The Challenges of Identifying Fibromyalgia in Adolescents.

Aim: Fibromyalgia (FM) is a noninflammatory disorder of the nervous system characterized by widespread musculoskeletal pain and somatic complaints of at least 3 months duration. There are no current diagnostic criteria for fibromyalgia in children to guide clinicians in recognition, thus leading to many subspecialty referrals and extensive imaging and tests. The purpose of this retrospective review is to compare two diagnostic criteria for juvenile fibromyalgia. Methods: A retrospective chart review of 20 children diagnosed with juvenile fibromyalgia from a singular pain physician practice was performed. Both the Yunus diagnostic criteria and the 2016 American College of Rheumatology (ACR) diagnostic criteria were applied and compared. Results: 85% of patients met criteria for fibromyalgia under both criteria. 15% of patients met only ACR criteria as the Yunus criteria excluded those with underlying conditions. Of the children who fulfilled criteria with use of both diagnostic tools, this cohort reported a high somatic symptom burden as demonstrated by the ACR symptom severity scales of 12 and satisfaction of at least 4 Yunus and Masi minor criteria on average. Widespread pain was noted with an ACR Widespread Pain Index (WPI) of 7, and tender points were 4.8 on average across the cohort. Effective therapeutic regimens among patients varied widely from medical monotherapy to multimodal treatment. Patients presented with pain for 1.8 yrs on average prior to a diagnosis. All of the cohort had a normal laboratory evaluation; half the cohort received additional imaging and testing. Conclusion: This case series suggests the need for an updated diagnostic tool for pediatric fibromyalgia to facilitate recognition and treatment.

Safety and Efficacy of Single-Dose Ketorolac for Postoperative Pain Management After Primary Palatoplasty: A Prospective Cohort Study With Historical Controls.

OBJECTIVE: To analyze safety and efficacy of single-dose ketorolac after primary palatoplasty (PP). DESIGN: Consecutive cohort of patients undergoing PP, comparing to historical controls. Setting: A large academic children's hospital. PATIENTS, PARTICIPANTS: A consecutive cohort of 111 patients undergoing PP (study n = 47) compared to historical controls (n = 64). INTERVENTIONS: All patients received intraoperative acetaminophen, dexmedetomidine, and opioids while the study group received an additional single dose of ketorolac (0.5 mg/kg) at the conclusion of PP. MAIN OUTCOME MEASURES: Safety of ketorolac was measured by significant bleeding complications and need for supplementary oxygen. Efficacy was assessed through bleeding, Face Legs Activity Cry Consolability (FLACC) scale, and opioid dose. RESULTS: Length of stay was similar for both groups (control group 38.5 hours [95% CI: 3.6-43.3] versus study group 37.6 hours [95% CI: 31.3-44.0], P = .84). There were no significant differences in all postoperative FLACC scales. The mean dose of opioid rescue medication measured as morphine milligram equivalents did not differ between groups (P = .56). Significant postoperative hemorrhage was not observed. CONCLUSIONS: This is the first prospective study to evaluate the safety and efficacy of single-dose ketorolac after PP. Although lack of standardization between study and historical control groups may have precluded observation of an analgesic benefit, analysis demonstrated a single dose of ketorolac after PP is safe. Further investigations with more patients and different postoperative regimens may clarify the role of ketorolac in improving pain after PP.

IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-based mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not significantly affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

Sickle cell disease subjects and mouse models have elevated nitrite and cGMP levels in blood compartments.

