Anestesia Pediatrica e Neonatale

Ringraziamo eMedicine.com, Inc per la cortese collaborazione ai fini della realizzazione di questo articolo oltre agli Autori dello stesso, Napoleon Burt, MD e Jeana Havidich, MD
(Dario Galante, MD, Scientific Manager)

Editor(s): Shelley C Springer, MD, MBA, MSc , Neonatologist; Medical Director of Pediatric Transport Team, Assistant Professor of Pediatrics, Department of Pediatrics, Gundersen Lutheran Hospital; Robert Konop, PharmD , Clinical Assistant Professor, Department of Pharmacy, Section of Clinical Pharmacology, University of Minnesota; Arun Pramanik, MD , Professor, Department of Pediatrics, Division of Neonatology, Louisiana State University Health Science Center; Carol L Wagner, MD , Associate Professor, Department of Pediatrics, Division of Neonatology, Medical University of South Carolina; and Neil N Finer, MD , Director, Division of Neonatology, Professor, Department of Pediatrics, University of California at San Diego.

The practice of medicine has become progressively more sophisticated. Physicians can now achieve the goal of facilitating the healing process while simultaneously minimizing or even eliminating the pain once thought necessary to achieve this goal. Adults were the first to benefit from these advances. Only within the last 2 decades has the sophisticated medical establishment realized that pediatric patients, including neonates, also feel pain and require medical intervention to alleviate unnecessary suffering.

Medical intervention to alleviate unnecessary suffering is significantly affected by the beliefs of the caregiver. Before the late 1980s and early 1990s, the belief remained commonplace that neonates experienced no pain or less pain than adults, children, or infants who underwent similar surgical procedures. A health care provider who believes that neonates feel less pain tends to observe fewer clinical signs of pain in neonates. Furthermore, this group of practitioners tends to believe that narcotic administration is associated with increased risk in neonates.

These practitioners may administer narcotic analgesics; however, less aggressive intervention and, frequently, subtherapeutic regimens are employed in preverbal patients as compared to adults.

The fear of respiratory depression most significantly limits the administration of narcotics postoperatively, especially in nonintubated neonates or neonates undergoing minor surgical procedures. While these concerns may have some pharmacologic basis, they should not prevent the appropriate administration of narcotic analgesics to neonates who have experienced significant surgery.

Furthermore, other therapeutic regimens formerly reserved for adults, adolescents, and older children may also be used safely to manage postoperative pain for the neonate. This article expressly and specifically considers the application of medical advances in pain management to the care of our youngest perioperative patients, neonatal surgical patients.

Suffering can be minimized during the preoperative visit when physicians avoid unnecessary laboratory studies, especially those that require phlebotomy. Furthermore, inappropriately long NPO (ie, nothing by mouth) periods can be eliminated, thereby avoiding unwarranted patient agitation. Postoperative pain management should be discussed when the surgical neonate and family are seen preoperatively. Issues that may eventually affect decisions about postoperative pain management, and should therefore be addressed, include coexisting disease states, surgical site, postoperative disposition, and family consent for pain management techniques that are being considered.

Neonates who are unstable, septic, or likely to remain intubated postoperatively are frequently managed with narcotic administration intraoperatively and are continued on narcotics as needed postoperatively. Narcotic administration is pursued more cautiously in neonates who will be in a non-ICU setting postoperatively. Neonates undergoing outpatient surgery or surgery associated with minor postoperative pain are frequently managed postoperatively with acetaminophen with regional or local anesthetic infiltration. Neonates who undergo lower extremity, abdominal, or thoracic surgery are excellent candidates for regional anesthesia, whether undergoing inpatient or outpatient surgery. As in adults, coexisting pulmonary disease in neonates may be an excellent reason to consider regional anesthesia for postoperative pain management. Finally, anxiety among family members concerning a pain control strategy should be thoroughly addressed and considered in postoperative pain management decision-making.

