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1.  Comparison of three techniques for ultrasound-guided femoral nerve catheter insertion: A randomized, blinded trial 
Anesthesiology  2014;121(2):239-248.
Background
Ultrasound guidance for continuous femoral perineural catheters may be supplemented by electrical stimulation through a needle or through a stimulating catheter. We tested the primary hypothesis that ultrasound guidance alone is noninferior on both postoperative pain scores and opioid requirement and superior on at least one of the two. Secondarily, we compared all interventions on insertion time and incremental cost.
Methods
Patients having knee arthroplasty with femoral nerve catheters were randomly assigned to catheter insertion guided by: 1) ultrasound alone (n=147); 2) ultrasound and electrical stimulation through the needle (n=152); or, 3) ultrasound and electrical stimulation through both the needle and catheter (n=138). Noninferiority between any two interventions was defined for pain as no more than 0.5 points worse on a 0–10 Verbal Response Scale (VRS) scale and for opioid consumption as no more than 25% greater than the mean.
Results
The stimulating needle group was significantly noninferior to the stimulating catheter (difference (95% CI) in mean VRS pain score [stimulating needle versus stimulating catheter] of −0.16 (−0.61, 0.29), P<0.001; percent difference in mean IV morphine equivalent dose of −5% (−25%, 21%), P=0.002) and to ultrasound only (difference in mean VRS pain score of −0.28 (−0.72, 0.16), P<0.001; percent difference in mean IV morphine equivalent dose of −2% (−22%, 25%), P=0.006). In addition, the use of ultrasound alone for femoral nerve catheter insertion was faster and cheaper than the other two methods.
Conclusion
Ultrasound guidance alone without adding either stimulating needle or needle/catheter combination thus appears to be the best approach to femoral perineural catheters.
doi:10.1097/ALN.0000000000000262
PMCID: PMC4110116  PMID: 24758775
2.  Intrathecal ketorolac does not improve acute or chronic pain after hip arthroplasty: a randomized controlled trial 
Journal of anesthesia  2014;28(5):790-793.
Hypersensitivity to mechanical stimuli following surgery has been reported in patients who subsequently develop chronic pain after surgery. In animals, peripheral injury increases prostaglandin production in the spinal cord, and spinal cyclooxygenase inhibitors reduce hypersensitivity after injury. We therefore tested the hypothesis that spinal ketorolac reduces hypersensitivity and acute and chronic pain after hip arthroplasty (www.clinicaltrials.gov NCT 00621530). Sixty-two patients having total hip arthroplasty with spinal anesthesia were randomized to receive 13.5 mg hyperbaric bupivacaine with spinal saline or 13.5 mg hyperbaric bupivacaine with 2 mg preservative-free ketorolac. The primary outcome was area of hypersensitivity surrounding the wound 48 hr after surgery, but this only occurred in 4 patients, precluding assessment of this outcome. The groups did not differ in acute pain, acute opioid use, or pain incidence or severity 2 and 6 months after surgery. There were no serious adverse events. Our results suggest that a single spinal dose of ketorolac does not substantially reduce acute surgical pain, and is thus unlikely to reduce the risk of persistent incisional pain.
doi:10.1007/s00540-014-1798-6
PMCID: PMC4136990  PMID: 24535482
Ketorolac; Postoperative analgesia; Spinal cord; Pain Mechanisms; intrathecal injection; human
3.  Economic Trends from 2003 – 2010 for Perioperative Myocardial Infarction: A Retrospective, Cohort Study 
Anesthesiology  2014;121(1):36-45.
Background
Perioperative myocardial infarction (PMI) is a major surgical complication which is costly and causes much morbidity and mortality. Diagnosis and treatment of PMI’s have evolved over time. Many treatments are expensive, but may reduce ancillary expenses including duration of hospital stay. The time-dependent economic impact of novel treatments for PMI remains unexplored. We thus evaluated absolute and incremental costs of PMI over time, and discharge patterns.
Methods
Approximately 31 million inpatient discharges were analyzed between 2003 and 2010 from the California State Inpatient Database. PMI was defined using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Propensity matching generated 21,637 pairs of comparable patients. Quantile regression modeled incremental charges as the response variable and year of discharge as the main predictor. Time trends of incremental charges adjusted to 2012 dollars, mortality, and discharge destination was evaluated.
Results
Median incremental charges decreased annually by $1,940 (95% CI: $620, $3,250); p < 0.001. Compared to non-PMI patients, the median length of stay of patients who experienced PMI decreased significantly over time: Yearly decrease was 0.16 (0.10, 0.23) days; p < 0.001. No mortality differences were seen; but over time, PMI patients were increasingly likely to be transferred to another facility.
