AJA Asian Journal of Anesthesiology

Advancing, Capability, Improving lives

Review Article
Volume 52, Issue 1, Pages 30-37
Souvik Maitra 1 , Dalim Kumar Baidya 1 , Puneet Khanna 2 , Bikash Ranjan Ray 2 , Shasanka Shekhar Panda 3 , Minu Bajpai 3
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Abstract

Current literature lacks systematic data on acute perioperative pain management in neonates and mainly focuses only on procedural pain management. In the current review, the neurophysiological basis of neonatal pain perception and the role of different analgesic drugs and techniques in perioperative pain management in neonates are systematically reviewed. Intravenous opioids such as morphine or fentanyl as either intermittent bolus or continuous infusion remain the most common modality for the treatment of perioperative pain. Paracetamol has a promising role in decreasing opioid requirement. However, routine use of ketorolac or other nonsteroidal anti-inflammatory drugs is not usually recommended. Epidural analgesia is safe in experienced hands and provides several benefits over systemic opioids such as early extubation and early return of bowel function.

Keywords

analgesia, epiduralanalgesics, opioidinfant, newbornpain, postoperative;


1. Introduction

Pain is the most common complaint when a patient presents to a physician. Pain management in neonates warrants special consideration because the present knowledge of developmental neurophysiology is improving every day. Neonates are a special group of the population where a fine balance between optimal pain relief and adverse drug effects is of utmost importance. With the advancement of various surgical techniques and improved perioperative care, an increasing number of sick neonates undergo surgery, and optimal perioperative pain management may improve clinical outcomes in these neonates. In this evidence-based review, we have reviewed the neurophysiology of neonatal pain perception, long-term effects of suboptimal pain relief, and role of various drugs and techniques used in acute perioperative pain management in neonates.

2. Methods

Electronic searches were performed in MEDLINE, PubMed Central, Embase, and Scopus using the keywords “neonate”, “postoperative”, “pain”, and “acute pain”. The following professional society/organization's web-based guidelines were also searched “Association of Pediatric Anesthesiologists”, “American Association of Pediatrics”, and “British Pain Society”.

The level of evidences (LOEs) was decided according to the following guidelines1:

Level I: Evidence obtained from at least one properly designed randomized controlled trial (RCT).

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

3. Developmental neurobiology of pain

The immature nervous system develops from early gestation and continues to change in the postnatal period. Nociception involves peripheral sensory receptors, afferent sensory nerve fibers, the spinal dorsal horn, spinothalamic and thalamocortical tracts, and the sensory cortex. During maturation, C-fiber projections are the last group of primary afferents to enter the dorsal gray matter, after proprioceptive and low-threshold A fibers. By Week 30, nerve tracts are myelinated up to the thalamic level. Afferent neurons in the thalamus project axons migrating into the neocortex. Synaptic connections of these thalamocortical tracts might occur at 24 weeks' gestation. After reviewing the literature, Lee et al2 concluded that direct thalamocortical fibers that are not specific for pain begin to emerge between 21 and 28 weeks' developmental age (23 and 30 weeks' gestational age). Fitzgerald stated that most pain responses in preterm infants, <32 weeks of age, including facial expressions, seem to be largely subcortical.3 Involvement of fetal cerebral cortex in pain pathway may be minimal and predominantly brain stem is important.4 However, premature neonates show behavioral and physiological reactions and hormonal stress responses to painful stimuli, and intravenous fentanyl has been found to attenuate the fetal stress response to intrahepatic vein needling (LOE II-3).5

4. Why should pain in neonates be treated?

Neonates in a hospital are routinely subjected to various degrees of painful procedures from very early in their lives ranging from venipuncture to major surgery. Apart from ethical reasons and expectation of the parents, there are several long-term and short-term effects of poorly managed acute pain in neonates.

