Optimizing anesthetic regimen for surgery in mice through minimization of hemodynamic, metabolic, and inflammatory perturbations

The role of anesthetics in animal research models is crucial, yet often ignored, and is almost never the primary focus of examination. Here, we investigated the impact of anesthetic regimens on different parameters of hemodynamics (blood pressure (BP) and heart rate (HR)), metabolism (glucose, insulin, and free fatty acids (FFA)), and inflammation (IL-6 and TNF-α) in two frequently used mouse strains (C57BL/6 and FVB). All animals were at a similar surgical plane of anesthesia, mechanically ventilated, and monitored for 60 min. The following anesthetic regimens were studied: (1) fentanyl-ketamine-midazolam (FKM), (2) fentanyl-midazolam-haldol (FMH), (3) pentobarbital (P), (4) fentanyl-fluanisone-midazolam (FFM), (5) fentanyl-midazolam-acepromazine (FMA), (6) ketamine-medetomidine-atropine (KMA), (7) isoflurane (ISO), and (8) propofol-fentanyl-midazolam (PFM). Metabolic and inflammatory parameters were compared with those obtained from non-anesthetized animals. Hemodynamics: BP >80 mm Hg were only obtained with KMA, whereas hypotension (BP 500 beats/min was observed with ISO and PFM, whereas HR <400 beats/min was induced with KMA, FMH (BL/6), P (BL/6), and FKM (FVB). Metabolism: Glucose and insulin were most disturbed by KMA and ISO and mildly disturbed by FMA, whereas FFM, PFM, and P did not have any effect. FFA increased largely by FMA, with ISO and FKM having no effects. Inflammation: Cytokines were increased least with ISO/FFM/FMA, whereas FKM and KMA induced the largest increases in cytokines. When aiming at achieving surgical anesthesia without large disturbances in hemodynamic, metabolic, and inflammatory profiles, FFM, ISO, or PFM may be the most neutral anesthetic regimens in mic

Dutch Travel Health Nurses: Prepared to Prescribe?

Background. In travel medicine, as in other specialties, independent prescribing of medication has traditionally been the domain of practitioners like physicians, dentists, and midwives. However, a 2011 ruling in the Netherlands expands independent prescribing and introduces supplementary prescribing by nurses, with expected implementation over the next few years. As specialist nurses will not be eligible for independent prescribing, this study addresses supplementary prescribing, specifically by travel health nurses. Such nurses will work in partnership with an independent prescriber, usually a physician. After the physician evaluates a patient's condition and needs, the nurse may prescribe from an open or limited formulary. This supplementary approach seems appropriate in travel medicine, which is highly protocolized. A questionnaire survey was conducted to assess whether travel health nurses themselves aspire and feel competent to prescribe, and what training they might need. Methods. All travel health nurses in the Netherlands received a questionnaire seeking their anonymous response. Results. The response rate was 58%. Self-reported compliance with protocols and quality criteria was high; 82% of respondents aspire to prescribe and 77% feel competent to prescribe. Of the latter, 22% indicated that ongoing access to a doctor would remain important, and 14% preferred to prescribe under certain conditions like a restricted number of medicines. The reason most frequently given for not feeling competent was the need for additional education before obtaining prescribing rights (40%). Aspiration to prescribe was the only significant predictor for feeling competent to prescribe (odds ratios: 6.8; 95% confidence intervals: 3.5-13). Of all the responding nurses, 95% reported one or more educational needs related to prescribing, particularly in pharmacology. Conclusions. Most Dutch travel health nurses aspire to prescribe and feel competent for the supplementary approach, but require further education before the approach is implemented in travel medicin

Anesthesia's effects on plasma glucose and insulin and cardiac hexokinase at similar hemodynamics and without major surgical stress in fed rats

