Compartmental pharmacokinetics of nefopam during mild hypothermia

Background Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam. Methods We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling. Results A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (se): V1=24.13 (2.8) litre; V2=183.34 (13.5) litre; Clel=0.54 (0.07) litre min−1; Cldist=2.84 (0.42) litre min−1]. Conclusions The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermi

Ondansetron does not reduce the shivering threshold in healthy volunteers

Background. Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control, and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (triggering core temperatures) in humans. Methods. Control (placebo) and ondansetron infusions at the target plasma concentration of 250 ng ml−1 were studied in healthy volunteers on two different days. Each day, skin and core temperatures were increased to provoke sweating; then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction and shivering thresholds after compensating for changes in mean-skin temperature. Data were analysed using t-tests and presented as means (sds); P<0.05 was taken as significant. Results. Ondensetron plasma concentrations were 278 (57), 234 (55) and 243 (58) ng ml−1 at the sweating, vasoconstriction and shivering thresholds, respectively; these corresponded to ≈50 mg of ondansetron which is approximately 10 times the dose used for postoperative nausea and vomiting. Ondansetron did not change the sweating (control 37.4 (0.4)°C, ondansetron 37.6 (0.3)°C, P=0.16), vasoconstriction (37.0 (0.5)°C vs 37.1 (0.3)°C; P=0.70), or shivering threshold (36.3 (0.5)°C vs 36.3 (0.6)°C; P=0.76). No sedation was observed on either study day. Conclusions. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermi

Perceiving your hand moving: BOLD suppression in sensory cortices and the role of the cerebellum in the detection of feedback delays

Sensory consequences of self-generated as opposed to externally-generated movements are perceived as less intense and lead to less neural activity in corresponding sensory cortices, presumably due to predictive mechanisms. Self-generated sensory inputs have been mostly studied in a single modality, using abstract feedback, with control conditions not differentiating efferent from re-afferent feedback. Here we investigated the neural processing of 1) naturalistic action-feedback associations of 2) self-generated vs. externally-generated movements, and 3) how an additional (auditory) modality influences neural processing and detection of delays. Participants executed wrist movements using a passive movement device (PMD) as they watched their movements in real time or with variable delays (0-417ms). The task was to judge whether there was a delay between the movement and its visual feedback. In the externally- generated condition, movements were induced by the PMD to disentangle efferent from re- afferent feedback. Half of the trials involved auditory beeps coupled to the onset of the visual feedback. We found reduced BOLD activity in visual, auditory, and somatosensory areas during self-generated compared with externally-generated movements, in unimodal and bimodal conditions. Anterior and posterior cerebellar areas were engaged for trials in which action- feedback delays were detected for self-generated movements. Specifically, the left cerebellar lobule IX was functionally connected with the right superior occipital gyrus. The results indicate efference copy-based predictive mechanisms specific to self-generated movements, leading to BOLD suppression in sensory areas. In addition, our results support the cerebellum’s role in the detection of temporal prediction errors during our actions and their consequences

Combining navigator and optical prospective motion correction for high-quality 500 μm resolution quantitative multi-parameter mapping at 7T

Purpose: High-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients. Methods: Camera-based optical prospective motion correction (PMC) and FID navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics. Results: NAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs. 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections. Conclusion: Navigator correction and PMC significantly improved the quality of PD, R1, and R2* maps, particularly in less compliant elderly volunteers and dementia patients. <br

Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations

Modulation der Signalübertragung des Thromboxan A 2 -Rezeptors durch Anästhetika

Thromboxan A2 ist ein wichtiger Mediator (Thrombozytenaktivierung, Vasokonstriktion) der während chirurgischer Behandlung vermehrt freigesetzt wird. Es wird deshalb für eine Reihe von Komplikationen wie Myokardinfarkt und Lungenembolie verantwortlich gemacht. Diese Ereignisse geschehen selten intraoperativ sondern meist postoperativ. Nach Regionalanästhesien sind solche Komplikationen signifikant seltener. Deshalb untersucht diese Arbeit die Wirkung volatiler Anästhetika (Halothan, Isofluran, Sevofluran) und von Lokalanästhetika (Bupivacain, Ropivacain und Lidocain) auf den TXA2-Rezeptor und dessen intrazellulären Signalübertragungsweg. Verwendet wurde dazu das Xenopus-laevis-Modell, mit dem isolierte G-Protein gekoppelte Rezeptoren untersucht werden können. Die verwendeten Anästhetika, außer Sevofluran, suppremieren die Funktion des Rezeptors dosisabhängig und reversibel. Ihre Wirkung entfalten sie am Rezeptor, bzw. G-Protein und beeinflussen die intrazelluläre Signalkaskade nicht

Modulation der Signalübertragung des Thromboxan A 2 -Rezeptors durch Anästhetika

Thromboxan A2 ist ein wichtiger Mediator (Thrombozytenaktivierung, Vasokonstriktion) der während chirurgischer Behandlung vermehrt freigesetzt wird. Es wird deshalb für eine Reihe von Komplikationen wie Myokardinfarkt und Lungenembolie verantwortlich gemacht. Diese Ereignisse geschehen selten intraoperativ sondern meist postoperativ. Nach Regionalanästhesien sind solche Komplikationen signifikant seltener. Deshalb untersucht diese Arbeit die Wirkung volatiler Anästhetika (Halothan, Isofluran, Sevofluran) und von Lokalanästhetika (Bupivacain, Ropivacain und Lidocain) auf den TXA2-Rezeptor und dessen intrazellulären Signalübertragungsweg. Verwendet wurde dazu das Xenopus-laevis-Modell, mit dem isolierte G-Protein gekoppelte Rezeptoren untersucht werden können. Die verwendeten Anästhetika, außer Sevofluran, suppremieren die Funktion des Rezeptors dosisabhängig und reversibel. Ihre Wirkung entfalten sie am Rezeptor, bzw. G-Protein und beeinflussen die intrazelluläre Signalkaskade nicht

Compartmental pharmacokinetics of nefopam during mild hypothermia

Background Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam. Methods We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling. Results A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (se): V1=24.13 (2.8) litre; V2=183.34 (13.5) litre; Clel=0.54 (0.07) litre min−1; Cldist=2.84 (0.42) litre min−1]. Conclusions The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermi

Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.status: publishe

Ondansetron does not reduce the shivering threshold in healthy volunteers

BACKGROUND: Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control, and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (triggering core temperatures) in humans. METHODS: Control (placebo) and ondansetron infusions at the target plasma concentration of 250 ng ml(-1) were studied in healthy volunteers on two different days. Each day, skin and core temperatures were increased to provoke sweating; then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction and shivering thresholds after compensating for changes in mean-skin temperature. Data were analysed using t-tests and presented as means (sds); P. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermia