Involvement of KCa3.1 channel activity in immediate perioperative cognitive and neuroinflammatory outcomes.

BACKGROUND: Potassium channels (KCa3.1; Kv1.3; Kir2.1) are necessary for microglial activation, a pivotal requirement for the development of Perioperative Neurocognitive Disorders (PNDs). We previously reported on the role of microglial Kv1.3 for PNDs; the present study sought to determine whether inhibiting KCa3.1 channel activity affects neuroinflammation and prevents development of PND. METHODS: Mice (wild-type [WT] and KCa3.1-/-) underwent aseptic tibial fracture trauma under isoflurane anesthesia or received anesthesia alone. WT mice received either TRAM34 (a specific KCa3.1 channel inhibitor) dissolved in its vehicle (miglyol) or miglyol alone. Spatial memory was assessed in the Y-maze paradigm 6 h post-surgery/anesthesia. Circulating interleukin-6 (IL-6) and high mobility group box-1 protein (HMGB1) were assessed by ELISA, and microglial activitation Iba-1 staining. RESULTS: In WT mice surgery induced significant cognitive decline in the Y-maze test, p = 0.019), microgliosis (p = 0.001), and increases in plasma IL-6 (p = 0.002) and HMGB1 (p = 0.001) when compared to anesthesia alone. TRAM34 administration attenuated the surgery-induced changes in cognition, microglial activation, and HMGB1 but not circulating IL-6 levels. In KCa3.1-/- mice surgery neither affected cognition nor microgliosis, although circulating IL-6 levels did increase (p < 0.001). CONCLUSION: Similar to our earlier report with Kv1.3, perioperative microglial KCa3.1 blockade decreases immediate perioperative cognitive changes, microgliosis as well as the peripheral trauma marker HMGB1 although surgery-induced IL-6 elevation was unchanged. Future research should address whether a synergistic interaction exists between blockade of Kv1.3 and KCa3.1 for preventing PNDs.

Adenosine Diphosphate and the P2Y13 Receptor Are Involved in the Autophagic Protection of Ex Vivo Perfused Livers From Fasted Rats: Potential Benefit for Liver Graft Preservation.

Studies on how to protect livers perfused ex vivo can help design strategies for hepatoprotection and liver graft preservation. The protection of livers isolated from 24-hour versus 18-hour starved rats has been previously attributed to autophagy, which contributes to the energy-mobilizing capacity ex vivo. Here, we explored the signaling pathways responsible for this protection. In our experimental models, 3 major signaling candidates were considered in view of their abilities to trigger autophagy: high mobility group box 1 (HMGB1), adenosine monophosphate-activated protein kinase (AMPK), and purinergic receptor P2Y13. To this end, ex vivo livers isolated from starved rats were perfused for 135 minutes, after which perfusate samples were studied for protein release and biopsies were performed for evaluating signaling protein contents. For HMGB1, no significant difference was observed between livers isolated from rats starved for 18 and 24 hours at perfusion times of both 0 and 135 minutes. The phosphorylated and total forms of AMPK, but not their ratios, were significantly higher in 24-hour fasted than in 18-hour fasted livers. However, although the level of phosphorylated AMPK increased, perfusing ex vivo 18-hour fasted livers with 1 mM 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, did not protect the livers. In addition, the adenosine diphosphate (ADP; and not adenosine monophosphate [AMP]) to AMP + ADP + adenosine triphosphate ratio increased in the 24-hour starved livers compared with that in the 18-hour starved livers. Moreover, perfusing 24-hour starved livers with 0.1 mM 2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde (MRS2211), a specific antagonist of the P2Y13 receptor, induced an increase in cytolysis marker levels in the perfusate samples and a decrease in the levels of autophagic marker microtubule-associated proteins 1 light chain 3 II (LC3II)/actin (and a loss of p62/actin decrease), indicating autophagy inhibition and a loss of protection. The P2Y13 receptor and ADP (a physiological activator of this receptor) are involved in the protection of ex vivo livers. Therapeutic opportunities for improving liver graft preservation through the stimulation of the ADP/P2Y13 receptor axis are further discussed.

In- and out-hospital mortality rate in surgical patients.

