Kane O. Pryor

Propofol and midazolam inhibit conscious memory processes very soon after encoding: An event related potential study of familiarity and recollection in volunteers

Background:Intravenous drugs active via &ggr;-aminobutyric acid receptors to produce memory impairment during conscious sedation. Memory function was assessed using event-related potentials (ERPs) while drug was present. Methods:The continuous recognition task measured recognition of photographs from working (6 s) and long-term (27 s) memory while ERPs were recorded from Cz (familiarity recognition) and Pz electrodes (recollection recognition). Volunteer participants received sequential doses of one of placebo (n = 11), 0.45 and 0.9 &mgr;g/ml propofol (n = 10), 20 and 40 ng/ml midazolam (n = 12), 1.5 and 3 &mgr;g/ml thiopental (n = 11), or 0.25 and 0.4 ng/ml dexmedetomidine (n = 11). End-of-day yes/no recognition 225 min after the end of drug infusion tested memory retention of pictures encoded on the continuous recognition tasks. Results:Active drugs increased reaction times and impaired memory on the continuous recognition task equally, except for a greater effect of midazolam (P < 0.04). Forgetting from continuous recognition tasks to end of day was similar for all drugs (P = 0.40), greater than placebo (P < 0.001). Propofol and midazolam decreased the area between first presentation (new) and recognized (old, 27 s later) ERP waveforms from long-term memory for familiarity (P = 0.03) and possibly for recollection processes (P = 0.12). Propofol shifted ERP amplitudes to smaller voltages (P < 0.002). Dexmedetomidine may have impaired familiarity more than recollection processes (P = 0.10). Thiopental had no effect on ERPs. Conclusion:Propofol and midazolam impaired recognition ERPs from long-term memory but not working memory. ERP measures of memory revealed different pathways to end-of-day memory loss as early as 27 s after encoding.

Visual P2-N2 Complex and Arousal at the Time of Encoding Predict the Time Domain Characteristics of Amnesia for Multiple Intravenous Anesthetic Drugs in Humans

Background:Intravenous anesthetics have marked effects on memory function, even at subclinical concentrations. Fundamental questions remain in characterizing anesthetic amnesia and identifying affected system-level processes. The authors applied a mathematical model to evaluate time-domain components of anesthetic amnesia in human subjects. Methods:Sixty-one volunteers were randomized to receive propofol (n = 12), thiopental (n = 13), midazolam (n = 12), dexmedetomidine (n = 12), or placebo (n = 12). With drug present, subjects encoded pictures into memory using a 375-item continuous recognition task, with subsequent recognition later probed with drug absent. Memory function was sampled at up to 163 time points and modeled over the time domain using a two-parameter, first-order negative power function. The parietal event-related P2–N2 complex was derived from electroencephalography, and arousal was repeatedly sampled. Each drug was evaluated at two concentrations. Results:The negative power function consistently described the course of amnesia (mean R2 = 0.854), but there were marked differences between drugs in the modulation of individual components (P < 0.0001). Initial memory strength was a function of arousal (P = 0.005), whereas subsequent decay was related to the reaction time (P < 0.0001) and the P2–N2 complex (P = 0.007/0.002 for discrete components). Conclusions:In humans, the amnesia caused by multiple intravenous anesthetic drugs is characterized by arousal-related effects on initial trace strength, and a subsequent decay predicted by attenuation of the P2–N2 complex at encoding. The authors propose that the failure of normal memory consolidation follows drug-induced disruption of interregional synchrony critical for neuronal plasticity and discuss their findings in the framework of memory systems theory.

