Michael Haile

Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model.

BackgroundInhalational anesthetics are neuroprotective in rat models of global ischemia. To determine whether isoflurane at a clinically relevant concentration is neuroprotective in a canine model of cardiac arrest, we measured neurologic function and hippocampal Ca2+/calmodulin-dependent protein kinase II (CaMKII) content 20 h after cardiac arrest. MethodsWe tested the neuroprotective effect of 30 min of 1.5% isoflurane exposure before 8 min of global ischemia induced with ventricular fibrillation. Animals were randomized to four groups: control, isoflurane–control, ischemia, and isoflurane–ischemia. After resuscitation and 20 h of intensive care, each animal’s neurologic deficit score was determined by two blinded evaluators. The hippocampal content of CaMKII, determined by immunoblotting, was measured by an individual blinded to the treatment groups. CaMKII activity was measured in samples from the cortex, hippocampus, and striatum of animals in each group. ResultsIsoflurane–ischemic animals had a median neurologic deficit score of 22.6% compared with 43.8% for the ischemic animals (P < 0.05). Hippocampal levels of the &bgr;-subunit of CaMKII (CaMKII&bgr;) were relatively preserved in isoflurane–ischemic animals (68 ± 4% of control) compared with ischemic animals (48 ± 2% of control;P < 0.001), although both groups were statistically significantly lower than control (P < 0.001 ischemia vs. control and P < 0.05 isoflurane–ischemia vs. control). ConclusionsIsoflurane is an effective neuroprotective drug in a canine cardiac arrest model in terms of both functional and biochemical criteria.

The effect of intraoperative infusion of dexmedetomidine on the quality of recovery after major spinal surgery.

Background: Surgery induces a variety of metabolic, endocrine, and immune changes collectively known as the “stress response,” which may often lead to prolonged postoperative convalescence. Anesthetic management may modulate this physiological response, thus affecting the postoperative course. We hypothesized that the intraoperative administration of dexmedetomidine (DEX), a sympatholytic agent, would reduce the stress response and improve the quality of recovery in patients undergoing major surgery. Methods: We conducted a prospective randomized double-blinded study of 54 patients undergoing multilevel spinal fusion. Anesthesia was maintained using either propofol/fentanyl/dexmedetomidine (PFD) or propofol/fentanyl/placebo-saline (PFS). The quality of recovery (a primary endpoint) was assessed using a 40-item quality of recovery questionnaire and a 9-question Fatigue Severity Scores. The tests were carried out preoperatively on postoperative days (POD) 1, 2, 3, and 30. Blood samples were collected at baseline, in the postanesthesia care unit, and at POD 1 and were analyzed for levels of cortisol, C-reactive proteins (CRP), and cytokines interleukin (IL)-1&agr;, IL-1&bgr;, IL-1ra, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-&agr;. Data were analyzed using SPSS software (version 18) using a multivariate and mixed model approach to test for the effect of surgery and drug group. Pairwise comparisons were assessed by means of the t test or rank tests after correcting for multiple comparisons. Results: The global 40-item quality of recovery questionnaire scores showed a significant effect of time (F4,114=22.63, P<0.001) and drug (F1,51=4.368, P=0.042), with average scores decreasing to lower values on POD 1 (163.63±2.47) and POD 2 (170.94±2.38) compared with baseline (180.56±1.588, mean±SE, 2-tailed t tests, P<0.001). By POD 3, scores were significantly lower (−13.74 point difference, P=0.005) in the PFS group (169.3±3.87) than in the PFD group (183.04±2.76). All patients reported significantly higher levels of fatigue postoperatively, but intergroup difference in Fatigue Severity Scores was detected on POD 3 only, with scores in the PFS group higher than in the PFD group (50.0±4.0 vs. 36.3±4.9, P=0.035). In both groups, plasma cortisol levels were highest in the postanesthesia care unit, whereas CRP levels were elevated on POD 1. DEX significantly reduced the levels of cortisol, but not those of CRP. Levels of cytokines IL-6, IL-8, and IL-10 were significantly higher immediately after surgery and at POD 1. Plasma levels of other cytokines were not affected by surgery. DEX delayed postoperative rise in IL-10 but not in IL-6 or IL-8. Conclusions: DEX infusion during multilevel spinal fusions moderately improved the quality of recovery and possibly reduced fatigue in the early postoperative period. Moreover, it reduced plasma levels of cortisol and IL-10 in comparison with the control group. Our sample size was not sufficient to detect differences either in the incidence of complications or in clinically relevant outcomes.

