Stable plasma concentrations of unbound ropivacaine during postoperative epidural infusion for 24-72 hours in children.

BACKGROUND AND OBJECTIVES: The aim of this open, non-controlled, multi-centre study was to evaluate the pharmacokinetics and safety of a 24-72 h continuous epidural ropivacaine infusion in children aged 1-9 yr. METHODS: After induction of general anaesthesia, 29 ASA I-II children, scheduled for major surgery in dermatomes below T10 had lumbar epidural catheters placed. A bolus of ropivacaine, 2 mg kg(-1), was given over 4 min, followed immediately by an infusion of 2 mg mL(-1) ropivacaine 0.4 mg kg(-1) h(-1) for the next 24-72 h. RESULTS: Plasma concentrations of total ropivacaine (mean 0.83 and 1.06 mg L(-1) at 16-31 and 59-72 h, respectively) and alpha1-acid-glucoprotein (mean 13 and 25 micromol L(-1) at baseline and 59-72 h) increased over the course of the infusion. Plasma concentrations of unbound ropivacaine were stable throughout the epidural infusion (mean 0.021 range 0.011-0.068 and mean 0.016 range 0.009-0.023 mg L(-1) at 16-31 and 59-72 h, respectively) and were well below threshold levels associated with central nervous system toxicity in adults (0.35 mg L(-1)). Apparent unbound clearance (mean 346, range 86-555 mL min(-1) kg(-1)) showed no age-dependency. No signs of systemic toxicity or cardiovascular effects were observed. All patients received additional analgesics with morphine. CONCLUSION: Following a 24-72 h epidural infusion of ropivacaine 0.4 mg kg(-1) h(-1) in 1-9-yr-old children, the plasma concentrations of unbound ropivacaine were stable over time with no age-dependency.

Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals.

The expression and distribution of the neuronal glutamate transporter, excitatory amino acid carrier-1 (EAAC1), are demonstrated in the dorsal root ganglion neurons and their central terminals. Reverse transcriptase-polymerase chain reaction shows expression of EAAC1 mRNA in the dorsal root ganglion. Immunoblotting analysis further confirms existence of EAAC1 protein in this region. Immunocytochemistry reveals that approximately 46.6% of the dorsal root ganglion neurons are EAAC1-positive. Most EAAC1-positive neurons are small and around 250-750 microm2 in surface area, and some co-label with calcitonin gene-related peptide (CGRP) or isolectin IB4. In the spinal cord, EAAC-1 immunoreactive small dot- or patch-like structures are mainly localized in the superficial dorsal horn, and some are positive for CGRP or labeled by isolectin IB4. Unilateral dorsal rhizotomy experiments further show that EAAC1 immunoreactivity is less intense in superficial dorsal horn on the side ipsilateral to the dorsal rhizotomy than on the contralateral side. The results indicate the presence of EAAC1 in the dorsal root ganglion neurons and their central terminals. Our findings suggest that EAAC1 might play an important role in transmission and modulation of nociceptive information via the regulation of pre-synaptically released glutamate.

Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats.

The activation of spinal cord N-methyl-D-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 microg/10 microl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function. The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance.

A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles.

UNLABELLED: Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after. IMPLICATIONS: The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.

A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II. Perioperative breathing patterns in neonates and infants with pyloric stenosis.

UNLABELLED: Although former preterm birth infants are at risk for postoperative apnea after surgery, it is unclear whether the same is true of full-term birth infants. We evaluated the incidence of apnea in 60 full-term neonates and infants undergoing pyloromyotomy both before and after anesthesia. All subjects were randomized to a remifentanil- or halothane-based anesthetic. Apnea was defined by the presence of prolonged apnea (>15 s) or frequent brief apnea, as observed on the pneumocardiogram. Apnea occurred before surgery in 27% of subjects and after surgery in 16% of subjects, with no significant difference between subjects randomized to remifentanil or halothane anesthesia. This apnea was primarily central in origin, occurred throughout the recording epochs, and was associated with severe desaturation in some instances. Of the subjects with normal preoperative pneumocardiograms, new onset postoperative apnea occurred in 3 (23%) of 13 subjects who received halothane-based anesthetics versus 0 (0%) of 22 subjects who received remifentanil-based anesthetics (P = 0.04). Thus, postoperative apnea can follow anesthesia in otherwise healthy full-term infants after pyloromyotomy and is occasionally severe with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic. IMPLICATIONS: Abnormal breathing patterns can follow anesthesia in infants after surgical repair of pyloric stenosis. Occasionally, these patterns can be associated with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic.

