Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose-insulin-potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial.

In this open-label multicentre randomised controlled trial, we investigated three peri-operative treatment strategies to lower glucose and reduce the need for rescue insulin in patients aged 18-75 years with type-2 diabetes mellitus undergoing non-cardiac surgery. Patients were randomly allocated using a web-based randomisation program to premedication with liraglutide (liraglutide group), glucose-insulin-potassium infusion (insulin infusion group) or insulin bolus regimen (insulin bolus group), targeting a glucose < 8.0 mmol.l-1 . The primary outcome was the between group difference in median glucose levels 1 h after surgery. We analysed 150 patients (liraglutide group n = 44, insulin infusion group n = 53, insulin bolus group n = 53) according to the intention-to-treat principle. Median (IQR [range]) plasma glucose 1 h postoperatively was lower in the liraglutide group compared with the insulin infusion and insulin bolus groups (6.6 (5.6-7.7 [4.2-13.5]) mmol.l-1 vs. 7.5 (6.4-8.3 [3.9-16.6]) mmol.l-1 (p = 0.026) and 7.6 (6.4-8.9 [4.7-13.2]) mmol.l-1 ) p = 0.006, respectively). The incidence of hypoglycaemia and postoperative complications did not differ between the groups. Six patients had pre-operative nausea in the liraglutide group, of which two had severe nausea, compared with no patients in the insulin infusion and insulin bolus groups (p = 0.007). The pre-operative administration of liraglutide stabilised peri-operative plasma glucose levels and reduced peri-operative insulin requirements, at the expense of increased pre-operative nausea rates.

Exploring the relationship between α-actinin-3 deficiency and obesity in mice and humans.

Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. α-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.

Hyperglycemia and ambulatory surgery.

BACKGROUND: Perioperative hyperglycemia is associated with postoperative complications after major surgery. However, more than 50% of surgical procedures are performed in an ambulatory setting, where glucose is not routinely measured. The objectives of this study were to investigate the change in capillary glucose during ambulatory surgery, to identify patients at risk for perioperative increasing glucose and to evaluate whether hyperglycemia predisposes for complications after ambulatory surgery. METHODS: In this prospective multicenter cohort study, adult patients planned for ambulatory surgery, were included and capillary glucose was measured 1 hour before and 1 hour after surgery. Patients were contacted 90 days after surgery to determine the occurrence of postoperative complications. RESULTS: Nine hundred and nine patients were included, 48 (5.3%) patients had diabetes mellitus (DM). Overall median glucose increased from 5.4 mmol L-1 preoperatively to 5.6 mmol L-1 postoperatively (P<0.001). Hyperglycemia, glucose ≥7.8 mmol L-1, occurred in 8.8% of the patients. Dexamethasone administration (given in 406 [44.7%] patients) was a risk factor for glucose increase (P<0.001). Hyperglycemia was not a risk factor for postoperative complications (OR 1.19, 95%CI 0.57-2.48, P=0.646). However, prediagnosed DM was a risk factor for postoperative complications, independent of hyperglycemia (OR 2.56, 95%CI 1.10-5.97, P=0.030). CONCLUSION: Minor ambulatory surgery is not associated with a clinically relevant increase in glucose. The very small glucose increase we observed could be attributed to the administration of dexamethasone for PONV prophylaxis. Hyperglycemia during ambulatory surgery is not associated with complications after discharge.

Sequence analysis of the equine ACTN3 gene in Australian horse breeds.

The sarcomeric α-actinins, encoded by the genes ACTN2 and ACTN3, are major structural components of the Z-line and have high sequence similarity. α-Actinin-2 is present in all skeletal muscle fibres, while α-actinin-3 has developed specialized expression in only type 2 (fast, glycolytic) fibres. A common single nucleotide polymorphism (SNP) in the human ACTN3 gene (R577X) has been found to influence muscle performance in elite athletes and the normal population. For this reason, equine ACTN3 (eACTN3) is considered to be a possible candidate that may influence horse performance. In this study, the intron/exon boundaries and entire coding region of eACTN3 have been sequenced in five Australian horse breeds (Thoroughbred, Arabian, Standardbred, Clydsdale and Shire) and compared to the eACTN3 GenBank sequence. A total of 34 SNPs were identified, of which 26 were intronic and eight exonic. All exonic SNPs were synonymous; however, five intronic SNPs showed significant differences between breeds. A total of 72 horses were genotyped for a SNP located in the promoter region of the eACTN3 gene (g. 1104 G>A) which differed significantly between breed groups. We hypothesize that this polymorphism influences eACTN3 expression and with further studies may provide a novel marker of horse performance in the future.

