Premedication for non‐urgent endotracheal intubation for preventing pain in neonates
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective is to assess the effectiveness and safety of premedication in reducing pain/stress in neonates undergoing non‐urgent endotracheal intubation.
Subgroups analysis will be conducted based on four gestational age (GA) categories: under 28 weeks; 28 weeks to under 32 weeks; 32 weeks to under 37 weeks; and 37 weeks or more to under 44 weeks' postmenstrual age (PMA), to encompass all intubation procedures.
Background
Description of the condition
Endotracheal intubation is a common procedure performed in neonatal intensive care units (NICUs) especially in infants of less than 28 weeks' gestational age (Johnston 1997; Johnston 2011). The procedure involves placing an endotracheal tube into the trachea via the nares or the mouth using a laryngoscope. Intubations are performed either as an emergency procedure at birth as part of resuscitation; or later in the NICU in response to worsening respiratory status on non‐invasive ventilation, apnoea secondary to preterm birth, seizures or medications (e.g. prostaglandin infusion) and reintubation for blocked tubes or accidental extubations. Intubations may also be performed electively prior to surgical, diagnostic (e.g. magnetic resonance imaging (MRI)) or interventional procedures (e.g. percutaneously inserted central venous catheters).
Adults and children who undergo 'awake intubation' (intubation without premedication) exhibit pain and mount physiological responses such as systemic hypertension, tachycardia, increase in blood flow velocity in the common carotid artery and middle cerebral artery, and reduction in femoral blood flow velocity (King 1951; Shribman 1987; Moorthy 1994). In neonates, similar changes in physiological responses have been documented including systemic hypertension, bradycardia, hypoxaemia, and raised intracranial pressure secondary to the stimulation of vagal and mechanical pressure reflexes by insertion of the laryngoscope blade and the tube (Raju 1980; Kelly 1984; Marshall 1984; Xie 2001). Systemic hypertension is also related to catecholamine release in response to painful and stressful stimuli (Shribman 1987).
There is cumulative evidence that multiple and prolonged exposures to painful stimuli have a negative impact on neonatal pain processing and long‐term neurobehavioral outcome, hence the need to alleviate procedure‐related pain in this vulnerable population (Fitzgerald 1989; Grunau 2002; Grunau 2009; Smith 2011; Brummelte 2012). Repeated exposure to painful procedures in preterm infants of 32 weeks' gestation or less is associated with reduced white matter and subcortical grey matter after adjusting for confounders (Brummelte 2012; Ranger 2013; Vinall 2013); and higher internalising behaviours and impaired cognitive function at 7 years of age (Ranger 2014).
Several professional organizations recommend that tracheal intubation without the use of analgesia or sedation should be performed only for resuscitation in the delivery room or for life‐threatening situations associated with the unavailability of intravenous access (Anand 2001; Lago 2009; Kumar 2010; CPS 2011). Premedication should be used prior to elective and non‐urgent intubation in neonates, with the goals of reducing discomfort, distress, intubation‐related airway trauma and physiological instability (Kumar 2010; CPS 2011). Both the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS) recommend the combination of vagolytic, analgesic and neuromuscular blocker for premedication for intubation. Further, AAP recommends that muscle relaxants or sedatives should not be used alone without analgesic agents and that each unit should develop protocols with a list of preferred medications (Kumar 2010). Based on the current evidence the CPS recommends the combination of atropine, fentanyl and succinylcholine for premedication in clinical practice. However, the optimal drug/combination of drugs for premedication has not been established in neonates, and further research is recommended with the availability of rapid acting agents with shorter duration of action.
Wide variation exists in the frequency and type of premedication used for intubation (Vogel 2000; Whyte 2000; Durrmeyer 2013). In a prospective observational study conducted in 13 NICUs in France, 44% of intubations were performed without any prior sedation or analgesia with 13 different regimens used (Carbajal 2008; Durrmeyer 2013). Similarly in Canadian NICUs, 37% of intubations were carried out with no prior analgesia. Only five of the 14 NICUS had guidelines for premedication for intubation (Johnston 2011). The findings of the above studies are consistent with those from surveys on self‐reported premedication practices in the United States (Sarkar 2006; Muniraman 2015) and Italy (Lago 2013).Therefore, despite the evidence that intubation is associated with pain and physiological instability, discomfort and stress premedication for intubation is not routinely used in clinical practice.
Description of the intervention
The classes of drugs that have been considered for premedication for endotracheal intubation include anticholinergics, analgesics, anxiolytics/sedatives, anaesthetics and neuromuscular blockades either in isolation or in combination.
