative Medicine] explode all trees 0

#4 MeSH descriptor: [Perioperative Care] explode all trees 12788

#5 MeSH descriptor: [Perioperative Period] explode all trees 9247

#6 MeSH descriptor: [Perioperative Nursing] explode all trees 130

#7 MeSH descriptor: [Catheterization] explode all trees 9854

#8 MeSH descriptor: [Catheters] this term only 350

#9 MeSH descriptor: [Cannula] explode all trees 177

#10 MeSH descriptor: [Catheter Obstruction] explode all trees 28

#11 MeSH descriptor: [Catheters, Indwelling] explode all trees 1058

#12 MeSH descriptor: [Urinary Catheters] explode all trees 107

#13 MeSH descriptor: [Vascular Access Devices] explode all trees 424

#14 MeSH descriptor: [Cardiac Catheters] explode all trees 93

#15 MeSH descriptor: [Central Venous Catheters] explode all trees 195

#16 MeSH descriptor: [Chest Tubes] explode all trees 281

#17 MeSH descriptor: [Retinopathy of Prematurity] explode all trees 416

#18 MeSH descriptor: [Spinal Puncture] explode all trees 309

#19 (catheter* OR cannula* OR surgery OR surgical* OR retinopathy OR puncture OR needle OR needles OR "heel lanc*" OR heellanc* OR "chest tube" OR "chest tubes"):ti,ab,kw (Word variations have been searched) 314092

#20 (operativ* OR postoperat* OR post‐operat* OR perioperativ* OR peri‐operativ* OR preopera* OR pre‐opera*):ti,ab,kw (Word variations have been searched) 171168

#21 MeSH descriptor: [Pain, Postoperative] explode all trees 17178

#22 MeSH descriptor: [Pain Perception] explode all trees 532

#23 MeSH descriptor: [Stress, Psychological] explode all trees 6817

#24 (presurgi* OR pre‐surgi* OR "procedural pain" OR "pain procedure*" OR “painful procedure*” OR "invasive procedure*"):ti,ab,kw (Word variations have been searched) 6818

#25 MeSH descriptor: [Blood Specimen Collection] explode all trees 741

#26 MeSH descriptor: [Punctures] explode all trees 3074

#27 MeSH descriptor: [Sutures] explode all trees 1116

#28 MeSH descriptor: [Injections] explode all trees 23407

#29 MeSH descriptor: [Phlebotomy] explode all trees 494

#30 (injection* OR intravenous* OR drainage OR suction*):ti,ab,kw (Word variations have been searched) 193688

