Joel Yarmush

The Recovery of Cognitive Function After Remifentanil- Nitrous Oxide Anesthesia Is Faster than After an Isoflurane-nitrous Oxide-fentanyl Combination in Elderly Patients

We tested the hypothesis that remifentanil-nitrous oxide (N2O) anesthesia shortens postoperative emergence and recovery compared with an isoflurane-N2O-fentanyl combination in elderly patients undergoing spinal surgery. A total of 60 patients (>65 yr old) were randomly assigned to one of two groups for maintenance of anesthesia. After the induction with 3.6 ± 1.2 mg/kg IV thiopental and endotracheal intubation facilitated with 1.4 ± 0.5 mg/kg succinylcholine, patients were maintained with either 0.5%–1.5% isoflurane, 70% N2O, and up to 7 &mgr;g/kg fentanyl (iso/fent group) or 48 ± 11 &mgr;g/kg remifentanil and 70% N2O (remi group). A mini-mental status examination was used to assess cognitive ability preoperatively, at 15, 30, and 60 min after arrival at the postanesthesia care unit and again 12–24 h postoperatively. The time from the conclusion of anesthesia to spontaneous respiration was similar in both groups. Times to eye opening (4.8 ± 2.6 vs 2.3 ± 1.1 min), extubation (6.8 ± 3.8 vs 3.2 ± 2.1 min), and verbalization (9.9 ± 6.2 vs 3.9 ± 2.6 min) were significantly shorter for the remi group (P < 0.05). Postoperative mini-mental status examination scores were significantly lower in the iso/fent group at 15 (16.3 ± 5.8 vs 23.7 ± 3.3), 30 (20.2 ± 5.2 vs 26.3 ± 2.7), and 60 min (23.5 ± 4.4 vs 27.5 ± 2.0) (P < 0.001); however, the scores equalized after 12 h. Requirements for postoperative analgesics were similar in the two groups. More patients in the remi group were treated with antiemetics (21 vs 7, P = 0.06). Use of remifentanil-N2O for maintenance did not shorten the overall length of stay in the postanesthesia care unit; a stay is often related to multiple administrative issues, rather than cognitive recovery. Implications Maintenance of anesthesia with remifentanil-nitrous oxide (N2O), compared with isoflurane-N2O-fentanyl, can safely shorten postoperative recovery of cognitive function in a geriatric population. Earlier recovery may facilitate postoperative neurological assessment. Use of remifentanil-N2O for maintenance did not shorten the overall length of stay in the postanesthesia care unit, a stay often related to multiple administrative issues, rather than cognitive recovery.

Nifedipine-Induced Analgesia After Epidural Injection in Rats

We explored the analgesic effect of epidural nifedipine in male Sprague-Dawley rats. By using an implanted epidural catheter, the rats were given 35 microL of dimethylsulfoxide (DMSO) alone or DMSO containing 2.5, 5, 10, or 20 microM of nifedipine. Analgesia was measured by tailflick (TF) involving spinal reflexes, and by hotplate (HP) requiring an intact central nervous system. The latencies were recorded up to 120 min after the injection. The cutoff time of the noxious stimuli was 20 s in the TF and 60 s in the HP to prevent tissue damage. The TF technique revealed a significant difference from the control at doses of 5, 10, and 20 microM with no difference among the groups. Maximum latencies (cutoff time) lasted for 15, 30, and 40 min at doses of 5, 10, and 20 microM, respectively. The HP technique disclosed a dual effect: a significant decrease at the dose of 2.5 microM, no effect at 5 microM, and an increase at 10 and 20 microM. However, the median latency did not reach the cutoff time. We conclude that nifedipine, given epidurally, possesses antinociceptive properties at the dose of 5 microM and higher, detected better by the TF than HP. Our data suggest that the antinociceptive effect of nifedipine, at the studied doses, is more prominent at the spinal than the supraspinal level.

Ultrasensitive detection of low-abundance surface-marker protein using isothermal rolling circle amplification in a microfluidic nanoliter platform.

