بررسی عملکرد داروهای بی‌حسی موضعی در تسکین درد ناشی از سوزن در نوزادان تازه متولد شده
چکیده
پیشینه
نوزادان تازه متولد شده و بستری در بیمارستان اغلب تحت پروسیجرهای تهاجمی دردناکی قرار می‌گیرند که شامل وارد کردن سوزن به پوست و دیگر بافت‌ها می‌شود. یکی از مداخلاتی که می‌توان پیش از پروسیجر قرار دادن سوزن استفاده کرد، بی‌حسی موضعی است.
اهداف
ارزیابی اثربخشی و بی‌خطری (safety) بی‌حس کننده‌های موضعی مانند آمتوکائین (amethocaine) و EMLA در نوزادان ترم یا نارس تازه متولد شده که نیاز به یک پروسیجر تهاجمی شامل سوراخ کردن پوست و دیگر بافت‌ها با سوزن دارند.
روش‌های جست‌وجو
پایگاه مرکزی ثبت کارآزمایی‌های کنترل شده کاکرین (CENTRAL)؛ PubMed؛ Embase و CINAHL را تا 15 می 2016؛ مرورهای پیشین شامل ارجاعات متقابل (cross‐references)، چکیده مقالات، و خلاصه مقالات کنفرانس‌ها را جست‌وجو کردیم. با کارشناسان در این زمینه تماس گرفتیم. با نویسندگان مطالعه هم مستقیما تماس گرفتیم تا داده‌های بیشتری را به دست آوریم. هیچ محدودیتی را از نظر زبان نگارش مقاله اعمال نکردیم.
معیارهای انتخاب
کارآزمایی‌های تصادفی‌سازی، شبه‐تصادفی‌سازی شده و کنترل شده، و کارآزمایی‌های خوشه‌ای (cluster) تصادفی‌سازی شده و متقاطع (cross‐over) که بی‌حس کننده‌های موضعی آمتوکائین و مخلوط یوتکتیک بی‌حس کننده‌های موضعی (eutectic mixture of local anaesthetics; EMLA) را از نظر اثربخشی و بی‌خطری بی‌حس کننده در نوزادان ترم یا نارس تازه متولد شده مقایسه کردند که نیاز به پروسیجر تهاجمی پونکسیون پوست و دیگر بافت‌ها با سوزن داشتند.
گردآوری و تجزیه‌وتحلیل داده‌ها
از گزارش‌های به دست آمده از کارآزمایی‌های بالینی، داده‌های مربوط به پیامدهای بالینی را از جمله درد، تعداد نوزادان با سطح متاموگلوبین (methaemoglobin) %5 و بالاتر، تعداد تلاش‌ها برای وارد کردن سوزن پیش از پروسیجر موفقیت‌آمیز مرتبط با سوزن، گریه، زمان صرف شده برای تکمیل پروسیجر، اپیزودهای آپنه، اپیزودهای برادی‌کاردی (bradycardia)، اپیزودهای عدم اشباع اکسیژن (oxygen desaturation)، ناتوانی تکامل سیستم عصبی و دیگر عوارض جانبی، استخراج کردیم.
نتایج اصلی
هشت کارآزمایی تصادفی‌سازی و کنترل شده کوچک، معیارهای ورود را داشتند (n = 506). این مطالعات EMLA و دارونما (placebo) یا آمتوکائین و دارونما را با هم مقایسه کردند. هیچ مطالعه‌ای EMLA و آمتوکائین را بررسی نکرد. به دلیل معیارهای پیامد و روش‌های گزارش‌دهی متفاوت، نتوانستیم پیامد درد را متاآنالیز کنیم. برای EMLA، دو مطالعه مجزا، کاهش قابل‌توجه درد را حین پونکسیون کمری و سوراخ کردن ورید (venipuncture) در مقایسه با دارونما گزارش کردند. سه مطالعه هیچ تفاوت آماری را بین گروه‌ها در طول خون‌گیری از پاشنه پا مشاهده نکردند. برای آمتوکائین در مقایسه با دارونما، سه مطالعه کاهش قابل‌توجه درد را حین سوراخ کردن ورید و یک مطالعه کاهش قابل‌توجه درد را حین کانولاسیون گزارش کردند. یک مطالعه هیچ تفاوت آماری را بین دو گروه در طول تزریق عضلانی گزارش نکرد.
یک مطالعه هیچ تفاوت آماری را بین EMLA و گروه دارونما برای سوراخ کردن موفقیت‌آمیز ورید در اولین تلاش گزارش نکرد. یک مطالعه به‌طور مشابهی، هیچ تفاوتی را با اهمیت آماری بین آمتوکائین و گروه دارونما برای کانولاسیون موفق در اولین تلاش نشان نداد.
خطر قرمزی، تورم یا سفید شدن موضعی با EMLA به‌طور قابل‌توجهی بیشتر بود (خطر نسبی (RR) معمول: 1.65؛ 95% فاصله اطمینان (CI): 1.24 تا 2.19؛ تفاوت خطر (RD) معمول: 0.17؛ 95% CI؛ 0.09 تا 0.26؛ n = 272؛ تعداد افراد مورد نیاز جهت درمان تا بروز یک پیامد مضر بیشتر (number needed to treat for an additional harmful outcome; NNTH): 6؛ 95% CI؛ 4 تا 11؛ I 2 = 92% نشان‌دهنده ناهمگونی قابل‌توجه است) اگرچه برای آمتوکائین خطر این عوارض بالا نبود (RR معمول: 2.11؛ 95% CI؛ 0.72 تا 6.16؛ RD معمول: 0.05؛ 95% CI؛ 0.02‐ تا 0.11؛ n = 221). این واکنش‌های پوستی موضعی برای EMLA و آمتوکائین کوتاه‌مدت بودند. دو مطالعه متاموگلوبینمی (methaemoglobinaemia) را با یک بار استفاده از EMLA گزارش نکردند. کیفیت شواهد مربوط به پیامدها بر اساس ارزیابی با رویکرد درجه‌بندی توصیه، ارزیابی، توسعه و ارزشیابی (Grading of Recommendations Assessment, Development and Evaluation; GRADE)، در سطح پائین تا متوسط بود.
نتیجه‌گیری‌های نویسندگان
به‌طور کلی، همه کارآزمایی‌ها کوچک بودند، و تاثیرات بالینی نامطمئنی داشتند. شواهد مربوط به اثربخشی یا بی‌خطری مداخلات مورد مطالعه، برای حمایت از توصیه‌های بالینی کافی نیست. در مورد تاثیرات طولانی‌مدت داروهای بی‌حس کننده موضعی در نوزادان تازه متولد شده، هیچ ارزیابی‌ای انجام نشده است.