BACKGROUND: Death rates after surgery are increasingly analysed for clinical audit and quality assessment. Many studies commonly provide information only on deaths that occur during hospital stay, known as in-hospital death rates. By using hospital data set linked to death certificate registry, we recorded in- and out-hospital deaths within 30 and 60 post-operative days. METHODS: The study included all consecutive surgical procedures (denominator) under general or locoregional anaesthesia in adult patients admitted for elective or non-elective inpatient surgery. Patients undergoing planned day-case surgery or obstetrical procedures were excluded. The primary outcome was 30- and 60-day post-operative mortality rate (numerator) whether before or after discharge. RESULTS: The study material consisted of a sample of 36,494 surgical procedures corresponding to 28,202 patients. At 30-day, 384 (crude mortality rate of 1.1%) patients died, 314 (82%) during their hospitalisation and 70 (18%) after discharge. Factors that were associated with in-hospital mortality are ASA scores, emergency, duration of surgery and rate of admission to critical care unit. Within the 30-60 days interval, we recorded 231 supplemental deaths, 103 (45%) after discharge. CONCLUSION: In-hospital mortality alone is an incomplete measure of mortality even within 30 days of care. To identify the missing deaths, hospital records need to be linked to data from death certificate. This connection with the national death registry will allow obtaining the rate of in-hospital and out-hospital death.

Protection in a model of liver injury is parallel to energy mobilization capacity under distinct nutritional status.

OBJECTIVE: Dietary and energetic restrictions are endowed with protection against experimental injuries. However, a drop in cell energetic status under a critical threshold may prevent protection, as previously observed for livers isolated from rat donors undergoing 18-h fasting versus feeding. The aim of this study was to further explore, in the latter model, links between nutritional status, energy availability, and protection through lengthening of rat fasting to 24 h and withdrawal of energy sources from perfusions. METHODS: Energy-free perfused ex vivo livers from fed, 18-h-fasted, and 24-h-fasted rats were studied during 135 min for cytolysis (potassium, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase releases in perfusates), cell deaths (activated caspase-3 [apoptosis], LC3 II/actin and p62/actin ratios [autophagy]), glycogen stores, glucose, and lactate production. RESULTS: Cytolysis was significantly increased by 18-h and 24-h fasting versus feeding but unexpectedly the increase was less for 24-h fasting than it was for 18-h fasting. Apoptotic marker caspase 3 significantly increased under fed and 18-h fasting but not 24-h fasting conditions. Autophagic marker LC3 II/actin significantly increased during perfusion in the 24-h fasted group but neither fed nor 18-h fasted groups. Autophagic induction also was supported by a drop in the p62/actin ratio. Under perfusion with 3-methyladenine, a standard autophagy inhibitor, protection and enhanced autophagy provided by 24-h but not 18-h fasting were lost without affecting apoptosis. CONCLUSIONS: Liver protections are obviously influenced by nutritional status in a way that is parallel to hepatic energy mobilization capacities (glycogen plus autophagy) with a decreased order of protection: Fed >24-h fasted >18-h fasted >24-h fasted + 3-methyladenine livers. By showing that autophagy induction limits starvation-induced cytolysis, the present work supports the emerging view that autophagy inducers might improve health benefits of diet restriction.

Intralipid minimizes hepatocytes injury after anoxia-reoxygenation in an ex vivo rat liver model.

OBJECTIVE: Ischemia-reperfusion injury is a determinant in liver injury occurring during surgical procedures, ischemic states, and multiple organ failure. The pre-existing nutritional status of the liver, i.e., fasting, might contribute to the extent of tissue injury. This study investigated whether Intralipid, a solution containing soybean oil, egg phospholipids, and glycerol, could protect ex vivo perfused livers of fasting rats from anoxia-reoxygenation injury. METHODS: The portal vein was cannulated, and the liver was removed and perfused in a closed ex vivo system. Isolated livers were perfused with glucose 5.5 and 15 mM, and two different concentrations of Intralipid, i.e., 0.5:100 and 1:100 (v/v) Intralipid 10%:medium (n = 5 in each group). The experiment consisted of perfusion for 15 min, warm anoxia for 60 min, and reoxygenation during 60 min. Hepatic enzymes, potassium, glucose, lactate, bilirubin, dienes, trienes, and cytochrome-c were analyzed in perfusate samples. The proportion of glycogen in hepatocytes was determined in biopsies. RESULTS: Intralipid attenuated transaminases, lactate dehydrogenase, potassium, diene, and triene release in the perfusate (dose-dependant) during the reoxygenation phase when compared with glucose-treated groups. The concentration of cytochrome-c in the medium was the highest in the 5.5-mM glucose group. The glycogen content was low in all livers at the start of the experiment. CONCLUSION: Intralipid presents, under the present experimental conditions, a better protective effect than glucose in anoxia-reoxygenation injury of the rat liver.