With advances in immunology and cancer biology, there is an unmet need for increasingly sensitive systems to monitor the expression of specific cell markers for the development of new diagnostic and therapeutic tools. To address this challenge, a highly sensitive labeling method that translates antigen-antibody recognition processes into DNA detection events that can be greatly amplified via isothermal rolling circle amplification (RCA) is applied. By merging the single-molecule detection power of RCA reactions with microfluidic technology, it is demonstrated that the identification of specific protein markers can be achieved on tumor-cell surfaces in miniaturized nanoliter reaction droplets. Furthermore, this combined approach of signal amplification in a microfluidic format could extend the utility of existing methods by reducing sample and reagent consumption and enhancing the sensitivities and specificities for various applications, including early diagnosis of cancer.

Propofol induces MAPK/ERK cascade dependant expression of cFos and Egr-1 in rat hippocampal slices

BackgroundPropofol is a commonly used intravenous anesthetic agent, which produce rapid induction of and recovery from general anesthesia. Numerous clinical studies reported that propofol can potentially cause amnesia and memory loss in human subjects. The underlying mechanism for this memory loss is unclear but may potentially be related to the induction of memory-associated genes such as c-Fos and Egr-1 by propofol. This study explored the effects of propofol on c-Fos and Egr-1 expression in rat hippocampal slices.FindingsHippocampal brain slices were exposed to varying concentrations of propofol at multiple time intervals. The transcription of the immediate early genes, c-Fos and Egr-1, was quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). MAPK/ERK inhibitors were used to investigate the mechanism of action. We demonstrate that propofol induced the expression of c-Fos and Egr-1 within 30 and 60 min of exposure time. At 16.8 μM concentration, propofol induced a 110% increase in c-Fos transcription and 90% decrease in the transcription of Egr-1. However, at concentrations above 100 μM, propofol failed to induce expression of c-Fos but did completely inhibit the transcription of Egr-1. Propofol-induced c-Fos and Egr-1 transcription was abolished by inhibitors of RAS, RAF, MEK, ERK and p38-MAPK in the MAPK/ERK cascade.ConclusionsOur study shows that clinically relevant concentrations of propofol induce c-Fos and down regulated Egr-1 expression via an MAPK/ERK mediated pathway. We demonstrated that propofol induces a time and dose dependant transcription of IEGs c-Fos and Egr-1 in rat hippocampal slices. We further demonstrate for the first time that propofol induced IEG expression was mediated via a MAPK/ERK dependant pathway. These novel findings provide a new avenue to investigate transcription-dependant mechanisms and suggest a parallel pathway of action with an unclear role in the activity of general anesthetics.

Impact of Regional versus General Anesthesia on the Clinical Outcomes of Patients Undergoing Major Lower Extremity Amputation

