Itraconazole lung concentrations in haematological patients.

Itraconazole distribution is largely dependent on its high liposolubility. Intrapulmonary lung concentrations remain unknown in haematological patients. We report itraconazole lung concentrations in such patients treated with itraconazole. Itraconazole and hydroxyitraconazole were measured by high-performance liquid chromatography in concomitant blood samples and lung post-mortem biopsies (three cases) or lung lobectomy (one case). These itraconazole and metabolite lung concentrations were sufficient to be active on Aspergillus.

[The value of anesthesia consultation in relation to the single preanesthetic visit]. / Intérêt de la consultation d'anesthésie par rapport à la seule visite préanesthésique.

OBJECTIVE: In France, a preanaesthetic assessment (PAA) several days prior to hospital admission for a scheduled surgical or diagnostic procedure under anaesthesia, associated with a preanaesthetic visit (PAV) the day before, are compulsory. This study aimed at comparing the benefits of PAA with those of a PAV not preceded by a PAA. STUDY DESIGN: Prospective, controlled, randomized study. PATIENTS: The study included 296 patients undergoing either a urologic, or ophthalmologic, or ENT procedure, randomly allocated either to a PAA (followed by a PAV) group or a PAV (without previous PAA) group. METHODS: The main criterion of comparison was the duration of preanaesthetic hospital stay and the secondary criteria were the incidence of procedure postponements and patients' satisfaction respectively. RESULTS: In the PAA group, the preanaesthetic hospital stay was shorter by 0.4 days (P = 0.001). Out of the 19 postponed procedures (7%), the cause of postponement was a medical one in 15 patients: 13 in the PAV group and 2 in the PAA group respectively (P = 0.009). The PAA was not considered as a constraint by most patients. CONCLUSION: The PAA shortens the duration of preanaesthetic hospital stay and decreases the incidence of procedures postponed for a medical cause.

[The circulation of anesthetic agents at Edouard-Herriot Hospital]. / Le circuit du médicament en anesthésie à l'hôpital Edouard-Herriot.

In order to improve quality, practice evaluation is a major tool for hospital management. For many years anaesthesia has been monitored by some form of quality assurance programme. However, despite the improvement in anaesthetic techniques, major problems persist, particularly with the use of anaesthetic agents. Drug administration is the first cause for malpractice and death in anaesthesia. The aim of this study was to analyse drug circuits in anaesthesia, with special reference to French regulations. In 13 theatres, doctors and nurse anaesthetists were interviewed by a pharmacist with a focus on following items: prescription, preparation, administration, management, storage, conservation, information, and regulations. Results demonstrated that practice organisation and information transfers were mainly by oral route. The low proportion of written information, especially for preoperative prescription, did not comply with regulations. Nurse anaesthetists were the main actors in drug handling. Common practice patterns throughout the hospital were non existing. In each theatre, a storage of usual drugs for four weeks was found, whereas in pharmacies drugs were stocked for a 2-week period only. Standardised and written procedures, as well as pharmaceutical practice guidelines, are essential for decreasing the risk and improving quality. Such a procedure requires the full participation of anaesthetists and nurses.

[Central venous catheterization...don't forget the caval filter]. / Cathétérisme veineux central ... pensons au filtre cave!

Among the complications of central venous line insertion, entrapment of guidewire by inferior vena cava filter has been exceptionally reported. Usually the disengagement attempts resulted in a filter migration. We report a case of guidewire entrapment successfully treated with interventional radiology techniques.

Acetate-free biofiltration for acute renal failure.

