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Local anaesthetic eye drops for prevention of pain in preterm infants undergoing screening for retinopathy of prematurity

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Authors

Eugene Dempsey1, Kathryn McCreery2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Neonatology, Cork University Maternity Hospital, Cork, Ireland [top]
2Neonatology, Our Ladys Hospital, Dublin, Ireland [top]

Citation example: Dempsey E, McCreery K. Local anaesthetic eye drops for prevention of pain in preterm infants undergoing screening for retinopathy of prematurity. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD007645. DOI: 10.1002/14651858.CD007645.pub2.

Contact person

Eugene Dempsey

Neonatology
Cork University Maternity Hospital
Cork
Ireland

E-mail: gene.dempsey@hse.ie

Dates

Assessed as Up-to-date: 08 November 2010
Date of Search: 30 October 2010
Next Stage Expected: 08 November 2012
Protocol First Published: Issue 1, 2009
Review First Published: Issue 9, 2011
Last Citation Issue: Issue 9, 2011

Abstract

Background

Screening examinations for retinopathy of prematurity (ROP) are performed routinely in the neonatal intensive care unit and are a recognised cause of pain in the newborn.

Objectives

To determine the effect of instillation of topical anaesthetic eye drops compared with placebo or no treatment on pain in infants undergoing ROP screening.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included a search of the Cochrane Neonatal Group register and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 10, 2010). We identified relevant studies by searching the following: (1) computerised bibliographic databases: MEDLINE (1966 to October 2010), EMBASE (1988 to October 2010) and Web of Science (1975 to March 2010; (2) the Oxford Database of Perinatal Trials. We searched electronically abstracts from PAS from 2000 to 2010 and handsearched abstracts from ESPR from 2000 to 2009.

Selection criteria

All randomised, or quasi-randomised controlled trials, or randomised cross-over trials.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Results

We identified two studies for inclusion. Both studies were randomised cross-over trials performed in single centres. Both studies used the Premature Infant Pain Profile (PIPP) score as a measure of pain response. Different methods of evaluating PIPP scores are presented including the absolute PIPP score, a PIPP score > 10 or > 12 and an increase in PIPP greater than/or equal to 4 from the baseline value. There is a nonsignificant reduction in pain scores at one minute and a nonsignificant increase at five minutes post insertion of the speculum. PIPP score > 12 at one minute resulted in a statistically significant reduction in the number of patients who experienced pain (typical risk ratio (RR) 0.56, 95% CI 0.36 to 0.89; typical risk difference (RD) -0.23, 95% CI -0.39 to -0.86; number needed to treat to benefit (NNTB) 4). When pain was defined as an increase in PIPP > 4 there was a statistically significant reduction in the absolute number of patients who experienced pain at one minute (typical RR 0.70, 95% CI 0.52 to 0.94; typical RD -0.19, 95% CI -0.34 to -0.04; NNTB 5.3).

Authors' conclusions

The administration of topical proparacaine 30 seconds prior to the ophthalmological evaluation was associated with a reduction in pain scores especially at the time of speculum insertion. However, despite treatment, screening remains a painful procedure and the role of nonpharmacological and pharmacological intervention including different local anaesthetic agents should be ascertained in future randomised trials.

Plain language summary

Local anaesthetic eye drops for prevention of pain in preterm infants undergoing screening for retinopathy of prematurity

Infants born less than 1500 g or less than 32 weeks are at increased risk of retinopathy of prematurity, a potentially blinding eye condition, and so have routine ophthalmological assessment. This process is a recognised source of pain and discomfort for preterm infants. This review highlights that retinopathy of prematurity is a painful examination and that instillation of local anaesthetic eyedrops immediately prior to examination of the eye is associated with a reduction in pain scores, as assessed by validated pain scores. Ongoing research is required to determine the optimum local anaesthetic eyedrop and other potentially important methods of reducing pain, including swaddling, and sucrose.