انجام مطالعاتی با کیفیت بالا برای ارزیابی اثربخشی و بی‌خطری داروهای بی‌حس کننده موضعی مانند آمتوکائین و EMLA در تسکین درد ناشی از سوزن در نوزادان ترم یا نارس تازه متولد شده مورد نیاز است. این مطالعات باید با هدف تعیین اثربخشی این بی‌حس کننده‌های موضعی و بر گروه‌های همگون از نوزادان برای سن بارداری انجام شوند. در حالی که در مطالعاتی که متاموگلوبین را گزارش کردند، متاموگلوبینمی وجود نداشت، اثربخشی و بی‌خطری EMLA، به‌ویژه در نوزادان بسیار نارس، و برای استفاده مکرر، نیاز به ارزیابی بیشتر در مطالعات آینده دارد.
PICO
خلاصه به زبان ساده
بررسی عملکرد داروهای بی‌حسی موضعی در تسکین درد ناشی از سوزن در نوزادان تازه متولد شده
عنوان مبسوط
داروهای بی‌حسی موضعی برای نوزادان تازه متولد شده‌ای که به پروسیجر مرتبط با سوزن نیاز دارند.
سوال مطالعه مروری
آیا استفاده از بی‌حس کننده موضعی روی پوست موجب کاهش درد در نوزادان تازه متولد شده‌ای می‌شود که برای پونکسیون پوست نیاز به پروسیجر دارند؟
پیشینه
برخی از نوزادان تازه متولد شده نیاز به یک پروسیجر دردناک دارند که شامل سوراخ کردن پوست از جمله خون‌گیری از پاشنه پا و سوراخ کردن ورید (venepuncture) (پونکسیون ورید برای گرفتن نمونه خون یا تزریق دارو) یا تزریق عضلانی است. پروسیجرهای دردناک می‌توانند برای نوزادان تازه متولد شده استرس‌زا بوده و مشاهده آنها برای والدین ناراحت کننده است. یکی از مداخلاتی که می‌توان پیش از پروسیجر قرار دادن سوزن استفاده کرد، بی‌حسی موضعی برای بی‌حس کردن پوست است.
ویژگی‌های مطالعه
هشت کارآزمایی بالینی معیارهای ورود ما را داشتند که 506 نوزاد تازه به دنیا آمده را وارد کردند.
نتایج و کیفیت شواهد
این مرور از کارآزمایی‌ها نشان داد که به‌طور کلی شواهدی کافی با کیفیت خوب وجود ندارد که بر اساس آنها بگوییم استفاده از بی‌حس کننده‌های موضعی روی پوست به تسکین درد ناشی از سوزن در نوزادان تازه متولد شده کمک می‌کند یا خیر. انجام کارآزمایی‌های بالینی در مقیاس بزرگ و با طراحی خوب مورد نیاز است.
Authors' conclusions
Summary of findings
| EMLA compared with placebo for needle‐related pain in newborn infants | ||||||
| Patient or population: preterm infants Settings: NICU Intervention: EMLA Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with EMLA | |||||
| Pain using PIPP score | The mean pain using PIPP score was 0 | MD 0.27 higher (1.45 lower to 1.99 higher) | ‐ | 38 (1 study) | ⊕⊕⊝⊝ | Single study |
| Pain using NIPS score | The mean pain using NIPS score was 0 | MD 0.27 higher (0.75 lower to 1.29 higher) | ‐ | 38 (1 study) | ⊕⊕⊝⊝ | Single study |
| Successful venepuncture first attempt | Study population | RR 0.98 (0.93 to 1.03) | 111 (1 study) | ⊕⊕⊝⊝ | Single study | |
| 1000 per 1000 | 980 per 1000 | |||||
| Adverse effects (short‐lasting skin reactions) | Study population | RR 1.65 (1.24 to 2.19) | 272 (3 studies) | ⊕⊕⊝⊝ | High heterogeneity | |
| 269 per 1000 | 444 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EMLA: eutectic mixture of local anaesthetics; MD: mean difference; NICU: neonatal intensive care unit; NIPS: Neonatal Infant Pain Scale; PIPP: Premature Infant Pain Profile; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| Amethocaine compared with placebo for needle‐related pain | ||||||
| Patient or population: preterm infants Settings: NICU Intervention: amethocaine Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with amethocaine | |||||
| Pain | The mean pain was 0 | MD 5 lower (17.34 lower to 7.34 higher) | ‐ | 110 (1 study) | ⊕⊕⊝⊝ | Single small study |
| Successful cannulation first attempt | Study population | RR 1.21 (0.82 to 1.81) | 39 (1 study) | ⊕⊝⊝⊝ Very low | Single small study, risk of selection bias | |
| 650 per 1000 | 787 per 1000 | |||||
| Adverse effects (short‐lasting skin reactions) | Study population | Not estimable | 181 (3 studies) | ⊕⊕⊕⊝ | Risk of selection bias | |
| 43 per 1000 | 0 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EMLA: eutectic mixture of local anaesthetics; MD: mean difference; NICU: neonatal intensive care unit; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
Background
Description of the condition
Hospitalised newborn neonates frequently undergo painful invasive procedures that involve penetration of the skin and other tissues by a needle, often multiple times per procedure. These procedures include needle‐related painful procedures associated with venepuncture, arterial puncture, heel lancing, lumbar puncture, supra‐pubic aspiration of urine, percutaneous venous catheter placement and intramuscular injection. Compared with adults, both preterm and term infants display a hypersensitivity to sensory stimuli (Fitzgerald 2001). Neonates have difficulty communicating the experience of pain to those managing it. Anatomical maturation of nociceptive pathways is complete by mid‐to‐late second trimester and painful stimuli result in immediate hormonal, physiological and behavioural responses (Anand 1987). Prior pain experience in term infants increases subsequent behavioural responses to pain, whereas preterm neonates may have a diminished subsequent behavioural response, but not necessarily altered experience of pain (Whitfield 2000). Ongoing pain and distress may also have long‐term consequences for brain development and behaviour (Anand 2000). Importantly too, several studies have highlighted that one of the most salient sources of stress for parents of hospitalised infants is the witnessing of painful procedures inflicted upon their infant (Foster 2008; Franck 2004).
Assessment of pain and the efficacy of treatment modalities is challenging in non‐verbal neonates. Multi‐dimensional pain measurement tools have been developed including the Neonatal Infant Pain Scale (NIPS) (Lawrence 1993) and the Premature Infant Pain Profile (PIPP) (Stevens 1996). Physiological and behavioural responses to painful stimuli can be minimised and even ameliorated by appropriate analgesia (Anand 2001; Bell 1994).
