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1.  Nitrous Oxide Analgesia in Selected Dental Patients 
Anesthesia Progress  1982;29(3):78-80.
Nitrous oxide analgesia is presented as the analgesic method of choice in medically compromised patients. The resemblance between the action of nitrous oxide and that of morphine is emphasized. The combination of the opiate-like action of nitrous oxide with the advantages of an inhalation technique makes it preferable and superior to parenteral opiate administration. It may thus be termed as an inhalation “opiate”.
Since its introduction into clinical use by Wells in 1844 (1), nitrous oxide (N20) has been applied as an anesthetic and analgesic agent in various medical situations, including dentistry (2). The development of equipment affording safe administration of accurate concentrations of either pre-mixed or adjustable N20 and oxygen enabled the application of “relative analgesia” as an important technique in the relief of pain. The pharmacological action and analgesic properties of N20 received renewed interest after Berkowitz et al (3) showed the resemblance between its mode of action and that of opiates. Recent human and animal studies indicated that N20 activates the endogenous opiate system(s) in a manner similar to that of morphine (4). The availability of an analgesic gas which, on the one hand, mimics opiate action whilst on the other hand its administration is continuously adjustable, as opposed to other modes of sedation, makes it into an ideal adjunct in dental procedures. Owing to its minimal side effects, the use of N20 is especially recommended in the management of anxious children and medically compromised patients.
This report presents three illustrative patients in whom nitrous oxide proved to be the drug of choice during dental procedures.
PMCID: PMC2515463  PMID: 6214199
2.  The Effect of Nitrous Oxide Anesthesia on Early Postoperative Opioid Consumption and Pain 
Background and Objectives
Many patients experience moderate to severe postoperative pain. Nitrous oxide exerts analgesia by inhibition of N-Methyl-D-aspartate (NMDA) receptors. Ketamine, another NMDA receptor-antagonist, reduces postoperative opioid consumption and pain. A similar effect of nitrous oxide is plausible, yet understudied. The goal of this study was to determine the effects of nitrous oxide anesthesia on early postsurgical opioid consumption and pain.
Methods
This was a retrospective, secondary analysis of the Vitamins In Nitrous Oxide trial, where 500 patients undergoing general anesthesia for noncardiac surgery received 60% nitrous oxide and 125 received no nitrous oxide (otherwise, inclusion/exclusion criteria were identical). Exclusion criteria for this study were regional anesthesia; not extubated after surgery; transfer to ICU; no available PACU record; postsurgical sedation; or treated with naloxone. Primary outcomes were cumulative opioid consumption measured in morphine equivalents and pain scores during the immediate recovery phase.
Results
Four hundred forty-two patients met inclusion criteria. No difference in intraoperative and postoperative opioid consumption was observed between patients who received nitrous oxide (n=353) and patients who did not (n=89). The median [interquartile range] postoperative morphine equivalent dose was 6.7 mg [1.7–14.1] for patients who received nitrous oxide and 6.7 mg [2.1–15.4] for patients who did not (P = 0.73). The maximum pain score was 6 [4–8] for patients who received nitrous oxide versus 6 [3–8] for patients who received nitrous oxide-free anesthesia (P = 0.52). The prevalence of moderate to severe pain was 69% for patients who received nitrous oxide and 68% for patients who did not (P = 0.90).
Conclusions
Nitrous oxide anesthesia was not associated with decreased opioid administration, pain, or incidence of moderate to severe pain in the early postoperative phase.
doi:10.1097/AAP.0000000000000039
PMCID: PMC3919543  PMID: 24310050
Analgesia; Nitrous Oxide; Pain; Postoperative; Anesthesia; General
3.  Measurement of Opening and Closing Angles of Aortic Valve Prostheses In Vivo Using Dual-Source Computed Tomography: Comparison with Those of Manufacturers' in 10 Different Types 
Korean Journal of Radiology  2015;16(5):1012-1023.
Objective
The aims of this study were to compare opening and closing angles of normally functioning mechanical aortic valves measured on dual-source computed tomography (CT) with the manufacturers' values and to compare CT-measured opening angles according to valve function.
Materials and Methods
A total of 140 patients with 10 different types of mechanical aortic valves, who underwent dual-source cardiac CT, were included. Opening and closing angles were measured on CT images. Agreement between angles in normally functioning valves and the manufacturer values was assessed using the interclass coefficient and the Bland-Altman method. CT-measured opening angles were compared between normal functioning valves and suspected dysfunctioning valves.
Results
The CT-measured opening angles of normally functioning valves and manufacturers' values showed excellent agreement for seven valve types (intraclass coefficient [ICC], 0.977; 95% confidence interval [CI], 0.962-0.987). The mean differences in opening angles between the CT measurements and the manufacturers' values were 1.2° in seven types of valves, 11.0° in On-X valves, and 15.5° in ATS valves. The manufacturers' closing angles and those measured by CT showed excellent agreement for all valve types (ICC, 0.953; 95% CI, 0.920-0.972). Among valves with suspected dysfunction, those with limitation of motion (LOM) and an increased pressure gradient (PG) had smaller opening angles than those with LOM only (p < 0.05).
Conclusion
Dual-source cardiac CT accurately measures opening and closing angles in most types of mechanical aortic valves, compared with the manufacturers' values. Opening angles on CT differ according to the type of valve dysfunction and a decreased opening angle may suggest an elevated PG.
doi:10.3348/kjr.2015.16.5.1012
PMCID: PMC4559772  PMID: 26356549
Mechanical aortic valve; Opening and closing angles; Measurement; Dual-source computed tomography
4.  Comparative evaluation of recovery characteristics of fentanyl and butorphanol when used as supplement to propofol anaesthesia 
Background and Aim:
Narcotics have been used since long as a component of balanced anaesthesia, thus minimizing the anaesthetic requirement both during induction and maintenance as well as attenuating the pressor response during laryngoscopy and intubation. Equally significant is their role in provision of smoother recovery period by minimizing postoperative pain. Other than pain, the factors like postoperative nausea and vomiting (PONV), shivering, sedation and respiratory depression are equally important in recovery from the effects of anaesthetic drugs. The present study aimed at comparing the postoperative recovery characterstics of fentanyl and butorphanol in patients undergoing open cholecystectomy under general anaesthesia.
Materials and Methods:
The present study configured one hundred adults patients of American Society of Anaesthesiologists (ASA) grade 1 or 2 of either sex scheduled to undergo elective open cholecystectomy and were randomly assigned to receive fentanyl (group F; n = 50) or butorphanol (group B; n = 50). Both group were premedicated with midazolam 0.04 mg/kg intravenously followed by injection fentanyl 2 mcg/kg or butorphanol 40 mcg/kg. Standard induction was done with propofol 2 mg/kg and vecuronium 0.1 mg/kg was used for intubation. Anaesthesia was maintained with propofol infusion and 67% nitrous oxide in oxygen. Intraoperative hemodynamic parameters were observed and recorded. Postoperatively analgesia, sedation, PONV, shivering, respiratory depression and recovery score were observed.
Results:
The recovery time was less in group F (P > 0.05) while post operative analgesia (P < 0.001) and sedation (P > 0.05) was more in group B. The incidence of respiratory depression was more in group B (P > 0.05). PONV was comparable in both the groups. Postoperative shivering was significantly low in group B (P < 0.05).
Conclusion:
It is concluded that besides easy availability and lower cost, butorphanol decreased propofol consumption intraoperatively and provided better analgesia and prophylaxis against shivering in postoperative period.
doi:10.4103/2229-516X.106350
PMCID: PMC3678702  PMID: 23776820
Butorphanol; fentanyl; propofol; recovery
5.  Reduced Leaflet Stress in the Stentless Quadrileaflet Mitral Valve: A Finite Element Model 
PLoS ONE  2013;8(7):e67683.
Background
Failure of bioprosthetics is usually caused by calcification of the leaflets as a consequence of high tensile stresses. The stentless valve resembles native mitral valve anatomy, has a flexible leaflet attachment and a suspension at the papillary muscles, and preserves annuloventricular continuity. In this study, the effects of the stentless valve design on leaflet stress were investigated with a finite element model.
Methods
Finite element models of the stentless quadrileaflet mitral valve were created in the close and open configurations. The geometry of the stented trileaflet mitral valve was also analyzed for comparative purposes. Under the designated pressures, the regional stresses were evaluated, and the distributions of stresses were assessed.
Results
Regardless of whether the valve is in the open or close configuration, the maximum first principal stress was significantly lower in the stentless valve than in the stented valve. For the stentless valves, limited stress concentration was discretely distributed in the papillary flaps under both close and open conditions. In contrast, in the stented valve, increased stress concentration was evident at the central belly under the open condition and at the commissural attachment under close condition. In either configuration, the maximum second principal stress was markedly lower in the stentless valve than in the stented valve.
Conclusions
The stentless valve was associated with a significant reduction in leaflet stress and a more homogeneous stress distribution compared to the stented valve. These findings are consistent with recent reports of the clinical effectiveness of the stentless quadrileaflet mitral valve.
doi:10.1371/journal.pone.0067683
PMCID: PMC3699618  PMID: 23844060
6.  The Measurement of Opening Angle and Orifice Area of a Bileaflet Mechanical Valve Using Multidetector Computed Tomography 
Korean Circulation Journal  2009;39(4):157-162.
Background and Objectives
The aim of this study was to assess mechanical valve function using 64-slice multidetector computed tomography (MDCT).
Subjects and Methods
In 20 patients (mean age, 50±12 years; male-to-female ratio, 10:10), 30 St. Jude bileaflet mechanical valves (15 aortic and 15 mitral valves) were evaluated using MDCT. We selected images vertical and parallel to the mechanical valve. The valve orifice area (OA) and valve length were determined by manual tracing and the opening and closing angles were measured using a protractor. The OA and length of the mechanical valves were compared with the manufacturer's values.
Results
The geometric orifice areas (GOAs) based on the manufacturer's values and the OAs determined by MDCT were 3.4±0.2 cm2 and 3.4±0.3 cm2 for the mitral valves and 2.1±0.3 cm2 and 2.1±0.4 cm2 for the aortic valves, respectively. The correlation coefficients between the OA measures were 0.433 for the mitral valves and 0.874 for the aortic valves (both p<0.001). The lengths based on the manufacturer's values and determined by MDCT were 29.3±1.99 mm and 29.6±1.65 mm for the mitral valves and 21.5±2.1 mm and 20.7±2.3 mm for the aortic valves, respectively. The correlation coefficients between the measures were 0.651 for the mitral valve and 0.846 for the aortic valve (both p<0.001). The opening and closing angles determined by MDCT were 10.9±0.6° and 131.1±3.2° for the mitral valves and 11.1±0.9° and 120.6±1.7° for the aortic valves, respectively.
Conclusion
MDCT is an accurate modality with which to assess the function and morphology of bileaflet mechanical valves.
doi:10.4070/kcj.2009.39.4.157
PMCID: PMC2771814  PMID: 19949605
Valve; Heart; Computed tomography
7.  Nitrous oxide analgesia during intra-articular injection for juvenile idiopathic arthritis 
Archives of Disease in Childhood  2002;86(6):416-418.
Aims: To evaluate the efficacy and safety of nitrous oxide–oxygen for children with juvenile idiopathic arthritis (JIA) undergoing intra-articular corticosteroid injection.
Methods: A total of 55 consecutive patients with JIA undergoing intra-articular corticosteroid injection, using self administered nitrous oxide–oxygen for analgesia were studied. Patient, nurse, and parent pain scores were compared using a 0–10 cm visual analogue scale (VAS) immediately after the procedure.
Results: A total of 70 joints were injected in 55 patients (median age 13.54 years). The median pain score for patient, nurse, and parent was 1 (0–10 cm VAS). The mean rank patient score was 2.12, which was greater than the nurse score (1.97), which was greater than the parent score (1.91). These differences were significant. There were no serious adverse events in any patient.
Conclusions: Nitrous oxide–oxygen provides safe and effective analgesia for intra-articular injection in children. In some cases, nurses and parents underestimated pain related to the procedure compared to the child.
doi:10.1136/adc.86.6.416
PMCID: PMC1762988  PMID: 12023171
8.  NOP Receptor Mediates Anti-analgesia Induced by Agonist-Antagonist Opioids 
Neuroscience  2013;257:139-148.
Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ~90 minutes after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69,593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia.
doi:10.1016/j.neuroscience.2013.10.061
PMCID: PMC3947912  PMID: 24188792
κ-opioids; anti-analgesia; nalbuphine; Nociceptin/orphanin FQ receptor
9.  Analgesic and physiological effects in conscious sedation with different nitrous oxide concentrations 
Objectives: to study the physiological changes, as well as the psychosedative and analgesic effects of nitrous oxide, in experimental conditions. Study Design: 101 dental students volunteers participated in a single nitrous oxide sedation session without dental treatment. Signs and symptoms were registered during and after the procedure. Pulse rate and hemoglobin oxygen saturation were monitored at: 100 per cent O2, 30 per cent N2O, 50 per cent N2O and 5 minutes after 100 per cent O2. A Likert scale was used to evaluate pain perception. The analgesic effects of nitrous oxide were evaluated at: 30 per cent N2O, 50 per cent N2O, and five minutes postoperatively. Results: Pulse rate and hemoglobin oxygen saturation decreased significantly through all the procedure and after recovery. However, oxygen saturation recovered after the final oxygenation. Only 8.2% of subjects reported the pain stimulus as being quite annoying when they inhaled 30 per cent N2O, while this percentage was of 15.8 % when inhaling 50 per cent N2O, and of 32.7 % during the recovery period. The most common effects of nitrous oxide sedation were bright eyes (99%), voice change (98%) and smiling (91%). Most of the subjects reported tingling (98%) and relax (91.1%) Conclusions: nitrous oxide causes a significant decrease in heart rate and oxygen saturation, but always within safety limits. Maintaining an appropriate level of consciousness was confirmed as a feature in 50 per cent dose in this study. The analgesic effect of nitrous oxide was confirmed but a dose dependency could not be established.
Key words:Nitrous oxide, conscious sedation, anxiolysis, safety, physiogical parameters, signs, symptoms, analgesia.
doi:10.4317/jced.52034
PMCID: PMC4368020  PMID: 25810844
10.  Thrombogenic potential of transcatheter aortic valve implantation with trivial paravalvular leakage 
Background
Significant paravalvular leakage after transcatheter aortic valve implantation (TAVI) correlates with increased morbidity and mortality, but adverse consequences of trivial paravalvular leakage have stimulated few investigations. Using a unique method distinctly different from other diagnostic approaches, we previously reported elevated backflow velocities of short duration (transients) in mechanical valve closure. In this study, similar transients were found in a transcatheter valve paravalvular leakage avatar.
Methods
Paravalvular leakage rate (zero to 58 mL/second) and aortic valve incompetence (volumetric back flow/forward flow; zero to 32%) were made adjustable using a mock transcatheter aortic valve device and tested in quasi-steady and pulsatile flow test systems. Projected dynamic valve area (PDVA) from the back illuminated mock transcatheter aortic valve device was measured and regional backflow velocities were derived by dividing volumetric flow rate by the PDVA over the open and closing valve phase and the total closed valve area derived from backflow leakage.
Results
Aortic incompetence from 1-32% generated negative backflow transients from 8 to 267 meters/second, a range not dissimilar to that measured in mechanical valves with zero paravalvular leakage. Optimal paravalvular leakage was identified; not too small generating high backflow transients, not too large considering volume overload and cardiac energy loss caused by defective valve behavior and fluid motion.
Conclusions
Thrombogenic potential of transcatheter aortic valves with trivial aortic incompetence and high magnitude regional backflow velocity transients was comparable to mechanical valves. This may have relevance to stroke rate, asymptomatic microembolic episodes and indications for anticoagulation therapy after transcatheter valve insertion.
doi:10.3978/j.issn.2305-5839.2014.05.04
PMCID: PMC4200687  PMID: 25333018
Transcatheter aortic valve implantation (TAVI); paravalvular; leakage; transients; incompetence
11.  The effects of idazoxan combined with 30% nitrous oxide on the jaw-opening reflex in the rat. 
Anesthesia Progress  1997;44(3):96-100.
In rats, the jaw-opening reflex is elicited by activation of a nociceptive receptor by the electric stimulation of the tooth pulp. This study was undertaken to assess the effects of 30% nitrous oxide and 30% nitrous oxide with idazoxan, an alpha 2-adrenergic antagonist, on this reflex. Each rat received electric stimulation for the jaw-opening reflex at 3, 5, 7, 10, 15, and 20 min after both the start of inhalation and the withdrawal of 100% oxygen or 30% nitrous oxide in oxygen. Idazoxan, 400 micrograms/ kg, was administered intravenously at the start of the inhalation period. Amplitudes significantly decreased during inhalation of nitrous oxide, but they returned gradually to control levels after cessation of nitrous oxide inhalation. In the cases of 100% oxygen, 100% oxygen with idazoxan, and 30% nitrous oxide in oxygen with idazoxan, amplitudes did not change from controls during and after 30% nitrous oxide inhalation. The latency remained unchanged irrespective of the treatment. Since in rats the degree of inhibition by 30% nitrous oxide in oxygen is partially diminished by administration of idazoxan, we conclude that nitrous oxide affects an alpha 2-adrenergic receptor in the central nervous system.
PMCID: PMC2148931  PMID: 9481969
12.  Practices and opinions on nitrous oxide/oxygen sedation from dentists licensed to perform relative analgesia in Brazil 
BMC Oral Health  2012;12:21.
Background
Relative analgesia (RA), defined as the use of inhalation sedation with nitrous oxide and oxygen, is one of the most common pharmacological behavior management techniques used to provide sedation and analgesia for dental patients. This study aimed to assess RA licensed Brazilian dentists’ practices and opinions about nitrous oxide/oxygen sedation in the dental setting.
Methods
A cross sectional national survey was conducted with 281 dentists who were certified to perform RA, using an electronically mailed self-administered questionnaire containing closed questions about their practices and opinions regarding RA. Practice and opinion were individually analyzed by descriptive statistics. Non-parametric tests assessed the relationships between RA practice and independent variables. To test the interplay between practices and opinions, a k-means clusters analysis was used to divide the group for statistical comparisons.
Results
The response rate was 45.2%. Women made up 64.6% of the respondents, the mean age was 39.1 years (SD = 9.8), and the mean time since graduation in dentistry was 16 years (SD = 9.7). Seventy-seven percent of respondents reported the use of RA in clinical practice, most of them ‘sometimes’ (53.5%), and focusing more on adult patients. Patients with certain physical or mental deficiencies were indications associated with RA practice. ‘Equipment acquisition’ (p < 0.001) and ‘living in Southeast and South regions’ (p < 0.02) were also associated with RA practice. The scores for dentists’ opinions ranged from 15 to 41 points (mean 29.2, SD = 5.6), based on nine items scored from 1 to 5. Two clusters representing more favorable (n = 65) and less favorable (n = 55) opinions were established. Dentists who were women (p = 0.04), practiced RA in dental settings (p < 0.01) or practiced it frequently (p < 0.001), had more favorable opinions about RA.
Conclusion
Most of the RA licensed Brazilian dentists interviewed currently use RA. Current practice of RA and frequency of use determined the degree of favorable opinion about this inhalation sedation among this group of respondents.
doi:10.1186/1472-6831-12-21
PMCID: PMC3412732  PMID: 22808942
Relative Analgesia; Nitrous Oxide; Dental Clinics; Cross Sectional Survey
13.  Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency 
Background
Valve dysfunction is a common cardiovascular pathology. Despite significant clinical research, there is little formal study of how valve dysfunction affects overall circulatory dynamics. Validated models would offer the ability to better understand these dynamics and thus optimize diagnosis, as well as surgical and other interventions.
Methods
A cardiovascular and circulatory system (CVS) model has already been validated in silico, and in several animal model studies. It accounts for valve dynamics using Heaviside functions to simulate a physiologically accurate "open on pressure, close on flow" law. However, it does not consider real-time valve opening dynamics and therefore does not fully capture valve dysfunction, particularly where the dysfunction involves partial closure. This research describes an updated version of this previous closed-loop CVS model that includes the progressive opening of the mitral valve, and is defined over the full cardiac cycle.
Results
Simulations of the cardiovascular system with healthy mitral valve are performed, and, the global hemodynamic behaviour is studied compared with previously validated results. The error between resulting pressure-volume (PV) loops of already validated CVS model and the new CVS model that includes the progressive opening of the mitral valve is assessed and remains within typical measurement error and variability. Simulations of ischemic mitral insufficiency are also performed. Pressure-Volume loops, transmitral flow evolution and mitral valve aperture area evolution follow reported measurements in shape, amplitude and trends.
Conclusions
The resulting cardiovascular system model including mitral valve dynamics provides a foundation for clinical validation and the study of valvular dysfunction in vivo. The overall models and results could readily be generalised to other cardiac valves.
doi:10.1186/1475-925X-10-86
PMCID: PMC3271239  PMID: 21942971
14.  Efficacy and Safety of Clonidine as an Adjuvant to Bupivacaine for Caudal Analgesia in Paediatric Infra-Umbilical Surgeries 
Introduction
Caudal analgesia, has gained popularity in paediatric intraoperative and postoperative pain management, more so with the use of adjuvants to prolong its duration, each of them having various results. Clonidine, an alpha2-adrenergic agonist is being used for its analgesic effects in various doses with 0.25% Bupivacaine.
Aim
The study was conducted to compare the analgesic efficacy, haemodynamic safety and side effects of 1 μg/kg Clonidine added to 1 ml/kg of 0.125% Bupivacaine solution for caudal analgesia.
Materials and Methods
A prospective, randomised, double-blind, controlled study was carried out in 60 children of ASA Physical Status I, aged 1-10 years, scheduled for infraumbilical operations in a tertiary care centre. They were randomly assigned for caudal analgesia, to either group B: 1ml/kg of 0.125% Bupivacaine solution or group BC: 1ml/kg of 0.125% Bupivacaine and preservative free Clonidine 1μ/kg. All were premedicated with midazolam 0.75 mg/kg orally 30 minutes prior to induction of anaesthesia. Heart rate (HR), Mean Arterial blood Pressure (MAP) and oxygen saturation (SpO2) were monitored. General anaesthesia was induced with thiopentone (1.25%) 5mg/kg and inhalation of oxygen, nitrous oxide and sevoflurane. Postoperative pain, sedation and motor block was assessed by the various scores and patients were monitored for adverse effects.
Results
The mean duration of postoperative analgesia was 3 times longer in group BC. Group B received significantly more doses of rescue analgesic than group BC (p-value of 0.004). There was no significant bradycardia, hypotension, sedation or urinary retention in either of the groups. There was no residual motor blockade at 6 hours. Incidence of vomiting was similar in both the groups.
Conclusion
Caudal Clonidine in the dose of 1 μg/kg in children is a satisfactory and efficacious adjuvant to caudal Bupivacaine for producing prolonged postoperative analgesia with minimum side effects.
doi:10.7860/JCDR/2016/19404.8491
PMCID: PMC5072055  PMID: 27790555
Caudal additive; Paediatric regional anaesthesia; Postoperative analgesia
15.  Clinical Trials of Different Concentrations of Oxygen and Nitrous Oxide for Obstetric Analgesia: Report to the Medical Research Council of the Committee on Nitrous Oxide and Oxygen Analgesia in Midwifery* 
British Medical Journal  1970;1(5698):709-713.
Trials have been organized by a Medical Research Council committee to assess the effectiveness and safety for analgesia in labour of oxygen and nitrous oxide mixtures in different proportions. In a preliminary trial concentrations of 50% and 60% v/v nitrous oxide were compared, but, as the replies of 409 mothers revealed little difference between the two, the results of administering either 50% or 70% nitrous oxide to 778 mothers were then compared. The data relating to normal labour, obtained on 501 of the mothers in this main trial, showed that the relief of pain given was much the same. There was a suggestion, however, that the higher concentration of nitrous oxide might be useful in abnormal labour. The proportion of mothers with normal deliveries who lost consciousness, though very small, was significantly higher with 70% nitrous oxide than with the lower concentration. Ninety-two per cent. of mothers found the gas and oxygen machine helpful, and midwives reported complete or good co-operation by 77% of those using it. It is concluded that the 50% oxygen and 50% nitrous oxide mixture can safely be used by unsupervised midwives.
PMCID: PMC1699836  PMID: 5440545
16.  The effects of temperature on nitrous oxide and oxygen mixture homogeneity and stability 
BMC Anesthesiology  2010;10:19.
Background
For many long standing practices, the rationale for them is often lost as time passes. This is the situation with respect to the storage and handling of equimolar 50% nitrous oxide and 50% oxygen volume/volume (v/v) mixtures.
Methods
A review was undertaken of existing literature to examine the developmental history of nitrous oxide and oxygen mixtures for anesthesia and analgesia and to ascertain if sufficient bibliographic data was available to support the position that the contents of a cylinder of a 50%/50% volume/volume (v/v) mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage and if justification could be found for the standard instructions given for handling before use.
Results
After ranking and removing duplicates, a total of fifteen articles were identified by the various search strategies and formed the basis of this literature review. Several studies were identified that confirmed that 50%/50% v/v mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage. The effect of temperature on the change of phase of the nitrous oxide in this mixture was further examined by several authors. These studies demonstrated that although it is possible to cause condensation and phase separation by cooling the cylinder, by allowing the cylinder to rewarm to room temperature for at least 48 hours, preferably in a horizontal orientation, and inverting it three times before use, the cylinder consistently delivered the proper proportions of the component gases as a homogenous mixture.
Conclusions
The contents of a cylinder of a 50%/50% volume/volume (v/v) mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage. The standard instructions given for handling before are justified based on previously conducted studies.
doi:10.1186/1471-2253-10-19
PMCID: PMC2967548  PMID: 20950473
17.  Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial 
BMC Anesthesiology  2010;10:14.
Background
Recent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium.
Methods
70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period.
Results
Controller performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively.
Conclusions
Nitrous oxide does not affect the infusion requirements of cisatracurium.
Trial registration
ClinicalTrials.gov NCT01152905; European Clinical Trials Database at http://eudract.emea.eu.int/2006-006037-41.
doi:10.1186/1471-2253-10-14
PMCID: PMC2931508  PMID: 20718983
18.  Effects of Leaflet Stiffness on In Vitro Dynamic Bioprosthetic Heart Valve Leaflet Shape 
Advances in the development of replacement heart valves require a deeper understanding of the valve dynamics. In the present study, dynamic aortic valve (AV) leaflet geometries were quantified in vitro using a structured laser-light imaging system (Iyengar et al., ABME 29(11):963–973, 2001). Native AV leaflets were first imaged under simulated physiological flow conditions within a rigid glass conduit with simulated anatomic sinuses. Next, the valve/glass conduit combination was removed from the loop and immersed in a 0.625% aqueous glutaraldehyde solution at room temperature for 24 h to produce a bioprosthetic heart valve (BHV). The BHV leaflets were then re-imaged under identical flow conditions while kept in the same position in the glass conduit to minimize artifacts associated with removal/reinsertion of the valve. We observed that: (1) the native leaflet exhibited small, high frequency shifts in shape; (2) the BHV leaflet demonstrated a more stabile shape, as well as focal regions of prolonged, high curvature; (3) the BHV leaflet opened and closed faster by ~10 ms compared to native leaflet; (4) in both the BHV and native states, the AV opened from basal region leading to free edge (5) when closing, both the native and BHV close with both free edge and circumferential together. The high bending observed in the BHV leaflet correlated with known locations of tissue deterioration previously reported in our laboratory. Thus, in order to minimize leaflet tissue damage, methods of chemical modification utilized in BHVs that maintain leaflet flexibility are necessary to minimize the onset and progression of tissue damage. We conclude that leaflet stiffness can have a considerable effect on dynamic valve motion, and can induce deleterious bending behaviors that may be associated with tissue breakdown and valve failure. Moreover, these unique data can provide much needed quantitative information for computational simulation of heart valve leaflet stiffness on heart valve function.
doi:10.1007/s13239-013-0117-y
PMCID: PMC3640301  PMID: 23646095
Cardiac valve bioprostheses; Imaging; Aortic; Valve; Curvature; Geometry
19.  A Novel Implantable Glaucoma Valve Using Ferrofluid 
PLoS ONE  2013;8(6):e67404.
Purpose
To present a novel design of an implantable glaucoma valve based on ferrofluidic nanoparticles and to compare it with a well-established FDA approved valve.
Setting
Massachusetts Eye & Ear Infirmary, Boston, USA.
Methods
A glaucoma valve was designed using soft lithography techniques utilizing a water-immiscible magnetic fluid (ferrofluid) as a pressure-sensitive barrier to aqueous flow. Two rare earth micro magnets were used to calibrate the opening and closing pressure. In-vitro flow measurements were performed to characterize the valve and to compare it to Ahmed™ glaucoma valve. The reliability and predictability of the new valve was verified by pressure/flow measurements over a period of three months and X-ray diffraction (XRD) analysis over a period of eight weeks. In vivo assessment was performed in three rabbits.
Results
In the in vitro experiments, the opening and closing pressures of the valve were 10 and 7 mmHg, respectively. The measured flow/pressure response was linearly proportional and reproducible over a period of three months (1.8 µl/min at 12 mmHg; 4.3 µl/min at 16 mmHg; 7.6 µl/min at 21 mmHg). X-ray diffraction analysis did not show oxidization of the ferrofluid when exposed to water or air. Preliminary in vivo results suggest that the valve is biocompatible and can control the intraocular pressure in rabbits.
Conclusions
The proposed valve utilizes ferrofluid as passive, tunable constriction element to provide highly predictable opening and closing pressures while maintaining ocular tone. The ferrofluid maintained its magnetic properties in the aqueous environment and provided linear flow to pressure response. Our in-vitro tests showed reliable and reproducible results over a study period of three months. Preliminary in-vivo results were very promising and currently more thorough investigation of this device is underway.
doi:10.1371/journal.pone.0067404
PMCID: PMC3696055  PMID: 23840691
20.  Analgesia effect of a fixed nitrous oxide/oxygen mixture on burn dressing pain: study protocol for a randomized controlled trial 
Trials  2012;13:67.
Background
Procedural burn pain is the most intense acute pain and most likely type of burn injury pain to be undertreated due to the physician’s fear of the adverse effect of analgesia and lack of anesthetist present. At our institution, in most of the cases, local burn detersion and debridement were performed at the ward level without any analgesics. This article describes a study designed to test the analgesia effect of a fixed nitrous oxide/oxygen mixture on burn dressing pain.
Methods/design
The experiment was carried out in three centers. The patients were given a number from 1 to 240. A randomization list was produced by a statistician according to our preliminary study. Due to the severity of the pain suffered, ethically it was decided to help as many as possible, so patients given the letters A, B or C were treated using a canister with the appropriate letter containing preprepared nitrous oxide/oxygen mixture (NOOM). Those with D were given oxygen only, from an identical-looking canister labeled D. Neither patients, nor doctors, nor nurses, nor data collector knew what was in each canister, thus they were all blind. The nursing officer who implemented the intervention handed the doctors envelopes containing the patients’ name and allocation of A, B, C or D. Thus, patients receiving NOOM or oxygen were in the ratio 3:1. Parameters, including pain severity, blood pressure, heart rate, digital oxygen saturation and the Chinese version of the burn specific pain anxiety scale (C-BSPAS), were taken before, during and after dressing for each group. A video and audio record was taken individually for later communication coding and outcome analysis. Rescue analgesic was recorded.
Discussion
Based on the findings from our previous qualitative study that physician’s reluctance to order narcotic analgesia is due to its adverse effect and from our pilot experiment, this study aims to test the hypothesis that a fixed nitrous oxide/oxygen mixture will promote better burn dressing pain alleviation and outcomes. Analyses will focus on the effects of the experimental intervention on pain severity during dressing (primary outcomes); physiological parameters, C-BSPAS and acceptance of both health care professionals and patients (secondary outcomes). If this model of analgesia for burn pain management implemented by nurses proves successful, it could potentially be implemented widely in hospital and prehospital settings and improve patients’ satisfaction and quality of life.
Trial registration
(Clinical Trials Identifier: CHICTR-TRC11001690).
doi:10.1186/1745-6215-13-67
PMCID: PMC3404913  PMID: 22624697
Analgesia; Burn procedural pain; Nitrous oxide
21.  Extracellular matrix remodeling and cell phenotypic changes in dysplastic and hemodynamically altered semilunar human cardiac valves 
Introduction
Congenital cardiac valve disease is common, affecting ~1% of the population, with substantial morbidity and mortality, but suboptimal treatment options. Characterization of the specific matrix and valve cell phenotypic abnormalities in these valves could lend insight into disease pathogenesis and potentially pave the way for novel therapies.
Methods
Thirty-five human aortic and pulmonic valves were categorized based on gross and microscopic assessment into control valves (n=21); dysplastic valves, all except one also displaying hemodynamic changes (HEMO/DYSP, n=6); and hemodynamically altered valves (HEMO, n=8). Immunohistochemistry was performed on valve sections and flow cytometry on valvular interstitial cells.
Results
While both hemodynamically altered aortic and pulmonic valves demonstrated increased collagen turnover and cell activation, prolyl 4-hydroxylase and hyaluronan increased in hemodynamically altered aortic valves but decreased in hemodynamically altered pulmonic valves relative to control valves (P<.001). HEMO/DYSP aortic valves demonstrated decreased collagen and elastic fiber synthesis and turnover compared to both hemodynamically altered aortic valves and control aortic valves (each P<.006). Valvular interstitial cells from both hemodynamically altered and HEMO/DYSP pulmonic valves showed altered cell phenotype compared to control valves (each P<.032), especially increased non-muscle myosin. Furthermore, valvular interstitial cells from hemodynamically altered pulmonic valves and HEMO/DYSP aortic and pulmonic valves each demonstrated greater size and complexity compared to control valves (each P<.05).
Conclusions
Dysplastic semilunar valves displayed alterations in collagen and elastic fiber turnover that were distinct from valves similarly exposed to altered hemodynamics as well as to control valves. These results demonstrate that dysplastic valves are not simply valves with gross changes or loss of leaflet layers, but contain complex matrix and cell phenotype changes that, with future study, could potentially be targets for novel nonsurgical treatments.
doi:10.1016/j.carpath.2010.07.004
PMCID: PMC4664042  PMID: 20817569
Extracellular matrix; Semilunar valve; Valvular interstitial cell; Dysplastic; Hemodynamics; Congenital valve
22.  Nitrous oxide plus isoflurane induces apoptosis and increases β-amyloid protein levels 
Anesthesiology  2009;111(4):741-752.
Background
Some anesthetics have been suggested to induce neurotoxicity including promotion of Alzheimer’s disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. Here, we set out to assess effects of nitrous oxide and/or isoflurane on apoptosis and β-amyloid (Aβ) levels in H4 human neuroglioma cells and primary neurons from naïve mice.
Methods
The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for six hours. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Aβ levels were determined.
Results
Treatment with a combination of 70% nitrous oxide and 1% isoflurane for six hours induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for six hours induced caspase-3 activation and apoptosis, and increased levels of β-site amyloid precursor protein-cleaving enzyme and Aβ in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Aβ generation was reduced by a broad caspase inhibitor Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by γ-secretase inhibitor L-685,458, but potentiated by exogenously added Aβ.
Conclusion
These results suggest that common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. The generated Aβ may further potentiate apoptosis to form another round of apoptosis and Aβ generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.
doi:10.1097/ALN.0b013e3181b27fd4
PMCID: PMC2797570  PMID: 19741497
23.  Liposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes☆ 
Background
Opioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms.
Methods
We analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs.
Results
Eighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine.
Conclusions
Compared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.
doi:10.1016/j.curtheres.2013.12.001
PMCID: PMC3994919  PMID: 25031661
hospitalization cost; laparoscopic colectomy; length of stay; multimodal analgesia; opioid-related adverse events; surgery
24.  Are anticoagulant independent mechanical valves within reach—fast prototype fabrication and in vitro testing of innovative bi-leaflet valve models 
Background
Exploration for causes of prosthetic valve thrombogenicity has frequently focused on forward or post-closure flow detail. In prior laboratory studies, we uncovered high amplitude flow velocities of short duration close to valve closure implying potential for substantial shear stress with subsequent initiation of blood coagulation pathways. This may be relevant to widely accepted clinical disparity between mechanical and tissue valves vis-à-vis thrombogenicity. With a series of prototype bi-leaflet mechanical valves, we attempt reduction of closure related velocities with the objective of identifying a prototype valve with thrombogenic potential similar to our tissue valve control. This iterative design approach may find application in preclinical assessment of valves for anticoagulation independence.
Methods
Tested valves included: prototype mechanical bi-leaflet BVs (n=56), controls (n=2) and patented early prototype mechanicals (n=2) from other investigators. Pulsatile and quasi-steady flow systems were used for testing. Projected dynamic valve area (PDVA) was measured using previously described novel technology. Flow velocity over the open and closing periods was determined by volumetric flow rate/PDVA. For the closed valve interval, use was made of data obtained from quasi-steady back pressure/flow tests. Performance was ranked by a proposed thrombogenicity potential index (TPI) relative to tissue and mechanical control valves.
Results
Optimization of the prototype valve designs lead to a 3-D printed model (BV3D). For the mitral/aortic site, BV3D has lower TPI (1.10/1.47) relative to the control mechanical valve (3.44/3.93) and similar to the control tissue valve (ideal TPI ≤1.0).
Conclusions
Using unique technology, rapid prototyping and thrombogenicity ranking, optimization of experimental valves for reduced thrombogenic potential was expedited and simplified. Innovative mechanical valve configurations were identified that merit consideration for further development which may bring the anti-coagulation independent mechanical valve within reach.
doi:10.3978/j.issn.2305-5839.2015.08.18
PMCID: PMC4560704  PMID: 26417581
Prosthetic valve; thrombogenicity; flow velocities; rebound
25.  Entonox® inhalation to reduce pain in common diagnostic and therapeutic outpatient urological procedures: a review of the evidence 
INTRODUCTION
Entonox® (50% nitrous oxide and 50% oxygen; BOC Healthcare, Manchester, UK) is an analgesic and anxiolytic agent that is used to successfully reduce pain and anxiety during dental, paediatric and emergency department procedures. In this article we review the application and efficacy of Entonox® in painful local anaesthesia urological procedures by performing a systematic review of the literature.
METHODS
A MEDLINE® search was performed using the terms ‘nitrous oxide’, ‘Entonox’, ‘prostate biopsy’, ‘flexible cystoscopy’ and ‘extracorporeal shock wave lithotripsy’. English language publications of randomised studies were identified and reviewed.
RESULTS
The search yielded five randomised studies that investigated the clinical efficacy of Entonox® as an analgesic for day case urological procedures. Three randomised controlled trials (RCTs) investigated Entonox® in transrectal ultrasonography guided prostate biopsy. All three reported significant reductions in pain score in the Entonox® versus control groups. One RCT reported significant reduction in pain during male flexible cystoscopy in the Entonox® group compared with the control group. One RCT, which examined the use of Entonox® during extracorporeal shock wave lithotripsy, found its use significantly decreased the pain score compared with the control group and this was comparable to intravenous pethidine.
CONCLUSIONS
Evidence from varied adult and paediatric procedures has shown Entonox® to be an effective, safe and patient acceptable form of analgesia. All published studies of its use in urological day case procedures have found it to significantly reduce procedural pain. There is huge potential to use this cheap, safe, effective analgesic in our current practice.
doi:10.1308/003588412X13171221499702
PMCID: PMC3954179  PMID: 22524905
Urology; Analgesia; Pain

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