E. Sarton - Academia.edu (original) (raw)

Papers by E. Sarton

Research paper thumbnail of Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers

British Journal of Anaesthesia, 2018

Background: Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) hypofunction and su... more Background: Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(þ)-and R(e)-ketamine isomers, or esketamine, containing just the S(þ)-isomer. Methods: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 mg kg À1 min À1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. Results: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P¼0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P¼0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. Conclusions: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(e)-but not S(þ)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. Clinical trial registration: NTR 5359.

Research paper thumbnail of Esketamine counters opioid-induced respiratory depression

British Journal of Anaesthesia, 2018

Background: Opioids can produce life-threatening respiratory depression. This study tested whethe... more Background: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. Methods: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO 2-chemosensitivity, or both. Results: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO 2 6.5 kPa) by approximately 40% (from 20 to 12 litre min À1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO 2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO 2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO 2 sensitivity. The remifentanil concentration that reduced ventilatory CO 2 sensitivity by 50% (C 50) was doubled at an esketamine concentration of 127 (84-191) ng ml À1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. Conclusions: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO 2 chemosensitivity.

Research paper thumbnail of Benefit versus Severe Side Effects of Opioid Analgesia

Anesthesiology, 2018

Background Previous studies integrated opioid benefit and harm into one single function—the utili... more Background Previous studies integrated opioid benefit and harm into one single function—the utility function—to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example. Methods Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic–pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression. Results The four conditions were successfully identified with probabilities varying depending on the opioi...

Research paper thumbnail of ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density

Molecular medicine (Cambridge, Mass.), Jan 8, 2013

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is assoc... more Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also as...

Research paper thumbnail of Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men

The Journal of Physiology, 2002

A major defence of the mammalian body to acute hypoxia is a rapid increase in pulmonary ventilati... more A major defence of the mammalian body to acute hypoxia is a rapid increase in pulmonary ventilation called the acute hypoxic response (AHR). This vital chemoreflex is primarily mediated by the carotid bodies located at the bifurcations of the common carotid arteries (Gonzalez et al. 1994). During the past decade, considerable progress has been made in unravelling the cascade of events within carotid body type I cells upon exposure to a hypoxic environment, although there are still many areas of controversy (Gonzalez et al. 1994; Lopez-Barneo et al. 2001). The general picture emerging from most studies is that low oxygen decreases the open probability of potassium channels, which causes membrane depolarization and influx of Ca 2+ ions. In several species, various types of potassium channels are described that may serve as an oxygen-sensing element to initiate the transduction cascade in hypoxia, for example, K v channels in rabbits (Perez-Garcia & Lopez-Lopez, 2000; Perez-Garcia et al. 2000) and maxi-K and TASK channels in rats (Buckler et al. 2000; Riesco-Fagundo et al. 2001). Although potassium channels possess redox sensitivity and are sensitive to changes in the concentration of reactive oxygen species (ROS), it is unclear by which mechanism low oxygen is able to decrease the conductance of these channels (Kourie, 1998; Lopez-Barneo et al. 1999; Kobertz et al. 2000). Volatile anaesthetics, e.g. halothane, can open potassium channels in various cell types, such as TASK channels in rat carotid body (Patel et al. 1999; Buckler et al. 2000; Sirois et al. 2000; Patel & Honore, 2001a,b). At the same time, volatile anaesthetics, particularly halothane, are known to depress the acute hypoxic response, an effect that may be mediated through a preferential and potent action on the carotid bodies (Knill & Clement, 1984; Dahan et al. 1994).

Research paper thumbnail of Ketamine for the treatment of chronic non-cancer pain

Expert Opinion on Pharmacotherapy, 2010

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and... more Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-D-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing longterm (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.

Research paper thumbnail of An observational study on the effect of S(+)-ketamine on chronic painversusexperimental acute pain in Complex Regional Pain Syndrome type 1 patients

European Journal of Pain, 2010

The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NM... more The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. Results: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2 ± 0.2 to 0.4 ± 0.3 cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS = 2.8 ± 1.0 cm at 5-h), when measured plasma ketamine concentrations were low (<100 ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion. Discussion: The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.

Research paper thumbnail of Einfluss von Anästhetika auf die Atemkontrolle

Der Anaesthesist, 2002

Einfluss von Anästhetika auf die Atemkontrolle Dieses Manuskript ist eine Zusammenfassung zweier ... more Einfluss von Anästhetika auf die Atemkontrolle Dieses Manuskript ist eine Zusammenfassung zweier Vorträge mit den Titeln "Sex differences in morphine pharmacokinetics and respiratory dynamics"und "Factors influencing the control of breathing" , die von E.Sarton und A.Dahan anlässlich des 4th Annual Meeting of the European Society for Intravenous Anaesthesia (Eu-roSIVA) am 6.und 7.April 2001 in Göteborg (Schweden) gehalten wurden.EuroSIVA ist eine junge und aktive Gesellschaft, die sich der Erforschung, Ausbildung und Verbreitung der angewandten Pharmakologie intravenöser Anästhetika widmet und durch Vorträge und Workshops im Rahmen jährlicher Konferenzen in Zusammenarbeit mit der Jahrestagung der ESA ein Forum für interessierte Wissenschaftler und Ärzte bietet.Für weitere Informationen hierzu und zu EuroSIVA: www.eurosiva.org.

