Trimetazidine does not alter metabolic substrate oxidation in cardiac mitochondria of target patient population.

BACKGROUND AND PURPOSE: Trimetazidine, known as a metabolic modulator, is an anti-anginal drug used for treatment of stable coronary artery disease (CAD). It is proposed to act via modulation of cardiac metabolism, shifting the mitochondrial substrate utilization towards carbohydrates, thus increasing the efficiency of ATP production. This mechanism was recently challenged; however, these studies used indirect approaches and animal models, which made their conclusions questionable. The goal of the current study was to assess the effect of trimetazidine on mitochondrial substrate oxidation directly in left ventricular myocardium from CAD patients. EXPERIMENTAL APPROACH: Mitochondrial fatty acid (palmitoylcarnitine) and carbohydrate (pyruvate) oxidation were measured in permeabilized left ventricular fibres obtained during coronary artery bypass grafting surgery from CAD patients, which either had trimetazidine included in their therapy (TMZ group) or not (Control). KEY RESULTS: There was no difference between the two groups in the oxidation of either palmitoylcarnitine or pyruvate, and in the ratio of carbohydrate to fatty acid oxidation. Activity and expression of pyruvate dehydrogenase, the key regulator of carbohydrate metabolism, were also not different. Lastly, acute in vitro exposure of myocardial tissue to different concentrations of trimetazidine did not affect myocardial oxidation of fatty acid. CONCLUSION AND IMPLICATIONS: Using myocardial tissue from CAD patients, we found that trimetazidine (applied chronically in vivo or acutely in vitro) had no effect on cardiac fatty acid and carbohydrate oxidation, suggesting that the clinical effects of trimetazidine are unlikely to be due to its metabolic effects, but rather to an as yet unidentified intracardiac mechanism.

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion.

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan.

Remifentanil reversibly abolished phrenic long term facilitation in rats subjected to acute intermittent hypoxia.

The aim was to investigate whether intravenous infusion of remifentanil would depress phrenic long term facilitation (pLTF) evoked by acute intermittent hypoxia (AIH) in adult, male, urethane anaesthetized Sprague-Dawley rats, bilaterally vagotomized, paralyzed and mechanically ventilated. The experimental group received a remifentanil infusion (0.5 µg/kg/min i.v., n=12), whereas the control group (n=6) received saline. Rats were exposed to AIH protocol. Phrenic nerve amplitude (PNA), burst frequency (f) and breathing rhythm parameters (Ti, Te, Ttot) were analyzed during 5 hypoxias and at 15, 30, and 60 minutes after the final hypoxia, and compared to baseline values. At the end of the experiment, the infusion of remifentanil was stopped and phrenic nerve activity was compared to baseline values prior to remifentanil infusion. In the control group, peak phrenic nerve activity (pPNA) significantly increased at 60 min (T60, increase by 138.8±28.3%, p=0.006) after the last hypoxic episode compared to baseline values, i.e. pLTF was induced. In remifentanil treated rats, there were no significant changes in peak phrenic nerve activity at T60 compared to baseline values (decrease by 5.3±16.5%, p>0.05), i.e. pLTF was abolished. Fifteen minutes following cessation of remifentanil infusion, pPNA increased by 93.2±40.2% (p<0.05) and remained increased compared to pre-remifentanil-infusion values for more than 30 minutes, i.e. pLTF could be observed after cessation of the remifentanil infusion. In conclusion, the short acting µ-opioid receptor agonist, remifentanil, reversibly abolished phrenic long term facilitation in urethane anesthetized rats.

Propofol abolished the phrenic long-term facilitation in rats.

The aim was to investigate the effect of propofol anesthesia on the phrenic long-term facilitation (pLTF) in rats. We hypothesized that pLTF would be abolished during propofol-compared with urethane anesthesia. Fourteen adult, male, anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague-Dawley rats (seven per group), were exposed to the acute intermittent hypoxia (AIH) protocol. Peak phrenic nerve activity (PNA), burst frequency (f), and breathing rhythm parameters (Ti, Te, Ttot) were analyzed during the first hypoxia (TH1), as well as at 15 (T15), 30 (T30), and 60min (T60) after the final hypoxic episode, and compared to the baseline values. In propofol-anesthetized rats no significant changes of PNA were recorded after the last hypoxic episode, i.e. no pLTF was induced. There was a significant increase of PNA (59.4+/-6.6%, P<0.001) in urethane-anesthetized group at T60. AIH did not elicit significant changes in f, Ti, Te, Ttot in either group at T15, T30, and T60. The pLTF, elicited by AIH, was induced in the urethane-anesthetized rats. On the contrary, pLTF was abolished in the propofol-anesthetized rats.

