The substance P receptor antagonist CP-99,994 reduces acute postoperative pain.

BACKGROUND: Animal studies suggest that substance P, a peptide that preferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammation. METHODS: The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surgery: 750 microg/kg CP-99,994 infused intravenously over 5 hours on a tapering regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects were randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset. RESULTS: In the first study, ibuprofen significantly reduced pain, as measured by visual analog scale, from 90 to 240 minutes postoperatively compared with placebo. CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 60, 90, and 120 minutes (P < 0.05). The incidence of side effects was similar across groups. CONCLUSIONS: This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis that substance P contributes to the generation of pain in humans. The reduction in postoperative pain at doses not producing side effects suggests that NK1 antagonists may be clinically useful.

Regional analgesia on pediatric medical and surgical wards.

Regional anesthetic approaches to pain management were examined in 72 children and young adults (ages 3 weeks to 31 years) who were observed on the surgical or medical wards of a children's hospital separate from intensive care areas. A protocol was devised to permit safe conduct of these techniques on the ward. Full resuscitation supplies were kept at each bedside. All patients receiving epidural narcotics had an apnea monitor, hourly counting of respiratory rates, and restriction of systemic analgesics. All bolus re-injections into the catheters were performed by an anesthesiologist who monitored the patient for 20 min. Minor side-effects, including pruritus, nausea, and urinary retention were common, but manageable. Significant complications included: one case of decubitus ulcers requiring skin-grafting, one episode of mild hypotension in a patient with terminal malignancy, requiring ephedrine and phenylephrine, and one mild toxic reaction on test dosing due to presumed intravascular migration of a lumber sympathetic catheter. Regional analgesic techniques can provide excellent analgesia on the wards for selected children and young adults, provided precautions are taken. Further study is required to define specific indications, risks and benefits relative to simpler techniques.

Chest wall motion of infants during spinal anesthesia.

To test the extent to which diaphragmatic contraction moves the rib cage in awake supine infants during quiet breathing, we studied chest wall motion in seven prematurely born infants before and during spinal anesthesia for inguinal hernia repair. Infants were studied at or around term (postconceptional age 43 +/- 8 wk). Spinal anesthesia produced a sensory block at the T2-T4 level, with concomitant motor block at a slightly lower level. This resulted in the loss of most intercostal muscle activity, whereas diaphragmatic function was preserved. Rib cage and abdominal displacements were measured with respiratory inductance plethysmography before and during spinal anesthesia. During the anesthetic, outward inspiratory rib cage motion decreased in six infants (P less than 0.02, paired t test); four of these developed paradoxical inward movement of the rib cage during inspiration. One infant, the most immature in the group, had inward movement of the rib cage both before and during the anesthetic. Abdominal displacements increased during spinal anesthesia in six of seven infants (P less than 0.05), suggesting an increase in diaphragmatic motion. We conclude that, in the group of infants studied, outward rib cage movement during awake tidal breathing requires active, coordinated intercostal muscle activity that is suppressed by spinal anesthesia.

Efficacy of simulated epinephrine-containing epidural test dose after intravenous atropine during isoflurane anesthesia in children.

BACKGROUND AND OBJECTIVES: A double-blind, randomized study was performed to investigate heart rate (HR) and blood pressure responses to 2 doses of intravenous (IV) epinephrine (0.5 and 0.75 microg/kg) in 61 children, ages 3 months to 12 years. METHODS: Anesthesia was maintained with isoflurane (age-adjusted 1 minimal alveolar concentration [MAC]) in oxygen. All patients received IV atropine (10 microg/kg) and 5 minutes later were randomized to receive IV solutions (0.1 mL/kg) containing 1% lidocaine (n = 19, group I) with saline; lidocaine 1% with epinephrine 0.5 microg/kg (n = 21, group II); or lidocaine 1% with epinephrine 0.75 microg/kg (n = 21, group III). HR was recorded at 0, 15, 30, 45, 60, 90 seconds, and 2, 3, 4, and 5 minutes after test-dose injection. Systolic blood pressure (SBP), diastolic blood pressure, and end-tidal carbon dioxide were recorded at steady-state isoflurane anesthesia, after the injection of atropine, and at 45-second intervals after test-dose injections. RESULTS: Median maximum increases in HR were similar in groups II and III at 19 and 22 beats per minute (beats/min), respectively. An HR increase of > or =10 beats/min was observed in 19 of 21 patients who received 0.5 microg/kg epinephrine and 21 of 21 patients receiving 0.75 microg/kg. None of the patients in group I developed HR increases > or =10 beats/min. SBP increased > or =15 mm Hg in 17 of 21 patients in group II and 19 of 21 in group III. No dysrhythmias or T-wave amplitude change was noted. CONCLUSIONS: A simulated epidural test dose containing lidocaine 1 mg/kg with epinephrine 0.75 microg/kg, administered IV following atropine, may reliably increase HR to indicate unintentional injection into epidural vessels of children anesthetized with 1 MAC isoflurane.

