The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data.

While analyzing clinical data where an anesthetic was titrated based on an objective measure of drug effect, we observed paradoxically that greater effect was associated with lesser dose. With this study we sought to find a mathematical explanation for this negative correlation between dose and effect, to confirm its existence with additional clinical data, and to explore it further with Monte Carlo simulations. Automatically recorded dosing and effect data from more than 9,000 patients was available for the analysis. The anesthetics propofol and sevoflurane and the catecholamine norepinephrine were titrated to defined effect targets, i.e., the processed electroencephalogram (Bispectral Index, BIS) and the blood pressure. A proportional control titration algorithm was developed for the simulations. We prove by deduction that the average dose-effect relationship during titration to the targeted effect will associate lower doses with greater effects. The finding of negative correlations between propofol and BIS, sevoflurane and BIS, and norepinephrine and mean arterial pressure confirmed the titration paradox. Monte Carlo simulations revealed two additional factors that contribute to the paradox. During stepwise titration toward a target effect, the slope of the dose-effect data for the population will be "reversed," i.e., the correlation between dose and effect will not be positive, but will be negative, and will be "horizontal" when the titration is "perfect." The titration paradox must be considered whenever data from clinical titration (flexible dose) studies are interpreted. Such data should not be used naively for the development of dosing guidelines.

Multimodal assessment of sleep in men and women during treatment for opioid use disorder.

BACKGROUND: Sleep disturbance is common in patients with opioid use disorder (OUD) receiving medication for addiction treatment. Differences between patients on the two primary agonist medications-methadone and buprenorphine-are not well understood. METHODS: In patients receiving either methadone or buprenorphine treatment for OUD, we examined sleep continuity and architecture using ambulatory monitoring to gather both an objective measure (daily sleep EEG; M = 5.76 days, SD = 1.46) and a subjective measure (daily sleep diary; M = 54.10 days, SD = 25.10) of sleep. RESULTS: Patients treated with buprenorphine versus methadone did not differ on any measure of sleep continuity or architecture. Women had longer EEG-derived total sleep time than men (d = -0.68, 95 % CI -1.32 to -0.09), along with lower %N2 (d = 0.94, 95 % CI 0.34-1.64) and greater %N3 (d = -0.94, 95 % CI -1.61 to -0.32). Self-reported sleep differed from EEG-derived estimates: wake after sleep onset was greater by EEG than by diary (d = 2.58, 95 % CI 1.74-3.63), and total sleep time and sleep efficiency were lower by EEG than by diary (d for sleep time = 2.93, 95 % CI 2.06-4.14; d for efficiency = 1.69, 95 % CI 0.98-2.49). CONCLUSIONS: Patients treated with buprenorphine or methadone did not substantively differ in ambulatory measures of sleep. With both medications, there was a discrepancy between objective and subjective sleep measures. Further confirmatory evidence would inform the development of sleep-related recommendations for OUD patients undergoing agonist treatment.

Assessment of School-Aged Children of Mothers With Idiopathic Generalized Epilepsy.

The aim is to examine the cognitive domains, behavioral domains, and electroencephalogram (EEG) findings in children of mothers with idiopathic generalized epilepsy who had been exposed to antiepileptic drugs (AEDs) in utero. Forty school-aged children born to 23 mothers with idiopathic generalized epilepsy were compared with 40 healthy children born to 34 healthy mothers. Stanford-Binet Intelligence Scale was applied to all children to assess their cognitive functions. Child Behavior Checklist was used to assess their behavioral characteristics. EEG was done for the epileptic mothers and their children. Children exposed to AEDs showed significantly lower scores in the verbal reasoning, visual reasoning, and global intelligence quotient (IQ). There was a significantly positive correlation between children's global IQ and maternal global IQ. Multiple regression analysis showed that in utero exposure to valproate and maternal IQ were the most independent factors affecting children's IQ. EEG findings of participating children were normal. Exposure to valproic acid during fetal life and maternal IQ represent confounding factors affecting the IQ of children with in utero exposure to AEDs.

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex.

BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P>0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1-4Hz) band (P=0.03) and increased the activity in the alpha (8-12Hz) band (P=0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P=0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P>0.05). CONCLUSIONS: Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated.

Safety pharmacology investigations on the nervous system: An industry survey.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

Real-time depth of anaesthesia assessment using strong analytical signal transform technique.

This paper introduces a new method addressing depth of anaesthesia (DoA) assessment for real-time monitoring. The new method uses a combination of phase and amplitude of electroencephalogram (EEG) signals to assess the DoA level. A strong analytical signal transform is applied to extract the phase and amplitude information of the recorded EEG signals. Based on the extracted features from the EEG signal in each different frequency band, a new DoA index is developed. The proposed new DoA index is evaluated using data from adult patients in an age range from 22 to 75 years. The results show that the new DoA index is able to detect the changing pattern of EEG signals early and agree with the clinical notes of an attending anaesthetist. The results are also closely correlated with the popular BIS index. Furthermore, the proposed new DoA index is able to detect the state changes earlier than the BIS index.

A pharmaco-EEG-based assessment of the interaction between ethanol and zonisamide.

AIMS: Recent research suggests a potential role for a new generation of anticonvulsant drugs, including zonisamide, in the treatment of alcohol dependence. Some elements of the central mechanism of action that zonisamide has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. METHODS: This study uses a pharmaco-EEG method to examine the interaction of ethanol with zonisamide. The influence of zonisamide on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Zonisamide was administered p.o. as a single dose (20 or 60 mg/kg) or repeatedly at a dose of 30 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 180 min after the administration of zonisamide. RESULTS: Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 and 30-45 Hz). Changes in the EEG recordings after zonisamide alone were more significant compared with these after repeated doses. In the hippocampus after single dose of drug the proportion of the low frequency (0.5-4 Hz) increased, whereas the proportion of high frequencies decreased. Combined administration of ethanol and zonisamide (60 mg/kg) resulted in a markedly synergistic effect in the examined structures. A beneficial effect of repeatedly administered zonisamide on ethanol-induced EEG changes was observed, especially in the hippocampus. CONCLUSION: Zonisamide in repeated doses decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

Epilepsy biomarkers.

A biomarker is defined as an objectively measured characteristic of a normal or pathologic biologic process. Identification and proper validation of biomarkers of epileptogenesis (the development of epilepsy) and ictogenesis (the propensity to generate spontaneous seizures) might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.

A novel approach to pharmaco-EEG for investigating analgesics: assessment of spectral indices in single-sweep evoked brain potentials.

AIMS: To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl. METHODS: Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps. RESULTS: Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90). CONCLUSION: In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

Active emergence from propofol general anesthesia is induced by methylphenidate.

BACKGROUND: A recent study showed that methylphenidate induces emergence from isoflurane general anesthesia. Isoflurane and propofol are general anesthetics that may have distinct molecular mechanisms of action. The objective of this study was to test the hypothesis that methylphenidate actively induces emergence from propofol general anesthesia. METHODS: Using adult rats, the effect of methylphenidate on time to emergence after a single bolus of propofol was determined. The ability of methylphenidate to restore righting during a continuous target-controlled infusion (TCI) of propofol was also tested. In a separate group of rats, a TCI of propofol was established and spectral analysis was performed on electroencephalogram recordings taken before and after methylphenidate administration. RESULTS: Methylphenidate decreased median time to emergence after a single dose of propofol from 735 s (95% CI: 598-897 s, n = 6) to 448 s (95% CI: 371-495 s, n = 6). The difference was statistically significant (P = 0.0051). During continuous propofol anesthesia with a median final target plasma concentration of 4.0 µg/ml (95% CI: 3.2-4.6, n = 6), none of the rats exhibited purposeful movements after injection of normal saline. After methylphenidate, however, all six rats promptly exhibited arousal and had restoration of righting with a median time of 82 s (95% CI: 30-166 s). Spectral analysis of electroencephalogram data demonstrated a shift in peak power from δ (less than 4 Hz) to θ (4-8 Hz) and ß (12-30 Hz) after administration of methylphenidate, indicating arousal in 4/4 rats. CONCLUSIONS: Methylphenidate decreases time to emergence after a single dose of propofol, and induces emergence during continuous propofol anesthesia in rats. Further study is warranted to test the hypothesis that methylphenidate induces emergence from propofol general anesthesia in humans.

Auditory evoked potential index does not correlate with observer assessment of alertness and sedation score during 0.5% bupivacaine spinal anesthesia with nitrous oxide sedation alone.

