Propofol metabolites in man following propofol induction and maintenance.

BACKGROUND: The pharmacokinetics of propofol in man is characterized by a rapid metabolic clearance linked to glucuronidation of the parent drug to form the propofol-glucuronide (PG) and sulfo- and glucuro-conjugation of hydroxylated metabolite via cytochrome P450 to produce three other conjugates. The purpose of this study was to assess the urine metabolite profile of propofol following i.v. propofol anaesthesia in a Caucasian population. METHODS: The extent of phase I and phase II metabolism of propofol was studied in 18 female and 17 male patients after an anaesthesia induced and maintained for at least 4 h with propofol. The infusion rates (mg kg(-1) h(-1)) of propofol were (mean (SD)) 4.1 (1.0) and 4.5 (1.3) for males and females, respectively. Urine was collected from each patient for the periods 0-4, 4-8, 8-12, and 12-24 h after the start of propofol administration. In a preliminary study, the three main glucuro-conjugated metabolites were isolated from urine and characterized by magnetic resonance spectroscopy. The quantification of these metabolites for the different collection periods was then performed by a HPLC-UV assay. RESULTS: Total recovery of propofol in the metabolites studied amounts to 38%, of which 62% was via the PG metabolite and 38% via cytochrome P-450. This percentage is significantly higher than that previously reported from patients after a bolus dose of propofol. Extreme values for PG (0-24 h period) were included from 73 to 49%. There was no significant difference between female and male patients in the metabolite ratio. CONCLUSIONS: We conclude that the extent of hydroxylation in propofol metabolism was higher than in previous findings after administration of anaesthetic doses of propofol. Moreover, the ratio between hydroxylation and glucuronidation of propofol is subject to an inter-patient variability but this does not correlate with the dose of propofol. However, the variation of the metabolite profile observed in the present report does not seem to indicate an extended role of metabolism in pharmacokinetic variability.

EEG bispectral index and hypnotic component of anaesthesia induced by sevoflurane: comparison between children and adults.

This prospective study was designed to evaluate the correlation between the electroencephalographic bispectral index (BIS) and the hypnotic component of anaesthesia (CA) induced by sevoflurane in 27 children and 27 adult patients. BIS and CA were compared at loss of consciousness (LOC) and on recovery of consciousness (ROC). Mean (SD) BIS decreased significantly at LOC in children and adults from 94 (2.7) to 87.4 (4) and from 96.2 (2) to 86.7 (4.4), respectively, without any difference between groups. Correlation coefficients (p) between BIS and CA at LOC were -0.761 in children and -0.911 in adults. BIS increased significantly at ROC in children and adults from 74.1 (4.2) to 86.7 (2) and from 80.2 (5) to 90.7 (3), respectively, without any difference between groups. Correlation coefficients between BIS and CA in ROC were -0.876 in children and -0.837 in adults. BIS values at ROC were not different from those at LOC in either group. These data demonstrate that BIS correlates with the hypnotic component of anaesthesia induced by sevoflurane in children as well as in adults.

Remifentanil and controlled hypotension; comparison with nitroprusside or esmolol during tympanoplasty.

