Propofol versus flunitrazepam for inducing and maintaining sleep in postoperative ICU patients.

CONTEXT: Sleep deprivation is a common problem on intensive care units (ICUs) influencing not only cognition, but also cellular functions. An appropriate sleep-wake cycle should therefore be maintained to improve patients' outcome. Multiple disruptive factors on ICUs necessitate the administration of sedating and sleep-promoting drugs for patients who are not analgo-sedated. AIMS: The objective of the present study was to evaluate sleep quantity and sleep quality in ICU patients receiving either propofol or flunitrazepam. SETTINGS AND DESIGN: Monocentric, randomized, double-blinded trial. MATERIALS AND METHODS: A total of 66 ICU patients were enrolled in the study (flunitrazepam n = 32, propofol n = 34). Propofol was injected continuously (2 mg/kg/h), flunitrazepam as a bolus dose (0.015 mg/kg). Differences between groups were evaluated using a standardized sleep diary and the bispectral index (BIS). STATISTICAL ANALYSIS USED: Group comparisons were performed by Mann-Whitney U-Test. P < 0.05 was considered to be statistically significant. RESULTS: Sleep quality and the frequency of awakenings were significantly better in the propofol group (Pg). In the same group lower BIS values were recorded (median BIS propofol 74.05, flunitrazepam 78.7 [P = 0.016]). BIS values had to be classified predominantly to slow-wave sleep under propofol and light sleep after administration of flunitrazepam. Sleep quality improved in the Pg with decreasing frequency of awakenings and in the flunitrazepam group with increasing sleep duration. CONCLUSIONS: Continuous low-dose injection of propofol for promoting and maintaining night sleep in ICU patients who are not analgo-sedated was superior to flunitrazepam regarding sleep quality and sleep structure.

Do variations in the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B) influence the occurrence of postoperative vomiting?

BACKGROUND: Postoperative nausea and vomiting are unpleasant side effects of general anesthesia. Besides known risk factors (female gender, nonsmoker, history, and opioids), a genetic influence of the serotonin receptor system on the development of nausea and vomiting has repeatedly been proposed. In this pilot study, we therefore investigated the genes of the serotonin receptor subunits A and B (HTR3A and HTR3B) for genetic variants. METHODS: We included 95 patients who had suffered from postoperative vomiting (POV) after general anesthesia and 94 control patients. After DNA isolation, the entire HTR3A and HTR3B coding regions, the 5' flanking regions, and exon/intron boundaries were screened for genetic variants. Correlation of identified genetic variants with POV was determined by logistic regression. RESULTS: We identified 16 different variants in the HTR3A gene and 19 in the HTR3B gene. By using a multivariate logistic regression model that also included classical risk factors, the HTR3A variant c1377A>G was associated with a significantly higher risk (odds ratio [OR] 2.972; 95% confidence interval [CI] 1.466-6.021; P = 0.003) and the HTR3B variants c5+201_+202delCA (OR 0.421; 95% CI 0.257-0.69; P = 0.001) and c6-137C>T (OR 0.034; 95% CI 0.003-0.332; P = 0.004) were associated with a lower risk for POV. However, all significant genetic variants were located in noncoding regions of their gene. CONCLUSIONS: Genetic variations in the HTR3A and HTR3B gene seem to be associated with the individual risk of developing POV. How strong their influence is within the multifactorial genesis of POV needs to be investigated in additional studies with an appropriate sample size.

Transesophageal echocardiography for verification of the position of the electrocardiographically-placed central venous catheter.

