[Off label use of recombinant activated factor VII: a practice survey]. / Le facteur VII activé recombinant hors Autorisation de mise sur le marché à l'heure de la tarification à l'activité: enquête de pratique.

OBJECTIVES: To evaluate the impact of local recommendations on off label use of recombinant activated factor VII. TYPE OF STUDY: Observational, retrospective. MATERIAL AND METHODS: Recommendations have been diffused by a local working group in 2004, concerning seven groups of indications (traumatology, cardiac, hepatic and various surgeries, obstetrics, neurology and haematology). Conformity to recommendations was studied according to 4 axes: respect of prescribing procedure, indication, posology, and pre ones required with the administration. RESULTS: There were thirty-one uses from 2004 to 2006. Thirty patients presented a massive haemorrhage (blood products before administration of recombinant activated factor VII expressed in median [min-max]: red blood cell unit=15 [0-37], fresh frozen plasma=11 [0-21]). Gravity score at the admission: SAPSII=55+/-22 (average+/-SD), 87% patients presented haemorrhagic shock. Prescribing procedure was in conformity with recommendations in 45%, indications were correct in 74%, posology in 55%, and 16% of prescriptions were completely conform. CONCLUSION: With the tariffing to the activity reform, the reimbursement of off label use of expensive molecules will depend on the respect of the evidence-based medicine. According to this study, the observance of local recommendations was insufficient. Rationalizing prescriptions for practice improvement seemed to be difficult and challenging.

[Necrotizing bacterial skin and software tissue infection with muscular involvement revealing of cancer of the colon]. / Dermohypodermite bactérienne nécrosante (DHBN) avec atteinte musculaire à Clostridium septicum révélatrice d'un cancer du côlon.

We report the case of a 38-year-old woman with a necrotizing bacterial skin and soft tissue infection with muscular involvement. The clinical picture was similar to a gaseous gangrene of the right lower limb with a septic shock and multiple organ failure, without predisposing factor such as trauma, and necessitating a hip amputation. The primary site of the disease was a perforated colic adenocarcinoma with peritoneal and retroperitoneal infection. The association of necrotizing skin and soft tissue infection with muscular involvement due to Clostridium septicum to a neoplasma is classical and in front of such an infection a neoplasma should be researched.

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.

Detection of new propofol metabolites in human urine using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry techniques.

Using hyphenated analytical techniques, gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a study on minor propofol metabolites in human urine was conducted. These techniques allowed identification of two new phase I metabolites (2-(omega-propanol)-6-isopropylphenol and 2-(omega-propanol)-6-isopropyl-1,4-quinol). In addition, their four corresponding conjugates (three glucuronides and one sulphate) were detected. Thus in human urine at least eight conjugate metabolites are produced, derived from four different aglycones (propofol; 2, 6-diisopropyl-1,4-quinol; 2-(omega-propanol)-6-isopropylphenol and 2-(omega-propanol)-6-isopropyl-1,4-quinol).

[Clinical evaluation of alarm efficieny in intensive care]. / Evaluation clinique de la pertinence des alarmes en réanimation.

OBJECTIVE: To evaluate the efficiency of haemodynamic and respiratory monitoring system by a clinical analysis of the alarms. STUDY DESIGN: Observational prospective study. PATIENTS: 25 patients who presented acute respiratory distress syndrome and who were monitored with haemodynamic and respiratory monitoring. METHODS: Each minute, a bedside clinical observer analysed alarms from the monitoring according to detection or absence to clinical events. Four situations were defined to statistical descriptive analysis: a) false positive (FP); b) true positive (TP); c) false negative (FN); and d) true negative (TN). True positive alarm which induced consequences on patients care were also analysed. RESULTS: 15,013 minutes allowed the recordings of 3,665 alarms, 44% from arterial pressure, 17% from SpO2 and 12% from airways maximal pressure. 46% were false positive alarms inducing a noisy pollution. The positive predictive value PPV = TP/(TP + FP) of these alarms were respectively 51% for arterial pressure, 18% for SpO2 and 100% for Paw. Only 5% of true positive alarms induced consequences on patients care. CONCLUSION: This protocol allowed the evaluation of monitoring efficiency. This kind of evaluation may help to improve monitoring capacity with reducing noisy pollution from false positive alarms.

Initial versus delayed acute renal failure in the intensive care unit. A multicenter prospective epidemiological study. Rhône-Alpes Area Study Group on Acute Renal Failure.

