Changes in the corrected carotid flow time can predict spinal anesthesia-induced hypotension in patients undergoing cesarean delivery: an observational study.

PURPOSE: Spinal anesthesia is a standard technique for cesarean delivery; however, it possesses a risk of hypotension. We hypothesised that the changes in the corrected flow time induced by the Trendelenburg position could predict the incidence of hypotension after spinal anesthesia for cesarean delivery. METHODS: Patients undergoing elective cesarean delivery under spinal anesthesia were enrolled. Before anesthesia induction, corrected flow time was measured in the supine and Trendelenburg positions (FTc-1 and FTc-2, respectively). Additionally, a percent change in corrected flow time induced by the Trendelenburg position was defined as ΔFTc. The primary endpoint was to investigate the ability of ΔFTc to predict the incidence of spinal anesthesia-induced hypotension until delivery. The receiver operating characteristics curves to assess the ability of FTc-1, FTc-2, and ΔFTc to predict the incidence of hypotension were generated. RESULTS: Finally, 40 patients were included, and of those, 26 (65%) developed spinal anesthesia-induced hypotension. The areas under the curve for FTc-1, FTc-2, and ΔFTc were 0.591 (95% CI: 0.424 to 0.743) (P = 0.380), 0.742 (95% CI: 0.579 to 0.867) (P = 0.004), and 0.882 (95% CI: 0.740 to 0.962) (P < 0.001) respectively, indicating ΔFTc as the best predictor among these three parameters. The best threshold for ΔFTc was 6.4% (sensitivity: 80.8% (95% CI: 53.8 to 96.2), specificity: 85.7% (95% CI: 42.9 to 100.0)). CONCLUSIONS: This study demonstrated that changes in the corrected carotid flow time induced by the Trendelenburg position could serve as a good predictor of spinal anesthesia-induced hypotension for cesarean delivery.

Validation of Continuous Noninvasive Blood Pressure Monitoring Using Error Grid Analysis.

BACKGROUND: Error grid analysis was recently proposed to compare blood pressure obtained by 2 measurement methods. This study aimed to compare continuous noninvasive blood pressure (CNBP) with invasive blood pressure (IBP) using the error grid analysis and investigate the confounding risk factors attributable to the differences between CNBP and IBP. METHODS: Sixty adult patients undergoing general anesthesia were prospectively enrolled. Simultaneous comparative data regarding CNBP and IBP were collected. The Bland-Altman analysis was conducted to compare CNBP and IBP for systolic blood pressure (SBP) and mean blood pressure (MBP; acceptable accuracy: mean bias <5 mm Hg; standard deviation <8 mm Hg). The clinical relevance of the discrepancies between CNBP and IBP was evaluated by the error grid analysis, which classifies the differences into 5 zones from "no risk" (A) to "dangerous risk" (E). Additionally, an ordinal logistic regression analysis was performed to evaluate the relationship between the risk zones for MBP, classified by the error grid analysis and covariates of interest. RESULTS: A total of 10,663 pairs of CNBP/IBP were finally analyzed. The Bland-Altman analysis showed an acceptable accuracy with a bias of -3.3 ± 5.6 mm Hg for MBP but a poor accuracy with a bias of 5.4 ± 10.5 mm Hg for SBP. The error grid analysis showed the proportions of zones A to E as 96.7%, 3.2%, 0.1%, 0%, and 0% for SBP, respectively, and 72.0%, 27.9%, 0.1%, 0%, and 0% for MBP, respectively. The finger cuff missed 23.9% of epochs when SBP <90 mm Hg and 55.3% of epochs when MBP <65 mm Hg. The ordinal logistic regression analysis revealed that older age (adjusted odds ratio for decade: 1.54, 95% confidence interval [CI], 1.15-2.08; P = .004) and length of time from the initiation of finger cuff inflation (adjusted odds ratio for 60 minutes: 1.40, 95% CI, 1.13-1.73; P = .002) were significant factors of being in a more dangerous zone of the error grid. CONCLUSIONS: The error grid analysis revealed the larger clinical discrepancy between CNBP and IBP in MBP compared with that in SBP. Old age and longer finger cuff inflation time were significant factors of being in a more dangerous zone of the error grid, which could affect the hemodynamic management during surgery.

