Naloxone dosage for opioid reversal: current evidence and clinical implications.

Opioid-related mortality is a growing problem in the United States, and in 2015 there were over 33,000 opioid-related deaths. To combat this mortality trend, naloxone is increasingly being utilized in a pre-hospital setting by emergency personnel and prescribed to laypersons for out-of-hospital administration. With increased utilization of naloxone there has been a subsequent reduction in mortality following an opioid overdose. Reversal of opioid toxicity may precipitate an opioid-withdrawal syndrome. At the same time, there is a risk of inadequate response or re-narcotization after the administration of a single dose of naloxone in patients who have taken large doses or long-acting opioid formulations, as the duration of effect of naloxone is shorter than that of many opioid agonists. As out-of-hospital use of this medication is growing, so too is concern about effective but safe dosing.

Toxicity of a novel therapeutic agent targeting mitochondrial complex I.

R118 is an experimental compound that completed preclinical development as a potential medical therapy for the exercise limitation in peripheral artery disease. Animal studies established that R118 provided partial and reversible mitochondrial complex I inhibition with consequent increases in adenosine monophosphate (AMP) kinase activation in liver and skeletal muscle. After demonstration of improved exercise performance in a mouse model and safety in rodent and primate models, a phase I trial was performed in 24 subjects randomized to R118 vs. placebo (5:1) in escalating doses. Plasma lactic acid levels were transiently elevated in 20% of subjects at the lowest dose and in 100% of subjects using a different formulation at the highest dose, which was associated with hospitalization in all subjects and severe metabolic acidosis requiring prolonged intubation in two subjects. Thus, inhibition of mitochondrial complex I with R118 resulted in severe lactic acidosis, representing unacceptable toxicity from this mechanism of action.

Ondansetron pharmacokinetics in pregnant women and neonates: towards a new treatment for neonatal abstinence syndrome.

Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). The pharmacokinetics of ondansetron have not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 nonpregnant and 40 pregnant women following a single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (P > 0.05), but influenced by dose (P < 0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates.

Awareness in children: a secondary analysis of five cohort studies.

Five recent cohort studies have shown a frequency of awareness in paediatric anaesthesia of between 0.2% and 1.2%, but they were not individually large enough to identify risk factors. This study pooled raw data from these five studies to identify factors associated with awareness in children. The outcome of awareness was taken as the cases judged to be most likely awareness cases in each study. Logistic regression was used to identify awareness-associated factors. A combined sample of 4486 anaesthetics revealed 33 cases of awareness. Unadjusted analysis demonstrated weak evidence that nitrous oxide used as an anaesthetic maintenance adjunct was associated with awareness (OR 2.04 (95% CI 0.97-4.33), p=0.06), and some evidence that use of a tracheal tube was associated with awareness (OR 2.78 (95% CI 1.11-6.94), p=0.03). Multivariable regression analysis revealed that nitrous oxide maintenance and use of a tracheal tube were independently associated with awareness (nitrous oxide, OR 2.4 (95% CI 1.08-5.32), p=0.03; tracheal tube, OR 3.0 (95% CI 1.20-7.56), p=0.02).

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.

Anesthesia for fetoscopic fetal surgery: twin reverse arterial perfusion sequence and twin-twin transfusions syndrome.

IMPLICATIONS: Twin reversed arterial perfusion sequence and twin-twin transfusion syndrome can be managed by fetoscopic fetal surgery. It is important to consider the fetal, uteroplacental, and maternal issues when choosing an anesthetic technique. We report on three patients with differing anesthetic issues using fetoscopic surgery for umbilical cord coagulation.

Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia.

