Pharmacological interventions for the management of pain and discomfort during lumbar puncture in newborn infants

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non‐pharmacological interventions, or other pharmacological interventions.

Background

Description of the condition

Lumbar puncture (LP) is a common invasive procedure in which a needle is inserted between two lumbar vertebrae to collect a small amount of cerebrospinal fluid (CSF; fluid that surrounds the brain and spinal cord). Newborn infants undergo LP for different reasons, the most common being to diagnose infection. LP is the definitive diagnostic procedure for meningitis, and it is often performed in acutely ill newborns with signs and symptoms of sepsis. The microbiological diagnosis of acute infections such as bacterial, viral, and fungal meningitis requires the collection and analysis of CSF; but this procedure may also form part of the initial evaluation of newborns with congenital infections such as syphilis, tuberculosis, toxoplasmosis, or cytomegalovirus. Diagnostic LP also plays a role in confirming or ruling out the suspicion of inborn errors of metabolism. 

LP has therapeutic as well as diagnostic purposes. For example, it can be part of an expectant management strategy for decreasing intracranial pressure (ICP) in posthemorrhagic hydrocephalus while waiting for external ventricular drain (EVD; Veldez Sandoval 2019; Whitelaw 2017). LP can also be performed for intrathecal administration of drugs such as nusinersen for spinal muscular atrophy (Hoy 2021).

Physicians perform LP with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure (Atlas of Procedures in Neonatology 2007). Without adequate analgesia, LP can cause considerable pain and discomfort. Research has shown that newborns have increased sensitivity to pain, and that repeated exposure to stressors may have deleterious short‐ and long‐term consequences (Anand 1998; Anand 2000). For this reason, it is important to adequately manage the procedural pain of LP in this population.

Description of the intervention

Methods for managing pain during LP in newborns include non‐pharmacological measures (swaddling, non‐nutritive sucking, sucrose administration), topical anesthetics, opioids, benzodiazepines, clonidine, and non‐opioid analgesics.

EMLA cream (Eutectic Mixture of Local Anesthetics; lidocaine 2.5% and prilocaine 2.5%) has been available for topical anesthesia of intact skin since the early 1980s. To achieve acceptable analgesia, the cream must be applied at least one hour before the procedure and covered with an occlusive bandage. Maximum effect is achieved within two to three hours. Maximum application doses, areas, and times are usually lower in newborns than in older children. Clinicians use EMLA cream for procedural pain management in newborns during venipuncture, arterial puncture, LP, circumcision, and intramuscular immunization, applying doses of 0.5 g to 2 g for up to 90 minutes (Weise 2005). While the application of EMLA cream is completely painless, there have been reports of local and systemic adverse effects.

Lidocaine, administered at a dose of up to 4.5 mg/kg through subcutaneous injection, is one alternative to EMLA cream. Potential disadvantages of this procedure are that it may cause some discomfort and it does not appear to minimize physiologic response to pain during lumbar puncture (Goldman 2019). The needle‐free jet injection constitutes a new method of lidocaine administration. With this technique, lidocaine is forced through the skin into the subcutaneous tissue by the action of pressurized carbon dioxide. It appears to achieve analgesia after two minutes, and it has been used in the emergency department to manage LP procedural pain (Ferayorni 2012).

Systemic analgesia is another pain management strategy for neonates undergoing LP. Opioids are widely used in neonatal intensive care units (NICUs) to control moderate to severe pain. Although procedural pain is not the first indication for their use, continuous administration of low‐dose opioid or small boluses is a potential analgesic strategy for some painful procedures (Anand 2005). The pharmacokinetics and pharmacodynamics of opioids are highly variable in different populations and are strongly associated with the age of the person. Close monitoring is required during opioid administration to lower the incidence of adverse effects (Allegaert 2007).

Oral or intravenous morphine is one of the most commonly used opioids in neonatal care. The nervous system of neonates is more sensitive to morphine compared with older children, which is why experts recommend a lower initial dose with titration based on evaluation (Schiller 2018).

Another opioid that could be considered for managing procedural pain during LP is fentanyl, which has a rapid onset of action and a short half‐life. The recommended dose is a 2 mcg/kg bolus, administered slowly before the procedure. To minimize the risk of respiratory depression, the most common and concerning adverse event of opioids, it is important to monitor the infant carefully and customize the therapy (Lynn 1993). 

N‐methyl‐D‐aspartate (NMDA) receptor antagonists provide a sedative, analgesic, and amnesic effect. Ketamine belongs to this class of drug. It is effective for somatic pain but should not be considered a drug of choice for visceral pain. Ketamine can be administered intravenously or intramuscularly, but also through minimally invasive routes (e.g. rectal, oral, subcutaneous, transdermal, or intranasal). It has a rapid‐onset effect and a quick recovery time (Bhutta 2007). 

Ibuprofen is a non‐steroidal anti‐inflammatory drug (NSAID) that is commonly used in pediatrics. The analgesic activity of this drug has a quick onset (15 minutes) and a long duration (eight to 12 hours). Ibuprofen can be administered orally and intravenously. The recommended oral dosage is 10 mg/kg every six to eight hours, as needed, with a maximum daily dose of 30 mg/kg.