Continuous caudal anesthesia for inguinal hernia repair in former preterm infants.

STUDY OBJECTIVE: To determine the feasibility of continuous caudal anesthesia with 2-chloroprocaine in conscious former preterm infants undergoing inguinal hernia repair. DESIGN: Prospective study. SETTING: University-affiliated children's hospital. PATIENTS: Ten former preterm infants, ASA physical status II and III, who were 35 to 49.5 weeks postconceptional age at the time of surgery. INTERVENTIONS: Caudal anesthesia was administered via an indwelling catheter using a loading dose of 1 ml/kg (30 mg/kg) of 3% 2-chloroprocaine, followed by incremental doses of 0.3 ml/kg (9 mg/kg) to achieve a level of T4 to T2. The block was maintained by a minimum infusion rate of 30 mg/kg/hr (1 ml/kg/hr) of the same local anesthetic solution. MEASUREMENTS AND MAIN RESULTS: The mean cumulative dose of 2-chloroprocaine was 2.8 +/- 1.0 ml/kg/hr (84 +/- 30 mg/kg/hr) infused over a mean duration of 95 +/- 35 minutes. Serum cholinesterase concentration and plasma 2-chloroprocaine concentration were measured in five infants. CONCLUSIONS: Three percent 2-chloroprocaine can be used effectively for continuous caudal anesthesia in conscious, former preterm infants for inguinal hernia and penoscrotal surgical procedures lasting 85 to 170 minutes.

Continuous subarachnoid analgesia in two adolescents with severe scoliosis and impaired pulmonary function.

We report postoperative pain management of two adolescents after upper abdominal procedures, one with Hurler-Scheie syndrome and a second with Duchenne muscular dystrophy, and both had progressive spinal scoliosis with poor pulmonary function. A combined technique of subarachnoid and general anesthesia was used during surgery. Postoperative administration of small intermittent doses of subarachnoid morphine produced profound analgesia, which eliminated the need for systemic opioids, restored preoperative arterial oxygenation within 48 hours after the operation, and expedited postoperative recovery.

Cardiac arrest following inhalation induction of anaesthesia in a child with Duchenne's muscular dystrophy.

Cardiac arrest occurred in a 5 1/2-year-old child with suspected Duchenne's muscular dystrophy ten minutes following induction of anaesthesia with halothane, nitrous oxide and oxygen. No muscle relaxants were administered. The cardiac arrest was associated with hyperkalaemia, acidosis, myoglobinuria, elevated serum creatine phosphokinase and a 1.6 degrees C rise in temperature. The child made a complete recovery after receiving 90 minutes of cardiopulmonary resuscitation.

Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control.

A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.

Laser Doppler measurements of skin blood flow before, during, and after lumbar sympathetic blockade in children and young adults with reflex sympathetic dystrophy syndrome.