Research paper thumbnail of Buprenorphine induces ceiling in respiratory depression but not in analgesia

British Journal of Anaesthesia, 2006

Background. We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg... more Background. We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical m-opioid protein-(MOP) receptor effects. Methods. Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal PCO 2 of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. Results. After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (SD 1.8) litre min À1 in the 0.2 mg group vs 12.0 (SD 1.3) litre min À1 in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (SD 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (SD 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). Conclusions. While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Research paper thumbnail of Influence of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on dynamic ventilatory response to hypercapnia in humans

British Journal of Anaesthesia, 1998

Research paper thumbnail of Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ-opioid receptor deficient mice

British Journal of Anaesthesia, 2003

Background. Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic proper... more Background. Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The in¯uence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the m-opioid receptor (MOR) and compared with morphine. Methods. Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The in¯uence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail¯ick and hotplate tests. Results. In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration. Conclusions. The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid-and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our ®ndings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.

Research paper thumbnail of Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats

British Journal of Anaesthesia, 2005

Background. There is evidence from animal studies suggesting the existence of a ceiling effect fo... more Background. There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. Methods. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO 2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 mg kg À1 (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 mg kg À1 (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO 2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 mg kg À1 and fentanyl 0, 50, 68 and 90 mg kg À1. Results. In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses >2.9 mg kg À1 ; buprenorphine caused depression of minute ventilation which levelled off at doses >3.0 mg kg À1 to about 50% of baseline. In rats, the relationship of arterial PCO 2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum Pa CO 2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on Pa CO 2 , with a ceiling effect at doses >1.4 mg kg À1. The effect on Pa CO 2 was modest (maximum value measured, 5.5 kPa). Conclusions. Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Research paper thumbnail of Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study

British Journal of Anaesthesia, 2013

† Dysfunction of central inhibition of pain processing has been implicated in the pathogenesis of... more † Dysfunction of central inhibition of pain processing has been implicated in the pathogenesis of chronic pain states. † The effects of morphine and ketamine on conditioned pain modulation (CPM) were studied in 10 adults with chronic peripheral neuropathic pain. † Morphine, ketamine, and placebo all provided CPM in proportion to their analgesic effects, suggesting a role for CPM in the treatment of chronic pain. Background. Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients. Methods. CPM responses were obtained in 10 adult neuropathic pain subjects (two men/ eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg-1 h-1 for 1 h) and morphine (0.065 mg kg 21 h 21 for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm. Results. Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P,0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief. Conclusions. The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.

Research paper thumbnail of Sex-related difference in opioid-induced ventilatory depression is located within the peripheral chemoreflex loop

Research paper thumbnail of The neuronal NO-synthase inhibitor 7-nitroindazole and morphine have independent effects on the control of breathing in the anesthetized cat

Research paper thumbnail of Acute Pain and Central Nervous System Arousal Do Not Restore Impaired Hypoxic Ventilatory Response during Sevoflurane Sedation

Anesthesiology, 1996

Background To quantify the effects of acute pain on ventilatory control in the awake and sedated ... more Background To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value sligh...

Research paper thumbnail of Respiratory Sites of Action of Propofol

Anesthesiology, 2001

Background Propofol has a depressant effect on metabolic ventilatory control, causing depression ... more Background Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. Methods In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, c...

Research paper thumbnail of Estimation of the Contribution of Norketamine to Ketamine-induced Acute Pain Relief and Neurocognitive Impairment in Healthy Volunteers

Anesthesiology, 2012

Background The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into... more Background The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin. Methods In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine-induced analgesia and cognition was quantified; the S-ketamine dosage was 20 mg/h for 2 h. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model. Results S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment and reduced psychomotor speed, reaction time, and cognitive fle...

Research paper thumbnail of Response Surface Modeling of Alfentanil-Sevoflurane Interaction on Cardiorespiratory Control and Bispectral Index

Anesthesiology, 2001

Background Respiratory depression is a serious side effect of anesthetics and opioids. The author... more Background Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation (Vi), HR, hypoxic Vi, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. R...

Research paper thumbnail of Propofol for Monitored Anesthesia Care

Anesthesiology, 2000

Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the a... more Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. Methods Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. Results Blood propofol concentrations varied among subjects but were stable over time (mean blood concentr...

