One-year follow-up on liraglutide treatment for prediabetes and overweight/obesity in clozapine- or olanzapine-treated patients.

OBJECTIVE: Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period. METHOD: One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels. RESULTS: From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide. CONCLUSION: The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

The significance of sampling time in therapeutic drug monitoring of clozapine.

OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis. CONCLUSION: The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.

Grass-green urine from propofol infusion.

Green urine from propofol infusion is a benign and rare side effect. The discolouration appears when clearance of propofol exceeds hepatic elimination, and extrahepatic elimination of propofol occurs. This case report presents a 24-year-old male with grass green discolouration of urine based on propofol infusion.

Heart rate limitation and cardiac unloading in sevoflurane post-conditioning.

BACKGROUND: Sevoflurane post-conditioning (SePost) has been found to alleviate ischemic myocardial reperfusion injury through the activation of prosurvival kinases. Lowered myocardial oxygen demand from reduced cardiac work may also contribute to cardioprotection, and is much less well-studied. Our aim was to examine the simultaneous effects of SePost on cardiac work (here, rate-pressure product, RPP) and myocardial infarct size in a porcine model. METHODS: Anesthetized 25 kg pigs were randomly allocated to two groups and underwent 45 min regional coronary artery balloon occlusion and subsequent 2 h reperfusion. SePost (n = 10) was given as sevoflurane 1.5-3% end-tidal concentration during reperfusion while controls (n = 12) were untreated. Aortic blood pressure was measured directly, while mixed-venous oxygen saturation and cardiac output were measured in the pulmonary artery. Cardiac work was determined as RPP. Post-mortem, histologic myocardial infarct size (IS), and area at risk were determined in transverse heart slices after tetrazolium stain. RESULTS: Myocardial infarct size was reduced from (control) 55.0 (mean) ± 13.6% (standard deviation) to 32.5 ± 13.4% in group SePost (P = 0.0009). During reperfusion, SePost resulted in lower heart rate (P = 0.0003), cardiac output (P = 0.0123), mixed-venous oxygen saturation (P = 0.0103), blood pressure, and RPP (P < 0.0001). RPP was highly correlated to IS (P = 0.0055). CONCLUSION: SePost (1.5-3%) reduced infarct size after regional myocardial ischemia in vivo and reduced cardiac work was significantly correlated to myocardial salvage.

Hypertrophied hearts: what of sevoflurane cardioprotection?

BACKGROUND: Recent studies have demonstrated that inhalation anaesthetics, like sevoflurane, confer cardioprotection both experimentally and clinically. However, coexisting cardiac disease might diminish anaesthetic cardioprotection and could partly explain why the clinical results of cardioprotection with anaesthetics remain controversial--in contrast to solid experimental evidence. Concomitant left ventricular hypertrophy is found in some cardiac surgery patients and could change cardioprotection efficacy. Hypertrophy could potentially render the heart less susceptible to sevoflurane cardioprotection and more susceptible to ischaemic injury. We investigated whether hypertrophy blocks sevoflurane cardioprotection, and whether tolerance to ischaemia is altered by left ventricular hypertrophy, in an established experimental animal model of ischaemia-reperfusion. METHODS: Anaesthetized juvenile pigs (n=7-12/group) were subjected to 45 min distal coronary artery balloon occlusion, followed by 120 min of reperfusion. Controls were given pentobarbital, while sevoflurane cardioprotection was achieved by 3.2% inhalation throughout the experiment. Chronic banding of the ascending aorta resulted in left ventricular hypertrophy development in two further groups and these animals underwent identical ischaemia-reperfusion protocols, with or without sevoflurane cardioprotection. Myocardial infarct sizes were compared post-mortem. RESULTS: The mean myocardial infarct size (% of area-at-risk) was reduced from mean 55.0 (13.6%) (+/-SD) in controls to 17.5 (13.2%) by sevoflurane (P=0.001). Sevoflurane reduced the infarct size in hypertrophied hearts to 14.6 (10.4%) (P=0.001); however, in hypertrophic controls, infarcts were reduced to 34.2 (10.2%) (P=0.001). CONCLUSION: Sevoflurane abrogated ischaemic injury to similar levels in both normal and left ventricular hypertrophied hearts.