The characteristics of acetate-free biofiltration (AFB) are now well documented in patients with chronic renal failure: hemodynamic tolerance, correction of acid-base imbalance, buffer-free dialysate (without acetate) and absence of backfiltration. This hemodialysis technique can be beneficial to patients with acute renal failure (ARF). In our intensive care unit, we prospectively studied 29 patients with isolated ARF or ARF associated with failure of other organs. All eligible patients were randomly assigned to undergo dialysis with bicarbonate hemodialysis (BH) or with (AFB). All used the same high flux biocompatible dialysis membranes. Effectiveness and hemodynamic tolerance of hemodialysis sessions and evolution of patients were analyzed. Correction of metabolic disorders, although better in the AFB group was not statistically different from that in the BH group. Re-equilibration of acid-base balance was also similar, with or without mechanical ventilation. Heparin consumption was significantly higher in the AFB group, with no effect on haemorrhagic complications. Analysis of hypo- and hypertensive episodes, defined as arterial pressure (AP) variations 20% greater than initial pressure, showed no difference in terms of number or degree of AP variation. However, weight loss and the rate of ultrafiltration led to a higher hypotensive risk in the BH group (p < 0.05). Finally, the clinical course and prognosis was similar in both groups. In summary, AFB may be considered as effective a hemodialysis technique as BH in patients with ARF. Weight loss was better tolerated in the AFB group and can be a favorable factor considering the deleterious effect of overhydration in patients admitted to an intensive care unit. This study invites a comparison of longer dialysis session of AFB therapy and continuous hemodiafiltration.

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie.

BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.

Influence of acute renal failure on FPIA rapid serum assay of midazolam and its main metabolite.

We recently developed a simple and fast assay technique, providing the possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its main and pharmacologically active metabolite, in the serum of sedated ICU patients; this activity referred to as M-like. We identified certain patients in whom M-like activity appeared abnormally high in comparison with HPLC assays. Their common denominators were: long-term sedation with M, and seriously impaired renal function. Further, the conjugates of OM (OMG) accumulated in patients with acute renal failure could contribute to the sedation. We compared the metabolic and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either presenting with normal renal functions (group 1) or with a picture of acute renal failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis was performed before and after hydrolysis of OMG. Before hydrolysis there was a dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results were not different within group 1, while in group 2 the FPIA response exceeded that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in group 2, in each group (vs HPLC) and from one group to another, the FPIA signal (the M-like activity) showed a significant increase. It would be important to take OMG into account as a coprotagonist in sedation whenever circumstances predispose to its accumulation.

CD4 monoclonal antibody administration in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory dermatosis that probably involves a dysregulated activation of helper T cells, type 2 (Th2 cells). Severe refractory AD can be controlled by cyclosporine treatment. OBJECTIVE: We attempted to determine whether short-term CD4 monoclonal antibody (mAb) therapy could improve severe AD in adults. METHODS: The CD4 mAb, B-F5, was infused over 2 days in three patients with severe refractory AD and, for control purposes, in two patients with severe psoriasis. RESULTS: Administration of B-F5 was well tolerated, despite moderate first dose side effects. Clinical improvement was observed in two patients. In the third patient, a dramatic worsening occurred between 8 and 30 days after treatment, associated with an increased percentage of activated CD4+, CD25+, HLA-DR+, and CD45RO+ cells and peripheral blood eosinophilia. The same CD4 mAb administered to two patients with severe psoriasis induced marked clinical improvement of the lesions. CONCLUSION: Although CD4 mAb infusion may be potentially useful in the treatment of AD, the risk of aggravating the Th1/Th2 imbalance in AD should be considered in the design of future protocols.

[Role of non-steroidal anti-inflammatory agents in the perioperative period. Usefulness and limitations]. / Place des anti-inflammatoires non stéroïdiens en période périopératoire. Intérêt et limites.

Nonsteroidal antiinflammatory drugs (NSAIDs), including various chemical families of drugs, inhibit prostaglandin synthesis and act on the central nervous system. Prostaglandins are involved in regulation of regional circulations, cell turn-over in the gastrointestinal tract, and in primary haemostasis. The patterns of action of NSAIDs result in analgesic properties, but also in adverse effects. NSAIDs are increasingly used perioperatively, alone or associated with opioids or local anaesthetics, because of their analgesic and opioid sparing properties. Some of their adverse effects, especially ischaemic acute renal failure and gastrointestinal complications, can be life-threatening, and increased haemorrhagic risk is an issue for spinal or epidural anaesthesia in patients taking aspirin. Safe use of NSAIDs is possible in consideration of contraindications (elderly patient, hypovolaemia, cirrhosis, congestive heart failure, renal failure, active gastrointestinal ulcer, bleeding diathesis, pregnancy), and requires close monitoring of renal function if they must be used in patients at risk for renal failure. NSAIDs are not ulcerogenic in the short-term in healthy subjects. They must be used with caution in patients with a preexisting haemostatic defect or undergoing haemorrhagic surgical procedures.