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Background

Description of the condition

Retinopathy of prematurity (ROP), is one of the causes of childhood visual disability and blindness is largely preventable with appropriate screening and intervention. Retinopathy as a cause of complete or partial blindness decreased from 5% to 8% of all childhood visual disability prior to 1990 to 3% in 2000 (Rah 2003) in a UK based population study, despite an overall increased survival of high-risk neonates at lower gestational ages.Retinopathy of prematurity is a vasoproliferative disorder of the immature retina that can result in retinal detachment and blindness. Screening examinations are performed routinely in the neonatal intensive care unit in preterm infants at risk of this condition. Various screening guidelines exist. These are based on gestational age, birth weight and postnatal age criteria. The American Academy of Pediatrics and American Academy of Ophthalmology have recently issued a policy statement on screening examinations (AAP 2006). The recommendations include screening all infants less than 30 weeks or a birthweight less than 1500 g. The timing of subsequent examinations and screening intervals are based on findings at any particular ocular examination. In the United Kingdom the screening guideline states that all infants less than 1500 g or less than 32 weeks should have an eye examination performed, and an estimated 8200 newborns annually have at least one ocular examination performed (Haines 2002). Some extremely preterm newborns may have a number of ocular examinations performed. A recent consensus statement has identified ROP screening examination as a painful procedure (Anand 2001). The examination has been associated with an increase in pain as assessed by validated pain scores (Premature Infant Pain Profile, CRIES) (Belda 2004; Mitchell 2004). The procedure is also associated with other adverse consequences including episodes of desaturations, bradycardia, hypertension and prolonged crying times (Laws 1996; Rush 2004). Repeated painful procedures may lower the pain threshold and lead to hyperalgesia (Menon 1998).

Description of the intervention

The procedure involves instillation of mydriatics to dilate the pupils followed by the placement of an eyelid speculum and indirect ophthalmoscopy to visualise the retina. Scleral indentation is used to aid in visualising the peripheral retina. Different interventions have been employed to reduce the adverse effects of the screening examination. These include nonpharmacological interventions such as nesting and swaddling. Pharmacological agents include sucrose and local anaesthetic eye drops. Various anaesthetic eyedrops can be used including amethocaine, proxymetacaine, tetracaine and oxybuprocaine. These agents may differ in their onset, duration of action and possible side effects.

How the intervention might work

Drops are placed directly on the eye and provide a brief superficial block of sensory nerve impulses to the eye. The instillation of topical anaesthetics may provide local anaesthesia and thereby reduce the pain associated with the screening examination including pain associated with insertion of the eyelid speculum and pain associated with scleral indentation.

Why it is important to do this review

In the United Kingdom, an estimated 8200 newborns annually have at least one ocular examination performed (Haines 2002). Some extremely preterm newborns may have a number of ocular examinations performed. Therefore, many preterm babies have this painful but necessary procedure performed, often repeatedly. It is also associated with physiological instability and It is, therefore, important that approaches aimed at reducing pain and physiological instability associated with this examination are identified. The instillation of topical anaesthetics may be one such approach.

Objectives

To determine the effect of instillation of topical anaesthetic eye drops compared with placebo or no treatment, on pain as assessed by a validated pain profile score, in infants undergoing ROP screening.

We evaluated the following comparisons:

  1. any local anaesthetic eyedrop versus placebo or no treatment;
  2. any local anaesthetic eyedrop versus placebo or no treatment in extremely low birth weight infants (birth weight less than 1000 g);
  3. studies of any local anaesthetic eyedrop versus placebo or no treatment restricted to the first eye examination only.

We planned to do subgroup analyses of individual agents versus placebo.

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Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised, or quasi-randomised controlled trials, or randomised cross-over trials. We included randomised controlled cross-over trials.

Types of participants

Preterm infants less than 1500 g or less than 32 weeks undergoing ophthalmological screening for ROP.

Types of interventions

Trials using local anaesthetic eyedrops compared with placebo or no treatment for ROP eye examination. The anaesthetic eye drops could either be a single topical anaesthetic or a combination of anaesthetics. These should have been administered at least 30 seconds prior to the examination. The placebo had to be either 0.9% NaCl or no treatment (control group).

Types of outcome measures

Primary outcomes

The primary outcomes for this review were a measure of pain using a validated pain score. We considered pain scores could include, but not be limited to, PIPP (Premature Infant Pain Profile), CRIES (C-Crying, R-Requires increased oxygen administration, I-Increased vital signs, E-Expression, S-Sleeplessness), NPASS (Neonatal Pain, Agitation and Sedation Scale) amongst others. Standardised assessment of pain score had to be made at prespecified time points prior to the examination, during the examination and following the examination.