Neonates, even the premature ones, also feel pain and elicit stress response, which was first scientifically described in a landmark study by Anand et al6 in 1987. They also concluded that blunting the stress response by fentanyl may be associated with improved outcomes. Subsequently in 1992, Anand and Hickey7 showed that management of postoperative pain after cardiac surgery by potent opioids is associated with improved outcomes. The stress response, activated by afferent neuronal impulses from the site of injury, was found to be greater in magnitude but shorter in duration in neonates compared with adults during the same operation.8 The stress response initiates a series of metabolic changes leading to catabolism of protein, fat, and carbohydrate. In premature or sick infants, this might cause metabolic acidosis, hypoglycemia, hyperglycemia, and electrolyte imbalances leading to increased morbidity and mortality.9

Altered and heightened pain responses in the subsequent painful procedures are the most common long-term effect (LOE II-1),1011 and this may persist until adolescence12 (LOE II-2). A proper analgesic regimen may also prevent heightened pain response.10 Behavioral response may also be altered by stress exposure in the neonatal intensive care unit (NICU).13 The current consensus is that neonatal pain must be managed regardless of their age and severity of coexisting illness.14

5. Neonates feel more pain than their older counterparts

Clinical and laboratory investigations of neonatal pain suggest that preterm neonates have an increased sensitivity to pain.15 Anatomic studies have shown that the density of nociceptive nerve endings in the skin of newborns is similar to or greater than that in adult skin.16 Lack of myelination was suggested as an argument to support the hypothesis that neonates are not capable of perceiving pain. However, nociceptive impulses in the peripheral nerves are conducted through unmyelinated (C fibers) and thinly myelinated fibers (A-δ fibers).17 Lower pain thresholds and the lack of inhibitory controls contribute to hypersensitivity in the most premature neonates. Repeated tactile stimulation leads to a significant lowering of the threshold (sensitization) in neonates up to 35 weeks' postconceptional age (PCA).18 The low pain threshold in preterm neonates is accentuated by an increased excitability of nociceptive neurons in the dorsal horn of the spinal cord after exposure to any painful stimulus (wind-up phenomenon). In neonates, prolonged activity in the nociceptive pathways may be perceived as chronic noxious stimulation.

6. Preoperative issues

An appropriate pain management plan should be formulated in the preoperative visit and communicated to the parents to minimize their anxiety. Unnecessary laboratory investigations should be avoided to minimize pain associated with invasive procedures. Fasting period beyond the stipulated guidelines should not be extended to avoid unnecessary discomfort. Patient's present clinical conditions, presence of other coexisting medical illness, nature of the surgical procedure to be done, and the area where the neonate will be managed in the postoperative period should be taken into consideration.

For blood sampling, the heel is preferable, as it is less painful (LOE I) and mother should be encouraged to breast-feed the baby whenever feasible or sucrose solution should be used (LOE I). Topical anesthesia (LOE I) or morphine (LOE II) alone is insufficient for lancinating pain. However, a topical local anesthetic cream (eutectic mixture of local anesthetic) may be used during venous/arterial puncture and insertion of peripherally inserted central catheter in neonates aged more than 26 weeks and it is safe in single dose (LOE I).19

Since then, numerous studies and reviews have addressed the issue of procedural pain in neonates, and the primary aim of this article is to highlight acute postoperative pain.

7. Assessment of pain in neonates

Because preverbal age children are not able to vocalize, the anesthesiologist has to rely on behavioral and physiological markers of acute pain. Various reliable pain measures exist to assess pain in full-term and preterm neonates. Behavioral indicators of pain (e.g., crying, facial activity, body language, complex behavioral responses) and physiological indicators of pain (e.g., changes in heart rate, respiratory rate, blood pressure, oxygen saturation, vagal tone, palmar sweating, and plasma cortisol or catecholamine levels) can be used to assess pain in neonates.