Changes in the skin capillary blood flow (SBF) and temperature before, during, and 1 hour after unilateral lumbar paravertebral sympathetic blockade (LSB) were studied simultaneously with laser Doppler flowmetry and thermometry in patients with reflex sympathetic dystrophy syndrome. The baseline flow measurements in the toes on the affected limb were significantly lower than in the contralateral limb (p less than 0.01). During LSB, a 10-fold increase in SBF was detected within 4 minutes after injection of a local anesthetic agent when the sympathetic blockade was effective; an increase of more than 1 degrees C in the skin temperature occurred within 11 minutes. Measurements 1 hour after blockade showed an 18-fold (mean) increase in SBF in the toes (p less than 0.0001) and a 2-fold (mean) increase in SBF in the thighs (p less than 0.001). There was a significant decrease in the skin blood flow in the contralateral toes after the sympathetic blockade (p less than 0.01). We conclude that laser Doppler flow measurements can be used to detect immediate onset of sympathetic blockade in patients under general anesthetic or conscious sedation.

The response of patients with Duchenne's muscular dystrophy to neuromuscular blockade with vecuronium.

BACKGROUND: The authors hypothesized that patients with Duchenne's muscular dystrophy (DMD) are more sensitive to nondepolarizing muscle relaxants. METHODS: Eight children with DMD and eight healthy children having orthopedic procedures were studied. Anesthesia consisted of thiopental, 60% nitrous oxide in 40% oxygen, and intravenous fentanyl and midazolam. Using electromyography, the ulnar nerve was stimulated and the electromyographic train-of-four ratio (TOFr) of the first dorsal interosseous muscle was recorded every 60 s. After baseline TOFr recording, all patients received 50 microg/kg vecuronium and the TOFr at 3 min was compared. Vecuronium (10 microg/kg) was then administered every minute until TOFr was < or =0.1. The TOFr was followed until TOFr was > or =0.01. Then 10 microg/kg of vecuronium were administered to maintain TOFr < or = 0.1. At the conclusion of the procedure, TOFr was allowed to recover to 0.25, and then neostigmine and glycopyrrolate were administered. Data are presented as medians and ranges. RESULTS: The initial dose of vecuronium resulted in greater TOFr depression in patients with DMD than in controls (0.14 vs. 0.86). Less vecuronium was needed to produce TOFr < or = 0.1 in the patients with DMD than in the control patients (55 microg/kg vs. 95 microg/kg). Recovery time for the TOFr to > or =0.1 after the initial dose was longer in the patients with DMD than in the controls (28 vs. 20 min; P = 0.03), and the maintenance dose of vecuronium was less in patients with DMD (0.6 vs. 1.3 microg x kg[-1] min[-1]; P < 0.01). The time for TOFr recovery from 0.1 to 0.25 was 36 min in the patients with DMD and 6 min in the controls (P < 0.01). After neostigmine, the TOFr was 1.0 in the controls and 0.91 (P = 0.03) in the patients with DMD. CONCLUSION: There is increased sensitivity to vecuronium from neuromuscular blockade in patients with DMD.

Intravenous isoproterenol as a marker for epidural test-dosing in children.

The purpose of this study was to determine if isoproterenol would be an effective marker of intravascular injection in anesthetized children. Forty-four ASA 1 children, aged 2 mo to 10 yr, were randomly assigned to two groups. Children in group 1 (n = 21) received 0.05 microgram/kg isoproterenol, and children in group 2 (n = 23) received 0.075 microgram/kg isoproterenol. A blinded observer continuously recorded heart rate and arterial blood pressure. Measurements were recorded before the surgical incision at steady-state halothane concentration of 1.2 minimum alveolar concentration adjusted for age. Isoproterenol produced a graded increase in heart rate with mean maximum increases of 16.5 +/- 8.7 beats/min in group 1 and 21.5 +/- 9.2 beats/min in group 2. No episodes of hypotension and arrhythmia were noted. Isoproterenol, 0.075 microgram/kg, is more sensitive but still is an imperfect marker of an intravascular injection. It produces a heart rate increase in 96% of children anesthetized with halothane and nitrous oxide in 50% oxygen. The application of isoproterenol as an epidural test dose appears promising, but cannot be recommended until its full reliability and neurotoxicity are evaluated.

Pediatric pain clinics: recommendations for their development.

Preliminary considerations regarding the development of pediatric programs for acute and chronic pain management are discussed. Adult clinics serve as models for pediatric pain programs, although there are substantial differences in the nature of adult and pediatric pain syndromes. Recommendations are given for the design of a pediatric pain program, and experience from our program is outlined.