Secondary outcomes
  1. Duration of crying time (absolute time spent crying in minutes, percentage of time spent crying).
  2. Alteration of neurobehavioural activity: the number of movements (trunk, proximal and distal limb) identified over two-minute time periods prior to, during and after the examination.
  3. Physiological responses including the following.
    • Cardiovascular effects: (i) bradycardia (a) heart rate less than 100 beats per minute at any time during the examination (b) duration of time (seconds) heart rate less 100 beats per minute (ii) tachycardia (a) heart rate greater than > 180 beats per minute at any time during the examination (b) duration of time (seconds) heart rate > 180 beats per minute.
    • Respiratory side effects: (i) saturation less than 80% at any time during the examination (ii) lowest arterial saturation (iii) duration of time arterial saturation less than 80% and (iv) changes in PaO2 (partial pressure of oxygen in arterial blood) measured transcutaneously .
  4. Biochemical parameters including alteration in serum glucose and serum cortisol values.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group. This included a search of the Cochrane Neonatal Group register and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 10). We identified relevant studies by searching the following: (1) computerised bibliographic databases: MEDLINE (1966 to October 2010), EMBASE (1988 to October 2010) and Web of Science (1975 to October 2010; (2) the Oxford Database of Perinatal Trials.

We planned to include published and unpublished studies, or studies published only as abstracts if assessment of study quality was possible and if other criteria for inclusion were fulfilled. However, we only included published studies as we did not find any unpublished trials.

We searched electronically abstracts from PAS from 2000 to 2010 and handsearched abstracts from ESPR from 2000 to 2009. In addition, we searched for ongoing trials in the following databases at the following web sites: ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy. We did not apply any language restrictions. The search used the following MESH terms and keywords: topical anaesthetic eye drops, local anaesthetic eye drops, analgesia, pain, ROP, retinopathy of prematurity, limited to newborn and clinical trials dependent on service provider.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group. In particular, this included analysis of randomised cross-over trials.

Selection of studies

Both review authors independently performed trial searches, assessments of methodology and extraction of data with comparison and resolution of any differences found at each stage. We evaluated randomised cross-over trials for risk of carry-over effect and period effect, which could have implications for the overall results.

Data extraction and management

The two review authors independently extracted data from the included studies using standardised data extraction forms. Both review authors then compared the extracted data to enable them to correct errors and resolve any disagreements through discussion. We used Review Manager (RevMan 2008) software to enter all the data.

Assessment of risk of bias in included studies

We assessed methodology with regard to blinding of randomisation, intervention and outcome measurements as well as completeness of follow-up.

Both review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  1. Sequence generation (checking for possible selection bias)

    • For each included study, we assessed whether the method used to generate the allocation sequence was described in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as:
    • low risk of bias (any truly random process, for example, random number table; computer random number generator);
    • high risk of bias (any non random process, for example, odd or even date of birth; hospital or clinic record number);
    • unclear risk of bias.
  2. Allocation concealment (checking for possible selection bias)

    • For each included study, we assessed whether the method used to conceal the allocation sequence was described in sufficient detail and determined whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as:
    • low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear risk of bias.
  3. Blinding (checking for possible performance bias)

    • For each included study, we assessed the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We judged studies to be at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes. We assessed the methods as:
    • low risk, high risk or unclear risk of bias for participants;
    • low risk, high risk or unclear risk of bias for personnel;
    • low risk, high risk or unclear risk of bias for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

    • For each included study, we assessed the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total number of randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where additional information could be supplied by the trial authors, we planned to re-include missing data in the analyses. We assessed methods as:
    • low risk of bias;
    • high risk of bias;
    • unclear risk of bias.
  5. Selective reporting bias

    • For each included study, we investigated the possibility of selective outcome reporting bias. We assessed the methods as:
    • low risk of bias (where it was clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review were reported);
    • high risk of bias (where not all of the study’s pre-specified outcomes were reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that we would have expected to have been reported);
    • unclear risk of bias.
  6. Other sources of bias

    • For each included study, we described important concerns we had regarding other possible sources of bias. We assessed whether each study was free of other problems that could put it at risk of bias:
    • low risk of bias;
    • high risk of bias;
    • unclear risk of bias.
  7. Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings.

Measures of treatment effect

We extracted categorical data for each intervention group, and we calculated risk ratio (RR), relative risk reduction, risk difference (RD) and number needed to treat (NNT). We obtained mean and standard deviation (SD) for continuous data and performed the analysis using the mean difference (MD) when the units provided were compatible. For each measure of effect, we provided the 95% confidence intervals (CI).