Hypocapnia measured by end-tidal carbon dioxide tension during anesthesia is associated with increased 30-day mortality rate.

STUDY OBJECTIVE: To evaluate the relationship between intraoperative end-tidal carbon dioxide (etco2) values and clinical outcomes with special attention on 30-day postoperative mortality and secondarily on hospital length of stay (LOS). DESIGN: Retrospective, observational study. SETTING: Surgical theaters of the University Hospital Center of Charleroi. PATIENTS: Five thousand three hundred seventeen patients ASA I-IV undergoing various surgical procedures (except pediatric and cardiac surgery) under general anesthesia. INTERVENTIONS: No intervention on the patients. MEASUREMENTS: The mean etco2 level measured during anesthesia was secondarily extracted from an electronic information management system. Patients were divided into 2 separate groups based on etco2 values less than or greater than or equal to 35 mm Hg. The primary end point was the in- and outhospital mortality in the 30-day period after surgery. The second was the LOS more than 6 days. MAIN RESULTS: Hypocapnia occurred in 66% of the patients. Mortality rate at 30-day was 84 of 3554 (2.4%) in the low etco2 group vs 15 of 1763 (0.9%) in the other (odds ratio, 2.99 [1.69-5.28]; P<.001). In multivariate analysis, age and ASA scores had significant independent associations with mortality rate. Adjusting for these factors had an effect on the relative odds ratio of etco2 on mortality of 1.99 ([1.11-3.56]; P<.001). Patients with low etco2 experienced higher LOS (14.1±9.4 vs 13.1±8.9 days; P<.001). Thirty five percent of the patients in the low etco2 group were still hospitalized more than 6 days compared with 30% in the other (P<.001). CONCLUSION: Low etco2 level during anesthesia is associated with an increase in postoperative mortality rate and LOS. These results emphasize the importance of preventing hypocapnia during anesthesia to improve surgical outcomes.

Short fasting does not protect perfused ex vivo rat liver against ischemia-reperfusion. On the importance of a minimal cell energy charge.

OBJECTIVE: Dietary restriction or reduced food intake was supported to protect against renal and hepatic ischemic injury. In this vein, short fasting was recently shown to protect in situ rat liver against ischemia-reperfusion. Here, perfused ex vivo instead of in situ livers were exposed to ischemia-reperfusion to study the impact of disconnecting liver from extrahepatic supply in energetic substrates on the protection given by short-term fasting. METHODS: Perfused ex vivo livers using short (18 h) fasted compared with fed rats were submitted to ischemia-reperfusion and studied for release of cytolysis markers in the perfusate. Energetic stores are differently available in time and cell energetic charges (ratio of adenosine triphosphate plus half of the adenosine diphosphate concentrations to the sum of adenosine triphosphate + adenosine diphosphate + adenosine monophosphate concentrations), adenosine phosphates, and glycogen, which were further measured at different time points in livers. RESULTS: Short fasting versus feeding failed to protect perfused ex vivo rat livers against ischemia/reperfusion, increasing the release of cytolysis markers (potassium, cytochrome c, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) in the perfusate during reoxygenation phase. Toxicity of short fasting versus feeding was associated with lower glycogen and energetic charges in livers and lower lactate levels in the perfusate. CONCLUSION: High energetic charge, intracellular content in glycogen, and glycolytic activity may protect liver against ischemia/reperfusion injury. This work does not question how much the protective role previously demonstrated in the literature for dietary restriction and short fasting. In fact, it suggests that exceeding the energy charge threshold value of 0.3 might trigger the effectiveness of this protective role.