Pain management in the critically ill child.

Children frequently received no treatment, or inadequate treatment, for pain and for painful procedures. The newborn and critically ill children are especially vulnerable to no treatment or under-treatment. Nerve pathways essential for the transmission and perception of pain are present and functioning by 24 weeks of gestation. The failure to provide analgesia for pain results in rewiring the nerve pathways responsible for pain transmission in the dorsal horn of the spinal cord and results in increased pain perception for future painful results. Many children would withdraw or deny their pain in an attempt to avoid yet another terrifying and painful experiences, such as the intramuscular injections. Societal fears of opioid addiction and lack of advocacy are also causal factors in the under-treatment of pediatric pain. False beliefs about addictions and proper use of acetaminophen and other analgesics resulted in the failure to provide analgesia to children. All children even the newborn and critically ill require analgesia for pain and painful procedures. Unbelieved pain interferes with sleep, leads to fatigue and a sense of helplessness, and may result in increased morbidity or mortality.

Tunneled epidural catheters for prolonged analgesia in pediatric patients.

UNLABELLED: We conducted this retrospective study to document the efficacy and safety, and demonstrate the spectrum of indications for subcutaneously tunneled epidural catheters in the management of prolonged pain in pediatric patients. The charts of 25 patients with prolonged pain that was unresponsive to conventional opioid therapy (10: end stage malignancy, 8: extensive abdominal surgery, 7: trauma, etc.) and who received thoracic, lumbar, or caudal tunneled epidural catheters between 1995 and 1999 were reviewed for efficacy and catheter-related complications (infection or bleeding at the insertion site, toxicity related to local anesthetics, tachyphylaxis and respiratory depression). Tunneled epidural catheters were effective in providing extended analgesia in all subjects. In 14 patients with chronic pain, cumulative 48-h enteral and parenteral opioid requirements were reduced or eliminated after catheter insertion. Catheters remained in place for a median of 11 days (range, 4--240 days) until there was no further need for parenteral analgesia (n = 15), death because of the underlying disease (n = 6), accidental removal (n = 2), or possible infection (n = 2). No serious local or systemic complications (meningitis, epidural abscess, systemic infection, epidural hematoma, or spinal cord injury; seizures, local anesthetic toxicity) occurred related to this technique. Five patients were discharged from the hospital with the catheter for home analgesic therapy. The use of a percutaneously inserted, subcutaneously tunneled epidural catheter is safe, effective, and provides pain relief in situations in which conventional analgesic therapy either fails or is impractical. The technique is one that may be of great value to children suffering from pain. IMPLICATIONS: Children and adolescents with pain may safely have a spinal catheter placed for a period of time without undo risk of infection or other complications. Spinal catheters provide excellent pain relief, often eliminating the need for riskier medications for painful events such as wound cleansing and dressing changes.

Perioperative management issues in pediatric patients.

Recent developments in perioperative practice, emphasizing issues that are of greatest concern in pediatric patients, are reviewed in this article. Many areas bear further evaluation in the evolving field of perioperative medicine: Effective techniques of psychologic preparation for children and their parents in an era in which the family rarely encounters the hospital environment before the day of surgery Application of newer intraoperative anesthetics, such as new narcotics and muscle relaxants, to shorten PACU and pediatric ICU stay while maintaining safety and comfort Critical evaluation of current methods of pain management to optimize comfort, while minimizing cost of such management in an increasingly cost-conscious health care environment The recent advent of a process for credentialing pediatric anesthesia fellowship programs, which requires a research component, bodes well for the prospect of finding answers to some of these questions.

