Increased risk of arterial thromboembolic events after Staphylococcus aureus bacteremia: A matched cohort study.

OBJECTIVES: An association between infection and arterial thromboembolic events (ATE) has been suggested. Here we examined the risk of myocardial infarction (MI), stroke and other ATE after Staphylococcus aureus bacteremia (SAB). METHODS: Danish register-based nation-wide observational cohort study between 1995 and 2008 with matched control subjects from the general population. RESULTS: Within a year, 278 of 15,669 SAB patients and 2570 of 156,690 controls developed MI, stroke or another ATE. The incidence rates among SAB patients were highest within the first 30 days and decreased over a year. The adjusted relative risk of MI, stroke and other ATE during the first 30 days after SAB in patients compared to controls were 2.2 (95% CI: 1.6-3.1), 5.5 (95% CI: 3.8-8.3) and 15.5 (95% CI: 6.9-35), respectively. Compared to controls, the increased adjusted relative risk persisted for 30 days for MI, 180 days for stroke and one year for other ATE. Increasing age, hypertension, atrial flutter/fibrillation, prior ATE and endocarditis in SAB patients were associated with an increased risk of ATE. CONCLUSIONS: SAB was associated with a short-term increased risk of ATE that persisted longer dependent on type of event. Studies are warranted to investigate treatment strategies to diminish ATE after SAB.

Increased risk of venous thromboembolism within the first year after Staphylococcus aureus bacteraemia: a nationwide observational matched cohort study.

OBJECTIVES: Recent evidence suggests that there is an association between infection and venous thromboembolism (VTE). Here, we examined the risk of VTE after Staphylococcus aureus bacteraemia (SAB) compared to the risk in control subjects. DESIGN AND SETTING: Register-based nationwide observational cohort study of hospitalized patients and matched control subjects from the general population in Denmark between 1995 and 2008. RESULTS: Amongst 15 669 SAB cases and 156 690 controls, 182 and 511, respectively, experienced VTE within 1 year. The overall incidence rate (IR) of VTE amongst cases was highest within the first 30 days [IR of deep vein thrombosis (DVT), 39.3 (95% confidence interval (CI) 28.9-53.4)/1000 person-years (PYs); IR of pulmonary embolism (PE), 16.3 (95% CI 10.1-26.2)/1000 PYs]. IRs of DVT were particularly increased amongst cases with a previous diagnosis of VTE, community-acquired infection, a history of injection drug use and in younger age groups. The overall hazard ratio of VTE for cases compared to controls declined from 15.6 (95% CI 10.3-23.5) in the first 30 days after SAB to 4.5 (95% CI 3.2-6.2) from 181 to 365 days after infection. The increased risk of VTE amongst SAB patients persisted after excluding cases with identified VTE risk factors. CONCLUSIONS: There was a particularly high risk of VTE during the first month following an episode of SAB. The risk declined over time, but remained at a threefold increased level compared to control subjects, suggesting that there are shared risk factors for SAB and VTE. Patients with SAB and well-documented risk factors for VTE may benefit from thromboprophylaxis.

Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis.

BACKGROUND: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype. METHODS: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12h after clarithromycin 500 mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension. RESULTS: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 µg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4 µg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05). CONCLUSION: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity.

Propofol-remifentanil or sevoflurane for children undergoing magnetic resonance imaging? A randomised study.

BACKGROUND: Magnetic resonance imaging (MRI) of children is generally performed under sedation or with general anaesthesia (GA), but the ideal regimen has not been found. The aim of this study was to see if propofol-remifentanil would be a suitable alternative for the maintenance of anaesthesia in this category of patients. PATIENTS AND METHODS: Children aged 1-10 years, American Society of Anesthesiologists physical status 1-2 were included. After induction with thiopental or sevoflurane, the children were randomised to maintenance of anaesthesia with an infusion of propofol and remifentanil (group PR) (56 µg/kg/min of propofol and 0.06 µg/kg/min of remifentanil) or with sevoflurane 1.3 MAC (group S). A binasal catheter was placed in group PR and a laryngeal mask airway in group S. The children breathed spontaneously. The Paediatric Anaesthesia Emergence Delirium (PAED) score (primary end point), the number of movements during MRI, and the length of stay in the recovery room (secondary endpoints) were recorded. RESULTS: Sixty children were included in each group. A lower level of emergence delirium (measured as a lower PAED score) was found in group PR compared with group S, and the children in group PR were discharged earlier from the recovery room than the children in group S. However, 15 children in group PR vs. 0 in group S moved during the scan (P < 0.001). CONCLUSION: The PR infusion ensured a satisfactory stay in the recovery room, but additional boluses were necessary during the MRI. Sevoflurane was reliable during the MRI, but emergence delirium was a concern.