Sevoflurane improves myocardial ischaemic tolerance in a closed-chest porcine model.

AIMS: Volatile anaesthetics prevent experimental myocardial ischaemia-reperfusion injury (I/R) in several species, but this finding is partially inconsistent with clinical evidence. Some experimental models may not accurately represent the complex signal transduction pathways triggered by volatile anaesthetics. We therefore investigated sevoflurane I/R prevention in vivo in a porcine model with greater likeness to human physiology than models previously used and compared it with neutral anaesthetic. METHODS AND RESULTS: Myocardial infarct size [IS/AAR] was compared in three groups of pigs (N=35) randomised to Control anaesthesia (pentobarbital infusion, n=12), sevoflurane inhalation alone (end-tidal concentration 3.2%) (Sevo, n=9), or both Combined (n=14), throughout ischaemia and reperfusion. Anterior/septal myocardial infarcts resulted from distal LAD coronary artery occlusion by balloon catheter for 45 min followed by 120 min of reperfusion. [IS/AAR] was measured in tetrazolium-stained heart slices after standardised image processing with computer-assisted planimetry. Measurements included full invasive monitoring. Control animals developed infarction in 55.0 +/- 3.9% (SEM) of the area at risk, Sevo in 17.5 +/- 4.4% (P=0.0002), and Combined with pentobarbital in 24.3 +/- 3.8% (P=0.0001) of the AAR, sevoflurane reducing infarct size significantly (68% and 60%, respectively). CONCLUSIONS: Sevoflurane markedly decreased myocardial infarct size after prolonged coronary occlusion in a porcine model. In addition to novel sevoflurane cardioprotection in the closed-chest model, which is more comparable to normal human hearts than models previously used, sevoflurane cardioprotection is substantiated in the juvenile intact organism. The perspectives underline recommending volatile anaesthetics in risk patients and in cardiac surgery.

High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study.

AIMS/HYPOTHESIS: The risk of dying of cardiovascular disease (CVD) before the age of 40 years is increased nearly 20-fold in patients with type 1 diabetes compared with non-diabetic persons. The aim of this study was to evaluate the prevalence of CVD risk factors in a population-based study of children and adolescents with type 1 diabetes. METHODS: CVD risk factors were examined according to the American Diabetes Association criteria in 2005. Of 26 paediatric clinics in Norway, 25 participated with 1,658 patients, 85% of those eligible. Mean age was 13.1 years and mean diabetes duration 5.7 years. RESULTS: HbA(1c) was above the target level in 71.4%. A positive family history of early CVD and/or diabetes was found in 33% of participants. LDL-cholesterol was >2.6 mmol/l in 34.5% and HDL-cholesterol was <1.1 mmol/l in 6.9% of participants. Blood pressure was above the 90th percentile by age, sex and height in 7% and above the 95th percentile in 4% of participants. Four per cent of participants were obese, 3% of those >or=12 years of age reported smoking and 1% of all participants had persistent microalbuminuria. Only 0.2% of the patients were receiving statin and 0.3% anti-hypertensive treatments. Dietary habits and physical activity level were evaluated in some patients. Almost all had higher intake of dietary fat and lower intake of fibre than recommended. A large part was less active and watched more TV than recommended. CONCLUSIONS/INTERPRETATION: Of the participants, 86% had at least one, 45% at least two and 15% at least three CVD risk factors. Few patients were treated with statins and anti-hypertensive drugs.

Does the pre-ischaemic administration of sevoflurane reduce myocardial stunning? A porcine experimental model.