Surgery and Brain Atrophy In Cognitively Normal Elderly Subjects and Subjects Diagnosed with Mild Cognitive Impairment

Background: Structural magnetic resonance imaging is used to longitudinally monitor the progression of Alzheimer disease from its presymptomatic to symptomatic phases. Using magnetic resonance imaging data from the Alzheimers Disease Neuroimaging Initiative, we tested the hypothesis that surgery would impact brain parameters associated with progression of dementia. Methods: Brain images from the neuroimaging initiative database were used to study normal volunteer subjects and patients with mild cognitive impairment for the age group 55 to 90 inclusive. We compared changes in regional brain anatomy for three visits that defined two intervisit intervals for a surgical cohort (n = 41) and a propensity matched nonsurgical control cohort (n = 123). The first interval for the surgical cohort contained the surgical date. Regional brain volumes were determined with Freesurfer and quantitatively described with J-image software (University of California at San Francisco, San Francisco, California). Statistical analysis used Repeated Measures ANCOVA (SPSS, v.18.0; Chicago, IL). Results: We found that surgical patients, during the first follow-up interval (5–9 months), but not subsequently, had increased rates of atrophy for cortical gray matter and hippocampus, and lateral ventricle enlargement, as compared with nonsurgical controls. A composite score of five cognitive tests during this interval showed reduced performance for surgical patients with mild cognitive impairment. Conclusions: Elderly subjects after surgery experienced an increased rate of brain atrophy during the initial evaluation interval, a time associated with enhanced risk for postoperative cognitive dysfunction. Although there was no difference in atrophy rate by diagnosis, subjects with mild cognitive impairment suffered greater subsequent cognitive effects.

Does mild cognitive impairment increase the risk of developing postoperative cognitive dysfunction

BACKGROUND Increasingly, postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly. We sought to determine whether patients with mild cognitive impairment (MCI) would have an accelerated progression of dementia postoperatively when compared with the patients without MCI. METHODS The Center for Brain Health at the New York University (NYU) Medical Center maintains records of volunteers who undergo a series of neurological assessments. We reviewed records of 670 patients who received at least 2 evaluations and whose surgery occurred before the second assessment. Longitudinal differences of several cognitive domains were examined. RESULTS Individuals with MCI and surgery had a greater decline in performance on the Digit Span Forward test compared with those with MCI without surgery on their postoperative evaluation (F(3,158) = 3.12, P = .03). No performance changes were detected in the normal subjects. CONCLUSION These preliminary findings suggest that surgery negatively impacts attention/concentration in patients with MCI but not in normal individuals. This is the first study that identified a specific subgroup of patients who are predisposed to POCD.

Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice.

Context Surgery-induced neuroinflammation has been implicated in the development of postoperative cognitive dysfunction (POCD). Objective To test the hypothesis that meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, preserves postoperative cognitive function and inhibits surgery-induced neuroinflammation in a mouse model. Design A mouse model of splenectomy-induced inflammation. Methods Sixty Swiss Webster male mice (6–8 week old) were randomised into six groups that underwent splenectomy. Animals in groups 1–4 were tested once on day 1, 5, 9 or 14 to determine the time course of delayed transient cognitive dysfunction associated with splenectomy. Animals in groups 5 and 6 were tested once on day 5 or 9 to determine the ability of the NSAID meloxicam to attenuate cognitive dysfunction. Intervention Animals in groups 1–4 received one dose 500 &mgr;l intraperitoneal physiological saline 24 h after splenectomy. Animals in groups 5 and 6 received one dose of intraperitoneal meloxicam (60 mg kg in 500 &mgr;l saline) 24 h after splenectomy. Main outcome measures Short-term working memory as determined by Object Recognition Test (ORT) index on days 1, 5, 9 and 14 was the first main outcome. Tomato lectin staining histochemistry of glial cells was assessed on days 1, 5, 9 and 14 as a second main outcome. Results Compared with day 1 (group 1), the mean ORT indices at day 5 (group 2) and day 9 (group 3) were decreased by 27.5% [95% confidence interval (CI): 0.9 to 54.1%, P = 0.04] and 23.8% (95% CI, 4.3 to 51.9%, P = 0.09), respectively. At day 5 (group 5) and day 9 (group 6), the ORT indices in the meloxicam groups were reduced by 6.6% (95% CI: −11.4 to 24.5%) and 4.3% (95% CI: −25.3 to 34.0). Thus, the administration of meloxicam attenuated the decrease in ORT indices (P = 0.031). Histochemical staining with tomato lectin showed features of microglia activation at day 5 and 9, which was reduced by the administration of meloxicam. Conclusion These findings suggest that COX-2-dependent mechanisms may play a role in the development of POCD. This effect may be dependent on the modulation of glial cell activation.

Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice.

Background Cognitive changes associated with moderate hypoxia may be related to the elevation of cytosolic calcium (Ca2+) levels which may, in turn, affect neurotransmitter synthesis and metabolism. We tested whether treatment with nimodipine (NIMO), an L-type Ca2+ channel blocker, would preserve working memory after hypoxic hypoxia. Methods We randomized 157 Swiss-Webster, 30 to 35 g mice (6 to 8 wk) to 6 groups, which were exposed to the following gas mixtures for 1 hour: (1) O2 21%; (2) O2 21% followed by 0.1 mg/kg of subcutaneous NIMO; (3) O2 21% followed by vehicle (60% polyethylene glycol/40% methanol); (4) O2 10%; (5) O2 10% then NIMO; (6) O2 10% then vehicle. The Object Recognition Test (ORT) was given once either on Day 1 or Day 7 to assess changes in short-term memory. ORT exploits the tendency of mice to prefer novel over familiar objects. Two identical objects were placed in an arena for 15 minutes of training. During the testing 1 hour later, one of the objects was replaced by a new object. Recognition Index (RI) was used to compare performance. It is defined as the time spent exploring the novel object divided by the time spent exploring both objects, the novel plus the familiar, and this ratio is converted to a percentage. RI was analyzed with analysis of variance. Tukey Honestly Significant Difference tests were used for post hoc comparisons when appropriate. P values <0.05 were considered significant. Results RI for the control group was 68.3% (SE±3.6%). RI was 53.7% (SE±3.8%) for the 10% O2 group on the first posttreatment day. O2 saturation (SpO2) for the hypoxic group was 71.7% (SE±0.5%). By Day 7, RI for the 10% O2 group increased to 64.2% (SE±4.7%), which was not significantly different from control. On Day 1, RI was 68.6% (SE±5.2%) for hypoxic rodents treated with NIMO. These results were statistically significant. Low RI indicates impaired working memory and high RI indicates intact working memory. These results suggest that NIMO prevented impairment of working memory after moderate hypoxia. Conclusions NIMO reverses the disturbance of short-term working memory caused by moderate hypoxia in mice. The results may have implications for cognitive changes linked to Ca2+ homeostasis in the postoperative period.

Efficacy of Clevidipine in Controlling Perioperative Hypertension in Neurosurgical Patients: Initial Single-center Experience

Background Acute blood pressure (BP) elevations in neurosurgical patients are associated with serious neurologic, cardiovascular, or surgical site complications. Clevidipine, an ultra-short-acting dihydropyridine calcium antagonist, has been shown to be efficacious and safe for acute hypertension in cardiac surgery. This study assessed the efficacy and safety of clevidipine in controlling perioperative hypertension in the neurosurgical setting. Methods Patients scheduled for intracranial surgery were prospectively enrolled after giving consent. Clevidipine (0.5 mg/mL in 20% lipid solution, which was to be initiated at 10 mg/h and titrated to effect) was administered as the primary antihypertensive agent for perioperative hypertension, with target BPs of less than 130 mm Hg. Other vasoactive drugs were administered as needed for treating systolic BP (SBP) less than 90 mm Hg or greater than 130 mm Hg. The primary study endpoint was the proportion of patients not requiring rescue antihypertensives to maintain target SBP (<130 mm Hg). Results Twenty-two patients were enrolled. One patient did not require antihypertensive therapy. Seventeen patients (17 of 21, 81%) were treated with clevidipine alone; one received clevidipine in the postanesthesia care unit only. Twenty-eight hypertensive episodes (defined as any new acute BP elevation requiring clevidipine initiation) were documented. SBP was reduced to target level within 15 minutes in 22 of 28 episodes (78.6%). Two mild hypotensive episodes occurred after the initiation of clevidipine infusion; these transient decreases in BP were treated with vasoactive drugs and resolved within 5 minutes. Conclusions Clevidipine is effective and safe for perioperative hypertension in patients undergoing intracranial procedures. Rapid control of BP is possible with higher starting doses. Drug effects resolved rapidly after drug discontinuation.