#31 MeSH descriptor: [Needles] explode all trees 1287

#32 MeSH descriptor: [Anesthesia, Intravenous] explode all trees 1955

#33 MeSH descriptor: [Immunoglobulins, Intravenous] explode all trees 900

#34 MeSH descriptor: [Administration, Intravenous] explode all trees 19221

#35 MeSH descriptor: [Fat Emulsions, Intravenous] explode all trees 484

#36 MeSH descriptor: [Anesthetics, Intravenous] explode all trees 3757

#37 MeSH descriptor: [Infusions, Intravenous] explode all trees 10561

#38 MeSH descriptor: [Drainage] this term only 1724

#39 MeSH descriptor: [Suction] explode all trees  953

#40 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39   509136

#41 MeSH descriptor: [Pain] explode all trees 55146

#42 MeSH descriptor: [Pain Management] explode all trees 4343

#43 MeSH descriptor: [Pain Measurement] explode all trees 22766

#44 MeSH descriptor: [Pain Threshold] explode all trees 1797

#45 MeSH descriptor: [Anxiety] explode all trees 9119

#46 MeSH descriptor: [Crying] explode all trees 336

#47 MeSH descriptor: [Facial Expression] explode all trees 704

#48 MeSH descriptor: [Behavior] explode all trees 98654

#49 MeSH descriptor: [Fear] explode all trees 1687

#50 MeSH descriptor: [Gestures] explode all trees 71

#51 MeSH descriptor: [Heart Rate] explode all trees 20013

#52 MeSH descriptor: [Infant Behavior] explode all trees 342

#53 MeSH descriptor: [Oxygen Consumption] explode all trees 6932

#54 MeSH descriptor: [Panic] explode all trees 265

#55 MeSH descriptor: [Wakefulness] explode all trees 1050

#56 (anxiet* OR anxious OR behavior* OR behaviour* OR crying OR discomfort* OR distress* OR "Douleur Aigue du Nouveau ne" OR "facial expression*" OR fear* OR fright* OR gesture* OR grimac* OR "heart rate*"):ti,ab,kw OR ("Median Premature Infant Pain Profile score*" OR "Neonatal Facial Action*" OR "Neonatal Facial Activity Coding System" OR "Neonatal Facial Coding Score*" OR NFCS OR "neonatal facial coding system"):ti,ab,kw OR ("nociceptive reaction*" OR "orosensorial antinociceptive effect*" OR "oxygen consumption" OR "oxygen saturation*" OR pain* OR panic* OR "sleep wake state*" OR wakefulness):ti,ab,kw (Word variations have been searched) 456794

#57 #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56   850863

#58 MeSH descriptor: [Ibuprofen] explode all trees 2136

#59 MeSH descriptor: [Fenoprofen] explode all trees 39

#60 MeSH descriptor: [Indoprofen] explode all trees 38

#61 MeSH descriptor: [Ketoprofen] explode all trees 582

#62 MeSH descriptor: [Suprofen] explode all trees 38

#63 MeSH descriptor: [Phenylpropionates] explode all trees 2985

#64 MeSH descriptor: [Diclofenac] explode all trees 1992

#65 MeSH descriptor: [Chloral Hydrate] explode all trees 128

#66 MeSH descriptor: [Propofol] explode all trees 5233

#67 MeSH descriptor: [Ketamine] explode all trees 2463

#68 MeSH descriptor: [Indomethacin] explode all trees 2740

#69 MeSH descriptor: [Ketorolac] explode all trees 954

#70 MeSH descriptor: [Analgesics, Non‐Narcotic] explode all trees 9619

#71 MeSH descriptor: [Cyclooxygenase Inhibitors] explode all trees 1589

#72 MeSH descriptor: [Analgesics, Short‐Acting] explode all trees 0

#73 MeSH descriptor: [Anti‐Inflammatory Agents, Non‐Steroidal] explode all trees 7907

#74 MeSH descriptor: [Receptors, N‐Methyl‐D‐Aspartate] explode all trees 379

#75 (ibuprofen OR fenoprofen OR indoprofen OR ketoprofen OR suprofen OR Phenylpropionate* OR diclofenac OR "cyclooxygenase inhibit*" OR "chloral hydrate" OR propofol OR ketamine OR NMDA OR N‐methylaspartate OR N‐Methyl‐D‐Aspartate OR NSAID* OR "nonsteroidal anti‐inflammator*" OR "nonsteroidal antiinflammator*" OR ketorolac OR indomethacin):ti,ab,kw (Word variations have been searched) 42889

#76 #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 47859

#77 MeSH descriptor: [Infant, Newborn] explode all trees 17498

#78 MeSH descriptor: [Intensive Care, Neonatal] explode all trees 353

#79 MeSH descriptor: [Intensive Care Units, Neonatal] explode all trees 857

#80 MeSH descriptor: [Gestational Age] explode all trees 2766

#81 ("babe" or "babes" or baby* or "babies" or "gestational age?" or infant? or "infantile" or infancy or "low birth weight?" or "low birthweight?" or neonat* or "neo‐nat*" or newborn* or "new born?" or "newly born" or "premature" or "pre‐mature" or "pre‐matures" or prematures or prematurity or "pre‐maturity" or "preterm" or "preterms" or "pre term?" or "preemie" or "preemies" or "premies" or "premie" or "VLBW" or "VLBWI" or "VLBW‐I" or "VLBWs" or "LBW" or "LBWI" or "LBWs" or "ELBW" or "ELBWI" or "ELBWs" or "NICU" or "NICUs"):ti,ab,kw (Word variations have been searched) 100358

#82 #77 OR #78 OR #79 OR #80 OR #81  100358

#83 #57 AND #76 AND #82  1696

 

Embase.com (Elsevier, 1947‐present)

Date of search: 02 June 2022

 

#39. #12 AND #17 AND #20 AND #38 2,758 

#38. #34 NOT #37 2,641,875 

#37. #36 NOT #35 7,508,174 

#36. 'animal'/exp OR 'invertebrate'/exp OR 'animal 32,342,902 

 experiment'/de OR 'animal model'/de OR 'animal 

 tissue'/de OR 'animal cell'/de OR 'nonhuman'/de

#35. ('animal'/exp OR 'invertebrate'/exp OR 'animal 24,834,728 

 experiment'/de OR 'animal model'/de OR 'animal 

 tissue'/de OR 'animal cell'/de OR 'nonhuman'/de) 

 AND ('human'/de OR 'normal human'/de OR 'human 

 cell'/de)

#34. #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR 3,079,287 

 #28 OR #29 OR #30 OR #31 OR #32 OR #33

#33. (control* NEAR/2 (group$ OR random*)):ti,ab,kw 1,193,828 

#32. quasirandom*:ti,ab,kw OR 'quasi random*':ti,ab,kw 1,467,005 

 OR randomi*:ti,ab,kw OR randomly:ti,ab,kw

#31. (open NEAR/2 label):ti,ab 96,883 

#30. ((assign* OR match OR matched OR allocation) 379,642 

 NEAR/5 (alternate OR group$ OR intervention$ OR 

 patient$ OR subject$ OR participant$)):ti,ab

#29. crossover:ti,ab OR 'cross over':ti,ab 116,834 

#28. 'parallel group$':ti,ab 29,375 

#27. (controlled NEAR/7 (study OR design OR 418,086 

 trial)):ti,ab,kw

#26. 'double blind procedure'/de  195,894 

#25. ((double OR single OR doubly OR singly) NEAR/2 260,453 

 (blind OR blinded OR blindly)):ti,ab,kw

#24. placebo:ti,ab,kw 342,763 

#23. 'randomization'/de  93,896 

#22. random*:ti,ab,kw 1,799,414 

#21. 'randomized controlled trial'/de OR 'controlled 889,273 

 clinical trial'/de

#20. #18 OR #19 1,554,348 

#19. babe:ti,ab,kw OR babes:ti,ab,kw OR baby*:ti,ab,kw 1,245,792 

 OR babies:ti,ab,kw OR ‘gestational age$’:ti,ab,kw 

 OR infant$:ti,ab,kw OR infantile:ti,ab,kw OR 

 infancy:ti,ab,kw OR 'low birth weight':ti,ab,kw 

 OR 'low birthweight':ti,ab,kw OR neonat*:ti,ab,kw 

 OR 'neo‐nat*':ti,ab,kw OR newborn*:ti,ab,kw OR 

 ‘new born$’:ti,ab,kw OR 'newly born':ti,ab,kw OR 

 premature:ti,ab,kw OR 'pre mature':ti,ab,kw OR 

 'pre matures':ti,ab,kw OR prematures:ti,ab,kw OR 

 prematurity:ti,ab,kw OR 'pre maturity':ti,ab,kw 

 OR preterm:ti,ab,kw OR preterms:ti,ab,kw OR ‘pre 

 term$’:ti,ab,kw OR preemie:ti,ab,kw OR 

 preemies:ti,ab,kw OR premies:ti,ab,kw OR 

 premie:ti,ab,kw OR vlbw:ti,ab,kw OR 

 vlbwi:ti,ab,kw OR 'vlbw i':ti,ab,kw OR 

 vlbws:ti,ab,kw OR lbw:ti,ab,kw OR lbwi:ti,ab,kw 

 OR lbws:ti,ab,kw OR elbw:ti,ab,kw OR 

 elbwi:ti,ab,kw OR elbws:ti,ab,kw OR nicu:ti,ab,kw 

 OR nicus:ti,ab,kw

#18. 'newborn'/de OR 'prematurity'/de OR 'newborn 827,536 

 intensive care'/de OR 'newborn care'/de OR

 'gestational age'/de

#17. #13 OR #14 OR #15 OR #16 1,419,753 

#16. ibuprofen:ti,ab OR fenoprofen:ti,ab OR  262,547 

 indoprofen:ti,ab OR ketoprofen:ti,ab OR 

 suprofen:ti,ab OR phenylpropionate*:ti,ab OR 

 diclofenac:ti,ab OR 'cyclooxygenase 

 inhibit*':ti,ab OR 'chloral hydrate':ti,ab OR 

 propofol:ti,ab OR ketamine:ti,ab OR nmda:ti,ab OR 

 'n methylaspartate':ti,ab OR 'n methyl d 

 aspartate':ti,ab OR nsaid*:ti,ab OR 'nonsteroidal 

 anti‐inflammator*':ti,ab OR 'nonsteroidal 

 antiinflammator*':ti,ab OR ketorolac:ti,ab OR 

 indomethacin:ti,ab

#15. 'prostaglandin synthase inhibitor'/exp OR 'short 1,276,996 

 acting analgesic agent'/exp OR 'nonsteroid

 antiinflammatory agent'/exp OR 'n methyl dextro 

 aspartic acid receptor'/exp

#14. 'chloral hydrate'/exp OR 'propofol'/exp OR 201,215 

 'ketamine'/exp OR 'indometacin'/exp OR 

 'ketorolac'/exp

#13. 'ibuprofen'/exp OR 'fenoprofen'/exp OR 98,312 

 'indoprofen'/exp OR 'ketoprofen'/exp OR 

 'suprofen'/exp OR 'phenylpropionic acid 

  derivative'/exp OR 'diclofenac'/exp

#12. #9 OR #10 OR #11 14,662,185 

#11. anxiet*:ti,ab OR anxious:ti,ab OR behavior*:ti,ab 3,563,959 

 OR behaviour*:ti,ab OR crying:ti,ab OR 

