Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggest Dentate Gyrus Pathology Linked to NMDA Receptor Hypofunction.

BACKGROUND: Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here, we sought to examine if this deficit is already present in first-episode psychosis and if NMDA receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. METHODS: We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 patients with first-episode psychosis and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 min, then 0.25 mg/kg/hour for 50 min, 0.01 mL/s). We calculated response bias-corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. RESULTS: We reported a deficit in pattern separation performance in patients with first-episode psychosis compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Pattern recognition was lower in patients with first-episode psychosis than in control subjects (p < .01). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in patients with first-episode psychosis or with ketamine serum levels. CONCLUSIONS: We observed a mnemonic discrimination deficit in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and NMDA receptor hypofunction.

Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy associated with mechanical and electrical changes, culminating in increased vascular resistance, right ventricular (RV) failure, and death. With a main focus on invasive tools, there has been an underutilization of echocardiography, electrocardiography, and biomarkers to non-invasively assess the changes in myocardial and pulmonary vascular structure and function during the course of PAH. Methods: A SU5416-hypoxia rat model was used for inducing PAH. Biventricular functions were measured using transthoracic two-dimensional (2D) echocardiography/Doppler (echo/Doppler) at disease onset (0 week), during progression (3 weeks), and establishment (5 weeks). Similarly, electrocardiography was performed at 0, 3, and 5 weeks. Invasive hemodynamic measurements and markers of cardiac injury in plasma were assessed at 0, 3, and 5 weeks. Results: Increased RV systolic pressure (RVSP) and rate of isovolumic pressure rise and decline were observed at 0, 3, and 5 weeks in PAH animals. EKG showed a steady increase in QT-interval with progression of PAH, whereas P-wave height and RS width were increased only during the initial stages of PAH progression. Echocardiographic markers of PAH progression and severity were also identified. Three echocardiographic patterns were observed: a steady pattern (0-5 weeks) in which echo parameter changed progressively with severity [inferior vena cava (IVC) expiratory diameter and pulmonary artery acceleration time (PAAT)], an early pattern (0-3 weeks) where there is an early change in parameters [RV fractional area change (RV-FAC), transmitral flow, left ventricle (LV) output, estimated mean PA pressure, RV performance index, and LV systolic eccentricity index], and a late pattern (3-5 weeks) in which there is only a late rise at advanced stages of PAH (LV diastolic eccentricity index). RVSP correlated with PAAT, PAAT/PA ejection times, IVC diameters, RV-FAC, tricuspid systolic excursion, LV systolic eccentricity and output, and transmitral flow. Plasma myosin light chain (Myl-3) and cardiac troponin I (cTnI) increased progressively across the three time points. Cardiac troponin T (cTnT) and fatty acid-binding protein-3 (FABP-3) were significantly elevated only at the 5-week time point. Conclusion: Distinct electrocardiographic and echocardiographic patterns along with plasma biomarkers were identified as useful non-invasive tools for monitoring PAH progression.

Baseline Functional Connectivity Predicts Connectivity Changes Due to a Small Dose of Midazolam in Older Adults.

BACKGROUND: In the perioperative context, benzodiazepines are widely used as anxiolytics. They affect cognition in general, but it is unclear whether the effects of a small dose of the short-acting benzodiazepine midazolam can be assessed objectively. To address this scientific question, we conducted a prospective observational study in adults 55-73 years of age. Using both validated psychometric and functional imaging techniques, we determined whether a 2-mg intravenous (IV) dose of midazolam affects cognitive function. METHODS: We measured the effect of 2 mg IV of midazolam with both the well-established Repeatable Battery for the Assessment of Neuropsychological Status test and resting-state functional magnetic imaging (rs-fMRI) in older adults. RESULTS: Midazolam reduces immediate and delayed memory and has a profound and robust effect on rs-fMRI. Baseline resting-state connectivity predicts memory decline after midazolam administration. CONCLUSIONS: Observed effects of midazolam on brain networks were statistically significant even in a small group of volunteers. If validated by other investigators, resting-state brain connectivity may have utility as a measure to predict sensitivity to midazolam in older adults.