PURPOSE: The aim of this study was to evaluate the auditory evoked potential (AEP) index as a hypnosis monitor during nitrous oxide (N(2)O) sedation added to spinal analgesia. METHODS: Forty-five patients scheduled to undergo surgery under spinal anesthesia were recruited after giving informed consent. Adequate anesthesia levels were confirmed, and a disposable AEP index sensor (aepEX, Medical Device Management) was placed. A tight facemask was fitted, and a fresh gas flow of 100% oxygen 10 L/min was provided. AEP index monitoring was then initiated, and measurements and observer assessment of alertness/sedation (OAA/S) scores were recorded manually. N(2)O was administered in stepwise increases in the end-tidal concentration of 33%, 50%, and 67%. Paired AEP index and OAA/S scores were obtained immediately before each change in N(2)O concentration. RESULTS: Sixteen patients were excluded from final analysis because of nausea, vomiting, or abnormal excitatory behaviors. The increases in N(2)O concentration induced significant decreases in OAA/S scores and no substantial AEP index changes. Although OAA/S scores of 1 and 2 were observed in only two and five patients, respectively, a reduction in the OAA/S score from 5 to 1 was associated with a significant decrease in AEP index to the level indicative of moderate sedation. CONCLUSION: The AEP index might not be a suitable indicator of light hypnosis as defined by an OAA/S score of ≥3 during sedation with N(2)O alone.

Clinical and electroencephalographic assessment of cefepime during treatment of nosocomial infections in neurological patients.

OBJECTIVE: Cefepime neurotoxicity usually occurs in patients with renal impairment. The aim of this study was to evaluate the neurotoxicity of cefepime administered by continuous intravenous infusion during treatment of nosocomial infections in neurological patients with normal renal function. METHODS: This was an open pilot study of neurological patients with infections caused by cefepime sensitive bacteria. Patients had baseline neurological assessment and electroencephalogram (EEG). Cefepime plasma concentrations were determined 48 hours after infusion was initiated and at end of treatment (EOT). RESULTS: Eleven patients were included. These were diagnosed with a brain tumor (9), cerebrovascular disease (1) and polyneuropathy (1). Infections were surgical site infection in 5, clinically defined nosocomial pneumonia in 4, and bacterial meningitis associated to postoperative CSF fistula in 2. Gram-negative organisms were isolated in 10 patients. Cefepime dose was 2 g/day in 9 patients and 4 g/day in 2. Mean cefepime plasma concentration at 48h was 13.6 ± 2.0 µg/mL (range 4.6 to 24.5 µg/mL), at EOT was 11.9 ± 1.8 µg/mL (range 3.0 to18.9 µg/mL ). EEG interpreted by two experts showed at baseline alpha background rhythm in 5 and theta-alpha rhythm in 6 patients. On EEG at EOT background rhythm was alpha in 4 and theta-alpha in 7, one patient presented isolated sharp and slow wave activity. No mental status changes or seizures occurred and all infections resolved. CONCLUSION: Significant EEG change was observed in 1of 11 patients. A preserved mental status may correlate with cefepime safety in neurological patients with normal renal function during cefepime treatment.

Closed-loop isoflurane administration with bispectral index in open heart surgery: randomized controlled trial with manual control.

OBJECTIVE: Improved anesthetic agent delivery system (IAADS), a modification of closed-loop anesthesia delivery system (CLADS), is designed to deliver inhalational anesthetics and propofol through closed-loop control with bispectral index (BIS) as target. We compared the performance of IAADS with the manual control isoflurane administration during cardiac surgery. METHODS: Forty patients of ASA (American Society of Anesthesiologists) physical status class II-III, undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) in a tertiary care hospital in India were randomized to receive isoflurane through a closed-loop system (IAADS group) or through a Tech 7 vaporizer adjusted manually (manual group) to achieve a target BIS of 50. Patients were induced with a propofol infusion and isoflurane was started after intubation. During CPB, patients received propofol; isoflurane was restarted after separation from CPB. The efficacy of IAADS in controlling depth of anesthesia and hemodynamic variations was compared with that of manual control. RESULTS: IAADS was able to maintain BIS within ± 10 of target for significantly longer period (84.6 ± 7.2% in IAADS group vs. 75.9 ± 11.2 in manual group, p < 0.01). Both overall performance, as assessed by global score (p < 0.01), and precision, as judged by median absolute performance error (MDAPE) (p < 0.04), were significantly better in the IAADS group. The IAADS group required significantly less propofol for induction (1.3 ± 0.4 mg/kg in IAADS vs. 1.6 ± 0.5 mg/kg in manual, p < 0.05) and less isoflurane during maintenance of anesthesia (3.3 ± 0.8 ml/h vs. 3.4 ± 0.9 ml/h, p < 0.01). CONCLUSION: The present study proves the feasibility and efficacy of inhalation anesthetic administration through closed-loop control. This is the first system that has been developed to control intravenous and inhalational anesthetic agents in a closed-loop model using BIS.