Assessment of heterogeneity

We assessed heterogeneity using the I2 statistic. We planned to explore high levels of heterogeneity among the trials (exceeding 50%) and P value of < 0.1 by subgroup analysis.

Data synthesis

We considered cross-over trials suitable for evaluating the effects of local anaesthetic eye drops for the prevention of pain in preterm infants. The assessment of suitability was based on the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions(chapter 16.4) .Two types of potential biases may occur, a carry-over effect and a period effect. A carry-over effect (a type of period-by-intervention interaction) was not thought to be a problem with this intervention due to the short duration of action of the local anaesthetic eye drops and the rather long duration of time between screening. A possible period effect was of concern, but we felt this would be true for both the intervention and control group.

We incorporated meta-analysis of the data in Revman using the generic inverse-variance method. We applied the fixed-effect model for meta-analysis. Where different pain scores were used, we performed a standardised mean difference (SMD). The SMD describes the difference between the treatments in terms of units of SD.

Subgroup analysis and investigation of heterogeneity

We planned the following comparisons:

  1. any local anaesthetic eyedrop versus placebo or no treatment;
  2. any local anaesthetic eyedrops and sucrose versus sucrose alone;
  3. any local anaesthetic eyedrops and scleral depression versus scleral depression with placebo or no treatment;
  4. any local anaesthetic eyedrop versus placebo or no treatment in extremely low birth weight infants (birth weight less than 1000 g) ;
  5. studies of any local anaesthetic eyedrop versus placebo or no treatment restricted to the first eye examination only.

We planned to do a subgroups analysis of individual agents versus placebo for comparisons (1), (2), (3)

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Results

Description of studies

See table Characteristics of Included Studies and Characteristics of excluded studies.

We identified two studies for inclusion (Marsh 2005; Metha 2010). Both studies were randomised cross-over trials performed in single centres. Both studies utilised the PIPP score as a measure of pain response. Metha 2010 included infants less than 31 weeks and less than 1500 g. Marsh 2005 included infants less than 30 weeks, with no specific weight group categorisation. Metha 2010 provided gestational ages at which the two examinations were performed (33 weeks and 35 weeks corrected gestational age) whereas, Marsh 2005 presents data on the mean gestational age of the infants included, but does not provide details on the mean gestational age at which the examinations were performed. Instead they include the postnatal age at which the examination occurred (27 to 60 days). However, the gestational ages of those studied were similar in both groups, range 24 to 32 weeks in Marsh 2005 and 26 to 31 weeks in the Metha 2010 study suggesting that the study groups were similar.The proparacaine preparation used was proparacaine 0.5% and the placebo was normal saline for both studies (Marsh 2005; Metha 2010). Neither study included sucrose. Babies were swaddled in the Marsh 2005 trial, they were swaddled and non nutritive sucking was performed in the Metha 2010 trial. A single ophthalmologist performed the eye examination in the Marsh 2005 study; two ophthalmologists performed the examinations in the Metha 2010 study. Four study nurses were involved in scoring for the Marsh 2005 trial, a single nurse trained in PIPP score performed data collection for Metha 2010 study. Infants receiving sedation or analgesia were excluded in both studies. In the Mehta study infants on mechanical ventilation or CPAP, muscle relaxants or exogenous steroids were also excluded.

Risk of bias in included studies

We included only randomised controlled studies comparing proparacaine versus normal saline.

Randomisation:

In Marsh 2005, randomisation is not entirely clear but consisted of treatment allocation in groups of six based on the roll of a dice. Metha 2010 used a computer-generated randomisation program.The order of the two treatments was randomised using a permuted block allocation scheme, with random block sizes of two, four and six.

Blinding of treatment:

In both studies (Marsh 2005; Metha 2010), the eye drops were pre prepared by the hospital pharmacist in tuberculin syringes and these were labelled as study drug. The hospital pharmacist was the only person aware of group assignment. The sequence of treatment assignments was available only to the hospital research pharmacist (Marsh 2005). Eye drop bottles were prepared by the central pharmacy, and saline drops (balanced salt solution) were used as control for the proparacaine drops. Both types of drops were placed in identical bottles. In both studies, each infant got saline at one examination and proparacaine at the other exam.

Blinding of outcome assessment:

In Marsh 2005, the PIPP scores were evaluated by nurses trained in PIPP score evaluation and were unaware of group assignment. There was one nurse scoring the PIPP score who was unaware of group assignment in Metha 2010.