A nationwide study of comorbidity and risk of reinfection after Staphylococcus aureus bacteraemia.

BACKGROUND: Data on risk factors and rates of reinfection associated with Staphylococcus aureus bacteraemia (SAB) are sparse. METHODS: We conducted a nationwide cohort study of cases of SAB diagnosed between 1995 and 2008. Reinfection was defined as an episode of SAB more than 90 days after the initial episode of SAB. Comorbidity was evaluated by the Charlson Comorbidity Index (CCI). Cox proportional hazards modelling was used to estimate hazard rates (HR). RESULTS: Of 10,891 eligible patients, 774 (7.1%) experienced reinfection a median of 458 days (range 90-5021 days) after their primary SAB episode corresponding to a reinfection rate of 1459 (95% confidence interval (CI): 1357-1562) per 100,000 personyears. In multivariate analysis, sex, origin, a vascular or peritoneal device, endocarditis and comorbidity were associated with reinfection. The association was more than two-fold higher among patients in dialysis and for patients with severe comorbidity (CCI ≥ 2). HIV infection (Hazard ratio (HR) 6.18, 95% CI: 4.17-9.16), renal disease (HR 3.92, 95% CI: 3.22-4.78), diabetes with complications (HR 2.11, 95% CI: 1.69-2.62), diabetes without complications (HR 1.61, 95% CI: 1.34-1.93), mild (HR: 1.94, 95% CI: 1.36-2.76) and severe liver disease (HR 2.08, 95% CI: 1.08-4.03), peptic ulcer (HR 1.33, 95% CI: 1.03-1.72), and paraplegia (HR 2.15, 95% CI: 1.02-4.54) were each associated with an increased risk of reinfection. CONCLUSIONS: Patients with previous SAB have a 60-fold higher risk of SAB compared to the general population. Patients with HIV infection, renal disease, diabetes, liver disease, peptic ulcer and paraplegia had the highest rates of reinfection.

Quality-of-care initiative in patients treated surgically for perforated peptic ulcer.

BACKGROUND: Mortality and morbidity are considerable after treatment for perforated peptic ulcer (PPU). Since 2003, a Danish nationwide quality-of-care (QOC) improvement initiative has focused on reducing preoperative delay, and improving perioperative monitoring and care for patients with PPU. The present study reports the results of this initiative. METHODS: This was a nationwide cohort study based on prospectively collected data, involving all hospitals caring for patients with PPU in Denmark. Details of patients treated surgically for PPU between September 2004 and August 2011 were reported to the Danish Clinical Register of Emergency Surgery. Changes in baseline patient characteristics and in seven QOC indicators are presented, including relative risks (RRs) for achievement of the indicators. RESULTS: The study included 2989 patients. An increasing number fulfilled the following four QOC indicators in 2010-2011 compared with the first 2 years of monitoring: preoperative delay no more than 6 h (59·0 versus 54·0 per cent; P = 0·030), daily monitoring of bodyweight (48·0 versus 29·0 per cent; P < 0·001), daily monitoring of fluid balance (79·0 versus 74·0 per cent; P = 0·010) and daily monitoring of vital signs (80·0 versus 68·0 per cent; P < 0·001). A lower proportion of patients had discontinuation of routine prophylactic antibiotics (82·0 versus 90·0 per cent; P < 0·001). Adjusted 30-day mortality decreased non-significantly from 2005-2006 to 2010-2011 (adjusted RR 0·87, 95 per cent confidence interval 0·76 to 1·00), whereas the rate of reoperative surgery remained unchanged (adjusted RR 0·98, 0·78 to 1·23). CONCLUSION: This nationwide quality improvement initiative was associated with reduced preoperative delay and improved perioperative monitoring in patients with PPU. A non-significant improvement was seen in 30-day mortality.

Scandinavian clinical practice guidelines on general anaesthesia for emergency situations.