BACKGROUND Patients undergoing major lower extremity amputation (MLEA) for peripheral arterial disease are often elderly, debilitated, and fraught with medical comorbid conditions that place them at high risk for surgical intervention. Data from lower extremity revascularization surgeries are often extrapolated to determine which anesthetic modality to use for amputations, with preference given to regional anesthesia. However, there is little evidence to support the use of one mode of anesthesia over another. We conducted this study to determine the effect of anesthetic modality on the clinical outcomes of patients undergoing above- or below-knee amputations. METHODS This study is a retrospective review of consecutive patients who underwent MLEA at a single center between 2002-2011. The study population was divided into 2 groups based on anesthetic modality (i.e., regional vs. general anesthesia). These groups were compared based on demographics and comorbidities. Major outcomes analyzed included death, myocardial infarction (MI), and pulmonary complications. Secondary outcome measures included cardiac arrhythmias, venous thromboembolism (VTE), and duration of stay in the intensive care unit and hospital. RESULTS Four hundred sixty-three patients were identified; 56 patients were excluded for incomplete data, leaving 407 patients in the 2 groups combined. Of these, 259 patients underwent amputation under regional anesthesia; 148 underwent amputation under general anesthesia. Patients in the regional anesthesia group were older (76.6 vs. 71.6 years; P=0.001) and had a lower body mass index (25.2 vs. 26.9 kg/m2; P=0.013). They were also less likely to be on preoperative antiplatelet therapy (aspirin or clopidogrel) or anticoagulation (27% vs. 45%; P<0.001). Regional anesthesia was associated with a lower incidence of overall postoperative pulmonary complications (15% vs. 24%; P=0.02) and postoperative arrhythmia (14% vs. 25%; P=0.001). Duration of stay in the intensive care unit (1.92 vs. 3.85 days; P=0.001) and hospital (19.4 vs 23.1 days; P=0.037) were significantly longer in the group receiving general anesthesia. No significant differences in postoperative MI (12% vs. 9%; P=not significant [NS]), VTE (5% vs. 7%; P=NS) or mortality (10% vs. 13%; P=NS) was seen between groups. Controlling for procedure, above- versus below-knee amputation did not significantly alter these results. CONCLUSIONS Regional anesthesia for patients undergoing MLEA is associated with a lower incidence of postoperative pulmonary complications and cardiac arrhythmias. It is also associated with lower resource use. As such, regional anesthesia should likely be the favored anesthetic modality for patients undergoing MLEA.

Efficacy of ginger on intraoperative and postoperative nausea and vomiting in elective cesarean section patients

OBJECTIVE To evaluate the efficacy of dry powdered ginger, given orally, on nausea and vomiting during and after an elective cesarean section performed under combined spinal epidural anesthesia. STUDY DESIGN 239 women, ginger (n=116) and placebo (n=123), who underwent elective cesarean section at term under combined spinal-epidural anesthesia were provided with standard preoperative antiemetic treatment in addition to a randomized study drug. They were given two capsules (1g each) of either dry powdered ginger or placebo, one capsule a half-hour before induction of anesthesia and the second 2h after surgery. The study was double-blinded and the incidences of nausea and vomiting were assessed both intraoperatively and postoperatively. Levels of pain and pruritus were also assessed postoperatively. RESULTS The intraoperative incidence of nausea was 52% and 61%, ginger versus placebo (p=0.149). The number of episodes of intraoperative nausea was less in the ginger group compared to placebo (mean difference was -0.396, 95% CI -0.738, -0.054) and the result was statistically significant (p=0.023). The incidence of intraoperative vomiting was 27.35% in the ginger group and 36.59% in the placebo group, and the difference was not statistically significant (p=0.126). The number of episodes of vomiting during surgery was less in the ginger group compared to placebo: (mean difference -0.158, 95% CI -0.626, 0.311) although statistically insignificant (p=0.505). Furthermore, postoperatively, there was no statistical difference in the incidence of nausea and vomiting assessed at 0, 2, 2 ½ and 24h after surgery. There were also no differences in postoperative pain or pruritus. CONCLUSION Ginger given in dry powdered form reduced the number of episodes of intraoperative nausea compared to a placebo, but it had no effect on incidence of nausea, vomiting, or pain during and after an elective cesarean section performed under combined spinal epidural anesthesia.

Propofol induces ERK-dependant expression of c-Fos and Egr-1 in neuronal cells.

This study explored the effects of propofol on c-Fos and Egr-1 in neuroblastoma (N2A) cells. We demonstrate that propofol induced the expression of c-Fos and Egr-1 within 30 and 60 min of exposure time. At 16.8 μM concentration, propofol induced a 6 and 2.5-fold expression of c-Fos and Egr-1, respectively. However, at concentrations above 100 μM, propofol failed to induce expression of c-Fos or Egr-1. Propofol-induced c-Fos and Egr-1 transcription was unaffected by bicuculline, a &ggr;-aminobutyric acid-A receptor antagonist, but was abolished by PD98059, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor. Our study shows that clinically relevant concentrations of propofol induce c-Fos and Egr-1 expression through an extracellular signal-regulated kinase mediated and &ggr;-aminobutyric acid-A independent pathway.

