Fatal outcome after heart transplantation caused by Aspergillus lentulus.

Opportunistic invasive fungal infections are a major cause of mortality in immunocompromised patients. Early diagnosis of invasive aspergillosis and proper identification of the causative agent is crucial for guidance of therapy. Accurate differentiation of Aspergillus lentulus, a filamentous fungus often misidentified as atypical Aspergillus fumigatus, is of concern as multiple antifungal drugs show a reduced susceptibility. This is the first report, to our knowledge, of a proven pulmonary invasive fungal infection caused by A. lentulus after heart transplantation.

How useful is routine amniotic fluid and neonatal surface swab microbiology at Caesarean section?

BACKGROUND: Our aim was to evaluate the clinical impact of routine amniotic fluid and neonatal surface swab microbiology at Caesarean section. MATERIALS AND METHODS: Microbiology data from 1 537 neonates delivered by Caesarean section were analysed in the light of clinical outcome. RESULTS: 1 340 (87%) neonates had non-pathogenic bacteria or negative culture results from both amniotic fluid and surface swab samples. Of the 197 (13%) neonates with pathogenic bacteria, 22 (1.4%) were diagnosed with infection, but only in 6 (0.4%) were the bacteria presumed to be responsible for the infection. Amniotic fluid and surface swab culture had sensitivities of 54% and 35%, and positive predictive values of 14% and 17%, respectively, for detecting a neonate at risk of infection. CONCLUSION: Amniotic fluid and neonatal surface swab microbiology at Caesarean section contributes little if anything to postnatal management and can be safely dropped from operative routine.

recA-based PCR assay for accurate differentiation of Streptococcus pneumoniae from other viridans streptococci.

Proper identification of Streptococcus pneumoniae by conventional methods remains problematic. The discriminatory power of the 16S rRNA gene, which can be considered the "gold standard" for molecular identification, is too low to differentiate S. pneumoniae from closely related species such as Streptococcus pseudopneumoniae, Streptococcus mitis, and Streptococcus oralis in the routine clinical laboratory. A 313-bp part of recA was selected on the basis of variability within the S. mitis group, showing <95.8% interspecies homology. In addition, 6 signature nucleotides specific for S. pneumoniae were identified within the 313-bp recA fragment. We show that recA analysis is a useful tool for proper identification to species level within the S. mitis group, in particular, for pneumococci.

Evaluation of the colorimetric VITEK 2 card for identification of gram-negative nonfermentative rods: comparison to 16S rRNA gene sequencing.

Ninety strains of a collection of well-identified clinical isolates of gram-negative nonfermentative rods collected over a period of 5 years were evaluated using the new colorimetric VITEK 2 card. The VITEK 2 colorimetric system identified 53 (59%) of the isolates to the species level and 9 (10%) to the genus level; 28 (31%) isolates were misidentified. An algorithm combining the colorimetric VITEK 2 card and 16S rRNA gene sequencing for adequate identification of gram-negative nonfermentative rods was developed. According to this algorithm, any identification by the colorimetric VITEK 2 card other than Achromobacter xylosoxidans, Acinetobacter sp., Burkholderia cepacia complex, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia should be subjected to 16S rRNA gene sequencing when accurate identification of nonfermentative rods is of concern.

Clinical validation of electromyography and acceleromyography as sensors for muscle relaxation.

BACKGROUND AND OBJECTIVE: The aim of this study was to determine which of two clinically applied methods, electromyography or acceleromyography, was less affected by external disturbances, had a higher sensitivity and which would provide the better input signal for closed loop control of muscle relaxation. METHODS: In 14 adult patients, anaesthesia was induced with intravenous opioids and propofol. The response of the thumb to ulnar nerve stimulation was recorded on the same arm. Mivacurium was used for neuromuscular blockade. Under stable conditions of relaxation, the infusion-rate was decreased and the effects of turning the hand were investigated. RESULTS: Electromyography and acceleromyography both reflected the change of the infusion rate (P = 0.015 and P < 0.001, respectively). Electromyography was significantly less affected by the hand-turn (P = 0.008) than acceleromyography. While zero counts were detected with acceleromyography, electromyography could still detect at least one count in 51.1%. CONCLUSIONS: Electromyography is more reliable for use in daily practice as it is less influenced by external disturbances than acceleromyography.