Protective effects of remote ischemic preconditioning against spinal cord ischemia-reperfusion injury in rats.

OBJECTIVES: We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ventral horn. METHODS: Male Sprague-Dawley rats were divided into 5 groups (n = 6 in each group) as follows: sham; SCI (only spinal cord ischemia); RIPC/SCI (perform remote ischemic preconditioning before spinal cord ischemia); MK-801/RIPC/SCI (administer MK-801, N-methyl-D-aspartate receptor antagonist, before remote ischemic preconditioning); and MK-801/SCI (administer MK-801 without remote ischemic preconditioning). Remote ischemic preconditioning was achieved by brief limb ischemia 80 minutes before spinal cord ischemia. MK-801 (1 mg/kg, intravenous) was administered 60 minutes before remote ischemic preconditioning. The glutamate concentration in the ventral horn was measured by microdialysis for 130 minutes after spinal cord ischemia. Immunofluorescence was also performed to evaluate the expression of N-methyl-D-aspartate receptor 2B subunit in the ventral horn 130 minutes after spinal cord ischemia. RESULTS: The glutamate concentrations in the spinal cord ischemia group were significantly higher than in the sham group at all time points (P < .01). Remote ischemic preconditioning attenuated the spinal cord ischemia-induced glutamate increase. When MK-801 was preadministered before remote ischemic preconditioning, glutamate concentration was increased after spinal cord ischemia (P < .01). Immunofluorescence showed that remote ischemic preconditioning prevented the increase in the expression of N-methyl-D-aspartate receptor 2B subunit on the surface of motor neurons (P = .047). CONCLUSIONS: Our results showed that remote ischemic preconditioning prevented spinal cord ischemia-induced extracellular glutamate increase in ventral horn and suppressed N-methyl-D-aspartate receptor 2B subunit expression.

Protective effects of hydrogen gas against spinal cord ischemia-reperfusion injury.

OBJECTIVE: This experimental study aimed to assess the efficacy of hydrogen gas inhalation against spinal cord ischemia-reperfusion injury and reveal its mechanism by measuring glutamate concentration in the ventral horn using an in vivo microdialysis method. METHODS: Male Sprague-Dawley rats were divided into the following 6 groups: sham, only spinal ischemia, 3% hydrogen gas (spinal ischemia + 3% hydrogen gas), 2% hydrogen gas (spinal ischemia + 2% hydrogen gas), 1% hydrogen gas (spinal ischemia + 1% hydrogen gas), and hydrogen gas dihydrokainate (spinal ischemia + dihydrokainate [selective inhibitor of glutamate transporter-1] + 3% hydrogen gas). Hydrogen gas inhalation was initiated 10 minutes before the ischemia. For the hydrogen gas dihydrokainate group, glutamate transporter-1 inhibitor was administered 20 minutes before the ischemia. Immunofluorescence was performed to assess the expression of glutamate transporter-1 in the ventral horn. RESULTS: The increase in extracellular glutamate induced by spinal ischemia was significantly suppressed by 3% hydrogen gas inhalation (P < .05). This effect was produced in increasing order: 1%, 2%, and 3%. Conversely, the preadministration of glutamate transporter-1 inhibitor diminished the suppression of spinal ischemia-induced glutamate increase observed during the inhalation of 3% hydrogen gas. Immunofluorescence indicated the expression of glutamate transporter-1 in the spinal ischemia group was significantly decreased compared with the sham group, which was attenuated by 3% hydrogen gas inhalation (P < .05). CONCLUSIONS: Our study demonstrated hydrogen gas inhalation exhibits a protective and concentration-dependent effect against spinal ischemic injury, and glutamate transporter-1 has an important role in the protective effects against spinal cord injury.

Participation of the descending noradrenergic inhibitory system in the anti-hyperalgesic effect of acetaminophen in a rat model of inflammation.