Indomethacin, another NSAID, has been used in newborns to induce patent ductus arteriosus closure; however, in different studies against ibuprofen, indomethacin was associated with a greater risk of necrotizing enterocolitis and transient renal insufficiency (Mitra 2018). 

Paracetamol, also known as acetaminophen, is used to treat fever, pain, and, in preterm infants, patent ductus arteriosus. The Cochrane Review on paracetamol for treatment of prevention of pain in newborns included nine trials on the pain management of heel lance, assisted vaginal birth, retinopathy of prematurity examination, and postoperative care (Ohlsson 2020). The authors of Ohlsson 2020 were unable to draw firm conclusions on the effects of paracetamol in newborns owing to the low certainty of the evidence.

Ketorolac and ketoprofen are two other NSAIDs with the same mechanism of action and similar adverse effects. Ketoprofen is administered at a dose of 1 to 2 mg/kg every six to eight hours, up to a maximum daily dose 5 mg/kg. Ketorolac dosage is 0.3 to 0.5 mg/kg every six to eight hours, up to a maximum daily dose of 2 mg/kg (Kokki 2003).

Benzodiazepines such as midazolam and lorazepam, though not analgesics, are often used in the NICU to reduce pain and discomfort (AAP 2016). These drugs provide sedation and muscle relaxation (Hall 2014). Midazolam is the most commonly used benzodiazepine, often administered for mechanical ventilation, sedation, procedural pain, or sedation during diagnostic imaging such as computerized tomography (CT) scans. It acts rapidly and is often used in combination with opioids (Nelson 2014). Although midazolam has a positive effect on postoperative pain scores, a general lack of studies on long‐term effects hinders its application in clinical practice (Ranger 2013). According to the American Academy of Pediatrics (AAP), midazolam and other benzodiazepines are frequently used in the NICU for sedation (AAP 2016).

Propofol, a sedative, is used for procedural pain in newborns, mainly for endotracheal intubation (Carbajal 2015). It has rapid onset and recovery, but has been associated with arterial hypotension (Welzing 2010). The Cochrane Review on propofol for procedural sedation and anesthesia in neonates (Shah 2011) included one small trial (Ghanta 2007). Efficacy and safety outcomes were similar in the propofol group and control group (morphine‐atropine‐suxamethonium), but intubation time and recovery time were shorter in the propofol group.

Clonidine is an alpha‐2 agonist that decreases sympathetic outflow and thereby provides sedation and pain relief without causing respiratory depression. Clonidine can reduce the need for opioids or benzodiazepines and may be useful for infants with neonatal abstinence syndrome (Donato 2019). Clearance of clonidine can be prolonged in neonates due to pathway immaturity or renal disease (Donato 2019). Compared to clonidine, dexmedetomidine has greater selectivity for alpha‐2 receptors and, as a result, is a more potent sedative. Dexmedetomidine can be administered by the intravenous, intranasal, or buccal route (Weerink 2017). 

How the intervention might work

LP is a common procedure in NICUs and emergency departments. Research has revealed an underutilization of analgesic drugs during LP, especially in children and newborns (Gorchynski 2008; Hoyle 2011). These interventions may alleviate the pain and discomfort of the LP procedure for the infant, and we know that effective pain control has positive consequences on health outcomes both during the neonatal period and in later life (Anand 1998; Anand 2000). In addition, if the infant is comfortable, the physician is more likely to successfully execute the procedure on the first attempt (Baxter 2006).

Different drugs used for procedural pain management have specific mechanisms of action.

Both EMLA cream and lidocaine provide topical anesthesia; they can stabilize neuronal membranes by inhibiting ion transportation and reducing the neuronal conduction of stimuli.

Opioids act on the mu‐opioid receptor in the central and peripheral nervous systems (Leite Junior 2019). They have an activating effect on the descending inhibitory pathways in the central nervous system (CNS), and a negative effect on the afferent neurons carrying nociceptive signals in the peripheral nervous system (PNS).

The mechanism of action of NSAIDs (ibuprofen, indomethacin, ketoprofen, ketorolac) involves an inhibiting effect on COX1 and COX2 enzymes, which reduces the production of prostaglandins from arachidonic acid, reducing inflammation and pain (Burian 2005; Katzung 2021). 

The action of ketamine on channel blockage varies with dosage: it provides analgesic effects at low doses and shows anesthetic properties at higher concentrations.

Benzodiazepines act on GABA‐induced channels by increasing the frequency of their openings, thus allowing a greater chloride ions influx into the neuronal cells. The increased concentration of chloride ions inside the cells reduces the likelihood of neuronal activation (Nordt 1997).

Clonidine and dexmedetomidine activate inhibitory neurons by stimulating alpha‐2 adrenergic receptors in the brainstem, thus decreasing sympathetic outflow and providing sedation and pain relief (Nguyen 2017).

Through different mechanisms of action, these drugs may reduce pain and discomfort and facilitate the success of LP. However, owing to concerns about their potential adverse effects, their use has been limited in procedural pain management.

Some people have had local reactions to EMLA application. EMLA may also cause a rise in methemoglobin concentration, especially in newborns and younger infants; however, different studies in these populations found that methemoglobin levels did not reach the upper limit of 5% to 6% (Acharya 1998; Taddio 1998)

The risk of respiratory depression is the most common and concerning adverse event related to opioid administration. Careful monitoring and customization of the therapy can minimize this risk (Lynn 1993). 