After extensive work in the 1980s and 1990s, the fact that neonates experience pain and mount a stress response has been established and appreciated. Metabolic and hormonal indicators of the degree of stress a surgical patient experiences have been monitored during and after surgery. These indicators are, in fact, elevated in neonates perioperatively. Even premature neonates undergoing surgery are capable of mounting a significant stress response, as measured by hormonal and metabolic indicators. Stress indicators include plasma adrenaline, noradrenaline, glucagon, insulin, and cortisol as well as blood glucose, lactate, pyruvate, and alanine.

The mounting of a surgical stress response results in catabolic responses, including glycogenolysis, gluconeogenesis, and lipolysis during the perioperative period. These catabolic responses, when unmodulated by medical intervention, may have a detrimental effect on the clinical course of a neonatal surgical patient. Adverse circulatory and respiratory events are also more likely during the postoperative course of neonates who have had inadequate interventions to minimize stress response. Tachycardia, systemic hypertension, pulmonary hypertension, respiratory embarrassment, and intraventricular hemorrhage may be associated with inadequate pain control in neonates. Furthermore, inadequate treatment of pain in neonates may have implications that extend beyond the neonatal period, including hypersensitivity to noxious stimuli later in life.

To a large extent, management of the surgical stress response in neonates can be accomplished with the same pharmacologic interventions that characterize anesthetic care of other surgical patients. Volatile anesthetic agents remain the most common means of providing anesthesia and analgesia intraoperatively. This is probably because they meet, at least to some degree, each of the criteria required for a complete anesthetic, including some degree of hypnosis, amnesia, analgesia, and muscle relaxation. Anand demonstrated that blood levels of hormonal and metabolic indicators of the stress response were lower in neonates who received volatile anesthetics during surgery. Furthermore, clinical stability of neonates during and after surgery was improved by adequate administration of volatile anesthetic agents intraoperatively.

The relative potency of each volatile anesthetic agent is measured in terms of the minimum alveolar concentration (MAC) of an inhaled anesthetic agent at which 50% of patients do not have skeletal muscle movement in response to surgical incision or another noxious stimulus. The patient's age appears to influence the MAC of a given volatile anesthetic, and MAC is higher in infants than in any other age group. MAC may be 15-25% lower in neonates than in infants and is even lower in premature neonates. Volatile anesthetic agents are potent myocardial depressants and vasodilators.

Consequently, systolic blood pressure and mean arterial blood pressure may decrease when these agents are administered. In some neonates, other analgesic agents may be used to decrease volatile anesthetic agent requirements intraoperatively, thereby avoiding some of the hemodynamic changes that may occur with volatile anesthetic administration.

In fact, surgical anesthesia can be accomplished without the use of any volatile anesthetic agents.

Narcotics are not complete anesthetic agents; they do not provide muscle relaxation or amnesia, which are essential functions of complete anesthetics. However, they are potent analgesic medications. Administration of these agents intraoperatively may be associated with less of a decrease in blood pressure in neonates than might occur with volatile anesthetic administration. Furthermore, narcotics are useful adjuncts to anesthetics based on volatile agents because they can reduce the volatile agent requirement, thereby reducing any hemodynamic lability. Narcotic-based anesthetics are commonly used during cardiovascular procedures in neonates.

Physicians should note that the pharmacokinetics of narcotics administered to neonates differs from that of older infants, children, and adolescents. Neonates have a lower clearance, greater volume of distribution, longer elimination half-life, and higher plasma concentration after narcotic boluses than older patients. Consequently, the postoperative disposition of neonates may be affected when narcotics are used intraoperatively. Narcotics commonly used for intraoperative analgesia in neonates include morphine, fentanyl, sufentanil, and remifentanil.