The safety and efficacy of parent-/nurse-controlled analgesia in patients less than six years of age.

UNLABELLED: Over the past 5 yr, we have treated nonsurgical and postoperative pain in children <6 yr of age by using a patient-controlled analgesia pump to deliver small-dose continuous IV opioid infusions supplemented by parent- and nurse-controlled opioid bolus dosing. We call this technique parent-/nurse-controlled analgesia (PNCA). Because the safety and efficacy of PNCA have not been previously evaluated, we have undertaken a prospective, 1-yr observational study to determine patient demographics, effectiveness of analgesia, and the incidence of complications (pruritus, vomiting, and respiratory depression) in patients receiving PNCA. Data were collected on 212 children (98 female) who were treated on 240 occasions with PNCA for episodes of pain. Patients averaged 2.3 +/- 1.7 yr of age and 11 +/- 5 kg, and received a median of 4 (range 2-54) days of PNCA therapy. Maximum daily pain scores were < or =3/10 (objective pain scale) or < or =2/5 (objective or self-report pain scale) in more than 80% of all occasions of PNCA use. PNCA usage was associated with an 8% incidence of pruritus and a 15% incidence of vomiting on the first day of treatment. Nine children studied received naloxone, four (1.7%) for treatment of PNCA-related apnea or desaturation. All had improvement in their symptoms after naloxone administration. IMPLICATIONS: Parent-/nurse-controlled analgesia provided effective pain relief in most children <6 yr of age experiencing nonsurgical or postoperative pain. The observed incidence of vomiting and pruritus was similar to that seen in older patients treated with patient-controlled analgesia. However, significant respiratory depression, although uncommon, did occur, thus reinforcing the need for close patient monitoring.

Pediatric acute pain management.

The past decade has brought about an explosion of knowledge about the physiology of nociception and many new techniques for pain relief, new analgesic drugs, and new applications of old analgesic drugs. These techniques include methods of opioid administration by transdermal and transmucosal absorption and the use of neuraxial analgesia for the management of pain in children. Interest in the use of regional anesthesia in children has been rekindled, and analgesic properties and pre-emptive analgesic properties of many agents not typically considered analgesics, such as clonidine and ketamine, have been recognized. Perhaps the greatest advance has been the paradigm shift in the recognition that pain not only exists in infants and children but also is a significant cause of morbidity and even mortality. Given the unprecedented interest in pain management in adults and children, physicians can now look forward to the development of new methods of drug delivery and of receptor-specific drugs that divorce analgesia from the untoward side effects of existing analgesics. Improvement in the quality of life of hospitalized children also will occur.

The management of pain in sickle cell disease.

The pain of vaso-occlusive crisis in patients with sickle cell disease is excruciating, incapacitating, and sometimes refractory to even the most advanced analgesic treatments. A comprehensive, multimodal approach to therapy that includes education, cognitive therapies, anti-inflammatory drugs, opioids, and psychostimulant adjuvant drugs has been presented. Until a cure for the underlying disease is found, these are the best approaches available. The authors hope that future research will find even better modalities of analgesic care.

Pain and symptom control in terminally ill children.

The management of pain in terminally ill pediatric patients has incalculable benefits to patients, their families, and physicians and nurses. A therapeutic management plan is dependent on a thorough understanding of the causes of pain in these patients, on pain assessment, and on the myriad drugs and drug strategies that are essential in pain treatment. Aggressive symptom control of treatment-related side effects can ensure successful implementation of such a plan.

Anterograde and retrograde memory in children anesthetized with propofol.

Prior to anesthesia with propofol for gastrointestinal endoscopy, sets of pictures were presented to 20 children and adolescents (M age = 12 years). Word pairs (e.g., "hiking-woods") were presented via earphones after the children were anesthetized. Upon regaining consciousness, the children were tested for explicit memory of both the picture sets and word pairs by free recall, cued recall, and yes/no recognition. Implicit memory was tested by free association to category cues for the pictures and by word association for the word pairs. Postoperative testing revealed retrograde memory for material presented preoperatively but total amnesia for material presented intraoperatively. There was no evidence of implicit memory for material not available explicitly. The finding of uninterrupted ability to retain and retrieve information presented prior to anesthesia despite total anterograde amnesia has implications for preoperative communication directed toward pediatric patients as well as for intraoperative communication among surgical staff.