Anticholinergic drugs like atropine inhibit the muscarinic actions of acetylcholine on sinoatrial nodes, salivary and mucus glands (Kelly 1984). They reduce oral secretions and vagally mediated bradycardia stimulated by intubation and laryngoscope insertion (Cordero 1971; Kelly 1984), thus facilitating better visualization of the vocal cord and increasing the success of the procedure.
Opiates like morphine and fentanyl activate specific neurotransmitter receptors (µ‐opioid receptors) located in the central and peripheral nervous system and activate signal transduction (Dhawan 1996; Bruchas 2010). They decrease behavioural and physiological response of pain and stress during intubation and minimize spikes in blood pressure which further lessen the rise in intracranial pressure (Guinsburg 1998). The adverse effects of morphine are hypotension, decreased gastrointestinal motility and respiratory depression (Anand 2004; Hall 2005; Menon 2008). Chest wall rigidity is one of the major side effects that is observed with fentanyl especially with rapid administration (Fahnenstich 2000).
Anxiolytics act as sedatives by facilitating the action of receptors of γ‐aminobutyric acid A (GABA), a major inhibitory neurotransmitter (Blumer 1998). The sedative and muscle relaxant effects of anxiolytics reduce physiological instability and may facilitate intubation (Blumer 1998). Major complications of benzodiazepines include respiratory depression and hypotension (Harte 1997).
Neuromuscular blockers act by blocking transmission of the nerve impulse at the neuromuscular junction (Rubin 1996). They facilitate rapid intubation by relaxing the skeletal muscle and ameliorate struggling against the intubation process (Barrington 1989; Feltman 2011). Neuromuscular blockers may cause hypotension, hypoxaemia, bradycardia and hyperkalaemia (Philips 1979; McIntosh 1985; Honsel 2014).
How the intervention might work
Awake intubation in vigorous infants can cause increase in intrathoracic pressure which can further impair venous return and cardiac output (Millar 1994). It can also obscure vital anatomic landmarks, increase the risk of iatrogenic trauma to the airways and subsequent subglottic stenosis. The adverse physiological effects of intubation can be attenuated by the use of anticholinergics, analgesics, anxiolytics and neuromuscular blockers. The use of premedication reduces both the number of intubation attempts and the time required for successful intubation (Oei 2002). Anticholinergics help prevent reflex bradycardia during intubation and decrease oropharyngeal secretions leading to better visualization of the glottis. Acute physiological changes caused by painful or stressful stimuli can be prevented by the use of analgesics. Sedatives can reduce the irritability or agitation associated with the procedure, facilitating intubation. Neuromuscular blockers suppress muscle activity, relax jaw and vocal cords and ameliorate struggling, which helps to minimize the increase in intracranial pressure that occurs during intubation (Kelly 1984; Millar 1994).
Why it is important to do this review
The efficacy of premedication to prevent pain in neonates undergoing intubation has been reviewed by Shah 2002. This review was not conducted using the rigorous methodology of the Cochrane Collaboration and included randomised controlled trials and cohort studies. The authors concluded that “awake intubation” is inappropriate in most newborn infants. Multiple studies have been published since that review, justifying this Cochrane Review on this important topic.
Objectives
The primary objective is to assess the effectiveness and safety of premedication in reducing pain/stress in neonates undergoing non‐urgent endotracheal intubation.
Subgroups analysis will be conducted based on four gestational age (GA) categories: under 28 weeks; 28 weeks to under 32 weeks; 32 weeks to under 37 weeks; and 37 weeks or more to under 44 weeks' postmenstrual age (PMA), to encompass all intubation procedures.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs), quasi‐RCTs, cluster‐RCTs and randomised cross‐over trials.
Types of participants
We will include studies of infants of 44 weeks’ postmenstrual age (PMA) or under admitted for medical or surgical intervention, or both, and requiring non‐urgent endotracheal intubation during their hospital stay. We will include infants who were intubated on more than one occasion, but only the first attempt per occasion will be included (refer to the section Unit of analysis issues).
Types of interventions
We will include the use of drugs from the following therapeutic classifications (irrespective of the route of administration): anticholinergics, analgesics, anxiolytics/sedatives, anaesthetics and neuromuscular blockers. We plan the following comparisons.
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Single agent from one therapeutic class vs. placebo/no intervention.
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Single agent from one therapeutic class vs. single agent from same/another therapeutic class.
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Combination of therapeutic classes of drugs vs. placebo/no intervention.
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Combination of therapeutic classes of drugs vs. single agent from a therapeutic class.
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Combination of therapeutic classes of drugs vs. a different combination of therapeutic classes of drugs.
Types of outcome measures
Studies that report on the incidence or occurrence of one or more of the following outcomes amongst all randomised trials will be included.