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

Background Delirium and pain are common and serious postoperative complications. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia and to spare postoperative opioids. Some evidence also suggests that ketamine prevents delirium. The primary purpose of this trial was to evaluate the effectiveness of ketamine in preventing postoperative delirium in older adults after major surgery. Secondary outcomes, viewed as strongly related to delirium, were postoperative pain and opioid consumption. Methods This was a multicentre, international, randomised trial that enrolled adults older than 60 undergoing major cardiac and noncardiac surgery under general anaesthesia. Participants were enrolled prior to surgery and gave written informed consent. We used a computer-generated randomisation sequence. Patients at study sites were randomised to one of three study groups in blocks of 15 to receive intraoperative administration of (i) placebo (intravenous normal saline), (ii) low dose ketamine (0.5 mg/kg) or (iii) high dose ketamine (1 mg/kg). Study drug was administered following induction of anaesthesia, prior to surgical incision. Participants, clinicians, and investigators were all masked to group assignment. Delirium and pain were assessed twice daily in the first three postoperative days using the Confusion Assessment Method and Visual Analog Scale, respectively. Postoperative opioid use was recorded, and hallucinations and nightmares were assessed. Analyses were performed by intention-to-treat and adverse events were evaluated. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] trial is registered in clinicaltrials.gov; NCT01690988 Findings Between February 6, 2014 and June 26, 2016, 1360 patients assessed and 672 were randomised, with 222 in the placebo group, 227 in the low dose ketamine group, and 223 in the high dose ketamine group. There was no difference in postoperative delirium incidence between those in the combined ketamine groups and those who received placebo (19.45% vs. 19.82%, respectively; absolute difference, 0.36%; 95% CI, −6.07% to 7.38%; p=0.92). There were no significant differences among the three groups in maximum pain scores (p=0.88) or median opioid consumption (p=0.47) over time. There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with escalating doses of ketamine. Adverse events (cardiovascular, renal, infectious, gastrointestinal, bleeding), whether viewed individually (P value for each >0.40) or collectively (82/222 [36.9%] in placebo group, 90/227 [39.6%] in low dose ketamine group, 91/223 in high dose ketamine group [40.8%]; P=0.69), did not differ significantly across the three groups. Interpretation The administration of a single subanaesthetic dose of ketamine to older adults during major surgery did not show evidence of reducing postoperative delirium, pain, or opioid consumption, and might cause harm by inducing negative experiences. Given current evidence and guidelines related to ketamine and postoperative analgesia, the unexpected secondary findings regarding pain and opioid consumption warrant replication or refutation in subsequent research. Funding The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigators (MSA and GAM) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Low Dose Propofol-induced Amnesia Is Not Due to a Failure of Encoding: Left Inferior Prefrontal Cortex Is Still Active

Background:Propofol may produce amnesia by affecting encoding. The hypothesis that propofol weakens encoding was tested by measuring regional cerebral blood flow during verbal encoding. Methods:Seventeen volunteer participants (12 men; aged 30.4 ± 6.5 yr) had regional cerebral blood flow measured using H2O15 positron emission tomography during complex and simple encoding tasks (deep vs. shallow level of processing) to identify a region of interest in the left inferior prefrontal cortex (LIPFC). The effect of either propofol (n = 6, 0.9 &mgr;g/ml target concentration), placebo with a divided attention task (n = 5), or thiopental at sedative doses (n = 6, 3 &mgr;g/ml) on regional cerebral blood flow activation in the LIPFC was tested. The divided attention task was expected to decrease activation in the LIPFC. Results:Propofol did not impair encoding performance or reaction times, but impaired recognition memory of deeply encoded words 4 h later (median recognition of 35% [interquartile range, 17–54%] of words presented during propofol vs. 65% [38–91%] before drug; P < 0.05). Statistical parametric mapping analysis identified a region of interest of 6.6 cm2 in the LIPFC (T = 7.44, P = 0.014). Regional cerebral blood flow response to deep encoding was present in this region of interest in each group before drug (T > 4.41, P < 0.04). During drug infusion, only the propofol group continued to have borderline significant activation in this region (T = 4.00, P = 0.063). Conclusions:If the amnesic effect of propofol were solely due to effects on encoding, activation in the LIPFC should be minimal. Because LIPFC activation was not totally eliminated by propofol, the amnesic action of propofol must be present in other brain regions and/or affect other memory processes.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

Introduction Postoperative delirium is one of the most common complications of major surgery, affecting 10–70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. Methods The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1–3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. Ethics and dissemination The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. Registration details The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). Trial registration number NCT01690988 (last updated December 2013).

Dynamical criticality during induction of anesthesia in human ECoG recordings

In this work we analyze electro-corticography (ECoG) recordings in human subjects during induction of anesthesia with propofol. We hypothesize that the decrease in responsiveness that defines the anesthetized state is concomitant with the stabilization of neuronal dynamics. To test this hypothesis, we performed a moving vector autoregressive analysis and quantified stability of neuronal dynamics using eigenmode decomposition of the autoregressive matrices, independently fitted to short sliding temporal windows. Consistent with the hypothesis we show that while the subject is awake, many modes of neuronal activity oscillations are found at the edge of instability. As the subject becomes anesthetized, we observe statistically significant increase in the stability of neuronal dynamics, most prominently observed for high frequency oscillations. Stabilization was not observed in phase randomized surrogates constructed to preserve the spectral signatures of each channel of neuronal activity. Thus, stability analysis offers a novel way of quantifying changes in neuronal activity that characterize loss of consciousness induced by general anesthetics.

Association of pre-operative brain pathology with post-operative delirium in a cohort of non-small cell lung cancer patients undergoing surgical resection.