The hypothesis of decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD) proposes that multiple factors leading to decreased NO production and increased consumption contributes to vaso-occlusion, pulmonary hypertension, and pain. The anion nitrite is central to NO physiology as it is an end product of NO metabolism and serves as a reservoir for NO formation. However, there is little data on nitrite levels in SCD patients and its relationship to pain phenotype. We measured nitrite in SCD subjects and examined its relationship to SCD pain. In SCD subjects, median whole blood, red blood cell and plasma nitrite levels were higher than in controls, and were not associated with pain burden. Similarly, Townes and BERK homozygous SCD mice had elevated blood nitrite. Additionally, in red blood cells and plasma from SCD subjects and in blood and kidney from Townes homozygous mice, levels of cyclic guanosine monophosphate (cGMP) were higher compared to controls. In vitro, hemoglobin concentration, rather than sickle hemoglobin, was responsible for nitrite metabolism rate. In vivo, inhibition of NO synthases and xanthine oxidoreductase decreased nitrite levels in homozygotes but not in control mice. Long-term nitrite treatment in SCD mice further elevated blood nitrite and cGMP, worsened anemia, decreased platelets, and did not change pain response. These data suggest that SCD in humans and animals is associated with increased nitrite/NO availability, which is unrelated to pain phenotype. These findings might explain why multiple clinical trials aimed at increasing NO availability in SCD patients failed to improve pain outcomes.

First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18.

BACKGROUND: This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents. PATIENTS AND METHODS: This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised. Adverse events were monitored throughout the trial. RESULTS: Forty-four patients who received a single dose of 1 mg/kg tapentadol OS were included in this investigation. Maximum serum concentrations of tapentadol (111 ng/mL) and tapentadol-O-glucuronide (2,400 ng/mL) observed in this trial were within the range of individual maximum concentrations observed in healthy adults administered a comparable dose (range for tapentadol 23.2-129 ng/mL, for tapentadol-O-glucuronide 1,040-4,070 ng/mL). Following tapentadol administration, pain intensity scores improved from baseline at all timepoints. Treatment-emergent adverse events, none of which were serious, were experienced by 45.5% of the patients; the most commonly reported were vomiting (29.5%) and nausea (9.1%). CONCLUSIONS: Tapentadol OS administered as a single dose of 1 mg/kg in children aged 6 to <18 years was generally well tolerated and produced similar serum concentrations as administration of 50-100 mg tapentadol immediate-release tablets in adults. A decrease in postsurgical pain was observed using exploratory subject-reported pain assessments. Tapentadol OS may provide a new treatment option in the management of moderate to severe acute pain in children and adolescents.

Molecular Biology of Opioid Analgesia and Its Clinical Considerations.

Understanding the molecular biology of opioid analgesia is essential for its proper implementation and mechanistic approach to its modulation in order to maximize analgesia and minimize undesired effects. By appreciating the molecular mechanisms intrinsic to opioid analgesia, one can manipulate a molecular target to augment or diminish a specific effect using adjuvant drugs, select an appropriate opioid for opioid rotation or define a molecular target for new opioid drug development. In this review, we present the cellular and molecular mechanisms of opioid analgesia and that of the associated phenomena of tolerance, dependence, and hyperalgesia. The specific mechanisms highlighted are those that presently can be clinically addressed.

Association between Pain Sensitivity, Central Sensitization, and Functional Disability in Adolescents With Joint Hypermobility.

PURPOSE: The purpose of this study was to examine the association between pain sensitivity, central sensitization, and functional disability in adolescents with joint hypermobility. DESIGN AND METHODS: A cross-sectional descriptive design was utilized for this study. A sample of 40 adolescents being evaluated for chronic pain and autonomic nervous system dysfunction were recruited. Subjects were evaluated for pain, function, central sensitization, and sensitivity on pain and touch sensory nerve fiber types. Data were analyzed to detect associations between variables. RESULTS: Joint hypermobility had a moderately significant correlation with central sensitization measured by the Central Sensitization Inventory, as well as increased pain sensitivity as evidenced by hypersensitivity of Aδ sensory nerve fibers. The presence of central sensitization was also positively associated with level of functional disability. CONCLUSIONS: Findings implicate joint hypermobility as a possible antecedent to pain hypersensitivity and central sensitization syndromes that when recognized and addressed effectively may reduce functional disability in those affected. PRACTICE IMPLICATIONS: It is important for pediatric nurses that work with adolescents that have chronic pain to understand variables that may impact pain and functional disability in order to develop methods to increase function, reduce pain, and increase perceived quality of life.

Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease.