AIMS: This study investigated the relationship between the analgesic efficacy of acetaminophen and the descending noradrenergic systems using rodent models of inflammatory pain. MAIN METHODS: Inflammatory pain models were established by carrageenan injection into rats' paws. The models were defined as acute (4 h after carrageenan injection), subacute (24 h after carrageenan injection), and late (1 week after carrageenan injection) phase. To evaluate intravenous acetaminophen treatment, the withdrawal threshold to mechanical stimuli was assessed simultaneously with in vivo microdialysis assay of noradrenaline levels in the locus coeruleus (LC). Further analyses were performed to observe the effect of yohimbine on the treatment and the impact of AM404 treatment, a metabolite of acetaminophen, on noradrenaline levels in the LC. KEY FINDINGS: In all phases, intravenous acetaminophen had a significant anti-hyperalgesic effect (p < 0.05). There was a significant time-dependent increase in the noradrenaline concentration within the LC (acetaminophen versus saline treatment; at 30 min, p < 0.001; 60 min, p < 0.01) in the subacute pain model, but not in the acute and late phase pain models. Intrathecal pre-injection of yohimbine attenuated the anti-hyperalgesic effect after acetaminophen injection only in the subacute model (p < 0.05). In the subacute pain model, intracerebroventricular administration of AM404 showed the same trend in noradrenaline levels as acetaminophen administration (AM404 versus vehicle group at 30 min, p < 0.001). SIGNIFICANCE: We found the descending noradrenergic inhibitory system is involved in the antinociceptive action of acetaminophen in the subacute phase of inflammatory pain.

Hemodynamic Changes via the Lung Recruitment Maneuver Can Predict Fluid Responsiveness in Stroke Volume and Arterial Pressure During One-Lung Ventilation.

BACKGROUND: We aimed to evaluate the ability of lung recruitment maneuver-induced hemodynamic changes to predict fluid responsiveness in patients undergoing lung-protective ventilation during one-lung ventilation (OLV). METHODS: Thirty patients undergoing thoracic surgery with OLV (tidal volume: 6 mL/kg of ideal body weight and positive end-expiratory pressure: 5 cm H2O) were enrolled. The study protocol began 30 minutes after starting OLV. Simultaneous recordings were performed for hemodynamic variables of heart rate, mean arterial pressure (MAP), stroke volume (SV), pulse pressure variation (PPV), and stroke volume variation (SVV) were recorded at 4 time points: before recruitment maneuver (continuous airway pressure: 30 cm H2O for 30 seconds), at the end of recruitment maneuver, and before and after volume loading (250 mL over 10 minutes). Patients were recognized as fluid responders if the increase in SV or MAP was >10%. Receiver operating characteristic curves for percent decrease in SV and MAP by recruitment maneuver (ΔSVRM and ΔMAPRM, respectively) were generated to evaluate the ability to discriminate fluid responders from nonresponders. The gray-zone approach was applied for ΔSVRM and ΔMAPRM. RESULTS: Of 30 patients, there were 17 SV-responders (57%) and 12 blood pressure (BP)-responders (40%). Area under the curve (AUC) for ΔSVRM to discriminate SV-responders from nonresponders was 0.84 (95% confidence interval [CI], 0.67-0.95; P < .001). The best threshold for ΔSVRM to discriminate the SV-responders was -23.7% (95% CI, -41.2 to -17.8; sensitivity, 76.5% [95% CI, 50.1-93.2]; specificity, 84.6% [95% CI, 54.6-98.1]). For BP-responders, AUC for ΔMAPRM was 0.80 (95% CI, 0.61-0.92, P < .001). The best threshold for ΔMAPRM was -17.3% (95% CI, -23.9 to -5.1; sensitivity, 75.0% [95% CI, 42.8-94.5]; specificity, 77.8% [95% CI, 52.4-93.6]). With the gray-zone approach, the inconclusive range of ΔSVRM for SV-responders was -40.1% to -13.8% including 13 (43%) patients, and that of ΔMAPRM was -23.9% to -5.1%, which included 16 (53%) patients. CONCLUSIONS: ΔSVRM and ΔMAPRM could predict hemodynamic responses after volume expansion during OLV.