Research paper thumbnail of Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers

British Journal of Anaesthesia, 2018

Background: Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) hypofunction and su... more Background: Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(þ)-and R(e)-ketamine isomers, or esketamine, containing just the S(þ)-isomer. Methods: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 mg kg À1 min À1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. Results: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P¼0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P¼0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. Conclusions: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(e)-but not S(þ)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. Clinical trial registration: NTR 5359.

Research paper thumbnail of Esketamine counters opioid-induced respiratory depression

British Journal of Anaesthesia, 2018

Background: Opioids can produce life-threatening respiratory depression. This study tested whethe... more Background: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. Methods: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO 2-chemosensitivity, or both. Results: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO 2 6.5 kPa) by approximately 40% (from 20 to 12 litre min À1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO 2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO 2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO 2 sensitivity. The remifentanil concentration that reduced ventilatory CO 2 sensitivity by 50% (C 50) was doubled at an esketamine concentration of 127 (84-191) ng ml À1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. Conclusions: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO 2 chemosensitivity.

Research paper thumbnail of Benefit versus Severe Side Effects of Opioid Analgesia

Anesthesiology, 2018

Background Previous studies integrated opioid benefit and harm into one single function—the utili... more Background Previous studies integrated opioid benefit and harm into one single function—the utility function—to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example. Methods Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic–pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression. Results The four conditions were successfully identified with probabilities varying depending on the opioi...

Research paper thumbnail of ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density

Molecular medicine (Cambridge, Mass.), Jan 8, 2013

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is assoc... more Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also as...

Research paper thumbnail of Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men

The Journal of Physiology, 2002

A major defence of the mammalian body to acute hypoxia is a rapid increase in pulmonary ventilati... more A major defence of the mammalian body to acute hypoxia is a rapid increase in pulmonary ventilation called the acute hypoxic response (AHR). This vital chemoreflex is primarily mediated by the carotid bodies located at the bifurcations of the common carotid arteries (Gonzalez et al. 1994). During the past decade, considerable progress has been made in unravelling the cascade of events within carotid body type I cells upon exposure to a hypoxic environment, although there are still many areas of controversy (Gonzalez et al. 1994; Lopez-Barneo et al. 2001). The general picture emerging from most studies is that low oxygen decreases the open probability of potassium channels, which causes membrane depolarization and influx of Ca 2+ ions. In several species, various types of potassium channels are described that may serve as an oxygen-sensing element to initiate the transduction cascade in hypoxia, for example, K v channels in rabbits (Perez-Garcia & Lopez-Lopez, 2000; Perez-Garcia et al. 2000) and maxi-K and TASK channels in rats (Buckler et al. 2000; Riesco-Fagundo et al. 2001). Although potassium channels possess redox sensitivity and are sensitive to changes in the concentration of reactive oxygen species (ROS), it is unclear by which mechanism low oxygen is able to decrease the conductance of these channels (Kourie, 1998; Lopez-Barneo et al. 1999; Kobertz et al. 2000). Volatile anaesthetics, e.g. halothane, can open potassium channels in various cell types, such as TASK channels in rat carotid body (Patel et al. 1999; Buckler et al. 2000; Sirois et al. 2000; Patel & Honore, 2001a,b). At the same time, volatile anaesthetics, particularly halothane, are known to depress the acute hypoxic response, an effect that may be mediated through a preferential and potent action on the carotid bodies (Knill & Clement, 1984; Dahan et al. 1994).

Research paper thumbnail of Ketamine for the treatment of chronic non-cancer pain

Expert Opinion on Pharmacotherapy, 2010

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and... more Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-D-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing longterm (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.

Research paper thumbnail of An observational study on the effect of S(+)-ketamine on chronic painversusexperimental acute pain in Complex Regional Pain Syndrome type 1 patients

European Journal of Pain, 2010

The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NM... more The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. Results: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2 ± 0.2 to 0.4 ± 0.3 cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS = 2.8 ± 1.0 cm at 5-h), when measured plasma ketamine concentrations were low (<100 ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion. Discussion: The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.

Research paper thumbnail of Einfluss von Anästhetika auf die Atemkontrolle

Der Anaesthesist, 2002

Einfluss von Anästhetika auf die Atemkontrolle Dieses Manuskript ist eine Zusammenfassung zweier ... more Einfluss von Anästhetika auf die Atemkontrolle Dieses Manuskript ist eine Zusammenfassung zweier Vorträge mit den Titeln "Sex differences in morphine pharmacokinetics and respiratory dynamics"und "Factors influencing the control of breathing" , die von E.Sarton und A.Dahan anlässlich des 4th Annual Meeting of the European Society for Intravenous Anaesthesia (Eu-roSIVA) am 6.und 7.April 2001 in Göteborg (Schweden) gehalten wurden.EuroSIVA ist eine junge und aktive Gesellschaft, die sich der Erforschung, Ausbildung und Verbreitung der angewandten Pharmakologie intravenöser Anästhetika widmet und durch Vorträge und Workshops im Rahmen jährlicher Konferenzen in Zusammenarbeit mit der Jahrestagung der ESA ein Forum für interessierte Wissenschaftler und Ärzte bietet.Für weitere Informationen hierzu und zu EuroSIVA: www.eurosiva.org.