OBJECTIVE: Compare changes in P-wave amplitude of the intra-atrial electrocardiogram (ECG) and its corresponding transesophageal echocardiography (TEE)-controlled position to verify the exact localization of a central venous catheter (CVC) tip. DESIGN: A prospective study. SETTING: University, single-institutional setting. PARTICIPANTS: Two hundred patients undergoing elective cardiac surgery. INTERVENTIONS: CVC placement via the right internal jugular vein with ECG control using the guidewire technique and TEE control in 4 different phases: phase 1: CVC placement with normalized P wave and measurement of distance from the crista terminalis to the CVC tip; phase 2: TEE-controlled placement of the CVC tip; parallel to the superior vena cava (SVC) and measurements of P-wave amplitude; phase 3: influence of head positioning on CVC migration; and phase 4: evaluation of positioning of the CVC postoperatively using a chest x-ray. MEASUREMENTS AND MAIN RESULTS: The CVC tip could only be visualized in 67 patients on TEE with a normalized P wave. In 198 patients with the CVC parallel to the SVC wall controlled by TEE (phase 2), an elevated P wave was observed. Different head movements led to no significant migration of the CVC (phase 3). On a postoperative chest-x-ray, the CVC position was correct in 87.6% (phase 4). CONCLUSION: The study suggests that the position of the CVC tip is located parallel to the SVC and 1.5 cm above the crista terminalis if the P wave starts to decrease during withdrawal of the catheter. The authors recommend that ECG control as per their study should be routinely used for placement of central venous catheters via the right internal jugular vein.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

The impact of isoflurane, desflurane, or sevoflurane on the frequency and severity of postoperative nausea and vomiting after lumbar disc surgery.

STUDY OBJECTIVE: To test the hypothesis that anesthesia with the low-soluble inhalation anesthetics, sevoflurane, and desflurane, may result in a lower frequency and severity of postoperative nausea and vomiting (PONV) than anesthesia with isoflurane. DESIGN: Prospective, observational study. SETTING: Postoperative care unit and neurosurgical ward at a university hospital. PATIENTS: 625 ASA physical status I, II, and III patients undergoing elective lumbar disc surgery with general anesthesia were included in this study. INTERVENTIONS: Patients were enrolled sequentially to receive either 0.7%-1.2% isoflurane (year 2002), 3.5%-5.5% desflurane (year 2003), or 1.2%-1.9% sevoflurane (year 2004) for maintenance of anesthesia without nitrous oxide. Study personnel, general anesthesia management, and surgical technique remained unchanged over the three-year study period. MEASUREMENTS: Occurrence of PONV within 24 hours of the end of surgery was recorded. Secondary outcome measures were occurrence of multiple PONV episodes, maximum severity, time to the first PONV event, need for rescue medication, difference between the occurrence of PONV (indicator variable) and the expected risk of PONV (based on the Apfel score). MAIN RESULTS: Type of inhalation anesthetic had no influence on PONV frequency (9.3%, 11.2%, and 10.8% after isoflurane, desflurane, and sevoflurane, respectively; P = 0.8) or its severity (numerical rating scale, 4.5 +/- 2.0, 4.4 +/- 2.4, and 4.2 +/- 2.1; P = 0.9). Patients who received isoflurane experienced fewer early events but had a late peak of PONV frequency (P = 0.031). For every 10 minutes by which the total duration of the anesthesia exceeded the net time between incision and suture, the risk of PONV increased by a factor of 1.36 (95% confidence interval, 1.15-1.61; P < 0.001). CONCLUSIONS: There is no difference between the three inhalation anesthetics currently used with regard to frequency or severity of postoperative nausea, vomiting, or both.

Epidemiology of sepsis in Germany: results from a national prospective multicenter study.

OBJECTIVE: To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size. DESIGN: Prospective, observational, cross-sectional 1-day point-prevalence study. SETTING: 454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003). PATIENTS: Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay. MEASUREMENTS AND RESULTS: Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (

Comparative evaluation of Bispectral Index and Narcotrend Index in children below 5 years of age.

BACKGROUND: The use of electroencephalogram (EEG) monitoring devices for assessing the depth of hypnosis is most difficult in children under 5 years of age. METHODS: Forty five children aged 0-60 months were included in a prospective observational study. A direct comparison of the processed EEG variables Bispectral Index (BIS, version 3.4) and Narcotrend Index (NI, version 2.0AF) was to be achieved by simultaneous recording. The ability of these parameters to differentiate between various clinical states was evaluated by using the prediction probability (P(k)). Age-related effects on the BIS and NI were analyzed by dividing the children into three age groups: 0-6, 7-18 and 19-60 months. RESULTS: The preanesthesia, conscious children were differentiated from anesthetized patients by the BIS and NI with no overlap (P(k) = 1.0). In the awake period the BIS was superior to the NI (P(k) to differentiate 'end of anesthesia' from 'awakening' was 0.97 vs 0.73 respectively; P = 0.002). Patients aged 7-18 months showed higher BIS and NI values in the course of anesthesia than the younger and older children (P = 0.001). On awakening, children aged 0-6 months showed the lowest mean BIS (n.s.) and NI (P = 0.006) values. CONCLUSIONS: The BIS currently seems to be superior to the NI, but age-related processing algorithms of the raw EEG must be implemented in both BIS and NI in order to be useful in children younger than 5 years of age.

Anaesthetic considerations for endoscopic extraperitoneal and laparoscopic transperitoneal radical prostatectomy.

We focus on the anaesthesiology and requirements for minimally invasive procedures for treating localized prostate cancer. The management of anaesthesia for laparoscopic and endoscopic radical prostatectomy (RP) can be more complex than expected. Numerous groups, especially early in their experience, have had problems (e.g. hypercarbia) with the anaesthesiology of the procedure. Co-operation between the surgeon and the anaesthesiologist is of paramount importance for a safe and effective laparoscopic or endoscopic RP. Nevertheless, the relative anaesthetic equipment and trained personnel should be available before embarking on such technically proficient procedures.

Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial.

OBJECTIVES: To determine whether 10 mg, 25 mg, or 50 mg metoclopramide combined with 8 mg dexamethasone, given intraoperatively, is more effective in preventing postoperative nausea and vomiting than 8 mg dexamethasone alone, and to assess benefit in relation to adverse drug reactions. DESIGN: Four-armed, parallel group, double blind, randomised controlled clinical trial. SETTING: Four clinics of a university hospital and four district hospitals in Germany. PARTICIPANTS: 3140 patients who received balanced or regional anaesthesia during surgery. MAIN OUTCOME MEASURES: Postoperative nausea and vomiting within 24 hours of surgery (primary end point); occurrence of adverse reactions. RESULTS: Cumulative incidences (95% confidence intervals) of postoperative nausea and vomiting were 23.1% (20.2% to 26.0%), 20.6% (17.8% to 23.4%), 17.2% (14.6% to 19.8%), and 14.5% (12.0% to 17.0%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide. In the secondary analysis, 25 mg and 50 mg metoclopramide were equally effective at preventing early nausea (0-12 hours), but only 50 mg reduced late nausea and vomiting (> 12 hours). The most frequent adverse drug reactions were hypotension and tachycardia, with cumulative incidences of 8.8% (6.8% to 10.8%), 11.2% (9.0% to 13.4%), 12.9% (10.5% to 15.3%), and 17.9% (15.2% to 20.6%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide. CONCLUSION: The addition of 50 mg metoclopramide to 8 mg dexamethasone (given intraoperatively) is an effective, safe, and cheap way to prevent postoperative nausea and vomiting. A reduced dose of 25 mg metoclopramide intraoperatively, with additional postoperative prophylaxis in high risk patients, may be equally effective and cause fewer adverse drug reactions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31625370 [controlled-trials.com].

Auditory processing during deep propofol sedation and recovery from unconsciousness.

OBJECTIVE: Using evoked potentials, this study investigated effects of deep propofol sedation, and effects of recovery from unconsciousness, on the processing of auditory information with stimuli suited to elicit a physical MMN, and a (music-syntactic) ERAN. METHODS: Levels of sedation were assessed using the Bispectral Index (BIS) and the Modified Observer's Assessment of Alertness and Sedation Scale (MOAAS). EEG-measurements were performed during wakefulness, deep propofol sedation (MOAAS 2-3, mean BIS=68), and a recovery period. Between deep sedation and recovery period, the infusion rate of propofol was increased to achieve unconsciousness (MOAAS 0-1, mean BIS=35); EEG measurements of recovery period were performed after subjects regained consciousness. RESULTS: During deep sedation, the physical MMN was markedly reduced, but still significant. No ERAN was observed in this level. A clear P3a was elicited during deep sedation by those deviants, which were task-relevant during the awake state. As soon as subjects regained consciousness during the recovery period, a normal MMN was elicited. By contrast, the P3a was absent in the recovery period, and the P3b was markedly reduced. CONCLUSIONS: Results indicate that the auditory sensory memory (as indexed by the physical MMN) is still active, although strongly reduced, during deep sedation (MOAAS 2-3). The presence of the P3a indicates that attention-related processes are still operating during this level. Processes of syntactic analysis appear to be abolished during deep sedation. After propofol-induced anesthesia, the auditory sensory memory appears to operate normal as soon as subjects regain consciousness, whereas the attention-related processes indexed by P3a and P3b are markedly impaired. SIGNIFICANCE: Results inform about effects of sedative drugs on auditory and attention-related mechanisms. The findings are important because these mechanisms are prerequisites for auditory awareness, auditory learning and memory, as well as language perception during anesthesia.