Neurophysiological and cognitive effects of smoked marijuana in frequent users.

RATIONALE: Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects. OBJECTIVES: In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana. METHODS: Research volunteers (N=24), who reported smoking approximately 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% (9)-THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions. RESULTS: Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling "new" words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and "positive" subjective-effect ratings were increased in a (9)-THC concentration-dependent manner. CONCLUSIONS: Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.

Pharmaco-EEG-based assessment of the interaction between ethanol and oxcarbazepine.

Oxcarbazepine is a representative molecule for a new class of anticonvulsant drugs that can treat alcohol dependence in addition to other disorders. Interestingly, the central mechanism of action in oxcarbazepine is very similar to ethanol, suggesting that these two agents may interact and cause enhanced effects in the central nervous system. In this study, we used a pharmaco-EEG method to examine the influence of oxcarbazepine on the effect of ethanol on the EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex). Oxcarbazepine was administered po as a single dose (20 mg/kg or 80 mg/kg) or repeatedly at a dose of 40 mg/kg/day for 14 days. Ethanol was injected iv at a dose of 0.8 g/kg 60 min after the administration of oxcarbazepine. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recordings, and it caused a marked decrease in higher frequencies (13-30 Hz and 30-45 Hz). Oxcarbazepine altered the EEG pattern in rabbits; this interaction was dependent on the dose of the drug and whether it was administered as a single dose or as multiple doses. Oxcarbazepine administered at a lower dose had a synergistic effect with ethanol in the frontal cortex and midbrain reticular formation, and a similar effect was observed in the hippocampus at a higher dose. Changes in EEG recordings after the administration of oxcarbazepine alone were more pronounced after multiple administrations. The drug decreased the sensitivity of the hippocampus to ethanol, an observation that may be important for the treatment of alcohol addiction.

[Neuromonitoring in anaesthesia]. / Narkosetiefenmessung in der Anästhesie - Neue Möglichkeiten und Ziele der Narkoseüberwachung.

Modern computer-based methods to monitor anesthesia are widespread. They are used in order to avoid awareness, to reduce consumption of anesthetics, to optimize recovery times and to detect prolonged times of deep anesthesia and associated immunsuppression, mortality and morbidity. This review illustrates the evidence with which these goals were achieved until now. Finally, a recommendation for each indication is given. The useage of EEG-monitoring may help to avoid awareness and allows a reduced of consumption of anesthetics. The question if a cumulated time of deep anesthesia is associated with elevated mortality might be of a certain importance in the future.

[Changing lamotrigine preparations in epilepsy patients. Experiences of a university epilepsy outpatient centre]. / Umstellungen zwischen Lamotrigin-Präparaten bei Epilepsiepatienten. Erfahrungen einer universitären Epilepsieambulanz.

An increasing number of second-generation antiepileptic drugs have become available as generics. There is an ongoing debate as to whether this opens up ways to save costs or if efficacy and tolerability of an established treatment are at stake. We here present a retrospective analysis of outpatients treated with lamotrigine regarding the frequency of treatment switches and its effects on seizure control and tolerability. In 13 of 285 patients under treatment with lamotrigine the prescribed drug was changed; in 6 of these seizure relapse occurred after a period of 3 months to 6 years of seizure freedom and 3 patients experienced new side effects. Compared to matched controls, the risk for loss of seizure control was significantly elevated by a factor of 17; adverse events were three times more frequent (n.s.). Consecutive determinations of serum levels suggest that these problems were related to changes in the pharmacokinetics of different formulations. Frequent problems related to a switch of medication are discussed under medical and socio-economic aspects.

Assessing the clinical or pharmaco-economical benefit of target controlled desflurane delivery in surgical patients using the Zeus anaesthesia machine.