Studies that assessed the gastrointestinal and renal toxicity of NSAIDs found no statistically significant differences in hospitalization for gastrointestinal bleeding and renal failure after short‐term use of ibuprofen in children with normal renal function and circulating volume, but recommended caution in the use of ibuprofen in children who are dehydrated or who were born prematurely (Ashraf 1999; Lesko 1997). The scientific literature contains contradictory results on the risk of postsurgical bleeding after use of NSAIDs. These drugs can interfere with platelet function by inhibiting thromboxane A2 synthesis. However, one meta‐analysis found no significant increase in bleeding events after ibuprofen usage (Lewis 2013). Some studies found a greater risk of bleeding after ketorolac administration, but more data are needed to fully assess the safety of these NSAIDs in the neonatal population (Kokki 2003; Stone 2021).

NMDA receptor antagonists can cause laryngospasm, respiratory depression, and increased respiratory secretions. There have been reports of cardiovascular hypertension and increased cerebral blood flow after ketamine administration. Emergence agitation, nystagmus, and tonic‐clonic movements are possible adverse effects of ketamine; they can be alleviated by co‐treatment with benzodiazepines (Lin 2005: Poonai 2017). Experts have raised concerns about ketamine neurotoxicity in the developing brain. Experimental studies have shown that ketamine promotes neuronal apoptosis and interferes with normal neurogenesis. While there is also evidence that ketamine may have a neuroprotective effect, further research is needed to reach a full understanding of this drug's mechanism of action on cellular signaling pathways (Bhutta 2007; Dong 2013; Kalopita 20217). 

Benzodiazepines can increase the risk of harms associated with opioids, such as respiratory depression and hypotension. In addition, there are concerns about the risk of neurotoxicity following midazolam administration in newborn infants (Ng 2017). Potential adverse effects in this population include myoclonic jerking, excessive sedation, respiratory depression, and hypotension (Duerden 2017; Hall 2014; Nelson 2014). There is little evidence on their applicability in preterm neonates owing to the risk of intraventricular hemorrhage, periventricular leukomalacia, and death (Anand 1999; Nelson 2014). 

Adverse effects of alpha‐2 agonists are mainly restricted to hemodynamic alterations such as hypotension, rebound hypertension, and bradycardia (Donato 2019).

Why it is important to do this review

Repeated painful procedures during the neonatal period can have both short‐ and long‐term negative consequences. For this reason, analgesic interventions are a priority in neonatal care (Walker 2019; Williams 2020). LP is one of many painful procedures conducted on neonates. Other than causing pain, it may also lead to circulatory instability, intraventricular hemorrhage, or need for re‐intubation (Atlas of Procedures in Neonatology 2007). Therefore, adequate pain management during LP could improve the success rate of the procedure, stability of vital signs during the procedure, and long‐term effects such as neurodevelopmental outcomes and pain response in later life. It is important to investigate the effect of any pharmacological intervention for pain and discomfort management during LP to determine which interventions provide the best pain control while limiting drug‐related adverse events. A separate Cochrane Review will investigate the most effective position for performing LP (lateral decubitus position, sitting position, or prone position; Pessano 2022).

Objectives

To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non‐pharmacological interventions, or other pharmacological interventions.

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

We will include preterm and term infants of up to 46 weeks and 0 days' postmenstrual age (PMA), irrespective of their gestational age (GA) at birth, undergoing LP for any indication. We will address studies including both newborn infants and older children by contacting study authors to obtain outcome data for the newborn infants. If unsuccessful, and if the mean age of participants is over 46 weeks and 0 days' PMA, we will exclude the study.

Types of interventions

We will include studies that investigate drugs used for pain management, sedation, or both, during LP. This includes topical anesthetics (e.g. EMLA, lidocaine), opioids (e.g. morphine, fentanyl), alpha‐2 agonists (e.g. clonidine, dexmedetomidine), NMDA receptor antagonists (e.g. ketamine), other analgesics (e.g. paracetamol), and sedatives (e.g. benzodiazepines such as midazolam).

We will include the following comparisons.

• Comparison 1. Topical anesthetics versus placebo, no intervention, or non‐pharmacological interventions

  • Topical anesthetics versus placebo or no intervention

  • Topical anesthetics versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 2. Opioids versus placebo, no intervention, or non‐pharmacological interventions

  • Opioids versus placebo or no intervention

  • Opioids versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 3. Non‐steroidal anti‐inflammatory drugs versus placebo, no intervention, or non‐pharmacological interventions

  • NSAID versus placebo or no intervention

  • NSAID versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 4. Alpha‐2 agonists versus placebo, no intervention, or non‐pharmacological interventions

  • Alpha‐2 agonists versus placebo or no intervention

  • Alpha‐2 agonists versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 5. N‐Methyl‐D‐aspartate receptor antagonists versus placebo, no intervention, or non‐pharmacological interventions

  • NMDA receptor antagonists versus placebo or no intervention

  • NMDA receptor antagonists versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 6. Other analgesics versus placebo, no intervention, or non‐pharmacological interventions

  • Other analgesics versus placebo or no intervention

  • Other analgesics versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 7. Sedatives versus placebo, no intervention, or non‐pharmacological interventions

  • Sedatives versus placebo or no intervention

  • Sedatives versus non‐pharmacological interventions (e.g. non‐nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, music therapy, therapeutic touch/massage, sensorial saturation, or acupuncture)

• Comparison 8. Drug A versus drug B (e.g. morphine versus fentanyl or morphine versus midazolam)

  • This can include comparisons within or between classes of interventions (topical anesthetics, opioids, alpha‐2 agonists, NMDA receptor antagonists, other analgesics, and sedatives).