PURPOSE: To determine whether remifentanil, combined with propofol, could induce controlled hypotension, reduce middle ear blood flow (MEBF) measured by laser-Doppler flowmetry, provide a "dry" operative field, and could be compared with nitroprusside or esmolol combined with alfentanil and propofol. METHODS: Thirty patients undergoing tympanoplasty and anesthetized with 2.5 mg x kg(-1) propofol iv followed by a constant infusion of 120 microg x kg(-1) x min(-1), were randomly assigned in three groups to receive either 1 microg x kg(-1) remifentanil iv followed by a continuous infusion of 0.25 to 0.50 microg x kg(-1) x min(-1), or nitroprusside iv, or esmolol iv combined for the latter two groups with alfentanil iv. RESULTS: Controlled hypotension was achieved at the target pressure of 80 mmHg within 107 +/- 16, 69 +/- 4.4, 53.3 +/- 4.4 sec for remifentanil, nitroprusside and esmolol respectively. MEBF decreased by 24 +/- 0.3, 22 +/- 3.3, 37 +/- 3% and preceded the decrease in SABP, within 30 +/- 6.1, 11.2 +/- 3.1, 15 +/- 2.8 sec for remifentanil, nitroprusside and esmolol respectively. Remifentanil, and nitroprusside decreased MEBF autoregulation less than esmolol (0.36 +/- 0.1, 0.19 +/- 0.2, -0.5 +/- 0.2). Controlled hypotension was sustained in all three groups throughout surgery, and the surgical field rating decreased in a range of 80% in all three groups. Nitroprusside decreased pH and increased PaCO2. There were no postoperative complications in any of the groups. CONCLUSIONS: Remifentanil combined with propofol enabled controlled hypotension, reduced middle ear blood flow and provided good surgical conditions for tympanoplasty with no need for additional use of a potent hypotensive agent.

High-performance liquid chromatographic assay to detect hydroxylate and conjugate metabolites of propofol in human urine.

This paper describes a HPLC method for the simultaneous detection of phase I (2,6-diisopropyl-1-4-quinol and 2,6-diisopropyl-1-4-quinone) and phase II (4-(2,6-diisopropyl-1-4-quinol)-sulphate, 1-(2,6-diisopropyl-1-4-quinol)-glucuronide, 4-(2,6-diisopropyl-1-4-quinol)-glucuronide, and propofol-glucuronide) metabolites of propofol in human urine samples. Separation was based on a simple mobile phase and a reversed-phase chromatographic column. Metabolite identification was performed by UV spectrum on a diode-array detector and by LC-APCI-MS. The identification was also carried out using in vitro incubation mixtures (cytosol and microsomes prepared from liver) from several species: human, rat and rabbit. This assay was performed using UV, fluorescence and electrochemical detection modes. Each of these was analyzed and discussed.

Sympathetic nerve regulation of cochlear blood flow during increases in blood pressure in humans.

The purpose of this work was to show that regulation of the blood flow to the cochlea by the sympathetic nervous system occurs in humans at the level of the cochlear microcirculation during increases in blood pressure and that its involvement depends on the pressure level. Eight anaesthetized patients undergoing tympanoplasty for hearing disease took part in a pharmacological protocol of stimulation and inhibition of the autonomic nervous system (ANS) to provide variations in systolic blood pressure (BPS) and cochlear blood flow (CBF). The CBF was measured by laser-Doppler flowmetry. Changes in autonomic nerve activity were brought about by changes in baroreceptor activity (BR) initiated by the injection of an alpha adrenergic agent before and after sympathetic and parasympathetic blockade. The CBF variations (delta CBF) were plotted against BPS increases at each stage of the ANS inhibition. The BR diminished significantly after alpha blockade, after alpha and beta blockade, and after alpha and beta blockade and atropine, by 50% (P < 0.01), 29% (P < 0.05), and 95% (P < 0.001) respectively. The BPS increased significantly (P < 0.01) by 36 (SD 9)%, 47 (SD 1)%, and 67 (SD 16)% respectively. The CBF response to an increase in BPS exhibited two opposing variations in the patients: CBF decreased significantly in one group, and increased significantly in the other group. In both groups, delta CBF decrease and delta CBF increase, respectively, were significant after ANS blockade; even so the decrease and increase, respectively, levelled off at BPS around 160 mmHg before ANS blockade. For BPS below 160 mmHg, correlations between delta CBF and BPS were significant before inhibition and after inhibition of ANS. For BPS below 160 mmHg, BPS and delta CBF were not correlated before inhibition of ANS, and were significantly correlated after inhibition of ANS. For BPS below 160 mmHg, CBF response to the BPS increase was the same before and after ANS blockade, i.e. ANS control did not predominate: even so, for BPS above 160 mmHg, the CBF response to BPS increase was different before and after ANS blockade: CBF varied significantly after ANS blockade as it varied for BPS below 160 mmHg, while it remained constant before ANS blockade that elicited ANS control of CBF. In conclusion, sympathetic nerve regulation via its vasomotor tone at the level of cochlear microcirculation occurred markedly when the blood pressure was above 160 mmHg; the autonomic nervous system would appear to control the cochlear blood flow against large variations in blood flow in response to hypertensive phenomena.