 discomfort*:ti,ab OR distress*:ti,ab OR 'douleur 

 aigue du nouveau ne':ti,ab OR 'facial 

 expression*':ti,ab OR fear*:ti,ab OR 

 fright*:ti,ab OR gesture*:ti,ab OR grimac*:ti,ab 

 OR 'heart rate*':ti,ab OR 'median premature 

 infant pain profile score*':ti,ab OR 'neonatal 

 facial action*':ti,ab OR 'neonatal facial 

 activity coding system':ti,ab OR 'neonatal facial 

 coding score*':ti,ab OR nfcs:ti,ab OR 'neonatal 

 facial coding system':ti,ab OR 'nociceptive 

 reaction*':ti,ab OR 'orosensorial antinociceptive 

 effect*':ti,ab OR 'oxygen consumption':ti,ab OR 

 'oxygen saturation*':ti,ab OR pain*:ti,ab OR 

 panic*:ti,ab OR 'sleep wake state*':ti,ab OR 

 wakefulness:ti,ab

#10. 'pain'/exp OR 'analgesia'/exp OR 'pain 6,823,271 

 measurement'/exp OR 'pain threshold'/exp OR 

 'anxiety'/exp OR 'crying'/exp OR 'facial 

 expression'/exp OR 'behavior'/exp OR 'fear'/exp 

 OR 'gesture'/exp OR 'heart rate'/exp OR 'child 

 behavior'/exp OR 'oxygen consumption'/exp OR 

 'panic'/exp OR 'wakefulness'/exp

#9. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 8,406,154 

#8. 'needle'/exp OR 'intravenous immunoglobulin'/exp 482,982 

 OR 'intravenous drug administration'/exp OR 

 'intravenous anesthesia'/exp OR 'intravenous 

 anesthetic agent'/exp OR 'drainage'/de OR 

 'suction'/exp

#7. injection*:ti,ab OR intravenous*:ti,ab OR 1,390,402 

 drainage:ti,ab OR suction*:ti,ab

#6. 'blood sampling device'/exp OR 'puncture'/exp OR 297,531 

 'suture'/exp OR 'injection'/exp OR 

 'phlebotomy'/exp

#5. presurgi*:ti,ab OR 'pre surgi*':ti,ab OR 55,910 

 'procedural pain':ti,ab OR 'pain 

 procedure*':ti,ab OR 'painful procedure*':ti,ab 

 OR 'invasive procedure*':ti,ab

#4. 'postoperative pain'/exp OR 'nociception'/exp OR 341,571 

 'mental stress'/exp

#3. operativ*:ti,ab OR postoperat*:ti,ab OR 'post 1,444,635 

 operat*':ti,ab OR perioperativ*:ti,ab OR 'peri 

 operativ*':ti,ab OR preopera*:ti,ab OR 'pre 

 opera*':ti,ab

#2. catheter*:ti,ab OR cannula*:ti,ab OR 3,356,823 

 surgery:ti,ab OR surgical*:ti,ab OR 

 retinopathy:ti,ab OR puncture:ti,ab OR 

 needle:ti,ab OR needles:ti,ab OR 'heel 

 lanc*':ti,ab OR heellanc*:ti,ab OR 'chest 

 tube':ti,ab OR 'chest tubes':ti,ab

#1. 'general surgery'/de OR 'surgery'/exp OR 5,892,379 

 'perioperative medicine'/exp OR 'perioperative 

 period'/exp OR 'perioperative nursing'/exp OR 

 'catheterization'/exp OR 'catheter'/de OR 

 'catheter occlusion'/exp OR 'indwelling 

 catheter'/exp OR 'urinary catheter'/exp OR

 'vascular access device'/exp OR 'heart 

 catheter'/exp OR 'central venous catheter'/exp OR 

 'chest tube'/exp OR 'retrolental fibroplasia'/exp 

 OR 'lumbar puncture'/exp

Total number of records from databases: 6,407

 

Trial Registry Strategies

ClinicalTrials.gov (US National Library of Medicine)

Date of search: 02 June 2022

Advanced search 
Intervention/treatment: ibuprofen OR fenoprofen OR indoprofen OR ketoprofen OR suprofen OR Phenylpropionate* OR diclofenac OR "cyclooxygenase inhibitors" OR "chloral hydrate" OR propofol OR ketamine OR NSAID*
Other terms: premature OR prematurity OR preterms OR preterm OR “very low birth” OR “low birth weight” OR newborn OR newborns OR neonate OR neonates OR infant OR infants 
Age group: Child
No further limits applied  146

 

International Clinical Trials Registries Platform Search Portal, ICTRP (World Health Organization)

Date of search:  02 June 2022

Advanced search 

Title: infant* OR infantile OR infancy OR newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU

Intervention: ibuprofen OR fenoprofen OR indoprofen OR ketoprofen OR suprofen OR Phenylpropionate* OR diclofenac OR "cyclooxygenase inhibitors" OR "chloral hydrate" OR propofol OR ketamine OR NSAID*