We will include any dose, duration, and route of administration.

We will include studies where the interventions are initiated to prevent or treat pain or discomfort associated with lumbar puncture.

Types of outcome measures

Outcome measures do not form part of the eligibility criteria.

Primary outcomes

• Successful lumbar puncture on first attempt

• Total number of lumbar puncture attempts

• 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

• Pain assessed with the following scales 

  • ABC scale (Acuteness of the first cry, Burst rhythmicity and temporal Constancy of cry intensity), for both term and preterm infants (Bellieni 2005)

  • Behavioral Indicators of Infant Pain (BIIP), for preterm infants only (Holsti 2008)

  • Acute Pain in Newborn infants (APN; English version of Douleur Aiguë du Nouveau‐né [DAN]) for both term and preterm infants (Carbajal 1997)

  • Neonatal Infant Pain Scale (NIPS), for both term and preterm infants (Lawrence 1993)

  • Neonatal Pain, Agitation, and Sedation Scale (N‐PASS), for both term and preterm infants (Hummel 2008)

  • Premature Infant Pain Profile (PIPP)/PIPP‐revised (PIPP‐R), for both term and preterm infants (Gibbins 2014; Stevens 1996)

  • Neonatal Facial Coding System (NFCS), for both term and preterm infants (Peters 2003)

  • Face, Legs, Activity, Cry and Consolability (FLACC), for term infants only (Merkel 1997)

If a study reports more than one pain scale among those listed above, we will report them separately. We plan to report the mean values of each pain scale assessed at the following time points.

• During the procedure

• Up to 10 minutes after the procedure

• Between 11 and 59 minutes after the procedure

• One to two hours after the procedure

If a study reports more than one time point among those listed above, we will report them all. We will report the worst score within each timeframe.

Secondary outcomes

• Episodes of desaturation, defined as a decrease of arterial oxygen saturation (SpO₂) to less than 80%, with no minimum duration

• Apnea: number of episodes (defined as interruption of breathing for more than 20 seconds) during the procedure

• Apnea: number of infants with one or more episodes (defined as interruption of breathing for more than 20 seconds) during the procedure

• Hypotension requiring medical therapy (vasopressors or fluid boluses)

• Time to perform the lumbar puncture 

• Need for additional pain/sedation medication to perform the lumbar puncture 

• Intraventricular hemorrhage on brain ultrasound (any and severe [Papile grade 3 to 4; Papile 1978]) 

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

• Adverse events as reported by study authors

Search methods for identification of studies

The Cochrane Sweden Information Specialist developed a draft search strategy for PubMed (National Library of Medicine) in consultation with the review authors (Appendix 1). This strategy will be peer reviewed by an Information Specialist using the PRESS Checklist (McGowan 2016a; McGowan 2016b). We will adapt the MEDLINE strategy to other databases using appropriate syntax.

We will use population and methodological filters developed by Cochrane Neonatal Group. We will apply no language, publication year, publication type, or publication status restrictions.

Electronic searches

We will search the following databases.

• Cochrane CENTRAL Register of Controlled Trials (CENTRAL), via Wiley

• PubMed (National Library of Medicine; 1946 to present)

• Embase.com (Elsevier; 1974 to present)

Searching other resources

We will identify trial registration records using CENTRAL and by independent searches of the following registries.

• ISRCTN registry (www.isrctn.com)

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov)

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; trialsearch.who.int)

We will screen the reference lists of included studies and related systematic reviews for studies not identified by the database searches.

We will search for errata or retractions of included studies published on PubMed (www.ncbi.nlm.nih.gov/pubmed).

Data collection and analysis

We will collect information from each report on the methods of randomization, blinding, intervention, stratification, and whether the trial was single or multicenter. We will record information related to trial participants including birth weight, GA, number of participants, indication for LP, modality of administration, and dose of pharmacological interventions for the management of pain and discomfort. We will analyze the clinical outcomes listed in Types of outcome measures.

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management software and remove duplicates. If the number of search results exceeds 1000, we will use Cochrane's Screen4Me to reduce screening activities by the review authors. Screen4Me includes the following three components.

• Known assessments (a service that matches records in the search results to records that have been screened by Cochrane Crowd and labeled as 'RCT' or 'not an RCT')

• The RCT classifier (a machine‐learning model that distinguishes RCTs from non‐RCTs)

• Cochrane Crowd (Cochrane’s crowdsourcing platform, where contributors from around the world help to identify randomized trials and other types of healthcare‐related research)

We will add any references rejected as not‐RCTs by Screen4Me to the 'Irrelevant' segment of Covidence and we will save results in an RIS formatted text file suitable for import into bibliographic management or other software. This approach will ensure references are available for deduplication when the review is updated, and for verification purposes should questions arise about the accuracy of Screen4Me categorization. We will present the results of Screen4Me in an appendix of the review.