Effect of nitric oxide blockade on the lower limit of the cortical cerebral autoregulation in pentobarbital-anaesthetized rats.

The role of nitric oxide (NO) in cerebral autoregulation is controversial. The purpose of this study was to compare the effects on the lower limit of the cortical cerebral autoregulation of the inhibition of NO synthesis by N omega-nitro-L-arginine (L-NNA) infusion to saline and phenylephrine in pentobarbital-anaesthetized rats. Variations of the cortical cerebral blood flow (CBF), the cortical cerebrovascular resistances, the mean arterial pressure and the lower limit of cerebral autoregulation were compared in three groups: a group pretreated with L-NNA (n = 8), a group pretreated with saline (n = 8) and a group pretreated with phenylephrine (n = 5). The laser-Doppler flowmetry continuously measured CBF. Controlled haemorrhage was performed after the intravenous infusion of L-NNA, saline, or phenylephrine. The lower limit of cerebral autoregulation of each rat was computed by the least-squares method. The lower limit of cerebral autoregulation was significantly higher after L-NNA infusion (74 +/- 5 mm Hg) than after saline (43 +/- 3 mm Hg; p < 0.01) or phenylephrine infusions (52 +/- 5 mm Hg; p < 0.05). In conclusion, the role of NO on the cerebral autoregulation has been controversial; our results confirm the hypothesis that NO exerts a significant role in maintaining the lower limit of cerebral autoregulation in pentobarbital-anaesthetized rats.

Quantitation of propofol in whole blood by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric assay, using selected-ion monitoring (GC-MS-SIM) with thymol as internal standard, was developed for quantitating propofol, an intravenous anaesthetic. The method described is rapid and sensitive for the determination of propofol in whole blood. The sensitivity of the present method is 10 ng/ml. The recovery of propofol added to human whole blood in the concentration range 10-10,000 ng/ml ranged between 95 and 100%. A single extraction procedure was used with chloroform-ethyl acetate. The assay allowed the detection of two metabolites formed during propofol metabolism: 2,6-diisopropyl-1,4-quinone and 2,6-diisopropyl-1,4-quinol.

[Effects of buflomedil and naftidrofuryl on the human cochlear microcirculation measured by laser-Doppler]. / Les effets du Buflomedil et du Naftidrofuryl sur la microcirculation cochléaire humaine mesurée par laser-Doppler.

The aim of this study was to assess the effects on cochlear blood flow measured by laser-Doppler of two vasoactive agents known for their supposed effectiveness in the presbyacousy treatment (buflomedil, naftidrofuryl), 16 patients undergoing acoustic neurinoma surgery were studied. Cochlear blood flow (CBF) was continuously recorded after the head of the probe was inserted into the internal ear through the round window. Systolic arterial pressure (SAP) and heart rate (HR) were continuously recorded via an arterial cannula. Hemodynamic variations due to buflomedil (400 mg in bolus) and to naftidrofuryl (200 mg in bolus) were compared with those of sodium nitroprusside (500 micrograms in bolus) in each case with anova. Buflomedil did not alter CBF (0%), SAP (+0.14 +/- 1.7%), HR (+3.4 +/- 3.4%). Naftidrofuryl provoked a significant decrease (P < 0.05) of CBF (-14.5 +/- 7.55%), SAP (-13.7 +/- 4%), and a significant increase (P < 0.05) of HR (+8.5 +/- 3.5%); there is a relationship between CBF and SAP (r = 0.88 P < 0.05). NPS provoked a significant decrease (P < 0.01) of CBF (-34.7 +/- 7.7%) SAP (-26.8 +/- 5.4%) and a significant increase (P < 0.01) of HR(+14.7 +/- 7.3%) in the same way of naftidrofuryl (P < 0.01). In conclusion, human cochlear microcirculation depends upon pharmacological hemodynamic variations such as animal models or middle ear microcirculation. If buflomedil did not alter it, naftidrofuryl provoked a reduction by a direct vasodilator effect inducing hypotension like sodium nitroprusside.