Emergency patients need special considerations and the number and severity of complications from general anaesthesia can be higher than during scheduled procedures. Guidelines are therefore needed. The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine appointed a working group to develop guidelines based on literature searches to assess evidence, and a consensus meeting was held. Consensus opinion was used in the many topics where high-grade evidence was unavailable. The recommendations include the following: anaesthesia for emergency patients should be given by, or under very close supervision by, experienced anaesthesiologists. Problems with the airway and the circulation must be anticipated. The risk of aspiration must be judged for each patient. Pre-operative gastric emptying is rarely indicated. For pre-oxygenation, either tidal volume breathing for 3 min or eight deep breaths over 60 s and oxygen flow 10 l/min should be used. Pre-oxygenation in the obese patients should be performed in the head-up position. The use of cricoid pressure is not considered mandatory, but can be used on individual judgement. The hypnotic drug has a minor influence on intubation conditions, and should be chosen on other grounds. Ketamine should be considered in haemodynamically compromised patients. Opioids may be used to reduce the stress response following intubation. For optimal intubation conditions, succinylcholine 1-1.5 mg/kg is preferred. Outside the operation room, rapid sequence intubation is also considered the safest method. For all patients, precautions to avoid aspiration and other complications must also be considered at the end of anaesthesia.

Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia between 1981 and 2000.

Staphylococcus aureus is a leading cause of bacteraemia. This study analysed temporal trends from 18,702 adult cases of S. aureus bacteraemia in Denmark between 1981 and 2000. After stratification for mode of acquisition, 57% of cases were hospital-acquired (HA), 28% were community-acquired (CA) and 15% were of undetermined acquisition (UA). Incidence rates increased from 18.2 to 30.5 cases/100,000 population. Annual rates increased by 6.4% for CA, by 2.2% for HA and by 3.6% for UA cases, respectively. Case-mortality associated with HA bacteraemia decreased from 36.2% to 20.7% (43% rate reduction, p 0.0001), compared with a decrease from 34.5% to 26.5% (23% rate reduction, p 0.0001) for CA bacteraemia. Following multivariate analysis, age, pneumonia, endocarditis and chronic illness were associated with increased mortality, regardless of the mode of acquisition. Overall, mortality associated with S. aureus bacteraemia declined significantly between 1981 and 2000, but incidence rates doubled, so that the total number of deaths increased. These data emphasise the public health importance of S. aureus bacteraemia and the need for further preventive measures and improved care in order to reduce incidence rates and improve outcomes.

Importance of focus identification in the treatment of Staphylococcus aureus bacteraemia.

Staphylococcus aureus bacteraemia increases in frequency, and it is still a life-threatening disease. In recent years, some interesting studies such as the need for focus identification and the focus eradication have been performed. The aim of this review is to present an up-to-date assessment of the current challenges in the management of S. aureus bacteraemia in order to improve the outcome.

Direct identification and susceptibility testing of enteric bacilli from positive blood cultures using VITEK (GNI+/GNS-GA).

OBJECTIVE: To study the possibility of reporting results of identification and susceptibility testing of Gram-negative bacilli the same day as bacteremia is detected by using direct inoculation from positive blood cultures (Bactec 9240) into VITEK GNI+ and GNS-GA cards. METHODS: All blood cultures with Gram-negative enteric bacillus-like morphology on microscopy found to be positive on workdays between 15 June 1999 and 29 February 2000 were included. Identification and susceptibility testing were done by three methods: the direct method using a suspension made by differential centrifugation of positive blood culture broth for inoculation of the VITEK cards; the standard method using an inoculum made from an overnight culture on a solid media; and the routine method (reference method) using conventional testing. RESULTS: Of 169 isolates, the direct method resulted in 75% correct identifications, 9% misidentifications and 17% non-identifications. All misidentified isolates were Escherichia coli, of which 80% were reported as Salmonella arizonae. Five biochemical tests yielded most of the aberrant results; correcting the citrate and malonate reactions in most cases led to correct identification by the VITEK database. Despite a negative H2S reaction, 11 E. coli isolates were reported as S. arizonae. Two-thirds (69%) of identifications were reported within 6 h, and 95% of these were correct. The direct susceptibility testing method was assessable for 140 isolates. Correct results were found in 99% of isolate-antimicrobial combinations, and 85% were reported within 6 h. CONCLUSION: The direct VITEK method could correctly report identifications and susceptibility patterns within 6 h, making same-day reporting possible for almost two-thirds (63%) of bacteremic episodes with Gram-negative bacilli. These results could probably be improved by modification of the identification algorithms of the VITEK software.