Primary outcomes
Pain or distress or both are considered the primary outcome. The pain response in neonates should be assessed by validated pain measures. These include:
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behavioural responses e.g. Neonatal Facial Coding System (Grunau 1990); and
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physiological responses as measured by:
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bradycardia defined as heart rate (HR) < 100 beats/min (Bredemeyer 2012) or more than 30% below baseline for 10 seconds or longer (Henderson‐Smart 1986);
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oxygen saturation < 85% for 10 seconds or longer;
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blood pressure (systolic, diastolic or mean) > 20% above baseline for 10 seconds or longer;
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intracranial pressure (cmH₂O) levels as a change from baseline values or as the difference between absolute values in intervention and control groups and measured by invasive or non‐invasive technique;
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hormonal response e.g. plasma, salivary or urinary cortisol levels (nmol/L or µg/dL) as a change from baseline values or as the difference between absolute values in intervention and control groups;
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the Premature Infant Pain Profile (PIPP), which is a seven‐indicator measure that includes behavioural, physiological and contextual indicators (Stevens 1996).
We will group the absolute level of the outcome measured at the same time points, e.g. pre‐procedure, during the procedure and in the recovery phase (after the completion of the procedure), and the difference in the outcome levels between the same time points among the included trials under the same outcomes.
Secondary outcomes
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Time to successful intubation (defined as time commencing from insertion of the laryngoscope blade to placement of endotracheal tube and removal of the blade ≤ 30 seconds) (Kattwinkel 2011).
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Number of intubation attempts (defined as the number of times the laryngoscope is inserted for the purpose of intubation until successful intubation; ≥ 1 attempt);
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Duration of ventilation (days);
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Potential adverse events, including:
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chest wall rigidity;
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hyperkalaemia (potassium level > 6.2 mmol/L);
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hypotension requiring treatment with inotropic agents;
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bradycardia requiring chest compression/ epinephrine;
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trauma (e.g. nasal injury) and oropharyngeal bleeding reported during or immediately after the attempt.
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Intraventricular haemorrhage (IVH) all grades (Papile 1978), evident on head ultrasound as reported by the study authors.
Search methods for identification of studies
Electronic searches
We will use the criteria and standard methods of Cochrane and Cochrane Neonatal. We will conduct a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL, current issue) in the Cochrane Library; MEDLINE via PubMed (1966 to current); Embase (1980 to current); and CINAHL (1982 to current). See Appendix 1 for the full search strategy. We will not apply language restrictions. We will search clinical trials' registries for ongoing or recently completed trials (ClinicalTrials.gov; the World Health Organization’s International Trials Registry and Platform www.who.int/ictrp/search/en/; and the ISRCTN Registry).
We will search the reference lists of any cited articles.
Searching other resources
We will conduct a search of personal files, bibliographies, relevant neonatal, paediatric and pain journals and paediatric pain conference proceedings including the Perinatal Society of Australia and New Zealand (PSANZ) (2010 to current) and Pediatric Academic Societies (PAS) (2010 to current).
Data collection and analysis
The standard methods and guidelines of Cochrane and the Cochrane Neonatal Review Group will be employed, as per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
All randomised and quasi‐RCTs, cluster RCTs and randomised cross‐over trials fulfilling the selection criteria described in the previous section will be included. All three review authors will review the results of the search and separately select the studies for inclusion. We will resolve disagreements through discussion amongst all review authors. We will list excluded studies in the ‛Characteristics of excluded studies’ table, along with reasons for exclusion.
Data extraction and management
For the studies identified as abstracts, we will contact primary authors to obtain further information. Each review author will extract data separately on a data abstraction form. We will then compare the information and resolve differences by consensus.
One review author (MA) will enter data into Review Manager 5 software (RevMan 2014); and the other authors will cross‐check the printout against their own data abstraction forms to ensure errors are corrected.
Assessment of risk of bias in included studies
The standard methods of the Cochrane Neonatal Review Group will be used to assess the methodological quality of studies. Two review authors (MA, VS) separately will assess each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by the third author (AT) or discussion.
We will assess each specific feature of the study and will categorize it into 'low risk', 'high risk', or 'unclear risk' of bias. We will report the following domains: selection bias (random sequence generation and allocation concealment); performance bias; detection bias; attrition bias and other bias. We will assess each study according to these domains and enter them into the 'Risk of bias' table. For cluster randomised trials we will report on the following biases: recruitment bias, baseline imbalance, loss of clusters, incorrect analysis and comparability with individually randomised trials.
Measures of treatment effect
The standard methods of the Cochrane Neonatal Review Group will be used. Statistical analyses will be performed using RevMan 2014. Categorical data will be analysed using relative risk (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). Continuous data will be analysed using mean difference (MD). The 95% confidence interval (CI) will be reported on all estimates.