One intervention that can be used prior to a needle insertion procedure is application of a topical local anaesthetic. Topical anaesthetics are effective in minimising the pain of venepuncture and intravenous cannulation in children (Lander 1996; Lawson 1995; Manner 1987; Maunuksela 1986; Woolfson 1990). One Cochrane Review comparing EMLA (eutectic mixture of local anaesthetics) and amethocaine in children concluded that although EMLA is an effective topical anaesthetic, amethocaine is superior in preventing pain associated with needle procedures (Lander 2006).
Description of the intervention
EMLA and amethocaine are the two most widely used percutaneous topical local anaesthetics for use on intact skin. EMLA is a water‐based cream and each gram contains lidocaine 25 mg (2.5%) and prilocaine 25 mg (2.5%). Lidocaine and prilocaine are amide‐type local anaesthetic agents (AstraZeneca 2008). Prior to the procedure, EMLA is applied using an occlusive dressing to cover the cream and numbing of the skin usually occurs approximately one hour after application and lasts for one to two hours after removal of the cream. Approximately 1 g is sufficient to cover up to 10 cm2 (approximately 3 x 3 cm) of skin (AstraZeneca 2008).
One more recently introduced alternative to EMLA is amethocaine. Amethocaine belongs to the family of local, aminoester‐type anaesthetics and is a white opalescent gel with each gram containing tetracaine base 40 mg (4% amethocaine) (Smith & Nephew 2012). As with EMLA, amethocaine gel is applied to the site and sealed with an occlusive dressing. Amethocaine reportedly has a faster anaesthetic effect than EMLA, and can usually be achieved following a 30‐minute application time for venepuncture, and a 45‐minute application time for venous cannulation. Amethocaine gel should be removed with a gauze swab, and the site prepared with an antiseptic wipe prior to the procedure. Anaesthesia is reported to also last longer than EMLA, remaining for four to six hours in most people after a single application (Smith & Nephew 2012). Approximately 1 g is sufficient to cover and anaesthetise an area of up to 30 cm2 (6 cm x 5 cm) of skin. Smaller areas of anaesthetised skin may be adequate in infants and small children (Smith & Nephew 2012). Numbing of the skin can take between 45 and 60 minutes, an unsuccessful attempt for venous cannulation may require a new application of topical anaesthetic at another site, and thus a further delay in attempting to cannulate until numbing of the skin occurs.
Although the adverse effects of EMLA are usually mild and include transient local skin reactions, potential life‐threatening complications have been reported in infants. Compared with children and adults, infants are believed to be at increased risk of methaemoglobinaemia (MetHb) because they have a deficiency in the enzyme that reduces MetHb, nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (Camp 2007; Nilsson 1990; Taddio 1998; Weinberger 2001). The higher body surface area to weight ratio in infants compared with adults may result in higher systemic exposure. In addition, preterm infants may be at even greater risk because immaturity of their skin may enhance drug absorption of drugs (Taddio 1999). As methaemoglobin levels increase, oxygen delivery to tissues is impaired and cellular hypoxia develops (Stephens 2007; Wright 1999; Zaky 2009). Normal physiological levels of methaemoglobin are 0% to 2% but levels less than 5% may be acceptable upon discussion with the medical team. Methaemoglobin levels of 5% and above are generally regarded as clinically significant. The half‐life of methaemoglobin is 55 minutes (Coleman 1996; Sashdeva 2003). MetHb has been shown to inhibit surfactant activity directly (Weinberger 2001). Infants with severe MetHb will exhibit signs such as cyanosis, respiratory distress/increasing ventilator requirements and lethargy (Weinberger 2001).
One Cochrane Review compared EMLA and a range of pain‐relieving measures during circumcision (Brady‐Fryer 2004). One Cochrane Review compared EMLA with placebo or no treatment for boys undergoing circumcision (Taddio 1999). Both reviews found that a single dose of EMLA was safe and did not cause MetHb; however, there were insufficient data to assess the risk of MetHb with multiple doses (Brady‐Fryer 2004; Taddio 1999). One non‐Cochrane systematic review found EMLA to be effective during circumcision, venepuncture, arterial puncture and percutaneous venous catheter placement in newborns but it did not diminish the pain from heel‐lancing (Taddio 1998). One case of MetHb was reported in 1995 by Tse 1995 after injection of prilocaine for a neonatal circumcision. One study by Browne 1999 reported that vasoconstriction following the use of EMLA may render cannulation more difficult in adults. A reported benefit of amethocaine is that it causes vasodilation of the blood vessels and, therefore, may make cannulation easier. Hypersensitivity reactions to amethocaine such as erythema, oedema, pruritus and blistering of the skin have been reported in adults (Smith & Nephew 2012).
How the intervention might work
Both EMLA and amethocaine topical anaesthetics act by causing a reversible block to conduction along nerve fibres. Amethocaine is believed to block nerve conduction mainly by inhibiting sodium ion flux across the axon membrane. Amethocaine achieves this by acting upon specific receptors that control gating mechanisms responsible for conductance changes in specialised proteinaceous sodium channels (Smith & Nephew 2012). EMLA similarly works by stabilising the neuronal membrane preventing the initiation and conduction of nerve impulses (AstraZeneca 2008).
Why it is important to do this review
Invasive procedures such as venepuncture or heel puncture are painful and can cause considerable stress to the neonate and the parents. EMLA (AstraZeneca 2008) and amethocaine (Smith & Nephew 2012) are not recommended for use in preterm or term newborn infants by their respective manufacturing pharmaceutical companies but both topical anaesthetics are used and studied in these populations. This review will help determine which topical anaesthetic preparation (amethocaine or EMLA) is superior in relation to its efficacy and safety for needle‐related procedures in newborn infants.
Objectives
To evaluate the efficacy and safety of topical anaesthetics such as amethocaine and EMLA in newborn term or preterm infants requiring an invasive procedure involving puncture of skin and other tissues with a needle.
Methods
Criteria for considering studies for this review
Types of studies
We considered all published and unpublished randomised controlled trials (RCTs) or quasi‐RCTs for inclusion in this review.
We intended to include cluster and cross‐over randomised trials.
Types of participants
Newborn term or preterm (or both) infants up to a postnatal age of one month requiring an invasive procedure involving puncture of skin and other tissues with a needle (heel lance, venepuncture, arterial puncture, arterial cannulation, supra‐pubic aspiration of urine, lumbar puncture, intramuscular injection, percutaneous venous catheter). We excluded infants previously exposed to a topical anaesthetic prior to enrolment.
Types of interventions
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EMLA versus placebo.
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EMLA versus amethocaine.
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EMLA versus other topical anaesthetic.
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Amethocaine versus placebo.
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Amethocaine versus other topical anaesthetic.