Effects of interventions

Primary Outcome

Pain scores: The PIPP score was used in both studies. Different methods of evaluating PIPP scores are presented. These include the absolute PIPP score, a PIPP score > 10 or > 12 and an increase in PIPP greater than/or equal to 4 from the baseline value. As the screening process may involve different techniques, we evaluated various time points.

PIPP score prior to examination (Outcome 1.1)

Marsh 2005 documented PIPP scores one minute prior to the examination. There was no difference between both groups one minute prior to the examination, 4.6 in the proparacaine group versus 4.8, MD -0.2 ( -2.07 to 1.67). In the Metha 2010 study, baseline PIPP scores prior to the exam were 3.625 (proparacaine) versus 3.825 in saline group.

Insertion of speculum (Outcome 1.2)

Marsh 2005 identified a significant reduction in PIPP scores from 13.5 to 11, MD -2.5 (-4.48 to -0.52) in the proparacaine group at insertion of the speculum.

One minute following insertion (Outcome 1.3)

At one minute post insertion there is a nonsignificant reduction in absolute PIPP scores from 10.5 to 9.3, MD -1.2 (-3.33 to 0.93) in the study by Marsh 2005. Metha 2010 identified a nonsignificant reduction in PIPP score at one minute of -1.35 (-3.00 to 0.3). When combined there is a nonsignificant reduction in pain scores of -1.29 (-2.60 to 0.01).

Five minutes post insertion (Outcome 1.4)

Marsh 2005 at five minutes post examination identified a nonsignificant reduction from 5.8 to 4.5, MD -1.3 (-3.00 to 0.4). Metha 2010 found a nonsignificant increase in PIPP score of 1.33 (-0.23 to 2.89). When both studies were combined there is a nonsignificant increase of 0.12 (-1.03 to 1.27).

PIPP score > 10 (Outcome 1.5)

One study evaluated a PIPP score > 10 (Marsh 2005) and found a nonsignificant reduction in the absolute number of patients who experienced pain, RR 0.75 (0.55 to 1.03).

PIPP score > 12 at one minute (Outcome 1.6)

Both studies recorded a PIPP score > 12 at one minute. Defining pain as a PIPP score > 12 resulted in a significant reduction in the absolute number of patients who experienced pain, RR 0.56 (0.36 to 0.89). The RD was -0.23 (-0.39 to -0.86). The NNTB was four to prevent one patient having an increase in a PIPP score > 12 at one minute post insertion of the speculum.

PIPP score > 12 at five minutes (Outome 1.7)

Metha 2010 recorded PIPP scores > 12 at five minutes and found no difference RR 1.00 (0.06 to 15.44).

Increase in PIPP > 4 at one minute (Outcome 1.8)

Both studies recorded an increase in PIPP scores > 4 at one minute. When pain was defined as an increase in PIPP > 4 there was a significant reduction in the absolute number of patients who experienced pain at one minute, RR 0.70, CI (0.52 to 0.94). The RD was -0.19 (-0.34 to -0.04). The NNTB was 5.3.

Increase in PIPP > 4 at five minutes (Outcome 1.9)

Both studies recorded an increase in PIPP > 4 at five minutes, the RR was 0.38 (0.10 to 1.53).

Secondary outcomes

None of the a priori secondary outcomes were available from either of the studies (Marsh 2005; Metha 2010).

Outcomes 2.1 and 2.2

We included two other secondary outcomes a posteriori, namely oxygen desaturation > 10% at speculum insertion and oxygen desaturation > 10% post examination. These were evaluated for the Marsh 2005 trial. The RR was 0.46 (0.21 to 0.99) in favour of proparacaine use. The RD was -0.32 (-0.60 to -0.04). The NNT was 3 to prevent one baby having a desaturation > 10%. There was a trend towards an increase in the number of desaturations >10% post examination, RR 2.00 (0.57 to 7.01).

All of the above results pertain to comparisons (a) and (c). Sucrose was not used in either trial; therefore, we did not perform comparison (b). The information was not available also for comparisons (d) and (e).

Subgroup analysis for individual eyedrops was not possible as only proparacaine was used in both studies (Marsh 2005; Metha 2010).