Limit: search for clinical trials in children  28

Total number of records from registries: 174

Total combined number (literature databases and registries) 6,681

Appendix 2. Risk of bias tool

We used the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of the included trials. For each trial, we sought information regarding the method of randomization, blinding, and reporting of all outcomes of all the infants enrolled in the trial. We assessed each criterion as being at a low, high, or unclear risk of bias. Two review authors separately assessed each study, with any disagreements resolved by discussion. We added this information to the Characteristics of included studies table. We evaluated the following issues and entered the findings into the risk of bias table.

Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorized the method used to generate the allocation sequence as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk.

Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorized the method used to conceal the allocation sequence as:

• low risk (e.g. telephone or central randomization; consecutively numbered, sealed, opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk.

Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorized the methods used to blind study participants and personnel from the knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or class of outcomes. We categorized the methods as:

• low risk, high risk, or unclear risk for participants; and

• low risk, high risk, or unclear risk for personnel.

Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorized the methods used to blind outcome assessment. We assessed blinding separately for different outcomes or class of outcomes. We categorized the methods as:

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re‐included missing data in the analyses. We categorized the methods as:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data); or

• unclear risk.

Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we compared the prespecified outcomes versus outcomes reported in the published results. If the study protocol was not published in advance, we contacted the study authors to gain access to the study protocol. We assessed the methods as:

• low risk (where it was clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (where not all of the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; the study fails to include results of a key outcome that would be expected to have been reported); or

• unclear risk.

Other sources of bias. Did the study appear to be free of other problems that could put it at high risk of bias?

For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk; or

• unclear risk.

If needed, we plan to explore the impact of the level of bias by undertaking sensitivity analyses.

Data and analyses

Comparison 1. NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non‐pharmacological intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pain score (NIPS) during the procedure	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.95 [‐1.32, ‐0.58]

Comparison 2. Head‐to‐head comparison of different analgesics.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Pain score (PIPP‐R) up to 10 minutes after the procedure	1	124	Mean Difference (IV, Fixed, 95% CI)	0.98 [0.75, 1.20]
2.2 Episodes of apnea	1	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.08, 1.18]
2.3 Need for supplemental oxygen	1	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.12, 0.89]
2.4 Hypotension requiring medical therapy	1	124	Risk Ratio (M‐H, Fixed, 95% CI)	5.53 [0.27, 112.30]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Madathil 2021.