Ketamine, a phencyclidine derivative, produces amnesia and intense analgesia. This drug affects opioid receptors and N -methyl-D-aspartate (NDMA) receptors, as well as voltage-sensitive calcium ion channels as it induces its analgesic effects. Ketamine actually stimulates the cardiovascular system and thus is frequently associated with increases in both systolic and mean arterial blood pressure, as well as heart rate, when administered intraoperatively. While ketamine may not be associated with increased blood pressure in preterm neonates, it is certainly associated with smaller decreases in mean arterial pressure and systolic blood pressure than the other analgesic medications commonly used intraoperatively. Beneficial effects of ketamine include production of bronchodilation and less depression of ventilation. Adverse effects that may occur in neonates include increased salivary and tracheobronchial secretion production, cerebral vasodilation, and apnea in neonates with increased intracranial pressure

One factor that has contributed to inadequate pain management in neonates has been the pervasive belief that neonates do not feel pain. This misconception has been perpetuated, at least in part, by the conspicuous absence of adequate tools to assess pain levels in this patient population. To a large extent, pain assessment in older patients relies upon the patient's ability to report pain level in some form to the caregiver. When patients cannot express pain verbally, pain assessment depends more on evaluations by the caregiver. Even when pain is evident, quantifying the pain level is not easy. An effective pain assessment tool must be able to objectively quantify the pain level of the patient so that the healthcare provider can accurately measure the effectiveness of interventions designed to alleviate unnecessary suffering. Although no perfect tool exists yet for assessing pain in neonates, infants, and preverbal children, several very useful tools are available.

The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) was one of the first observational pain scales. This tool includes the categories of (1) cry, (2) facial expression, (3) verbal response, (4) torso position, (5) leg activity, and (6) arm movement in relationship to the surgical wound. In general, each category is scored 0, 1, 2, or 3, with higher scores indicating higher pain levels, but the scale varies with each category evaluated. Originally, CHEOPS was used to evaluate postoperative pain in children aged 1-7 years. Evaluators determined that it was both valid and reliable for assessing pain in this patient group. Admittedly, a pain assessment tool that is appropriate for other preverbal children may not be appropriate for neonates. However, the development of CHEOPS has provided a tool against which the validity of other pediatric pain assessment tools can be measured.

The Objective Pain Scale (OPS), developed by Broadman and Hannallah, has demonstrated both validity and reliability in pain assessment. OPS assesses (1) blood pressure, (2) crying, (3) movement, (4) agitation, (5) posture, and (6) verbalization. Each parameter is scored 0, 1, or 2, with higher scores indicating greater distress. This instrument is important because it includes a cardiovascular parameter in the assessment of postoperative pain. Many advocate use of cardiovascular parameters as the most objective means of measuring the pain response in preverbal children. However, the utility of cardiovascular parameters is limited because other causes of distress may also cause dramatic changes in these parameters. Cardiovascular parameters, while not sufficient as the sole means of assessing pain in this patient population, may be helpful. Unfortunately, OPS, like CHEOPS, has been used largely for infants and children, not neonates.

The COMFORT scale has been favorably received as a tool to assess postoperative pain in the neonatal population. This tool was originally developed to assess distress in ventilated patients in the pediatric ICU. However, the COMFORT scale demonstrated reliability and validity for assessing pain in postoperative patients in one large study that evaluated pain in 158 neonates along with older infants and children.

This scale is composed of 6 behavioral items, (1) alertness, (2) calmness, (3) muscle tone, (4) movement, (5) facial tension, and (6) respiratory response, and 2 physiologic items, (1) heart rate and (2) mean arterial blood pressure. Each item may be scored 1, 2, 3, 4, or 5, with a higher score indicating a greater level of distress. The greater number of variables assessed and the increased number of scores possible for each variable may enable this tool to identify more subtle changes in patient discomfort. On the other hand, greater complexity may be a disadvantage in terms of the clinical utility of this scale.

A fourth scale, CRIES, may also be useful to assess the pain of neonates postoperatively. This scale analyzes 5 variables, (1) crying, (2) requirement of increased oxygen administration, (3) increased vital signs, (4) expression, and (5) sleeplessness. Each variable is scored 0, 1, or 2. This instrument has demonstrated validity, reliability, user friendliness, and acceptance as a postoperative pain assessment tool among neonatal intensive care nurses.