Error grid analysis for risk management in the difference between invasive and noninvasive blood pressure measurements.

PURPOSE: Invasive arterial blood pressure (IAP) and noninvasive blood pressure (NIBP) measurements are both common methods. Recently, a new method of error grid analysis was proposed to compare blood pressure obtained using two measurement methods. This study aimed to compare IAP and NIBP measurements using the error grid analysis and investigate potential confounding factors affecting the discrepancies between IAP and NIBP. METHODS: Adult patients who underwent general anesthesia in the supine position with both IAP and NIBP measurements were retrospectively investigated. The error grid analyses were performed to compare IAP and NIBP. In the error grid analysis, the clinical relevance of the discrepancies between IAP and NIBP was evaluated and classified into five zones from no risk (A) to dangerous risk (E). RESULTS: Overall, data of 1934 IAP/NIBP measurement pairs from 100 patients were collected. The error grid analysis revealed that the proportions of zones A-E for systolic blood pressure were 96.4%, 3.5%, 0.05%, 0%, and 0%, respectively. In contrast, the proportions for mean blood pressure were 82.5%, 16.7%, 0.8%, 0%, and 0%, respectively. The multiple regression analysis revealed that continuous phenylephrine administration (p = 0.016) and age (p = 0.044) were the significant factors of an increased clinical risk of the differences in mean blood pressure. CONCLUSIONS: The error grid analysis indicated that the differences between IAP and NIBP for mean blood pressure were not clinically acceptable and had the risk of leading to unnecessary treatments. Continuous phenylephrine administration and age were the significant factors of an increased clinical risk of the discrepancies between IAP and NIBP.

Automated Assessment of Existing Patient's Revised Cardiac Risk Index Using Algorithmic Software.

BACKGROUND: Previous work in the field of medical informatics has shown that rules-based algorithms can be created to identify patients with various medical conditions; however, these techniques have not been compared to actual clinician notes nor has the ability to predict complications been tested. We hypothesize that a rules-based algorithm can successfully identify patients with the diseases in the Revised Cardiac Risk Index (RCRI). METHODS: Patients undergoing surgery at the University of California, Los Angeles Health System between April 1, 2013 and July 1, 2016 and who had at least 2 previous office visits were included. For each disease in the RCRI except renal failure-congestive heart failure, ischemic heart disease, cerebrovascular disease, and diabetes mellitus-diagnosis algorithms were created based on diagnostic and standard clinical treatment criteria. For each disease state, the prevalence of the disease as determined by the algorithm, International Classification of Disease (ICD) code, and anesthesiologist's preoperative note were determined. Additionally, 400 American Society of Anesthesiologists classes III and IV cases were randomly chosen for manual review by an anesthesiologist. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve were determined using the manual review as a gold standard. Last, the ability of the RCRI as calculated by each of the methods to predict in-hospital mortality was determined, and the time necessary to run the algorithms was calculated. RESULTS: A total of 64,151 patients met inclusion criteria for the study. In general, the incidence of definite or likely disease determined by the algorithms was higher than that detected by the anesthesiologist. Additionally, in all disease states, the prevalence of disease was always lowest for the ICD codes, followed by the preoperative note, followed by the algorithms. In the subset of patients for whom the records were manually reviewed, the algorithms were generally the most sensitive and the ICD codes the most specific. When computing the modified RCRI using each of the methods, the modified RCRI from the algorithms predicted in-hospital mortality with an area under the receiver operating characteristic curve of 0.70 (0.67-0.73), which compared to 0.70 (0.67-0.72) for ICD codes and 0.64 (0.61-0.67) for the preoperative note. On average, the algorithms took 12.64 ± 1.20 minutes to run on 1.4 million patients. CONCLUSIONS: Rules-based algorithms for disease in the RCRI can be created that perform with a similar discriminative ability as compared to physician notes and ICD codes but with significantly increased economies of scale.

The Sum of Early Diastolic Annulus Velocities in the Mitral and Tricuspid Valve Can Predict Adverse Events After Cardiac Surgery.

OBJECTIVES: To assess whether a tissue Doppler imaging (TDI)-based parameter consisting of the sum of early diastolic velocities of the mitral annulus (Me') and tricuspid annulus (Te') can serve as a predictor of adverse outcomes after cardiac surgery. DESIGN: Prospective, observational study. SETTING: University hospital. PARTICIPANTS: The study comprised 100 patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After anesthetic induction, transesophageal echocardiography was performed to obtain the values of the early transmitral flow velocity (E), Me', and Te'. The primary endpoint was the incidence of postoperative major organ morbidity and mortality (MOMM) events, including death, redo surgery, prolonged ventilation, stroke, sternal infection, and dialysis. Receiver operating characteristic and multivariate logistic analyses were used to examine the prognostic performance of TDI-based parameters for predicting MOMM incidence. The secondary endpoint was the incidence of death or rehospitalization for cardiovascular disease within 1 year post-discharge. TDI-based parameters were measured in 87 of the 100 patients enrolled. Me' plus Te' had better prognostic ability (area under the curve 0.771; threshold 13 cm/s; sensitivity 86.7%; specificity 64.9%) than that of Me' or E to Me' (E/Me')% and was an independent predictor of MOMM (odds ratio 0.45; 95% confidence interval 0.28-0.74, p = 0.001), whereas Me' was not. Lower Me' plus Te' (≤13 cm/s) was associated with a significantly higher incidence and earlier onset of cardiovascular events within 1 year post-discharge (p = 0.012). CONCLUSIONS: Compared with Me' and E/Me', which traditionally are used for assessing diastolic function, Me' plus Te' showed better prognostic ability for both short- and long-term outcomes of cardiac surgery.

Impact of Enhanced Recovery After Surgery and Opioid-Free Anesthesia on Opioid Prescriptions at Discharge From the Hospital: A Historical-Prospective Study.

BACKGROUND: The United States is in the midst of an opioid epidemic, and opioid use disorder often begins with a prescription for acute pain. The perioperative period represents an important opportunity to prevent chronic opioid use, and recently there has been a paradigm shift toward implementation of enhanced recovery after surgery (ERAS) protocols that promote opioid-free and multimodal analgesia. The objective of this study was to assess the impact of an ERAS intervention for colorectal surgery on discharge opioid prescribing practices. METHODS: We conducted a historical-prospective quality improvement study of an ERAS protocol implemented for patients undergoing colorectal surgery with a focus on the opioid-free and multimodal analgesia components of the pathway. We compared patients undergoing colorectal surgery 1 year before implementation (June 15, 2015, to June 14, 2016) and 1 year after implementation (June 15, 2016, to June 14, 2017). RESULTS: Before the ERAS intervention, opioids at discharge were not significantly increasing (1% per month; 95% confidence interval [CI], -1% to 3%; P = .199). Immediately after the ERAS intervention, opioid prescriptions were not significantly lower (13%; 95% CI, -30% to 3%; P = .110). After the intervention, the rate of opioid prescriptions at discharge did not decrease significantly 1% (95% CI, -3% to 1%) compared to the pre-period rate (P = .399). Subgroup analysis showed that in patients with a combination of low discharge pain scores, no preoperative opioid use, and low morphine milligram equivalents consumption before discharge, the rate of discharge opioid prescription was 72% (95% CI, 61%-83%). CONCLUSIONS: This study is the first to report discharge opioid prescribing practices in an ERAS setting. Although an ERAS intervention for colorectal surgery led to an increase in opioid-free anesthesia and multimodal analgesia, we did not observe an impact on discharge opioid prescribing practices. The majority of patients were discharged with an opioid prescription, including those with a combination of low discharge pain scores, no preoperative opioid use, and low morphine milligram equivalents consumption before discharge. This observation in the setting of an ERAS pathway that promotes multimodal analgesia suggests that our findings are very likely to also be observed in non-ERAS settings and offers an opportunity to modify opioid prescribing practices on discharge after surgery. For opioid-free anesthesia and multimodal analgesia to influence the opioid epidemic, the dose and quantity of the opioids prescribed should be modified based on the information gathered by in-hospital pain scores and opioid use as well as pain history before admission.