Discussion

We evaluated the efficacy of local anaesthetic eye drops in ROP screening. We identified two studies, both of which used proparacaine eye drops and both of which used the PIPP pain score. The administration of proparacaine local anaesthetic eye drops at least 30 seconds prior to the examination was associated with a significant reduction in PIPP score at insertion of the speculum (MD -2.5). There was a nonsignificant reduction in absolute PIPP scores at one minute (MD of -1.29) and essentially no change in PIPP scores at five minutes (MD of 0.12) post examination. It is probable that a MD of -1.29 in PIPP score does not translate into any clinical significance. This raises the question regarding the usefulness of pain scales in the newborn and whether these truly reflect pain responses. Slater et al evaluated the premature infant pain profile and the relationship between different components of the PIPP and cortical activity as assessed by near infrared spectroscopy. While they did identify a good correlation between PIPP scores and cortical activity, there were some babies who had cortical responses yet did not display a change in facial expression (Slater 2008). A recent review of the PIPP score found that it continues to be a reliable and valid measure of acute pain in infants and that there was substantial support for the use of the PIPP as an effective outcome measure in pain intervention studies in infants (Stevens 2010).

When we evaluated the number of patients with a PIPP score > 12 at one minute we found a significant RD of -0.23 (-0.39 to -0.86) with anaesthetic use (NNT = 5) and when evaluated by an increase in baseline PIPP by > 4 points we again identified a significant RD of -0.19 (-0.34 to -0.04) between the two groups. At five minutes there was no difference in pain as assessed by an absolute PIPP score, the number of patients with a PIPP score > 10, the absolute number of patients with a PIPP score > 12 and the absolute number who had an increase in PIPP score by > 4. The difference in efficacy at one and five minutes may be explained by the relatively lower pain scores at five minutes as compared with one minute. The duration of action of proparacaine may also explain this difference. However, even though the administration of proparacaine was associated with improved pain scores, these scores were still high as evaluated by a PIPP score > 12 (Stevens 1996) suggesting that alternative strategies for pain reduction are warranted.

These options not only include other non pharmacological and pharmacological methods, but also include different screening methods of clinical examination. One such option may be the use of the Retcam (Dhaliwal 2010). However, the only trial comparing Retcam with indirect ophthalmoscopy failed to identify any reduction in pain. Avoidance of speculum insertion and scleral indentation may be another option (Kirchner 2009). However, this method will fail to adequately visualise the peripheral retina resulting in failure to identify significant pathology. Kirchner 2009 assessed pain during ROP examination both with and without the use of a lid speculum and scleral indentation. They found that examination without a speculum and scleral indentation resulted in less pain, as evaluated by the neonatal infant pain score (NIPS). However, concerns were raised about the ability to identify potentially serious and possibly blinding ROP involving the peripheral retina without the aid of a lid speculum and use of scleral indentation during examination.

Two potential problems encountered in interpreting randomised cross-over trials are the carry-over effect and the period effect. We felt that the carry-over effect is not likely due to the short duration of action of the local anaesthetic eye drops and the rather long duration of time ('washout period') between screening. The second and more difficult aspect to address is the possibility of a period effect. We felt a priori the period effect was difficult to foresee and could modify the effect in either direction. One concern we had a priori was that babies who had screening performed would in fact have higher PIP scores on the second examination because of potentially anticipating the effect of the examination, as has been identified in previous studies where hyperalgesia was identified following repetitive heel lance procedures (Taddio 2002). However, this finding was not replicated in the study by Metha 2010 where the follow-up pain scores were lower in the follow-up examination. This may be a reflection of a lower score attributed to advanced gestational age as the newborn is a number of weeks older when the second examination is performed. We felt that the potential period effect may not be serious as it applied equally to both treatments groups.

Other local anaesthetic eyedrop preparations may provide greater pain relief than the proparacaine preparation. However, the efficacy of other local anaesthetic eyedrops needs further evaluation. The use of sucrose has been shown to reduce pain scores in many procedures in neonatal care, including ROP screening (Sun 2010). This review also addressed the role of topical anaesthesia for ROP screening and included two studies (Saunders 1993; Marsh 2005). We excluded the study by Saunders 1993 as they did not utilise a validated pain profile to assess pain responses, instead evaluating a number of physiological parameters and also crying time duration. We included the study by Metha 2010, which had not been included in the Sun 2010 review. Nonpharmacological methods such as nonnutritive sucking and swaddling are also beneficial. Both methods were utilised in the Metha 2010 study and swaddling alone in the Marsh 2005 trial. Neither of these studies used sucrose analgesia.

