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Cochrane Database of Systematic Reviews Protocol - Intervention

Local wound analgesia in infants undergoing thoracic or abdominal surgery

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Abstract

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

To assess whether local wound analgesia provides better pain relief than other analgesic regimens (epidural analgesia, intravenous opioids, other analgesics and supportive care regimens) and decreases the need for systemic analgesic agents in term or preterm neonates undergoing thoracic or abdominal surgery.

Background

Description of the condition

Acute pain has long been underestimated and untreated in the paediatric population, as it was thought that infants could not feel pain and that older children did not remember it. In addition, fear of overdosing or adverse effects prevented administration of adequate pain relief in children. However, acute pain should be considered as the fifth vital sign along with heart rate, respiratory rate, blood pressure and temperature. It is most often 'nociceptive' and results from injury, surgery, internal disease, or a combination of these. Specialized nerve endings called 'nociceptors' that are attached to nerve fibres collect the pain message at the site of tissue injury and forward it to spinal targets and eventually to cortical structures resulting in conscious pain perception, and conscious and subconscious responses to the pain. Different receptors and neurochemicals are involved in the transmission of pain messages; therefore, treatment of acute pain should be multimodal and involve medications which target different receptors. Chosen combinations of analgesics would then enhance the analgesic potency of each other; thereby finding the optimal combination and mode of delivery has the potential to reduce both the required dose of each drug and the incidence of adverse effects (Astuto 2009). It is likely that pain will be under treated if it is not assessed appropriately and regularly. Assessment of pain must be age‐appropriate and easily implemented at the bedside, and result in a reasoned and prompt adjustment of the analgesic dose. As children do not express the same pain behaviours as adults, several pain score scales have been developed and validated for paediatric populations. There are around 16 defined pain scales used for neonates (Committee on Fetus and Newborn 2016). The most frequently used pain scales are the Neonatal Infant Pain Scale (NIPS) and the Neonatal Pain, Agitation and Sedation Scale (N‐PASS) (Hillman 2015); the Premature Infant Pain Profile (PIPP) (Jonsdottir 2005); the COVERS Neonatal Pain Scale (Hand 2010); the Pain Assessment Tool (PAT) (Krechel 1995; Spence 2005); and the Crying Requires Increased oxygen administration, Increased vital signs, Expression, Sleeplessness (CRIES) (Krechel 1995).

Description of the intervention

Systemic opioids are commonly used to provide postsurgery analgesia in both adults and children. However, opioid therapy is associated with serious adverse effects including respiratory depression, hypotension and withdrawal often needing slow opioid weaning. Very preterm infants given morphine took significantly longer to reach full enteral feeding than infants in control groups (Bellu 2008). Therefore, to avoid or diminish potential risks caused by sole use of opioid analgesia, other pain control measures (i.e. additional analgesic preparations (non‐steroidal anti‐inflammatory drugs (NSAIDs), paracetamol), ultrasound‐guided transversus abdominis plane (TAP) block or epidural analgesia were trialled in infants undergoing surgical procedures. Intravenous paracetamol showed opioid‐sparing effects even after major abdominal surgery, but usage is limited by gestational age and birth weight, in addition to hepatic and renal impairment and its potential effects on neurodevelopment (Avella‐Garcia 2016; Ceelie 2013; Ohlsson 2015). Epidural analgesia achieves very good results in pain relief and reduces incidence of postoperative respiratory failure, specifically in high‐risk infants undergoing major surgery (Park 2001; Rigg 2002). However, it is widely recognised that the epidural technique is not universally successful and that inadequate analgesia is experienced by 20% to 30% of adults (Burstal 1998; McLeod 2001). Epidural‐associated hypotension is a frequent problem. Infrequent but potentially devastating complications such as epidural haematoma or abscess formation must always be considered (Cook 2009).

As a result, researchers are in search of alternative analgesic regimens. Local anaesthetic wound infiltration after chest and abdominal procedures and TAP blocks for abdominal wounds are some of the strategies (Hermansson 2013). There is an overlap in terminology used for local anaesthetic wound infiltration for postsurgical abdominal wounds and TAP blocks. Though both provide local anaesthetic infusion through a catheter entering the surgical wound, it is the location of the catheter tip that is the key difference. For local wound infiltration, the tip is placed in the subcutaneous space, muscle fascia or preperitoneal space. However, for the TAP block, the catheter tip is between the transverse abdominis and internal oblique laterally, and in the posterior rectus sheath medially. For this review, local wound analgesia will include local anaesthetic wound infiltration (catheter tip in the subcutaneous space, muscle fascia or preperitoneal) and TAP block (catheter tip between the transverse abdominis and internal oblique laterally, and in the posterior rectus sheath medially) for postsurgical abdominal wounds. For wound analgesia after procedures in the thoracic region, the catheter tip is usually inserted in the thoracotomy or sternotomy incision, or parasternally and into mediastinum (Kocabas 2008).

