Abstract
Introduction
Preterm or ill neonates may undergo 1 to 21 heel punctures or venepunctures per day. These punctures are likely to be painful. Heel punctures comprise 61% to 87% and venepunctures comprise 8% to 13% of the invasive procedures performed on ill infants. Analgesics are rarely given specifically for blood sampling procedures, but 5% to 19% of infants receive analgesia for other indications.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to reduce pain-related distress and morbidity during venepuncture in preterm or term babies aged under 12 months in a neonatal unit? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: oral sweet solutions; pacifiers; and topical anaesthetics (lidocaine–prilocaine cream, tetracaine).
Key Points
Blood samples are usually taken from infants via heel punctures or venepuncture.
Both procedures are likely to be painful, especially in younger infants, but analgesia is rarely given.
Infants who have already experienced pain during heel punctures seem more likely to show signs of pain during later blood sampling than infants not experiencing such pain initially.
High concentrations of oral sugar solutions are likely to reduce pain, either given together with a pacifier, or directly into the mouth before blood sampling.
Oral 24% to 30% sucrose and 25% to 30% glucose solutions reduce signs of pain, especially crying, compared with water or no treatment in term and preterm infants. Oral 30% dextrose solution may also be effective.
Lower concentrations of sugar solutions (10–12%) do not seem to be effective at reducing pain.
Long-term use of oral sugar solutions has theoretical risks of hyperglycaemia and necrotising enterocolitis.
Pacifiers without sugar solutions may also reduce pain responses compared with no treatment.
Transient choking and oxygen desaturation may occur with the use of pacifiers, or after giving oral sugar solutions directly into the mouth.
Topical anaesthetics may reduce pain responses to blood sampling compared with placebo.
Topical lidocaine–prilocaine cream and tetracaine gel or patches reduced signs of pain in most studies of term and preterm infants.
Adverse effects tend to be minor and transient, but systemic absorption may occur in young infants, which increases the risk of methaemoglobinaemia.
We do not know whether oral sugars are more or less effective than topical anaesthetics in reducing pain from blood sampling.
Clinical context
About this condition
Definition
Methods of sampling blood in infants include heel puncture, venepuncture, and arterial puncture. Venepuncture involves aspirating blood through a needle from a peripheral vein. Heel puncture involves lancing the lateral aspect of the infant's heel, squeezing the heel, and collecting the pooled capillary blood. Heel puncture and arterial blood sampling are not discussed in this review. For this review, we included premature and term infants up to 12 months in a hospital setting.
Incidence/ Prevalence
Preterm or ill neonates may undergo from 1 to 21 heel punctures or venepunctures per day.[1] [2] These punctures are likely to be painful. Heel punctures comprise 61% to 87% and venepunctures comprise 8% to 13% of the invasive procedures performed on ill infants. Analgesics are rarely given specifically for blood sampling procedures, but 5% to 19% of infants receive analgesia for other indications.[1] [2] In one study, comfort measures were provided during 63% of venepunctures and 75% of heel punctures.[2]
Aetiology/ Risk factors
Blood sampling in infants can be difficult to perform, particularly in preterm or ill infants. Young infants may have increased sensitivity and prolonged response to pain compared with older age groups.[3] Factors that may affect the infant's pain responses include corrected gestational age, previous pain experience, and procedural technique.
Prognosis
Pain caused by blood sampling is associated with acute behavioural and physiological deterioration.[3] Experience of pain during heel puncture seems to heighten pain responses during subsequent blood sampling.[4] Other adverse effects of blood sampling include bleeding, bruising, haematoma, and infection.
Aims of intervention
To obtain an adequate blood sample by venepuncture, with minimal pain-related stress and morbidity for the infant and minimal adverse effects of treatments.
Outcomes
The assessment of pain is difficult in preverbal children. We found no easily administered, widely accepted assessment of pain in infants. Where available, we have analysed the proportion of infants crying, or the duration of crying. Other pain-related responses measured in the studies included facial expressions (the number of specific expressions, or the duration of those expressions), heart rate, and transcutaneous oxygen saturation levels. Studies used composite scales composed of behavioural and cardiorespiratory signs of pain-related distress, only some of which have been validated, such as the Premature Infant Pain Profile scale. We did not pool differences in pain-related responses or for different pain scales. Pain assessment methods varied in the RCTs, and a validated scale was not always used. Some measurements (e.g., facial expression) are difficult to score objectively. In many RCTs, blinding was not possible (e.g., where pacifiers were used).
Methods
Clinical Evidence search and appraisal July 2007, and additional hand searches by contributors. The following databases were used to identify studies for this review: Medline 1966 to July 2007, Embase 1980 to July 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, Issue 2, 2007. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as “open”, “open label”, or not at least single-blinded where blinding was possible (blinding not possible where pacifiers were used). In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Blood sampling in infants (reducing pain and morbidity).
| Important outcomes | Response to pain | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions to reduce pain-related distress and morbidity during venepuncture in preterm or term babies under 12 months in a neonatal unit? | |||||||||
| 3 (109) | Response to pain | Oral sucrose versus oral water | 4 | –1 | +1 | –1 | 0 | Moderate | Quality point deducted for sparse data. Consistency point added for dose response. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (50) | Response to pain | Oral sucrose plus pacifiers versus pacifiers alone | 4 | –1 | 0 | –1 | 0 | Low | Quality points deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 4 (228) | Response to pain | Oral glucose versus water or no glucose | 4 | 0 | 0 | –1 | 0 | Moderate | Consistency point deducted for conflicting results using different measures of outcomes, but added for dose response. Directness points deducted for co-intervention in one RCT |
| 1 (less than 51) | Response to pain | Oral sucrose versus topical anaesthetics | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (201) | Response to pain | Oral glucose versus topical anaesthetics | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for uncertainty about method of assessing outcome |
| 1 (52) | Response to pain | Oral dextrose versus water | 2 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (less than 60) | Response to pain | Different concentrations of oral glucose versus each other | 4 | –1 | 1 | –1 | 0 | Moderate | Quality point deducted for sparse data. Directness point deducted for not using a validated method of assessing outcomes. Consistency point added for dose response |
| 1 (50) | Response to pain | Oral sucrose versus oral glucose | 4 | –2 | 0 | –1 | 0 | Unset | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (50) | Response to pain | Pacifiers versus oral water | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (50) | Response to pain | Pacifiers versus oral sucrose | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (50) | Response to pain | Pacifiers versus oral glucose | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (50) | Response to pain | Pacifiers plus oral sucrose versus oral water | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 1 (60) | Response to pain | Lidocaine–prilocaine cream versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about method of assessing outcome |
| 4 (249) | Response to pain | Tetracaine gel or patches versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for uncertainty about method of assessing outcome |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Pacifier
A device with a teat that a baby sucks on for comfort. Some pacifiers can deliver a liquid to the baby. Also known as a “dummy”, “soother”, or “plug” in some countries.
- Premature Infant Pain Profile (PIPP)
A 7-item composite scale that scores various behavioural and cardiorespiratory pain responses over 30 seconds after the painful response, each from 0 to 3 (with a maximum score of 21).
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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