BackgroundN-methyl-D-aspartate receptor activation has been implicated in the pathobiology of inflammatory, nociceptive and neuropathic pain, opioid tolerance, opioid-induced hyperalgesia, and central sensitization. Some of those mechanisms underlie sickle cell disease(SCD)-associated pain.MethodsWe conducted an exploratory cohort study of SCD patients who during vaso-occlusive episodes (VOEs) received subanesthetic doses of the N-methyl-D-aspartate receptor antagonist, ketamine, as an adjunct to opioids. We sought to identify predictors of changes in pain scores and of the percentage of ketamine infusions associated with meaningful changes (≥20% reduction) in pain and opioid consumption.ResultsEight-five patients received 181 ketamine infusions for VOE-associated pain. Combined with opioids, ketamine yielded significant decrease in pain scores and opioid consumption. Ketamine administered to males and to younger patients yielded greater pain score decrease compared with females (P=0.013) and older patients (P=0.018). Fifty-four percent of infusions yielded meaningful reductions in pain scores, and in multivariate analysis, sex, age group, pain location, and infusion duration independently predicted pain score changes.ConclusionThis study suggests that in SCD patients admitted with VOE-associated pain, ketamine has age- and sex-dependent effects. These data can inform sample and effect size calculations for controlled trials to determine which SCD patients would benefit most from ketamine.

Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study.

BACKGROUND: Subanesthetic doses of ketamine, an N-methyl-d-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults. PURPOSE: We examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting. METHODS: This is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake. RESULTS: The study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38-6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06-4.69]), p<0.001. Importantly, the effect of ketamine on pain scores varied according to clinical diagnosis (p=0.011), infusion duration (p=0.004), and pain location (p=0.004). Interestingly, greater reductions in pain scores were observed in patients with cancer pain and patients with pain associated with pancreatitis and Crohn's disease. There were no records of psychotomimetic side effects requiring therapy. CONCLUSION: These data suggest that administration of subanesthetic ketamine for pain management is feasible and safe in regular inpatient care units and may benefit children, adolescents, and young adults with acute and chronic pain. This study is informative and can be helpful in determining sample and effect sizes when planning clinical trials to determine the role of subanesthetic ketamine infusions for pain management in pediatric patients.

The Use of Dexmedetomidine in Pediatric Palliative Care: A Preliminary Study.

OBJECTIVE: To evaluate the effect of dexmedetomidine infusions in patients with advanced malignancies, advanced heart disease, or after stem cell transplantation (SCT), who during end-of-life care had pain and/or agitation unresponsive to conventional therapies. BACKGROUND: Pediatric patients with intractable advanced malignancies, end-stage congenital heart diseases, or after SCT can suffer a great deal during end of life. Pain, drowsiness, fatigue, irritability, and worrying are experienced frequently, considered distressing, and are strongly associated with reductions in health-related quality-of-life scores. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use can be ineffective and can be associated with increasing pain during end of life. Dexmedetomidine, a α2-adrenoreceptor agonist with sedative and analgesic properties but without respiratory depressant effects, has been shown to reduce opioid requirement and to facilitate opioid weaning. METHODS: Observational cohort study of consecutive patients treated with dexmedetomidine during end of life in a pediatric hospital. Primary outcomes included pain scores and morphine-equivalent intake. RESULTS: We identified nine patients [median age 8 (interquartile range; IQR 0.55-17 years)] who during end of life had received dexmedetomidine infusions. In these patients, dexmedetomidine infusions had a median duration of two days (IQR 1.5-12 days) and were associated with significant (p < 0.001) reductions in pain scores and a trend toward decreasing morphine-equivalent intake. There were no hemodynamic changes requiring vasoactive or anticholinergic agents. CONCLUSIONS: These preliminary findings of beneficial effects of dexmedetomidine support the hypothesis that dexmedetomidine has a role in palliative care of children and adolescents during end of life.

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

BACKGROUND: Chronic 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. METHODS: Longitudinal 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. RESULTS: Over 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 (p = 0.029). 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 (p = 0.007). In 37% of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3). CONCLUSIONS: These 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.

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 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.

Sickle cell disease in mice is associated with sensitization of sensory nerve fibers.