Transcutaneous near-infrared spectroscopy for monitoring spinal cord ischemia: an experimental study in swine.

We aimed to assess the ability of near-infrared spectroscopy (NIRS) to detect spinal cord ischemia, and to evaluate changes in regional oxygen saturation (rSO2) following recovery of spinal cord circulation and cerebrospinal fluid drainage. Four 12-month-old female swine weighing 28.7-29.5 kg were acquired for this study. NIRS probes were placed along the midline of the upper (T6/7) and lower (T9/T10) thoracic vertebrae. The thoracic aorta was clamped distal of the left subclavian artery to induce spinal ischemia. Aortic cross-clamping was maintained for 30 min. Fifteen minutes after aortic de-clamping, the cerebrospinal fluid drainage catheter was opened to air, and cerebrospinal fluid drainage was initiated. Following aortic clamping, rSO2 in both upper and lower regions of the spinal cord decreased by 15 % within 5 min and by 20 % within 10 min (relative change). After aortic de-clamping, rSO2 values in both regions returned to baseline within 5 min. No changes in rSO2 in either the upper or lower vertebrae were observed following initiation of cerebrospinal fluid drainage. Histological analysis revealed that ischemic changes had occurred in all spinal levels. NIRS may be used to detect decreases in and recovery of spinal cord circulation following aortic clamping and de-clamping, whereas it may not reflect minor changes in spinal cord circulation due to cerebrospinal fluid drainage. Further clinical studies are required to investigate the potential for NIRS as an index of spinal cord circulation.

Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

BACKGROUND: Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. METHODS: Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). RESULTS: Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P < 0.01), while intracerebroventricular methysergide lowered the seizure threshold (P < 0.05 vs. saline). CONCLUSIONS: The authors determined that serotonin-reduced rats were predisposed to tramadol-induced seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

Relationship between noradrenaline release in the locus coeruleus and antiallodynic efficacy of analgesics in rats with painful diabetic neuropathy.

AIMS: In animal models of neuropathic pain, the noradrenergic descending pain inhibitory pathways from the locus coeruleus (LC) may be suppressed. However, no study has investigated the correlation between noradrenaline (NA) release in the LC and efficacy of analgesics in rats with painful diabetic neuropathy. Using microdialysis and analysis of mechanical hypersensitivity, we investigated the correlation between NA release in the LC and efficacy of morphine, tramadol, and clomipramine in rats with diabetic mellitus (DM). MAIN METHODS: In freely moving rats, basal NA concentrations in LC perfusate were quantitated 72 to 96 h after microdialysis probe implantation. Following intravenous administration of each drug, NA concentrations were expressed as a percentage of basal values. We concurrently measured the threshold to elicit a paw withdrawal response every 20 min for 80 min. KEY FINDINGS: NA concentrations in the LC perfusate were significantly higher in the tramadol and clomipramine groups compared to the morphine group. Naloxone administration did not significantly affect NA concentrations. In the morphine group, NA release in the LC was not significantly correlated with the pain threshold. In contrast, in the tramadol and clomipramine groups, NA release in the LC was significantly correlated with the pain threshold. The correlation coefficient was higher in the clomipramine group than in the tramadol group. SIGNIFICANCE: Our results suggest that the descending noradrenergic pathway can play an important role in analgesia for DM neuropathy and that there is a significant correlation between NA release in the LC and the efficacy of tramadol and clomipramine.

Flurbiprofen axetil provides a prophylactic benefit against mesenteric traction syndrome associated with remifentanil infusion during laparotomy.