7.1. Behavioral indicators

Facial expression is regarded as the most sensitive indicator of acute and short-term pain in neonates. Total facial activity and a cluster of specific facial features (brow bulge, eye squeeze, nasolabial furrow, and open mouth) have been shown to be significantly associated with acute and postoperative pain.20 Body movement as a pain indicator focuses on the observation of arm and leg activities. Increased activity is thought to indicate more pain. Posture and muscle tone are thought to be tenser when pain is present. Cry features have been extensively studied using spectrographic devices. Short latency to onset of cry, longer duration of the first cry cycle, higher fundamental frequency, and greater intensity in the upper ranges are pain-specific cry features.21

7.2. Physiological indicators

Variations in heart rate, blood pressure, oxygen saturation, and breathing patterns (frequency or irregularity) are the most frequently used physiological indicators of pain. Even the most premature infant has the capacity to increase its heart rate in response to a painful event, reflecting sympathetic nervous system activation22 (LOE I). Despite the good correlation between behavioral and physiological parameters, the most significant limitation of these parameters is that the variations might also be caused by the underlying illness and interventions used to manage them, making them less specific for pain23 (LOE I). Moreover, physiological indicators are less valid in an ongoing pain, as vital sign fluctuations cannot be maintained over longer periods.24

7.3. Biological markers of pain

Although serum or salivary cortisol may serve as a parameter of neonatal pain and stress response, its use in clinical practice is limited.25 Sweating in the palm and sole as a result of neurophysiological arousal with increased activity in the sympathetic nervous system during a heel lance procedure is measured as skin conductance or galvanic skin response. The number of fluctuations in skin conductance may be a useful parameter in assessing acute pain in neonates (LOE I).26

Other biological markers of pain might include changes in intracranial pressure (measured through the anterior fontanelle), thresholds for the dorsal cutaneous flexion reflex or abdominal skin reflex, cerebral blood flow, processed electroencephalography measured by detailed electrical mapping, or neuroimaging techniques such as functional magnetic resonance imaging.27 However, the clinical feasibility of these methods is limited.

7.4. Pain assessment scales in neonates

Various pain assessment instruments have been developed, based on behavioral indicators of pain alone or using a combination of behavioral and physiological indicators. Whereas combined instruments are multidimensional by nature, others tend to focus on one behavioral aspect. An excellent and detailed review of the individual scales is available in literature.28 There is a considerable overlap in between the scales, with facial expression being included in all scales. A majority of pain scales also include body movement, cry, behavioral state/sleep, posture/tone, and physiological variables. The Neonatal Infant Pain Scale (NIPS),29 Premature Infant Pain Profile,30 Crying, Requires oxygen saturation, Increased vital signs, Expression, Sleeplessness (CRIES),31 and the Neonatal Facial Coding System20 were selected by an international consensus neonatal pain group.14 Among these scales, the CRIES is primarily aimed at measuring postoperative pain in neonates.

According to the International Consensus Guidelines, pain assessment in neonates should be multidimensional; that is, consisting of contextual, behavioral, and physiological variables, and should be specific for the specific age group and different types of pain.14 The validity of NIPS and CRIES has been studied in postoperative neonates.32 The authors found that CRIES and NIPS were all valid and reliable. However, NIPS was the most practical scale because the items were easy to score and there was no need to calculate the change of vital signs, which may be an obstacle in a busy clinical practice with limitations of man power.

The COMFORT Scale (Alertness, Calmness/agitation, Respiratory response, Physical movement, Blood pressure, Heart rate, Muscle tone, Facial tension)33 was originally designed to assess distress/comfort in mechanically ventilated children in an intensive care environment; however, it has good reliability in assessing acute postoperative pain as well (LOE II-2).34

The Neonatal Pain Agitation and Sedation Scale was developed as a clinically relevant tool to assess primarily acute prolonged pain and sedation in infants and it has been validated in acute postoperative pain in neonates kept under mechanical ventilation in ICU.35

8. Postoperative pain management

Neonates undergo a variety of surgeries ranging from simple herniotomy to major thoracoabdominal surgery. The analgesic regimen should also vary according to the severity of surgical trauma and depends on where the baby is being managed in the postoperative period.