Study characteristics
Methods	Randomized controlled trial
Participants	124 hemodynamically stable neonates with type 1 ROP requiring laser photocoagulation. Trial conducted in a neonatal unit in India between 16 April 2018 and 5 May 2019.
Interventions	1st intervention group: intravenous fentanyl  2nd intervention group: intravenous ketamine  Intervention groups further split between initial phase and revised regimen phase.  Initial phase (n = 97) Fentanyl (n = 51): neonates received 2 μg/kg over 5 minutes 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion thereafter until the end of the procedure.  Ketamine (n = 46): neonates received a bolus dose of 0.5 mg/kg of ketamine 1 minute before procedure. Revised regimen phase (n = 27) Fentanyl (n = 13): the infusion rate was titrated by 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour.  Ketamine (n = 14): additional intermittent bolus doses of 0.5 mg/kg were given every 10 minutes up to a maximum of 2 mg/kg (total of 4 boluses).
Outcomes	Primary outcome Pain score (PIPP‐R) up to 10 minutes after the procedure Secondary outcomes  Episodes of apnea Need for supplemental oxygenation  Hypotension requiring medical therapy
Funding	The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not‐for‐profit sectors. Competing interests: none declared
Notes	Authors were contacted and provided further information on quantitative PIPP‐R scores.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was unclear how the random sequence was generated. Several infants were also excluded for unjustifiable reasons.
Allocation concealment (selection bias)	Low risk	Well‐described allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding was not possible due to the obvious nature of the intervention (infusion versus intermittent boluses). However, knowledge of the kind of anesthesia likely had little impact on the overall recorded results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Authors reported (quote): "We could not analyze outcome of cry duration/proportion of cry in four infants during the first phase of the study due to inadequate cry recordings" and "small number of infants enrolled in the second phase of the study due to logistical constraints as we had to stop the trial after achieving the target sample size"
Selective reporting (reporting bias)	High risk	Authors reported (quote): “…intermittent video recording of the infant focusing on the face…prior to the procedure…followed by every 15 minutes until the end... . Each recording was done for a duration of 30 seconds. Two independent assessors…analysed all the recorded videos by comparing the infant’s reaction with that of the ‘reference’... . The discrepancies were resolved through mutual discussions.”
Other bias	Low risk	No other concerns detected.

Modekwe 2021.

Study characteristics
Methods	Randomized controlled trial
Participants	145 male neonates undergoing circumcision in a hospital in Nigeria, from March 2015 to December 2015 Exclusion criteria: neonates delivered preterm, those with penile lesions, such as rashes and ulcers, and congenital penile anomalies, such as hypospadias or epispadias
Interventions	Intervention group: neonates received 10 mg of oral ketamine per kilogram of body weight Control group: neonates received simple sucrose (66.7% w/w) at 1 mL/kg body weight as a placebo
Outcomes	Primary outcome Neonatal Infant Pain Scale (NIPS) score Secondary outcomes Life‐threatening adverse effects of ketamine, such as apnea, laryngeal spasm, and aspiration Continuous pulse oximetry Pulse rate
Funding	The authors have declared no financial or other competing interests.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Neonates were randomized using a simple ballot method weekly.
Allocation concealment (selection bias)	Unclear risk	1 assistant was responsible for the balloting, and another assistant was responsible for administering the medications; however, information on concealment was insufficient to permit a judgement of low or high risk of bias.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The surgeon, parent or caregiver, anesthetists, and the assistant that recorded the details were all blinded to the type of oral medication received.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The surgeon, parent or caregiver, anesthetists, and the assistant who recorded the details were all blinded to the type of oral medication received.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Study authors do not mention incomplete outcome data.
Selective reporting (reporting bias)	High risk	14 infants in group A and 10 in group B excluded for (quote) "technical hitches", but no further explanation given.
Other bias	Low risk	No other concerns detected.