[Gas embolism during endonasal YAG laser surgery]. / Embolie gazeuse au cours d'une intervention endonasale par laser YAG.

The authors describe a case of air embolism during an endonasal YAG laser surgery in a 10-year-old child. This accident was caused by the coaxial air cooling system of the laser ruby tip. The importance of end tidal CO2 monitoring and precordial auscultation during laser surgery even in patients without risk factors is underlined.

Transesophageal echocardiographic assessment of left ventricular function in brain-dead patients: are marginally acceptable hearts suitable for transplantation?

BACKGROUND: The brain-dead donor supply has become one of the criteria limiting the performance of heart transplantation. Conventional screening criteria are too limiting and exclude suitable heart donors. Echocardiography is now widely available and is a reliable tool to assess left ventricular dysfunction in brain-dead donors. Yet few data are available on the degree of left ventricular dysfunction where a transplantation is possible. METHODS: Fifty-five potential brain-dead heart donors (age 38 +/- 11 years) were prospectively evaluated by transesophageal echocardiography (TEE) before harvesting. Fractional area change (FAC) was used to assess left ventricular function in potential brain-dead donors. Transplanted hearts were evaluated on the fifth postoperative day. The transplantation was considered a success if the recipient was alive, not retransplanted, without an assistance device or an epinephrine infusion of more than 1 mg/h and showed an ejection fraction above 40%. RESULTS: Of the 55 potential heart donors, 20 exhibited an FAC of less than 50%. Forty hearts were harvested, 36 of which were successfully transplanted. Nine patients had an FAC below 50% (group H2) and 27 had an FAC over 50% (group H1). Four patients died: 2 from hemorrhage (FAC > 50% in donors); 1 from right and one from left ventricular dysfunction (FAC < 50% in donors). The FAC increased significantly from 51 +/- 15% to 57 +/- 11% in 18 hearts that underwent TEE in donors and afterwards in recipients. Overall actuarial survival was 86.2% versus 64.6% at 1 and 2 years in group H1 and group H2, respectively (p = NS). CONCLUSIONS: TEE is useful to assess left ventricular function in potential brain-dead donors. An FAC less than 50% is present in 36% of potential heart donors. Because left ventricular dysfunction is often reversible shortly after transplantation, an FAC below 50% may not necessarily preclude the use of hearts for transplantation.

Comparison of high-performance liquid chromatography and polyclonal fluorescence polarization immunoassay for the monitoring of midazolam in the plasma of intensive care unit patients.

Midazolam (M) is used as an induction agent for anesthesia. The main metabolite is alpha-hydroxymidazolam (OM), which is pharmacologically active. Use of M for sedation is a recent application, rapidly gaining favor. Monitoring of the level of sedation is fundamental in that an excessive and prolonged effect is associated with the risk of complications. Thus, it was felt both necessary and useful to measure circulating M levels. We compared a high-performance liquid chromatography (HPLC) assay with fluorescence polarization immunoassay (FPIA) for the measurement of M in the serum of 138 sedated patients in the intensive care unit (i.e., 179 samples). Response of the OM was also assessed. The degree of crossover of the metabolite was between 76.8 and 32.7%. The equation of the regression line for sigma HPLC (i.e., the sum M + OM) versus FPIA was TDx = 1.1585 sigma HPLC + 143.42 (R = 0.966). The 95% confidence interval for the slope was 1.1551, 1.1619. The regression slope differed significantly from 1 (p < 0.001) and shows that FPIA measurements overestimated concentrations obtained by HPLC on the order of 19%. The discrepancy between the two techniques was all the more notable when concentrations were > 1,000 ng/ml. The relative selectivity of Abbott industrial reagent in terms of benzodiazepines leads to the identification of what might be called a midazolam-like (M-like) activity covering both M and OM. The development of a global FPIA method for measurement of this M-like activity in sedated patients provides a satisfactory solution to the question raised.

Concentration of teicoplanin in the serum of adults with end stage chronic renal failure undergoing treatment for infection.