Comparing Bupivacaine, Lidocaine, and a Combination of Bupivacaine and Lidocaine for Labor Epidural Activation: A Prospective, Randomized, Double-Blind Study

Objective: Epidural anesthesia for the parturient is often provided in a clinical context where rapid onset of segmental analgesia is important; however, little is published on the ideal local anesthetic to safely achieve this onset. To fi ll this gap in knowledge, we studied bupivacaine and lidocaine, two local anesthetics (LA) commonly used for labor epidural activation, either as a single drug or in combination to determine the onset of epidural analgesia. Methods: In this double-blinded study, seventy-five patients were randomized into three groups (n = 25 each) for labor epidural activation: 10 mL of 0.25% bupivacaine, 10 mL of 1% lidocaine, or 5 mL of 0.25% bupivacaine plus 5 mL of 1% lidocaine. Patients were assessed for the fi rst 20 min after drug administration at 5-min intervals. Data collected included sensory level to pinprick, maternal blood pressure, vasopressor administration, and peak motor blockade. Results: Data were analyzed on 71 of 75 patients. Time to loss of sensation to pinprick at the T10 dermatome in the bupivacaine group was signifi cantly longer than the lidocaine group (p = 0.006), but the time to loss of sensation to pinprick at the T10 dermatome did not signifi cantly differ in the bupivacaine plus lidocaine group when compared to both the bupivacaine (p = 0.114) as well as the lidocaine (p = 0.203) groups. Phenylephrine usage did not signifi cantly differ amongst the three groups (p = 0.062). Conclusion: Lidocaine provides statistically signifi cant faster onset of epidural analgesia when compared to bupivacaine only. Combining the two LA did not signifi cantly affect onset.

Comparing low-dose bupivacaine with epidural volume extension to standard bupivacaine dosing for short obstetric procedures: a prospective, randomized study.

BACKGROUND: Intrathecal bupivacaine's long duration of action can unnecessarily increase the time to meet Postanesthesia Care Unit (PACU) discharge criteria for patients undergoing short obstetric procedures. We sought to use a technique known as epidural volume extension (EVE) to determine if we could provide an adequate surgical block while significantly decreasing the time required to meet PACU discharge criteria for patients undergoing short obstetric procedures. METHODS: Fifty participants were randomized into two groups. The control group received a 10 mg of 0.5% isobaric bupivacaine plus 15 µg of fentanyl injection in the intrathecal space via a combined spinal-epidural technique. The EVE group received a 5 mg of 0.5% isobaric bupivacaine plus 15 µg of fentanyl injection in the intrathecal space followed immediately by a 10 mL injection of sterile saline through the epidural needle for the EVE. RESULTS: Data were analyzed on 45 of the 50 patients. Time to meet PACU discharge criteria was significantly reduced in the EVE group when compared to the control group (50 vs. 135 minutes, P<0.001). The EVE group had a faster time to complete motor recovery when compared to the control group (66 vs. 181 minutes, P<0.001). Peak block height was similar in both groups at the time of surgery start (T5 vs. T5, P=0.44). CONCLUSIONS: The use of low-dose isobaric bupivacaine in combination with 10 mL of saline EVE allows for faster motor recovery and time to meet PACU discharge criteria in patients undergoing short obstetric procedures.