The Zeus anaesthesia machine includes an auto-control mode which allows targeting of end-tidal volatile and inspired oxygen concentrations. We assessed the clinical benefits and economic impact of this target-controlled anaesthesia compared with conventional manually controlled anaesthesia. Eighty patients were randomly assigned to receive desflurane either with a fresh gas flow set by the anaesthetist or in auto-control mode. Drug delivery was adjusted to maintain bispectral index between 40-60 units and systolic arterial pressure under 15 mmHg above its pre-induction value (upper limit) and over 90 mmHg (lower limit). Blood pressure was maintained in the desired range for 89% and 91% of the maintenance period for auto-control and manual control respectively (p = 0.49). Bispectral index was in the desired range for 82% and 79% of the maintenance period, for auto-control and manual control respectively (p = 0.46). Oxygen consumption was more than halved by the use of auto-control mode, and mean (SD) desflurane consumption during surgery was 0.07 (0.04) vs 0.2 (0.07) ml.min(-1) in auto-control and manual control respectively (p < 0.0001). The number of drug delivery adjustments per hour was significantly lower in auto-control mode (mean (SD) 7 (2) vs 15 (12); p < 0.0001). Thus, the auto-control mode provided similar haemodynamic stability and bispectral control as did conventional manually controlled anaesthesia, but led to a reduction in gas and vapour consumption with a more clinically acceptable workload.

[Propofol administration systems. Handling, hemodynamics and propofol consumption]. / Propofolapplikationssysteme: Handhabung, Kreislaufverhalten und Propofolverbrauch.

BACKGROUND: During anaesthesia propofol is administered either by manual controlled infusion (MCI) or by target controlled infusion (TCI) techniques. In this study two different TCI systems for propofol administration were evaluated with regard to handling, patient safety, and costs and compared to administration of propofol by the MCI technique. METHODS: In a prospective study, 90 patients scheduled for elective surgery of the nose or nasal sinuses were randomly enrolled in three groups. The two TCI systems were examined in two groups of 30 patients: one group received propofol following the pharmacokinetic TCI model of Schnider (TCI-Schnider) and the other group received propofol following the TCI model of Marsh (TCI-Marsh). A manual perfusion technique (MCI, n=30) was used in the control group. Depth of anesthesia was controlled using the bispectral index (BSI) which was adjusted to fall within the range of 40-55. Hemodynamics, extubation times and time of awaking, rate and quality of propofol dose adjustment, total drug requirements, costs, and quality of recovery were documented. The incidence of postoperative nausea and vomiting (PONV) as well as shivering and patient satisfaction were also documented. RESULTS: Demographics, hemodynamics and perioperative data did not differ between the groups. Propofol consumption within the first 60 min also showed no significant differences. In the course of extended anaesthesia, propofol consumption was significantly less in both TCI groups compared to the control group (MCI) and the TCI-Schnider group also showed less episodes of bradycardia. The necessity of propofol dose adjustment did not differ significantly between the TCI groups. Administration and consumption of anaesthesia co-medication (fentanyl, remifentanil, cisatracurium) did not differ between the groups. CONCLUSION: The investigated propofol administration procedures using the MCI or TCI techniques were safe and easy to handle under BIS monitoring. No differences were found concerning extubation times and time of awaking. During extended anaesthesia procedures (>60 min), propofol consumption was lower with both TCI techniques and thus costs could be saved.

A randomized evaluation of bispectral index-augmented sedation assessment in neurological patients.

OBJECTIVE: To assess whether monitoring sedation status using bispectral index (BIS) as an adjunct to clinical evaluation was associated with a reduction in the total amount of sedative drug used in a 12 h period. DESIGN: Prospective randomized controlled clinical trial. SETTING: Tertiary care neurocritical care unit. PATIENTS: Sixty-seven mechanically ventilated adult patients receiving continuous intravenous sedation with propofol. INTERVENTIONS: Sedation monitoring using clinical assessment with the Ramsay scale (Ramsay-alone group) or clinical assessment plus BIS monitoring (BIS-augmentation group). Subjects were randomized to Ramsay-alone (n = 35), or BIS-augmentation (n = 32). Nurses adjusted the dose of propofol to a Ramsay of 4, or a Ramsay of 4 and BIS between 60 and 70. MEASUREMENTS AND MAIN RESULTS: Patients in the BIS-augmentation group received significantly less propofol by volume (93.5 ml vs. 157.8 ml, respectively; P < .015), and had lower infusion rates (14.6 vs. 27.9 mcg/kg/min; P = .003). There is a lower risk of propofol infusion exceeding manufacturer's recommended dosing guides in the BIS-augmentation group versus the Ramsay-alone group (0 vs. 23%, P = .0052). The BIS-augmentation group woke up much quicker than those in the Ramsay-alone group (1.2 vs. 7.5 min; P < .0001). CONCLUSIONS: BIS-augmented sedation monitoring resulted in a marked reduction in the total dose of sedative used to achieve the same level of clinical sedation resulting in shortened time to wake up without any measurable adverse effects. Physiologic sedation assessment tools may provide a useful means of improving the care of sedated critically ill patients.