The options of postoperative pain management range from simple analgesics such as paracetamol to central neuraxial block such as caudal or epidural blocks. However, an anesthesiologist should remember that a neonate is not a “small child”. There is immense anatomical and physiological uniqueness in a neonate that affects the pharmacodynamics and pharmacokinetic characteristics of drugs to a considerable extent.

9. Systemic analgesia in neonates

9.1. Paracetamol

Paracetamol is long being known as an effective analgesic in pediatric populations.36 Its efficacy in mild to moderate pain in neonates is now well documented. For mild to moderate pain, paracetamol may be used via the oral or rectal route; however, in cases with severe pain, it may be used for its opioid sparing effects and a recent RCT has documented its opioid sparing effects in neonates.37 Although rectal paracetamol has a bioavailability almost similar to the oral formulation in neonates, many factors regulate ultimate absorption and at times it may be erratic. Paracetamol can be administered intravenously as its prodrug propacetamol, which is hydrolyzed very rapidly by plasma esterase to paracetamol even in neonates.

Paracetamol is an inhibitor of prostaglandin (PG) synthesis in the central nervous system and also acts peripherally by blocking impulse generation within the bradykinin-sensitive chemoreceptors responsible for the generation of afferent nociceptive impulses. Paracetamol may also inhibit substance P-mediated hyperalgesia and reduce nitric oxide generation involved in spinal hyperalgesia.38

Absorption of paracetamol is slower in neonates, probably due to a sluggish and prolonged gastric emptying.39 The hepatic enzyme systems responsible for the metabolism of paracetamol are incompletely developed in neonates.40 Preterm neonates have lower plasma albumin concentration that may give rise to a higher plasma concentration of free paracetamol. Total body water is higher in lower gestational age and more water is distributed in the extracellular space. The volume of distribution (Vd) of paracetamol may be greater with lower gestational age.41 However, the higher Vd in preterm infants is of minor significance and is unlikely to influence the loading dose.

The clearance of paracetamol is lower in neonates, particularly in preterm babies, and in addition, multiple doses of paracetamol should be given with a longer time interval (8–12 hours), or the total daily doses should be lowered to prevent progressive increasing of plasma concentrations. The plasma concentration of paracetamol should be 10–20 mg/mL to achieve antipyretic and analgesic effects.36 The dosing regimen suggested by Allegaert et al is the most widely used42 and is also recommended in a recent review43 (Table 1).

Table 1. Recommended paracetamol dosage in neonates.
Table 1.
Download full-size image

The reserves of glutathione needed for detoxification of the toxic metabolic intermediate from paracetamol (N-acetyl-p-benzoquinone) may be depleted after repeated therapeutic doses. The metabolic activation of paracetamol is a prerequisite for hepatotoxicity. Neonates can produce these potentially hepatotoxic metabolites, but there are suggestions of a lower activity of cytochrome P450 in neonates.44 This may explain the resistance to paracetamol-induced hepatotoxicity seen in neonates.

However, at present, the use of intravenous paracetamol in preterm neonates with a PCA of less than 32 weeks may not be justified before further pharmacokinetic/pharmacodynamic studies are conducted.45

9.2. Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of drugs having antipyretic, analgesic, and anti-inflammatory effects. They act by reducing PG biosynthesis through inhibition of cyclooxygenase (COX), which exists as two major isoforms (COX-1 and COX-2). The PGs produced by the COX-1 isoenzyme protect the gastric mucosa, regulate renal blood flow, and induce platelet aggregation. The anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2.