Model-based control of neuromuscular block using mivacurium: design and clinical verification.

BACKGROUND: Short-acting agents for neuromuscular block (NMB) require frequent dosing adjustments for individual patient's needs. In this study, we verified a new closed-loop controller for mivacurium dosing in clinical trials. METHODS: Fifteen patients were studied. T1% measured with electromyography was used as input signal for the model-based controller. After induction of propofol/opiate anaesthesia, stabilization of baseline electromyography signal was awaited and a bolus of 0.3 mg kg-1 mivacurium was then administered to facilitate endotracheal intubation. Closed-loop infusion was started thereafter, targeting a neuromuscular block of 90%. Setpoint deviation, the number of manual interventions and surgeon's complaints were recorded. Drug use and its variability between and within patients were evaluated. RESULTS: Median time of closed-loop control for the 11 patients included in the data processing was 135 [89-336] min (median [range]). Four patients had to be excluded because of sensor problems. Mean absolute deviation from setpoint was 1.8 +/- 0.9 T1%. Neither manual interventions nor complaints from the surgeons were recorded. Mean necessary mivacurium infusion rate was 7.0 +/- 2.2 microg kg-1 min-1. Intrapatient variability of mean infusion rates over 30-min interval showed high differences up to a factor of 1.8 between highest and lowest requirement in the same patient. CONCLUSIONS: Neuromuscular block can precisely be controlled with mivacurium using our model-based controller. The amount of mivacurium needed to maintain T1% at defined constant levels differed largely between and within patients. Closed-loop control seems therefore advantageous to automatically maintain neuromuscular block at constant levels.

Model-based control of mechanical ventilation: design and clinical validation.

BACKGROUND: We developed a model-based control system using end-tidal carbon dioxide fraction (FE'(CO(2))) to adjust a ventilator during clinical anaesthesia. METHODS: We studied 16 ASA I-II patients (mean age 38 (range 20-59) yr; weight 67 (54-87) kg) during i.v. anaesthesia for elective surgery. After periods of normal ventilation the patients were either hyper- or hypoventilated to assess precision and dynamic behaviour of the control system. These data were compared with a previous group where a fuzzy-logic controller had been used. Responses to different clinical events (invalid carbon dioxide measurement, limb tourniquet release, tube cuff leak, exhaustion of carbon dioxide absorbent, simulation of pulmonary embolism) were also noted. RESULTS: The model-based controller correctly maintained the setpoint. No significant difference was found for the static performance between the two controllers. The dynamic response of the model-based controller was more rapid (P<0.05). The mean rise time after a setpoint increase of 1 vol% was 313 (sd 90) s and 142 (17) s for fuzzy-logic and model-based control, respectively, and after a 1 vol% decrease was 355 (127) s and 177 (36) s, respectively. The new model-based controller had a consistent response to clinical artefacts. CONCLUSION: A model-based FE'(CO(2)) controller can be used in a clinical setting. It reacts appropriately to artefacts, and has a better dynamic response to setpoint changes than a previously described fuzzy-logic controller.

Blood/gas partition coefficients of halothane, isoflurane and sevoflurane in horse blood.