How the intervention might work

Continuous infiltration of local anaesthetic via a flexible catheter (tip for local wound infiltration in the subcutaneous space, muscle fascia or preperitoneal; however, for TAP block, the catheter tip is between the transverse abdominis and internal oblique laterally, and in the posterior rectus sheath medially) inside or alongside surgical wounds enables continuous, evenly spread infiltration of local anaesthetic over an indefinite period. It relieves pain by direct inhibition of noxious afferent generator potentials from peripheral nerve fibres and attenuation of the local inflammatory response to injury. Considered advantages include: ease of placement and fewer complications during insertion in comparison to epidural analgesia, in addition to the potential for reduced postoperative opioid requirements and increased postoperative mobility (Thornton 2011).

The effectiveness of the technique seems to be determined by: positioning of the catheter, and choice and concentration of local anaesthetic agent. Catheter placement within the preperitoneal space after laparotomy has been shown to reduce postoperative pain and accelerate recovery along with some potential benefits on postoperative pulmonary function (Beaussier 2007). In contrast, catheter placement superficial to muscular fascia has been so far shown to be largely ineffective (Chan 2010). One randomised controlled trial in children between three months and 12 years of age concluded that continuous subfascial bupivacaine infusion is reliable, safe and effective in paediatric postoperative pain control with considerably reduced opiate requirements (Machoki 2015). Studies have demonstrated that the placement of catheters in the appropriate muscle layers (TAP) after open nephrectomy and colorectal resection can achieve a significant reduction in requirements for additional opiates (Beaussier 2007; Forastiere 2008). One randomised controlled trial of ultrasound‐guided TAP versus local wound infiltration in children undergoing appendectomy reported that TAP block provided prolonged postoperative analgesia and reduced analgesia use without any clinical adverse effects (Shaaban 2014). One systematic review comparing TAP versus local anaesthetic wound infiltration in lower abdominal surgery in adults reported comparable short‐term postoperative analgesia, but TAP block had better long‐lasting effects (Yu 2014). Similarly, placement of the catheter either in the thoracotomy or sternotomy wound, or parasternally and into the mediastinum after cardiac surgery, was effective in reducing postoperative morphine consumption (Kocabas 2008). The effectiveness of local anaesthetic wound infiltration and opioid analgesia combinations in the provision of superior pain relief and reduction in opioid consumption after cardiothoracic surgery has been demonstrated in both adults and children (Kocabas 2008; Tirotta 2009).

Various local anaesthetic infusion regimens contribute vastly to the effectiveness of the analgesia. It appears that in the setting of laparotomy, a relatively high concentration of long‐acting agent (e.g. bupivacaine 0.5%) provides superior analgesia to placebo while lower concentrations of bupivacaine (e.g. 0.25%) have not ensured adequate analgesia in majority of adults. In contrast, lower concentrations of ropivacaine (0.2%) achieved sufficient analgesia and lower rescue opioid requirements (Beaussier 2007; Chan 2010).

Why it is important to do this review

A brief scoping search of the Cochrane database revealed no studies on use of local wound analgesia postsurgery in neonates. In the literature, there is limited information on the physiological benefits of local wound analgesia in neonates in terms of return of bowel function, need for indwelling catheterisation, hospital stay, rates of surgical site infection and short‐term wound complications (White 2010). Therefore, it seems appropriate to explore the benefits and disadvantages of local wound analgesia and currently used systemic pain control in neonatal postsurgical procedures. A more comprehensive review is required to summarise the evidence base and provide recommendations for future trials comparing this new technique to others.

Objectives

To assess whether local wound analgesia provides better pain relief than other analgesic regimens (epidural analgesia, intravenous opioids, other analgesics and supportive care regimens) and decreases the need for systemic analgesic agents in term or preterm neonates undergoing thoracic or abdominal surgery.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials, quasi‐randomised controlled trials and cluster randomised controlled trials.