Effects of posture, hypotension and locally applied vasoconstriction on the middle ear microcirculation in anaesthetized humans.

Studies by laser-Doppler flowmetry of middle ear microcirculation changes induced by physical and chemical stimuli in the animal have only recently been made. This prospective study, performed in humans, was designed to compare the effects of a postural manoeuvre (headup tilt 30 degrees), hypotension and locally applied vasoconstriction on middle ear blood flow during anaesthesia. Circulatory changes provoked by a headup tilt of 30 degrees, and successive intravenous boluses of potent vasodilators, were compared with circulatory changes provoked by locally applied adrenaline, in ten healthy patients in good physical states undergoing middle ear surgical repair. Heart rate and direct arterial pressure were continuously recorded via a radial artery cannula. Middle ear blood flow was continuously recorded via a laser-Doppler probe placed on the promontorium cavi tympani. Metabolic parameters (partial pressure of O2 and CO2 in arterial blood, pH, arterial lactate concentrations) and arterial concentrations of propofol were measured just before and just after the experiment. Headup tilt did not modify heart rate, mean arterial pressure or middle ear blood flow. Vasodilators (nicardipine, nitroprusside, nitroglycerin) provoked a fall in arterial pressure (P < 0.0001, P < 0.0001, P < 0.019, respectively), but did not induce any significant variations in heart rate; variations occurred in middle ear blood flow (P > 0.05, not significant) which were different according to patients and agents. Locally applied adrenaline provoked a fall in the middle ear blood flow (P < 0.0012), with no effect on heart rate and arterial pressure. There were no significant changes in metabolic values, or propofol serum concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Local analgesic action by direct effect of pethidine on the nervous trunks]. / Action analgésique locale par effet direct sur les troncs nerveux de la péthidine.

The aim of this paper is to study the analgesic effects of meperidine (pethidine) on nervous trunks. First we compared the analgesic effect of pethidine in surgery of knee and femur. Meperidine was randomly administered either by femoral block or intravenously. The onset of analgesia was shorter with femoral block (5 minutes against 146 minutes). In the surgery of shoulder, nerve block with meperidine was performed using intersclalenic block. Plasma concentrations ar lower (maximum of 0.29 mg per liter) than intravenous therapeutic concentrations (between 0.5 and 0.7 mg per liter). So we can conclude as do other papers, there is a direct effect of meperidine on nervous trunks. This effect is probably mediated by receptors located on nervous trunks.

The effect of nerve blockade on forearm and finger skin blood flow during body heating and cooling.