Two review authors (SP, EO) will independently screen the remaining titles/abstracts, then independently assess the full‐text articles of all potentially eligible studies. They will resolve any disagreements that occur during the study selection process by discussion or by consulting a third review author (EH). We will document reasons for excluding studies during the full‐text review in a 'Characteristics of excluded studies' table. Possible reasons for exclusion will be the absence of one or more elements of PICO(S): population, intervention, comparison, outcome, or study type; where a study omits more than one PICO(S) element, we will document only one. We will collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will also provide any information we can obtain about ongoing studies. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Liberati 2009).

Data extraction and management

Two review authors (SP, EO) will independently extract data using a data extraction form integrated with a modified version of the Cochrane Effective Practice and Organisation of Care Group data collection checklist (Cochrane EPOC Group 2017). We will pilot the form within the review team using a sample of included studies.

We will extract the following characteristics from each included study.

• Administrative details: study author(s), published or unpublished, year of publication, study dates, presence of vested interest, details of other relevant papers cited

• Study characteristics: study registration, study design type, study setting, number of study centers and location, informed consent, ethics approval, details of any 'run‐in' period (if applicable), completeness of follow‐up (e.g. greater than 80%)

• Participants: number randomized, number lost to follow‐up/withdrawn, number analyzed, mean GA, GA range, mean chronological age (CA), CA range, sex, severity of condition, diagnostic criteria, inclusion, criteria and exclusion criteria

• Interventions: initiation, dose, and duration of administration

• Outcomes listed in Types of outcome measures

We will resolve any disagreements by discussion.

We will describe ongoing studies identified by our search and document available information such as the primary author, research question(s), methods, outcome measures, and estimated reporting date in the 'Characteristics of ongoing studies' table.

If we have any queries or require more information, we will contact study authors for clarification. Two review authors (SP, MB) will use the Cochrane statistical software Review Manager 5 (RevMan 5) or Review Manager Web (RevMan Web) for data entry (Review Manager 2020; RevMan Web 2022). We will replace any standard error of the mean (SEM) by the corresponding standard deviation (SD).

Assessment of risk of bias in included studies

Two review authors (SP, EH) will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane risk of bias tool (RoB 1) for the following domains (Higgins 2011).

• Random 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

We will resolve any disagreements by discussion or by consulting a third review author (MB). See Appendix 2 for a more detailed description of risk of bias for each domain. We will assess the overall risk of bias of each trial as follows.

• Low risk of bias: all domains are classified at low risk of bias.

• Unclear risk of bias: one or more domains is classified at unclear risk of bias, and no domain is at high risk of bias.

• High risk of bias: at least one domain is classified at high risk of bias.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results using risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals (CIs). We will calculate the number needed to treat for an additional beneficial outcome (NNTB), or number needed to treat for an additional harmful outcome (NNTH) with 95% CIs if there is a statistically significant RD.

Continuous data

For continuous data, we will use the mean differences (MDs) when outcomes are measured in the same way between trials. We will use the standardized mean difference (SMD) to combine trials that measure the same outcome with different methods. Where trials report continuous data as median and interquartile range (IQR) and data pass the test of skewness, we will convert mean to median and estimate the SD as IQR/1.35.

If data are not reported in an RCT in a format that can be entered directly into a meta‐analysis, we will convert them to the required format as recommended in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

Unit of analysis issues

We will perform the primary analysis per individual randomized.

For cluster‐randomized trials, we will extract information on the study design and unit of analysis for each study, indicating whether clustering of observations is present due to allocation to the intervention at the group level or clustering of individually randomized observations (e.g. infants within clinics). We will extract available statistical information needed to account for the implications of clustering on the estimation of outcome variances, such as design effects or intraclass correlation coefficients (ICCs), and whether the study adjusted the results for correlations in the data. In cases where the study does not account for clustering, we will make appropriate adjustments to the effective sample size following Cochrane guidance (Higgins 2020). Where possible, we will derive the ICC for these adjustments from the trial itself, or from a similar trial. If an appropriate ICC is unavailable, we will conduct sensitivity analyses to investigate the potential effect of clustering by imputing a range of ICC values.

If any trials have multiple arms that are compared against the same control condition, and these arms will be included in the same meta‐analysis, we will either combine groups to create a single pair‐wise comparison, or select one pair of interventions and exclude the others. We will list all treatment arms in the 'Characteristics of included studies' table, even if they are not used in the review.

In the meta‐analysis and data synthesis, we will only include the first‐phase data from cross‐over trials.

Dealing with missing data

Where feasible, we will carry out analysis on an intention‐to‐treat basis for all outcomes. This means we will analyze all participants in the treatment group to which they were randomized, regardless of the actual treatment received. If we identify important missing data (in the outcomes) or unclear data, we will request the missing data by contacting the study authors. We will make explicit the assumptions of any methods used to deal with missing data. We may perform sensitivity analyses to assess how sensitive results are to reasonable changes in the undertaken assumptions. We will address the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

We will describe the clinical diversity and methodological variability of the evidence narratively and in tables. Tables will include data on study characteristics such as design features, population characteristics, and intervention details.