The contribution of screening guidelines has been central to the reduction in visual impairment as a result of ROP. Now all babies less than 1500 g have at least one ophthalmological evaluation performed, and in some cases many examinations are needed. The examination is recognised to be painful. The administration of proparacaine eyedrops at least 30 seconds prior to the examination was associated with a reduction in pain scores, but pain was not eliminated. Future studies should address the role of both nonpharmacological and pharmacological interventions, including different local anaesthetic agents, to reduce pain associated with this common procedure.

Authors' conclusions

Implications for practice

Retinopathy of prematurity screening is routinely performed in the neonatal intensive care unit. The administration of topical proparacaine 30 seconds prior to the ophthalmological evaluation was associated with a reduction in pain scores and topical anaesthesia should be routinely administered prior to eye exams.

Implications for research

While the administration of topical anaesthesia was associated with an improvement in pain scores compared with placebo, screening remains a painful procedure. A multi-modal approach to eliminating pain is required. Future studies should focus on alternative methods of assessment including use of the Retcam, avoidance of speculum insertion and avoidance of scleral indentation. The role of nonpharmacological and pharmacological intervention including different local anaesthetic agents should be ascertained.

Acknowledgements

  • None noted.

Contributions of authors

Dr. Dempsey devised the concept of performing this review. Both review authors were involved in preparing the original protocol. Both reviewers performed individual searches.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Marsh 2005

Methods

Randomised cross-over trial.

Participants

Neonates born at less than/or equal to 30 weeks' gestation and expected to have at least 2 examinations for ROP.

Interventions

Proparacaine HCl ophthalmic solution 0.5% or NaCl 0.9% (saline) eye drops.

Outcomes

Pain assessed by PIPP.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Groups of 6 based on a roll of a dice.

Allocation concealment (selection bias) Low risk

Hospital pharmacist only.

Blinding (performance bias and detection bias) Low risk

All individuals involved in direct care were blinded to treatment.

Incomplete outcome data (attrition bias) Low risk

Stopped after 22 patients; planned 24.

Selective reporting (reporting bias) Low risk

Metha 2010

Methods

Randomised cross-over trial.

Participants

Neonates born at < 31 weeks' gestation and expected to have at least 2 examinations for ROP.

Interventions

Proparacaine HCl ophthalmic solution 0.5% or NaCl 0.9% (saline) eye drops.

Outcomes

Pain assessed by PIPP.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated block randomisation.

Allocation concealment (selection bias) Low risk

Only pharmacist was aware of allocation.

Blinding (performance bias and detection bias) Low risk

Neither physician nor nurse recording score was aware of treatment group.

Incomplete outcome data (attrition bias) Low risk

10 patients did not have both examinations.

Selective reporting (reporting bias) Low risk

PIPP: Premature Infant Pain Profile
ROP: retinopathy of prematurity

Characteristics of excluded studies

Saunders 1993

Reason for exclusion

While this was a randomised controlled trial, only 42 of the 55 enrolled patients were analysed. The study evaluated infant stress and corneal clarity. No validated pain scale was used for the study.

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

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References to studies

Included studies

Marsh 2005

Marsh VA, Young WO, Dunaway KK, Kissling GE, Carlos RQ, Jones SM, et al. Efficacy of topical anesthetics to reduce pain in premature infants during eye examinations for retinopathy of prematurity. Annals of Pharmacotherapy 2005;39(5):829-33.

Metha 2010

Mehta M, Mansfield T, Vanderveen DK. Effect of topical anaesthesia and age on pain scores during retinopathy of prematurity screening. Journal of Perinatology 2010;30(11):731-5.

Excluded studies

Saunders 1993

Saunders RA, Miller KW, Hunt HH. Topical anaesthesia during infant eye examinations: does it reduce stress? Annals of Ophthalmology 1993;25(12):435-9.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

AAP 2006

Section on Ophthalmology American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2006;117(2):572-6.

Anand 2001

Anand KJ; International Evidence- Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Archives of Pediatrics and Adolescent Medicine 2001;155(2):173-80.

Belda 2004

Belda S, Pallás CR, De la Cruz J, Tejada P. Screening for retinopathy of prematurity: is it painful? Biology of the Neonate 2004;86(3):195-200.