We performed a prospective study in the 28 multidisciplinary intensive care units (ICUs) in the Rhône-Alpes area in France to investigate the role of initial versus delayed occurrence of acute renal failure (ARF) in patient outcome. ARF was defined as a serum creatinine concentration > 300 micromol/L, urine output < 500 ml/24 h (or < 180 ml/8 h), or hemodialysis requirement. Over the 1-yr study period, 1,086 patients presented with ARF on ICU admission or during the first 2 d of ICU stay (Group A; 736 patients), from Day 3 to Day 6 (Group B; 202 patients), or from Day 7 (Group C; 148 patients). The overall hospital mortality rate was 66% (61% in Group A, 71% in Group B, and 81% in Group C; p < 0.0001). Logistic regression analysis of a random sample of 510 patients showed that SAPS II score on ICU admission, number of ARF episodes, previous health status, absence of oliguria, absence of hemodialysis, and absence of ischemic acute tubular necrosis were predictive of patient survival. This model was tested and validated on the basis of the remaining patients. Thus, in this population, late ARF was not a predictive factor for patient outcome.

Respiratory mechanics during laparoscopic cholecystectomy: the effects of the abdominal wall lift.

UNLABELLED: The abdominal wall lift (AWL) has been proposed for laparoscopic cholecystectomy to reduce hemodynamic effects caused by carbon dioxide (CO2) and high intraabdominal pressures (IAP). Data concerning effects of AWL on respiratory mechanics are scant. We therefore used a noninvasive method to evaluate whether the AWL could offset these effects. The PETCO2, airflow, and airway pressure were continuously measured in nine patients undergoing laparoscopic cholecystectomy using an AWL with minimal CO2 insufflation. We used a least-squares method to calculate maximal airway pressure (Pmax), elastance (Ers), and resistances (Rrs) of the respiratory system. After CO2 insufflation, the initiation of AWL resulted in a significantly decreased IAP (from 13 to 6 mm Hg; P < 0.001) and Rrs (from 20.6 to 17.8 cm H2O.L(-1).s(-1); P = 0.029), whereas Ers was partly modified (34.0 to 33.3 cm H2O/L; not significantly different). With AWL, we hypothesized that the diaphragm remained flat and stiff, outweighing the beneficial effect of the decrease of IAP on Ers. PETCO2 significantly increased after AWL and at the end of the procedure. We conclude that AWL partly reverses the impairment of the respiratory mechanics induced by CO2 insufflation during laparoscopic surgery. IMPLICATIONS: The abdominal wall lift (AWL), acting on the abdominal chest wall, had some benefits during laparoscopic surgery by limiting CO2 peritoneal insufflation and several side effects, such as hemodynamics. We examined the consequences of this technique on respiratory mechanics in nine patients undergoing laparoscopic cholecystectomy. Our findings suggest that the AWL decreases intraabdominal pressure and respiratory resistances without a significant effect on respiratory elastance.

Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol.

Previous studies of propofol (2,6-diisopropylphenol) pharmacology have shown that this widely used anaesthetic drug is extensively cleared from the body by conjugation of the parent molecule or its quinol metabolite. On the basis of potential influence of propofol on the metabolism of co-administered agents, many investigators have evaluated the effects of propofol on cytochrome P450 (CYP) activities. CYP isoforms involved in propofol metabolism are not defined. In this study, our objective was to elucidate further the CYP isoforms responsible for the hydroxylation of propofol. Using microsomes from 12 different human livers, we investigated CYP isoforms involved in propofol hydroxylase activity, using selective chemical inhibitors of CYP isoforms, correlation with immunoquantified specific CYP isoform content, immunoinhibition, and 11 functionally active human CYP isoforms expressed in a heterologous system (yeast and human B-lymphoblastoid cells). We found a low variability in the production of the hydroxylated metabolite of propofol, 2,6-diisopropyl-1,4-quinol. This activity was mediated by CYP and followed Michaelis-Menten kinetics with apparent K(M) and Vmax values of 18 microM (95% Cl 15.1-20.1) and 2.6 nmol min-1 mg-1 (95% Cl 2.45-2.68) respectively. Part of the propofol hydroxylase activity was mediated by CYP2C9 in human liver, especially at low substrate concentration. Moreover, propofol was likely to be metabolized by additional isoforms such as CYP2A6, 2C8, 2C18, 2C19 and 1A2, especially when substrate concentrations are high. This low specificity among CYP isoforms may contribute to the low interindividual variability (two-fold) and may contribute to the low level of metabolic drug interactions observed with propofol.