Nimodipine prevents memory impairment caused by nitroglycerin-induced hypotension in adult mice.

BACKGROUND: Hypotension and a resultant decrease in cerebral blood flow have been implicated in the development of cognitive dysfunction. We tested the hypothesis that nimodipine (NIMO) administered at the onset of nitroglycerin (NTG)-induced hypotension would preserve long-term associative memory. METHODS: The passive avoidance (PA) paradigm was used to assess memory retention. For PA training, latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock was automatically delivered. Latencies were recorded 48 h later for a testing trial. Ninety-six Swiss-Webster mice (30–35 g, 6–8 wk), were randomized into 6 groups 1) saline (control), 2) NTG immediately after learning, 3) NTG 3 h after learning, 4) NTG and NIMO, 5) vehicle, and 6) NIMO alone. The extent of hypotension and changes in brain tissue oxygenation (PbtO2) and in cerebral blood flow were studied in a separate group of animals. RESULTS: All groups exhibited similar training latencies (17.0 ± 4.6 s). Mice subjected to hypotensive episodes showed a significant decrease in latency time (178 ± 156 s) compared with those injected with saline, NTG + NIMO, or delayed NTG (580 ± 81 s, 557 ± 67 s, and 493 ± 146 s, respectively). A Kruskal-Wallis 1-way analysis of variance indicated a significant difference among the 4 treatment groups (H = 15.34; P < 0.001). In a separate group of mice not subjected to behavioral studies, the same dose of NTG (n = 3) and NTG + NIMO (n = 3) caused mean arterial blood pressure to decrease from 85.9 ± 3.8 mm Hg sem to 31.6 ± 0.8 mm Hg sem and from 86.2 ± 3.7 mm Hg sem to 32.6 ± 0.2 mm Hg sem, respectively. Mean arterial blood pressure in mice treated with NIMO alone decreased from 88.1 ± 3.8 mm Hg to 80.0 ± 2.9 mm Hg. The intergroup difference was statistically significant (P < 0.05). PbtO2 decreased from 51.7 ± 4.5 mm Hg sem to 33.8 ± 5.2 mm Hg sem in the NTG group and from 38.6 ± 6.1 mm Hg sem to 25.4 ± 2.0 mm Hg sem in the NTG + NIMO groups, respectively. There were no significant differences among groups. CONCLUSION: In a PA retention paradigm, the injection of NTG immediately after learning produced a significant impairment of long-term associative memory in mice, whereas delayed induced hypotension had no effect. NIMO attenuated the disruption in consolidation of long-term memory caused by NTG but did not improve latency in the absence of hypotension. The observed effect of NIMO may have been attributable to the preservation of calcium homeostasis during hypotension, because there were no differences in the PbtO2 indices among groups.

Rivastigmine in the treatment of postoperative delirium: a pilot clinical trial.

Postoperative delirium (POD) is a common complication among the older people that is associated with increased mortality, morbidity, and prolonged hospital stay. Delirium represents the clinical manifestation of a diffuse, reversible impairment of cerebral oxidative metabolism and an ensuing imbalance of neurotransmitters. Cerebral acetylcholine synthesis is particularly sensitive to perioperative physiologic disturbances. Several recent trials have considered commercially available cholinesterase inhibitors in the treatment of POD in patients undergoing cardiac (Gamberini et al., 2009) and non-cardiac surgery (Liptzin et al., 2005, Sampson et al., 2007) with mixed results. However, methodological issues and erratic and unpredictable absorption of the oral formulation of the drugs and postoperative ileus precluded the authors from reaching definitive conclusions. We designed a clinical trial to examine whether preoperative administration of transdermal rivastigmine (Exelon Patch, Novartis Corporation, Basel, Switzerland) reduces the incidence of POD in older patients undergoing major surgery. The objective of the study was to estimate the proportion of older patients with one or more episodes of postoperative confusion following the administration of transdermal rivastigmine or placebo.

Nimodipine-induced hypotension but not nitroglycerin-induced hypotension preserves long- and short-term memory in adult mice.

BACKGROUND: Acute hypotension may be implicated in cognitive dysfunction. L-Type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG). METHODS: Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for IP injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given IP injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO2) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment. RESULTS: The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant. CONCLUSION: Acute hypotension induced by NIMO was protective of 2 categories of memory formation relevant to the clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed short-term working memory function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. These results indicate the utility of further investigation of L-type calcium channel blockers as a potential means of preserving cognition in the setting of hypotensive and low flow states.