We examined the adequacy of the following schedule for the administration of i.v. teicoplanin to patients with chronic renal failure: three doses of 6 mg/kg at 12 h intervals, a fourth dose 24 h later and then subsequent doses every 72 h. Eight infected patients undergoing dialysis were investigated, with serum antibiotic concentrations measured ten minutes before and one hour after administration. Mean trough concentrations were 6.9 +/- 3.1 mg/L on day two, 9.8 +/- 4.4 mg/L (day three), 9.2 +/- 4.8 mg/L (day six), 10.9 +/- 5.5 mg/L (day nine), 12.1 +/- 6.1 mg/L (day 12) and 14.8 +/- 8.0 mg/L (day 15). The proposed schedule achieved adequate trough serum teicoplanin concentrations by 48 h in six out of eight patients examined. The dosage regimen was well tolerated.

Evaluation of the informed consent procedure in cancer patients candidate to immunotherapy.

By addressing questionnaires to 24 cancer patients candidate to immunotherapy, we evaluated both the effects and the effectiveness of the medical information provided to the patient on their knowledge of the disease and the treatment. Most patients had correctly understood the information but 69% stated that they had been unable to ask all the questions they wished, and 62% required additional information. Most patients admitted to being emotionally distressed throughout the interview. These results are not significantly different from those obtained in patients candidate to new chemotherapy agents, but show that important improvements in the informed consent procedure are required.

Clinical application of retroviral gene transfer in oncology: results of a French study with tumor-infiltrating lymphocytes transduced with the gene of resistance to neomycin.

PURPOSE: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) has been reported to mediate tumor regression in some human cancers. To define better the biologic characteristics of TIL, especially survival and distribution in vivo, we performed a gene-marker study in patients with advanced malignancies. PATIENTS AND METHODS: We treated five patients with metastatic melanoma or renal cell carcinoma with adoptive immunotherapy. TIL were genetically modified, before their infusion, using a recombinant retroviral vector that contained the marker gene coding for resistance to neomycin (NeoR). RESULTS: All of the patients tolerated the treatment well and none of the theoretic safety hazards due to the retroviral gene transduction was observed. The presence of the NeoR gene in TIL was detected by Southern blot analysis, with an efficiency of transduction that ranged from 1% to 26%. With polymerase chain reaction (PCR) analysis, we demonstrated that gene-modified TIL can survive for several months after reinjection, since positive blood samples were observed up to day 260 following reinjection. Eight malignant biopsy specimens were obtained from three patients after cell infusion. TIL were detected in only four of these eight tumor deposits on days 7 and 260. CONCLUSION: These results confirm the feasibility and safety of using in vitro retroviral gene transduction in human lymphocytes to analyze their in vivo distribution for further therapeutic applications. However, a selective and prolonged retention of TIL at the tumor site was not found in this study.

Intensive regimen of cytokines with interleukin-2 and interferon alfa-2b in selected patients with metastatic renal carcinoma.

We conducted a Phase II trial using an intensive regimen combining interleukin-2 (IL2), interferon-alfa-2b (IFN), and lymphokine-activated killer (LAK) cells. The aim of this study was to evaluate the toxicity and the efficacy of this combination in selected patients with metastatic renal cell carcinoma. Thirty-one assessable patients were treated with at least one cycle of a regimen consisting of 20 x 10(6) IU/day s.c. IFN for 5 days, followed 2 days later by i.v. injections of 24 x 10(6) IU/m2/day IL2 every 8 h together with i.v. bolus of 5 x 10(6) IU/m2/day IFN every 8 h during 5 days. After a 6-day break, during which four leukophereses were performed, this i.v. combination was administered along with the LAK cell reinjections for a maximum of 5 days. Twenty-seven patients underwent the two parts of the first course of treatment; respectively, 42% and 46% of the planned dose of IL2 and IFN were administered. Several severe toxicities were observed including two treatment-related deaths. Significant tumor responses were observed in seven patients, including two complete remissions. Two of these patients remain alive without evidence of disease 36 and 40 months after treatment, respectively. This intensive regimen of IL2 together with IFN and LAK cells cannot be recommended even in selected patients with metastatic renal cell carcinoma. In addition, our results argue against the concept of a dose-response relationship in this setting.