Gas chromatographic-mass spectrometry and gas chromatographic-Fourier transform infrared spectroscopy assay for the simultaneous identification of fentanyl metabolites.

Fentanyl, a synthetic opioid, undergoes important biotransformation to several metabolites. A gas chromatographic-mass spectrometric assay was applied for the simultaneous analysis of fentanyl and its major metabolites in biological samples. The identification of different metabolites was performed by gas chromatography-mass spectrometry (electronic impact and chemical ionisation modes) and gas chromatography-Fourier transform infrared spectroscopy. In the present study, rat and human microsomes incubation mixtures and human urines were analysed. In vitro formation of already known fentanyl metabolites was confirmed. The presence of metabolites not previously detected in human urine is described.

[Correction to the airflow measurement in the presence of a leak between the trachea and endotracheal tube]. / La correction du débit en présence d'une fuite entre trachée et sonde endotrachéale.

PURPOSE: To estimate the leak between the endotracheal tube and the trachea in newborns in order to compensate for errors in airflow measurement and to monitor mechanical variables from pressure and flow signals. METHODS: Assuming that the leak resistance (Rf) is constant during a respiratory cycle, the resistive properties of the endotracheal tube were evaluated. The method was validated in the intensive care unit with a mechanical test lung and assessed on recordings of three newborns during mechanical ventilation for RDS. We have used a least squares method for the estimation of positive end expiratory pressure (PEEP) on both newborns and simulated data. RESULTS: Direct measurements of simulated leak resistances on the mechanical lung are in agreement with our estimation of leak resistances. In newborns, the success of flow correction is evidenced on end inspiratory pauses: corrected flow drops to zero while raw data show a constant nonzero flow. On the simulated lung, the PEEP underestimation with uncorrected flow ranges from 10 to 20 cm H20 while the corresponding, underestimation with corrected flow is less than 2 cm H2O. In newborns, the flow correction shifts the estimated PEEP from negative values (-0.3 +/- 1.3 cm H2O before correction) to positive values (3.6 +/- 0.7 cm H2O after correction) higher than the imposed PEEP (2 cm H2O). CONCLUSIONS: The efficiency of this simple method has been demonstrated. It could be used successfully on adult patients, as there will not be flow correction in the absence of leaks.

A computer program for automatic measurement of respiratory mechanics in artificially ventilated patients.

A program for automatic and periodic determination of respiratory mechanics in artificially ventilated patients is described. Airway pressure and flow signals are obtained from the ventilator in the controlled ventilation mode with constant flow inflation and end-inspiratory pause. Periodically, the program records both signals for a given time and it delimits a ventilatory cycle and its components out of this record. Then, four mechanical parameters of the respiratory system are calculated: (1) Rinit, the resistance obtained with the end-inflation occlusion technique; (2) Ers, the elastance (inspiratory) calculated from the slope of the airway pressure profile during inflation; (3) tau, the expiratory time constant; (4) PEEP, the global positive end expiratory pressure. All parameter measurements have been evaluated in experimental conditions, and are in good agreement with reference values. The complete software includes the display of the signals and of the trends together with automatic disk file backups. An additional program allows one to display the trends again and to create table text files containing all the recorded data for further analysis. The system proved to work in ICU and anaesthesia patients with various ventilators.

Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline.

The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necrosis factor (TNF)-alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-alpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole-blood model in which cytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 micrograms/ml) and phytohemagglutinin (PHA) (5 micrograms/ml) in 1:10 diluted whole blood. The stimulation test was performed in blood from healthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the production of IL-2 is strongly diminished (26-32% of the basal level), followed by diminution of IFN-gamma (30-40%). As expected, of the proinflammatory cytokines TNF was the most strongly suppressed (50% of baseline) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10(-4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate that PTX possesses a much broader spectrum of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent.

Intraoperative chemohyperthermia in the management of digestive cancers. A general review of literature.

Intraoperative chemohyperthermia is a new method in the treatment of peritoneal seedings from digestive cancers, which combines surgery, intraperitoneal chemotherapy (mitomycin C and/or cisplatyl) and peritoneal hyperthermia. After a brief reminder on the general principles concerning high temperature action, a review of literature is made: 5 teams have performed this technique. We differentiate the indications, design features and results of each team. The results show a mean survival after 2 years of 35% (in peritoneal carcinomatosis) up to 78% (in gastric serosal invasion, peritoneal seeding free). The best result of the method is the drying up of cancerous ascites, allowing a more comfortable survival.