Quantitative assessment of cutaneous thermal and vibration sensation and thermal pain detection thresholds in healthy children and adolescents.

Quantitative sensory testing (QST) is a noninvasive, computer-assisted method for assessing function in peripheral small and large sensory fibers. In order to use QST for clinical neurological assessment in children, it is necessary: (1) to determine whether children can reliably perform these tests and (2) to characterize normal ranges in healthy children. Values of cold sensation, warm sensation, cold pain, heat pain, and vibration sensation detection thresholds were determined in the hand and foot with the method of limits (MLI) and method of levels (MLE) in 101 healthy children aged 6-17 years using a commercially available device. Both MLI and MLE were well-accepted by children, and there was good reproducibility between two sessions. The MLE takes longer to perform but produces lower thermal detection thresholds than the MLI. In the MLI, vibration and warm sensation showed higher thresholds in the foot than hand, whereas cold pain showed lower thresholds in the foot than hand. Based on these results, QST may be used to document and monitor the clinical course of sensory abnormalities in children with neurological disorders or neuropathic pain.

Patient-controlled analgesia in children and adolescents: a randomized, prospective comparison with intramuscular administration of morphine for postoperative analgesia.

A randomized, prospective trial of patient-controlled analgesia (PCA), that is, a method of analgesia administration involving a computer-driven pump activated by patients to receive small doses within defined limits was performed in 82 children and adolescents after major orthopedic surgery to compare (1) intramuscularly administered morphine, (2) PCA morphine and (3) PCA morphine with a low-dose continuous morphine infusion (PCA-plus). Patients receiving PCA and PCA-plus had lower pain scores and greater satisfaction than patients receiving intramuscularly administered morphine. The three groups used equal amounts of morphine and most measures of recovery were identical in the groups. In particular, PCA and PCA-plus did not increase the incidence of opioid-related complications, and patients receiving PCA-plus were less sedated than patients receiving intramuscular therapy. We conclude that PCA and PCA-plus are safe and effective methods of pain relief in children and adolescents after orthopedic surgery, are better accepted than intramuscular injections, and do not increase perioperative morbidity.

Unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents.

We report difficulty with conscious sedation of a child taking methylphenidate for attention deficit disorder and possible delayed adverse interaction of ketamine and methylphenidate resulting in severe nausea, vomiting and dehydration. The effects of methylphenidate and its potential interactions with anaesthetic agents is discussed. We suggest that anaesthesiologists who provide sedation or anaesthesia to patients receiving methylphenidate be aware of the potential need for high sedative doses and the possibility of undesirable interactions.

Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects.

UNLABELLED: Combinations of opioids and N-methyl-D-aspartate (NMDA) antagonists enhance acute antinociception and reduce opioid tolerance in some animal experiments but have received little rigorous study in humans. To quantitatively assess the nature of the interaction of these two classes of drugs in producing analgesia and cognitive impairment, we compared i.v. infusions of ketamine, alfentanil, and ketamine-alfentanil combinations in 12 normal volunteers after an intradermal injection of capsaicin. Drug doses for a 70-kg subject in this six-session, randomized, double-blind, cross-over study were: ketamine 20 mg, ketamine 5 mg, alfentanil 2 mg, alfentanil 0.5 mg, ketamine 10 mg + alfentanil 1 mg, and ketamine 2.5 mg + alfentanil 0.25 mg, given over 35 min. Outcome measures were background pain, area and magnitude of hyperalgesia to pinprick, and cognitive performance on the Digit Symbol Substitution Test and the Perception Speed Test. The results demonstrated simple additivity for the effects of ketamine and alfentanil on pain, pinprick hyperalgesia, and cognitive impairment. We conclude that, at least in this experimental pain model, there is no clear advantage or disadvantage of a ketamine-alfentanil combination over equianalgesic doses of either component. IMPLICATIONS: In a double-blind, controlled trial, we administered doses of an opioid analgesic (alfentanil), an N-methyl-D-aspartate receptor antagonist (ketamine), or their combination to normal volunteers and found no advantage of the combination over a larger dose of either drug alone in relieving pain caused by painful chemical stimulation.

Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children.

A randomized, double-blind, prospective study was performed to determine the effects of perioperative administration of morphine or methadone on postoperative analgesic requirements and pain scores in 35 children aged 3 to 7 years undergoing major surgery. After a standardized induction of anesthesia, methadone or morphine, 0.2 mg/kg, was blindly administered, and supplemental doses were titrated to achieve comfort in the recovery room. Pain was assessed during the next 36 hours with a combination of validated behavioral and self-report measures. Patients in the methadone group required fewer supplemental opioid analgesic drugs during the next 36 hours, and reported lower pain scores. No patient had prolonged emergence from anesthesia, and no patient required naloxone or postoperative ventilatory assistance. No major adverse events occurred. We conclude that perioperative intravenous administration of methadone is an effective, inexpensive, and technologically simple means for providing prolonged analgesia for children after surgery.

Safety of intravenous ketorolac therapy in children and cost savings with a unit dosing system.

OBJECTIVE: To determine the incidence of side effects with the short-term use of intravenously administered ketorolac in children and the overall cost savings with a unit dosing system. STUDY DESIGN: We prospectively examined the incidence of complications arising from the intravenous administration of ketorolac to 1747 children (14,810 doses) during a 3-year, 3-month period and assessed cost savings resulting from dividing 60 mg syringes into 7.5, 15, 30, and 60 mg unit doses. Complications were recorded prospectively into a computerized database. Estimated drug costs to the pharmacy were calculated on the basis of the total numbers of each drug fraction administered, with allowance for 1O% wastage as a result of drug expiration. RESULTS: Side effects occurring with ketorolac administration were rare. Four patients (0.2%) had hypersensitivity reactions to the drug, two of them possibly on the basis of latex allergy. Two patients (O.1%) had renal complications but were subsequently found to have underlying causes that could account for their renal symptoms. One patient (0.05%) had massive gastrointestinal bleeding in the postoperative period. With fractionation of 60 mg syringes, total drug cost to the pharmacy was $34,786, rather than the $86,639 that would have been spent had a single syringe been used for each dose. CONCLUSION: Ketorolac proved safe for short-term intravenous use in children more than 1 year of age when patients with known contraindications to the use of non-steroidal antiinflammatory drugs were excluded. A considerable reduction in drug costs can be achieved with fractionation of premixed syringes into unit doses.

The pharmacokinetics of epidural ropivacaine in infants and young children.

UNLABELLED: The pharmacokinetic variables of ropivacaine were characterized after epidural bolus injection in pediatric patients. The subjects, 7 infants (aged 3-11 mo) and 11 young children (aged 12-48 mo), received 1.7 mg/kg of ropivacaine via a lumbar epidural catheter. Total plasma concentrations of ropivacaine measured over 24 h were assayed by high-pressure liquid chromatography, and pharmacokinetic modeling was performed by Nonlinear Mixed Effects Modeling analysis. The median peak venous plasma concentrations (C(max)) in infants and young children were 610 microg/L (interquartile range [IQR], 550-725 microg/L) and 640 microg/L (IQR, 540-750 microg/L), respectively. The median times to maximum plasma ropivacaine concentration (T(max)) were 60 min (IQR, 60-120 min) in infants and 60 min (IQR, 30-90 min) in young children. There were no statistical differences between median values of C(max) and T(max) between infants and young children. The calculated clearance (CL) in infants was 4.26 mL x min(-1) x kg(-1) (9% coefficient of variation), and in young children it was 6.15 mL x min(-1) x kg(-1) (11% coefficient of variation). The CL for infants was significantly less than the CL for young children (P < 0.01). The volume of distribution was estimated to be 2370 mL/kg (9% coefficient of variation) for both young children and infants. No systemic toxicity was observed in either group. IMPLICATIONS: This study revealed that the pharmacokinetic variables of lumbar epidural bolus ropivacaine in pediatric patients aged 3 to 48 mo are similar to those of adults, except that drug clearance was less in infants compared with older children.