The responsive amygdala: treatment-induced alterations in functional connectivity in pediatric complex regional pain syndrome.

The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear, and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-sex matched control subjects before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared with control subjects, with differences predominantly in the left amygdala in the pretreated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy control subjects from time 1 to time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related fear scores; and (4) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity after an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response.

Pain sensitivity and modulation in primary insomnia.

Sleep of good quantity and quality is considered a biologically important resource necessary to maintain homeostasis of pain-regulatory processes. To assess the role of chronic sleep disturbances in pain processing, we conducted laboratory pain testing in subjects with primary insomnia. Seventeen participants with primary insomnia (mean ± SEM 22.6 ± 0.9 yrs, 11 women) were individually matched with 17 healthy participants. All participants wore an actigraph device over a 2-week period and completed daily sleep and pain diaries. Laboratory pain testing was conducted in a controlled environment and included (1) warmth detection threshold testing, (2) pain sensitivity testing (threshold detection for heat and pressure pain), and (3) tests to access pain modulatory mechanisms (pain facilitation and inhibition). Primary insomnia subjects reported experiencing spontaneous pain on twice as many days as healthy controls during the at-home recording phase (p < 0.05). During laboratory testing, primary insomnia subjects had lower pain thresholds than healthy controls (p < 0.05 for heat pain detection threshold, p < 0.08 for pressure pain detection threshold). Unexpectedly, pain facilitation, as assessed with temporal summation of pain responses, was reduced in primary insomnia compared to healthy controls (p < 0.05). Pain inhibition, as assessed with the diffuse noxious inhibitory control paradigm (DNIC), was attenuated in insomnia subjects when compared to controls (p < 0.05). Based on these findings, we propose that pain-inhibitory circuits in patients with insomnia are in a state of constant activation to compensate for ongoing subclinical pain. This constant activation ultimately may result in a ceiling effect of pain-inhibitory efforts, as indicated by the inability of the system to adequately function during challenge.

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.

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.

Use of the Bispectral Index monitor to aid titration of propofol during a drug-assisted interview.

We report two drug-assisted interviews with propofol in an 18-year-old with the diagnosis of Complex Regional Pain Syndrome type 1. We describe difficulty in titration of propofol in the first interview. Consequently, in the second interview, the Bispectral Index (BIS) monitor was applied to assist adjustment of the propofol infusion. This facilitated the achievement of a prolonged sedative-hypnotic state for a successful neuropsychological evaluation. Pertinent information was obtained from this patient. However, the role of drug-assisted interviews as a technique needs to be further elucidated.

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.

Ketorolac suppresses postoperative bladder spasms after pediatric ureteral reimplantation.

UNLABELLED: We evaluated the efficacy of ketorolac in suppressing postoperative bladder spasms after ureteroneocystostomy (ureteral reimplantation). Twenty-four pediatric patients undergoing intravesical ureteroneocystostomy were enrolled prospectively to receive either ketorolac or placebo via double-blinded randomization. Twelve patients in each group shared similar preoperative characteristics. All were maintained on an epidural infusion of bupivacaine (0.1%) with fentanyl (2 microg/mL) throughout the study. Patients were given either ketorolac (0.5 mg. kg(-1). dose(-1)) or placebo (equivalent volume saline) IV after surgery and every 6 h thereafter for 48 h. Parents were instructed to record bladder spasm episodes prospectively by using a standardized time-flow diary. Three patients (25%) in the ketorolac group experienced bladder spasms, compared with 10 patients (83%) in the placebo group (two-sided P < 0.05). The median severity score for the ketorolac group was 1.2 (mild = 1.0, severe = 3.0), compared with 2.6 for the placebo group (P = 0.003). We conclude that IV ketorolac reduces the frequency and severity of postoperative bladder spasms after intravesical ureteroneocystostomy. IMPLICATIONS: We studied the efficacy of ketorolac, a prostaglandin synthesis inhibitor, in the treatment of bladder spasm after ureteroneocystostomy (antireflux operation). Patients were randomized in a double-blinded manner to receive either ketorolac or placebo after the surgery. We demonstrate that ketorolac reduces the frequency and severity of postoperative bladder spasm.

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 anesthesia and analgesia.

Local and regional anesthetic techniques have a significant but limited place in the practice of infant pain control. In certain clinical circumstances, regional anesthetic techniques presumably afford many of the same advantages for the pediatric patient as in the adult patient. However, there are few controlled clinical trials on the advantages and adverse effects compared with conventional analgesic strategies. This article discusses the clinical application, effectiveness, safety, and outcomes of the available local and regional anesthetic techniques for control of postoperative and procedure-related pain in neonates and infants.

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.

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.

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.

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.

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.

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.

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.

Spinal fusion in Duchenne muscular dystrophy: a multidisciplinary approach.

We studied 27 Duchenne muscular dystrophy patients having spinal fusion for scoliosis. One patient died intraoperatively of cardiac arrest; all others have done well with no instances of malignant hyperthermia, postoperative ventilatory system dependence, pneumothorax, persisting infection, neurologic damage, nonunion, or pain. The anesthetic management included primarily intravenous general anesthetics with minimal myocardial depressant effects, avoiding succinylcholine and inhalation agents. Preoperative cardiac studies aided anesthetic management intra-operatively. There was an almost universal sinus tachycardia. Holter monitoring defined 4 of 16 with ventricular premature beats, 4 of 16 with atrial premature beats, and no ventricular tachycardia or atrial flutter or fibrillation. Echocardiogram demonstrated mitral prolapse in 2 of 22, frequent abnormal systolic performance with abnormal shortening fraction less than 28% in 7 of 16, and reduced rate-corrected velocity of fiber shortening in 9 of 15. Afterload was elevated in 7 of 15. The mean forced vital capacity (FVC) preoperatively was 45.3 +/- 15.9% with continuing diminution to 28.7 +/- 14.9% at 3.3 +/- 2.2 years after surgery. The main benefit of surgical stabilization is the relative ease and comfort of wheelchair seating compared with those nonoperated patients who develop progressive deformity. We have not seen lasting improvement or stabilization in FVC following surgery as decreasing function is related primarily to muscle weakness.