A randomized, prospective, double-blind trial comparing 3% chloroprocaine followed by 0.5% bupivacaine to 2% lidocaine followed by 0.5% bupivacaine for interscalene brachial plexus block.

BACKGROUND: The combination of 2-chloroprocaine and bupivacaine (C/B) for regional anesthesia has been described, but its use was largely abandoned due to equivocal results in efficacy. In this prospective, double-blind, randomized study, we compared the onset of an interscalene block using C/B versus a combination of lidocaine and bupivacaine (L/B). METHODS: Thirty patients scheduled for shoulder arthroscopy under interscalene block were divided into two groups of 15 each. One group (C/B) received 3% 2-chloroprocaine combined with bicarbonate and epinephrine, immediately followed by 0.5% bupivacaine and epinephrine, whereas the other group (L/B) received 2% lidocaine instead of 3% 2-chloroprocaine. Motor and sensory block were assessed every 15 s. The primary end-point was the time of onset to complete motor block. Time-to-event (survival) statistical analysis tests were applied. RESULTS: One L/B patient had a failed block, and was excluded. The median time to motor block for C/B and L/B was 90 (15–575) and 180 (15–3720) s, respectively (P = 0.0325), and to sensory block for C/B and L/B was 90 (30–600) and 210 (30–3900) s, respectively (P = 0.0185). Survival analysis showed that in 5 min, 13 of 15 patients from the C/B group but only 7 of 14 from the L/B group had a successful motor block. In 10 min, 15 of 15 patients from the C/B group but only 10 of 14 from the L/B group had a successful motor block. It took as long as 60 min to assess block success/failure for blocks in the L/B group. CONCLUSIONS: This study demonstrates that a successful block was more rapid using C/B than L/B for interscalene blocks.

Bicarbonate plus epinephrine shortens the onset and prolongs the duration of sciatic block using chloroprocaine followed by bupivacaine in sprague-dawley rats.

Background: Chloroprocaine is a fast-acting local anesthetic, whereas bupivacaine is a long-acting one. They have been coadministered with limited success. The objective of this study was to determine the effect of additives on the efficacy of regional blockade using chloroprocaine followed by bupivacaine. Methods: Four groups of Sprague-Dawley rats, 20 each, were administered chloroprocaine followed by bupivacaine to induce sciatic nerve blockade. Group 1 received chloroprocaine with isotonic sodium chloride solution followed by bupivacaine and was used as a control. Group 2 received chloroprocaine with isotonic sodium chloride solution and epinephrine followed by bupivacaine with epinephrine. Group 3 received chloroprocaine with sodium bicarbonate followed by bupivacaine, and group 4 received chloroprocaine with sodium bicarbonate and epinephrine followed by bupivacaine with epinephrine. The time to onset and duration of anesthesia were measured for all 4 groups. Results: The block using chloroprocaine followed by bupivacaine in group 1 had an onset of 2.5 mins (SD, 0.4 mins) and duration of 104 mins (SD, 16 mins). Adding epinephrine to both chloroprocaine and bupivacaine (group 2) did not significantly change the onset (2.8 mins [SD, 1.3 mins]; P = 0.35) or duration (110 mins [SD, 25 mins]; P = 0.23). With group 3, adding bicarbonate to chloroprocaine hastened the onset (1.2 mins [SD, 0.4 mins]; P < 0.0001) and shortened the duration (87 mins [SD, 13 mins]; P = 0.008). In group 4, adding bicarbonate and epinephrine to chloroprocaine and epinephrine to bupivacaine hastened the onset (1.4 mins [SD, 0.4 mins]; P < 0.0001) and increased the duration (130 mins [SD, 23 mins]; P < 0.0001). Conclusions: Sodium bicarbonate plus epinephrine shortens the onset and prolongs the duration of a chloroprocaine-bupivacaine sciatic block in Sprague-Dawley rats.

The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells.

Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist even after LA removal.