Julia C. Finkel

A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients.

UNLABELLEDnWe compared, in a double-blinded manner, the anesthetic maintenance and recovery properties of remifentanil with a clinically comparable fentanyl-based anesthetic technique in pediatric ambulatory surgical patients. Anesthesia was induced with either halothane or sevoflurane and nitrous oxide and oxygen. Patients were randomized (computer generated) to receive either remifentanil or fentanyl in a blinded syringe with nitrous oxide and oxygen in one of four possibilities: halothane/remifentanil, halothane/fentanyl, sevoflurane/remifentanil or sevoflurane/fentanyl. In patients receiving remifentanil, a placebo bolus was administered, and a continuous infusion (0.25 microg. kg(-1). min(-1)) was begun. In patients receiving fentanyl, a bolus (2 microg/kg) was administered followed by a placebo continuous infusion. The time from discontinuation of the anesthetic to extubation, discharge from the postanesthesia care unit (PACU), and discharge to home, as well as pain scores, were assessed by a blinded nurse observer. Systolic blood pressure and heart rate were noted at selected times, and adverse events were recorded. Remifentanil provided faster extubation times and higher pain-discomfort scores. PACU and hospital discharge times were similar. There were no statistical differences among the groups for adverse events. There were statistically, but not clinically, significant differences in hemodynamic variables. We noted that continuous infusions of remifentanil were intraoperatively as effective as bolus fentanyl. Although patients could be tracheally extubated earlier with remifentanil, this did not translate to earlier PACU or hospital discharge times. In addition, remifentanil was associated with higher postoperative pain scores. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanils use as an anesthetic for children.nnnIMPLICATIONSnThis is a study designed to examine the efficacy and safety of a short-acting opioid, remifentanil, when used in pediatric patients. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanils use as an anesthetic for children.

Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study

BackgroundChronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting.MethodsLongitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake.ResultsOver a 15-month period, 63 children and adolescents (median age 15, interquartile range 12–17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p <0.001) and yielded greater pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (pu2009=u20090.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (pu2009=u20090.007). In 37xa0% of infusions, patients had a greater than 20xa0% reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (pu2009=u20090.3).ConclusionsThese data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain. Further, patients with CRPS, POTS, and a history of trauma-related chronic pain are more likely to benefit from this therapeutic modality.

Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice

Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000Hz (Aβ-fiber) and 250Hz (Aδ-fiber)] and unmyelinated (5Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p=0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000Hz and 250Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000Hz [21Units (7, 35), mean difference (95% CI), p=0.009 for sex∗treatment interaction] and 250Hz [9Units (1, 16), p=0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000Hz(Aβ-fiber, r=0.58, p=0.01) and 250Hz(Aδ-fiber, r=0.6, p=0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD.

Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickle, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickle and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickle and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickle compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients.

Dexmedetomidine as an Adjuvant to Analgesic Strategy During Vaso-Occlusive Episodes in Adolescents with Sickle-Cell Disease.

Patients with sickle‐cell disease (SCD) can experience recurrent vaso‐occlusive episodes (VOEs), which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients with SCD, increasing opioid use is associated with continued and increasing pain. Dexmedetomidine, an α2‐adrenoreceptor agonist with sedative and analgesic properties, has been increasingly used in the perioperative and intensive care settings and has been shown to reduce opioid requirement and to facilitate opioid weaning. Therefore, there might be a role for dexmedetomidine in pain management during VOEs in patients with SCD. Here, we present the hospital course of 3 patients who during the course of VOEs had severe pain unresponsive to opioids and ketamine and were treated with dexmedetomidine. Dexmedetomidine infusions that lasted for 3 to 6 days were associated with marked reduction in daily oral morphine‐equivalent intake and decreases in pain scores (numeric rating scale). There were no hemodynamic changes that required treatment with vasoactive or anticholinergic agents. These preliminary findings of possible beneficial effects of dexmedetomidine in decreasing opioid requirements support the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate VOE‐associated pain in patients with SCD.