To determine the role of the active cutaneous vasodilatator response in forearm and finger skin, direct assessment of only skin blood flow was performed before and after musculocutaneous and median nerve blockade during whole body heating and cooling. Forearm laser Doppler flow (LDF forearm), forearm heat thermal clearance (HTC forearm), and finger laser Doppler flow (LDF finger) were monitored in the nerve blocked skin and contralateral untreated skin (control). In the pre-blockade period, no significant differences were found between experimental and control arm skin. After nerve block a significant increase occurred only in LDF finger, which rose from 4.3 +/- 0.6 to 6.0 +/- 0.5 volts (p less than 0.05). During whole body heating LDF forearm and HTC forearm increased significantly on both arms. The increase in LDF forearm was greater (p less than 0.05) in control (18.3 +/- 1.2 volts) than in nerve blocked skin (14.6 +/- 1.8 volts) and occurred earlier. The same tendency was observed in HTC forearm between nerve blocked skin (0.522 +/- 0.06 W.m-1.degrees C-1) and control 0.671 +/- 0.037 W.m-1.degrees C-1) (NS). LDF raise up to 6.6 +/- 0.5 and 6.8 +/- 0.5 volts in the blocked finger and in the control respectively. During cooling LDF finger in the control decreased to 1.3 +/- 0.1 volt and was significantly (p less than 0.05) lower than in the resting period, and lower than that in the nerve blocked finger (3.4 +/- 0.8 volts) (p less than 0.05). We conclude that the active vasodilatator system plays an important role as far as the timing and the amplitude of the cutaneous vasodilatator response to whole body heating in the forearm but not in the finger. At thermal neutrality, the vascular vasoconstrictor tone is high to the finger but not to the forearm. The vasoconstrictor response to cooling occurred only in the finger.

Mixed venous oxygen saturation in abdominal aortic surgery: intraoperative hypothermia and vasodilator therapy implications.

This prospective study was designed to test the hypothesis that intraoperative hypothermia occurring during abdominal aortic surgery and vasodilator therapy used to avoid severe consequences of aortic clamping could both disturb the mixed venous oxygen saturation signal (SVO2). Twenty high risk surgical patients, ASA physical status II or III, were catheterized with the standard pulmonary artery catheter; SVO2 was determined by direct spectrophotometric measurements of oxygen haemoglobin concentration of serial samples. The relationships between SVO2, haemodynamic, metabolic variables and core temperature were analyzed. Haemodynamic values and oxygen transport were stable while inadequate tissue oxygenation occurred. A significant correlation was found between SVO2 and CI (r = 0.59, p less than 0.01), SVO2 and SVRI (r = -0.4, p less than 0.01), SVO2 and CT (r = -0.46, p less than 0.01), SVO2 and VO2 (r = -0.76, p less than 0.001). SVO2 and Qs/Qt (r = 0.83, p less than 0.001), SVO2 and EO2 (r = -0.75, p less than 0.001. No correlation was observed between SVO2 and lactacidemia (r = 0.04, p less than 0.05). Satisfactory haemodynamic stability and oxygen transport steady-state were the main conditions for a significant correlation between SVO2 and haemodynamic factors. However, there was no correlation between SVO2 and inadequate tissue oxygenation. SVO2 reflected only oxygen extraction. Intraoperative hypothermia provided an increased haemoglobin affinity for oxygen. Vasodilator therapy which allowed a decrease in systemic vascular resistance produced an increase in the left-right shunt and in venous oxygen admission. Thus hypothermia and vasodilator therapy could be both responsible for the elevated SVO2 occurring during infrarenal abdominal aortic surgery.

Intraoperative glucose infusion and blood lactate: endocrine and metabolic relationships during abdominal aortic surgery.

The hypothesis that increased intraoperative blood lactate depends both on intraoperative glucose supply and inadequate tissue oxygenation occurring during surgery was tested in anesthetized patients undergoing infrarenal abdominal aortic surgery. Twenty surgical patients received either Ringer's solution or 5% glucose solution for intraoperative volume loading. Arterial blood lactate, arterial glucose, hemodynamic variables, insulin, glucagon, cortisol, epinephrine, and norepinephrine were determined preoperatively and intraoperatively. There were no significant changes in hemodynamic values, glucagon, norepinephrine, and epinephrine compared with control values in both groups. Oxygen consumption decreased only during aortic clamping. Cortisol and lactate increased significantly 10 min after aortic clamping until the end in both groups. Glucose 5% solution infusion resulted in significantly greater blood lactate accumulation and significantly greater blood glucose and insulin levels, whereas there were no changes in the patients receiving Ringer's solution. From control until aortic clamping, lactate and glucose were significantly correlated with each other in both groups; after aortic clamping until the end of the procedure, the correlation remained constant in patients in the Ringer's group, whereas no relationship could be demonstrated in those in the glucose group. The authors conclude that intraoperative glucose administration increases intraoperative blood lactate and that blood lactate accumulation depends both on glucose supply and tissue oxygen deficit. Furthermore, none of the hemodynamic metabolic and endocrine factors were reliable for assessing tissue perfusion and metabolic demands during surgery.