[Acute intestinal ischemia after voluntary drug poisoning]. / Ischémie intestinale aiguë dans les suites d'une intoxication médicamenteuse volontaire.

A case is reported of a patient who suffered from ischaemic enteritis after having taken an overdose of several drugs. The 42-year-old woman was found out no more than 7 h after she had taken a mixture of benzodiazepines, tricyclic antidepressants and barbiturates (4 mg.l-1 blood level on admission). She had been lying against a bedpost, resulting in compression of her anterior abdominal wall below the umbilicus, involving her right femoral nerve. There was a severe rhabdomyolysis. Despite clinical improvement, the patient being extubated the following day, her abdomen remained painful and swollen. A CT abdominal scan showed a peritoneal effusion and a distended small bowel. Laparatomy revealed severe ischaemia of the terminal 80 cm of ileum, with some gangrenous areas. This was resected, and a right-sided ileostomy performed. Histopathological examination demonstrated a mucosal necrosis without mesenteric arterial thrombosis. A bilateral pleural effusion occurred during postoperative course, requiring drainage. Thereafter, the clinical course was uneventful, with intestinal continuity being re-established three months later. The femoral paralysis receded spontaneously. It is likely that this unusual postural complication of coma may be attributed to a transient compression of mesenteric vessels.

[Practical aspects of indirect calorimetry in post-anesthesia recovery]. / Aspects pratiques de la calorimétrie indirecte en réanimation.

The application of indirect calorimetry among intensive care patients is usually considered as a complicate technique, owing to the difficulties to interpret the bulk of obtained data. As a matter of fact, the variability of energy expenditure (EE) among these patients leads to prefer continuous measurements. This variability is related to interindividual variations as well as variations in the same patient (variations due to body temperature, activity state, diet-induced thermogenesis...). A computer program of data storage and calculations was developed. It allows: on-line storage as well as numerical and graphic display of VO2, VCO2, RQ and EE; menu-driven storage of all occurring events; automatic suppression of the recordings made after ventilator alarms; graphic printing and metabolic calculations. The two main indications for indirect calorimetry are the determination of actual EE and VO2 monitoring in acute states.

[Regional anticoagulation with citrate in hemodialysis in patients with a high risk for hemorrhage]. / Anticoagulation régionale par le citrate au cours de l'hémodialyse chez les patients à haut risque hémorragique.

During haemodialysis in the patient at high risk for bleeding, heparin cannot be safely used to prevent clotting in the dialysis assembly. Among numerous procedures proposed to reduce the risk for bleeding, Pinnick et al. (N Engl J Med, 308: 258, 1983) proposed the use of citrate as the sole anticoagulant. Citrate toxicity and efficiency were studied during 44 haemodialyses carried out in thirteen patients with a high risk for bleeding or with active bleeding. Three patients had hepatic failure. Two types of citrate solution were used, the trisodium form of citrate (102 mmol.l-1 citrate) or the monosodium form (306 mmol.l-1 citrate). The solutions were infused with a calibrated, pressure insensitive pump, before the dialysis unit at a flow rate of 600 ml.h-1 and 200 ml.h-1 respectively. Sufficient citrate was infused to maintain a clotting time of the blood line and dialyser of more than 18 min. Standard 10% calcium chloride was infused at a constant rate of 7 mg.min-1 into the blood being returned to the patient. The patients were dialysed for 4 h for each haemodialysis with a single-pass system. The dialyses were uncomplicated; no active bleeding was noted. The patient's clotting time was significantly reduced during haemodialysis (18.1 +/- 8.9 min to 14.5 +/- 6.3 min; p less than 0.001). Two-hundred and twenty serum citrate levels were measured. Only nine were above the toxic value of 2 mmol.l-1. No clinical evidence of a decrease in ionized calcium was found: there was no change in the corrected QT intervals and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Corynebacterium JK: surgical infections in non-immunosuppressed patients.

Infection caused by Corynebacterium JK (CJK) has been recently described in immunocompromised patients. To evaluate the frequency of CJK infection among surgical and trauma intensive care patients, all patients with CJK isolations at clinical sites were reviewed. The criteria used were the presence of bacterial infection symptoms, isolation from significant sites and the efficiency of a vancomycin treatment. Eight patients were studied; 3 of them were considered infected, while 5 were judged only colonized. It is concluded that CJK infections can be a clinical problem in surgical trauma patients.