Each of the pain assessment instruments discussed has strengths and limitations. For optimal use of any pain assessment tool, the physicians and neonatal nursing staff of a given hospital should select a tool, familiarize staff with its use, and systematically integrate its use into the institution's policies. This maintains the validity and reliability of the tool in measuring pain in neonates and allows appropriate intervention to be undertaken, thereby minimizing unnecessary suffering in the postoperative neonatal patient.

After appropriate pain assessment practices are established, the most formidable hindrance to alleviating postoperative pain in neonates is unfamiliarity with the safety and practicality of the pain management options. Implementing an effective pain management strategy in the neonatal surgical patient is a complex process. The strategy for pain management should begin during the preoperative assessment and continue with the intraoperative anesthetic management as formerly discussed. Furthermore, the physician responsible for pain management must be aware that pain management has an impact upon the other components of postoperative care. When treating pain in neonates, one must consider the pharmacodynamic and pharmacokinetic issues unique to the neonatal period, the severity of the surgical insult and any coexisting diseases in the patient, the surgical site, the postoperative management plans of the surgeons and neonatal or pediatric physicians, and the disposition of the neonate postoperatively.

Opioid administration remains the most common means of achieving pain control in surgical patients. Neonates who are expected to have moderate-to-severe postoperative pain are no exception. Opioids may be administered safely to neonates when a well-constructed pain management plan is implemented. While certainly not prohibitive, the risk of apnea cannot be ignored. As during the intraoperative period, more than one opioid may be considered in managing postoperative pain in the surgical neonate. Fentanyl and morphine are the most common selections for postoperative opioid administration.

This drug is most appropriately administered by IV infusion to neonates who are ventilated preoperatively and are expected to remain ventilated for a period postoperatively. When administered by IV bolus (2 mcg/kg/h), fentanyl is associated with more severe episodes of apnea than continuous IV infusion (1-2 mcg/kg/h). However, respiratory depression may be less problematic when fentanyl is used in older infants. As with many other medications administered to neonates, fentanyl pharmacokinetics are highly variable. Of particular interest, neonates who postoperatively have increased abdominal pressure may have a prolonged fentanyl half-life because of impaired hepatic blood flow.

Morphine remains the opioid analgesic most commonly used for moderate-to-severe pain in neonates postoperatively. Surgical procedures that may be included in this category include craniotomy, thoracotomy, sternotomy, and laparotomy. Incremental IV boluses of 20 mcg/kg, not to exceed 100 mcg/kg, are typically administered for acute pain management in the postanesthesia recovery unit. When a continuous IV infusion is used for postoperative pain management in neonates, the initial rate varies depending upon the age of the neonate.

Initial IV infusion rates of 10 mcg/kg/h for neonates younger than 1 week are acceptable. Neonates older than 1 week tolerate 15 mcg/kg/h, while older infants may tolerate 20-40 mcg/kg/h. Supplemental IV boluses of up to 50 mcg/kg may be administered for breakthrough pain episodes in neonates receiving morphine by continuous infusion. No difference exists in the respiratory response to morphine in term neonates compared to older infants and children when identical plasma levels of morphine are achieved and maintained. Greater caution may be advisable when initiating morphine infusions in preterm neonates, who may require significantly lower infusion rates to achieve the same plasma levels of morphine as term neonates. Above a steady-state plasma concentration of 20 ng/mL, respiratory depression becomes more likely in all neonates.

Practitioners who administer morphine infusions for postoperative pain control should be aware of the pharmacokinetic disadvantages, which place neonates at risk for respiratory depression (because of increased plasma concentrations). Neonates have immature hepatic enzyme systems. This may result in a doubling of the elimination half-life of morphine in neonates (ie, 10-20 h) compared with older infants (ie, 5-10 h). Lower plasma protein levels in neonates may result in higher levels of free drug and slower plasma clearance of morphine. Morphine clearance in neonates may be as little 50% of that of older infants and 25% of adult values. Furthermore, the rate of glucuronidation (the primary metabolic pathway of morphine) is slower in neonates compared to older infants and adults.