Changes in skin thermal clearance during anaesthesia.

Thermal and vascular side effects occurring during general anaesthesia are related to skin blood flow. A new, noninvasive probe which measures skin thermal clearance, a variable closely related to skin blood flow, was used in nine patients under phenoperidine, droperidol, propanidid anaesthesia. Statistically significant increases in skin thermal clearance clearly preceded the drop in mean arterial blood pressure and the rise in skin temperature. It is concluded that general anaesthesia induced an early increase in skin blood flow and that thermal clearance is a better technique than skin thermometry to monitor skin blood flow.

Skin blood flow changes in anaesthetized humans: comparison between skin thermal clearance and finger pulse amplitude measurement.

The effect of general anaesthesia on skin blood flow in the left hand, measured by a new non-invasive probe using the thermal clearance method was examined. A mercury silastic gauge was placed around the third left finger and the plethysmographic wave amplitude was recorded to measure changes in finger pulse amplitude. Heart rate (HR), mean arterial blood pressure (MABP) and skin temperature were also recorded. General anaesthesia was induced by droperidol and phenoperidine injection and propanidid infusion in eight female patients. Skin thermal clearance, plethysmographic wave amplitude, HR, MABP and skin temperature were 0.40 +/- 0.02 w X m-1 degree C-1, 9 +/- 1 mm, 98 +/- 5 beats X min-1, 12.50 +/- 0.93 kPa and 33.3 +/- 3.4 degrees C respectively. The minimal value of MABP was 9.58 +/- 1.06 kPa, whereas skin thermal clearance, plethysmographic wave amplitude, HR and skin temperature increased to 0.45 +/- 0.02 w X m-1 degree C-1, 29 +/- 3 mm, 110 +/- 4 beats X min-1 and 34.4 +/- 0.4 degrees C. Changes in skin thermal clearance correlated well with plethysmographic wave amplitude. Statistically significant changes in these two parameters occurred before significant change in HR, MABP or skin temperature. The results show that the new non-invasive probe using the thermal clearance method appears to be a useful device for measuring cutaneous microcirculation in anaesthetized humans, and responds more quickly than change in skin temperature, which is a delayed effect of skin blood flow change. Our results also show that the intensity of cutaneous vasodilatation induced by general anaesthesia did not relate to the vascular tone before anaesthesia.

[Combination of nitroglycerin and vascular loading in abdominal aorta surgery]. / Association nitroglycérine et remplissage vasculaire dans la chirurgie de l'aorte abdominale.

Haemodynamic investigations were performed in nine patients during aortic surgery for Leriche's syndrome. Most of these patients had ischaemic heart disease without cardiac failure. Fluid loading was carried out before and during aortic clamping. It was controlled according to the optimal wedge pulmonary pressure determined the day before surgery. Only six of the nine patients receive nitroglycerin (NTG : 0.2 micrograms X kg-1 X min-1) throughout the operation. Before clamping, cardiac index was improved in patients treated with NTG. During clamping, the patients not treated with NTG showed a drop in cardiac index, an increase in peripheral resistance and in left cardiac work. After declamping, there were no haemodynamic differences between the two groups. Two patients not treated with NTG developed azotaemia postoperatively; one patient developed cardiac failure requiring a dopamine perfusion during surgery. In this series, the association of optimal volume loading with a peroperative perfusion of 0.2 micrograms X kg-1 X min-1 NTG gave a good haemodynamic stability.