The acute hypoxic ventilatory response under halothane, isoflurane, and sevoflurane anaesthesia in rats.

The relative order of potency of anaesthetic agents on the hypoxic ventilatory response has been tested in humans, but animal data are sparse. We examined the effects of 1.4, 1.6, 1.8, and 2.0 MAC halothane, isoflurane, and sevoflurane on phrenic nerve activity in euoxia (baseline) and during acute normocapnic hypoxia (inspired oxygen fraction 0.09) in adult male Sprague-Dawley rats. With halothane, all animals became apnoeic even in euoxia, and the hypoxic response was completely abolished at all anaesthetic levels. With isoflurane, 5 of 14 animals exhibited phrenic nerve activity in euoxia at 1.4 MAC and demonstrated a hypoxic response (302% of baseline activity), but all became apnoeic and lost the hypoxic response at higher doses. With sevoflurane, phrenic nerve activity and a hypoxic response was preserved in at least some animals at all doses (i.e. even the highest dose of 2.0 MAC). Similar to the rank order of potency previously observed in humans, the relative order of potency of depression of the hypoxic ventilatory response in rats was halothane (most depressive) > isoflurane > sevoflurane (p = 0.01 for differences between agents).

Rocuronium attenuates oculocardiac reflex during squint surgery in children anesthetized with halothane and nitrous oxide.

BACKGROUND: The oculocardiac reflex (OCR) may be activated during squint surgery. The aim of this study was to test whether rocuronium 0.4 mg kg(-1) could reduce the frequency of OCR, and also whether a single dose of succinylcholine 1 mg kg(-1) could affect the frequency of OCR during anesthesia with halothane in a nitrous oxide/oxygen mixture. METHODS: A total of 161 ASA I children, 3-10 years old, undergoing elective surgery of the medial rectus muscle (MRM) were randomly assigned to three groups. Group R (n = 51), received 0.4 mg kg(-1) of rocuronium intravenously before endotracheal intubation. Group S (n = 58) received 1 mg kg(-1) of succinylcholine. Group C (controls, n = 52) received no relaxant. Oculocardiac reflex was defined as a reduction in heart rate (HR) > or = 15% and/or the appearance of any other arrhythmias, during manipulation of the MRM. Analysis of variance (anova), chi-squared, Kruskal-Wallis, and Student's t-tests were used for statistical analysis; P< 0.05 was considered statistically significant. RESULTS: In group R, OCR occurred in 15/51 (29%) of children, in group S in 31/58 (53%), and in group C in 23/52 (44%) (chi2 = 6.46, P = 0.049). In group R, the incidence of arrhythmias such as nodal rhythms, supraventricular and ventricular premature beats was 6%, compared with 22% in group S and 19% in group C (chi2 = 6.01, P = 0.040). However, there was no reduction in the occurrence of bradycardia (chi2 = 0.16, P = 0.924). CONCLUSION: Rocuronium reduced the frequency of OCR, mainly by reducing the incidence of supraventricular and ventricular premature beats.

[Video thoracoscopic therapy of recurrent spontaneous pneumothorax]. / Videotorakoskopsko lijecenje recidivnoga spontanog pneumotoraksa.

We report our first experience in surgical treatment of recurrent spontaneous pneumothorax using video-assisted thoracic surgery (VATS). From May 1995 to April 1998, 38 cases of recurrent spontaneous pneumothorax were treated using the VATS approach. All patients were previously treated by other methods (conservative, thoracocentesis, chest-tube drainage). We successfully managed VATS procedure in all our patients (wedge resection 28, bullectomy 1, partial pleurectomy 2, pleural abrasions 36). Complications include persistent air leak (4), prolonged bleeding (1) and supraventricular tachycardia (1). The mean duration of chest drainage was 3.9 days (range 3 to 15 days). All patients received antimicrobial chemoprophylaxis with single-dose of 2 g Ceftriaxone intravenously prior to surgery and average postoperative patient-controlled analgesia with 0.15 mg of buprenorphin. Utilisation resource analysis showed great advantage in favour of VATS procedure compared to retrospectively analysed thoracotomied patients. We conclude that VATS is very useful alternative to conventional thoracotomy in managing cases of recurrent spontaneous pneumothorax.