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): V(1)=24.13 (2.8) litre; V(2)=183.34 (13.5) litre; Cl(el)=0.54 (0.07) litre min(-1); Cl(dist)=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 hypothermia.

The blood supply of the scaphoid bone.

Scaphoid vascularisation was investigated using macroscopic and microscopic techniques in 12 uninjured, formalin fixed cadaver hands. A good blood supply of the scaphoid bone from palmar, dorsal and radial vessel groups with a variety of anastomoses was found which should provide sufficient collateral blood flow from adjacent regions in some patients. Since blood supply is available from the palmar circulation, a dorsal approach to the scaphoid bone is possible.

Perioperative concentrations of catecholamines in the cerebrospinal fluid and plasma during spinal anesthesia.

BACKGROUND: Catecholamine release is a physiological response to stress. The extent to which perioperative stress provokes the central release of catecholamines, which modulate pain perception in the spinal cord, still remains unknown. The perioperative course of catecholamine concentrations in the cerebrospinal fluid (CSF) and plasma was examined. METHODS: A prospective study was performed in 25 patients (ASA III, 60-84 years) undergoing elective hip joint replacement in spinal catheter anesthesia. The concentrations of dopamine, epinephrine and norepinephrine in the CSF and plasma were measured before anesthesia, immediately after surgery, and 6 and 24 h post-operatively. RESULTS: In most patients, dopamine and epinephrine were not detectable in CSF. CSF-norepinephrine concentrations decreased from median [interquartile-range] 159 [124;216] pre-anesthesia to 116 [79;152] pmol/l immediately post-operatively and were slightly elevated 24 h post-operatively (180 [134;302] pmol/l) (P=0.05). Dopamine plasma concentrations were not detectable or were barely above the detection threshold. Plasma epinephrine increased from 61 [28;77] pmol/l pre-anesthesia to 112 [69;138] pmol/l 6 h post-operatively and returned to baseline 24 h post-operatively (P=0.001). Plasma norepinephrine concentrations increased intra-operatively from 298 [249;422] to 556 [423;649] pmol/l and remained elevated 24 h after surgery (P=0.009). There was no association between changes in CSF or plasma norepinephrine or epinephrine concentrations and changes in heart rate (HR) or mean arterial pressure (MAP). CONCLUSION: During spinal anesthesia for elective hip joint replacement, norepinephrine concentrations were greater in plasma than in CSF. CSF dopamine and epinephrine concentrations were essentially undetectable. The changes in CSF-norepinephrine concentrations and the changes of plasma norepinephrine concentrations showed no association with each other; nor were there correlations between clinical stress parameters (HR, MAP) or visual analog scale pain, and the changes in CSF norepinephrine concentrations.

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 approximately 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) degrees C, ondansetron 37.6 (0.3) degrees C, P=0.16), vasoconstriction (37.0 (0.5) degrees C vs 37.1 (0.3) degrees C; P=0.70), or shivering threshold (36.3 (0.5) degrees C vs 36.3 (0.6) degrees C; P=0.76). No sedation was observed on either study day. CONCLUSIONS: /b>. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermia.

Influence of volatile anesthetics on thromboxane A2 signaling.

BACKGROUND: Thromboxane A2 (TXA2) is a member of the prostaglandin family; activation of its receptor induces several important effects, including platelet aggregation and smooth muscle contraction. Because volatile anesthetics interfere with aggregation and contraction, the authors investigated effects of halothane, isoflurane, and sevoflurane on TXA2 signaling in an isolated receptor model. METHODS: mRNA encoding TXA2 receptors was prepared in vitro and expressed in Xenopus oocytes. The effects of halothane, isoflurane, and sevoflurane on Ca2+-activated Cl- currents induced by the TXA2 agonist U-46619 and on those induced by intracellular injection of inositol 1-4-5 trisphosphate or guanosine 5'-O-(2-thiodiphosphate) were measured using the voltage-clamp technique. RESULTS: Expressed TXA2 receptors were functional (half maximal effect concentration [EC50], 3.2 x 10(-7) +/- 1.1 x 10(-7) M; Hill coefficient (h), 0.8 +/- 0.2). Halothane and isoflurane inhibition of TXA2 signaling was reversible and concentration dependent (halothane half maximal inhibitory concentration [IC50], 0.46 +/- 0.04 mM; h, 1.6 +/- 0.21; isoflurane IC50, 0.69 +/- 0.12 mM; h, 1.3 +/- 0.27). 0.56 mM halothane (1%) right-shifted the U-46619 concentration-response relationship by two orders of magnitude (EC50, 1 x 10[-5] M). That h and maximal effect (Emax) were unchanged indicates that halothane acts in a competitive manner. In contrast, isoflurane acted noncompetitively, decreasing Emax by 30% (h and EC50 were unchanged). Both halothane and isoflurane had no effect on intracellular signaling pathways. Sevoflurane (0-1.3 mM) did not affect TXA2 signaling. CONCLUSIONS: Both halothane and isoflurane inhibit TXA2 signaling at the membrane receptor, but by different mechanisms. This suggests that the effects of these anesthetics on TXA2 signaling are evoked at different locations of the receptor protein: halothane probably acts at the ligand binding site and isoflurane at an allosteric site.