Properties of regenerated mouse extensor digitorum longus muscle following notexin injury.

Muscles of mdx mice are known to be more susceptible to contraction-induced damage than wild-type muscle. However, it is not clear whether this is because of dystrophin deficiency or because of the abnormal branching morphology of dystrophic muscle fibres. This distinction has an important bearing on our traditional understanding of the function of dystrophin as a mechanical stabilizer of the sarcolemma. In this study, we address the question: 'Does dystrophin-positive, regenerated muscle containing branched fibres also show an increased susceptibility to contraction-induced damage?' We produced a model of fibre branching by injecting dystrophin-positive extensor digitorum longus muscles with notexin. The regenerated muscle was examined at 21 days postinjection. Notexin-injected muscle contained 29% branched fibres and was not more susceptible to damage from mild eccentric contractions than contralateral saline-injected control muscle. Regenerated muscles also had greater mass, greater cross-sectional area and lower specific force than control muscles. We conclude that the number of branched fibres in this regenerated muscle is below the threshold needed to increase susceptibility to damage. However, it would serve as an ideal control for muscles of young mdx mice, allowing for clearer differentiation of the effects of dystrophin deficiency from the effects of fibre regeneration and morphology.

α-Actinin-3 deficiency alters muscle adaptation in response to denervation and immobilization.

Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in the absence of the fast fibre-specific protein, α-actinin-3 in ∼16% of humans worldwide. α-Actinin-3 deficiency is detrimental to optimal sprint performance and benefits endurance performance in elite athletes. In the general population, α-actinin-3 deficiency is associated with reduced muscle mass, strength and fast muscle fibre area, and poorer muscle function with age. The Actn3 knock-out (KO) mouse model mimics the human phenotype, with fast fibres showing a shift towards slow/oxidative metabolism without a change in myosin heavy chain (MyHC) isoform. We have recently shown that these changes are attributable to increased activity of the calcineurin-dependent signalling pathway in α-actinin-3 deficient muscle, resulting in enhanced response to exercise training. This led us to hypothesize that the Actn3 genotype influences muscle adaptation to disuse, irrespective of neural innervation. Separate cohorts of KO and wild-type mice underwent 2 weeks immobilization and 2 and 8 weeks of denervation. Absence of α-actinin-3 resulted in reduced atrophic response and altered adaptation to disuse, as measured by a change in MyHC isoform. KO mice had a lower threshold to switch from the predominantly fast to a slower muscle phenotype (in response to immobilization) and a higher threshold to switch to a faster muscle phenotype (in response to denervation). We propose that this change is mediated through baseline alterations in the calcineurin signalling pathway of Actn3 KO muscle. Our findings have important implications for understanding individual responses to muscle disuse/disease and training in the general population.

Intraoperative blood pressure changes as a risk factor for anastomotic leakage in colorectal surgery.

PURPOSE: Anastomotic leakage is a serious complication after colorectal surgery. Pre- and intraoperative factors may contribute to failure of colorectal anastomosis. In this study we have tried to determine risk factors for anastomotic leakage, with special emphasis on intraoperative blood pressure changes. METHODS: During a 24-month period, patients receiving a colorectal anastomosis were prospectively evaluated. For each patient preoperative characteristics, intraoperative adverse events and surgical outcome data were collected. Blood pressure changes were calculated as a relative decrease (>25% and >40%) from preoperative baseline values. RESULTS: During the study period, 285 patients underwent colorectal surgery with an anastomosis. Fifteen patients developed an anastomotic leakage (5.3%). All patients who developed a leakage had a left-sided procedure (P < 0.001). When blood loss was more than 250 mL (P = 0.003) or an intraoperative adverse event occurred (P = 0.050), the risk for developing an anastomotic leakage was significantly increased. A preoperative high diastolic blood pressure of ≥90 mmHg (P = 0.008) and severe intraoperative hypotension [>40% decrease in diastolic blood pressure (P = 0.049)] were identified as univariate risk factors for anastomotic leakage. CONCLUSIONS: The development of an anastomotic leakage after colorectal surgery is related to surgical, patient and anaesthetic risk factors. A high preoperative diastolic blood pressure and profound intraoperative hypotension combined with complex surgery, marked by a blood loss of ≥250 mL and the occurrence of intraoperative adverse events, is associated with an increased risk of developing anastomotic leakage.

Computerized model for preoperative risk assessment.

BACKGROUND: In order to improve the consistency of anaesthetic risk scoring, we have developed an automated method for the calculation of ASA (cASA) scores using decision logic programming. We investigated whether ASA scoring by anaesthetic caregivers could be matched or closely approximated by a cASA. METHODS: We used a web-based preoperative assessment system to present a structured questionnaire comprising 22 questions. These were designed to score and identify conditions that are known, from the literature and expert opinion, to be risk factors. The answers from 14,349 cases were processed using decision logic to provide a variety of risk scores including a computed overall anaesthetic risk (cASA), which was then compared with the ASA score estimated by anaesthesia caregivers (eASA). RESULTS: We found a close agreement between the two measures in almost all cases. In 159 cases (1.1%), there was an underestimation of cASA, in comparison with the eASA, which appeared to be a result predominantly of incorrect or incomplete answers, or an overestimation of the ASA score by the human classifier (43%). CONCLUSION: We showed that ASA scores estimated by a heterogeneous group of anaesthesia caregivers (anaesthetists, anaesthesia trainees, and physician assistants) could be mimicked by the cASA computed by our preoperative assessment system.

The effects of remifentanil and sufentanil on the quality of recovery after day case laparoscopic cholecystectomy: a randomized blinded trial.

BACKGROUND: Duration of hospitalization after laparoscopic cholecystectomy (LC) is mainly determined by temporary side effects such as pain, nausea, and vomiting. In this study we compared remifentanil, a short acting opioid, and sufentanil, a longer acting opioid, on their ability to reduce these postoperative effects and facilitate LC in day case surgery. METHOD: Seventy patients scheduled for elective LC were randomized in two groups. Remifentanil was used in group 1 as part of the anesthetic protocol, sufentanil was used in group 2. After surgery, patients were asked to evaluate pain and nausea on a verbal rate scale (VRS). Frequency of vomiting and analgesic medication consumption was registered. Time between surgery and to the start of micturition, drinking, mobilization, dressing, and discharge was recorded. Patients registered their satisfaction on a VRS. Details of any other adverse events throughout the study were recorded. RESULTS: Twenty-two patients (63%) of group 1 were treated as day cases vs. 27 (77%) in group 2 (P = NS). All patients who were not discharged as day cases left the hospital one day postoperatively. Immediately after surgery, patients in group 2 reported significantly less pain. There were no other significant differences between groups. CONCLUSION: The majority of patients scheduled for LC can be safely discharged on the day of surgery. Reported satisfaction one week postoperatively was high for all patients. We found no major relevant differences between the two anesthetic protocols.

Remifentanil-sevoflurane anaesthesia for laparoscopic cholecystectomy: comparison of three dose regimens.

The objective of this study was to determine a dosing regimen for remifentanil-sevoflurane anaesthesia that achieves an optimal balance between quality of anaesthesia and time to recovery. Patients undergoing elective laparoscopic cholecystectomy were randomly allocated to receive 0.4, 0.8 or 1.2 MAC (minimal alveolar concentration) of sevoflurane combined with remifentanil as required to maintain stable anaesthesia. For induction of anaesthesia, the remifentanil dose was 25 microg x kg(-1) x h(-1) and the mean propofol dose which was required to obtain loss of consciousness was 1.59 mg x kg(-1). During the maintenance phase, the mean remifentanil dose was 16.0, 14.1 and 13.0 microg x kg(-1) x h(-1) for the 0.4, 0.8 and 1.2 MAC groups, respectively. The mean sevoflurane maintenance dose was 0.91, 1.24 and 2.1% end-tidal for the 0.4, 0.8 and 1.2 MAC groups, respectively. The incidence of somatic responses was significantly higher in the 0.4 MAC sevoflurane group. Recovery times were significantly faster in the 0.4 compared to the 0.8 and 1.2 MAC groups and in the 0.8 compared to the 1.2 MAC group. The combination of 14 microg x kg(-1) x h(-1) remifentanil and 1.24% end-tidal sevoflurane achieved the optimal balance between the quality, and recovery from anaesthesia.