BACKGROUND: Recent evidence suggests that hexokinase mitochondria association attenuates cell death, and that plasma glucose and insulin concentrations can influence clinical outcome. In the present study, we examined how different anesthetics per se affect these variables of glucose metabolism, i.e., under similar hemodynamic conditions and in the absence of major surgical stress. METHODS: In fed rats, the effects of pentobarbital (PENTO), isoflurane (ISO), sevoflurane (SEVO), ketamine-medetomidine-atropine (KMA), and sufentanil-propofol-morphine (SPM) on the cardiac cellular localization of hexokinase (HK) and levels of plasma glucose and insulin were determined and compared with values obtained in nonanesthetized animals (control). The role of mitochondrial and sarcolemmal K-ATP-channels and alpha(2)-adrenergic receptor in ISO-induced hyperglycemia was also evaluated. RESULTS: Mean arterial blood pressure was similar among the different anesthetic strategies. PENTO (5.3 +/- 0.2 mM) and SPM (5.1 +/- 0.2 mM) had no significant effect on plasma glucose when compared with control (5.6 +/- 0.1 mM). All other anesthetics induced hyperglycemia: 7.4 +/- 0.2 mM (SEVO), 9.9 +/- 0.3 mM (ISO), and 14.8 +/- 1.0 mM (KMA). Insulin concentrations were increased with PENTO (2.13 +/- 0.13 ng/mL) when compared with control (0.59 +/- 0.22 ng/mL), but were unaffected by the other anesthetics. Inhibition of the mitochondrial K-ATP channel (5-hydroxydecanoate acid) or the alpha(2)-adrenergic receptor (yohimbine) did not prevent ISO-induced hyperglycemia. Only the nonspecific K-ATP channel inhibitor glibenclamide was able to prevent hyperglycemia by ISO. Cytoshc HK relative to total HK increased in the following sequence: control (35.5% +/- 2.1%), SEVO (35.5% +/- 2.7%), ISO (36.6% +/- 1.7%), PENTO (41.2% +/- 2.0%; P = 0.082 versus control), SPM (43.0% +/- 1.8%; P = 0.039 versus control), and KMA (46.6 +/- 2.3%; P = 0.002 versus control). CONCLUSIONS: Volatile anesthetics and KMA induce hyperglycemia, which can be explained, at least partly, by impaired glucose-induced insulin release. The data indicate that the inhibition of insulin release by ISO is mediated by sarcolemmal K-ATP channel activation. The use of PENTO and SPM is not associated with hyperglycemia. SPM and KMA reduce the antiapoptotic association of HK with mitochondri

Ischemic preconditioning affects hexokinase activity and HKII in different subcellular compartments throughout cardiac ischemia-reperfusion

Gurel E, Smeele KM, Eerbeek O, Koeman A, Demirci C, Hollmann MW, Zuurbier CJ. Ischemic preconditioning affects hexokinase activity and HKII in different subcellular compartments throughout cardiac ischemia-reperfusion. J Appl Physiol 106: 1909-1916, 2009. First published February 19, 2009; doi:10.1152/japplphysiol.90537.2008.-The glycolytic enzyme hexokinase (HK) is suggested to play a role in ischemic preconditioning (IPC). In the present study we determined how ischemic preconditioning affects HK activity and HKI and HKII protein content at five different time points and three different subcellular fractions throughout cardiac ischemia-reperfusion. Isolated Langendorff-perfused rat hearts (10 groups of 7 hearts each) were subjected to 35 min ischemia and 30 min reperfusion (control groups); the IPC groups were pretreated with 3 times 5-min ischemia. IPC was without effect on microsomal HK activity, and only decreased cytosolic HK activity at 35 min ischemia, which was mimicked by decreased cytosolic HKII, but not HKI, protein content. In contrast, mitochondrial HK activity at baseline and during reperfusion was elevated by IPC, without changes during ischemia. No effect of IPC on mitochondrial HK I protein content was observed. However, mitochondrial HK II protein content during reperfusion was augmented by IPC, albeit not following the IPC stimulus. It is concluded that IPC results in decreased cytosolic HK activity during ischemia that could be explained by decreased HKII protein content. IPC increased mitochondrial HK activity before ischemia and during reperfusion that was only mimicked by increased HK II protein content during reperfusion. IPC was without effect on the phosphorylation status of HK before ischemia. We conclude that IPC is associated with 1) a biphasic response of increased mitochondrial HK activity before and after ischemia, 2) decreased cytosolic HK activity during ischemia, and 3) cellular redistribution of HKII but not HK

Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid

Acute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R. Dependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R. 50 μM FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS(-/-) hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals. The protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many "lost-in-translation" drugs and unnecessary clinical studie