Coexisting surgical and medical conditions may impact the pharmacokinetics of morphine in neonates. As mentioned before, abdominal surgery that results in increased abdominal pressure postoperatively may impair drug metabolism or drug elimination, thus increasing the half-life of these medications. Additionally, the pharmacokinetics of medications may be different in neonates with cardiac comorbidity compared to those without congenital heart disease. Whether this is secondary to impaired cardiac performance or the impact of abnormal circulatory dynamics on hepatic or renal function is unclear. Use of preservative-free morphine should also be considered because neonates are more susceptible to respiratory depression caused by some preservatives.

Seldom used for postoperative management of pain in neonates, meperidine can be administered in doses of 1 mg/kg. However, its pharmacokinetic profile shows dramatic variability in individual neonates. Furthermore, meperidine has epileptogenic metabolites, which tend to accumulate in patients with impaired renal function, as is inherent in the neonatal period. In the author's opinion, the disadvantages of meperidine outweigh the advantages of its use in the neonatal patient.

Nonnarcotic pain management modalities are important in pain management of the postoperative neonate. Acetaminophen is useful either as a sole analgesic for mild discomfort or as an adjuvant medication for moderate-to-severe pain when narcotic or regional analgesia is employed. Either oral or rectal administration may be employed. Rectal administration is associated with lower plasma levels and a longer elimination half-life. While 15 mg/kg may be administered orally, this dose is associated with subtherapeutic plasma levels when administered rectally to neonates. An initial dose of 20-35 mg/kg is recommended for the initial preincision dose or the immediate postoperative dose administered per rectum.

Ketorolac is not approved by the Food and Drug Administration (FDA) for use in neonates, and reports of its use in this patient population are absent from the literature. Moreover, ketorolac may be no more effective than high-dose rectal acetaminophen in some older patients.

A discussion of nonnarcotic pain modalities would be incomplete without a discussion of nonpharmacologic interventions. While these modalities, in some fashion, may be employed with older patients, they are considered central to the pain management of neonates. These modalities include bundling, holding, and rocking the neonate, provision of a pacifier to alleviate distress, and minimization of environmental stimuli such as extraneous noise and unnecessary light.

Regional pain control techniques are increasingly employed to manage postoperative pain in neonates. Regional techniques may include single-dose administration of local anesthetics into the caudal space, plexus blockade of the upper or lower extremity, extrapleural catheter placement, or neuraxial catheter placement for continuous pain control postoperatively. The most common regional techniques in neonates include single-dose caudal administration and placement of epidural catheters for prolonged pain management.

Caudal anesthesia is a highly effective simple technique associated with a high success rate and a low complication rate. Caudal anesthesia is neuraxial anesthesia and thus is associated with some of the risks inherent to neuraxial access. However, because the neuraxial space is accessed at its most caudad entry point, the risk of neural injury or even inadvertent dural puncture is reduced. Sterile technique is required and may be accomplished by wearing sterile gloves or palpating the caudal space anatomy through an alcohol swab (ie, no-touch technique) before instilling a single dose of medication into the caudal space.

Use a short beveled needle to minimize the likelihood of inadvertent intravascular or intramedullary injection of the local anesthetic medication. A caudal anesthetic can be successfully administered in 96% of pediatric patients. Once the sacrococcygeal ligament has been penetrated with the regional anesthetic needle, lower the angle of the needle, advance the needle no more than 3-5 mm, aspirate the syringe to ensure the absence of cerebral spinal fluid or heme, and administer the local anesthetic. Most commonly, bupivacaine is administered for single-dose caudal blocks. Effective concentrations range from 0.125-0.25% bupivacaine. Volumes of 0.75-1 mL/kg are administered. Supplemental analgesics may not be required for up to 12 hours postoperatively when the caudal is effective.