Preferences for treatment during a first psychotic episode.

Psychiatric services providing care for patients and their families confronted with a first psychotic episode need to be sensitive towards patients' and families' preferences. Ten patients, ten family members and ten professional caregivers composed a list of 42 preferences in the treatment for a first psychotic episode. In total 99 patients, 100 family members and 263 professional caregivers evaluated these preferences, thus producing an order of priorities. There appears to be considerable agreement among the groups of respondents regarding their top ten priorities, especially concerning information on diagnosis and medication. However, we found important differences between groups of respondents. The results suggest that in psychiatric services great attention should be given to psycho-education and early outpatient intervention.

A double-blind, parallel-group, placebo-controlled, dose-ranging, multicenter study of intravenous granisetron in the treatment of postoperative nausea and vomiting in patients undergoing surgery with general anesthesia.

STUDY OBJECTIVE: To compare the effectiveness of granisetron with placebo in the treatment of established postoperative nausea and vomiting (PONV). DESIGN: Randomized, placebo-controlled study. SETTING: 34 hospitals in Europe, Scandinavia, and South Africa. PATIENTS: 519 ASA physical status I, II, and III patients who developed PONV within 4 hours of the end of surgery performed with general anesthesia. INTERVENTIONS: Patients received a single intravenous dose of granisetron 0.1 mg, 1 mg, or 3 mg, or placebo when symptoms of nausea or vomiting were experienced. Additional rescue medication could be given at the investigator's discretion if nausea and vomiting were not controlled. MEASUREMENTS AND MAIN RESULTS: At all doses investigated, granisetron was significantly more effective (p < or = 0.001) than placebo in controlling vomiting: 38%, 46%, and 49% of patients receiving granisetron, 0.1 mg, 1.0 mg, and 3.0 mg, respectively, experienced no vomiting in the first 24 hours following drug administration, compared with 20% receiving placebo. There was a statistically significant linear relationship between vomiting control and granisetron dose (p < 0.001). Survival distributions of time to resolution of vomiting confirmed the statistically significant difference between patients receiving granisetron and those receiving placebo. Granisetron was well tolerated: the most common adverse experiences were pain, constipation, anemia, and headache, and the incidence of adverse experiences was not statistically significantly higher in any of the granisetron groups than in the placebo group. CONCLUSION: Granisetron was significantly more effective than placebo in all groups. Further studies in specific subgroups may be warranted.

Comparison of the cardiovascular effects of intravenous, epidural and intrathecal sufentanil analgesia as a supplement to general anaesthesia for abdominal aortic aneurysm surgery.

Sixty ASA Grade II-III patients, without clinical symptoms of ventricular dysfunction and scheduled for elective bifemoral grafting for abdominal aneurysms, were allocated randomly to three equal groups to receive 150 micrograms sufentanil intravenously, epidurally or intrathecally. All patients received midazolam, vecuronium and nitrous oxide. Except for right ventricular stroke work index and pulmonary vascular resistance, all haemodynamic measurements decreased after sufentanil injection, but to the greatest extent after intravenous injection. Response to abdominal incision reversed the haemodynamic changes, although this was not accompanied by an increase in heart rate and coronary perfusion pressure after intrathecal injection. Four patients given intravenous, and four patients given epidural sufentanil required additional sufentanil after abdominal incision. Despite the changes in systemic vascular resistance and the concordant alterations in cardiac index after aortic cross-clamping and revascularization, intrathecal sufentanil provided more stability in heart rate than intravenous or epidural sufentanil. In conclusion, intrathecal sufentanil produced the most stable heart rate. Two patients in the intrathecal group developed spinal headaches post-operatively.

A haemodynamic comparison of intrathecal morphine and sufentanil supplemented with general anaesthesia for abdominal aortic surgery.

The haemodynamic changes associated with intrathecal morphine (IM) compared to intrathecal sufentanil (IS) as a supplement to general anaesthesia for elective bypass grafting in patients with aortoiliac occlusive disease were studied. Thirty-six, ASA Grade 2, patients randomly received morphine hydrochloride (0.1%) 50 micrograms kg-1 (n = 18) or undiluted sufentanil, 150 micrograms (n = 18) intrathecally at T12-L1, combined with light general anaesthesia. Haemodynamics were measured before and after endotracheal intubation, abdominal incision, aortic cross-clamping and the first revascularisation. The major differences were recorded after abdominal incision. Heart rate, systemic blood pressure and coronary perfusion pressure were significantly lower in the IS group. The probable cause was greater systemic absorption of sufentanil and its faster binding to the specific opiate receptors, resulting in a more efficacious supraspinal and spinal blockade during the first surgical period. However, both opioids provided adequate analgesia during the whole surgical procedure.

A haemodynamic comparison of epidural versus intrathecal sufentanil to supplement general anaesthesia for abdominal aortic surgery.

The present study was designed to evaluate the influence of epidural sufentanil (ES) and intrathecal sufentanil (IS) on the peri-operative haemodynamic responses during abdominal aortic surgery. Twenty-four ASA Grade II patients without clinical symptoms of coronary artery disease received, randomly, epidural (n = 12) or intrathecal (n = 12) sufentanil combined with light general anaesthesia for elective bifemoral grafting for aorto-iliac occlusive disease. The IS group contained significantly more hypertensive patients than the ES group. This resulted in a significantly higher systolic and mean blood pressure, which remained constant from the start to the end of the study. Following a single bolus injection of 150 micrograms of sufentanil epidurally or intrathecally, there was a significant decrease in heart rate (HR), systolic, mean and diastolic blood pressure, systemic vascular resistance (SVR) and coronary perfusion pressure in both groups. This suggests that IS and ES must be used with caution in patients with cardiovascular disease. The abdominal incision restored the haemodynamic changes produced by sufentanil administration, but these did not exceed pre-sufentanil values. There were no significant changes in filling pressure, cardiac index (CI) and left ventricular work after aortic cross-clamping in the two groups. Revascularization produced significant differences in HR, SVR and CI in both groups in comparison with the pre-declamping period. Notable was the maintenance of systemic blood pressure following revascularization due to preservation of sympathetic activity. It was concluded that both epidural and intrathecal sufentanil produce comparable and stable haemodynamics in this category of patients.

Epidural bupivacaine versus epidural sufentanil anesthesia: hemodynamic differences during induction of anesthesia and abdominal dissection in aortic surgery.

The present study was designed to compare the hemodynamic changes of epidural bupivacaine (EB) with epidural sufentanil (ES), supplemented by general anesthesia, in patients scheduled for abdominal aorto-iliac surgery. Twenty-eight ASA Grade 2 patients randomly received bupivacaine 0.5%, 1-1.5 mg kg-1 (n = 14) or sufentanil 150 micrograms (n = 14) epidurally at T12-L1, combined with light general anesthesia. Hemodynamics were measured before (T1) and after (T2) injection of EB or ES, after induction of general anesthesia (T3), and during the aortic dissection period (T4). EB or ES injection both produced a significant decrease in systolic, mean and diastolic blood pressure, left ventricular stroke work index (LVSWI) and coronary perfusion pressure (CPP). The induction of general anesthesia caused a significant fall in heart rate (HR) and cardiac index (CI) in the ES group. Abdominal dissection restored systemic pressure and cardiac index in the ES group. It was concluded that both ES and EB provided adequate analgesia and hemodynamics during tracheal intubation and abdominal dissection for aorto-iliac surgery.

Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery.

We have studied the plasma concentrations (Cp) and pharmacokinetics of sufentanil injected i.v. (IVS), intradurally (IS) or extradurally (ES) under general anaesthesia in 31 patients undergoing major abdominal surgery. Sufentanil appeared in plasma very rapidly and Cpmax was also attained rapidly after both extradural and intrathecal injection. Apart from the first 2 min after injection, Cp after ES and IVS were comparable until the end of the study. Cp after ES was greater than after IS up to 0.25 h. Cp after IS was significantly greater than that after ES at 1 h and 2.5 h, and was also greater than that after IVS at 3 h. At tracheal extubation there was no difference in Cp between groups. Peak Cp values were significantly different between ES and IS, but the times taken to reach Cpmax were comparable. Plasma pharmacokinetics after ES and IS were similar. The plasma mean residence time and volume of distribution of sufentanil at steady state after ES and IS were significantly different in comparison with those after IVS.