To assess statistical heterogeneity, we will visually inspect forest plots and describe the direction and magnitude of effects and the degree of overlap between CIs. We will use the I² statistic to quantify inconsistency among the trials in each analysis. We will also consider the P value from the Chi² test to assess if heterogeneity is significant (P < 0.1). If we identify substantial heterogeneity, we will report the finding and explore possible explanatory factors using prespecified subgroup analysis.

We will grade the degree of heterogeneity as follows.

• 0% to 40% might not represent important heterogeneity.

• 30% to 60% may represent moderate heterogeneity.

• 50% to 90% may represent substantial heterogeneity.

• More than 75% may represent considerable heterogeneity.

We will use this rough guideline to interpret the I² value rather than a simple threshold, and our interpretation will take into account the understanding that measures of heterogeneity (I² and Tau) are very uncertain when the number of studies is small (Deeks 2020).

Assessment of reporting biases

We will assess reporting bias by comparing the stated primary and secondary outcomes and reported outcomes. Where study protocols are available, we will compare these to the full publications to determine the likelihood of reporting bias. In the 'Characteristics of included studies' table, we will describe studies that used the interventions in a potentially eligible infant population but did not report any of the primary and secondary outcomes.

If we identify more than 10 studies that report the same outcome, we will use funnel plots to screen for publication bias. If we find funnel plot asymmetry on visual assessment, we will incorporate this in our assessment of certainty of the evidence (Egger 1997). If our review includes 10 or fewer studies eligible for meta‐analysis, we will note our inability to rule out possible publication bias or smalls study effects.

Data synthesis

If we identify multiple studies that we consider sufficiently similar, we will perform meta‐analysis using RevMan 5 or RevMan Web (Review Manager 2020; RevMan Web 2022). For categorical outcomes, we will calculate the typical estimates of RR and RD, each with its 95% CI; for continuous outcomes, we will calculate the MD or SMD, each with its 95% CI. We will use a fixed‐effect model to combine data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If we judge meta‐analysis to be inappropriate, we will analyze and interpret individual trials separately. If there is evidence of clinical heterogeneity, we will try to explain this based on the different study characteristics and subgroup analyses.

Subgroup analysis and investigation of heterogeneity

Tests for subgroup differences in effects will be interpreted with caution given the potential for confounding with other study characteristics and the observational nature of the comparisons (Deeks 2020). In particular, subgroup analyses with fewer than five studies per category are unlikely to be adequate to ascertain valid difference in effects and will not be highlighted in our results. When subgroup comparisons are possible, we will conduct stratified meta‐analysis and a formal statistical test for interaction to examine subgroup differences that could account for effect heterogeneity (e.g. Cochran’s Q test, meta‐regression; Borenstein 2013; Higgins 2020).

Given the potential differences in the effects of interventions related to GA and birthweight, as discussed in the Background section, we will conduct subgroup comparisons to investigate whether interventions are more effective for the management of pain and discomfort during LP in newborn infants.

We plan to carry out the following subgroup analyses of factors that may contribute to heterogeneity in the effects of the intervention:

• Prematurity: term, preterm

• Bodyweight: less than 1500 g; 1500 g to 2500 g; more than 2500 g

We will use the main outcomes in subgroup analyses if we identify sufficient studies to support valid subgroup comparisons (at least five studies per subgroup).

Sensitivity analysis

If we identify substantial heterogeneity, we will conduct sensitivity analysis to determine whether the findings are affected by the inclusion of only those trials considered at low risk of selection, performance, and reporting bias. We will report the results of sensitivity analyses for primary outcomes only.

As there is no formal statistical test for sensitivity analysis, we will provide informal comparisons between the different methods of estimating the effect under different assumptions. Changes in P values may not accurately reflect the difference between the main analysis and sensitivity analysis, since statistical significance may be lost with fewer studies.

We will report sensitivity analysis results in tables rather than forest plots.

Summary of findings and assessment of the certainty of the evidence

We will use the GRADE approach, as outlined in the GRADE Handbook, to assess the certainty of evidence for the primary outcomes (Schünemann 2013; Schünemann 2020).

• Successful lumbar puncture on first attempt

• Total number of lumbar puncture attempts

• 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

• Pain assessed with the following scales

  • ABC scale (Acuteness of the first cry, Burst rhythmicity and temporal Constancy of cry intensity), for both term and preterm infants (Bellieni 2005)

  • Behavioral Indicators of Infant Pain (BIIP), for preterm infants only (Holsti 2008)

  • Acute Pain in Newborn infants (APN; English version of Douleur Aiguë du Nouveau‐né [DAN]) for both term and preterm infants (Carbajal 1997)

  • Neonatal Infant Pain Scale (NIPS), for both term and preterm infants (Lawrence 1993)

  • Neonatal Pain, Agitation, and Sedation Scale (N‐PASS), for both term and preterm infants (Hummel 2008)

  • Premature Infant Pain Profile (PIPP)/PIPP‐revised (PIPP‐R), for both term and preterm infants (Gibbins 2014; Stevens 1996)

  • Neonatal Facial Coding System (NFCS), for both term and preterm infants (Peters 2003)

  • Face, Legs, Activity, Cry and Consolability (FLACC), for term infants only (Merkel 1997)

If a study reports more than one pain scale among those listed above, we will report them separately. We plan to report the mean values of each pain scale assessed at the following time points.