RETRACTED: Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). Retraction notice to: "Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction" by Nina Vanessa Kraguljac, Matthew Carle, Michael A. Frölich, Steve Tran, Michael A. Yassa, David Matthew White, Abhishek Reddy, and Adrienne Carol Lahti (Biol Psychiatry Cogn Neurosci Neuroimaging 2018; 3:231-238); https://doi.org/10.1016/j.bpsc.2017.02.005. This article has been retracted at the request of Cameron S. Carter, M.D., Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, with agreement from all authors. The authors discovered an error in the calculation of the response bias­corrected pattern recognition score in this article, which has significantly changed the results for experiment 1. Specifically, the authors discovered that the response bias corrected pattern recognition score was erroneously computed as P('old'|target) minus P('old'|lure) rather than P('old'|target) minus P('old'|foil). After re-running statistical analyses with the correct values, the authors found a significant difference in the response bias­corrected pattern recognition score in healthy volunteers (HV) compared with first-episode psychosis (FEP) patients (HV: 84.13 ± 10.96; FEP: 63.70 ± 21.83; t = 4.01; p < .01) in experiment 1. This finding is not consistent with the original report, where the authors reported no group differences in bias-corrected pattern recognition scores (originally reported values: t = 0.93, p = .36). The authors again found no significant correlations between pattern completion scores and BPRS total, positive, or negative symptom scores or RBANS scores, consistent with the original report. In experiment 2, bias-corrected pattern recognition scores did not differ between the saline and ketamine conditions (saline: 78.29 ± 28.04; ketamine: 73.59 ± 18.94; t = 0.81; p = 0.43), which is consistent with the original report (originally reported values: t = −0.69, p = .50). Contrary to the original report, task performance during the saline and ketamine infusions was no longer correlated at trend level for pattern recognition. Repeat analyses showed no correlations between pattern recognition scores during the ketamine challenge and BPRS total, positive, and negative symptom scores, or ketamine plasma levels at either time point, consistent with the original report. The authors have verified that bias-corrected pattern separation scores were calculated correctly for both experiments in the initial report. This error affects the abstract, the results, Figure 1, and discussion of the manuscript. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors are revising the paper, which the Journal will re-review and consider further for publication.

The Effect of Sedation on Cortical Activation: A Randomized Study Comparing the Effects of Sedation With Midazolam, Propofol, and Dexmedetomidine on Auditory Processing.

BACKGROUND: Every day, millions of people undergo surgical procedures facilitated by anesthesia. Yet, there is no clinically accepted measure to predict the effects of sedation or anesthesia on the central nervous system. Auditory brain activation may provide an objective and quantifiable method to measure of the effects of sedation on neuronal processing. METHODS: This is a randomized clinical trial. Forty-eight healthy volunteers were randomly assigned to receive 1 of 3 sedative drugs (midazolam [n = 11], propofol [n = 12], or dexmedetomidine [n = 12]) at a concentration adjusted to achieve mild sedation by self-rating, or to a no-drug control group (n = 13). Participants underwent functional magnetic resonance imaging while listening to music in a 5-minute block design experiment. We tested the hypothesis that mild sedation changes the magnitude or extent of cortical activation of an auditory stimulus. RESULTS: We observed a significant reduction in auditory activation in both the dexmedetomidine (P = .001) and midazolam (P = .029) but not the propofol group (P = .619) when compared with saline control. CONCLUSIONS: Our findings indicate that, compared with saline control, there is a significant reduction of brain activation in the auditory cortex in response to midazolam and dexmedetomidine but not propofol when given at mildly sedative doses. This method serves as a novel approach to quantify the effects of sedative agents in an objective fashion.

Risk factors for failed reactivation of a labor epidural for postpartum tubal ligation: a prospective, observational study.

STUDY OBJECTIVE: To determine specific risk factors that increase the failure rate of labor epidurals reactivated for use as a surgical block for postpartum tubal ligation. DESIGN: Prospective, observational study. SETTING: Labor and delivery suite and operating rooms at the Women and Infants Center. PATIENTS: One hundred patients undergoing postpartum tubal ligation with an existing labor epidural that is documented to be within 2 cm of initial placement. MEASUREMENTS: Body mass index, patient satisfaction with her epidural during labor and delivery, time from delivery to reactivation for tubal ligation, depth to loss of resistance, and the need for top-ups during labor were recorded preoperatively. Failure to reactivate was recorded and defined as any patient that (1) did not achieve a T6 level to pinprick, (2) had perceived pain (pain score >3) that required administration of an intravenous opioid or local anesthetic infiltration, or (3) required conversion to general anesthesia. MAIN RESULTS: The overall success rate of reactivation was 78%. Significant risk factors for failure to reactivate were (1) poor patient satisfaction (P = .016), (2) increased time from delivery to reactivation (P = .044), and (3) the need for top-ups during labor and delivery (P = .032). CONCLUSION: Poor satisfaction score of the epidural during labor and delivery, increasing time from delivery to epidural reactivation for tubal ligation, and the need for top-ups during labor and delivery increase the incidence of reactivation failure. No correlation was found with body mass index or loss of resistance and failure to reactivate.

Bladder Distension Increases Blood Flow in Pain Related Brain Structures in Subjects with Interstitial Cystitis.