Types of participants

Term (to a postnatal age of 90 days) or preterm infants (enrolled 90 days beyond the expected date of birth (i.e. after reaching 40 weeks' postmenstrual age (PMA)), requiring:

  • laparotomy, or

  • thoracotomy,

for congenital or acquired pathology.

We will exclude studies including infants with neonatal abstinence syndrome (NAS), as it is difficult to determine whether pain or withdrawal accounts for their need for opioid therapy.

Types of interventions

Local wound analgesia defined as any local anaesthetic agent (bupivacaine, ropivacaine, levo‐bupivacaine, lidocaine, mepivacaine, chloroprocaine, procaine, tetracaine) at any concentration, dose or duration, delivered by catheter infusion using one of the following approaches.

Transverse abdominis plane block for laparotomy

Between the transverse abdominis and internal oblique laterally, and in the posterior rectus sheath medially.

Non‐transverse abdominis plane block for laparotomy

Into the subcutaneous space, muscle fascia, preperitoneal layer or subfascial layer of an abdominal wound incision.

Non‐transverse abdominis plane block for thoracotomy

Into the subcutaneous space or muscle fascia of a thoracic wound incision.

We will analyse interventions for all of the approaches described above separately and they may be administered:

  • as sole therapy, or

  • in combination with analgesic regimens (epidural analgesia, intravenous opioids, paracetamol).

Compared with;

Analgesic regimens (epidural analgesia, intravenous opioids, paracetamol, separately or combined).

Specific comparisons

  • local wound analgesia;

  • local wound analgesia in combination with intravenous opioids;

  • local wound analgesia in combination with intravenous paracetamol;

  • local wound analgesia in combination with intravenous opioids and paracetamol.

versus any one of the following analgesic combinations:

  • epidural catheter;

  • epidural catheter and intravenous opioids;

  • epidural catheter and intravenous paracetamol;

  • epidural catheter and intravenous opioids plus paracetamol;

  • intravenous opioids;

  • intravenous paracetamol;

  • intravenous opioids plus paracetamol.

We will include studies reporting on the use of local wound analgesia versus epidural analgesia, intravenous opioids and paracetamol for multiple surgeries in the same infant.

We will include studies reporting supportive care regimens (swaddling, nesting, pacifier use, oral sucrose, breastfeeding, skin‐to‐skin mother care, infant cradling) as cointerventions or cocomparisons.

Types of outcome measures

Primary outcomes

  • Analgesic effectiveness in the immediate postoperative period up to 72 hours as measured using validated pain scores that assess both physical and behavioural aspects of the prolonged postoperative pain; PIPP and Premature Infant Pain Profile ‐ Revised (PIPP‐R), N‐PASS, PAT, CRIES (Committee on Fetus and Newborn 2016; Hillman 2015; Jonsdottir 2005; Krechel 1995; Ohlsson 2015; Spence 2005); with time points for measurements set to six hours or less, 12, 24, 48 and 72 hours postsurgery.

  • Time taken to wean infants off systemic analgesics according to a validated pain score (hours/days).

  • Total systemic analgesic requirements characterised by dose, type and duration.

Secondary outcomes

  • Requirement for additional analgesia (this may be considered as either a continuous or dichotomous variable)

  • Opioid‐related adverse effects (signs of withdrawal, sedation, hypotension, allergy)

  • Local anaesthetic‐related adverse effects (systemic injection, arrhythmia, cardiac arrest, central nervous system toxicity)

  • Complications related to local anaesthetic wound infusion (leaking with need to replace or reposition catheter, local irritation/redness, multiple attempts to place catheter, inadequate nerve block on skin prick testing)

  • Need for postoperative respiratory support and duration of postoperative respiratory support (hours/days).

  • Surgical site infection ‐ superficial incisional infection (involves only skin and subcutaneous tissue of the incision and occurs within 30 days' postsurgical procedure) (CDC Manual SSI).

  • Surgical site infection ‐ deep incisional infection (involves deep soft tissues of the incision, e.g. fascial and muscle layers and occurs within 30 to 90 days after surgical procedure) (CDC Manual SSI).

  • Surgical site infection ‐ organ/space (involves any part of the body deeper than the fascial/muscle layers, that is opened or manipulated during the operative procedure and occurs within 30 to 90 days after the surgical procedure) (CDC Manual SSI).