BACKGROUND: Many children are restless, disoriented, and inconsolable immediately after bilateral myringotomy and tympanosotomy tube placement (BMT). Rapid emergence from sevoflurane anesthesia and postoperative pain may increase emergence agitation. The authors first determined serum fentanyl concentrations in a two-phase study of intranasal fentanyl. The second phase was a prospective, placebo-controlled, double-blind study to determine the efficacy of intranasal fentanyl in reducing emergence agitation after sevoflurane or halothane anesthesia. METHODS: In phase 1, 26 children with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled for BMT received intranasal fentanyl, 2 microg/kg, during a standardized anesthetic. Serum fentanyl concentrations in blood samples drawn at emergence and at postanesthesia care unit (PACU) discharge were determined by radioimmunoassay. In phase 2, 265 children with ASA physical status I or II were randomized to receive sevoflurane or halothane anesthesia along with either intranasal fentanyl (2 microg/kg) or saline. Postoperative agitation, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, and satisfaction of PACU nurses and parents with the anesthetic technique were evaluated. RESULTS: In phase 1, the mean fentanyl concentrations at 10 +/- 4 min (mean +/- SD) and 34 +/- 9 min after administering intranasal fentanyl were 0.80 +/- 0.28 and 0.64 +/- 0.25 ng/ml, respectively. In phase 2, the incidence of severe agitation, highest CHEOPS scores, and heart rate in the PACU were decreased with intranasal fentanyl. There were no differences between sevoflurane and halothane in these measures and in times to hospital discharge. The incidence of postoperative vomiting, hypoxemia, and slow respiratory rates were not increased with fentanyl. CONCLUSIONS: Serum fentanyl concentrations after intranasal administration exceed the minimum effective steady state concentration for analgesia in adults. The use of intranasal fentanyl during halothane or sevoflurane anesthesia for BMT is associated with diminished postoperative agitation without an increase in vomiting, hypoxemia, or discharge times.

The effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in healthy volunteers.

UNLABELLED: We studied the effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in human volunteers. We hypothesized that nitrous oxide and sevoflurane would produce both opposing and potentiating effects within the same study. Over the course of three sessions, 20 subjects inhaled 0%, 0.2%, or 0.4% end-tidal sevoflurane for a 68-min period that was divided into four 17-min blocks. During either the second or fourth block, 30% end-tidal nitrous oxide was added to the concentration of sevoflurane being inhaled. Pain response, psychomotor performance, and mood were evaluated during the second and fourth blocks. Pain ratings were higher when sevoflurane and nitrous oxide were administered together than when nitrous oxide was administered alone, which indicates that sevoflurane attenuated the analgesic effects of nitrous oxide. Sevoflurane increased self-reported ratings of sleepiness, and the addition of nitrous oxide decreased these ratings. Nitrous oxide potentiated psychomotor impairment that was induced by sevoflurane. The combination of sevoflurane and nitrous oxide produced both opposing and potentiating effects within the same study. The results suggest that nitrous oxide and sevoflurane may act through different neurochemical mechanisms on some end points, such as analgesia and sleepiness. IMPLICATIONS: Healthy volunteers inhaled subanesthetic concentrations of sevoflurane and nitrous oxide. Sevoflurane made nitrous oxide less effective as an analgesic, and nitrous oxide made sevoflurane less effective as a sedative. The two drugs may work at cross purposes on different end points of anesthesia.

Effects of information on the reinforcing, subjective, and psychomotor effects of nitrous oxide in healthy volunteers.

The purpose of this study was to characterize the reinforcing, subjective, and psychomotor effects of nitrous oxide (N2O) in healthy volunteers who were given different amounts of information regarding the drugs they were being administered in the experiment. A choice procedure was used in which subjects first sampled a placebo and a given concentration of N2O and then chose between the two. N2O concentration varied across the four-session experiment from 10-40%. Besides choice, subjective and psychomotor effects served as dependent measures. In the INFORMED group (n = 11), subjects were told at the beginning of each sampling trial what concentration of N2O they were inhaling or whether they were inhaling 100% oxygen (placebo). They were also informed about the prototypic effects of N2O (e.g. tingling or numbing, euphoria, dysphoria) and oxygen (e.g. no discernible effects). In the NON-INFORMED group (n = 11), subjects were only told at the beginning of each sampling trial that the drugs they would be inhaling came from one of six classes of drugs. Thirty percent N2O was chosen by a significantly higher proportion of subjects than expected by chance in the INFORMED group, but not in the NON-INFORMED group. Further, the probability of choosing 20-40% N2O was higher in the INFORMED group than in the NON-INFORMED group. Subjective effects of N2O were not affected by the information manipulation. Psychomotor performance at the highest N2O concentration tested (40%) was impaired to a greater extent in the NON-INFORMED than in the INFORMED group. We conclude that the reinforcing effects of N2O, and perhaps the impairing effects, can be modulated by telling subjects beforehand that they are inhaling N2O and what effects they might be expected to experience from the drug.

Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of sevoflurane and nitrous oxide.