PURPOSE: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis. MATERIALS AND METHODS: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition. RESULTS: Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis. CONCLUSIONS: Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral blood flow increases in the full bladder state in regions of interest typically associated with pain, emotion and/or motor control, indicating altered processing of bladder related sensations.

The Association Between Progesterone, Estradiol, and Oxytocin and Heat Pain Measures in Pregnancy: An Observational Cohort Study.

BACKGROUND: Hormonal action has been implicated as a possible mechanism for pregnancy-induced analgesia. Previous investigators have reported an increase in heat pain tolerance during labor compared with nonpregnant controls and postulated it was because of the hormonal changes during pregnancy. However, these previous reports did not include measurement of hormonal values. The purpose of our study was to quantitatively test if changes in pregnancy hormone concentrations correlated with changes in temperature ratings. METHODS: This was a prospective cohort study consisting of 32 women scheduled for elective cesarean delivery at term between July 2010 and January 2013. Heat pain threshold and tolerance, estrogen, progesterone, and oxytocin levels were measured twice in each patient at term and again 4 to 8 weeks postpartum. RESULTS: All hormone levels decreased significantly between term pregnancy and the postpartum visit (all P values < 0.029). However, there were no statistically significant differences between term and postpartum heat pain measurements. The mean baseline heat pain threshold was 40.9°C at term compared with 40.3°C °postpartum (P = 0.47; mean change, -0.6°C; 95% confidence interval of change, -1.8°C to +0.7°C). The mean baseline heat pain tolerance was 46.1°C at term and 46.0°C postpartum (P = 0.59; mean change, -0.1°C; 95% confidence interval of change, -0.8°C° to +0.6°C). CONCLUSIONS: Our findings show that amounts of estradiol and progesterone changed significantly between the term and the postpartum visit; however, the thermal pain tolerance did not significantly change. In summary, we did not observe an association between hormonal changes and changes in pain threshold measures. This finding argues against the concept of simple progesterone- or estrogen-induced analgesia in humans.

Why do pregnant women die? A review of maternal deaths from 1990 to 2010 at the University of Alabama at Birmingham.

BACKGROUND: The number of reported pregnancy-related deaths in the United States steadily increased from 7.2 deaths per 100,000 live births in 1987 to a high of 17.8 deaths per 100,000 live births in 2009. Compared to Caucasian women, African American women were nearly 4 times as likely to die from childbirth. To better understand the reason for this trend, we conducted a case-control study at University of Alabama at Birmingham (UAB) Hospital. Our primary study hypothesis was that women who died at UAB were more likely to be African American than women in a control group who delivered an infant at UAB and did not die. We expected to find a difference in race proportions and other patient characteristics that would further help to elucidate the cause of a racial disparity in maternal deaths. METHODS: We reviewed all maternal deaths (cases) at UAB Hospital from January 1990 through December 2010 identified based on electronic uniform billing data and ICD-9 codes. Each maternal death was matched 2:1 with women who delivered at a time that most closely coincided with the time of the maternal death in 2-step selection process (electronic identification and manual confirmation). Maternal variables obtained were comorbidities, duration of hospital stay, cause of death, race, distance from home to hospital, income, prenatal care, body mass index, parity, insurance type, mode of delivery, and marital status. The strength of univariate associations of maternal variables and case/control status was calculated. The association of case/control status and race was also examined after controlling for residential distance from the hospital. RESULTS: There was insufficient evidence to suggest racial disparity in maternal death. The proportion of African American women was 57% (42 of 77) in the maternal death group and 61% (94 of 154) in the control group (P = 0.23). The univariate odds ratio for maternal death for African American to Caucasian race was 0.66 (95% confidence interval [CI], 0.37-1.19); the adjusted odds ratio was 1.46 (95% CI, 0.73-3.01). Longer compared with shorter distance of residence to the hospital was a highly significant predictor (P < 0.001) of maternal death. CONCLUSIONS: We did not observe a racial disparity in maternal deaths at UAB Hospital. We suggest that the next step toward understanding racial differences in maternal deaths reported in the United States should be directed at the health care delivery outside the tertiary care hospital setting, particularly at eliminating access barriers to health care for all women.