Research paper thumbnail of Buprenorphine induces ceiling in respiratory depression but not in analgesia

British Journal of Anaesthesia, 2006

Background. We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg... more Background. We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical m-opioid protein-(MOP) receptor effects. Methods. Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal PCO 2 of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. Results. After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (SD 1.8) litre min À1 in the 0.2 mg group vs 12.0 (SD 1.3) litre min À1 in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (SD 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (SD 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). Conclusions. While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Research paper thumbnail of Influence of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on dynamic ventilatory response to hypercapnia in humans

British Journal of Anaesthesia, 1998

Research paper thumbnail of Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ-opioid receptor deficient mice

British Journal of Anaesthesia, 2003

Background. Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic proper... more Background. Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The in¯uence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the m-opioid receptor (MOR) and compared with morphine. Methods. Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The in¯uence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail¯ick and hotplate tests. Results. In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration. Conclusions. The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid-and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our ®ndings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.

Research paper thumbnail of Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats

British Journal of Anaesthesia, 2005

Background. There is evidence from animal studies suggesting the existence of a ceiling effect fo... more Background. There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. Methods. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO 2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 mg kg À1 (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 mg kg À1 (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO 2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 mg kg À1 and fentanyl 0, 50, 68 and 90 mg kg À1. Results. In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses >2.9 mg kg À1 ; buprenorphine caused depression of minute ventilation which levelled off at doses >3.0 mg kg À1 to about 50% of baseline. In rats, the relationship of arterial PCO 2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum Pa CO 2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on Pa CO 2 , with a ceiling effect at doses >1.4 mg kg À1. The effect on Pa CO 2 was modest (maximum value measured, 5.5 kPa). Conclusions. Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Research paper thumbnail of Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study

British Journal of Anaesthesia, 2013

† Dysfunction of central inhibition of pain processing has been implicated in the pathogenesis of... more † Dysfunction of central inhibition of pain processing has been implicated in the pathogenesis of chronic pain states. † The effects of morphine and ketamine on conditioned pain modulation (CPM) were studied in 10 adults with chronic peripheral neuropathic pain. † Morphine, ketamine, and placebo all provided CPM in proportion to their analgesic effects, suggesting a role for CPM in the treatment of chronic pain. Background. Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients. Methods. CPM responses were obtained in 10 adult neuropathic pain subjects (two men/ eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg-1 h-1 for 1 h) and morphine (0.065 mg kg 21 h 21 for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm. Results. Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P,0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief. Conclusions. The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.

Research paper thumbnail of Sex-related difference in opioid-induced ventilatory depression is located within the peripheral chemoreflex loop

Research paper thumbnail of The neuronal NO-synthase inhibitor 7-nitroindazole and morphine have independent effects on the control of breathing in the anesthetized cat

Research paper thumbnail of Acute Pain and Central Nervous System Arousal Do Not Restore Impaired Hypoxic Ventilatory Response during Sevoflurane Sedation

Anesthesiology, 1996

Background To quantify the effects of acute pain on ventilatory control in the awake and sedated ... more Background To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value sligh...

Research paper thumbnail of Respiratory Sites of Action of Propofol

Anesthesiology, 2001

Background Propofol has a depressant effect on metabolic ventilatory control, causing depression ... more Background Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. Methods In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, c...

Research paper thumbnail of Estimation of the Contribution of Norketamine to Ketamine-induced Acute Pain Relief and Neurocognitive Impairment in Healthy Volunteers

Anesthesiology, 2012

Background The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into... more Background The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin. Methods In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine-induced analgesia and cognition was quantified; the S-ketamine dosage was 20 mg/h for 2 h. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model. Results S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment and reduced psychomotor speed, reaction time, and cognitive fle...

Research paper thumbnail of Response Surface Modeling of Alfentanil-Sevoflurane Interaction on Cardiorespiratory Control and Bispectral Index

Anesthesiology, 2001

Background Respiratory depression is a serious side effect of anesthetics and opioids. The author... more Background Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation (Vi), HR, hypoxic Vi, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. R...

Research paper thumbnail of Propofol for Monitored Anesthesia Care

Anesthesiology, 2000

Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the a... more Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. Methods Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. Results Blood propofol concentrations varied among subjects but were stable over time (mean blood concentr...