BACKGROUND: In a porcine model, the cardioprotective effect of sevoflurane was studied with regard to the preservation of myocardial contractility (myocardial stunning) after a myocardial ischaemic insult. METHODS: Twenty-seven pigs were randomized to receive either a dual 4% sevoflurane inhalation period as a supplement to pentobarbital anaesthesia or pentobarbital anaesthesia only before a 15-min ischaemic insult on the left anterior descending coronary artery. The ischaemic period was followed by 180 min of reperfusion. Myocardial contractility was assessed by myocardial sonomicrometry. RESULTS: A significant difference was found between the sevoflurane group and the control group at 5 min of reperfusion. However, subsequently, there was no overall difference between the two groups. CONCLUSION: Sevoflurane administered as a pre-ischaemic bolus does not provide long-term improvement of the myocardial contractility. However, it can be speculated that sevoflurane may induce an early improvement in contractility.

Pre-occlusion ischaemia, not sevoflurane, successfully preconditions the myocardium against further damage in porcine in vivo hearts.

BACKGROUND: Sevoflurane is proposed to possess important tissue protective effects based on experimental ischaemia-reperfusion studies from models with collateral coronary flow, unlike that of the normal human or the porcine heart. The objective was to evaluate the infarct-reducing capability of pre-ischaemic sevoflurane inhalation on myocardial infarct size in a porcine model. METHODS AND MATERIALS: The study comprised 33 pigs under pentobarbital anaesthesia. Animals were divided into three groups: control (CON), sevoflurane intervention (SEVO) and ischaemic preconditioning (IP). The distal left anterior descending coronary artery was occluded for 40 min with a percutaneous coronary intervention catheter. Before occlusion, group IP underwent two 5-min ischaemia cycles, whereas SEVO received two 5-min sevoflurane 4%v/v inhalation cycles. Animals were reperfused for 150 min. We then measured risk area (AAR) and infarct size (IS) after tetrazolium staining. The [IS/AAR-ratio] was calculated. Haemodynamics and transthoracic tissue-Doppler echocardiography were monitored. RESULTS: Control animals developed a myocardial infarction in 46.4 (+/- 6.2)% (mean +/- SEM) of the AAR. Both SEVO and IP groups had infarction mitigated, to 34.4 (5.7)% and 23.1 (5.3)%, respectively; however, only in the IP group was this significant. No significant differences between groups with respect to AAR, haemodynamics or echocardiographic variables were found. CONCLUSION: Pre-ischaemic sevoflurane was found to reduce the extent of myocardial necrosis, but the change was not significant, whereas IP reduced IS by 50% (P= 0.038). Cardioprotection is species related and no previous results from porcine models have found sevoflurane to reduce IS. Anaesthetic washout, insufficient exposure or collateral coronary blood supply, dissimilar to human, may account for positive results in rodent models.

Propofol reduces tissue-Doppler markers of left ventricle function: a transthoracic echocardiographic study.

BACKGROUND: Propofol is thought to minimally depress myocardial function, but mainly to reduce blood pressure by vasodilation. Transthoracic tissue-Doppler echocardiography (TDE) is a novel, validated method of quantifying myocardial function. It provides new insight into myocardial function by measuring myocardial motion. We examined the effects of propofol upon myocardial function by measuring changes in left ventricle function by TDE. METHODS: We assessed change in myocardial function in propofol anaesthetized ASA I patients tissue tracking displacement (TTD) before anaesthesia onset and repeated measurements after a single propofol bolus dose. Tissue tracking score (TTS), a marker of ejection fraction, was also used (n = 10). RESULTS: Propofol 1.5-2 mg kg(-1) significantly attenuated PSV from 5.64 (1.17) to 4.66 (0.55) cm s(-1) (P < 0.0001) and TTD from 10.2 (2.1) to 8.5 (1.4) mm (P = 0.0091), whereas TTP was unchanged [all data: mean (SD)]. TTS declined from 7.2 (1.3) to 6.1 (0.6) mm (P < 0.01). Non-invasive mean blood pressure declined 17% (P < 0.0001). CONCLUSIONS: The results indicate that myocardial contractile function is compromised concomitantly with reduced cyclic displacement after propofol dosing. Blood pressure declined accordingly. From these results, it is impossible to ascertain whether this was secondary to reduced cardiac filling or a consequence of a direct negative inotropic action of propofol, but it represents a left-shift of the Starling curve. The novel TDE yields new information on myocardial velocities and motion.