The effect of esmolol on cerebral blood flow, cerebral vasoreactivity, and cognitive performance: a functional magnetic resonance imaging study.

BACKGROUND: Esmolol is often applied perioperatively to maintain stable hemodynamic conditions in neurosurgical patients. Little is known, however, about its effects on cerebral circulation. The authors employed functional magnetic resonance imaging based on blood oxygenation level-dependent contrast to explore the effect of esmolol on the human brain. The purpose of the study was to investigate the effect of esmolol on cerebral blood flow, cerebral vasoreactivity, and cognitive performance. METHODS: Ten healthy volunteers were investigated in two separate experimental sessions using functional magnetic resonance imaging. During the first experimental session, a hyperventilation task and a cognitive task, subjects had to perform both tasks twice, once after administration of an esmolol bolus of 1 mg/kg followed by a continuous infusion of 150 microg.kg.min and once without beta-blockade, in a random order. During the second experimental session subjects were scanned at resting state after administration of esmolol. Furthermore, the effect of the esmolol dose on hemodynamic changes caused by beta-adrenergic stimulation with orciprenaline was investigated. RESULTS: Esmolol decreased heart rate and blood pressure during the various experimental conditions and blunted the increase in heart rate and blood pressure caused by orciprenaline. Infusion of esmolol affects neither the blood oxygenation level-dependent contrast during the functional challenges nor the reaction times during the cognitive task. However, the esmolol bolus caused a brief blood oxygenation level-dependent contrast increase. CONCLUSION: The results indicate that effective beta-blockade with esmolol does not affect cerebral blood flow, cerebrovascular reactivity, or cognitive performance.

Functional characterization of malignant hyperthermia-associated RyR1 mutations in exon 44, using the human myotube model.

Malignant hyperthermia (MH) is a pharmacogenetic disorder with an autosomal dominant inheritance. During exposure to triggering agents as volatile anaesthetics, affected individuals may develop a potentially fatal hypermetabolic syndrome caused by excessive calcium release from the sarcoplasmic reticulum in skeletal muscle. More than 60 MH associated mutations were found in the gene of skeletal muscle ryanodine receptor (RyR1), but only some of them have been functionally characterized. Primary human myotubes were cultured from carriers of RyR1 mutations in exon 44 (Ala2350Thr, Arg2355Trp, Gly2375Ala) and from MH non-susceptible individuals. Investigation of calcium homeostasis with the calcium sensitive probe Fura 2 showed a higher sensitivity to the ryanodine receptor agonists 4-chloro-m-cresol, caffeine and halothane for the myotubes derived from the mutation carriers as compared to those of the control group. The presence of RyR1 mutations with impact on calcium homeostasis emphasizes the functional significance of exon 44.

Sequential effects of increasing propofol sedation on frontal and temporal cortices as indexed by auditory event-related potentials.