Conclusions
Reduced incremental cost and unchanged mortality may reflect improving efficiency in the standard management of PMI. An increasing fraction of discharges to skilled nursing facilities seems likely a result from hospitals striving to reduce readmissions. It remains unclear whether this trend represents a transfer of cost and risk, or improves patient care.
doi:10.1097/ALN.0000000000000233
PMCID: PMC4062595  PMID: 24662375
4.  Chronic Intermittent Hypoxia Is Independently Associated with Reduced Postoperative Opioid Consumption in Bariatric Patients Suffering from Sleep-Disordered Breathing 
PLoS ONE  2015;10(5):e0127809.
Background
Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO2) < 90% and minimum nocturnal SaO2 on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery.
Methods
With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO2 < 90%, (b) the minimum nocturnal SaO2, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders.
Results
Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO2 < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO2 < 90% was not associated with pain. The minimum nocturnal SaO2 was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep.
Conclusions
Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.
doi:10.1371/journal.pone.0127809
PMCID: PMC4444020  PMID: 26010491
5.  The effects of topical and intravenous JM-1232(-) on cerebral pial microvessels of rabbits 
BMC Anesthesiology  2015;15:37.
Background
JM-1232(-) is a novel anesthetic agent which acts through gamma-aminobutyric acid receptors. Cerebral pial vascular effects of JM-1232(-) are unknown. We thus evaluated topical and intravenous effects of JM-1232(-) on cerebral pial microvessels in rabbits, and the extent to which carbon dioxide (CO2) reactivity is preserved.
Methods
Closed cranial windows were used to visualize cerebral pial circulation in 29 Japanese white rabbits. In the first experiment, the cranial window was superfused with increasing concentrations of JM-1232(-): 10-11, 10-9, 10-7, 10-5 mol/L, n = 8 per concentration. In the second experiment, we examined the effects of an intravenous bolus of 1 mg/kg bolus of JM-1232(-), followed by the continuous infusion at 0.3 mg/kg/minute on cerebral pial vascular alteration (n = 9). In the third, we examined CO2 reactivity of cerebral pial vessels under JM-1232(-) (n = 6) or sevoflurane anesthesia (n = 6).
Results
Topical application of JM-1232(-) did not change pial venular diameter, and constricted arterials only at the highest concentration. Intravenous administration of JM-1232(-) produced cerebral pial constriction which gradually diminished over time. Under intravenous administration of JM-1232(-) and inhaled sevoflurane, diameters of vessels increased in parallel with CO2 partial pressure. Slopes of linear regression and correlation coefficients in arterioles and venules were comparable for JM-1232(-) anesthesia and sevoflurane anesthesia.
Conclusions
Topical application of JM-1232(-) had little effect on cerebral pial vessels. Intravenous administration produced vasoconstriction of cerebral pial arterioles and venules, however those changes were clinically unimportant. In addition, JM-1232(-) did not impair CO2 responsiveness. At least from the perspective of vascular reactivity, JM-1232(-) thus appears safe for neurosurgical patients.
doi:10.1186/s12871-015-0016-x
PMCID: PMC4372327  PMID: 25805961
Anesthesia; JM-1232(-); Cranial window; Cerebral microcirculation; Sevoflurane
6.  Perioperative Assessment of Myocardial Deformation 
Anesthesia and analgesia  2014;118(3):525-544.
Evaluation of left ventricular performance improves risk assessment and guides anesthetic decisions. However, the most common echocardiographic measure of myocardial function, the left ventricular ejection fraction (LVEF), has important limitations. LVEF is limited by subjective interpretation which reduces accuracy and reproducibility, and LVEF assesses global function without characterizing regional myocardial abnormalities. An alternative objective echocardiographic measure of myocardial function is thus needed. Myocardial deformation analysis, which performs quantitative assessment of global and regional myocardial function, may be useful for perioperative care of surgical patients. Myocardial deformation analysis evaluates left ventricular mechanics by quantifying strain and strain rate. Strain describes percent change in myocardial length in the longitudinal (from base to apex) and circumferential (encircling the short-axis of the ventricle) direction and change in thickness in the radial direction. Segmental strain describes regional myocardial function. Strain is a negative number when the ventricle shortens longitudinally or circumferentially and is positive with radial thickening. Reference values for normal longitudinal strain from a recent meta-analysis using transthoracic echocardiography are (mean ± SD) −19.7 ± 0.4%, while radial and circumferential strain are 47.3 ± 1.9 and −23.3 ± 0.7%, respectively. The speed of myocardial deformation is also important and is characterized by strain rate. Longitudinal systolic strain rate in healthy subjects averages −1.10 ± 0.16 sec−1. Assessment of myocardial deformation requires consideration of both strain (change in deformation), which correlates with LVEF, and strain rate (speed of deformation), which correlates with rate of rise of left ventricular pressure (dP/dt). Myocardial deformation analysis also evaluates ventricular relaxation, twist, and untwist, providing new and noninvasive methods to assess components of myocardial systolic and diastolic function. Myocardial deformation analysis is based on either Doppler or a non-Doppler technique, called speckle-tracking echocardiography. Myocardial deformation analysis provides quantitative measures of global and regional myocardial function for use in the perioperative care of the surgical patient. For example, coronary graft occlusion after coronary artery bypass grafting is detected by an acute reduction in strain in the affected coronary artery territory. In addition, assessment of left ventricular mechanics detects underlying myocardial pathology before abnormalities become apparent on conventional echocardiography. Certainly, patients with aortic regurgitation demonstrate reduced longitudinal strain before reduction in LVEF occurs, which allows detection of subclinical left ventricular dysfunction and predicts increased risk for heart failure and impaired myocardial function after surgical repair. In this review we describe the principles, techniques, and clinical application of myocardial deformation analysis.
doi:10.1213/ANE.0000000000000088
PMCID: PMC4066464  PMID: 24557101
7.  Optimal site for ultrasound-guided venous catheterisation in paediatric patients: an observational study to investigate predictors for catheterisation success and a randomised controlled study to determine the most successful site 
Critical Care  2015;19(1):15.
Introduction
Venous catheterisation in paediatric patients can be technically challenging. We examined factors affecting catheterisation of invisible and impalpable peripheral veins in children and evaluated the best site for ultrasound-guided catheterisation.
Methods
Systolic pressure, age, sex, and American Society of Anaesthesiologists (ASA) physical status were determined in 96 children weighing less than 20 kg. Vein diameter and subcutaneous depth were measured with ultrasound. Logistic regression was used to evaluate the contribution of these factors to cannulation success with (n = 65) or without (n = 31) ultrasound guidance. Thereafter, we randomly assigned 196 patients for venous catheter insertion in the dorsal veins of the hand, the cephalic vein in the forearm, or the great saphenous vein. Success rates and vein diameters were evaluated by using Dunn tests; insertion time was evaluated by using Kaplan-Meier cumulative incidence analysis.
Results
Independent predictors of catheterisation were ultrasound guidance (odds ratio (OR) = 7.3, 95% confidence interval (CI) 2.0 to 26.0, P = 0.002), vein diameter (OR = 1.5 per 0.1 mm increase in diameter, 95% CI 1.1 to 2.0, P = 0.007), and ASA physical status (OR = 0.4 per status 1 increase, 95% CI 0.2 to 0.9, P = 0.03). Cephalic veins were significantly larger (cephalic diameter 1.8 mm, P = 0.001 versus saphenous 1.5 mm, P <0.001 versus dorsal 1.5 mm). Catheterisation success rates were significantly better at the cephalic vein than either the dorsal hand or saphenous vein (cephalic 95%, 95% CI 89% to 100%, P <0.001 versus dorsal 69%, 95% CI 56% to 82%, P = 0.03 versus saphenous 75%, 95% CI 64% to 86%).
Conclusions
The cephalic vein in the proximal forearm appears to be the most appropriate initial site for ultrasound-guided catheterisation in invisible and impalpable veins of paediatric patients.
Trial registry number
UMIN Clinical Trials Registry as UMIN000010961. Registered on 14 June 2013.
doi:10.1186/s13054-014-0733-4
PMCID: PMC4335777  PMID: 25600063
8.  Management of chronic neuropathic pain: a protocol for a multiple treatment comparison meta-analysis of randomised controlled trials 
BMJ Open  2014;4(11):e006112.
Introduction
Chronic neuropathic pain is associated with reduced health-related quality of life and substantial socioeconomic costs. Current research addressing management of chronic neuropathic pain is limited. No review has evaluated all interventional studies for chronic neuropathic pain, which limits attempts to make inferences regarding the relative effectiveness of treatments.
Methods and analysis
We will conduct a systematic review of all randomised controlled trials evaluating therapies for chronic neuropathic pain. We will identify eligible trials, in any language, by a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, DARE, PsychINFO and the Cochrane Central Registry of Controlled Trials. Eligible trials will be: (1) enrol patients presenting with chronic neuropathic pain, and (2) randomise patients to alternative interventions (pharmacological or non-pharmacological) or an intervention and a control arm. Pairs of reviewers will, independently and in duplicate, screen titles and abstracts of identified citations, review the full texts of potentially eligible trials and extract information from eligible trials. We will use a modified Cochrane instrument to evaluate risk of bias of eligible studies, recommendations from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes we will collect, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to evaluate our confidence in treatment effects. When possible, we will conduct: (1) in direct comparisons, a random-effects meta-analysis to establish the effect of reported therapies on patient-important outcomes; and (2) a multiple treatment comparison meta-analysis within a Bayesian framework to assess the relative effects of treatments. We will define a priori hypotheses to explain heterogeneity between studies, and conduct meta-regression and subgroup analyses consistent with the current best practices.
Ethics and Dissemination
We do not require ethics approval for our proposed review. We will disseminate our findings through peer-reviewed publications and conference presentations.
Trial registration number
PROSPERO (CRD42014009212).
doi:10.1136/bmjopen-2014-006112
PMCID: PMC4244486  PMID: 25412864
EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS
9.  Optimal doses of sevoflurane and propofol in rabbits 
BMC Research Notes  2014;7:820.
Background
Although sevoflurane and propofol are commonly used anesthetics in rabbits, optimal doses of remain unclear. We thus assessed the optimal hypnotic doses of sevoflurane and propofol, and evaluated the influence of dexmedetomidine on sevoflurane and propofol requirements.
Methods
Twenty-eight Japanese white rabbits were randomly assigned to one of four groups (n = 7 each). Rabbits were given either sevoflurane, propofol, sevoflurane + dexmedetomidine, or propofol + dexmedetomidine (injected 30 μg∙kg-1∙hr-1 for 10 min followed by an infusion of 3.5 μg∙kg-1∙hr-1). Hypnotic level was evaluated with Bispectral Index (BIS), a well-validated electroenchalographic measure, with values between 40 and 60 representing optimal hypnosis. BIS measurements were made 10 minutes after the adjustment of target end-tidal sevoflurane concentration in the sevoflurane group and sevoflurane + dexmedetomidine group, and at 10 min after the change of infusion rate in the propofol group and propofol + dexmedetomidine group.
Results
BIS values were linearly related to sevoflurane concentration and propofol infusion rate, with or without dexmedetomidine. Sevoflurane concentration at BIS = 50 was 3.9 ± 0.2% in the sevoflurane group and 2.6 ± 0.3% in the sevoflurane + dexmedetomidine group. The propofol infusion rate to make BIS = 50 was 102 ± 5 mg∙kg-1∙hr-1 in the propofol group, and 90 ± 10 mg∙kg-1∙hr-1 in the propofol + dexmedetomidine group.
Conclusions
The optimal end-tidal concentration of sevoflurane alone was thus 3.9%, and optimal infusion rate for propofol alone was 102 mg∙kg-1∙hr-1. Dexmedetomidine reduced sevoflurane requirement by 33% and propofol requirement by 11%.
doi:10.1186/1756-0500-7-820
PMCID: PMC4289294  PMID: 25409660
Bispectral index; Propofol; Sevoflurane; Rabbits; Anesthesia
10.  Blood Storage Duration and Biochemical Recurrence of Cancer After Radical Prostatectomy 
Mayo Clinic Proceedings  2011;86(2):120-127.
OBJECTIVE: To test the hypothesis that perioperative transfusion of allogeneic and autologous red blood cells (RBCs) stored for a prolonged period speeds biochemical recurrence of prostate cancer after prostatectomy.
PATIENTS AND METHODS: We evaluated biochemical prostate cancer recurrence in men who had undergone radical prostatectomy and perioperative blood transfusions from July 6, 1998, through December 27, 2007. Those who received allogeneic blood transfusions were assigned to nonoverlapping “younger,” “middle,” and “older” RBC storage duration groups. Those who received autologous RBC transfusions were analyzed using the maximum storage duration as the primary exposure. We evaluated the association between RBC storage duration and biochemical recurrence using multivariable Cox proportional hazards regression.
RESULTS: A total of 405 patients received allogeneic transfusions. At 5 years, the biochemical recurrence–free survival rate was 74%, 71%, and 76% for patients who received younger, middle, and older RBCs, respectively; our Cox model indicated no significant differences in biochemical recurrence rates between the groups (P=.82; Wald test). Among patients who received autologous transfusions (n=350), maximum RBC age was not significantly associated with biochemical cancer recurrence (P=.95). At 5 years, the biochemical recurrence–free survival rate was 85% and 81% for patients who received younger and older than 21-day-old RBCs, respectively.
CONCLUSION: In patients undergoing radical prostatectomy who require RBC transfusion, recurrence risk does not appear to be independently associated with blood storage duration.
The authors evaluated the association between duration of red blood cell storage and biochemical recurrence of cancer in men who had undergone radical prostatectomy and perioperative blood transfusions. Recurrence risk does not appear to be independently associated with blood storage duration.
doi:10.4065/mcp.2010.0313
PMCID: PMC3031436  PMID: 21282486
11.  Temperature Monitoring and Perioperative Thermoregulation 
Anesthesiology  2008;109(2):318-338.
Most clinically available thermometers accurately report the temperature of whatever tissue is being measured. The difficulty is that no reliably core-temperature measuring sites are completely non-invasive and easy to use — especially in patients not having general anesthesia. Nonetheless, temperature can be reliably measured in most patients. Body temperature should be measured in patients having general anesthesia exceeding 30 minutes in duration, and in patients having major operations under neuraxial anesthesia.
Core body temperature is normally tightly regulated. All general anesthetics produce a profound dose-dependent reduction in the core temperature triggering cold defenses including arterio-venous shunt vasoconstriction and shivering. Anesthetic-induced impairment of normal thermoregulatory control, and the resulting core-to-peripheral redistribution of body heat, is the primary cause of hypothermia in most patients. Neuraxial anesthesia also impairs thermoregulatory control, although to a lesser extant than general anesthesia. Prolonged epidural analgesia is associated with hyperthermia whose cause remains unknown.
doi:10.1097/ALN.0b013e31817f6d76
PMCID: PMC2614355  PMID: 18648241
12.  Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy protocol of an international randomised controlled trial 
BMJ Open  2014;4(3):e004842.