Post‐operative delirium is associated with pre‐operative cognitive difficulties and diminished functional independence, both of which suggest that brain pathology may be present in affected individuals prior to surgery. Currently, there are few studies that have examined imaging correlates of post‐operative delirium. To our knowledge, none have examined the association of delirium with existing structural pathology in pre‐operative cancer patients. Here, we present a novel, retrospective strategy to assess pre‐operative structural brain pathology and its association with post‐operative delirium. Standard of care structural magnetic resonance imaging (MRIs) from a cohort of surgical candidates prior to surgery were analyzed for white matter hyperintensities and cerebral atrophy.

Effect of propofol on the medial temporal lobe emotional memory system: a functional magnetic resonance imaging study in human subjects

BACKGROUND Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects. METHODS Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μg ml(-1), or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models. RESULTS Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia. CONCLUSIONS Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder. CLINICAL TRIAL REGISTRATION NCT00504894.

Surgical education at Weill Bugando Medical Centre: supplementing surgical training and investing in local health care providers

Global surgery initiatives increasingly are focused on strengthening education and local health care systems to build surgical capacity. The goal of this education project was to support local health care providers in augmenting the surgical curriculum at a new medical school, thus promoting long-term local goals and involvement. Working with local surgeons, residents, and medical and assistant medical officer students, we identified the most common surgical conditions presenting to Weill Bugando Medical Centre in Mwanza, Tanzania, and the areas of greatest need in surgical education. We developed an 8-week teaching schedule for undergraduate students and an electronic database of clinical surgery topics. In addition, we started teaching basic surgical skills in the operating theatre, bridging to an official and recurring workshop through a supporting international surgery organization. The medical and assistant medical officer students reported increased satisfaction with their clinical surgery rotations and mastery of key educational subjects. The initiation of an Essential Surgical Skills workshop through the Canadian Network for International Surgery showed students had improved comfort with basic surgical techniques. Short-term surgical missions may appear to fill a void in the shortage of health care in the developing world. However, we conclude that global health resources are more appropriately used through projects giving ownership to local providers and promoting education as a foundation of development. This results in better coordination among local and visiting providers and greater impact on education and long-term growth of health care capacity.

Amnesia of the Operating Room in the B-Unaware and BAG-RECALL Clinical Trials.

BACKGROUND:Patient memories of the operating room (OR) may serve as the informational basis for assessing satisfaction with individual anesthesiologists. Furthermore, the provision of clinically important information may assume that perioperative memories are retained. Studies assessing the extent of perioperative amnesia and factors associated with perioperative amnesia are sparse. Therefore, we assessed patient amnesia of the OR and of the preoperative holding area in hospitals where midazolam is typically administered in the preoperative holding area and evaluated whether midazolam dose administered in the preoperative holding area and patient age were associated with amnesia of the OR before induction of anesthesia. METHODS:This was a retrospective study among 7750 adult patients who had general anesthesia and participated in the B-Unaware and Bispectral Index or Anesthetic Gas to Reduce Explicit Recall (BAG-RECALL) clinical trials. The last location the patient remembered before induction of anesthesia and the first location they remembered after induction of anesthesia were determined through a modified Brice questionnaire administered over the phone 30 days postoperatively. Regarding the preoperative period, patients were excluded if their last memory was unclear with respect to location before induction of anesthesia or if they were recruited at Winnipeg, where midazolam was typically first administered in the OR. Midazolam dose (mg/kg) administered in the preoperative holding area was divided into quartiles. Poisson regression models were used to calculate age- and multivariable-adjusted odds ratios (95% confidence intervals [CIs]) for the association between midazolam dose and amnesia of the OR before induction of anesthesia. RESULTS:Of the 5339 patients included, 59.5% (95% CI, 58.2–60.9) of patients had amnesia of the OR before induction of anesthesia. In addition, 44.1% (95% CI, 42.8–45.7) last remembered the preoperative holding area, and 15.4% (95% CI, 14.4–16.4) only had preoperative memories before the holding area. The percentages of patients with amnesia of the OR before induction of anesthesia differed according to age groups: 50.7% (95% CI, 47.7%–53.7%) in patients aged 18 to 47 years versus 70.0% (95% CI, 67.0%–72.9%) in patients aged 73 to 99 years. Patients in the highest midazolam quartile had an adjusted prevalence ratio of 1.31 (95% CI, 1.22–1.42) for amnesia of the OR compared with those who did not receive midazolam. CONCLUSIONS:In hospitals where patients typically receive midazolam in the preoperative holding area, the majority of patients do not remember the OR, and a clinically relevant number of patients does not remember the preoperative holding area. If additional studies produce results indicating that a substantial proportion of patients has amnesia of the anesthesiologist, these findings would argue against the validity of assessing patient satisfaction with individual anesthesiologists providing exclusively OR care in such hospitals. Furthermore, if additional studies yield findings suggesting patient amnesia of the preoperative holding area, these results would suggest reconsideration of providing clinically important information only in the preoperative holding area. Older age and midazolam-induced anterograde amnesia are probably associated with impaired perioperative memories.