  • Sepsis ‐ laboratory‐confirmed bloodstream infections (LCBI) that are not secondary to an infection at another body site. The bloodstream infection (BSI) date of event will be the date when the FIRST element used to meet the LCBI criterion occurs for the first time within seven‐day infection window period (CDC Manual BSI).

  • Chest infection ‐ ventilator‐associated pneumonia (VAP) (a pneumonia where the infant is on mechanical ventilation for longer than two calendar days on the date of event, with day of ventilator placement being day one, AND the ventilator was in place on the date of event or the day before) (CDC Manual VAP).

  • Chest infection ‐ lower respiratory infection other than pneumonia (infant has organism(s) seen on Gram stain or identified from lung tissue or pleural fluid; has a lung abscess or other evidence of infection (e.g. empyema) on gross anatomic or histopathological examination; has imaging test evidence of abscess or infection) (CDC Manual LRTI).

  • Pneumothorax or pneumomediastinum (or both).

  • Time to removal of urethral catheter (hours/days) in view of potential urinary retention caused by intravenous opioids.

  • Time to reach full enteral feeds (days).

  • Hypotension requiring volume replacement or use of inotropic agents (or both) (hypotension defined as > 15 minutes mean blood pressure < gestational age in weeks).

  • Duration of inotropic agents for hypotension (defined as above) (hours/days).

  • All‐cause mortality (not limited to 28 days, but occurring prior to discharge from hospital).

  • Duration of hospital stay (days).

  • Discharge when prescribed oral opioids.

Search methods for identification of studies

Electronic searches

We will use the criteria and standard methods of Cochrane and the Cochrane Neonatal Review Group.

We will undertake a comprehensive search including:

  • Cochrane Central Register of Controlled Trials (CENTRAL to current issue) in the Cochrane Library;

  • MEDLINE via PubMed (January 1996 to current date);

  • Embase (January 1980 to current date);

  • CINAHL (1982 to current date);

  • Abstracts of the Pediatric Academic Societies (PAS) (2000 to current date).

We will use the following search terms: (Laparotomy OR abdominal surgery OR cardiac surgery OR open heart surgery OR postoperative OR thoracotomy) AND (local anaesthetic wound infusion OR wound analgesia OR local analgesia OR wound anaesthesia OR wound anaesthesia OR wound catheter OR sternal infusion OR transverse abdominis plane block OR nerve block) plus database‐specific terms for randomised controlled trials, infants and neonates (see Appendix 1 for the full search strategies for each database).

We will include relevant studies regardless of language or publication status (published, unpublished and in press). We will check the reference lists of all trials identified by the above methods.

Searching other resources

We will attempt to contact organisations and researchers in the field for information on unpublished and ongoing trials. We will search clinical trials registries for ongoing or recently completed trials (ClinicalTrials.gov; whoint/ictrp/search/en/; www.anzctr.org.au/; www.controlled‐trials.com).

Data collection and analysis

We will use the standard review methods of Cochrane and the Cochrane Neonatal Review Group.

Selection of studies

Two review authors will examine the titles and abstracts acquired from all searches listed above and remove clearly irrelevant studies. Two review authors will independently determine the eligibility of retrieved trials using predefined eligibility forms based on inclusion and exclusion criteria. We will resolve any disagreements or differences in opinion through discussion, and, if necessary, by consulting a third review author. We will retrieve the full text of all relevant and potentially relevant trials. We will tabulate the excluded studies in the 'Characteristics of excluded studies' table along with the reasons for excluding them. We will ensure that data from duplicate publications are entered only once in our review.

Data extraction and management

Two review authors will independently use a data extraction form to extract relevant information and data from each included study. We will compare data, correct errors and resolve any disagreements by discussion or consultation with another review author. If necessary, we will contact study authors to obtain additional data or to clarify data. For dichotomous outcomes, we will extract the total number of participants and participants who experienced the event. For continuous outcomes, we will extract the mean and standard deviation or compute these if other data are available.

Assessment of risk of bias in included studies

We will assess risk of bias for each study as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using the following criteria.

  • Random sequence generation: selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.

  • Allocation concealment: selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.

  • Blinding of participants and personnel: performance bias due to knowledge of the allocated interventions by participants and personnel during the study.

  • Blinding of outcome assessment: detection bias due to knowledge of the allocated interventions by outcome assessors.

  • Incomplete outcome data: attrition bias due to amount, nature or handling of incomplete outcome data.