Placement of a caudal, lumbar, or even thoracic catheter for continuous postoperative pain management has also been proven safe and effective in neonates. An epidural catheter may be successfully placed via the caudal approach and advanced cephalad to the lumbar or thoracic level. Using superficial anatomic landmarks as a guide, the level of the catheter may be accurately predicted. This catheter may then be used for postoperative infusion of narcotics or local anesthetic infusions. Epidural catheters have been successfully used for postoperative management of many major neonatal surgical procedures that require laparotomy or thoracotomy, including hepatic resection, abdominal wall defects (gastroschisis and omphalocele), tracheoesophageal fistula, congenital diaphragmatic hernia, and coarctation of the aorta. After successful placement and an initial bolus dose of the epidural catheter, pain management may be maintained with a continuous infusion of analgesic medications.

Epidural infusions provide an acceptable alternative to the intermittent top-up technique. Epidural infusions are both safe and effective in term and preterm neonates. Postoperative epidural bupivacaine infusions result in significantly less sedation, less depression of the respiratory rate, and improvement in oxygenation without supplemental oxygen administration, while providing similar analgesia and similar complication and hemodynamic profiles to a morphine infusion.

In 1992, Berde reported recommendations to facilitate safe use of epidural analgesia in pediatric patients after analysis of more than 20,000 pediatric regional anesthetic procedures in 15 institutions. Berde recommended bolus dosing of epidural bupivacaine not to exceed 2-2.5 mg/kg. Infusion rates of 0.2-0.25 mg/kg/h were recommended for neonates. This paper cautioned that children are probably not more resistant to local anesthetic toxicity than adults, as had been previously thought. Neonates, in particular, may be at risk for local anesthetic toxicity because of diminished plasma alpha1-acid glycoprotein levels, which could result in a higher free fraction and slower clearance of bupivacaine. Premonitory symptoms or signs of local anesthetic toxicity may be absent in neonates. Reduce infusion rates for patients at risk for seizures.

When the epidural catheter level is too low to provide adequate analgesia at the incision site for a neonatal patient, increasing the rate of the epidural infusion cannot safely overcome this low catheter level. In one study, plasma bupivacaine levels continued to increase over a 48-hour infusion period, reaching the upper limits of the safe range before the end of this 48-hour period. In addition, plasma levels of bupivacaine were higher in neonates who were at higher risk for increased abdominal pressure postoperatively. Furthermore, as with all drugs administered during the neonatal period, interindividual variability in plasma bupivacaine levels were considerable in neonates receiving epidural infusions. While plasma clearance is lower in neonates than in adults receiving epidural infusions, this difference is even more dramatic in preterm neonates.