Introduction
Steroids In caRdiac Surgery trial (SIRS) is a large international randomised controlled trial of methylprednisolone or placebo in patients undergoing cardiac surgery with the use of a cardiopulmonary bypass pump. At the time of surgery, compared with placebo, methylprednisolone divided into two intravenous doses of 250 mg each may reduce the risk of postoperative acute kidney injury (AKI).
Methods and analysis
With respect to the study schedule, over 7000 substudy eligible patients from 81 centres in 18 countries were randomised in December 2013. The authors will use a logistic regression to estimate the adjusted OR of methylprednisolone versus placebo on the primary outcome of AKI in the 14 days following surgery (a postoperative increase in serum creatinine of ≥50%, or ≥26.5 μmol/L, from the preoperative value). The stage of AKI will also be considered, as will the outcome of AKI in those with and without preoperative chronic kidney disease. After receipt of grant funding, the authors began to record additional perioperative serum creatinine measurements in consecutive patients enrolled at substudy participating centres, and patients were invited to enroll in a 6-month serum creatinine collection. In these trial subpopulations, the authors will consider the outcome of AKI defined in alternate ways, and the outcome of a 6-month change in kidney function from the preoperative value.
Ethics and dissemination
The authors were competitively awarded a grant from the Canadian Institutes of Health Research for this SIRS AKI substudy. Ethics approval was obtained for additional serum creatinine recordings in consecutive patients enrolled at participating centres. The additional kidney data collection first began for patients enrolled after 1 March 2012. In patients who provided consent, the last 6-month kidney outcome data will be collected in 2014. The results will be reported no later than 2015.
Clinical Trial Registration
Number NCT00427388.
doi:10.1136/bmjopen-2014-004842
PMCID: PMC3948633  PMID: 24598306
14.  Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads 
Anesthesiology  2005;102(3):509-514.
Background: Anesthetic requirement in redheads is exaggerated, suggesting that redheads may be especially sensitive to pain. We therefore tested the hypotheses that women with natural red hair are more sensitive to pain, and that redheads are resistant to topical and subcutaneous lidocaine.
Methods: We evaluated pain sensitivity in red-haired (n=30) or dark-haired (n=30) women by determining the electrical current perception threshold, pain perception, and maximum pain tolerance with a Neurometer CPT/C (Neurotron, Inc., Baltimore, MD). We evaluated the analogous warm and cold temperature thresholds with the TSA-II Neurosensory Analyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested with both devices at baseline and with the Neurometer after 1-hour exposure to 4% liposomal lidocaine and after subcutaneous injection of 1% lidocaine. Data are presented as medians [interquartile ranges].
Results: Current perception, pain perception, and pain tolerance thresholds were similar in the red-haired and dark-haired women at 2000, 250, and 5 Hz. In contrast, redheads were more sensitive to cold pain perception (22.6°C [15.1, 26.1] vs. 12.6°C [0, 20], P=0.004), cold pain tolerance (6.0°C [0, 9.7] vs. 0.0°C [0.0, 2.0], P=0.001), and heat pain (46.3°C [45.7, 47.5] vs. 47.7°C [46.6, 48.7], P=0.009). Subcutaneous, lidocaine was significantly less effective in redheads, e.g., pain tolerance threshold at 2000 Hz stimulation in redheads was 11.0 mA [8.5, 16.5] vs. >20.0 mA [14.5, >20] in others, P=0.005).
Conclusion: Red hair is the phenotype for mutations of the melanocortin 1 receptor. Our results indicate that redheads are more sensitive to thermal pain and are resistant to the analgesic effects of subcutaneous lidocaine. Mutations of the melanocortin 1 receptor, or a consequence thereof, thus modulate pain sensitivity.
PMCID: PMC1692342  PMID: 15731586
15.  Doxapram Only Slightly Reduces the Shivering Threshold in Healthy Volunteers 
Anesthesia and analgesia  2005;101(5):1368-1373.
We determined the effects of doxapram on the major autonomic thermoregulatory responses in humans. Nine healthy volunteers were studied on two days: Control and Doxapram (intravenous infusion to a plasma concentration of 2.4 ±0.8 μg/mL, 2.5 ±0.9 μg/mL, and 2.6 ±1.1 μg/mL at the sweating, vasoconstriction, and shivering thresholds, respectively). Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the sweating, vasoconstriction, and shivering thresholds with compensation for changes in skin temperature. Data were analyzed with paired t tests and presented as means ± SDs; P < 0.05 was considered statistically significant. Doxapram did not change the sweating (Control: 37.5±0.4°C, Doxapram: 37.3±0.4°C, P=0.290) or the vasoconstriction threshold (36.8±0.7 vs. 36.4±0.5°C; P=0.110). However, it significantly reduced the shivering threshold from 36.2±0.5 to 35.7±0.7°C (P=0.012). No sedation or symptoms of panic were observed on either study day. The observed reduction in the shivering threshold explains the drug's efficacy for treatment of postoperative shivering; however, a reduction of only 0.5°C is unlikely to markedly facilitate induction of therapeutic hypothermia as a sole agent.
doi:10.1213/01.ANE.0000180198.13467.DF
PMCID: PMC1552102  PMID: 16243996
Anesthesia; Hypothermia; Temperature; Thermoregulation
16.  Perioperative Acupuncture and Related Techniques 
Anesthesiology  2005;102(5):1031-1078.