  • Selective reporting: reporting bias due to selective outcome reporting.

  • Other bias: bias due to problems not covered elsewhere.

See Appendix 2 for a more detailed description of the risk of bias for each domain.

Measures of treatment effect

Dichotomous data

We will calculate the risk ratio (RR) or risk difference (RD) and their 95% confidence intervals (CI).

Where the RD is statistically significant, we will calculate the number needed to treat for an additional beneficial outcome (NNTB) and an additional harmful outcome (NNTH).

Continuous data

We will calculate the mean difference (MD) and the corresponding 95% CI for each effect estimate.

Unit of analysis issues

Where infants may have received the intervention more than once during the treatment phase, we will analyse these outcomes as rate ratios. In situations where multiple measurements are taken, we will describe, for each included trial, the observations on infants at selected time points until their discharge from hospital. We will adjust for clustering by applying the intracluster correlation coefficient if we include cluster trials. In all other circumstances, the unit of analysis will be the individual infant.

Dealing with missing data

We will attempt to overcome potential bias from missing data by one or more of the following.

  • Whenever possible, contacting the original investigators to request missing data.

  • Making explicit the assumptions of any methods that we use to cope with missing data: for example, that the data are assumed missing at random, or that missing values are assumed to have a particular value such as a poor outcome.

  • Performing sensitivity analyses to assess how sensitive the results are to reasonable changes in the assumptions that are made (see Section 9.7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)).

  • Addressing the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

We will use Review Manager 5 to assess the heterogeneity of treatment effects between trials (RevMan 2014). We will use the following.

  • The Chi2 test to assess whether observed variability in effect sizes between studies is greater than would be expected by chance. Since this test has low power when the number of studies included in the meta‐analysis is small, we will set the probability at the 10% level of significance.

  • The I2 statistic to ensure that pooling of data is valid. We will grade the degree of heterogeneity as less than 25% none or unimportant; 25% to 49% low; 50% to 74% moderate; 75% or greater high, heterogeneity.

We will assess the source of the heterogeneity using sensitivity and subgroup analyses, looking for evidence of bias or methodological differences between trials where there is evidence of apparent or statistical heterogeneity.

Assessment of reporting biases

We will assess publication bias using funnel plots if at least 10 clinical trials meet our inclusion criteria.

Data synthesis

We will use the standard methods of the Cochrane Neonatal Review Group to synthesise all available data using Review Manager 5 (RevMan 2014). We will perform meta‐analysis using a fixed‐effect model to calculate RR, RD and MD along with their 95% CIs. We will calculate RD, NNTB and NNTH in instances where the effect estimate is statistically significant. Where continuous outcomes are measured using different scales, we will express the treatment effect as standardised mean difference (SMD) with 95% CI. Narrative reviews will take place of meta‐analyses in the event that the participants, interventions, comparisons and outcomes for a particular outcome or outcome set are not judged sufficiently similar to ensure a clinically meaningful answer.

Quality of evidence

The quality of evidence reflects the extent to which we are confident that an estimate of the effect is correct (Schünemann 2013).

We will use the GRADE approach to assess the quality of evidence for the following (clinically relevant) outcomes (Schünemann 2013): effectiveness of analgesia, time taken to wean analgesia, total analgesic requirements, opioid‐related adverse effects, local anaesthetic‐related adverse effects, need for/duration of postoperative respiratory support and time to reach full enteral feeds.

Two review 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 (GRADEpro GDT 2014).

The GRADE approach results in an assessment of the quality of a body of evidence in one of 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

Subgroup analysis and investigation of heterogeneity

If appropriate, we will compare the effect of local wound analgesia in infants undergoing surgery in the following subgroups:

  • gestational age at birth: term infants (37 weeks' gestation and above); preterm infants (less than 37 weeks' gestation);

  • concentration and type of local anaesthetic agent used for local wound infusion;

  • site of catheter tip placement for local anaesthetic wound analgesia in laparotomy incisions: non‐TAP blocks (subcutaneous space, muscle fascia or preperitoneal vs. TAP blocks (laterally between the transverse abdominis and internal oblique, or medially in the posterior rectus sheath);

  • non‐TAP blocks: laparotomy vs. thoracotomy.

Sensitivity analysis

We will explore methodological heterogeneity using sensitivity analyses by including only those trials with adequate allocation concealment, randomisation or blinding of treatment and less than 10% losses to follow‐up.