BACKGROUND: Sevoflurane is a volatile general anesthetic that differs in chemical nature from the gaseous anesthetic nitrous oxide. In a controlled laboratory setting, the authors characterized the subjective, psychomotor, and analgesic effects of sevoflurane and nitrous oxide at two equal minimum alveolar subanesthetic concentrations. METHODS: A crossover design was used to test the effects of two end-tidal concentrations of sevoflurane (0.3% and 0.60%), two end-tidal concentrations of nitrous oxide (15% and 30%) that were equal in minimum alveolar concentration to that of sevoflurane, and placebo (100% oxygen) in 12 healthy volunteers. The volunteers inhaled one of these concentrations of sevoflurane, nitrous oxide, or placebo for 35 min. Dependent measures included subjective, psychomotor, and physiologic effects, and pain ratings measured during a cold-water test. RESULTS: Sevoflurane produced a greater degree of amnesia, psychomotor impairment, and drowsiness than did equal minimum alveolar concentrations of nitrous oxide. Recovery from sevoflurane and nitrous oxide effects was rapid. Nitrous oxide but not sevoflurane had analgesic effects. CONCLUSIONS: Sevoflurane and nitrous oxide produced different profiles of subjective, behavioral, and cognitive effects, with sevoflurane, in general, producing an overall greater magnitude of effect. The differences in effects between sevoflurane and nitrous oxide are consistent with the differences in their chemical nature and putative mechanisms of action.

Comparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of buprenorphine in nondrug-abusing volunteers and to compare and contrast the effects of equianalgesic doses of buprenorphine and morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 0.075, 0.15 or 0.3 mg/70 kg buprenorphine, or 10 mg/70 kg morphine, using a randomized, double-blind, cross-over design. The 0.3-mg buprenorphine dose and 10-mg morphine dose are considered to be equianalgesic and are doses commonly given for relief of postoperative pain. Buprenorphine increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and decreased scores on the Benzedrine Group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "skin itchy," and "turning of stomach," and increased visual analogue scale ratings of "dizzy," "nauseous" and "sleepy." Buprenorphine (0.3 mg) in general had subjective effects of greater magnitude than that of 10 mg morphine. Buprenorphine produced impairment on five measures of psychomotor performance in a dose-related fashion. Ten mg morphine produced minimal psychomotor impairment. Both buprenorphine and morphine induced miosis, but buprenorphine (0.3 mg) had a larger and longer effect than that of 10 mg morphine. Buprenorphine, but not morphine, decreased respiration rate. The results of our study demonstrate that 0.075 to 0.3 mg buprenorphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of buprenorphine, 0.3 mg, produced a greater magnitude of subjective and psychomotor-impairing effects than did an equianalgesic dose of morphine.

Determination and correlation of in vitro viability for hairless mouse and human neonatal whole skin and stratum corneum/epidermis.

BACKGROUND AND DESIGN: Viable tissue is essential to assess the rate and extent of biotransformation during percutaneous absorption in vitro. We assessed the viability of hairless mouse whole skin (WS) and stratum corneum/epidermis (SCE) and human neonatal SCE following separation from the dermis by EDTA phosphate-buffered saline (EDTA-PBS) incubation or by heat treatment by measuring the conversion of dextrose to lactate. Lactate concentrations in receptor fluid samples were determined using a Sigma diagnostic lactate determination kit. A standard curve was prepared and samples assayed spectrophotometrically at 340 nm using a lambda 2 beta spectrophotometer. Standard curves were prepared for each experiment and correlation coefficient values (r) were calculated. RESULTS: Our results showed that hairless mouse SCE was associated with glucose conversion to lactic acid at an increased rate if incubated in EDTA-PBS for 4 h and used immediately. Lactate production was greater with the dermis present (EDTA-PBS WS). The rate of glucose to lactate conversion in hairless mouse SCE was 20-25% of that found in WS. Compared with Dulbecco's modified PBS (DMPBS)-treated WS controls, the rate of lactate production in EDTA-PBS-treated WS was nearly a 50% less. Heat treatment in water at 60 degrees C to separate SCE from hairless mouse WS appeared to eliminate viability. Viability of hairless mouse SCE, as measured by glucose conversion to lactate, was comparable to human neonatal SCE. CONCLUSIONS: These results suggest that the dermis is a significant contributor to glucose metabolism and that incubation in EDTA-PBS is a contributing factor to the overall decrease in metabolic capacity of the tissue. As a result of these findings, hairless mouse SCE appears to be useful as a model for human neonatal SCE in percutaneous absorption studies.