BACKGROUND: It is an open question whether cognitive processes of auditory perception that are mediated by functionally different cortices exhibit the same sensitivity to sedation. The auditory event-related potentials P1, mismatch negativity (MMN), and early right anterior negativity (ERAN) originate from different cortical areas and reflect different stages of auditory processing. The P1 originates mainly from the primary auditory cortex. The MMN is generated in or in the close vicinity of the primary auditory cortex but is also dependent on frontal sources. The ERAN mainly originates from frontal generators. The purpose of the study was to investigate the effects of increasing propofol sedation on different stages of auditory processing as reflected in P1, MMN, and ERAN. METHODS: The P1, the MMN, and the ERAN were recorded preoperatively in 18 patients during four levels of anesthesia adjusted with target-controlled infusion: awake state (target concentration of propofol 0.0 microg/ml), light sedation (0.5 microg/ml), deep sedation (1.5 microg/ml), and unconsciousness (2.5-3.0 microg/ml). Simultaneously, propofol anesthesia was assessed using the Bispectral Index. RESULTS: Propofol sedation resulted in a progressive decrease in amplitudes and an increase of latencies with a similar pattern for MMN and ERAN. MMN and ERAN were elicited during sedation but were abolished during unconsciousness. In contrast, the amplitude of the P1 was unchanged by sedation but markedly decreased during unconsciousness. CONCLUSION: The results indicate differential effects of propofol sedation on cognitive functions that involve mainly the auditory cortices and cognitive functions that involve the frontal cortices.

A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation.

Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.

Is there a place for thyroidectomy in older patients with thyrotoxic storm and cardiorespiratory failure?

Early thyroidectomy is the treatment of choice for thyrotoxic storm in patients with thyroid autonomy often induced by iodine. However, older patients who are mostly affected by this condition often have underlying chronic cardiopulmonary diseases, apparently contradicting surgical intervention. The published evidence for suitable treatment strategies in these patients is limited. We report the outcome of a series of older critically ill patients who were treated by thyroidectomy because of thyrotoxic storm. We retrospectively analyzed the outcome of 10 patients (4 males, 6 females; 70 years of age, range, 54-79, Burch-Wartofsky point scale, 61; range, 40-85) with thyrotoxic storm, thyroid autonomy, and severe cardiorespiratory and renal failure with cardiac arrhythmia, coronary artery or chronic obstructive pulmonary disease, or acute inflammation. Thyroidectomy was performed for the following reasons: symptoms of thyrotoxic storm deteriorated or did not improve within 24-48 hours despite intensive medical treatment, or patients developed thionamide-induced agranulocytosis or severe thrombocytopenia. All patients with severe accompanying diseases survived thyroidectomy (early post-operative mortality, 0%). The two oldest patients died 2-3 weeks after thyroidectomy because of myocardial infarction or respiratory failure (late postoperative mortality, 20%). In contrast, in the few previous reports of patients who underwent thyroidectomy for thyrotoxic storm and severe accompanying diseases (n = 7), late postoperative mortality was 43%. The overall mortality for all reported patients including our own, who underwent thyroidectomy for thyrotoxic storm with and without severe accompanying disease (n = 49) was 10%. Our results suggest that early total thyroidectomy should be considered as the method of choice for older, chronically ill patients with thyrotoxic storm complicated by cardiorespiratory and renal failure, especially if high-dose thionamide treatment, iopanoic acid, glucocorticoids, and intensive care fail to improve the patient's conditions within 12-24 hours.

The Ile2453Thr mutation in the ryanodine receptor gene 1 is associated with facilitated calcium release from sarcoplasmic reticulum by 4-chloro-m-cresol in human myotubes.

Central core disease (CCD) is a congenital disorder of skeletal muscle that is characterised histologically by typical central cores in type 1 skeletal muscle fibres. This disease is associated with malignant hyperthermia susceptibility and has been linked to the gene of skeletal muscle ryanodine receptor RYR1. In this study, we present a family with the spontaneous occurrence of the RYR1 Ile2453Thr mutation. Affected individuals were diagnosed as susceptible to malignant hyperthermia in the in vitro contracture test (IVCT) and showed histological signs of CCD. Myotubes were derived from the index patient. The calcium homeostasis in response to the ryanodine receptor agonist 4-chloro-m-cresol (4CmC) was investigated by calcium imaging using the Ca(2+)-sensitive fluorescent probe FURA 2. In the myotubes derived from the mutation carrier, the EC(50) of 4CmC was reduced to 94 micro as compared to 201 microM in a control group of 16 individuals non-susceptible to malignant hyperthermia. In the myotubes of the non-affected family members, the EC(50) was found within the same range as that of the control group. The reduction of EC(50) indicates a facilitated calcium release from sarcoplasmic reticulum in the myotubes of the index patient suggesting that the RYR1 Ile2453Thr mutation is pathogenic for the malignant hyperthermia susceptibility and CCD of the two affected individuals.