Acupuncture and related techniques are increasingly practiced in conventional medical settings, and the number of patients willing to use these techniques is increasing. Despite more than 30 years of research, the exact mechanism of action and efficacy of acupuncture have not been established. Furthermore, most aspects of acupuncture have yet to be adequately tested. There thus remains considerable controversy about the role of acupuncture in clinical medicine.
Acupuncture apparently does not reduce volatile anesthetic requirement by a clinically important amount. However, preoperative sedation seems to be a promising application of acupuncture in perioperative settings. Acupuncture may be effective for postoperative pain relief but requires a high level of expertise by the acupuncture practitioner. Acupuncture and related techniques can be used for treatment and prophylaxis of postoperative nausea and vomiting in routine clinical practice in combination with, or as an alternative to, conventional antiemetics when administered before induction of general anesthesia.
Summary Statement: The use of acupuncture for perioperative analgesia, nausea and vomiting, sedation, anesthesia, and complications is reviewed.
PMCID: PMC1475803  PMID: 15851892
17.  Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial 
BMJ Open  2014;4(2):e004886.
Introduction
Perioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).
Methods and analysis
After receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.
Ethics and dissemination
The authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.
Clinical Trial Registration Number
NCT01082874.
doi:10.1136/bmjopen-2014-004886
PMCID: PMC3939660  PMID: 24568963
Surgery; Epidemiology
18.  Dantrolene Reduces the Threshold and Gain for Shivering 
Anesthesia and analgesia  2004;98(5):1318-contents.
Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. With IRB approval and informed consent, healthy volunteers were evaluated on two random days: control and dantrolene (≈2.5 mg/kg plus a continuous infusion). In study 1, 9 men were warmed until sweating was provoked and then cooled until arterio-venous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In study 2, 9 men were given cold Ringer's solution IV to reduce core temperature ≈2°C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption vs. core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3±0.3°C, P=0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7±0.2 to 36.3±0.3°C, P=0.01 and systemic gain from 353±144 to 211±93 ml·min−1·°C−1, P=0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition.
PMCID: PMC1454474  PMID: 15105208
Temperature: hyperthermia, fever; Pharmacology: dantrolene; Complications: shivering
19.  The Timing of Acupuncture Stimulation Does Not Influence Anesthetic Requirement 
Anesthesia and analgesia  2005;100(2):387-392.
Studies suggest that acupuncture is more effective when induced before induction of general anesthesia than afterwards. We tested the hypothesis that electro-acupuncture initiated 30 minutes before induction reduces anesthetic requirement more than acupuncture initiated after induction. Seven volunteers were each anesthetized with desflurane on 3 study days. Needles were inserted percutaneously at 4 acupuncture points thought to produce analgesia in the upper abdominal area and provide generalized sedative and analgesic effects: Zusanli (St36), Sanyinjiao (Sp6), Liangqiu (St34), and Hegu (LI4). Needles were stimulated at 2-Hz and 10-Hz, with frequencies alternating at two-second intervals. On Preinduction day, electro-acupuncture was started 30 minutes before induction of anesthesia and maintained throughout the study. On At-induction day, needles were positioned before induction of anesthesia, but electro-acupuncture stimulation was not initiated until after induction. On Control day, electrodes were positioned near the acupoints, but needles were not inserted. Noxious electrical stimulation was administered via 25-G needles on the upper abdomen (70 mA, 100 Hz, 10 seconds). Desflurane concentration was increased 0.5% when movement occurred and decreased 0.5% when it did not. These up-and-down sequences continued until volunteers crossed from movement to no-movement 4 times. The P50 of logistic regression identified desflurane requirement. Desflurane requirement was similar on the Control (5.2±0.6%, mean±SD), Preinduction (5.0±0.8%), and At-induction (4.7±0.3%, P=0.125) days. This type of acupuncture is thus unlikely to facilitate general anesthesia or decrease the need for anesthetic drugs.
doi:10.1213/01.ANE.0000142114.72117.E0
PMCID: PMC1360236  PMID: 15673863
Anesthetic technique: Acupuncture, Electro-acupuncture; Potency: anesthesia requirement; Anesthetics, volatile: desflurane
20.  Cutaneous Heat Loss with Three Surgical Drapes, One Impervious to Moisture 
Anesthesia and analgesia  2005;100(3):738-contents.
A new surgical drape, which is impervious to moisture, presumably reduces evaporative heat loss. We compared cutaneous heat loss and skin temperature in volunteers covered with this drape to two conventional surgical drapes (Large Surgical Drape and Medline Proxima). With IRB approval and informed consent, we calculated cutaneous heat loss and skin-surface temperatures from 15 area-weighted thermal flux transducers in 8 volunteers. In random order, each of the drapes was evaluated with dry transducers and moistened transducers (simulating wet skin). After a 20-minute uncovered control period, volunteers were covered from the neck down for 40 minutes. Data were recorded continuously and averaged over 10-minutes. Results were similar for all three drapes for dry or moist conditions. Under dry conditions, baseline heat loss was 82±14 watts (W) and decreased 30% with a surgical drape (P<0.001). Under moist conditions, baseline heat loss was 231±45 W and decreased 29% with a drape covering (P<0.001). Moist skin increased heat loss 282% (P<0.001). There were no clinically important differences in skin temperature among the covers with dry or moist skin. Moist skin increased heat loss nearly three-fold, but there were no differences among the drapes. We conclude that loss is comparable with impervious and conventional drapes with either moist or dry skin.
doi:10.1213/01.ANE.0000143954.98285.63
PMCID: PMC1351377  PMID: 15728062
Evaporation; Heat flux; Insulation; Surgical drapes; Sweat; Temperature; Thermoregulation
21.  Women with Red Hair Report A Slightly Increased Rate of Bruising, but Have Normal Coagulation Tests 
Anesthesia and analgesia  2006;102(1):313-318.
There is an anecdotal impression that redheads experience more perioperative bleeding complications than those with other hair colors. We, therefore, tested the hypothesis that perceived problems with hemostasis could be detected with commonly used coagulation tests. Se studied healthy female Caucasian volunteers, 18 to 40 years, comparable in terms of height, weight, and age, with natural bright red (n = 25) or black or dark brown (n = 26) hair. Volunteers were questioned about their bleeding history and the following tests were performed: complete blood count, prothrombin time/international normalized ratio, activated partial thromboplastin time, platelet function analysis (PFA-100), and platelet aggregation using standard turbidimetric methodology. Agonists for aggregation were adenosine diphosphate, arachidonic acid, collagen, epinephrine, and two concentrations of ristocetin. The red-haired volunteers reported significantly more bruising, but there were no significant differences between the red- and dark-haired groups in hemoglobin concentration, platelet numbers, prothrombin time/international normalized ratio, or activated partial thromboplastin time. Furthermore, no significant differences in platelet function, as measured with the PFA-100 or with platelet aggregometry, were observed. We conclude that if redheads have hemostasis abnormalities, they are subtle.
doi:10.1213/01.ANE.0000180769.51576.CD
PMCID: PMC1351323  PMID: 16368849
Anesthesia; Melanocortin; Platelets; Surgery; Coagulation
22.  Anesthetic Requirement is Increased in Redheads 
Anesthesiology  2004;101(2):279-283.
Background: Age and body temperature alter inhalational anesthetic requirement; however, no human genotype is associated with inhalational anesthetic requirement. There is an anecdotal impression that anesthetic requirement is increased in redheads. Furthermore, red hair results from distinct mutations of the melanocortin-1 receptor. We thus tested the hypothesis that the requirement for the volatile anesthetic desflurane is greater in natural redhead than in dark-haired women.
Methods: We studied healthy women with bright red (n=10) or dark (n=10) hair. Blood was sampled for subsequent analyses of melanocortin-1 receptor alleles. Anesthesia was induced with sevoflurane and maintained with desflurane randomly set at an end-tidal concentration between 5.5 and 7.5%. After an equilibration period, a noxious electrical stimulation (100 Hz, 70 mA) was transmitted through bilateral intradermal needles. If the volunteer moved in response to stimulation, desflurane was increased by 0.5%; otherwise it was decreased by 0.5%. This was continued until volunteers “crossed-over” from movement to non-movement (or vice versa) four times. Individual logistic regression curves were used to determine desflurane requirement (P50). Desflurane requirements in the two groups were compared using Mann-Whitney nonparametric two-sample test; P < 0.05 was considered statistically significant.
Results: The desflurane requirement in redheads (6.2 volume-percent [95% CI, 5.9 - 6.5]) was significantly greater than in dark-haired women (5.2 volume-percent [4.9 – 5.5], P = 0.0004). Nine of 10 redheads were either homozygous or compound heterozygotes for mutations on the melanocortin-1 receptor gene.
Conclusions: Red hair appears to be a distinct phenotype linked to anesthetic requirement in humans that can also be traced to a specific genotype.
PMCID: PMC1362956  PMID: 15277908
23.  The Intubating Laryngeal Mask Airway Allows Tracheal Intubation When the Cervical Spine Is Immobilized by a Rigid Collar 
British journal of anaesthesia  2004;93(5):655-659.