Effect of sedation on pain perception.

BACKGROUND: Sedation or anesthesia is used to facilitate many cases of an estimated 45 million diagnostic and therapeutic medical procedures in the United States. Preclinical studies have called attention to the possibility that sedative-hypnotic drugs can increase pain perception, but whether this observation holds true in humans and whether pain-modulating effects are agent-specific or characteristic of IV sedation in general remain unclear. METHODS: To study this important clinical question, the authors recruited 86 healthy volunteers and randomly assigned them to receive one of three sedative drugs: midazolam, propofol, or dexmedetomidine. The authors asked participants to rate their pain in response to four experimental pain tasks (i.e., cold, heat, ischemic, or electrical pain) before and during moderate sedation. RESULTS: Midazolam increased cold, heat, and electrical pain perception significantly (10-point pain rating scale change, 0.82 ± 0.29, mean ± SEM). Propofol reduced ischemic pain and dexmedetomidine reduced both cold and ischemic pain significantly (-1.58 ± 0.28, mean ± SEM). The authors observed a gender-by-race interaction for dexmedetomidine. In addition to these drug-specific effects, the authors observed gender effects on pain perception; female subjects rated identical experimental pain stimuli higher than male subjects. The authors also noted race-drug interaction effects for dexmedetomidine, with higher doses of drug needed to sedate Caucasians compared with African Americans. CONCLUSIONS: The results of the authors' study call attention to the fact that IV sedatives may increase pain perception. The effect of sedation on pain perception is agent- and pain type-specific. Knowledge of these effects provides a rational basis for analgesia and sedation to facilitate medical procedures.

Quantitative changes in regional cerebral blood flow induced by cold, heat and ischemic pain: a continuous arterial spin labeling study.

BACKGROUND: The development of arterial spin labeling methods has allowed measuring regional cerebral blood flow (rCBF) quantitatively and to show the pattern of cerebral activity associated with any state such as a sustained pain state or changes due to a neurotropic drug. METHODS: The authors studied the differential effects of three pain conditions in 10 healthy subjects on a 3 Tesla scanner during resting baseline, heat, cold, and ischemic pain using continuous arterial spin labeling. RESULTS: Cold pain showed the greatest absolute rCBF increases in left anterior cingulate cortex, left amygdala, left angular gyrus, and Brodmann area 6, and a significant rCBF decrease in the cerebellum. Changes in rCBF were characteristic of the type of pain condition: cold and heat pain showed increases, whereas the ischemic condition showed a reduction in mean absolute gray matter flow compared with rest. An association of subjects' pain tolerance and cerebral blood flow was noted. CONCLUSIONS: The observation that quantitative rCBF changes are characteristic of the pain task used and that there is a consistent rCBF change in Brodman area 6, an area responsible for the integration of a motor response to pain, should provide extremely useful information in the quest to develop an imaging biomarker of pain. Conceivably, response in BA6 may serve as an objective measure of analgesic efficacy.

What factors affect intrapartum maternal temperature? A prospective cohort study: maternal intrapartum temperature.

BACKGROUND: In recent years, several reports have indicated that maternal temperature elevations during labor may also be observed in the absence of an infection. Presumed noninfectious causes of maternal temperature elevations include epidural analgesia, endogenous heat production generated by the contracting uterus, and delivery in an overheated room. To investigate the potential causes of noninfectious maternal temperature changes during labor, we conducted a prospective cohort study in women scheduled for labor induction. METHODS: We recorded hourly oral temperatures from admission to delivery. We calculated whether temperature changed during labor in 81 women. We then determined if body mass index, and duration of labor, or time from rupture of amniotic sac to delivery, or oxytocin dose, would affect maternal temperature. To evaluate the possible role of epidural analgesia, we compared the temperature slope before and after starting epidural analgesia. RESULTS: We observed an overall significant linear trend of temperature over time with an estimated temperature slope of +0.017°C/h (P = 0.0093). Patients with a positive temperature trend had also a significantly longer time from rupture of membranes to delivery (P = 0.0077) and a higher body mass index (P = 0.0067). Epidural analgesia had no effect on the temperature trend. CONCLUSIONS: In our cohort of patients, there was an overall significant linear trend of temperature over time after correcting for heterogeneity among patients. Temperature increase was associated with higher body mass index values and longer time from rupture of membranes to delivery. Epidural analgesia had no effect on maternal temperature.