BACKGROUND: Blood/gas partition coefficients (lambda(b/g)) for volatile agents in horse blood are reported for halothane but not for isoflurane and sevoflurane. We measured the lambda(b/g) of halothane, isoflurane and sevoflurane in the blood of fasted horses. The correlation with age, weight and some haematological and biochemical variables was studied. The temperature correction factor for isoflurane solubility was calculated. METHODS: Twenty-four horses were randomly allocated to halothane (n=8), isoflurane (n=8) or sevoflurane (n=8). Blood samples were taken after 10 h' fasting. Calculation of lambda(b/g) was based on the measurement of anaesthetic partial pressures in blood at 37 degrees C, which was achieved with tonometer equilibration and headspace gas chromatography. RESULTS: Mean lambda(b/g) was 1.66 (SD 0.06) for halothane, 0.92 (0.04) for isoflurane, and 0.47 (0.03) for sevoflurane. The lambda(b/g) values were all significantly lower than in humans (P<0.001). No correlation was found between lambda(b/g) and weight, age, haematocrit, plasma triglycerides, cholesterol or total bilirubin. The change in isoflurane solubility per 1 degrees C temperature increase was -2.63 (0.13)%. CONCLUSION: The lambda(b/g) values of halothane, isoflurane and sevoflurane in fasted horses are significantly lower than those reported in humans. The lambda(b/g) for halothane in this study agrees with values reported in the literature but a positive correlation with plasma triglycerides could not be confirmed. Knowledge of lambda(b/g) can refine models of anaesthetic uptake.

Different benefit of bispectal index (BIS) in desflurane and propofol anesthesia.

BACKGROUND: Bispectal index (BIS) monitoring may reduce drug usage and hasten recovery in propofol and inhalation anesthesia. The faster emergence profile of desflurane may reduce the effect of BIS monitoring on recovery from desflurane compared with propofol. This study compared hypnotic drug usage, recovery, patient satisfaction and incidence of inadequate sedation in BIS monitored and nonmonitored women anesthetized with desflurane or propofol. METHODS: One hundred and sixty patients scheduled for elective gynecological surgery were randomly assigned to desflurane or propofol anesthesia with and without BIS monitoring. Fentanyl, vecuronium and remifentanil were administered according to clinical criteria. The BIS monitor was used in all patients, but the monitor screen was covered in the controls. A BIS level between 45 and 55 was targeted in the BIS monitored patients whereas depth of anesthesia was assessed by clinical criteria in the controls. RESULTS: The mean (SD) desflurane MAC-hours administered with and without BIS were 0.70 (0.15) and 0.76 (0.12), respectively, resulting in extubation times of 6.5 (4.1) and 8.3 (6.1) min. (NS). Bispectal index monitoring was associated with improved patient satisfaction, reduced postoperative nausea and antiemetic drug requirement, and fewer episodes with sustained BIS levels > 60. The mean (SD) propofol infusion rates were 6.0 (1.4) and 6.6 (0.9) mg kg(-1)h(-1) with and without the BIS monitor (P = 0.023), resulting in mean (SD) extubation times of 6.8 (4.6) and 10.5 min (5.9), respectively (P < 0.05). CONCLUSION: Bispectal index monitoring reduced propofol usage and hastened recovery after propofol anesthesia, whereas in desflurane anesthesia it was associated with improved patient satisfaction, probably because of decreased postoperative nausea and fewer episodes of inadequate hypnosis.

Prediction of the haemodynamic response to tracheal intubation: comparison of laser-Doppler skin vasomotor reflex and pulse wave reflex.