The NSAIDs are well established as a part of multimodal analgesia in older children. A recent meta-analysis46 of 27 RCTs concluded that use of perioperative NSAIDs is associated with less opioid consumption and postoperative nausea and vomiting. However, similar robust data in neonates are lacking until today. In 2004, a small observational study47 assessed the effect of ketorolac in neonates. They found ketorolac to be an effective analgesic at a dose of 1 mg/kg without any clinical and biochemical adverse effects on the renal, hepatic, or hematological system. Later, a retrospective review48 also reported similar results. In 2009, a study on the safety and efficacy of ketorolac in infants younger than 6 months of age concluded that intravenous ketorolac appears to be safe when used in infants less than 6 months of age with biventricular circulations following cardiothoracic surgery, but it does not decrease the use of standard analgesic therapy.49 However, in 2011, another retrospective analysis50 found that infants younger than 21 days and less than 37 weeks' completed gestational age are at significantly increased risk for bleeding events and should not be candidates for ketorolac therapy. In the absence of prospective RCTs, routine use of NSAIDs in neonates cannot be recommended at this time.

9.3. Opioids

Opioids are the mainstay of pain management following a major surgery even in neonates. Morphine is the most commonly used opioid in the postoperative period; however, fentanyl is also being increasingly used. Opioids exhibit narrow therapeutic window between analgesic doses and the dose that may cause respiratory depression.

Analgesia from opioid is mediated by spinal or supraspinal activation of opioid receptors, leading to decreased release of neurotransmitters from nociceptive neurons inhibiting the ascending neuronal pain pathways and altering the perception and response to pain.51 Opioid receptors also exist outside the central nervous system in the dorsal root ganglia and on the peripheral terminals of primary afferent neurons.52

Neonates receiving opioids should have continuous pulse oximetry monitoring and should be managed in a setting in which rapid intervention for airway management is possible, because respiratory-rate monitoring alone may be an inadequate predictor of impending apnea.53

9.4. Fentanyl

Fentanyl is almost 100 times more potent than morphine and is considered as a selective μ-receptor agonist. Fentanyl has a rapid, predictable onset of action with a short duration of action mostly due to its high lipid solubility. It is associated with greater hemodynamic stability.54 Fentanyl may be the preferred analgesic agent for critically ill patients with hemodynamic instability and patients with symptoms related to histamine release during morphine infusion.55 However, fentanyl may be associated with rapid development of tolerance5657 and chest wall rigidity.58

All metabolites of fentanyl are inactive and a small amount of fentanyl is eliminated by the renal route without metabolism. Fentanyl clearance can be impaired by decreased hepatic blood flow (e.g., from increased intra-abdominal pressure) in neonates after major abdominal surgery.59 The clearance of fentanyl is immature at birth but increases dramatically thereafter. Fentanyl clearance is 70–80% of adult values in term neonates and, standardized to a 70-kg person, appears to reach adult levels within the first 2 weeks of life.60

Fentanyl has been shown to effectively prevent preterm neonates from surgical stress responses and to improve postoperative outcomes.7 A large double-blind RCT concluded that fentanyl may be superior to morphine for short-term postnatal analgesia in newborn infants.61 Fentanyl may be used as bolus and/or as an intermittent dosing of 0.5–2.0 μg/kg or as a continuous infusion of 0.5–2.0 μg/kg/hour.62

9.5. Morphine

Morphine is the gold standard opioid with which all other opioids are compared and it is the most thoroughly investigated opioid in neonates. Morphine is water soluble and its solubility in lipids is poor compared with other opioids. Although morphine can also act on κ-opioid receptor subtypes,63 its analgesic effect is caused mainly by an activation of μ receptors.

Morphine alleviates postoperative pain,64 reduces behavioral and hormonal responses,65 improves ventilator synchrony,66 and may also reduce acute procedural pain.67

Morphine is metabolized in the liver by the enzyme uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).68 M3G has been shown to have higher analgesic potency than morphine and also has respiratory-depressive effects. M3G has been suggested to antagonize the antinociceptive and respiratory-depressive effects of morphine and M6G, and contributes to the development of tolerance. Although UGT2B7 is mainly found in the liver, it is also present in the intestines and kidneys.