Videotape increases parental knowledge about pediatric pain management.

UNLABELLED: Pediatric pain management often depends on parents recognition and assessment of their child's pain and their beliefs as to whether the pain should be treated. Parental misconceptions concerning pain assessment and pain management may therefore result in inadequate pain treatment, particularly in patients who are too young or too developmentally handicapped to self-report their pain. We hypothesized that viewing a concise, educational videotape would provide parents with instructive information that could correct misconceptions concerning pain and pain management in children. To do this, we evaluated the impact of an educational videotape on parental responses to a questionnaire about pediatric pain management. Parents of children scheduled for inpatient, postoperative hospital care were studied. After answering 30 questions, parents were randomly assigned to either view (Group 1) or not view (Group 2) a 19-min educational videotape. Immediately after viewing the videotape (Group 1), or 30 min after taking the first test (Group 2), parents were asked to answer the same questionnaire a second time. The effect of seeing the videotape was assessed by comparing post-pre test score differences using paired t-test. One-hundred parents were studied. Randomization was effective in assigning equitable groups. Initial scores of percent answers correct in each group were not different ([mean +/- SD] Group 1 [n = 50]: 68.7% +/- 18.8% vs Group 2 [n = 50]: 61.5% +/- 22.7%; P = 0.09). Viewing the videotape effectively increased test scores: paired t-test within groups demonstrated a significant difference in Group 1 (22.4% +/- 16.5%, P < 0.0001), whereas Group 2 scores changed to a much lesser degree (2.7% +/- 8.3%, P = 0.0271). All parents who viewed the videotape stated that it was informative regarding their understanding of their child's pain management. This study demonstrates the effectiveness of an educational videotape in changing parental knowledge concerning postoperative pediatric pain. This effective and efficient teaching medium may be useful in improving pain management in postoperative pediatric surgical patients. IMPLICATIONS: Pediatric pain management often depends on parents recognition and assessment of their child's pain and their beliefs as to whether the pain should be treated. This prospective, randomized, controlled study demonstrated the effectiveness of an educational videotape in changing parental knowledge concerning postoperative pediatric pain. This effective and efficient teaching medium may be useful in preventing inadequate pain management in postoperative pediatric surgical patients.

Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome.

OBJECTIVE: To provide the first comprehensive magnetic resonance imaging (MRI) assessment of brain in a series of patients with Lesch-Nyhan syndrome (LNS), with emphasis on basal ganglia measurements. DESIGN: Routine readings of MRI studies, repeated reading in random order blinded to subject diagnosis, and 3-dimensional volumetric measures of basal ganglia regions. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Seven patients with LNS who have hypoxanthine guanine phosphoribosyltransferase levels less than 1.6% and characteristic clinical features of the disorder, which include hyperuricemia, cognitive impairment, and dystonic movement disorder, were compared with 7 age-matched control subjects. Five of the 7 patients demonstrated self-injurious behavior. MRI studies were performed using general anesthesia because of the severity of the movement disorder. MAIN OUTCOME MEASURES: Measurement of brain regions from MRI-obtained images. RESULTS: Routine readings described mild cerebral atrophy in 2 of 7 patients, but no caudate or putamen abnormalities were reported. However, on the directed blinded rereading, small caudates were suspected in 5 of 7 cases, and abnormalities in cerebral size and cranium were identified. Volumetric studies of the patients with LNS confirmed a 34% decrease in caudate volume (P<.001), a 17% decrease in total cerebral volume (P<.03), and a 12% decrease in putamen volume (P=.19). CONCLUSIONS: To our knowledge, this is the first demonstration of consistent neuroanatomic abnormalities in LNS. The findings of reduced basal ganglia volume are consistent with the dystonic movement disorder.