BACKGROUND: The laser-Doppler skin vasomotor reflex (SVmR) caused by tetanic stimulation of the ulnar nerve may be a test that can predict the haemodynamic response to tracheal intubation. A decrease in pulse wave amplitude (pulse wave reflex, PWR) may be an alternative index of this response. We compared the abilities of PWR and SVmR to predict the haemodynamic response to tracheal intubation and studied how alfentanil, muscle relaxation, stimulation site and stimulation pattern affected the two reflexes. METHODS: Anaesthesia was induced and maintained with 2% sevoflurane and 50% nitrous oxide in two groups of 10 ASA status 1 patients. Tetanic stimuli were applied to the flexor muscles of the forearm and the ulnar nerve before and after administration of vecuronium. The change in skin blood flow (laser-Doppler) and pulse wave amplitude (pulse oximetry) after a 5 and 10 s stimulation was measured on the opposite hand. If skin blood flow (laser-Doppler) decreased by more than 10%, a computer-controlled infusion of alfentanil was started and the target plasma concentration was increased in steps until this response was suppressed (< 10%). The trachea was intubated and arterial pressure and heart rate responses were recorded. Plasma alfentanil concentration was measured. RESULTS: When PWR and SVmR were suppressed, the haemodynamic response to tracheal intubation was reduced in 100 and 53% of patients respectively. PWR and SVmR responses decreased with increasing plasma alfentanil concentration. The SVmR response to muscle stimulation was reduced by muscle relaxants. The pulse wave response to both muscle and neural stimulation was reduced by relaxants. The responses to 5 and 10 s stimulations were similar. CONCLUSION: An absent SVmR does not predict a blunted arterial pressure or heart rate response to tracheal intubation. The PWR may be a better predictor.

Modeling and closed-loop control of hypnosis by means of bispectral index (BIS) with isoflurane.

A model-based closed-loop control system is presented to regulate hypnosis with the volatile anesthetic isoflurane. Hypnosis is assessed by means of the bispectral index (BIS), a processed parameter derived from the electroencephalogram. Isoflurane is administered through a closed-circuit respiratory system. The model for control was identified on a population of 20 healthy volunteers. It consists of three parts: a model for the respiratory system, a pharmacokinetic model and a pharmacodynamic model to predict BIS at the effect compartment. A cascaded internal model controller is employed. The master controller compares the actual BIS and the reference value set by the anesthesiologist and provides expired isoflurane concentration references to the slave controller. The slave controller maneuvers the fresh gas anesthetic concentration entering the respiratory system. The controller is designed to adapt to different respiratory conditions. Anti-windup measures protect against performance degradation in the event of saturation of the input signal. Fault detection schemes in the controller cope with BIS and expired concentration measurement artifacts. The results of clinical studies on humans are presented.

Comparison of five experimental pain tests to measure analgesic effects of alfentanil.

BACKGROUND: Several experimental pain models have been used to measure opioid effects in humans. The aim of the current study was to compare the qualities of five frequently used experimental pain tests to measure opioid effects. METHODS: The increase of electrical, heat, and pressure pain tolerance and the decrease of ice-water and ischemic pain perception was determined at baseline and at four different plasma concentrations of alfentanil (n = 7) administered as target controlled infusion or placebo (n = 7). A linear mixed-effects modeling (NONMEM) was performed to detect drug, placebo, and time effect as well as interindividual and intraindividual variation of effect. RESULTS: Only the electrical, ice-water, and pressure pain tests are sensitive to assess a concentration-response curve of alfentanil. At a plasma alfentanil concentration of 100 ng/ml, the increase in pain tolerance compared with baseline was 42.0% for electrical pain, 22.2% for pressure pain, and 21.7% for ice-water pain. The slope of the linear concentration-response curve had an interindividual coefficient of variation of 58.3% in electrical pain, 35.6% in pressure pain, and 60.0% in ice-water pain. The residual error including intraindividual variation at an alfentanil concentration of 100 ng/ml was 19.4% for electrical pain, 6.1% for pressure pain, and 13.0% for ice-water pain. Electrical pain was affected by a significant placebo effect, and pressure pain was affected by a significant time effect. CONCLUSION: Electrical, pressure, and ice-water pain, but not ischemic and heat pain, provide significant concentration-response curves in the clinically relevant range of 200 ng/ml alfentanil or lower. The power to detect a clinically relevant shift of the curve is similar in the three tests. The appropriate test(s) for pharmacodynamic studies should be chosen according to the investigated drug(s) and the study design.