Clinical trials studying morphine for postoperative analgesia have shown large interindividual variability in morphine plasma levels and a wide range of morphine requirements.69 However, neonates, particularly those younger than 7 days,65 require significantly less morphine as they have significantly higher plasma concentrations of morphine, M3G, and M6G, and significantly lower M6G-to-morphine ratio than the older children.70 Moreover, morphine metabolism may be delayed during mechanical ventilation.65

In the postoperative period, morphine can be used as either continuous infusion or intermittent bolus. However, the relative safety and efficacy of either method is controversial. One large RCT in thoracic and abdominal surgical population showed that the efficacy of continuous intravenous infusion of 10 μg/kg/hour morphine is similar to that of infusion of 30 μg/kg morphine every 3 hours after surgery.6471 Ventilatory effects of the aforementioned two morphine regimen are also similar and routine monitoring is mandatory69 during either of the protocol. The recommended dosage of continuous morphine infusion is 10–30 μg/kg/hour and that of the intermittent dose is 50–100 μg/kg.62 A meta-analysis concluded that an initial morphine dose of 7 μg/kg/hour in term neonates is optimum for postoperative analgesia.72

The use of morphine in the NICU for either postoperative pain or mechanical ventilation is not free from adverse outcomes. In a spontaneously breathing neonate, obviously the most important adverse effect is respiratory depression,73 but most neonates after major surgical procedures are mechanically ventilated. Respiratory depression may occur at plasma morphine concentrations of 15 ng/mL, and when measured by carbon dioxide response curves or by arterial oxygen tension, similar results are obtained in children from 2 to 570 days of age at the same serum morphine concentration.74

In mechanically ventilated neonates, the important adverse effects are hypotension,75 prolonged requirement of ventilation, urinary retention, decreased gastrointestinal (GI) motility, risk of necrotizing enterocolitis,76 and may be long-term neurobehavioral abnormalities as some animal data indicate. At times, morphine may not provide adequate analgesia for short painful procedures.77

However, the Neurological Outcome and Pre-emptive Analgesia in Neonates trial concluded that continuous infusions of morphine do not increase the vulnerability of ventilated preterm neonates to early adverse neurological events, except in neonates who are hypotensive before morphine therapy or those receiving doses higher than 10 μg/kg/hour.78 They also suggested that intravenous morphine boluses should be used with caution in preterm neonates.

An RCT79 published in 2003 did not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support as this was not associated with better neurologic outcomes. A Cochrane review also did not recommend routine morphine infusion in the ventilated newborns.80 However, the review did not find any difference in mortality, duration of mechanical ventilation, short-term and long-term neurobehavioral abnormalities but reported a delayed oral feeding.

The main argument against the treatment of neonatal pain with opioids is the uncertainty about their side effects.81 Animal studies on long-term effects of neonatal opioid use do not provide enough insight, and data from the human studies are even sparser. A study82 in 2009 evaluated the effects of cumulative procedural pain and morphine exposure with subsequent growth and development, and found that greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months' corrected chronological age. A recent pilot study83 also concluded that morphine analgesia for procedural pain in preterm neonates may be associated with delayed growth and development. By contrast, in 2005, Grunau et al13 found that repeated neonatal procedural pain exposure among preterm infants was associated with downregulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. In another recent prospective observational study,84 it was found that repetitive procedural pain in preterm infants during a period of physiological immaturity appears to impact postnatal growth and development.

10. Regional anesthesia/analgesia

Although single-injection subarachnoid block (SAB) is the commonly performed regional technique in adults and usually provides immediate postoperative analgesia, SAB is of little use in neonates for postoperative analgesia due to its limited duration of action in this age group.

