Introduction:
The International Association of the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. However, identifying and quantifying pain in neonates is complex task as they cannot report or verbally communicate this subjective phenomenon. Due to these limitations, misconceptions existed amongst health care providers that neonates do not feel pain and that there is no need to provide pain-relieving interventions. These misconceptions have been put to rest based on extensive body of literature published over the last several decades that suggest that hospitalized preterm and term neonates are capable of mounting responses to noxious stimuli which can be ameliorated with non-pharmacological and non-pharmacological interventions. In addition, a considerable amount of research has established that untreated pain in the neonatal period may have detrimental effects on subsequent behavior and neurological outcome (e.g. results in altered pain response in later infancy and childhood). The goal then should be to prevent or reduce the amount and intensity of pain. In fact, pain is now considered to be the “fifth” vital signs and it is both our moral and ethical obligation to monitor for and prevent or provide pain reducing therapies to this vulnerable population. In view of these findings, several professional organizations across the world (North America, Europe, Australia) have identified that management of pain should be an integral part of neonatal care and have published evidence-based recommendations for implementation in clinical practice. It is recognized that for some procedures, evidence regarding effective pain management strategies do not exist and recommendations are based on good practice or expert opinions
In order to provide optimal/adequate pain management, we must be able to assess pain accurately (duration and intensity) and evaluate the effectiveness of various interventions. It is well known that neonates mount behavioral, physiological and hormonal responses when subjected to noxious stimuli. A wide array of validated uni-dimensional and multi-dimensional tools have been developed and described in the literature to measure and assess acute pain for integration in clinical practice. However, there are limitations for the available tools: 1) they are validated for acute procedural setting rather than for subacute or chronic pain or stress and 2) they do not account for the limited ability of extreme preterms to mount a behavioral or physiological response At my center, Mount Sinai Hospital, Toronto we use Premature Infant Pain Profile (PIPP) to assess pain. Individual institutions should identify a tool that they can use locally and then provide education and on-going training to the bed-site staff. Motivation of all caregivers regarding its use continues to be a major issue. Also, unit-specific treatment algorithms should be designed to provide guidance to the bed-site staff for provision of pain-relieving strategies.
Epidemiology of Pain:
Over the last several decades, investigators have conducted studies/surveys to identify the number of painful/stressful procedures hospitalized neonates are subjected to. In addition, with the availability of pain relieving interventions, investigators have attempted to identify what interventions are commonly used in clinical practice in NICUs. In a recent survey in 2008, Carbajal et al obtained data on all painful and stressful procedures and analgesic interventions used during the first 14 days of hospitalization in 430 neonates admitted to tertiary NICUs in the Paris region of France. They reported that each neonate was subjected to a median of 115 (range, 4-613) procedures and 16 (range, 0-62) procedures per day of hospitalization. Pharmacological interventions were used in 2.1%, non-pharmacological interventions in 18.2% and combination of pharmacological and non-pharmacological interventions in 20.8%. In ~80% of neonates procedures were performed without specific analgesia. Therefore, despite evidence pain relieving interventions are not consistently used. Similarly, Cignaco et al, 2009 from Switzerland, report on the number of painful procedures and pain management in ventilated preterm neonates during the first 14 days. The daily mean number of procedure was 22.9 per neonate. In this study, 99.2% of the infants received non-pharmacological and/or pharmacological intervention with 70.8% receiving glucose orally as pre-emptive analgesia. Morphine was the most common pharmacological agent used. Therefore, variation in pain management continues to exist amongst different centers across the world.
Management of Procedural pain:
Skin-breaking procedures:
Neonates in the NICUs are commonly subjected to minor procedures such as heel lance, venipuncture, venous cannulation and intramuscular injection. Various non-pharmacological and pharmacological interventions have been recommended to prevent or reduce pain from these procedures. Non-pharmacological interventions include the use of oral sucrose/glucose with or without pacifiers, breast feeding, non-nutritive sucking using a pacifier, kangaroo care, nesting/swaddling or facilitated tucking. Of these interventions, sucrose is the most commonly used intervention in our NICU and we have designed a protocol for its use. However there is marked variability in the dose used in the neonatal period. Further the effect of repeated administration of sucrose is unknown. Topical local anesthetics are the most common pharmacological intervention used and is shown to be effective for venipuncture, venous cannulation, lumbar puncture and PICC line. Topical local anesthetics are not effective for reducing pain from heel lance and intramuscular injection.
Endotracheal intubation:
Tracheal intubation is a frequently performed as an emergent procedure in the resuscitation room and as a semi-elective or non-urgent procedure in neonates with respiratory insufficiency. It is well documented that awake intubation is associated with physiological disturbances such as bradycardia, hypoxia and increase in systemic and intracranial pressure which can be deleterious. A wide range of pharmacological drugs (analgesics, sedatives and muscle relaxants) have been evaluated either as a single agent or in combination with sedative/analgesic and muscle relaxants. Shah V and Ohlsson A in 2002 and recently Carbajal R et al in 2007 have systematically reviewed the literature on the effectiveness of premedication for intubation. They conclude that use of premedication attenuates the physiological responses and premedication for intubation should be used when possible. Additional advantages include: reduction in the time and number of attempts required for intubation. However, what is still unknown is which is the most optimal drug or combination of drugs and the dose to be used? On the other hand reasons for non-use of these agents may include: lack of unfamiliarity of with the drugs, fear of adverse events and concerns regarding inability to successful establish airway especially if muscle relaxants are used.