PURPOSE: Mesenteric traction syndrome (MTS) is caused by PGI(2) release during abdominal procedures and is often observed during abdominal surgery. We have demonstrated that MTS occurs more frequently in cases using remifentanil than in those that are not. The aim of this study was to assess the prophylactic benefit of flurbiprofen axetil on MTS in patients undergoing abdominal surgery using remifentanil. METHODS: Thirty ASA physical status I and II patients were enrolled. They were scheduled to undergo abdominal surgery under general anesthesia with remifentanil and were randomly assigned to receive flurbiprofen axetil (group F) or saline (group C) preoperatively (n = 15 each). MTS was defined according to our simplified diagnostic criteria. Arterial blood pressure and heart rate were recorded, and the plasma 6-keto-PGF(1α) (a stable metabolite of PGI(2)) concentration was measured just before skin incision and at 20 and 60 min after skin incision (T(0), T(20), T(60)) to confirm the diagnosis of MTS. RESULTS: Twelve of 15 (80%) patients developed MTS in group C, whereas only 1 of 15 (6.7%) patients in group F developed MTS. At T(20), the group C patients showed significantly lower arterial blood pressure (P < 0.05) and a faster heart rate (P < 0.01) than those in group F. The mean plasma 6-keto-PGF(1α) concentration was significantly elevated in group C at T(20) (P < 0.01), whereas the plasma 6-keto-PGF(1α) level remained low throughout the observation period in group F. CONCLUSIONS: We found that preoperative administration of flurbiprofen axetil reduced the incidence of MTS during abdominal surgery with remifentanil analgesia.

Remifentanil increases the incidence of mesenteric traction syndrome: preliminary randomized controlled trial.

PURPOSE: The use of remifentanil is often associated with the observation of mesenteric traction syndrome (MTS) soon after manipulation of the intestine during abdominal surgery. MTS symptoms include facial flushing, hypotension, and tachycardia. In the study reported here, we prospectively investigated the effects of remifentanil on the incidence of MTS in abdominal surgery. METHODS: One hundred patients scheduled for abdominal surgery were randomly assigned to two groups. In one group (n = 50), fentanyl alone was used as intravenous analgesic (control, group C); in the second group (n = 50), both fentanyl and remifentanil were used (remifentanil group, group R). In all patients, anesthesia was induced with propofol and rocuronium and then maintained with sevoflurane inhalation. Remifentanil was continuously infused for patients in group R as an analgesic. Plasma concentration of 6-keto-PGF(1α) was measured before surgery and 20 min after the skin incision was made in six patients of group R and seven patients of group C. RESULTS: MTS occurred in 20 cases in group R (40.0%), but in only five cases in group C (10.0%). In both groups, the incidence of MTS was higher in laparotomy than in laparoscopic surgery. The plasma concentration of 6-keto-PGF(1α) was low in both groups before surgery and was elevated 20 min after skin incision in both groups in patients in whom MTS appeared. CONCLUSIONS: The results of this study suggest that the use of remifentanil in laparotomy facilitates MTS.

The pharmacokinetic properties of methamphetamine in rats with previous repeated exposure to methamphetamine: the differences between Long-Evans and Wistar rats.

Repeated treatment with methamphetamine (METH) causes long-term behavioral changes, so-called behavioral sensitization (BS), in humans as well as experimental animals. However, there are no reports as to whether repeated METH treatment can establish BS in stress-sensitive Long-Evans (LE) rats. Thus, we investigated the effect of repeated METH treatment (5 mg/kg x 5 days) on the establishment of BS in LE rats. Wistar (WIS) rats were used as a reference. In LE rats, repeated METH treatment failed to cause BS although it did enhance METH-induced hyperlocomotion in WIS rats. The levels of METH in brain dialysate and the ratio of the area under the concentration-time curve area in plasma to that in brain dialysate was increased in repeated METH-treated WIS rats as reported previously, but not in repeated METH-treated LE rats. METH increases plasma corticosterone (CORT) in both strains. However, the intensity of increment of CORT by repeated METH was lower in LE rats than that in WIS rats. Repeated METH treatment decreased the expression of METH-transposable and CORT-sensitive transporter, organic cation transporter 3 (OCT3), in the brain of WIS rats. However, the intensity of the decrement of OCT3 with repeated METH treatment was similar between both strains. Taken together, these results suggest that the lack of establishment of BS in LE rats might have been caused by the unchanged brain penetration of METH after repeated METH administration, and that the differential CORT response to METH is an important strain difference.

Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine.

The effects of minocycline on behavioral changes and neurotoxicity in the dopaminergic neurons induced by the administration of methamphetamine (METH) were studied. Pretreatment with minocycline (40 mg/kg) was found to attenuate hyperlocomotion in mice after a single administration of METH (3 mg/kg). The development of behavioral sensitization after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly attenuated by pretreatment with minocycline (40 mg/kg). A reduction in the level of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenyl acetic acid (DOPAC), in the striatum after the repeated administration of METH (3 mg/kg x 3, 3-h interval) was attenuated in a dose-dependent manner by pretreatment with and the subsequent administration of minocycline (10, 20, or 40 mg/kg). Furthermore, minocycline (40 mg/kg) significantly attenuated a reduction in DA transporter (DAT)-immunoreactivity in the striatum after repeated administration of METH. In vivo microdialysis study demonstrated that pretreatment with minocycline (40 mg/kg) significantly attenuated increased extracellular DA levels in the striatum after the administration of METH (3 mg/kg). In addition, minocycline was not found to alter the concentrations of METH in the plasma or the brain after three injections of METH (3 mg/kg), suggesting that minocycline does not alter the pharmacokinetics of METH in mice. Interestingly, METH-induced neurotoxicity in the striatum was significantly attenuated by the post-treatment and subsequent administration of minocycline (40 mg/kg). These findings suggest that minocycline may be able to ameliorate behavioral changes as well as neurotoxicity in dopaminergic terminals after the administration of METH. Therefore, minocycline could be considered as a useful drug for the treatment of several symptoms associated with METH abuse in humans.

Effect of Shiga-like toxin II from Escherichia coli O157:H7 on intestinal clearance of norfloxacin in rats.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection causes severe clinical symptoms, due to its bacterial toxin, called Shiga-like toxin (SLT). However, little is known about the information to establish a safe and efficient prescription to treat for EHEC O157:H7 patients. Thus, we investigated the effect of SLT-II on intestinal function in rats by using the antibiotic norfloxacin (NFLX) as a model drug. The intestinal clearance (CLi) of NFLX, determined by loop method in the jejunum, was significantly decreased by SLT-II. In histopathological experiment, epithalaxia was observed in SLT-II-treated rats without structural changes of tight junction suggesting the deterioration of active transport systems by SLT-II. CLi of NFLX in normal rats was decreased by carnitine (CAR), suggesting the possible involvement of CAR-sensitive transporter in CLi of NFLX. Taken together, these results suggest that the EHEC O157:H7 infection might affect the intestinal disposition of NFLX due to the changing intestinal expression/function of drug transporters by SLT-II.

Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice.

The organic cation transporter-3 (OCT3) can transport monoamines, similar to neuronal monoamine transporters. Due to the lack of selective ligands, however, the functional role of OCT3 is still unknown. Thus, we investigated behavioral effects of antisense against OCT3 (AS) in mice. AS (0.075-0.25 microg/0.25 microl/h, for 7 days) dose-dependently decreased immobility time. Moreover, although neither AS (0.075 microg/0.25 microl/h, for 7 days) or imipramine (4 mg/kg, i.p.) were effective, imipramine (4 mg/kg, i.p.) significantly decreased immobility time in mice treated with AS (0.075 microg/0.25 microl/h, for 7 days). Additionally, AS (0.25 microg/0.25 microl/h, for 7 days) significantly increased locomotor activity induced by methamphetamine (1 mg/kg, s.c.), but did not affect spontaneous locomotor activity. These results suggest that OCT3 might become a novel molecular target to treat depression and other diseases related to monoaminergic neuronal systems.