The pain phenotype in sickle cell disease (SCD) patients is highly variable. A small percentage of SCD patients experience many vaso-occlusive crises/year, 5% of patients account for over 30% of pain episodes, while 39% report few episodes of severe pain. Clearly, a better understanding of the pathobiology of SCD is needed to improve its therapy. Humanized sickle cell mice recapitulate several phenotypes of SCD patients and provide a model for the study of SCD pain. Researchers have shown that one strain of humanized SCD mice, the BERK strain, has abnormal pain phenotype. However, the nociception phenotype of another humanized SCD mouse strain, the Townes strain, has not been described. In a large cross-sectional study of BERK and Townes SCD mice, we examined thermosensory response and sensory nerve fiber function using sine-wave electrical stimulation at 2000, 250, and 5 Hz to stimulate preferentially Aß, Aδ, and C sensory nerve fibers, respectively. We found that BERK and Townes mice, compared to respective controls, had decreases in 2000, 250, and 5 Hz current vocalization thresholds in patterns that suggest sensitization of a broad spectrum of sensory nerve fibers. In addition, the pattern of sensitization of sensory fibers varied according to strain, sex, age, and mouse genotype. In a similarly variable pattern, Townes and BERKs also had significantly altered sensitivity to noxious thermal stimuli in agreement with what has been shown by others. In summary, the analysis of somatosensory function using sine-wave electrical stimulation in humanized sickle cell mice suggests that in SCD, both myelinated and unmyelinated, fibers are sensitized. The pattern of sensory fiber sensitization is distinct from that observed in pain models of neuropathic and inflammatory pain. These findings raise the possibility that sensitization of a broad spectrum of sensory fibers might contribute to the altered and variable nociception phenotype in SCD.

Prolonged perioperative infusion of low-dose ketamine does not alter opioid use after pediatric scoliosis surgery.

BACKGROUND: Opioid consumption after posterior spinal fusion is known to be high and often exceeds those reported in other major surgical procedures. A number of clinical trials provide evidence that the perioperative use of subanesthetic doses of ketamine reduces pain and opioid requirements in some surgical procedures, but the effect of prolonged perioperative low-dose ketamine infusion in patients undergoing posterior spinal fusion for pediatric scoliosis surgery is unknown. OBJECTIVE: To test the hypothesis that a 72-h perioperative low-dose ketamine infusion would decrease opioid use in pediatric patients undergoing posterior spinal fusion. METHODS: In a double-blind prospective controlled trial, patients undergoing posterior spinal fusion for scoliosis were randomized to receive perioperative low-dose ketamine or placebo control. Patients received general anesthesia, intraoperative remifentanil, and morphine patient-controlled analgesia postoperatively. Daily opioid consumption, self-reported pain scores, and sedation scores were measured. RESULTS: Fifty-four patients were enrolled and 50 completed the study. Contrary to our hypothesis, ketamine- and control-treated patients had similar postoperative opioid use, pain scores, and sedation scores measurements. In contrast, ketamine-treated patients required less intraoperative remifentanil compared with control (mean 2.9 mg vs. 4 mg, P = 0.0415). Number of vertebrae instrumented, time between end-of-surgery and 24 h assessment, or remifentanil doses did not impact on postoperative opioid use. Over 96-h postoperatively, morphine-equivalent consumption was lower (-0.40, P = 0.006) and sedation score was higher (0.47, P = 0.0211) in male patients, compared with female patients. CONCLUSIONS: These findings do not support the use of perioperative low-dose ketamine to decrease opioid use in children with scoliosis undergoing posterior spinal fusion.

Microfluidic-enabled liposomes elucidate size-dependent transdermal transport.

Microfluidic synthesis of small and nearly-monodisperse liposomes is used to investigate the size-dependent passive transdermal transport of nanoscale lipid vesicles. While large liposomes with diameters above 105 nm are found to be excluded from deeper skin layers past the stratum corneum, the primary barrier to nanoparticle transport, liposomes with mean diameters between 31-41 nm exhibit significantly enhanced penetration. Furthermore, multicolor fluorescence imaging reveals that the smaller liposomes pass rapidly through the stratum corneum without vesicle rupture. These findings reveal that nanoscale liposomes with well-controlled size and minimal size variance are excellent vehicles for transdermal delivery of functional nanoparticle drugs.