Dexmedetomidine for patients undergoing diagnostic cardiac procedures: A noninferiority study

When anesthetizing children with congenital heart disease for diagnostic cardiac catheterization, anesthesiologists and cardiologists seek to use anesthetic regimens that yield minimal hemodynamic changes and allow for spontaneous ventilations. Recently, dexmedetomidine has been used as an anesthesia adjunct because of its sedative and analgesic properties and minimal ventilatory depressive effects. We tested the hypothesis that the combination of sevoflurane and dexmedetomidine is non-inferior to sevoflurane alone as it refers to hemodynamic measurements during diagnostic cardiac catheterization in children with a transplanted heart, one ventricle (Fontan procedure), or normal cardiac physiology. Patients were anesthetized with inhalation of sevoflurane in nitrous oxide/oxygen and, after baseline hemodynamic measurements, successive boluses of dexmedetomidine followed by continuous infusion were administered. In this study, non-inferiority was shown when differences at steady-state (dexmedetomidinexa0+xa0sevoflurane) compared to baseline (sevoflurane alone) and its associated 95% confidence interval fell completely within the range of plus or minus 20%. Forty-one (26 normal physiology, 9 cardiac transplantation, and 6 Fontan) patients were enrolled. Non-inferiority of sevofluranexa0+xa0dexmedetomidine compared with sevoflurane alone was shown for heart rate, but not for arterial blood pressure in patients with normal and cardiac transplant physiology. In patients with normal cardiac physiology, non-inferiority was demonstrated for bispectral index. Therefore, while the lack of depressive respiratory effects and non-inferiority for heart rate are desirable, the lack of non-inferiority of dexmedetomidinexa0+xa0sevoflurane combination for arterial blood pressure do not justify the routine use of this combination compared with sevoflurane alone for children with congenital heart disease undergoing cardiac catheterization.

Use of nonsteroidal anti inflammatory drugs in preterm, term neonates and infants: analgesia by consensus?

There has been increasing interest for the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in preterm and term neonates and older infants to produce analgesia in a variety of settings and to modulate opioid analgesia by achieving opioid sparing effects so as to minimize opioid induced side-effects, reduce tolerance and enhance analgesia. The use of NSAIDs in this population has primarily been for its nonanalgesic applications targeting the management of the sequelae of prematurity including pharmacologic constriction of a patent ductus arteriosus. (1) The ability of NSAIDs to produce opioid sparing effects in children and adults makes them very attractive as a possible adjunct or even replacement for opioid analgesia in neonates and infants. Most recently, specific analgesic applications of NSAIDs have been considered. (2) Therapeutic settings discussed included procedural pain (3), analgesia during mechanical ventilation (4) and postoperative pain. (5) There were two concerns for the neonatal population and perhaps even for older infants. First, this class of drugs induces major physiologic derangements in this population by interruption of prostaglandin production. Second, there are insufficient data to indicate that analgesia is achieved in any of these clinical settings. Therefore, much work is needed to be done to clarify the role of NSAIDs as analgesics in the very young and to define the pharmacokinetic ⁄ pharmacodynamic relationships to ensure safety. Prostaglandins play a major role in the developing neonate. They are involved in autoregulation of blood flow to the brain, renal blood flow and regulation of the ductus arteriosus. (6) In the neonate, increased levels of prostanoids have been suggested to contribute to the genesis of intraventricular hemorrhage (7,8) and retinopathy of prematurity. (9) Given that NSAIDs decrease a variety of prostaglandins by inhibiting cyclooxygenase isoforms, it is expected that interrupting their production would have developmental implications. While virtually every organ system and tissue type is affected, of particular note and perhaps unique importance to this population is the impact on renal function and sleep. Both the COX-1 and COX-2 isoforms are important for development and function of the kidney. In clinical studies, the adverse renal effects are the same for COX-2 specific and conventional NSAIDs. (10) Neonates treated with indomethacin for PDA closure show a 40% incidence of renal impairment vs a 16% incidence with surgical PDA closure. (11) In a multivariate analysis of risk factors for acute renal failure in preterm neonates, five variables emerged as risk factors. Of note, maternal ingestion of NSAIDs led to a 7.4 times greater likelihood of renal failure (95% CI: 3.3–16.7) and ibuprofen led to a 2.6 times greater chance of renal failure (95% CI: 1.2–5.8) in their offspring. (12) Prostaglandins play an important role in modulating sleep via PGD2 which induces non-REM sleep. (13) This is especially critical for the neonate where sleep deprivation has been associated with impaired immunity, respiratory abnormalities, altered thermogenesis and has been implicated as a possible Correspondence to: Julia C. Finkel, Division of Anesthesiology and Pain Medicine, Children s National Medical Center, George Washington University School of Medicine, Washington, DC, USA (email: jfinkel@cnmc.org). Pediatric Anesthesia 2007 17: 915–917 doi:10.1111/j.1460-9592.2007.02320.x