Atherosclerosis in childhood and adolescent type 1 diabetes: early disease, early treatment?

Autopsy studies have shown that atherosclerosis begins in adolescence in otherwise healthy individuals, and imaging techniques have shown that atherosclerosis develops earlier and is more prevalent in children with diabetes than in age-matched healthy controls. Cardiovascular disease has now overtaken diabetic nephropathy as the leading cause of premature mortality in young adults with diabetes, and the emphasis on disease prevention has accordingly shifted to a younger age group. The majority of children and adolescents with diabetes have suboptimal blood glucose control, and this contributes to accelerated arterial disease in this age group. Other conventional risk factors for coronary heart disease also need to be considered and treated aggressively. Effective early prevention of cardiovascular disease will involve lifestyle modification and full implementation of existing treatment guidelines, and large-scale prospective studies will be needed to establish the risks and benefits of early pharmacological intervention in children and adolescents.

Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes.

AIMS/HYPOTHESIS: Intima media thickness (IMT) of the common carotid artery (CCA) is a validated surrogate marker of early atherosclerosis. The aim of our study was to assess the association between IMT in CCA and long-term mean HbA1c in type 1 diabetes. We also elucidated the association between carotid IMT and preclinical coronary atherosclerosis. METHODS: In 39 individuals with type 1 diabetes, HbA1c was measured prospectively over 18 years. The IMT examinations were performed with high-resolution ultrasound. The association between carotid IMT and preclinical coronary atherosclerosis (assessed by intravascular ultrasound [IVUS]) was tested in 29 of the patients. RESULTS: Mean HbA1c over 18 years was 8.2% (range: 6.6-11.3%). Mean age at follow-up after 18 years was 43 years and mean duration of diabetes was 30 years. IMT was significantly higher in diabetic patients than in an age- and sex-matched reference population. The IMT values were at the same level as for controls who were 20 years older. In women, HbA1c was significantly associated with mean average CCA IMT (r2=0.77, p<0.0001 when adjusted for age), whereas there was no significant association for men. Among women, a significant association was also found between carotid IMT and the percentage of coronary vessel area stenosis (r=0.65, p=0.03). CONCLUSIONS/INTERPRETATION: The present findings suggest an important role of long-term hyperglycaemia in the development of atherosclerosis, especially in women with type 1 diabetes. Type 1 diabetes patients have earlier development of, and more advanced, atherosclerosis compared with an age- and sex-matched reference population. In women, carotid IMT reflects preclinical coronary atherosclerosis.

Clinical performance of a new silver dressing, Contreet Foam, for chronic exuding venous leg ulcers.

OBJECTIVE: This study aimed to evaluate the safety and performance of a new sustained silver-releasing dressing, Contreet Foam (Coloplast A/S), in the treatment of moderately to highly exuding chronic venous leg ulcers in which healing is delayed due to the presence of bacteria. METHOD: The clinical performance of Contreet Foam was studied for four weeks in 25 patients with moderately to highly exuding delayed-healing venous leg ulcers. Healing was assessed on a weekly basis with reference to the wound-bed tissue composition, degree of odour and pain, dressing performance and the dressing's effect on the peri-ulcer area. Blood samples were analysed for silver content. RESULTS: Twenty-three out of 25 patients completed the study. One ulcer healed and no wound infections occurred during the study period. A mean 56% reduction in ulcer area (from 15.6 to 6.9 cm2) was recorded during the four weeks, and there was a mean 25% reduction in granulation tissue from dull to healthy after one week. Wound odour reduced significantly after one week. Mean dressing wear time was 3.1 days, and there were only minimal incidences of leakage. Serum silver levels did not exceed reference values. CONCLUSION: Contreet Foam was found to be safe and performed well when used in the treatment of delayed-healing chronic venous leg ulcers, combining effective antibacterial properties with excellent exudate management. DECLARATION OF INTEREST: This study was supported by Coloplast A/S, Humlebaek, Denmark.