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 (dexmedetomidine + sevoflurane) 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 sevoflurane + dexmedetomidine 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 dexmedetomidine + sevoflurane 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.

Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop.

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

The effect of dexmedetomidine during myringotomy and pressure-equalizing tube placement in children.

BACKGROUND: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. OBJECTIVES: To examine the effects of intranasal dexmedetomidine, an α(2)-adrenoceptor agonist, on time-averaged pain scores, pain control, need for rescue analgesia, and agitation scores in children undergoing BMT. METHODS: We designed a trial to enroll 160 children randomized to one of four groups: two study groups, dexmedetomidine (1 or 2 µg·kg(-1)), or two control groups representing our institutional standards of practice (intranasal fentanyl-2 µg·kg(-1) or acetaminophen as needed postoperatively). RESULTS: After 101 children were enrolled, patient caregivers observed that some enrollees were excessively sedated and required prolonged postanesthesia care unit (PACU) stay. This observation led to an unplanned interim analysis and early trial termination. After data were collected, severe nonnormality of pain and agitation scores necessitated a switch of the outcome to assess repeated measurements of the proportion of patients with pain, severe pain, and agitation. Demographics, time to emergence, and agitation were similar among all groups. The risk of requiring acetaminophen rescue (P < 0.0001) and proportion of patients having pain (P = 0.016) was significantly higher in one control group (rescue analgesia only) compared with fentanyl or dexmedetomidine groups. Importantly, length of stay in the PACU was significantly longer in dexmedetomidine-2 µg·kg(-1)-treated compared with dexmedetomidine-1 µg·kg(-1)-treated, fentanyl-treated, or the control group, P = 0.0037. CONCLUSIONS: In this trial, we were unable to answer the original question as to the role of dexmedetomidine on time-averaged pain and agitation scores after BMT. However, our findings clearly demonstrate that in children undergoing BMT, at higher doses, dexmedetomidine significantly prolongs length of stay in the PACU.

High-dose dexmedetomidine increases the opioid-free interval and decreases opioid requirement after tonsillectomy in children.

PURPOSE: Dexmedetomidine, a selective α(2) adrenoreceptor agonist, has analgesic and sedative properties, minimal impact on respiratory parameters, and reportedly decreases analgesic requirements after surgery. Given its pharmacodynamic profile, dexmedetomidine might have a role for postoperative pain control in children undergoing tonsillectomy. In this study, we hypothesized that dexmedetomidine would delay and decrease opioid requirements after tonsillectomy. METHODS: In a double-blind controlled trial, participants undergoing tonsillectomy were randomized to receive one intravenous dose of fentanyl (1 µg·kg(-1) or 2 µg·kg(-1)) or dexmedetomidine (2 µg·kg(-1) or 4 µg·kg(-1)) immediately after endotracheal intubation. Primary outcomes included requirement for rescue morphine in the initial postoperative period. RESULTS: One hundred and one children were enrolled. During the postoperative period, dexmedetomidine (2 and 4 µg·kg(-1) groups combined) significantly prolonged the opioid-free interval of children who underwent tonsillectomy compared with fentanyl (1 and 2 µg·kg(-1) groups combined) (P < 0.001). Children treated with dexmedetomidine 2 µg·kg(-1) vs dexmedetomidine 4 µg·kg(-1) had similar cumulative incidence curves for time to morphine rescue, whereas there was a small difference in time to first morphine rescue administration when comparing fentanyl 1 µg·kg(-1) vs fentanyl 2 µg·kg(-1). Furthermore, length of stay in the postanesthesia care unit was significantly longer for children treated with dexmedetomidine vs children treated with fentanyl (P = 0.0016). CONCLUSIONS: High-dose dexmedetomidine decreases opioid requirements, prolongs the opioid-free interval after tonsillectomy, and prolongs length of stay in the postanesthesia care unit. It is conceivable that these early opioid-sparing effects could benefit patients at risk for respiratory complications early in the postoperative course after tonsillectomy (e.g., patients with obstructive sleep apnea). (ClinicalTrials.gov number, NCT00654511).