Dhaliwal 2010

Dhaliwal CA, Wright E, McIntosh N, Dhaliwal K, Fleck BW. Pain in neonates during screening for retinopathy of prematurity using binocular indirect ophthalmoscopy and wide field digital retinal imaging: a randomised comparison. Archives of Disease in Childhood. Fetal and Neonatal edition 2010;95(2):F146-8.

Haines 2002

Haines L, Fielder AR, Scrivener R, Wilkinson AR. Retinopathy in the UK I: The organisation of services for screening and treatment. Eye 2002;16(3):33-8.

Higgins 2011

Higgins JPT, Green S, editors (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Kirchner 2009

Kirchner L, Jeitler V, Pollack A, Mullner-Eidenbock A, Weinzettel R, Kraschl R, et al. Must screening examinations for retinopathy of prematurity necessarily be painful? Retina 2009;29(5):586-91.

Laws 1996

Laws DE, Morton C, Weindling M, Clark D. Systemic effects of screening for retinopathy of prematurity. British Journal of Ophthalmology 1996;80(5):425-8.

Menon 1998

Menon G, Anand KJ, McIntosh N. Practical approach to analgesia and sedation in the neonatal intensive care unit. Seminars in Perinatology 1998;22(5):417-24.

Mitchell 2004

Mitchell A, Stevens B, Mungan N, Johnson W, Lobert S, Boss B. Analgesic effects of oral sucrose and pacifier during eye examinations for retinopathy of prematurity. Pain Management Nursing 2004;5(4):160-8.

Rah 2003

Rahi JS, Cable N; British Childhood Visual Impairment Study Group. Severe visual impairment and blindness in children in the UK. Lancet 2003;362(9393):1359-65.

Rush 2004

Rush R, Rush S, Nicolau J, Chapman K, Naqvi M. Systemic manifestations in response to mydriasis and physical examination during screening for retinopathy of prematurity. Retina 2004;24(2):242-5.

Slater 2008

Slater R, Cantarella A, Franck L, Meek J, Fitzgerald M. How well do clinical pain assessment tools reflect pain in infants? PLoS Medicine 2008;5(6):e129.

Stevens 1996

Stevens B, Johnston C, Petryshen P, Taddio A. Premature Infant Pain Profile: development and initial validation. The Clinical Journal of Pain 1996;12(1):13-22.

Stevens 2010

Stevens B, Johnston C, Taddio A, Gibbins S, Yamada J. The premature infant pain profile: evaluation 13 years after development. The Clinical Journal of Pain 2010;26(9):813-20.

Sun 2010

Sun X, Lemyre B, Barrowman N, O'Connor M. Pain management during eye examinations for retinopathy of prematurity in preterm infants: a systematic review. Acta Paediatrica 2010;99(3):329-34.

Taddio 2002

Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002;288(7):857-61.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

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Data and analyses

1 PIPP scores

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 PIPP score prior to examination 1 44 Mean Difference (IV, Fixed, 95% CI) -0.20 [-2.07, 1.67]
1.2 PIPP score at insertion of wire 1 44 Mean Difference (IV, Fixed, 95% CI) -2.50 [-4.48, -0.52]
1.3 PIPP score 1 minute following examination 2 124 Mean Difference (IV, Fixed, 95% CI) -1.29 [-2.60, 0.01]
1.4 PIPP score 5 minutes following examination 2 124 Mean Difference (IV, Fixed, 95% CI) 0.12 [-1.03, 1.27]
1.5 Significant pain response PIPP > 10 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.55, 1.03]
1.6 Significant pain response PIPP > 12 at 1 minute 2 124 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.36, 0.89]
1.7 Significant pain response PIPP > 12 at 5 minutes 1 80 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.06, 15.44]
1.8 Increase in PIPP score > 4 at 1 minute 2 124 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.52, 0.94]
1.9 Increase in PIPP score > 4 at 5 minutes 2 124 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.53]

2 Oxygen desaturation >10%

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Oxygen desaturation >10% at speculum insertion 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.21, 0.99]
2.2 Oxygen desaturation > 10% post examination 1 44 Risk Ratio (M-H, Fixed, 95% CI) 2.00 [0.57, 7.01]

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Sources of support

Internal sources

  • No sources of support provided.

External sources

  • Health Research Board (HRB) Ireland, Ireland
  • The HRB provided Dr. Dempsey with salary support to perform this review.

This review is published as a Cochrane review in The Cochrane Library, Issue 9, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.