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1.  Experimental Pain and Opioid Analgesia in Volunteers at High Risk for Obstructive Sleep Apnea 
PLoS ONE  2013;8(1):e54807.
Background
Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.
Methods
After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO2) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.
Results
Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO2 and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO2, P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).
Conclusions
Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.
Trial Registration: ClinicalTrials.gov
NCT00672737.
doi:10.1371/journal.pone.0054807
PMCID: PMC3558510  PMID: 23382975
2.  Magnesium Sulfate Only Slightly Reduces the Shivering Threshold in Humans 
British journal of anaesthesia  2005;94(6):756-762.
Background: Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous hemodynamic responses and prevents further hypothermia. Magnesium is an attractive antishivering agent because it is used for treatment of postoperative shivering and provides protection against ischemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness.
Methods: We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: 1) Control and 2) Magnesium (80 mg·kg-1 followed by infusion at 2 g·h-1). Lactated Ringer's solution (4°C) was infused via a central venous catheter over a period of approximately 2 hours to decrease tympanic membrane temperature ≈1.5°C·h-1. A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs. core temperature regression. Sedation was evaluated using verbal rating score (VRS, 0-10) and bispectral index of the EEG (BIS). Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analyzed using repeated-measures ANOVA; P<0.05 was statistically significant.
Results: Magnesium reduced the shivering threshold (36.3±0.4 [mean±SD] vs. 36.6±0.3°C, P=0.040). It did not affect the gain of shivering (Control: 437±289, Magnesium: 573±370 ml·min-1·°C-1, P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.
Conclusions: Magnesium significantly reduced the shivering threshold; however, due to the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.
doi:10.1093/bja/aei105
PMCID: PMC1361806  PMID: 15749735
Magnesium; Temperature; Thermoregulation; Therapeutic hypothermia; Brain protection; Cardiac protection; Shivering
3.  Induction Speed Is Not a Determinant of Propofol Pharmacodynamics 
Anesthesiology  2004;101(5):1112-1121.
Summary
We used individual pharmacodynamic modeling to demonstrate that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate of propofol.
Background
Evidence suggests that the rate at which they are infused may influence plasma-effect site equilibration of intravenous anesthetics. We used 5 different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. We concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration.
Methods
With Human Studies Committee approval, 18 healthy volunteers received 5 consecutive target-controlled propofol infusions. During each infusion the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 μg·ml−1·min−1. Bispectral index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM.
Results
Once the correct rate of plasma-effect site equilibration (ke0) was determined for each individual (ke0 = 0.17 min−1, time-to-peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of rise of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness.
Conclusions
Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM appears useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.
PMCID: PMC1249471  PMID: 15505446
4.  Concordance of Sleep and Pain Outcomes of Diverse Interventions: An Umbrella Review 
PLoS ONE  2012;7(7):e40891.
Background/Objective
Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep.
Methods
We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes.
Results
151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092).
Conclusions
Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.
doi:10.1371/journal.pone.0040891
PMCID: PMC3398909  PMID: 22815856
5.  Tissue Oxygenation Response to Mild Hypercapnia during Cardiopulmonary Bypass with Constant Pump Output 
British journal of anaesthesia  2006;96(6):708-714.
Background
Tissue oxygenation is the primary determinant of wound infection risk. Mild hypercapnia markedly improves cutaneous, subcutaneous, and muscular tissue oxygenation in volunteers and patients. However, relative contributions of increased cardiac output and peripheral vasodilation to this response remains unknown. We thus tested the hypothesis that increased cardiac output is the dominant mechanism.
Methods
We recruited 10 ASA III patients, aged 40–65 years, undergoing cardiopulmonary bypass for this crossover trial. After induction of anaesthesia, a Silastic tonometer was inserted subcutaneously in the upper arm. Subcutaneous tissue oxygen tension was measured with both polarographic electrode and fluorescence-based systems. Oximeter probes were placed bilaterally on the forehead to monitor cerebral oxygenation. After initiation of cardiopulmonary bypass, in random order patients were exposed to two arterial CO2 partial pressures for 30 minutes each: 35 (normocapnia) or 50 mmHg (hypercapnia). Bypass pump flow was kept constant throughout the measurement periods.
Results
Hypercapnia during bypass had essentially no effect on PaO2, mean arterial pressure, or tissue temperature. PaCO2 and pH differed significantly. Subcutaneous tissue oxygenation was virtually identical during the two PaCO2 periods (139 [50,163] vs. 145 [38,158], P=0.335) (median [range]). In contrast, cerebral oxygen saturation (our positive control measurement) was significantly less during normocapnia (57 [28,67]%) than hypercapnia (64 [37,89]%, P=0.025).