Amethocaine and EMLA could be given at any dose, location or length of time as determined in each of the included studies. The topical anaesthesia could be applied using any method of delivery and any product (gel, liquid, spray, cream and any other forms).
We excluded topical anaesthesia during circumcision.
Types of outcome measures
Primary outcomes
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Pain using validated pain score (measured during the procedure, up to one hour following painful procedure or both) such as:
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NIPS (Lawrence 1993);
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PIPP (Stevens 1996);
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Neonatal Facial Action Coding System (Grunau 1987);
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other validated pain measures.
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Secondary outcomes
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Number of infants with methaemoglobin levels 5% and above (Sashdeva 2003).
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Number of needle prick attempts prior to successful needle‐related procedure (e.g. intravenous or arterial cannulation).
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Total cry duration (seconds) from beginning of procedure to cessation of crying or within a specified time limit (e.g. up to 180 seconds).
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Time taken for completion of procedure (if trial used same procedure, e.g. intravenous cannulation).
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Episodes of apnoea ‐ defined as a cessation of breathing for more than 20 seconds or a shorter pause associated with bradycardia or cyanosis.
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Episodes of bradycardia ‐ defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer.
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Episodes of oxygen desaturation ‐ defined as a spontaneous fall in peripheral capillary oxygen saturation (SpO2) of 85% for 10 seconds or longer in duration.
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Neurodevelopmental disability (after at least 18 months' postnatal age) defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay more than two standard deviations (SDs) below population mean on a standardised test of development.
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Other adverse events (as determined by the study).
Search methods for identification of studies
Electronic searches
Two review authors (JF and CT) independently performed the electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 4), PubMed (to April 2015), Embase via Ovid (1980 to April 2015) and CINAHL via Ovid (1982 to April 2015). Text word fields and, where applicable, database subject heading fields (e.g. MeSH) were searched using the following terms: neonat* OR Infant* OR Newborn AND Venepuncture OR venipuncture OR arterial puncture OR lumbar puncture OR injection OR needle OR percutaneous venous catheter OR heel lanc* OR supra‐pubic aspiration AND Pain OR Analgesia OR Topical anaes* OR topical anesthes* OR Prilocaine OR Amethocaine OR Tetracaine OR EMLA OR Angel OR Ametop OR "eutectic mixture of local anesthetics" OR topical anesthe* OR topical anaesthe*. We applied no language restrictions.
Searching other resources
The search strategy included communication with expert informants, and searches of bibliographies of reviews and trials for references to other trials. We searched previous reviews including cross‐references, abstracts, and conferences and symposia proceedings of the Perinatal Society of Australia and New Zealand and Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 to April 2015. We intended to contact the corresponding investigators for information if we identified any unpublished trials. We considered unpublished studies or studies only reported as abstracts as eligible for review if methods and data were confirmed by the author. We intended to contact the corresponding authors of identified RCTs for additional information about their studies if we required further data. We searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled‐trials.com; and who.int/ictrp). There were no language restrictions.
Data collection and analysis
We used the standard systematic review methods of Cochrane documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
Two review authors (JF and CT) independently assessed the potential studies identified as a result of the search strategy for inclusion. We resolved any disagreements through discussion.
Specifically, we:
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merged search results using reference management software and remove duplicate records of the same report;
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examined titles and abstracts to remove irrelevant reports;
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retrieved full text of the potentially relevant reports;
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linked multiple reports of the same study;
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examined full‐text reports for compliance of studies with eligibility criteria;
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corresponded with investigators, when appropriate, to clarify study eligibility;
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noted reasons for inclusion and exclusion of articles;
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made final decisions on study inclusion and proceeded to data collection;
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resolved discrepancies through a consensus process.
Data extraction and management
We used the standardised review methods of the Cochrane Neonatal Review Group (CNRG) to assess the methodological quality of included studies (neonatal.cochrane.org/en/index.html). Two review authors (JF and CT) independently assessed study quality and risk of bias using the following criteria documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of risk of bias in included studies
Two review authors (JF and CT) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion.
(1) Sequence generation (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as:
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low risk (any truly random process, e.g. random number table; computer random number generator);
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high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk.
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal the allocation sequence 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:
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low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk.
(3) Blinding (checking for possible performance bias)
We described for each included study the methods used, if any, 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 the methods as:
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adequate, inadequate or unclear for participants;
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adequate, inadequate or unclear for personnel;
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adequate, inadequate or unclear for outcome assessors.
(4) Detection bias (checking for outcome assessment bias)
For each included study, we categorised the methods used to blind outcome assessors from knowledge of which intervention a participant received. As our study population consisted of neonates they would all be blinded to the study intervention. Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods used with regards to risk of detection bias as:
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low: adequate, follow‐up was performed with assessors blinded to group;
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high: inadequate, assessors at follow‐up were aware of group assignment;
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unclear: no or unclear information provided.
(5) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated 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 sufficient information was reported, or could be supplied by the trial authors, if applicable, we intended to re‐include missing data in the analyses that we undertook. We assessed methods as:
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adequate (less than 20% missing data);
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inadequate;
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unclear.
(6) Outcome reporting bias
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk (where it was clear that all the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);
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high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
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unclear risk.
(7) Other sources of bias
We described for each included study any important concerns we had about other possible sources of bias (e.g. early termination of trial due to data‐dependent process, extreme baseline imbalance, etc.). We assessed whether each study was free of other problems that could put it at risk of bias. We assessed other sources of bias as:
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yes;
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no;
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unclear.
(8) 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 (8) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We intended to explore the impact of the level of bias through undertaking sensitivity analyses.
We judged each criterion as being at 'low risk' of bias, 'high risk' of bias, or 'unclear' risk of bias (for either lack of information or uncertainty over the potential for bias).
Quality of evidence
We assessed the quality of evidence for the main comparison at the outcome level using the GRADE approach (Guyatt 2011a). This methodological approach considers evidence from RCTs as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias (Guyatt 2011a). 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 (Schünemann 2013).
The review authors independently assessed the quality of the evidence found for outcomes identified as critical or important for clinical decision making. These outcomes include: pain, successful venepuncture first attempt and adverse effects.
In cases where we considered the risk of bias arising from inadequate concealment of allocation, randomised assignment, complete follow‐up or blinded outcome assessment to reduce our confidence in the effect estimates, we downgraded the quality of evidence accordingly (Guyatt 2011b). We evaluated consistency by similarity of point estimates, extent of overlap of confidence intervals (CI) and statistical criteria including measurement of heterogeneity (I2 statistic). We downgraded the quality of evidence when large and unexplained inconsistency across studies results was present (i.e. some studies suggest important benefit and others no effect or harm without a clinical explanation) (Guyatt 2011c). Precision was assessed based on the width of the 95% CI and by calculating the optimal information size. If the total number of participants included in the pooled effect estimation was less than the number of participants generated by a conventional sample size calculation for a single adequately powered trial, we considered rating down for imprecision (Guyatt 2011d). When trials were conducted in populations other than the target population, we downgraded the quality of evidence because of indirectness (Guyatt 2011e).