Unit of analysis issues
The unit of analysis is the participating infant in individually randomised trials and the NICU for cluster randomised trials. We will include the first attempt of each intubation episode. Further attempts by the same intubator or other intubators will be excluded. A patient can be included more than once if they have more than one intubation episode, however each intubation would need to be treated as a separate study event and be randomised separately. For trials designs where the unit of randomisation is the individual intubation and infants may be allocated more than once, the unit of analysis will be the intubation. In studies where the unit of randomisation is the individual intubation, data on secondary outcomes such as duration of ventilation days and IVH will be included in the meta‐analysis only if the outcomes are reported per infant. The reviewers will make a judgement of whether the data should be included in a meta‐analysis or not; and if not, the data will be presented qualitatively.
We will include cluster‐randomised trials in the analyses along with individually randomised trials. We will analyse them using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intra‐cluster correlation coefficient (ICC) derived from the trial (if possible) or from another source (Higgins 2011). If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually randomised trials, we plan to synthesize the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
Analysis of cross‐over trials will depend on the risk of carry‐over or period effects. If the reviewers in their judgement do not consider that there is a risk of carry‐over effect, an effect estimate will be calculated using the generic inverse variance method in RevMan (Higgins 2011). If there are insufficient data to include a paired analysis in a meta‐analysis, data will be treated as two parallel arms, acknowledging the loss of statistical power. As this can result in a unit of analysis error, we will only include the results if they are demonstrably similar to the results of a paired analysis (Higgins 2011).
To address the issue of repeated measures in the included trials that arise from having multiple recording of pain score, heart rate and oxygen saturation from the same infants, we will follow the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions by analysing the data according to the different phases (Higgins 2011): 1) pre‐procedure phase (baseline); 2) during the procedure (i.e. insertion of the endotracheal tube); and 3) recovery phase (after completion of the procedure). Established methods will be used to pool data prior to inclusion in the meta‐analysis if data are available at multiple time points within the same procedure phase (Borenstein 2009).
Dealing with missing data
If we identify trials with missing data, we will approach the author(s) by email to provide us with additional information.
Assessment of heterogeneity
We plan to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. We will consider an I² value of greater than 50% as an indication of high heterogeneity. We will assess the degree of heterogeneity estimates as described by (Higgins 2003).
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< 25%: no heterogeneity.
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25% to 49%: low heterogeneity.
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50% to 74%: moderate heterogeneity.
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≥ 75%: high heterogeneity.
If we detect statistical heterogeneity (I² ≥ 75%), we plan to explore the possible causes (e.g. difference in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analysis.
Assessment of reporting biases
If at least 10 trials are included in one meta‐analysis we will assess reporting biases by performing funnel plots of the effect estimates. The plots will be visually interpreted.
Data synthesis
Statistical analyses will be performed according to the recommendations of the Cochrane Neonatal Review Group (neonatal.cochrane.org.myaccess.library.utoronto.ca). A fixed‐effect model will be used for meta‐analyses to combine the data. For any meta‐analyses analysing categorical outcomes, we plan to calculate typical estimates of relative risk (RR) and relative difference (RD), along with the accompanying 95% CI. For estimates of typical RR and RD we plan to use the Mantel‐Haenszel (MH) method. For any meta‐analyses analysing continuous outcomes, we plan to calculate the mean difference (MD) and standardized mean difference (SMD) with 95% CIs as appropriate. When meta‐analysis is judged to be inappropriate, we will analyse and interpret individual trials separately.
Quality of evidence
We will use the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes: pain response, time to successful intubation, number of intubation attempts, duration of ventilation and interventions' side effects.
Two authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomised controlled trials as high quality but downgrade 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 will use the GRADEpro Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.
The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades:
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High: We are very confident that the true effect lies close to that of the estimate of the effect.
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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.
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Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
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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.
Subgroup analysis and investigation of heterogeneity
We plan to conduct subgroup analyses as follows if possible.
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Gestational age: < 28 weeks, 28 to < 32 weeks; 32 to <37 weeks, ≥ 37 to < 44 weeks.
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Experience/category of person performing intubation: neonatologists, neonatal fellows, resident doctors, respiratory therapists and neonatal nurse practitioners.
We will assess subgroup differences by interaction tests available within RevMan 2014. We will report the results of subgroup analysis quoting the Chi² statistic, P value and I² value.
Sensitivity analysis
If sufficient data are available, we will explore methodological heterogeneity through sensitivity analyses. We will perform these by including only trials with adequate allocation concealment, randomisation or blinding of treatment and less than 10% loss to follow‐up.