Central hypersensitivity in chronic pain after whiplash injury.

OBJECTIVE: The mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck. DESIGN: Comparison of patients with healthy controls. SETTING: Pain clinic and laboratory for pain research, university hospital. PATIENTS: Fourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers. OUTCOME MEASURES: Pain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck. RESULTS: The whiplash group had significantly lower pain thresholds for all tests. except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds. CONCLUSIONS: The authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.

Improving regulation of mean arterial blood pressure during anesthesia through estimates of surgery effects.

In this paper, a scheme for improvement of the regulation of mean arterial blood pressure (MAP) during anesthesia based on model predictive control (MPC) and estimates of the effects of disturbances (surgical events) is proposed. A linear model for the combined effects of surgical stimulations and volatile anesthetics on MAP is derived from experimental data. Based on it the potential improvement in blood pressure regulation is evaluated via a simulation study. The simulation study shows that when information about the effect of the surgical events on MAP is utilized by the controller maximum MAP deviations can be reduced by as much as 50% even when this information is inaccurate. At worst, (highly inaccurate information) no improvement is obtained.

Artifact-tolerant controllers for automatic drug delivery in anesthesia.

This article presents a method for treating measurement artifacts in model-based control systems. A nonlinear modification to the usual observer structure is introduced to prevent the measurement artifacts from winding up the controller states. It is shown how stability of the closed loop system can be analyzed and an example of a successful application in a clinical study is provided.

A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia.

BACKGROUND: The authors applied an optimization model (direct search) to find the optimal combination of bupivacaine dose, fentanyl dose, clonidine dose, and infusion rate for continuous postoperative epidural analgesia. METHODS: One hundred ninety patients undergoing 48-h thoracic epidural analgesia after major abdominal surgery were studied. Combinations of the variables of bupivacaine dose, fentanyl dose, clonidine dose, and infusion rate were investigated to optimize the analgesic effect (monitored by verbal descriptor pain score) under restrictions dictated by the incidence and severity of side effects. Six combinations were empirically chosen and investigated. Then a stepwise optimization model was applied to determine subsequent combinations until no decrease in the pain score after three consecutive steps was obtained. RESULTS: Twenty combinations were analyzed. The optimization procedure led to a reduction in the incidence of side effects and in the mean pain scores. The three best combinations of bupivacaine dose (mg/h), fentanyl dose (microg/h), clonidine dose (microg/h), and infusion rate (ml/h) were: 9-21-5-7, 8-30-0-9, and 13-25-0-9, respectively. CONCLUSIONS: Given the variables investigated, the aforementioned combinations may be the optimal ones to provide postoperative analgesia after major abdominal surgery. Using the direct search method, the enormous number of possible combinations of a therapeutic strategy can be reduced to a small number of potentially useful ones. This is accomplished using a scientific rather than an arbitrary procedure.

Model-based automatic feedback control versus human control of end-tidal isoflurane concentration using low-flow anaesthesia.

We studied the clinical use of an automatic feedback control system to adjust the end-tidal anaesthetic concentration with a low-flow method. The end-tidal controller uses two input signals (the end-tidal and inspiratory concentrations) to control the isoflurane concentration in the fresh gas flow, using a model-based algorithm. We studied 22 ASA I-III patients during elective surgery lasting more than 2 h. The anaesthetist was asked to make four step changes of the target end-tidal concentration (+0.3, +0.6, -0.3, -0.6 vol%), either manually (Group A) or by setting the target value for the feedback controller (Group B), and then the control was changed and the step changes were repeated, in a crossover design. Eighty step changes with each control method were compared in terms of response time, maximal overshoot and stability. The automatic control system was more accurate and stable than the human controller for step increases and step decreases, with less overshoot/undershoot and greater stability [e.g. maximal overshoot 14.7 (SD 3.7)% and 18 (8.1)% respectively for +0.6 vol% step changes, and 19.8 (3.7)% and 30.7 (13.2)% respectively for +0.3 vol% step changes]. However, the automatic control system showed a faster response time than the manual method only with large increasing steps (e.g. 149 (32) s and 205 (57) s respectively for +0.6 vol% step changes) and was not different from manual control for decreasing steps. Automatic control of the end-tidal isoflurane concentration can be better than human control in a clinical setting, and this task could be done automatically.