In our institution we have established a protocol for use of premedication for intubation. We have chosen a combination of atropine, fentanyl and succinlycholine. The protocol is detailed and provides: providing information on the agents and dose to be used, contraindications to these drugs, individuals responsible for administering the drug and performing the procedures and availability of at least 2 skilled individuals who can perform the procedure. Individual institutions must design their own guideline/protocol depending on the agents available and the skill of the individual performing the procedure and expertise. It is important to remember that the first principle should be “primum non nocere” (i.e. “first do no harm”).
Ventilated infants:
Mechanical ventilation is commonly used in the NICU in neonates with respiratory insufficiency. Being on a ventilator is considered to be potentially painful, distressing or uncomfortable. Several studies have evaluated the effects of opioid analgesics on pain, duration of mechanical ventilation, mortality and short- and long-term effects in neonates with inconclusive evidence. Bellu et al (2009) systematically reviewed the literature regarding the effectiveness of opioids on pain, duration of mechanical ventilation and short and long term neurodevelopmental outcomes. No differences were noted between groups. They concluded that there is insufficient evidence to recommend the routine use of opioids in mechanically ventilated infants. Opioids may be used selectively in infants who are agitated and causing ventilator asynchrony. It is vital to recognize that use of opioids is associated with adverse effects on respiratory system (depression and need for prolonged ventilation), cardiovascular effects (hypotension and brain injury), decrease in gut motility and feeding intolerance, chest wall rigidity especially with fentanyl use, tolerance and opioid withdrawal syndrome. We do not routinely administer morphine in neonates who are mechanically ventilated.
Eye examinations for retinopathy of prematurity:
Indirect ophthalmic examination currently remains the gold standard and the method of screening for retinopathy of prematurity in NICUs. Several factors contribute to the pain and stress during eye examination: insertion of the eyelid speculum, scleral depression, physical restraints and brightness of the light. Even though the eye examination last for few minutes, infants are subjected to procedures prior to the eye examination (e.g., instillation of eye drops ~ 60 minutes prior to the eye examine). Samra et al performed a systematic review on this subject. Interventions that were evaluated include: 1) sucrose; 2) topical anesthetic eye drops; 3) NIDCAP; 4) RetCam; and 5) nesting without topical anesthesia. Two of the 5 studies that evaluated sucrose showed evidence of reduction in pain from eye examine with its use. The use of topical anesthetic agents has not been proven. Even though there is insufficient data to make recommendations, the use of topical anesthetic eye drops and oral sucrose seems to be a reasonable approach and this is what we currently use in our institution.
Other procedures:
Chest tube insertion:
There are no prospective studies of analgesia for insertion of chest tube in neonates and should be managed based on general principles. Management includes the use of topical local anesthetic for infiltration of the skin and use of opioids (morphine).
Surgery:
The use of anesthetic agents of sufficient depth to prevent intra-operative pain and stress is recommended. Post-operatively the most common agent used in opioids by continuous infusion or bolus. There is very limited data on the use of non-steroidal anti-inflammatory agents such as ketolorac in neonates and its use as an adjunct to post-operative anesthesia is not currently recommended.
In summary, neonates are capable of experiencing pain and mounting responses when subjected to various noxious stimuli which can be relieved by using pain-relieving strategies. However, prior to use of intervention the benefits and risks should be weighed. As prevention is better than cure, every effort should be made to minimize the number of painful or stressful procedures.
References:
1. American Academy of Pediatrics, Committee on Fetus and Newborn, Section on Surgery, and Section on Anesthesiology and Pain Medicine; and Canadian Paediatric Society, Fetus and Newborn Committee. Prevention and management of pain in the neonate: An update. Pediatrics 2006;118:2231-41.
2. Lago P, Garetti E, Merazzi D et al. Guidelines for procedural pain in the newborn. Acta Paediatr 2009;98:932-9.
3. Carbajal R, Rouseet A, Danan C et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 2008;2:60-70.
4. Cignacco E, Hamers J, van Lingen R et al. Neonatal procedural pain exposure and pain management in ventilated preterm infants during the first 14 days of life. Swiss Med Wkly 2009;139:226-32.
5. Taddio A, Yiu A, Smith RW et al. Variability in clinical practice guidelines for sweetening agents in newborn infants undergoing painful procedures. Clin J Pain 2009;25:153-5.
6. Shah PS, Aliwalas L, Shah V. Breastfeeding or breastmilk to alleviate procedural pain in neonates: a systematic review. Breastfeed Med 2007;2:74-82.
7. Shah VS, Taddio A, Hancock R et al. Topical amethocaine gel 4% for intramuscular injection in term neonates: a double-blind, placebo controlled, randomized trial. Clin Ther 2008;30:166-74.
8. Shah V and Ohlsson A. The effectiveness of premedication for endotracheal intubation in mechanically ventilated neonates: A systematic review. Clin Perinatol 2002;29:535-54.
9. Carbajal R, Eble B, Anand KJS. Premedication for tracheal intubation in neonates: Confusion or controversy? Semin Perinatol 2007;31:309-17.
10. Allegaert K, Veyckemans F, Tibboel D. Clinical practice: analgesia in neonates. Eur J Pediatr 2009;168:765-70.
11. Bellu R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2009 [Epub].
12. Menon G, McIntosh N. How should we manage pain in ventilated neonates? Neonatology 2009;93:316-23.
13. Samra HA, McGrath JM. Pain management during retinopathy of prematurity eye examinations. Adv Neonatal Care 2009;9:99-110.