Altimier L, Norwood S, Dick MJ: Postoperative pain management in preverbal children: the prescription and administration of analgesics with and without caudal analgesia. J Pediatr Nurs 1994 Aug; 9(4): 226-32 [Medline] .
Ambuel B, Hamlett KW, Marx CM: Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992 Feb; 17(1): 95-109 [Medline] .
American Academy of Pediatrics: Neonatal anesthesia. Pediatrics 1987 Sep; 80(3): 446 [Medline] .
Anand KJ, Sippell WG, Aynsley-Green A: Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response [published erratum appears in Lancet 1987 Jan 24;1(8526):234]. Lancet 1987 Jan 10; 1(8524): 62-6 [Medline] .
Anand KJ, Sippell WG, Schofield NM: Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J (Clin Res Ed) 1988 Mar 5; 296(6623): 668-72 [Medline] .
Anand KJ, Aynsley-Green A: Measuring the severity of surgical stress in newborn infants. J Pediatr Surg 1988 Apr; 23(4): 297-305 [Medline] .
Anand KJ, Brown MJ, Bloom SR: Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery. Horm Res 1985; 22(1-2): 115-28 [Medline] .
Anand KJ, Brown MJ, Causon RC: Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg 1985 Feb; 20(1): 41-8 [Medline] .
Andrews K, Fitzgerald M: The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain 1994 Jan; 56(1): 95-101 [Medline] .
Berde CB: Convulsions associated with pediatric regional anesthesia. Anesth Analg 1992 Aug; 75(2): 164-6 [Medline] .
Bosenberg AT: Epidural analgesia for major neonatal surgery. Paediatr Anaesth 1998; 8(6): 479-83 [Medline] .
Cameron CB, Robinson S, Gregory GA: The minimum anesthetic concentration of isoflurane in children. Anesth Analg 1984 Apr; 63(4): 418-20 [Medline] .
Campbell NN, Reynolds GJ, Perkins G: Postoperative analgesia in neonates: an Australia-wide survey. Anaesth Intensive Care 1989 Nov; 17(4): 487-91 [Medline] .
Cass LJ, Howard RF: Respiratory complications due to inadequate analgesia following thoracotomy in a neonate. Anaesthesia 1994 Oct; 49(10): 879-80 [Medline] .
Choonara I, Lawrence A, Michalkiewicz A: Morphine metabolism in neonates and infants. Br J Clin Pharmacol 1992 Nov; 34(5): 434-7 [Medline] .
Dalens B, Hasnaoui A: Caudal anesthesia in pediatric surgery: success rate and adverse effects in 750 consecutive patients. Anesth Analg 1989 Feb; 68(2): 83-9 [Medline] .
Farrington EA, McGuinness GA, Johnson GF: Continuous intravenous morphine infusion in postoperative newborn infants. Am J Perinatol 1993 Jan; 10(1): 84-7 [Medline] .
Friesen RH, Henry DB: Cardiovascular changes in preterm neonates receiving isoflurane, halothane, fentanyl, and ketamine. Anesthesiology 1986 Feb; 64(2): 238-42 [Medline] .
Greeley WJ, de Bruijn NP, Davis DP: Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg 1987 Nov; 66(11): 1067-72 [Medline] .
Gunter JB, Eng C: Thoracic epidural anesthesia via the caudal approach in children. Anesthesiology 1992 Jun; 76(6): 935-8 [Medline] .
Hannallah RS, Broadman LM, Belman AB: Comparison of caudal and ilioinguinal/iliohypogastric nerve blocks for control of post-orchiopexy pain in pediatric ambulatory surgery. Anesthesiology 1987 Jun; 66(6): 832-4 [Medline] .
Hertzka RE, Gauntlett IS, Fisher DM: Fentanyl-induced ventilatory depression: effects of age. Anesthesiology 1989 Feb; 70(2): 213-8 [Medline] .
Hopkins CS, Underhill S, Booker PD: Pharmacokinetics of paracetamol after cardiac surgery. Arch Dis Child 1990 Sep; 65(9): 971-6 [Medline] .
Kart T, Christrup LL, Rasmussen M: Recommended use of morphine in neonates, infants and children based on a literature review: Part 2--Clinical use. Paediatr Anaesth 1997; 7(2): 93-101 [Medline] .
Kart T, Christrup LL, Rasmussen M: Recommended use of morphine in neonates, infants and children based on a literature review: Part 1--Pharmacokinetics. Paediatr Anaesth 1997; 7(1): 5-11 [Medline] .
Koehntop DE, Rodman JH, Brundage DM: Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986 Mar; 65(3): 227-32 [Medline] .