We entered data (i.e. pooled estimates of the effects and corresponding 95% CI) and explicit judgements for each of the above aspects assessed into the Guideline Development Tool, the software used to create 'Summary of findings' tables (GRADEpro 2008). We explained all judgements involving the assessment of the study characteristics described above in footnotes or comments in summary of findings Table for the main comparison; summary of findings Table 2.
Measures of treatment effect
We analysed the results of the studies using the statistical package Review Manager 5 (RevMan 2014). We summarised data in a meta‐analysis if they were sufficiently statistically homogeneous.
Dichotomous data
We present results as risk ratio (RR) and risk difference (RD) with 95% CI for dichotomous data. If there was a statistically significant reduction in RD, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH) and associated 95% CI.
Continuous data
We used the mean difference (MD) if trials reported outcomes in the same way between trials for continuous data. We used the standardised mean difference (SMD) to combine trials that measured the same outcome, but used different methods.
Unit of analysis issues
The unit of randomisation and the unit of analysis was the individual infant.
Dealing with missing data
We contacted authors of published studies if we required clarification, or to request additional information. If we had identified missing data, we would have described the number of participants with the missing data in the Effects of interventions section and the Characteristics of included studies table.
Assessment of heterogeneity
We assessed the heterogeneity between the included trials using the formal and commonly applied statistics to assess heterogeneity using the I2 statistic. This test describes the percentage of total variation observed across studies due to heterogeneity rather than sampling (random) error (Higgins 2011). We graded the degree of heterogeneity as non‐existent or minimal for an I2 value of less than 25%, low for an I2 value of 25% to 49%, moderate for an I2 value of 50% to 74% and high for an I2 value of 75% to 100%. Whenever there was evidence of apparent or statistical heterogeneity, we intended to assess the source of the heterogeneity using sensitivity and subgroup analyses looking for sources of bias or methodological differences between the heterogeneous trials.
Assessment of reporting biases
We planned to assess reporting and publication bias by examining the degree of asymmetry of a funnel plot using Review Manager 5 (RevMan 2014).
Data synthesis
We used the fixed‐effect model in Review Manager 5 for meta‐analysis (RevMan 2014). There were limited data available so we performed none of the subgroup analyses. Sensitivity analyses were deemed inappropriate due to the lack of reporting of relevant outcomes in the included studies.
Subgroup analysis and investigation of heterogeneity
We intended to compare the effects of each topical anaesthetic in the following subgroups of participants:
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gestational age at birth (term infants 37 weeks' gestation and above); preterm infants (29 to 36 weeks' gestation); very preterm infants (less than 29 weeks' gestation);
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type of infants (e.g. healthy newborn infants (those in the normal newborn nursery) versus ill infants in the neonatal intensive care unit (NICU)).
We performed no subgroup analyses because of the small number of included studies.
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
The search identified 233 records through database searching and 107 additional records through other sources. After deduplication, we screened 259 records and excluded 225 records leaving 37 potential studies. After reading the full text, we excluded 29 records with reasons (see Characteristics of excluded studies table). We included eight RCTs in the review (see Characteristics of included studies table). See Figure 1 for study flow diagram.
Study flow diagram.
Included studies
Eight small RCTs were eligible for inclusion in this review (n = 506): Bonetto 2008 (n = 38); Jain 2000a (n = 39); Kaur 2003 (n = 60); Larsson 1995 (n = 110); Larsson 1998 (n = 111); Long 2003 (n = 32); Shah 2008 (n = 110); Stevens 1999 (n = 106). We found no studies comparing topical anaesthesia versus topical anaesthesia.
Eutectic mixture of local anaesthetics versus placebo
Bonetto 2008 was a single‐centre study performed in Argentina.
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Objective: to investigate the effect of EMLA on pain during heel lancing in newborn infants.
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Population: newborn infants, gestation 36 weeks or greater, aged greater than 24 hours after birth to less than 30 days' postnatal age undergoing routine heel lancing.
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Intervention: infants in the study group received EMLA cream or placebo cream to the skin and under occlusion for 60 minutes, then removed with a dry cloth with the procedure being performed 10 minutes later.
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Outcome: pain.
Kaur 2003 was a single‐centre study performed in India.
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Objective: to determine the efficacy of EMLA in alleviating pain associated with lumbar puncture in newborn infants.
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Population: newborn infants, gestation 34 weeks or greater and younger than four weeks' postnatal age undergoing diagnostic lumbar puncture.
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Intervention: infants received a EMLA cream 1 g or placebo cream to one square in at the site of the procedure and covered with an occlusive dressing for 60 to 90 minutes before the scheduled time of the procedure.
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Outcomes: heart rate, transcutaneous oxygen saturation, pain and adverse effects.
Larsson 1995 was a single‐centre study performed in Sweden.
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Objective: to evaluate the effect of EMLA when heel lancing for testing for phenylketonuria.
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Population: full‐term healthy newborn infants, gestation mean 39.8 weeks, range 36.8 to 42.6 weeks, on their third day of life.
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Intervention: infants received EMLA cream 1 g or placebo cream at the site of the procedure and covered with an occlusive dressing for 10, 20, 30, 40, 50, 60, 90 or 120 minutes before the scheduled time of the procedure.
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Outcomes: 'pain cry', flexor response, symptoms of MetHb and adverse effects.
Larsson 1998 was a single‐centre study performed in Sweden.
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Objective: to determine whether the pain from venepuncture on the dorsal aspect of the hand (for testing for phenylketonuria) in the neonate could be reduced by EMLA.
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Population: full‐term newborn infants, gestation mean 39.8 weeks, range 36.8 to 42.6 weeks. Postnatal age was three to eight days.
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Intervention: infants received a EMLA cream 0.5 g or placebo cream on the dorsal aspect of the hand and covered with an occlusive dressing for 60 minutes before the scheduled time of the procedure.
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Outcomes: pain, duration of first cry, latency to cry, total duration of cry, incidence of crying, number of attempts for successful venepuncture and time required for successful completion of procedure.
Stevens 1999 was a double‐centre study performed in Canada.
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Objective: to determine the safety and efficacy of EMLA when undergoing heel lancing.
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Population: preterm neonates, gestation 30 to 36 weeks. Postnatal age was one to five days.