• During the procedure

• Up to 10 minutes after the procedure

• Between 11 and 59 minutes after the procedure

• One to two hours after the procedure

If a study reports more than one time point among those listed above, we will report them all. We will report the worst score within each timeframe.

In addition, we will use the GRADE approach to assess the following clinically relevant secondary outcomes.

• Episodes of desaturation, defined as a decrease of arterial oxygen saturation (SpO₂) to less than 80%, with no minimum duration specified

• Apnea: number of episodes (defined as interruption of breathing for more than 20 seconds) during the procedure

• Apnea: number of infants with one or more episodes (defined as interruption of breathing for more than 20 seconds) during the procedure

Two review authors (SP, MB) will independently assess the certainty of the evidence for each of the outcomes listed above. Using GRADEpro GDT, we will create a summary of findings table for each of the comparisons listed in Types of interventions. We will consider evidence from RCTs as high certainty, downgrading by one level for serious (or two levels for very serious) limitations in the following domains.

• Design (risk of bias)

• Consistency across studies

• Directness of the evidence

• Precision of estimates

• Presence of publication bias. 

The GRADE approach categorizes the certainty of a body of evidence into one of the following four grades.

• 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.

Appendices

Appendix 1. Search strategy for MEDLINE (PubMed)

Information specialist: Maria Björklund, Krister Aronsson

Affiliation: Lund University, Faculty of Medicine, Library & ICT, Sweden

PICO(S)

• Population: term and preterm infants undergoing lumbar puncture*

• Interventions/Comparisons: any drug given for the management of pain and discomfort

• Study design: only RCTs.

*Cochrane Neonatal standard filter translated for PubMed (neonatal.cochrane.org/Literature-Search-Filters-for-Neonatal-Reviews)

Date of search: 23 August 2022

Publication date/language limitations: none

Search strategy

#1 ((("infant, newborn"[MeSH Terms]) OR ("intensive care, neonatal"[MeSH Terms])) OR ("intensive care units, neonatal"[MeSH Terms])) OR ("gestational age"[MeSH Terms])

707451 records

 

#2 babe[Text Word] OR babes[Text Word] OR baby*[Text Word] OR babies[Text Word] OR gestational age?[Text Word] OR infant?[Text Word] OR infantile[Text Word] OR infancy[Text Word] OR low birth weight[Text Word] OR low birthweight[Text Word] OR neonat*[Text Word] OR neo‐nat*[Text Word] OR newborn*[Text Word] OR new born?[Text Word] OR newly born[Text Word] OR premature[Text Word] OR pre‐mature[Text Word] OR pre‐matures[Text Word] OR prematures[Text Word] OR prematurity[Text Word] OR pre‐maturity[Text Word] OR preterm[Text Word] OR preterms[Text Word] OR pre term?[Text Word] OR preemie[Text Word] OR preemies[Text Word] OR premies[Text Word] OR premie[Text Word] OR VLBW[Text Word] OR VLBWI[Text Word] OR VLBW‐I[Text Word] OR VLBWs[Text Word] OR LBW[Text Word] OR LBWI[Text Word] OR LBWs[Text Word] OR ELBW[Text Word] OR ELBWI[Text Word] OR ELBWs[Text Word] OR NICU[Text Word] OR NICUs[Text Word]

1752818 records

 

#3 #1 OR #2

1752818 records

 

[Intervention]

 

#4 "spinal puncture"[MeSH Terms]

6648 records

 

#5  spinal puncture*[Text Word] OR lumbar puncture*[Text Word]

13489 records

 

#6 #4 OR #5

13489 records

 

#7 ("anesthesia and analgesia"[MeSH Terms]) OR ("anesthesia, local"[MeSH Terms])

247619 records

 

#8 anesthesia[Text Word] OR anaesthesia[Text Word] OR topical agent*[Text Word] OR anestetic*[Text Word] OR anaesthetic*[Text Word]

327536 records

 

#9 "Analgesics, Opioid"[Mesh] OR "Morphine Derivatives"[Mesh]

94471 records

 

#10 opioid*[Text Word] OR opiat*[Text Word]
153068 records

 

#11 alfentanil[Text Word] OR sulfentanil[Text Word] OR morphine[Text Word] OR meperidine[Text Word] OR codeine[Text Word] OR remifentanil[Text Word] OR piperidines[Text Word] OR opioid*[Text Word] OR fentanyl[Text Word] OR alfentanil[Text Word] OR sufentanil[Text Word] OR diamorphine[Text Word] OR meperidine[Text Word] OR pethidine[Text Word] OR codeine[Text Word] OR remifentanil[Text Word]

235494 records

 

#12 (((((("fentanyl"[MeSH Terms]) AND ("alfentanil"[MeSH Terms])) OR ("sufentanil"[MeSH Terms])) OR ("meperidine"[MeSH Terms])) OR ("codeine"[MeSH Terms])) OR ("remifentanil"[MeSH Terms])) OR ("piperidines"[MeSH Terms])