Adhyperforin as a contributor to the effect of Hypericum perforatum L. in biochemical models of antidepressant activity.

The present paper describe investigations which demonstrate that hyperforin is not the only phloroglucinol derivative in extracts of the medicinal plant Hypericum perforatum L., which possess a biological activity. Hyperforin was the major lipophilic constituent in two different extracts, whereas the amount of adhyperforin was approximately 10 times lower. Adhyperforin, like hyperforin, is a potent inhibitor of the uptake of dopamine, serotonin and noradrenaline. Neither hyperforin nor adhyperforin inhibited binding of the cocaine analogue, [3H]WIN 35,428 to the dopamine transporter. However, the known antidepressives imipramine, nomifensine and fluoxetine all inhibited binding of [3H]WIN 35,428, indicating that hyperforin and adhyperforin do not bind to the same site on the dopamine transporter as these compounds. Furthermore, hyperforin and adhyperforin did not prevent dopamine binding, but inhibited dopamine translocation. Our studies further support recent reports suggesting that the effect of hyperforin on uptake of monoamines is probably not caused by a direct effect of hyperforin on known sites on the transporters.

A case of Moraxella canis-associated wound infection.

Moraxella canis was isolated from an infected foot ulcer in a patient suffering from diabetes mellitus with neuropathy. Bacteriological findings and 16S rDNA data are presented.

Risk factors for hospital-acquired Staphylococcus aureus bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) acquired in hospitals continues to be a frequent and serious complication to hospitalization, and no previous case-control studies dealing with risk factors of this severe disease are available. METHODS: Based on a 1-year prospective analysis, the data from all patients with hospital-acquired SAB admitted to 4 hospitals in Copenhagen County, Denmark, from May 1, 1994, through April 30, 1995, were evaluated. Eighty-five patients with hospital-acquired SAB were matched to 85 control patients with a similar primary diagnosis at admission (matched controls). Of these, 62 patients with hospital-acquired SAB were compared with 118 other patients with a similar time of admission, who were randomly selected with no clinical evidence of SAB (unmatched controls). RESULTS: The incidence of hospital-acquired SAB was 0.71 per 1000 hospital admissions. The presence of a central venous catheter (odds ratio, 6.9; 95% confidence interval [CI], 2.8-17.0), anemia (odds ratio, 3.3; 95% CI, 1.4-7.6), and hyponatremia (odds ratio, 3.3; 95% CI, 1.5-7.0) was significantly associated with hospital-acquired SAB in a conditional and a usual logistic regression analysis. Nasal carriage was not an independent risk factor, but nasal carriers among patients in surgery (odds ratio, 4.0; 95% CI, 1.3-13.0) had a significantly higher risk for hospital-acquired SAB compared with matched and unmatched controls. The presence of hospital-acquired SAB increased the mortality rate 2.4-fold (95% CI, 1.1-5.2). CONCLUSIONS: The presence of a central venous catheter is an important risk factor, and hyponatremia and anemia are associated with the development of hospital-acquired SAB. Furthermore, hospital-acquired SAB in itself increases mortality.

Bacteremic Staphylococcus aureus spondylitis.

BACKGROUND: The incidence of hematogenous Staphylococcus aureus osteomyelitis of the vertebral column is rapidly increasing and few studies dealing with the diagnosis, treatment, and outcome of this severe disease are available. METHODS: Based on a nationwide registration, the clinical and bacteriological data were reviewed from 133 cases with a positive blood culture for S aureus and symptoms of vertebral osteomyelitis in Denmark for the period 1980 to 1990. RESULTS: The 133 cases of vertebral S aureus osteomyelitis reviewed were mainly community-acquired infections (82%) in older patients (median age, 65 years) and often occurred with underlying diseases. Both symptoms and laboratory values were relatively unspecific. Bone scan methods proved to be more optimal for diagnosis of vertebral S aureus osteomyelitis in the early stages compared with conventional radiography that proved a lack of consistency in the formative stages. The infection was mostly (70%) localized in the lower part of the column. The recurrence rate and rate of therapeutic failure depended on the duration and dosage of penicillinase-stable penicillins, respectively. Patients treated with fusidic acid in addition to penicillinase-stable penicillins had a significantly lower recurrence rate. Based on these findings, we recommend treatment with penicillinase-stable penicillins and fusidic acid for a total of 8 weeks, with a daily dosage of penicillinase-stable penicillins higher than 4 g. CONCLUSIONS: The diagnosis of vertebral S aureus osteomyelitis based on clinical findings is difficult to ascertain. Bone scans are necessary because radiographic methods do not detect disease as early. Treatment with penicillinase-stable penicillins, at least 4 g/d for at least 8 weeks, is recommended.