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Intervention: the study was undertaken in two phases. In phase one, infants in the study group receive EMLA 0.5 g on an occlusive dressing for 30 minutes. Five minutes before heel lancing, the dressing was removed. Infants in the control group received Glaxal base 0.5 g. In phase two, the method was the same as phase one except a larger automated lancet was used because of a change in unit policy. In addition, the placebo cream was changed. It contained all ingredients of EMLA except for the lidocaine and prilocaine, which were substituted with MCT oil, and the creams remained intact for 60 minutes.
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Outcomes: pain and methaemoglobin levels.
Amethocaine versus placebo
Jain 2000a was a single‐centre study performed in the UK.
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Objective: to investigate the effect of topical amethocaine on the pain of venepuncture in newborn infants.
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Population: newborn infants, gestation 27 to 41 weeks, aged two to 17 days' postnatal age undergoing routine venepuncture.
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Intervention: infants in the study group received 4% amethocaine gel a 1.5 g or placebo cream to the skin and occlusion for 60 minutes with the procedure being performed five minutes later.
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Outcomes: pain, total length of cry, number of attempts to obtain the blood sample and skin reactions.
Long 2003 was a single‐centre study performed in the UK.
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Objective: to determine whether the pain from venepuncture (for serum bilirubin measurement and Guthrie tests) in neonates could be reduced by using a tetracaine. (amethocaine)‐containing patch.
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Population: newborn infants, gestation 32 to 42 weeks (median 36 weeks). Postnatal age was three to 18 days.
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Intervention: infants received a tetracaine patch formulated from hydroxypropyl cellulose discs of uniform area (0.283 cm2) were cut from the dried tetracaine film which, because of the formulation method, was calculated to contain tetracaine base 0.283 mg. The discs were positioned onto pressure‐sensitive adhesive film to sandwich the tetracaine discs between the adhesive film and the release liner. Patches of 16 mm diameter were cut with the 6‐mm disc of tetracaine film at the centre. The tetracaine patch, or a 'placebo device' applied on the dorsal aspect of the hand for 30 minutes before venepuncture.
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Outcome: pain.
Shah 2008 was a single‐centre study performed in Canada.
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Objective: to evaluate the effectiveness and tolerability of topical amethocaine gel 4% in neonates undergoing intramuscular injection.
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Population: full‐term neonates, 37 weeks' gestation or greater undergoing routine antenatal intramuscular injection of vitamin K.
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Intervention: infants in the study group received amethocaine gel 4% or placebo to the skin and covered with an adhesive Tegaderm occlusive dressing for 30 minutes before the scheduled time of the procedure.
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Outcomes: pain and local adverse events
Excluded studies
We excluded 29 studies from the analysis. These are detailed in the Characteristics of excluded studies table, with reasons for their exclusion.
Risk of bias in included studies
Reviews that compared the topical anaesthetics amethocaine and EMLA in terms of anaesthetic efficacy and safety in newborn term or preterm infants requiring an invasive procedure involving puncture of skin and other tissues with a needle were included in the analysis. Overall, the eight included trials were of high quality (Figure 2; Figure 3). Specific methodological issues regarding the studies included are discussed below.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Randomisation: four studies used computer‐generated randomisation (Bonetto 2008; Kaur 2003; Shah 2008; Stevens 1999). One study used treated identical treatment patches randomly picked from a box (Long 2003). Three studies provided no information on the method of randomisation (Jain 2000a; Larsson 1995; Larsson 1998).
Allocation concealment: one study achieved allocation concealment by keeping the randomisation code in the pharmacy department (Shah 2008). Once an eligible neonate was identified, the pharmacist dispensed the single‐dose study medication. Each participant was identified by a number. In one study, the pharmacist allocated treatment groups (Jain 2000a). One study used creams prepared by the pharmacy department, individually packaged in dark glass ointment jars and labelled by code (Stevens 1999). In one study the neonates received either EMLA or placebo cream 'in a double‐blind manner' (Kaur 2003). Two studies were described as 'double‐blinded' (Bonetto 2008;Larsson 1998). In one study, infants were allocated to eight groups according to the time when EMLA or placebo was applied (Larsson 1995). One study randomly selected patches of identical appearance from a box, equally divided between placebo and active devices (Long 2003).
Blinding of participants and personnel: all eight studies reported that participants and personnel were blinded because the treatment and placebo were identical. One study reported that phase one of the study was not blinded to the research nurse because the colours and consistencies of the creams were different but for phase two, the creams were identical (Stevens 1999).
Blinding of outcome assessment: six studies reported blinding of outcome assessment (Bonetto 2008; Jain 2000a; Larsson 1998; Long 2003; Shah 2008; Stevens 1999). Two studies provided no information (Kaur 2003; Larsson 1995).
Exclusions after randomisation: there were minimal exclusions after randomisation.
Effects of interventions
See: Summary of findings for the main comparison EMLA compared with placebo for needle‐related pain in newborn infants; Summary of findings 2 Amethocaine compared with placebo for needle‐related pain
Results are presented for EMLA versus placebo and amethocaine versus placebo. No studies compared EMLA versus amethocaine, or EMLA versus another active topical anaesthetic, or amethocaine versus another active topical anaesthetic.
Eutectic mixture of local anaesthetics versus placebo
Pain (Outcomes 1.1; 1.2)
Five studies reported on pain but we were unable to perform meta‐analysis due to the different methods used, or reporting of the outcomes (Bonetto 2008; Kaur 2003; Larsson 1995; Larsson 1998; Stevens 1999).
Bonetto 2008 used the 0 to 18 PIPP score for infants over 36 weeks' gestation and Stevens 1999 used the 0 to 21 score for infants of lower gestational age at birth (i.e. less than 28 weeks' gestation). Bonetto 2008 reported no statistical difference between the EMLA and placebo groups from insertion of heel lance and up to three minutes, using the PIPP score (MD 0.27, 95% CI ‐1.45 to 1.99; n = 38). The PIPP score used was a seven‐indicator measure; a score of less than 8 indicated absence or minimal pain and a score greater than 8 indicated moderate pain from a maximum score of 18 (Analysis 1.1). The quality of evidence was low due to results from only one small study.
Bonetto 2008 measured pain during heel lancing using the NIPS and reported no significant difference between the EMLA and placebo groups (MD 0.27, 95% CI ‐0.75 to 1.29; n = 38). A NIPS score of 0 indicated no pain, and a maximum score of 7 indicated moderate‐to‐severe pain (Analysis 1.2). The quality of evidence was low due to results from only one small study.