Summary
An intubating laryngeal mask airway (ILMA) facilitates tracheal intubation with the neck in neutral position, which is similar to the neck position maintained by a rigid cervical collar. However, a cervical collar virtually obliterates neck movement, even the small movements that normally facilitate airway insertion. We therefore tested the hypothesis that the ILMA facilitates tracheal intubation even in patients wearing a rigid cervical collar. In 50 cervical spine surgery patients with a rigid Philadelphia collar in place and 50 general surgery patients under general anaesthesia, we performed blind tracheal intubation via an ILMA. The time required for intubation, intubation success rate, and numbers and type of adjusting manoeuvres employed were recorded. Inter-incisor distance was significantly smaller (4.1 [0.8] cm vs. 4.6 [0.7] cm, mean [SD], P<0.01) and Mallampati scores were significantly greater (P<0.001) in the collared patients. ILMA insertion took longer (30 [25] vs. 22 [6] seconds), more patients required 2 insertion attempts (15 vs. 3; P<0.005), and ventilation adequacy with ILMA was worse (P<0.05) in collared patients. However, there were no significant differences between the collared and control patients in terms of total time required for intubation (60 [41] vs. 50 [30] seconds), number of intubation attempts, overall intubation success rate (96 vs. 98%), or the incidence of intubation complications. Blind intubation through an ILMA is thus a reasonable strategy for controlling the airway in patients who are immobilized with a rigid cervical collar, especially when urgency precludes a fiberoptic approach.
doi:10.1093/bja/aeh248
PMCID: PMC1283102  PMID: 15321932
anaesthesia; intubation; tracheal; laryngeal mask; cervical collar
24.  Women Have the Same Desflurane MAC as Men: A Prospective Study 
Anesthesiology  2003;99(5):1062-1065.
Background:
Women generally report greater sensitivity to pain than do men, and healthy young women require 20% more anesthetic than healthy age-matched men to prevent movement in response to noxious electrical stimulation. In contrast, MAC for xenon is 26% less in elderly Japanese women than in elderly Japanese men. Whether anesthetic requirement is similar in men and women thus remains in dispute. We therefore tested the hypothesis that the desflurane concentration required to prevent movement in response to skin incision (MAC) differs in men and women.
Methods:
Using the Dixon “up and down” method, we determined MAC for desflurane in 15 female and 15 male patients undergoing surgery (18–40 yr).
Results:
MAC was 6.2 ± 0.4% desflurane for women vs. 6.0 ± 0.3% for men (P = 0.31), a difference of only 3%. These data provide 90% power to detect a 9% difference between the groups.
Conclusion:
MAC of desflurane did not differ between young men and women undergoing surgery with a true surgical incision. While pain sensitivity may differ in women versus men, MAC of desflurane does not.
Summary Statement:
MAC for desflurane was similar in young adult women and men (6.2 ± 0.4% desflurane for women vs. 6.0 ± 0.3% for men; P = 0.31). This contrasts with previous results in which anesthetic requirement was based on the response to electrical stimulation and with studies showing that women report more pain than men.
PMCID: PMC1552095  PMID: 14576540
25.  Low Vitamin D Concentration Is Not Associated with Increased Mortality and Morbidity after Cardiac Surgery 
PLoS ONE  2013;8(5):e63831.
Objective
To determine the effect of vitamin D on postoperative outcomes in cardiac surgical patients.
Design
Retrospective study.
Setting
Single institution-teaching hospital.
Participants
Adult cardiac surgical patients with perioperative 25-hydroxyvitamin D measurements.
Interventions
None. We gathered information from the Cardiac Anesthesiology Registry that was obtained at the time of the patients’ visit/hospitalization.
Measurements and Main Results
We used data of 18,064 patients from the Cardiac Anesthesiology Registry; 426 patients with 25-hydroxyvitamin D measurements met our inclusion criteria. Association with Vitamin D concentration and composite of 11 cardiac morbidities was done by multivariate (i.e., multiple outcomes per subject) analysis. For other outcomes separate multivariable logistic regressions and adjusting for the potential confounders was used. The observed median vitamin D concentration was 19 [Q1-Q3∶12, 30] ng/mL. Vitamin D concentration was not associated with our primary composite of serious cardiac morbidities (odds ratio [OR], 0.96; 95% CI, 0.86–1.07). Vitamin D concentration was also not associated with any of the secondary outcomes: neurologic morbidity (P = 0.27), surgical (P = 0.26) or systemic infections (P = 0.58), 30-day mortality (P = 0.55), or length of initial intensive care unit (ICU) stay (P = 0.04).
Conclusions
Our analysis suggests that perioperative vitamin D concentration is not associated with clinically important outcomes, likely because the outcomes are overwhelmingly determined by other baseline and surgical factors.
doi:10.1371/journal.pone.0063831
PMCID: PMC3665712  PMID: 23724006

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