Hemodynamic characteristics of midazolam, propofol, and dexmedetomidine in healthy volunteers.

STUDY OBJECTIVE: To study the effect of intravenous (IV) sedation on blood pressure (BP), heart rate (HR), and respiratory rates (RR) to determine if IV sedatives differ with respect to their effect on BP, HR, and RR. DESIGN: Prospective, randomized, single-blinded, placebo-controlled study. SETTING: Monitored patient care room at a clinical research center. SUBJECTS: 60 healthy ASA physical status 1 volunteers. INTERVENTIONS: Subjects were randomized to receive, in increasing doses, one of three IV sedatives: propofol, midazolam, or dexmedetomidine; or saline control. MEASUREMENTS: Blood pressure (systolic, diastolic), HR, and RR were recorded. MAIN RESULTS: A significant dose-dependent BP reduction occurred with dexmedetomidine and, to a lesser degree, with propofol; and there was good agreement of predicted versus measured drug concentrations for all sedatives. Blood pressure and HR of participants who received midazolam did not change. CONCLUSIONS: When administered in sedative doses, dexmedetomidine and, to a lesser extent, midazolam, reduces BP in a dose-dependent fashion. Dexmedetomidine also reduces HR. Midazolam does not affect BP or HR.

Intravenous lidocaine reduces ischemic pain in healthy volunteers.

BACKGROUND AND OBJECTIVES: Lidocaine, a local anesthetic and antiarrhythmic drug that alters depolarization in neurons by blocking the fast voltage-gated sodium (Na+) channels in the cell membrane, is used for regional anesthesia, as antiarrhythmic drug, and as analgesic for various painful conditions. It is unclear whether monotherapy with intravenous lidocaine has an analgesic effect in healthy individuals. To address this important question, we studied pain perception before, during, and after the administration of intravenous lidocaine in 16 human volunteers. Our hypothesis was that lidocaine, administered as a short intravenous infusion, does not have an analgesic effect in healthy volunteers. METHODS: Sixteen healthy human volunteers received systemic lidocaine at plasma concentration 2 mg/mL using a computer-assisted infusion. Participants underwent a series of sensory tests-thermal, electrical, and ischemic pain and normal pinprick sensation-at baseline, during, and 30 mins after administration of a 20-min lidocaine infusion at a 2 mg/mL effect site concentration. RESULTS: We found a sustained decrease in ischemic pain ratings and a limited analgesic effect for electrical pain, whereas thermal pain and normal sensation did not change. CONCLUSIONS: The observed sustained analgesic effect of systemic lidocaine in the ischemic pain model suggests that lidocaine may be used to treat acute pain.

Temporal characteristics of cold pain perception.

Adaptation to a sustained stimulus is an important phenomenon in psychophysical experiments. When studying the response to an experimental task, the investigator has to account for the change in perceived stimulus intensity with repeated stimulus application and, if the stimulus is sustained, for the change in intensity during the presentation. An example of a sustained stimulus is the cold pressor task (CPT). The task has been used both as an experimental pain task and to study cardiovascular physiology. In functional imaging research, the CPT has been used to evaluate cognitive processing of a noxious stimulus. Investigators typically model the stimulus in a block design as a categorical (on-off) stimulus and do not account for a temporal change in stimulus perception. If the perceived stimulus changes over time, the results may be misleading. Therefore, we characterized the time course of cold pain in human volunteers and developed a model of the temporal characteristics of perceived cold pain. Fifteen healthy participants underwent cold pain testing by immersing their right foot into a container filled with ice water (2 degrees C) for 30s alternating with a 30s immersion into a container filled with tepid water 32 degrees C (control). Participants rated the pain intensity using an electronic slide algometer. Using a mixed general linear model (effectively a polynomial regression model), we determined that pain ratings follow a crescendo-decrescendo pattern that can be described well using a quadratic model. We conclude that the time course of quantitative perception differs fundamentally from the time course of stimulus presentation. This may be important when looking for the physiological correlates of perception as opposed to the presence of a stimulus per se.