Koren G, Butt W, Chinyanga H: Postoperative morphine infusion in newborn infants: assessment of disposition characteristics and safety. J Pediatr 1985 Dec; 107(6): 963-7 [Medline] .
Krechel SW, Bildner J: CRIES: a new neonatal postoperative pain measurement score. Initial testing of validity and reliability. Paediatr Anaesth 1995; 5(1): 53-61 [Medline] .
Larsson BA, Lonnqvist PA, Olsson GL: Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg 1997 Mar; 84(3): 501-5 [Medline] .
Lerman J, Robinson S, Willis MM: Anesthetic requirements for halothane in young children 0-1 month and 1- 6 months of age. Anesthesiology 1983 Nov; 59(5): 421-4 [Medline] .
Lynn A, Nespeca MK, Bratton SL: Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg 1998 May; 86(5): 958-63 [Medline] .
Lynn AM, Nespeca MK, Opheim KE: Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993 Oct; 77(4): 695-701 [Medline] .
Lynn AM, Slattery JT: Morphine pharmacokinetics in early infancy. Anesthesiology 1987 Feb; 66(2): 136-9 [Medline] .
McCloskey JJ, Haun SE, Deshpande JK: Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesth Analg 1992 Aug; 75(2): 287-90 [Medline] .
McGrath PJ, Johnson G, Goodman JT: CHEOPS: A Behavioral Scale for Rating Postoperative Pain in Children. In: Advances in Pain Research and Therapy. Vol 9. New York, NY: Raven Press; 1985: 395-402.
McLaughlin CR, Hull JG, Edwards WH: Neonatal pain: a comprehensive survey of attitudes and practices. J Pain Symptom Manage 1993 Jan; 8(1): 7-16 [Medline] .
Murrell D, Gibson PR, Cohen RC: Continuous epidural analgesia in newborn infants undergoing major surgery. J Pediatr Surg 1993 Apr; 28(4): 548-52; discussion 552-3 [Medline] .
Pokela ML, Olkkola KT, Koivisto M: Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants. Clin Pharmacol Ther 1992 Oct; 52(4): 342-9 [Medline] .
Porter FL, Porges SW, Marshall RE: Newborn pain cries and vagal tone: parallel changes in response to circumcision. Child Dev 1988 Apr; 59(2): 495-505 [Medline] .
Purcell-Jones G, Dormon F, Sumner E: The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987 Dec; 42(12): 1316-20 [Medline] .
Purcell-Jones G, Dormon F, Sumner E: Paediatric anaesthetists' perceptions of neonatal and infant pain. Pain 1988 May; 33(2): 181-7 [Medline] .
Ralston DH, Shnider SM: The fetal and neonatal effects of regional anesthesia in obstetrics. Anesthesiology 1978 Jan; 48(1): 34-64 [Medline] .
Rasch DK, Webster DE, Pollard TG: Lumbar and thoracic epidural analgesia via the caudal approach for postoperative pain relief in infants and children. Can J Anaesth 1990 Apr; 37(3): 359-62 [Medline] .
Rusy LM, Houck CS, Sullivan LJ: A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy: analgesia and bleeding. Anesth Analg 1995 Feb; 80(2): 226-9 [Medline] .
Singleton MA, Rosen JI, Fisher DM: Plasma concentrations of fentanyl in infants, children and adults. Can J Anaesth 1987 Mar; 34(2): 152-5 [Medline] .
Taddio A, Goldbach M, Ipp M: Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet 1995 Feb 4; 345(8945): 291-2 [Medline] .
van Dijk M, de Boer JB, Koot HM: The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000 Feb; 84(2-3): 367-77 [Medline] .
Vaughn PR, Townsend SF, Thilo EH: Comparison of continuous infusion of fentanyl to bolus dosing in neonates after surgery. J Pediatr Surg 1996 Dec; 31(12): 1616-23 [Medline] .
Vetter TR: Pediatric patient-controlled analgesia with morphine versus meperidine. J Pain Symptom Manage 1992 May; 7(4): 204-8 [Medline] .
Wolf AR, Hughes D: Pain relief for infants undergoing abdominal surgery: comparison of infusions of i.v. morphine and extradural bupivacaine. Br J Anaesth 1993 Jan; 70(1): 10-6 [Medline] .

Perioperative Pain Management in Newborns

Napoleon Burt, MD (1), Jeana Havidich, MD (2)

(1) Director of Pediatric Anesthesia, Associate Professor, Assistant Program Director, Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, (2) Assistant Professor, Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina