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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.
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.
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).
Nitrous oxide anesthesia was not associated with decreased opioid administration, pain, or incidence of moderate to severe pain in the early postoperative phase.
PMCID: PMC3919543  PMID: 24310050
Analgesia; Nitrous Oxide; Pain; Postoperative; Anesthesia; General
3.  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.
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).
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.
PMCID: PMC3678702  PMID: 23776820
Butorphanol; fentanyl; propofol; recovery
4.  Reduced Leaflet Stress in the Stentless Quadrileaflet Mitral Valve: A Finite Element Model 
PLoS ONE  2013;8(7):e67683.
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.
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.
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.
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.
PMCID: PMC3699618  PMID: 23844060
5.  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.
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.
MDCT is an accurate modality with which to assess the function and morphology of bileaflet mechanical valves.
PMCID: PMC2771814  PMID: 19949605
Valve; Heart; Computed tomography
6.  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.
PMCID: PMC3947912  PMID: 24188792
κ-opioids; anti-analgesia; nalbuphine; Nociceptin/orphanin FQ receptor
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.
PMCID: PMC1762988  PMID: 12023171
8.  Thrombogenic potential of transcatheter aortic valve implantation with trivial paravalvular leakage 
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.
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.
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.
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.
PMCID: PMC4200687  PMID: 25333018
Transcatheter aortic valve implantation (TAVI); paravalvular; leakage; transients; incompetence
9.  Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency 
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.
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.
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.
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.
PMCID: PMC3271239  PMID: 21942971
10.  Practices and opinions on nitrous oxide/oxygen sedation from dentists licensed to perform relative analgesia in Brazil 
BMC Oral Health  2012;12:21.
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.
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.
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.
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.
PMCID: PMC3412732  PMID: 22808942
Relative Analgesia; Nitrous Oxide; Dental Clinics; Cross Sectional Survey
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.  Liposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes☆ 
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.
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.
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.
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.
PMCID: PMC3994919  PMID: 25031661
hospitalization cost; laparoscopic colectomy; length of stay; multimodal analgesia; opioid-related adverse events; surgery
13.  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.
PMCID: PMC3640301  PMID: 23646095
Cardiac valve bioprostheses; Imaging; Aortic; Valve; Curvature; Geometry
14.  A Novel Implantable Glaucoma Valve Using Ferrofluid 
PLoS ONE  2013;8(6):e67404.
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.
Massachusetts Eye & Ear Infirmary, Boston, USA.
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.
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.
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.
PMCID: PMC3696055  PMID: 23840691
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.
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.
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.
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.
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.
PMCID: PMC2967548  PMID: 20950473
17.  Analgesia effect of a fixed nitrous oxide/oxygen mixture on burn dressing pain: study protocol for a randomized controlled trial 
Trials  2012;13:67.
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.
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.
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).
PMCID: PMC3404913  PMID: 22624697
Analgesia; Burn procedural pain; Nitrous oxide
18.  Liposome bupivacaine (EXPAREL®) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial 
Journal of Pain Research  2013;6:605-610.
Postoperative opioid use following ileostomy reversal procedures contributes to postoperative ileus. We assessed the impact of a liposome bupivacaine-based, opioid-sparing multimodal analgesia regimen versus a standard opioid-based analgesia regimen on postsurgical opioid use. We also assessed health economic outcomes in patients undergoing ileostomy reversal at our institution, which employs an enhanced recovery discharge protocol.
In this single-center, open-label study, patients undergoing ileostomy reversal received postsurgical pain therapy via multimodal analgesia that included a single intraoperative administration of liposome bupivacaine or opioid-based patient-controlled analgesia (PCA) with intravenous morphine or hydromorphone. Rescue analgesia (intravenous [IV] opioids and/or oral opioid + acetaminophen) was available to all patients. Primary efficacy measures included postsurgical opioid use, hospital length of stay (LOS), and hospitalization costs. Secondary measures included: time to first rescue opioid use; patient satisfaction with analgesia; additional medical intervention; and opioid-related adverse events.
Forty-three patients were enrolled and met eligibility criteria (IV opioid PCA group = 20; liposome bupivacaine-based multimodal analgesia group = 23). Postsurgical opioid use was significantly less in the multimodal analgesia group compared with the IV opioid PCA group (mean [standard deviation]: 38 mg [46 mg] versus 68 mg [47 mg]; P = 0.004). Postsurgical LOS between-group differences (median: 3.0 days versus 3.8 days) and geometric mean hospitalization costs (US $6,611 versus US$6,790) favored the multimodal analgesic group but did not achieve statistical significance. Median time to first opioid use was 1.1 hours versus 0.7 hours in the multimodal analgesia and IV opioid PCA groups, respectively; P = 0.035. Two patients in the multimodal analgesia group and one in the IV opioid PCA group experienced opioid-related adverse events.
A liposome bupivacaine-based multimodal analgesic regimen reduced postoperative opioid consumption in patients undergoing ileostomy reversal under a fast-track discharge protocol. A reduction of 21% in LOS (0.8 days) was noted which, although not statistically significant, may be considered clinically meaningful given the already aggressive fast-track discharge program.
PMCID: PMC3735342  PMID: 23935387
surgery; ileostomy; multimodal analgesia; opioid-related adverse events; hospitalization cost; length of stay
19.  Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial 
BMC Anesthesiology  2010;10:14.
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.
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.
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.
Nitrous oxide does not affect the infusion requirements of cisatracurium.
Trial registration NCT01152905; European Clinical Trials Database at
PMCID: PMC2931508  PMID: 20718983
20.  Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. 
Anesthesia Progress  2004;51(4):114-121.
This article details a double-blind, randomized study evaluating the efficacy and safety of intranasal sufentanil and intranasal midazolam (S/M) when compared with intranasal ketamine and intranasal midazolam (K/M) for sedation and analgesia in pediatric patients undergoing dental surgery. Fifty healthy ASA status 1 children aged 5-7 years, weighing 15-20 kg, and having 6 or more teeth extracted, were randomly allocated to 2 groups of 25 patients each (n = 50). In the S/M group, 25 children received intranasal sufentanil 20 microg, and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. In the K/M group, 25 children received intranasal ketamine 5 mg/kg and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. Sevoflurane in nitrous oxide and oxygen was used for induction and maintenance of anesthesia. This study demonstrated the safety and efficacy of both methods with ease of administration, combined with a rapid onset of action. Both groups were equally sedated. A smooth mask induction of anesthesia was experienced in the majority of children. Effective postoperative analgesia for multiple dental extractions was provided. The intranasal administration of drugs for sedation and analgesia has some promising features in preschool children undergoing multiple dental extractions.
PMCID: PMC2007493  PMID: 15675259
21.  Nitrous oxide plus isoflurane induces apoptosis and increases β-amyloid protein levels 
Anesthesiology  2009;111(4):741-752.
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.
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.
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.
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.
PMCID: PMC2797570  PMID: 19741497
22.  Entonox® inhalation to reduce pain in common diagnostic and therapeutic outpatient urological procedures: a review of the evidence 
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.
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.
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.
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.
PMCID: PMC3954179  PMID: 22524905
Urology; Analgesia; Pain
23.  Extended pain relief trial utilizing infiltration of Exparel®, a long-acting multivesicular liposome formulation of bupivacaine: a Phase IV health economic trial in adult patients undergoing open colectomy 
Journal of Pain Research  2012;5:567-572.
The majority of surgical patients experience significant levels of pain after a procedure. While opioid analgesics have been a mainstay of postsurgical analgesic regimens, recent evidence has supported the use of multimodal therapy as a way to decrease opioid usage with its concomitant opioid-related adverse events. The goal of multimodal therapy is to minimize the negative effects of these events on clinical and economic outcomes. The purpose of this study was to assess the opioid burden and health economic outcomes in patients undergoing open colectomy who received a liposomal bupivacaine-based multimodal analgesic regimen as compared with a standard opioid-based regimen for postsurgical pain.
In this open-label, single-center, sequential-cohort study, adults undergoing open colectomy were assigned to treatment via patient-controlled analgesia with opioids (first cohort) or multimodal analgesia therapy including a single administration of liposomal bupivacaine (second cohort). Both treatment groups were offered rescue analgesia as needed. The main outcome measures were total mg amount of opioids consumed after surgery, total hospital costs, and length of hospital stay. Adverse events, including opioid-related adverse events, were recorded.
Thirty-nine patients were enrolled, 18 in the opioid-based analgesia group and 21 in the multimodal analgesia group. Mean total amount of postsurgical opioids consumed was significantly less in the multimodal analgesia group (57 mg) compared with the opioid analgesia group (115 mg; P = 0.025). The average total cost of hospitalization in the multimodal group was $8766 versus $11,850 in the opioid group (P = 0.027), and the median length of hospital stay was 2.0 days versus 4.9 days, respectively (P = 0.004).
This study confirmed that a liposomal bupivacaine–based multimodal analgesic regimen resulted in less opioid consumption, lower hospital costs, and a shorter length of stay than a standard opioid-based analgesic regimen for postsurgical pain in patients undergoing open colectomy.
PMCID: PMC3508659  PMID: 23204866
surgery; multimodal analgesia; opioid consumption; cost; length of stay
24.  Impact of Design Parameters on Bi-leaflet Mechanical Heart Valve Flow Dynamics 
A significant problem in the operation of mechanical heart valve prostheses is the propensity for thrombus formation near the valve leaflet and housing. This may be caused by the high shear stresses present in the leakage jet flows through small gaps between leaflets and the valve housing during the valve closure phase.
This two-dimensional study was undertaken to demonstrate that design changes in bi-leaflet mechanical valves result in notable changes in the flow-induced stresses and prediction of platelet activation. A Cartesian grid technique is used for the 2D simulation of blood flow through two models of the bi-leaflet mechanical valve and their flow patterns, closure characteristics and platelet activation potential are compared. A local mesh refinement algorithm allows efficient and fast flow computations with mesh adaptation based on the gradients of the flow field in the gap between the leaflet and housing at the instant of valve closure. Leaflet motion is calculated dynamically based on the fluid forces acting on it. Platelets are modeled and tracked as point particles by a Lagrangian particle tracking method which incorporates the hemodynamic forces on the particles.
The comparison of results shows that the velocity, wall shear stress, and simulated platelet activation parameter are lower in the valve model with a smaller angle of leaflet traverse between the fully open to the fully closed position. The parameters are also affected to a lesser extent by the local changes in the leaflet and housing geometry.
Computational simulations can be used to examine local design changes to help minimize the fluid induced stresses that may play a key role in thrombus initiation with the implanted mechanical valves.
PMCID: PMC2863996  PMID: 20099695
Bi-leaflet Valve; Platelet Activation; Cartesian Grid; Vortex Interaction; Comparison of valves
25.  A randomized, multicenter, pilot study comparing the efficacy and safety of a bupivacaine-collagen implant (XaraColl®) with the ON-Q PainBuster® Post-op Pain Relief System following open gynecological surgery 
Journal of Pain Research  2012;5:453-461.
XaraColl®, a collagen-based intraoperative implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. We compared the efficacy and safety of XaraColl for the prevention of postsurgical pain versus a slow postoperative perfusion of bupivacaine to the wound environment via the ON-Q PainBuster® Post-op Pain Relief System (ON-Q).
We randomized 27 women undergoing open gynecological surgery to receive either three XaraColl implants (each containing 50 mg bupivacaine hydrochloride) or ON-Q (900 mg bupivacaine hydrochloride perfused over 72 hours) in a 1:1 ratio. Following surgery, patients had access to intravenous morphine via a patient-controlled analgesia pump as rescue analgesia for the first 24 hours and to oral opioid medication thereafter. Total use of opioid analgesia was compared through 24, 48, 72, and 96 hours after surgery. Patients also evaluated overall pain control over the 96-hour period using a five-point numeric rating scale. Safety was assessed for 30 days after surgery.
XaraColl was non-inferior to ON-Q in total use of opioid analgesia for the first 24, 48, 72, and 96 hours after surgery, with a statistical trend towards reduced opioid use in favor of XaraColl over 24, 48, and 72 hours (P = 0.067, 0.100, and 0.089, respectively). The time to first use of opioid analgesia was also significantly delayed in patients treated with XaraColl (P = 0.024). There was no significant difference between groups in patients’ evaluation of pain control or their satisfaction with the treatment in general. Both treatments were considered safe and well tolerated.
Despite using only 17% of the ON-Q dose, XaraColl is as effective as ON-Q in providing postoperative analgesia for 4 days after open gynecological surgery. These preliminary findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants further definitive studies.
PMCID: PMC3496528  PMID: 23152696
pain; hysterectomy; opioid use; analgesia; anesthetic

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