Kaur 2003 reported statistically significant lower pain scores using the simplified Neonatal Facial Coding System (NFCS) for the EMLA group compared to the placebo group during lumbar puncture (mean 4.0 ± standard error (SE) 0.3 with EMLA versus mean 5.0 ± SE 2.7 with placebo; P = 0.004), and needle withdrawal (mean 1.8 ± SE 0.3 with EMLA versus mean 3.9 ± SE 0.3 with placebo; P < 0.001). The NFCS has a maximum score of 5 whereby presence of a pain behaviour scored 1 point and absence of a pain behaviour scored 0 points for each of the five variables.
Larsson 1995 reported no statistical difference between the EMLA and placebo groups for pain during heel lancing which was measured by the utterance of a 'pain cry' (54 out of 56 infants uttered a 'pain cry' with EMLA versus 52 out of 54 infants uttered a 'pain cry' with placebo; P = 0.97).
Larsson 1998 reported pain after venepuncture using the NFCS. There were statistically significant lower pain scores in the EMLA group than the placebo group at 0 to 15 seconds' post venepuncture (median 287 with EMLA versus median 374 with placebo; P = 0.016). There was no statistically significant difference between the scores at 60 to 70 seconds' post venepuncture (median 288 with EMLA versus median 407 with placebo). Each pain variable received a score from 0% to 100% so the total range was 0% to 600% for the six pain variables.
Stevens 1999 used the PIPP score and reported no statistical difference between the EMLA and placebo groups for EMLA applied for 30 minutes (mean 10.19, SD 4.09 with EMLA versus mean 9.45, SD 4.01 with placebo; P = 0.48) and 60 minutes (mean 13.08, SD 4.35 with EMLA versus mean 13.33, SD 3.49 with placebo; P = 0.83) during heel lancing. Pain scores were lower in phase one compared to phase two. The PIPP score used was a seven‐indicator measure, and gave a total range of scores of 0 to 21. A PIPP total score of 6 or less indicated minimal or no pain, whereas scores greater than 12 indicated moderate to severe pain.
Number of infants with methaemoglobin levels 5% and above
One study reported methaemoglobin levels of 5% or greater (Stevens 1999). They reported no methaemoglobin levels of 5% or greater with infants who received two separate doses of EMLA. The mean methaemoglobin concentration for all infants who received EMLA was 1.19%. Larsson 1995 reported no clinical symptoms of MetHb.
Number of needle prick attempts prior to successful needle‐related procedure (successful cannulation first attempt) (Outcome 1.3)
One study reported on successful cannulation at first attempt. There was no statistical difference between the two groups in the successful venepuncture (typical RR 0.98, 95% CI 0.93 to 1.03; typical RD ‐0.02, 95% CI ‐0.07 to 0.03; n = 111) (Analysis 1.3) (Larsson 1998). The quality of evidence was low due to results from only one small study. One study reported that lumbar puncture was traumatic on the first attempt in two cases with EMLA and three cases with placebo (Kaur 2003). No case required more than two attempts.
Total cry duration
One study reported total cry duration (Larsson 1998). They found no significant difference for median total duration of crying between the two groups during venepuncture (P = 0.89). There were no other data provided.
Time taken for completion of procedure
One study reported on time taken for completion of procedure (Larsson 1998). They reported that it took significantly less time to complete the venepuncture in the placebo group (median 145 seconds with EMLA versus median 125 seconds with placebo; P = 0.01).
Episodes of apnoea
No studies reported episodes of apnoea.
Episodes of bradycardia
No studies reported episodes of bradycardia
Episodes of oxygen desaturation
One study reported that oxygen saturation was comparable between the EMLA and placebo groups during lumbar puncture, with the maximum dip in oxygen saturation level observed at needle insertion (Kaur 2003).
Neurodevelopmental disability
No studies reported neurodevelopmental disability.
Other adverse effects (Outcome 1.4)
Three small studies reported adverse effects (Kaur 2003; Larsson 1995; Stevens 1999). There were statistically significant fewer adverse effects in the placebo group compared to the EMLA group (typical RR 1.65, 95% CI 1.24 to 2.19; typical RD 0.17, 95% CI 0.09 to 0.26; n = 272; NNTH 6, 95% CI 4 to 11). However, there was high heterogeneity (I2 = 92%). The adverse effects reported were: local pallor and redness (Larsson 1995), and temporary blanching (Kaur 2003; Stevens 1999) (Analysis 1.4). The quality of evidence was low due to high heterogeneity. One study reported temporary blanching of the skin during removal of the occlusive dressing but provided no data (Kaur 2003).
All three studies reported the effects as short lasting. One study reported that all the local adverse effects disappeared during the procedure (Larsson 1995). One study reported that overall 10% of the infants had minor skin reactions consisting primarily of redness and swelling at the application site (Stevens 1999). There was no significant difference in adverse reactions indicating that they were most likely the result irritation or sensitivity to the presence or removal of the occlusive dressing. All signs of skin irritation and blanching dissipated within one hour of removing the anaesthetic or placebo cream and dressing.
Subgroup analyses
We performed no subgroup analyses because of the small number of included studies.
Amethocaine versus placebo
Pain (Outcomes 2.1)
Three small studies reported on pain (Jain 2000a; Long 2003; Shah 2008). We were unable to include the following studies for meta‐analysis due to the different methods used, or reporting of the outcomes.
Jain 2000a used the NFCS and reported a significant difference in pain scores during venepuncture between amethocaine (median 3, interquartile range (IQR) 0 to 9) and placebo (median 16, IQR 8 to 16; n = 39). A cumulative NFCS score of 10 or less in the five seconds after insertion of the needle was defined as indicating no or minimal pain. In all, 16 of 19 (84%) amethocaine‐treated infants showed little or no pain in response to insertion of the needle compared with six of 20 (30%) in the placebo group (P = 0.001).
Long 2003 used the NFCS score and reported a significant difference in pain score during venepuncture between amethocaine group (median 0) compared to the placebo group (median 12.5) (P = 0.0002; n = 32) during venepuncture. A cumulative score of 10 or less in the five seconds following the procedure was defined as indicating clinically effective anaesthesia. Fourteen of 15 (93%) amethocaine‐treated neonates presented little or no pain in response to the procedure compared with six of 17 (35%) in the placebo group (P = 0.01), fulfilling the definition of clinically effective local anaesthesia.
Shah 2008 used the Facial Grimacing Score to measure pain during intramuscular injection. The score ranged from 0% to 100%. There was no statistically significant difference between the two groups (MD ‐5.00, 95% CI ‐17.34 to 7.34; n = 110) (Analysis 2.1). The quality of evidence was low due to results from only one small study.
Number of infants with methaemoglobin levels 5% and above
No studies reported number of infants with methaemoglobin levels 5% and above.