146258 records

 

#13 "Phenylpropionates"[Mesh] OR "Ibuprofen"[Mesh] OR "Fenoprofen"[Mesh] OR "Indoprofen"[Mesh] OR "Ketoprofen"[Mesh] OR "Suprofen"[Mesh] OR "Benzodiazepines"[Mesh:NoExp] OR "Midazolam"[Mesh] OR "Lorazepam"[Mesh] OR "Chloral Hydrate"[Mesh] OR "Propofol"[Mesh] OR "Ketamine"[Mesh] OR "Receptors, N‐Methyl‐D‐Aspartate"[Mesh] OR "Analgesics, Non‐Narcotic"[Mesh] OR "Analgesics, Short‐Acting"[Mesh] OR "Calcitonin Gene‐Related Peptide Receptor Antagonists"[Mesh] OR "Narcotics"[Mesh:NoExp]

217451 records

 

#14  ibuprofen[Text Word] OR fenoprofen[Text Word] OR indoprofen[Text Word] OR ketoprofen[Text Word] OR suprofen[Text Word] OR Phenylpropionate*[Text Word] OR midazolam[Text Word] OR lorazepam[Text Word] OR Benzodiazepine*[Text Word] OR propofol[Text Word] OR chloral hydrate[Text Word] OR ketamine[Text Word] OR NMDA[Text Word] OR N‐Methylaspartate[Text Word] OR N‐Methyl‐D‐Aspartate[Text Word]

186266 records

 

#15 ((("acetaminophen"[MeSH Terms]) OR ("lidocaine, prilocaine drug combination"[MeSH Terms])) OR ("lidocaine"[MeSH Terms])) OR ("tetracaine"[MeSH Terms])

47520 records

 

#16  lidocaine[Text Word] OR prilocaine[Text Word] OR paracetamol[Text Word] OR acetaminophen[Text Word] OR "eutectic mixture of local anesthetics"[Text Word] OR EMLA[Text Word] OR amethocaine[Text Word] OR tetracaine[Text Word]

69752 records

 

#17 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16

916980 records

 

[Pain management]

 

#18  "procedural pain"[Text Word] OR "pain* procedure*"[Text Word]

1721 records

 

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

4607695 records 

 

#20 #18 OR #19

4607695 records 

 

[Study design filter‐ Cochrane Neonatal standard RCT filter https://neonatal.cochrane.org/Literature‐Search‐Filters‐for‐Neonatal‐Reviews]

 

#21 randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab] 

5512862 records

 

#22 quasirandom*[tw] or quasi‐random*[tw] or randomi*[tw] or randomly[tw]
1259395 records

 

#23 control*[tw] AND (group[tw] OR groups[tw] OR random[tw] OR trial[tw] OR trials[tw] OR study[tw])

3719557 records

 

#24 #1 OR #2 OR #3 

7318910

 

#25 (animals [mh] NOT humans [mh])

5035843 records 

 

#26 #4 NOT #5 

6266105 records

 

[Combination search‐ population AND (Intervention OR Pain management)]

 

#27 #20 OR #17

5232839 records

 

#28 #3 AND #6 AND #27 AND #26

162 records

 

[Annotation: without pharmacological terms/ pain management terms, the number of records retrieved will be approximately 680.]

Appendix 2. Cochrane risk of bias tool (RoB 1)

We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of the trials. For each trial, we will seek information regarding the method of randomization, blinding, and reporting of all outcomes for all participants. We will assess each criterion at low, high, or unclear risk of bias. Two review authors will independently assess each study. We will resolve any disagreements by discussion. We will add this information to the 'Characteristics of included studies' table.

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

For each included study, we will categorize 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 will categorize 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 will categorize the methods used to blind study participants and personnel to the allocated interventions. We will assess blinding separately for different outcomes or class of outcomes. We will categorize 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 will categorize the methods used to blind outcome assessment. We will assess blinding separately for different outcomes or class of outcomes. We will categorize 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 will describe the completeness of data including attrition and exclusions from the analysis. We will note 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 is reported or supplied by the trial authors, we will re‐include missing data in the analyses. We will categorize 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 will describe 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 will compare prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we will contact study authors to gain access to the study protocol. We will assess the methods as:

• low risk (where it is 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 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 have been expected to have been reported); or

• unclear risk.

Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we will describe 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 will assess whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk;

• unclear risk.

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

Contributions of authors

OR: conceived and developed the review question, contributed to writing and editing, made an intellectual contribution, and approved the final version prior to submission.
SP: wrote the first draft, contributed to editing, made an intellectual contribution, and approved the final version prior to submission.
EH: made an intellectual contribution and approved the final version prior to submission.
EO: helped to develop the review question, contributed to writing and editing, made an intellectual contribution, and approved the final version prior to submission.
MB: made an intellectual contribution, approved the final version prior to submission, and is the guarantor of the protocol.

Sources of support

Internal sources

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

  MB and OR are 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

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

Declarations of interest

OR: none
SP: none
EH: none
EO: none
MB is an Associate Editor for the Cochrane Neonatal Group. However, he did not participate in the acceptance or editorial processes for this review.

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