Conclusions
Mild hypercapnia, which normally markedly increases tissue oxygenation, did not do so during cardiopulmonary bypass with fixed pump output. This suggests that hypercapnia normally increases tissue oxygenation by increasing cardiac output rather than direct dilation of peripheral vessels.
doi:10.1093/bja/ael093
PMCID: PMC1464052  PMID: 16675511
Carbon Dioxide; Hypercapnia; Hypercarbia; Acidosis; Respiratory; Oxygenation; Oxygen; Tissue; Cutaneous; Subcutaneous; Cerebral; Perfusion; Cerebrovascular; Cardiac Output
6.  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
7.  The New Perilaryngeal Airway (CobraPLA™)1 Is as Efficient as the Laryngeal Mask Airway (LMA™)2, But Provides Better Airway Sealing Pressures 
Anesthesia and analgesia  2004;99(1):272-278.
The Laryngeal Mask Airway (LMA) is a frequently-used efficient airway device, yet it sometimes seals poorly, thus reducing the efficacy of positive-pressure ventilation. The Perilaryngeal Airway (CobraPLA) is a novel airway device with a larger pharyngeal cuff (when inflated). We tested the hypothesis that the CobraPLA was superior to LMA with regard to insertion time and airway sealing pressure and comparable to LMA in airway adequacy and recovery characteristics. After midazolam and fentanyl, 81 ASA I-II outpatients having elective surgery were randomized to receive an LMA or CobraPLA. Anesthesia was induced with propofol (2.5 mg/kg, IV), and the airway inserted. We measured 1) insertion time; 2) adequacy of the airway (no leak at 15-cm-H2O peak pressure or tidal volume of 5 ml/kg); 3) airway sealing pressure; 4) number of repositioning attempts; and 5) sealing quality (no leak at tidal volume of 8 ml/kg). At the end of surgery, gastric insufflation, postoperative sore throat, dysphonia, and dysphagia were evaluated. Data were compared with unpaired t-tests, chi-square tests, or Fisher’s Exact tests; P<0.05 was significant. Patient characteristics, insertion times, airway adequacy, number of repositioning attempts, and recovery were similar in each group. Airway sealing pressure was significantly greater with CobraPLA (23±6 cm H2O) than LMA (18±5 cm H2O, P<0.001). The CobraPLA has insertion characteristics similar to LMA, but better airway sealing capabilities.
PMCID: PMC1364541  PMID: 15281543
Airway: Sealing. Cuff Pressure. Insertion. Leak. Pharynx; Equipment: Laryngeal mask airway. Perilaryngeal airway; Ventilation: Controlled. Spontaneous; Anesthesia
8.  Block-Dependent Sedation during Epidural Anaesthesia is Associated with Delayed Brainstem Conduction 
British journal of anaesthesia  2004;93(2):228-234.
Neuraxial anaesthesia produces a sedative and anesthetic-sparing effect. Recent evidence suggests that spinal cord anaesthesia modifies reticulo-thalamo-cortical arousal by decreasing afferent sensory transmission. We hypothesized that epidural anaesthesia produces sensory deafferentation-dependent sedation that is associated with impairment of brainstem transmission. We used brainstem auditory evoked potentials (BAEP) to evaluate reticular function in 11 volunteers. Epidural anaesthesia was induced with 2% 2-chloroprocaine. Hemodynamic and respiratory responses, sensory block level, sedation depth and BAEP were assessed throughout induction and resolution of epidural anaesthesia. Sedation was evaluated using verbal rating score (VRS), observer's assessment alertness/sedation (OAA/S) score, and bispectral index (BIS). Prediction probability (PK) was used to associate sensory block with sedation, as well as BIS with other sedation measures. Spearman rank order correlation was used to associate block level and sedation with the absolute and interpeak BAEP latencies. Sensory block level significantly predicted VRS (PK = 0.747), OAA/S score (PK = 0.748) and BIS. Bispectral index predicted VRS and OAA/S score (PK = 0.728). The latency of wave III of BAEP significantly correlated with sedation level (rho = 0.335, P < 0.01) and sensory block (rho = 0.394, P < 0.01). The other BAEP parameters did not change during epidural anaesthesia. Hemodynamic and respiratory responses remained stable throughout the study. Sedation during epidural anaesthesia depends on sensory block level and is associated with detectable block-dependent alterations in the brainstem auditory evoked responses. Sensory deafferentation may reduce CNS alertness through mechanisms related to brainstem neural activity.
doi:10.1093/bja/aeh192
PMCID: PMC1361808  PMID: 15220178
Afferentation theory; Brainstem auditory evoked potentials; Chloroprocaine; Deafferentation; Epidural anaesthesia; Sedation; Sensory block
9.  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
10.  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
11.  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

Results 1-11 (11)