The effects of atropine on dynamic compliance in healthy intubated adults.

In order to compare the effect of atropine and sodium chloride on the dynamic compliance of the respiratory system after tracheal intubation, we studied 20 patients allocated randomly into two groups to receive either: atropine after 5 min of steady state and sodium chloride after 10 min (group A) or in reverse order (group B) intravenously. The study was conducted in a randomized double-blinded manner. The patients were anaesthetized with thiopental 5 mg kg(-1) followed by thiopental 50 mg intravenously, as required. Intubation was facilitated by atracurium 0.5 mg kg(-1) intravenously and fentanyl 200 microg intravenously. During fixed volume ventilation (100 mL kg(-1), f=10), compliance and end-tidal carbon dioxide were measured every 10 s by a Datex AS/3-respiratory module connected to a portable IBM-pc. Five minutes was allowed to establish a steady state then either atropine or sodium chloride was administered according to the protocol. Respiratory dynamic compliance increased significantly after intravenous administration of atropine (P < 0.05). We conclude that atropine 1.0 mg given intravenously provides protection against an intubation-induced decline in respiratory dynamic compliance.

Ventricular tachycardia with ECT.

A case is presented in which a patient with ischemic heart disease developed episodic, nonsustained ventricular tachycardia (VT) during electroconvulsive therapy for major depression. The VT had a frequency of 200 beats/min and ceased spontaneously after 17 s. Altered autonomic discharge in the presence of ischemia is the probable cause. Predisposing factors, as well as management considerations, are discussed.

Fatal fulminant autoimmune haemolytic anaemia associated with tolmetin use and gastric carcinoma. Case report and literature review.

Presented is a case report of an 80-year-old man with dyspnoea and jaundice who died from autoimmune haemolytic anaemia (AIHA) within 12 hours of arrival at the emergency department. The patient had been taking tolmetin for osteoarthritis. On autopsy he was found to have a superficial gastric adenocarcinoma. A brief presentation on AIHA includes primary (idiopathic) and secondary types. Factors associated with AIHA include nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric carcinoma, although a direct cause cannot be demonstrated. After a discussion of the autoimmune mechanism of drug-associated hemolysis of which methyldopa is the prototype, a review of NSAIDs associated with AIHA is presented. All (18) NSAID cases of immune haemolysis were reviewed to determine which were more likely due to an autoimmune mechanism. These included 3 cases with tolmetin use: one probable and one possibly having an autoimmune basis for haemolysis, while with the third case immune haemolysis was by the drug adsorption mechanism. A review of gastric carcinoma associated with AIHA reveals only 2 previously reported cases. The associations of tolmetin use, as well as gastric carcinoma with AIHA, both rare, are noteworthy but cannot be proven as causative factors with our current level of knowledge and technology.

Clinical features and management of poisoning due to phenytoin.

The widespread use of phenytoin results in frequent accidental and intentional toxicity. Metabolism is enzymatic and can be described by Michaelis-Menten kinetics. This results in an increased half-life in overdose situations and a protracted clinical course which may last a week or more. The primary toxicity is on the central nervous system. The most common initial finding in mild toxicity is nystagmus. As concentrations increase ataxia, decreased coordination, hyper-reflexia, slurred speech and diplopia may develop. Progressive increases result in confusion, lethargy and coma. Various methods tried to increase elimination including dialysis, haemoperfusion, diuresis and plasmaphoresis have been ineffective and are not without risk. Meticulous supportive care including ventilation if necessary should provide a good clinical outcome. Multiple-dose activated charcoal may be helpful in shortening the duration of symptoms.