11. Epidural anesthesia in neonates: risk versus benefits

Epidural analgesia has been investigated as a modality of pain relief after major surgeries. There is only one RCT85 that has directly compared the safety and efficacy of epidural analgesia with systemic opioid administration after a major surgery in neonates. The authors reported a faster return of intestinal function and less incidence of pneumonia in neonates who received epidural analgesia. In 2011, a small RCT86 compared the benefits of combined spinal–epidural anesthesia with general anesthesia in neonates undergoing GI surgery. The authors found a significantly less pulmonary complication and more cardiovascular stability in the regional anesthesia group in the postoperative period. Somri et al87 reported that combined spinal–epidural anesthesia could be considered as an effective alternative to general anesthesia in high-risk neonates and infants undergoing upper GI surgery when cautiously used by a pediatric anesthesiologist.

Bösenberg88 in 1998 reported that use of lumbar/thoracic epidural analgesia in major abdominal surgeries in neonates was associated with a low risk of complication and advantages of reduced need for intraoperative muscle relaxants and opioid analgesics and postoperative ventilatory support.89 In 2009, Shenkman et al90 reported safe use of continuous epidural analgesia in small infants (1400–4300 g) undergoing major surgery. Neuraxial blockade was not found to be associated with hypotension or hemodynamic instability even in neonates with congenital heart disease.91 Regional analgesia may also have respiratory stimulant action,92 and has been associated with reduced need for mechanical ventilation. Surgical stress response is more effectively mitigated by regional anesthesia in comparison with systemic opioid and it is also free of immunosuppressive effects of opioids.9394

The most important consideration in central neuraxial block in neonates is the safety and possibility of inadvertent injury to the developing spinal cord. Serious complications including neurologic injury have been reported in neonates,95 and many authors8788 have mentioned that only an experienced pediatric anesthesiologist should perform central neuraxial block in neonates.

12. Epidural catheter insertion: thoracic catheter position through caudal route

Although thoracic epidural catheters have been described in neonates96 in some reports, its routine use at this moment cannot be advocated. However, relative fluidity of the epidural fat in neonates and young infants allows advancement of thoracic catheter inserted through the caudal or lumbar route.

In 1988, Bösenberg et al97 described the successful insertion of an 18G epidural catheter up to the thoracic level. A thicker gauge catheter is easier to advance but has a higher possibility of neural damage.9899 There are numerous ways of confirming epidural catheter position, including X-ray,100 electrocardiography,101 ultrasonography,102 and even transesophageal echocardiography.103

The lumbar epidural route is less preferred in neonates,104 and there are reports of paraplegia due to intraspinal hematoma during attempted lumbar epidural block.105 The advent of ultrasound may be especially useful in neonates as the ossification of the vertebral column is reduced and the cord structures may be better visualized.106

13. Local anesthetic dosing

The most important prerequisite of an epidural block is that the tip of the epidural catheter should be situated at an intraspinal level that corresponds to the dermatome center of the surgical procedure. Caudal bolus injection of 3 mg/kg ropivacaine or a continuous epidural infusion of 0.2–0.4 mg/kg/hour of the same drug was clinically effective and did not result in excessive plasma levels of the drug.107 In an Anesthesia Patient Safety Foundation–sponsored study, it was found that all the children who had systemic toxicity had infusion rates in excess of 0.5 mg/kg/hour of racemic bupivacaine.108 In a recent review, a maximum bolus dosage of 1.5–2.0 mg/kg followed by an infusion of 0.2 mg/kg/hour was recommended; in addition, this should only be continued beyond 48 hours when considerable benefits exist.107

14. Conclusion

Despite various opinions regarding the methods of optimum postoperative pain management in neonates, there is little doubt that neonates feel more pain than their older counterparts. Intravenous opioids with the use of morphine or fentanyl remain the most common modality of neonatal pain management. The role of acetaminophen in decreasing opioid requirement seems to be promising. Although ketorolac appears to be safe, further studies are required before its routine use can be recommended. Epidural analgesia/anesthesia when performed by an experienced anesthesiologist is quite safe and has several benefits over systemic opioids. In cases where technical and logistic feasibility is present, it may be a logical option as a part of balanced anesthesia technique.


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