Block of pinprick and cold sensation poorly correlate with relief of postoperative pain during epidural analgesia.

OBJECTIVE: To test the following hypotheses: there is a correlation between spread of epidural analgesia as assessed postoperatively by pinprick/cold test and postoperative pain intensity; block of pinprick/cold sensation is associated with absence of postoperative pain. DESIGN: Correlation analysis on prospectively collected data. SETTING: University hospital. PATIENTS: One hundred patients undergoing major surgery. Consecutive sample. INTERVENTIONS: Patients received an epidural infusion of bupivacaine 1 mg/ml, fentanyl 2 microg/ml, and epinephrine 2 microg/ml for at least 48 hours postoperatively. The infusion rate was adjusted according to pain intensity, occurrence of hypotension, or motor block. OUTCOME MEASURES: Assessments were made on three time points: 20-24 hours, 32-36 hours, and 4248 hours after extubation. Assessments included pinprick and cold sensitivity from C2 to S5, pain intensity (visual analogue scale, VAS) at rest, after cough, and after mobilization. Data were analyzed by multiple regression. RESULTS: VAS significantly decreased with increasing spread (number of dermatomes for which hyposensitivity to pinprick or cold was observed). Spread could explain only 2-5% of the variability of VAS. Absence of both pinprick and cold sensation at all dermatomes corresponding to the surgical wound was frequently associated with pain. A high proportion of patients manifesting an upper level of block above T5 had pain after abdominal surgery. CONCLUSIONS: Spread and efficacy of epidural analgesia as assessed by pinprick and cold stimulation correlate poorly with postoperative pain. These methods are of limited value both as clinical indicators of the efficacy of postoperative pain control and for investigating the effect of epidural drugs and techniques.

Epidural fentanyl, adrenaline and clonidine as adjuvants to local anaesthetics for surgical analgesia: meta-analyses of analgesia and side-effects.

BACKGROUND: The risk/benefit ratio of adding fentanyl, adrenaline and clonidine to epidural local anaesthetics for improving intraoperative analgesia is unclear. This meta-analysis was performed to clarify this issue. METHODS: Trials retrieved by search were considered if they were prospective, controlled, epidural analgesia (without combining general anaesthesia) was planned and occurrence of pain during surgery or side-effects were reported. Papers entered meta-analysis if they reached a predefined minimum quality score. Pooled odds ratios (OR) and confidence intervals (CI) were computed. P < 0.05 was considered as significant. RESULTS: Eighteen trials were included in the analysis for fentanyl. Fentanyl decreased the likelihood of pain (OR = 0.21, 95% CI = 0.15-0.30, P < 0.001) and increased the incidence of pruritus (OR = 5.59, 95% CI = 3.12-10.05, P < 0.001) and sedation (OR = 1.88, 95% CI = 1.19-2.98, P = 0.003), compared to control (local anaesthetic without fentanyl). Fentanyl had no effect on respiratory depression, nausea, vomiting and Apgar score. One case of respiratory depression of a newborn was observed. Because of the very low number of trials selected, evaluation of adrenaline and clonidine was not feasible. CONCLUSION: The analysis of current literature shows that the addition of fentanyl to local anaesthetics for intraoperative epidural analgesia is safe and advantageous. The reduction in the incidence of pain during surgery is quantitatively high and therefore clinically significant. Side-effects are mild. Randomized, controlled trials have to be performed in order to clarify the role of adrenaline and clonidine as epidural adjuvants for surgical analgesia.