Number of needle prick attempts prior to successful needle‐related procedure (successful cannulation on first attempt) (Outcome 2.2)
One study reported on successful cannulation at first attempt (Jain 2000a). There was no statistical difference between the two groups (typical RR 1.21, 95% CI 0.82 to 1.81; typical RD 0.14, 95% CI ‐0.14 to 0.42; n = 39) (Analysis 2.2). The quality of evidence was low due to results from only one small study and risk of selection bias.
Total cry duration
One small study reported on total cry duration (Jain 2000a). There was no significant difference (in infants that cried) between amethocaine (33 seconds, range 9 to 79; n = 4) and placebo (68 seconds, range 9 to 122; n = 15).
Time taken for completion of procedure
No studies reported time taken for completion of procedure.
Episodes of apnoea
No studies reported episodes of apnoea.
Episodes of bradycardia
No studies reported episodes of bradycardia.
Episodes of oxygen desaturation
No studies reported episodes of oxygen desaturation.
Neurodevelopmental disability
No studies reported neurodevelopmental disability.
Other adverse effects (Outcome 2.3)
Three small studies reported on adverse effects (Jain 2000a; Long 2003; Shah 2008). Jain 2000a and Long 2003 reported no adverse events (local skin reactions). There was no statistical difference between the amethocaine and placebo groups. Shah 2008 found no significant difference between the amethocaine and placebo for local erythema and blanching in the amethocaine and placebo groups but was short‐lasting and mild in nature (typical RR 2.00, 95% CI 0.64 to 6.26; typical RD 0.04, 95% CI ‐0.03 to 0.12); n = 181). There was no heterogeneity (I2 = 0%) (Analysis 2.3). The quality of evidence was moderate due to unclear risk of selection bias.
There were no other adverse effects.
Subgroup analyses
We performed no subgroup analyses because of the small number of included studies.
Discussion
The included studies in this review enrolled infants of 27 weeks' gestation or greater. Thus, there was no evidence on the use of topical anaesthetics in very preterm infants with the majority of the included studies using the preterm and term infant population. All the trials were small, and the effects of uncertain clinical significance. Mostly of the evidence regarding the effectiveness or safety of the interventions studied was inadequate to support clinical recommendations. The different methods of measuring pain and reporting of outcomes meant that the capacity to pool data was limited and this made interpretation difficult. We were unable to determine which topical anaesthetic preparation (amethocaine or EMLA) was superior in relation to its efficacy and safety for needle‐related procedures in newborn infants. None of the studies reported included measures of parental satisfaction or distress, or long‐term outcomes in the infants.
It has been proposed that the effectiveness of topical anaesthetics may be influenced by the type of painful procedure (e.g. intramuscular, heel lance or venepuncture or lumbar puncture). For example, Stevens 1999 and Larsson 1995 argued that topical anaesthetics are less effective during heel lancing because of the increased skin perfusion in the heel. Thus, we intend to include 'type of painful procedure' for subgroup analyses in the review update when there may be more published studies on this topic.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Eutectic mixture of local anaesthetics (EMLA) versus placebo, Outcome 1 Pain using Premature Infant Pain Profile (PIPP) score.
Comparison 1 Eutectic mixture of local anaesthetics (EMLA) versus placebo, Outcome 2 Pain using Neonatal Infant Pain Scale (NIPS) score.
Comparison 1 Eutectic mixture of local anaesthetics (EMLA) versus placebo, Outcome 3 Successful venepuncture first attempt.
Comparison 1 Eutectic mixture of local anaesthetics (EMLA) versus placebo, Outcome 4 Adverse effects.
Comparison 2 Amethocaine versus placebo, Outcome 1 Pain.
Comparison 2 Amethocaine versus placebo, Outcome 2 Successful cannulation first attempt.
Comparison 2 Amethocaine versus placebo, Outcome 3 Adverse effects.
| EMLA compared with placebo for needle‐related pain in newborn infants | ||||||
| Patient or population: preterm infants Settings: NICU Intervention: EMLA Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with EMLA | |||||
| Pain using PIPP score | The mean pain using PIPP score was 0 | MD 0.27 higher (1.45 lower to 1.99 higher) | ‐ | 38 (1 study) | ⊕⊕⊝⊝ | Single study |
| Pain using NIPS score | The mean pain using NIPS score was 0 | MD 0.27 higher (0.75 lower to 1.29 higher) | ‐ | 38 (1 study) | ⊕⊕⊝⊝ | Single study |
| Successful venepuncture first attempt | Study population | RR 0.98 (0.93 to 1.03) | 111 (1 study) | ⊕⊕⊝⊝ | Single study | |
| 1000 per 1000 | 980 per 1000 | |||||
| Adverse effects (short‐lasting skin reactions) | Study population | RR 1.65 (1.24 to 2.19) | 272 (3 studies) | ⊕⊕⊝⊝ | High heterogeneity | |
| 269 per 1000 | 444 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EMLA: eutectic mixture of local anaesthetics; MD: mean difference; NICU: neonatal intensive care unit; NIPS: Neonatal Infant Pain Scale; PIPP: Premature Infant Pain Profile; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| Amethocaine compared with placebo for needle‐related pain | ||||||
| Patient or population: preterm infants Settings: NICU Intervention: amethocaine Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with amethocaine | |||||
| Pain | The mean pain was 0 | MD 5 lower (17.34 lower to 7.34 higher) | ‐ | 110 (1 study) | ⊕⊕⊝⊝ | Single small study |
| Successful cannulation first attempt | Study population | RR 1.21 (0.82 to 1.81) | 39 (1 study) | ⊕⊝⊝⊝ Very low | Single small study, risk of selection bias | |
| 650 per 1000 | 787 per 1000 | |||||
| Adverse effects (short‐lasting skin reactions) | Study population | Not estimable | 181 (3 studies) | ⊕⊕⊕⊝ | Risk of selection bias | |
| 43 per 1000 | 0 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EMLA: eutectic mixture of local anaesthetics; MD: mean difference; NICU: neonatal intensive care unit; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain using Premature Infant Pain Profile (PIPP) score Show forest plot | 1 | 38 | Mean Difference (IV, Fixed, 95% CI) | 0.27 [‐1.45, 1.99] |
| 2 Pain using Neonatal Infant Pain Scale (NIPS) score Show forest plot | 1 | 38 | Mean Difference (IV, Fixed, 95% CI) | 0.27 [‐0.75, 1.29] |
| 3 Successful venepuncture first attempt Show forest plot | 1 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.93, 1.03] |
| 4 Adverse effects Show forest plot | 3 | 272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.24, 2.19] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain Show forest plot | 1 | 110 | Mean Difference (IV, Fixed, 95% CI) | ‐5.0 [‐17.34, 7.34] |
| 2 Successful cannulation first attempt Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.82, 1.81] |
| 3 Adverse effects Show forest plot | 3 | 181 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.64, 6.26] |