NIPS: Neonatal Infant Pain Scale; PIPP‐R: Premature Infant Pain Profile‐Revised; ROP: retinopathy of prematurity.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Choi 1997	No NMDA receptor antagonist or NSAID administration
Janevski 2010	No NMDA receptor antagonist or NSAID administration
Kamiyama 1980	Infants undergoing surgery
NCT03705468	Not a randomized trial
Saarenmaa 2001	Infants undergoing endotracheal suctioning
Trabold 2002	Infants undergoing anesthesia

NMDA: N‐methyl‐D‐aspartate; NSAID: non‐steroidal anti‐inflammatory drug.

Characteristics of studies awaiting classification [ordered by study ID]

ACTRN1261000025.

Methods	Randomized controlled trial
Participants	Infants and children (0 to 8 years) with a high risk for respiratory complications undergoing minor elective surgical procedures
Interventions	Intervention: intravenous induction of anesthesia with propofol (as per attending anesthetist 2 to 5 mg/kg)  Control: not reported
Outcomes	Incidence of respiratory complications in the perioperative period Presence of perioperative respiratory complication as defined by 1 or more of the following: bronchospasm, laryngospasm, severe coughing, desaturation < 95%, airway obstruction and/or stridor. The presence/absence of respiratory complications will be recorded during the time of anesthesia and the time spent in recovery. The overall presence of respiratory complications will be taken for the analysis (intraoperatively until discharge from the recovery area). Occurrence and frequency of the individual respiratory complications in both intraoperatively and in the recovery area. The outcome will be assessed by clinical monitoring (intraoperatively until discharge from the recovery area).
Notes	Author contacted for further details on study. No response to date

Meau‐Petit 2005.

Methods	Randomized controlled trial
Participants	Very premature infants
Interventions	Intervention: prophylactic ibuprofen  Control: placebo
Outcomes	Not reported
Notes	Author contacted for further details on study. No response received to date.

Pees 2003.

Methods	Randomized controlled trial
Participants	100 (aged 2 days to 11 years) undergoing cardiac catheterization
Interventions	Each participant received 0.5 mg/kg midazolam syrup orally 30 minutes before the procedure and 0.2 mg/kg midazolam syrup intravenously, later combined with the following. 1st intervention group (n = 50): an initial dose of 1 mg/kg racemic ketamine. Infants received repeated doses of 0.5 mg/kg depending on sedation.  2nd intervention group (n = 50): an initial dose of 1 mg/kg S(+)‐ketamine. Infants received repeated doses of 0.5 mg/kg depending on sedation.
Outcomes	Primary outcomes  Total dosage of sedative drugs  Side effects  Awakening and behavior judgment score for newborns and children
Notes	Authors contacted to provide outcome data for the neonatal population. No response received to date.

Differences between protocol and review

Though not listed in the protocol (Persad 2022), we included studies on neonatal circumcision, as we considered it to be a procedure rather than surgery.

Though not listed in the protocol, we included the outcome 'need for supplemental oxygen,' as we considered it to be a relevant outcome measure.

Though specified in the protocol, we did not search CINAHL Complete (EBSCOhost), conference abstracts using the Eastern Society for Pediatric Research (ESPR) and Pediatric Academic Societies (PAS) meetings (website not available), and Epistemonikos database of systematic reviews.

Christoper Alarcon‐Ruiz contributed to the protocol but not the review.

Contributions of authors

EP: developed, produced the first draft, contributed to writing and editing of the protocol and review; made an intellectual contribution to the review.

ABP: developed and contributed to editing of the protocol and review.

MB: developed, contributed to writing and editing of the protocol and review; made an intellectual contribution to; advised on; and is a guarantor of the review.

All authors read and approved the final version.

Sources of support

Internal sources

• Institute for Clinical Sciences, Lund University, Lund, Sweden, Sweden

  MB is employed by this organization.

External sources

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

• Region Skåne, Skåne University Hospital, Lund University and Region Västra Götaland, Sweden, Sweden, Sweden

  Cochrane Sweden is supported by Region Skåne, Skåne University Hospital Lund University and Region Västra Götaland.

Declarations of interest

EP is a member of Cochrane Governing Board. However, she had no involvement in the editorial processing of this review.

ABP has no interest to declare.

MB is an Associate Editor for the Cochrane Neonatal Group. However, he had no involvement in the editorial processing of this review.

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