The effect of general anaesthetics on brain lactate release

The effects of anaesthetic agents on brain energy metabolism may explain their shared neurophysiological actions but remain poorly understood. The brain lactate shuttle hypothesis proposes that lactate, provided by astrocytes, is an important neuronal energy substrate. Here we tested the hypothesis that anaesthetic agents impair the brain lactate shuttle by interfering with astrocytic glycolysis. Lactate biosensors were used to record changes in lactate release by adult rat brainstem and cortical slices in response to thiopental, propofol and etomidate. Changes in cytosolic nicotinamide adenine dinucleotide reduced (NADH) and oxidized (NAD+) ratio as a measure of glycolytic rate were recorded in cultured astrocytes. It was found that in brainstem slices thiopental, propofol and etomidate reduced lactate release by 7.4 ± 3.6% (P < 0.001), 9.7 ± 6.6% (P < 0.001) and 8.0 ± 7.8% (P = 0.04), respectively. In cortical slices, thiopental reduced lactate release by 8.2 ± 5.6% (P = 0.002) and propofol by 6.0 ± 4.5% (P = 0.009). Lactate release in cortical slices measured during the light phase (period of sleep/low activity) was ~25% lower than that measured during the dark phase (period of wakefulness) (326 ± 83 μM vs 430 ± 118 μM, n = 10; P = 0.04). Thiopental and etomidate induced proportionally similar decreases in cytosolic [NADH]:[NAD+] ratio in astrocytes, indicative of a reduction in glycolytic rate. These data suggest that anaesthetic agents inhibit astrocytic glycolysis and reduce the level of extracellular lactate in the brain. Similar reductions in brain lactate release occur during natural state of sleep, suggesting that general anaesthesia may recapitulate some of the effects of sleep on brain energy metabolism

Minimal access median sternotomy for aortic valve replacement in elderly patients

BACKGROUND: We report our clinical experience with a approach for aortic valve replacement (AVR) via minimal access skin incision and complete median sternotomy. This approach was used in patients with higher age and multiple co-morbidities, facilitating an easy access with short bypass and cross clamp times. It was especially performed in patients asking for an excellent cosmetic result, who did not qualifying for minimally-invasive AVR via partial upper sternotomy. METHODS: AVR via minimal-access median sternotomy, was performed in 58 patients between 01/2009 and 11/2011. Intra- and postoperative data including cross clamp time, cardiopulmonary bypass time, mortality, stroke, pacemaker implantation, re-operation for bleeding, ventilation time, ICU and hospital stay, wound infection, sternal dehiscence or fracture and 30 day mortality were collected. RESULTS: Mean patients age was 76.1 +/−9.4 years, 72% were female. Minimal-access AVR could be performed with a mean length of midline skin incision of 7.8 cm. Aortic cross-clamping time was 54.6 +/−6.3 min, cardiopulmonary bypass time 71.2+/−11.3 min and time of surgery 154.1 +/−26.8 min. Re-operation for bleeding had to be performed in 1 case (1.7%). There were no strokes or pacemaker implantations needed. Mean ventilation time was 4.5 h, ICU stay was 2 days and mean length of hospital stay was 6 days. 6 months follow up showed mortality of 0% and no sternal dehiscence or wound infection was observed. CONCLUSION: Minimal-access AVR via complete median sternotomy can be performed safely,in this elderly patient cohort without adding additional operative risk compared to conventional AVR. By avoidiance of large skin incisions this approach combines excellent cosmetic results with fast surgery time and excellent postoperative recovery

Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Prediction of folding equilibria of differently substituted peptides using one-step perturbation

Computer simulation using long molecular dynamics (MD) can be used to simulate the folding equilibria of peptides and small proteins. However, a systematic investigation of the influence of the side-chain composition and position at the backbone on the folding equilibrium is computationally as well as experimentally too expensive because of the exponentially growing number of possible side-chain compositions and combinations along the peptide chain. Here, we show that application of the one-step perturbation technique may solve this problem, at least computationally; that is, one can predict many folding equilibria of a polypeptide with different side-chain substitutions from just one single MD simulation using an unphysical reference state. The methodology reduces the number of required separate simulations by an order of magnitude