Intravenous versus intraperitoneal morphine before surgery to provide postoperative pain relief.

BACKGROUND: Opioid receptors have been demonstrated on peripheral afferent nerves throughout the body. The aim of the present study was to compare the effects of intravenous and intraperitoneal administration of morphine with regard to pain, postoperative morphine requirement, and recovery after major abdominal surgery, and to describe the pharmacokinetics of intraperitoneal morphine in humans. METHODS: In a double-blind manner, 30 patients scheduled for major abdominal surgery were randomized to either 50 mg of morphine intravenously (i.v.) or 50 mg of morphine intraperitoneally (i.p.) before operation. Pain was measured on a visual analogue scale and morphine requirements were registered for 3 days. Recovery was measured as time to oral intake of food, time to flatulence and days in hospital. Plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations were determined during the first 4 h after morphine administration. RESULTS: During the first postoperative hours there was less pain at rest (P = 0.02) and on coughing (P = 0.004) in the intravenous group. The requirement of additional morphine (P = 0.016) was lower in the intravenous group during the first postoperative day. No major differences in recovery were seen. The plasma concentrations of morphine measured as area under the curve (AUC) during the first 4 h were similar, but the intravenous group showed significantly higher concentrations of the active metabolite morphine-6-glucuronide, (P = 0.016), indicating a difference in pharmacokinetics after intraperitoneal compared to intravenous administration of morphine. CONCLUSION: Intraperitoneal administration of 50 mg of morphine before major abdominal surgery is less efficient in reducing pain and postoperative morphine requirements than the same amount of morphine given intravenously.

Increasing frequency of vertebral osteomyelitis following Staphylococcus aureus bacteraemia in Denmark 1980-1990.

From 1980 to 1990, 309 cases of haematogenous osteomyelitis were identified in Denmark. Haematogenous osteomyelitis of the vertebral column increased significantly (P < 0.01) from the first to the second half of the period due to an increased number of patients > 50 years of age with community-acquired infection. Vertebral osteomyelitis differed significantly from osteomyelitis of other bones in accordance to age distribution (median 66 vs. 16 years), male/female ratio (75/71 vs. 105/ 58) and patients with diabetes (13% vs. 6%). We found a higher risk of haematogenous osteomyelitis in patients > 50 years of age and among patients with community-acquired infection. The highest incidence (5%) of vertebral osteomyelitis in Staphylococcus aureus bacteraemia in this age group was found in cases without an identified portal of entry. The highest incidence (34%) of osteomyelitis of other bones was found in community-acquired cases in the age group 1-20 years and without an identified portal of entry. The present study discusses reasons for the continued increase of vertebral osteomyelitis among adults and describes incidence rates and major risk factors for developing haematogenous osteomyelitis among patients with S. aureus bacteraemia. We suggest that the localization of haematogenous S. aureus osteomyelitis is connected with the presence of red bone marrow.

A 6-month prospective study of hospital-acquired bacteremia in Copenhagen county.

During a 6-month period, 892 positive blood cultures were detected in the Copenhagen County hospitals. 302 (34%) were regarded as contaminations, and of the remaining cases 419 (71%) were community-acquired and 171 (29%) hospital-acquired, giving incidence rates of 6.8/1,000 admissions and 2.8/1,000 admissions, respectively. Both frequency and rate of hospital-acquired bacteremia were lower compared to most other studies. E. coli was more commonly found in community-acquired infections, while coagulase-negative staphylococci were the organisms most often considered as a contaminant. The main causative organisms in hospital-acquired infections were S. aureus (n = 37) and E. coli (n = 34). The proportion of polymicrobial bacteremias in this study was lower compared to most other studies (8%). E. coli from hospital-acquired infections were resistant to ampicillin in 42% of cases, but other Enterobacteriaceae showed higher percentage of resistance to beta-lactam antibiotics. S. aureus was penicillin-resistant in 92% of cases, but no methicillin-resistant strains were isolated. The frequency of antibiotic resistance was low compared to reports from other countries. A total of 136 hospital-acquired cases were followed prospectively. 61% of the patients were male and 46% were > or = 60 years of age. Most patients had predisposing diseases, 90% had foreign body and/or recent surgery performed, and 74 (54%) had an intraveneous catheter. The portal of entry was known in 132 (97%) of the cases, the most common being the urinary tract (42%), followed by an intravenous catheter (30%). The prevalence of urinary tract catheters gave an increased number of cases with E. coli bacteremia. The mortality was 16%.