Comparison of 2 concentrations of levobupivacaine in postoperative patient-controlled epidural analgesia.

STUDY OBJECTIVES: To evaluate the quality of analgesia and the incidence of side effects of 2 different concentrations of levobupivacaine given as an equal milligram-bolus dose (5 mg) via patient-controlled epidural analgesia after abdominal surgery. DESIGN: Prospective, randomized, blinded study. SETTING: Postanesthesia care unit and surgical wards of a university hospital. PATIENTS: Forty-nine patients (41 with complete file) undergoing major lower abdominal surgery. INTERVENTIONS: The patients were randomly assigned to 2 groups: 1.5 mg/mL (bolus 3.3 mL, lockout 20 minutes, n = 26) and 5 mg/mL (bolus 1 mL, lockout 20 minutes, n = 23). The epidural catheter was inserted in the low thoracic level (T9-T12) before induction of a standardized general anesthesia technique. MEASUREMENTS: Demography, upper sensory block, visual analog scale scores at rest and after coughing, levobupivacaine and rescue morphine consumption, motor blockade, hemodynamics, postoperative nausea and vomiting, sedation, and patient satisfaction were recorded within the first 48 hours. MAIN RESULTS: Both groups were similar with regard to demographics, upper level of sensory blockade (T8), and visual analog scale pain scores at rest and after coughing, as well as levobupivacaine and subcutaneous rescue morphine consumption. Motor blockade in the lower limbs was very low in both groups. Arterial blood pressure was slightly lower in the 5 mg/mL group during the first 24 hours (P = 0.052). Five patients in the 1.5 mg/mL and 7 in the 5 mg/mL group had postoperative nausea and vomiting (P = 0.43). No other side effects were recorded, and all of the patients were satisfied. CONCLUSIONS: Administering the same dose of levobupivacaine in either a low or high concentration via patient-controlled epidural analgesia mode provides an equal quality of analgesia with no difference in the incidence of side effects.

A cost-utility and cost-effectiveness analysis of an acute pain service.

STUDY OBJECTIVE: To analyze, from a societal perspective, the cost-effectiveness and cost-utility of acute pain management after inception of a nurse-based Acute Pain Service (APS) in a general hospital. DESIGN: Open, observational, interventional study. SETTING: Postanesthesia care unit and surgical wards of a university hospital center. PATIENTS: 1975 surgical inpatients who had undergone various types of surgery. INTERVENTIONS: Visual analog scale (VAS) pain scores and all systemic analgesics prescribed by anesthesiologists and administered by ward nurses were recorded before and after APS inception. All costs (drugs, disposal, and working time of nurses) related to the APS were identified. Pain measurements were performed by VAS every 4 hours over 3 consecutive days post-surgery and transformed into a health state scale, with 0 being equivalent to absence of pain and 10 to the worst imaginable pain.Using these data, analgesic effectiveness (cost-utility analysis) was expressed as postoperative pain days averted (PPDA) in the two surveys. To perform the cost-effectiveness analysis, we focused on postoperative complications, duration of hospital stay, and postoperative mortality rate. (Note: At the time of the study, 1 EURO = 0.85 US dollars.) MAIN RESULTS: VAS pain scores decreased in the post-APS phase (p < 0.001). One the first day, PPDA was 0.075, on the second day PPDA was 0.05, and the third day PPDA was 0.0375. Cost of analgesic drugs and disposal, as well as nursing hours, increased. The incremental cost of pain management after APS inception amounted to 19 EURO per patient per day, resulting in an incremental cost-effectiveness ratio of 350.77 EURO per PPDA gained. The cost-effectiveness analysis showed minor improvement (reduction of postoperative complication rate in some surgical specialties). Duration of hospital stay and postoperative mortality rate did not change. CONCLUSIONS: A hospital-wide, comprehensive, postoperative pain management program provides an overall positive result for the health care system by improving postoperative pain and morbidity. This service is cost-effective, costing 19 EURO per patient per day. A cost-utility analysis for short-term assessment of quality of life showed no benefit in determining usefulness of such a pain management program.

Case report: cerebral vein thrombosis after subarachnoid analgesia for labour.

PURPOSE: We report a case of sagittal sinus thrombosis occurring after spinal analgesia for labour to highlight the difficulty of such diagnosis in the presence of postpartum atypical headache following regional anesthesia/analgesia. CLINICAL FEATURES: A previously healthy 21-yr-old, primiparous, preeclamptic parturient was admitted to the hospital at 37 weeks gestation for uterine contractions. Before pregnancy she was taking no medication other than oral contraceptives and was a non-smoker. Spinal analgesia was established on the first attempt at 8 cm of cervical dilation, in the setting of rapid progression of labour. Following an uneventful delivery, on the third day postpartum, the patient experienced gradual onset of an atypical headache with unclear postural character, followed by focal neurological signs five days later. Emergency neuroimaging revealed direct evidence of thrombosis in the posterior sagittal venous sinus. Anticoagulation was initiated with iv heparin (500 UI x kg(-1) x day(-1)). The patient's headache decreased progressively and full motor recovery was noted by day 14 postpartum. After 24 days, the patient was discharged without any neurological disability. Common inherited thrombophilic dispositions were absent, with the exception of a decrease in protein S level. CONCLUSION: Central venous thrombosis, while rare, is a recognized cause of puerperium stroke. The present case highlights the importance of considering the diagnosis in the presence of postpartum atypical headache following spinal anesthesia/analgesia. Early intervention with systemic heparinization is critical when the diagnosis is confirmed.

Effect of nutritional status on oxidative stress in an ex vivo perfused rat liver.

BACKGROUND: Normothermic ischemia-reperfusion is a determinant in liver injury occurring during surgical procedures, ischemic state, and multiple organ failure. The preexisting nutritional status of the liver might contribute to the extent of tissue injury and primary nonfunction. The aim of this study was to determine the role of starvation on hepatic ischemia-reperfusion injury in normal rat livers. METHODS: Rats were randomly divided into two groups: one had free access to food, the other was fasted for 16 h. The portal vein was cannulated, and the liver was removed and perfused in a closed ex vivo system. Two modes of perfusion were applied in each series of rats, fed and fasting. In the ischemia-reperfusion mode, the experiment consisted of perfusion for 15 min, warm ischemia for 60 min, and reperfusion during 60 min. In the nonischemia mode, perfusion was maintained during the 135-min study period. Five rats were included in each experimental condition, yielding a total of 20 rats. Liver enzymes, potassium, glucose, lactate, free radicals, i.e., dienes and trienes, and cytochrome c were analyzed in perfusate samples. The proportion of glycogen in hepatocytes was determined in tissue biopsies. RESULTS: Transaminases, lactate dehydrogenase, potassium, and free radical concentrations were systematically higher in fasting rats in both conditions, with and without ischemia. Cytochrome c was higher after reperfusion in the fasting rats. Glucose and lactate concentrations were greater in the fed group. The glycogen content decreased in both groups during the experiment but was markedly lower in the fasting rats. CONCLUSIONS: In fed rats, liver injury was moderate, whereas hepatocytes integrity was notably impaired both after continuous perfusion and warm ischemia in fasting animals. Reduced glycogen store in hepatocytes may explain reduced tolerance.

Continuous epidural infusion of large concentration/small volume versus small concentration/large volume of levobupivacaine for postoperative analgesia.

UNLABELLED: In this randomized study, we evaluated the quality of postoperative analgesia and the incidence of side effects of continuous thoracic epidural levobupivacaine 15 mg/h in 2 different concentrations: 0.5%, 3 mL/h (n = 33) or 0.15%, 10 mL/h (n = 27). The following variables were registered within 48 h: sensory block, pain scores, rescue morphine consumption, motor blockade, hemodynamics, sedation, nausea and vomiting, and patient satisfaction. The two groups were similar with regard to demographics, cephalad level of sensory block, quality of analgesia, morphine consumption, side effects, and high satisfaction rate. Motor blockade was weaker in the 0.5% group (P = 0.025), with a significantly increased hemodynamic stability, compared with the 0.15% group (P = 0.004). In conclusion, the same dose of levobupivacaine provides an equal quality of analgesia in small- or large-volume continuous epidural infusion and decreases the incidence of motor blockade and hemodynamic repercussions. This is in accordance with the assumption that the total dose of local anesthetics determines the spread and quality of analgesia. IMPLICATIONS: We demonstrated that a large concentration/small volume of levobupivacaine given as a continuous thoracic epidural infusion provided an equal quality of postoperative analgesia as a small-concentration/large-volume infusion and induced less motor blockade and fewer hemodynamic repercussions.

Grand mal convulsion after an accidental intravenous injection of ropivacaine.

UNLABELLED: A 36-yr old, ASA physical status I patient scheduled for hip arthroplasty under regional anesthesia received at the end of surgery an i.v. injection of approximately 200 mL of a 0.15% ropivacaine solution (300 mg = 4.6 mg/kg) in approximately 5 min. The bag prepared for postoperative epidural infusion was accidentally connected to a peripheral i.v. line. The patient developed grand mal convulsions, hypotension, and respiratory arrest. No arrhythmias were observed. Twenty minutes after the event, the arterial plasma concentration of ropivacaine was 3.10 microg/mL. Using a pharmacokinetic model, the peak plasma concentration at the time of the accidental administration was estimated at 17.04 microg/mL. The patient recovered uneventfully. IMPLICATIONS: An accidental i.v. injection of approximately 300 mg of ropivacaine was followed by seizures without any arrhythmia. The patient recovered uneventfully.

Difference in risk factors for postoperative nausea and vomiting.

BACKGROUND: It is commonly stated that risk factors for postoperative nausea are the same as for vomiting. The authors designed a prospective study to identify and differentiate the risk factors for postoperative nausea and vomiting in various surgical populations in a clinical audit setting. METHODS: The study included 671 consecutive surgical inpatients, aged 15 yr or more, undergoing various procedures. The study focused on postoperative nausea visual analog scale scores every 4 h and vomiting episodes within 72 h. Both vomiting and retching were considered as emetic events. Patient-, anesthesia-, and surgery-related variables that were considered to have a possible effect on the proportion of patients experiencing postoperative nausea and/or vomiting were examined. The bivariate Dale model for binary correlated outcomes was used to identify selectively the potential risk factors of postoperative nausea and vomiting. RESULTS: Among the 671 patients in the study, 126 (19%) reported one or more episodes of nausea, and 66 patients (10%) suffered one or more emetic episodes during the studied period. There was a highly significant association between the two outcomes. Some risk factors were predictive of both nausea and vomiting (female gender, nonsmoking status, and general anesthesia). History of migraine and type of surgery were mainly responsible for nausea but not for vomiting. The predictive effect of risk factors was controlled for postoperative pain and analgesic drugs. CONCLUSION: This study shows that differences exist in risk factors of postoperative nausea and vomiting. These could be explained by differences in the physiopathology of the two symptoms.

An intervention study to enhance postoperative pain management.

UNLABELLED: This study, conducted before and after the implementation of an acute pain service (APS) in a 1000-bed hospital, describes the process of the implementation of an APS. The nursing, anesthesia, and surgery departments were involved. In this study we sought to evaluate the results of a continuous quality improvement program by defining quality indicators and using quality tools. A quality program in accordance with current standards of acute pain treatment (multimodal) was worked out to enhance pain relief for all surgical inpatients. A survey of nurses' knowledge with regard to postoperative pain was conducted, and a visual analog scale (VAS) was introduced to assess pain intensity. Both nurses and physicians became familiar with evidence-based guidelines concerning postoperative pain. The entire process was monitored in three consecutive surveys and enrolled 2383 surgical inpatients. Pain indicators based on VAS and analgesic consumption were recorded during the first 72 postoperative hours. After a baseline survey about current practices of pain treatment, a nurse-based, anesthesiologist-supervised APS was implemented. The improvement in pain relief, expressed as VAS scores, was assessed in two further surveys. A quality manual was written and implemented. A major improvement in pain scores was observed after the APS inception (P < 0.001). IMPLICATIONS: The implementation of an acute pain service, including pain assessment by a visual analog scale, standard multimodal pain treatment, and continuous quality evaluation, improved postoperative pain relief. Establishing teams of surgeons, anesthesiologists, and nurses is the prerequisite for this improvement.