Bacterial colonization and infection rate of continuous epidural catheters in children.

UNLABELLED: Continuous epidural infusions are widely used for postoperative analgesia in children. We prospectively studied the incidence of bacterial colonization of caudal and lumbar epidural catheters, as well as the incidence of serious systemic and local infection, in 210 children after short-term epidural analgesia. Using aseptic technique, epidural catheters were inserted into either the lumbar or the caudal epidural space based on the preferences of the anesthesia team and/or clinical indication. The integrity of the catheter and overlying transparent dressing site was evaluated by a member of the pediatric pain service at least once a day. The catheters were aseptically removed if the patient had a fever greater than 39 degrees C, if the dressing was compromised, or when epidural analgesia was no longer required. The subcutaneous portion of the catheter was semiquantitatively cultured. Cellulitis (erythema, swelling, purulent discharge, pustule formation, or tenderness) was diagnosed by examination of the epidural insertion site. The mean (+/- SD) age of patients in the caudal catheter group (n = 170) was 3 +/- 3 yr; their mean weight was 13 +/- 11 kg. The mean (+/- SD) age of patients in the epidural catheter group (n = 40) was 11 +/- 4 yr; their mean weight was 36 +/- 23 kg. All catheters remained in place for 3 +/- 1 days (range 1-5 days). There was no serious systemic infection (meningitis, epidural abscess, or systemic sepsis). Of all epidural catheters, 35% (73 of 210) were colonized. Gram-positive colonization was similar in caudal (25%; 43 of 170) and lumbar (23%; 9 of 40) catheters. Gram-negative organisms were cultured from 16% of the caudal catheters (27 of 170) and 3% of the lumbar catheters (1 of 40). In patients treated with caudal epidural catheters, children aged >3 yr were less likely to have colonized epidural catheters than younger children. Age did not affect the probability of developing cellulitis at the insertion site. Although patients aged <3 yr with caudal catheters had a slightly greater risk of cellulitis than children aged >3 yr (14% vs 9%), this association was very weak (P = 0.33). We observed that, despite bacterial colonization of caudal and lumbar epidural catheters, serious systemic and local infection after short-term epidural analgesia did not occur in our study. IMPLICATIONS: Continuous epidural infusions are widely used for postoperative analgesia in children. We found no serious systemic infections after short-term (3 days) continuous epidural analgesia in children.

Detection of intravascular injection of regional anaesthetics in children.

PURPOSE: Detection of intravascular injection of local anaesthetic during placement of regional blocks in children by using epinephrine-induced tachycardia or hypertension may produce false positive and false negative findings. This study evaluates ECG changes as markers of intravascular injection of local anaesthetics with epinephrine, during placement of epidural blocks in children. METHODS: Observational study in a teaching hospital of all epidural anaesthetics administered to paediatric patients during one year. General anaesthesia, where used, was not controlled. An ECG rhythm strip was recorded during test dose injection and analyzed for changes in rate, rhythm, and T-wave configuration. RESULTS: During the study period, 742 paediatric epidural blocks were administered. There were 644 caudal (284 without catheters), 97 lumbar, and one thoracic epidural anaesthetics. Satisfactory placement was achieved in 97.7% of patients. Intravascular injection was detected in 42 (5.6%) of epidural anaesthetics (3.8% and 6.7% of straight needle and catheter injections, respectively). Detection was by immediate aspiration of blood in six patients, and by heart rate increases > 10 bpm in 30. Five had heart rate decreases suggesting a baroreceptor response. Five had heart rate increases < 10 bpm that were possible responses to noxious stimuli. Of 30 patients with known intravascular injection and for whom ECG strips were available, 25 (83%) had T-wave amplitude increases > 25%, and 29 (97%) had ECG changes in T-wave or rhythm in response to the epinephrine injection. There were no false positives. CONCLUSION: In order to reduce risks associated with epidural anaesthesia in children, epinephrine should be added to the local anaesthetic test dose, the ECG should be monitored continuously for changes in heart rate, rhythm, and T-wave amplitude. Epidural injections should be given in small increments.