A comparison of propofol and isoflurane anaesthesia: the need for ephedrine and glycopyrrolate.

Sixty patients, ASA I-III, presenting for elective colonic surgery were studied to assess the stability of blood pressure and heart rate during anaesthesia with three equally potent anaesthetic techniques. Patients in group I (n = 20) received thiopentone induction, isoflurane and nitrous oxide; patients in group II (n = 20) received total intravenous anaesthesia with propofol; and patients in group III (n = 20) received intravenous propofol supplemented with nitrous oxide. Fentanyl and vecuronium were used in all three groups. The depth of anaesthesia was judged on clinical signs of adequate anaesthesia. Episodes of bradycardia (heart rate < 50 beats min-1), tachycardia (heart rate > 90 beats min-1), hypotension (mean arterial pressure > or = 30% below pre-operative blood pressure) or hypertension (mean arterial pressure > 30%, or systolic blood pressure > 15 mmHg, above pre-operative value) were recorded when lasting > 5 min. Any use of ephedrine or glycopyrrolate given to correct hypotension or bradycardia was documented: In group II, significantly more patients were given ephedrine (P < 0.01) to treat hypotension. The drug was administered after intubation but before skin incision in the majority of cases (9/11). Glycopyrrolate was given to significantly more patients in group III (P < 0.025) to treat bradycardia, and in 21 of a total of 34 patients given glycopyrrolate it was administered before surgery. With the use of these additional drugs, there were no differences in the number of patients with 5 min episodes of hypotension, hypertension, tachycardia or bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

A random trial comparing recovery after midazolam-alfentanil anesthesia with and without reversal with flumazenil, and standardized neurolept anesthesia for major gynecologic surgery.

STUDY OBJECTIVE: To compare the recovery characteristics of total intravenous anesthesia (TIVA) using midazolam-alfentanil, with or without reversal with flumazenil to a standardized neurolept anesthesia with nitrous oxide (N2O). DESIGN: Randomized, double-blinded clinical study. SETTING: University medical center. PATIENTS: 80 ASA physical status I and II women scheduled for major elective gynecologic surgery. INTERVENTIONS: Patients were anesthetized with one of three different anesthetic techniques. Patients in the TIVA group with reversal received midazolam-alfentanil reversed with flumazenil (Group 1), the TIVA group without reversal received midazolam-alfentanil reversed with placebo (Group 2), and patients in the neurolept group received anesthesia using thiopental sodium, droperidol, fentanyl, and N2O (Group 3). MEASUREMENTS AND MAIN RESULTS: Recovery was assessed by an observer blinded to the treatment allocation, using a Modified Steward Recovery Score and judgment of orientation and comprehension, collaboration and degree of sedation for the first 4 hours after extubation. Arterial blood gases were measured 30 minutes after extubation. A questionnaire regarding the degree of perioperative amnesia was presented to the patients 4 and 24 hours after surgery. The recovery scores were better in the TIVA group with reversal than in the other two groups from 0 to 30 minutes postoperatively. No difference between the groups could be found thereafter, although after 30 minutes some resedation occurred in the TIVA group with reversal. The median injected amount of flumazenil in Group 1 was 0.5 mg. Respiratory depression (breathing frequency below 10 breaths/min) was reversed with naloxone in one patient in the TIVA group with reversal, five patients in the TIVA group without reversal, and no patient in the neurolept group (p < 0.001). On blood gas analysis, there was no evidence of hypoxemia or carbon dioxide retention. No difference was seen between the groups regarding consumption of analgesics, degree of amnesia, or patient rating of the quality of anesthesia. One patient in Group 2, however, recorded awareness at skin incision when questioned 4 hours after the operation, but could not recall this 20 hours later. CONCLUSIONS: TIVA with midazolam and alfentanil can be used for major gynecologic surgery. Recovery in the neurolept group was equal to recovery in the TIVA group without reversal, and flumazenil improves the recovery after midazolam anesthesia. Overall, in comparison with the neurolept technique no major advantage could be demonstrated using TIVA with midazolam-alfentanil.