Clinical paperPre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats☆,☆☆
Introduction
In the United States and Europe approximately one million patients suffer from out-of-hospital cardiac arrest (CA). Although initially in 25–50% a restoration of spontaneous circulation (ROSC) can be achieved, only 2–10% survive without major neurological deficit. Main reason for this poor outcome is the so called post-resuscitation syndrome. Besides systemic ischaemia/reperfusion response and delayed apoptotic neuronal death this includes circulatory failure due to myocardial dysfunction, which can be observed in half of the successfully resuscitated patients.
Several experimental studies have shown a cardioprotective effect of volatile anaesthetics when administered before acute myocardial infarction. In patients undergoing cardiac surgery with cardiopulmonary bypass myocardial damage could be decreased by volatile anaesthetics resulting in a reduced morbidity and mortality. Beyond that so called anaesthetic induced preconditioning effect volatile anaesthetics have also been shown to attenuate myocardial injury when administered during reperfusion. In analogy to the preconditioning effect the term “postconditioning” was introduced.
Meybohm et al. have shown an improved ejection fraction up to 4 h after ROSC and reduced peak levels of cardiac troponin T by Sevoflurane postconditioning of pigs after CA. Therefore we investigate the hypothesis that the volatile anaesthetic Sevoflurane administered before, during or after cardiopulmonary resuscitation attenuates myocardial dysfunction by improving inotropy 24 h after cardiopulmonary resuscitation.
Research on pharmacological interventions in cardiopulmonary resuscitation can only be done in animal experiments. Rats are especially suitable for those experiments as a complete quantitative histological evaluation of the selective vulnerable areas of the brain is possible. Furthermore smaller laboratory animals like mice and rats allow a higher number of experiments than larger animals. The difference in vascularisation of rat brains is without relevance because of the global cerebral ischaemia.
Primary endpoints were ejection fraction and preload adjusted maximal power as parameters of cardiac inotropy in animals that were treated with Sevoflurane before, during or after cardiopulmonary resuscitation in comparison to animals without Sevoflurane treatment.
Secondary endpoint was maximal slope of systolic pressure increment, end diastolic volume, end-systolic pressure, and survival.
Section snippets
Ethical statement
The experimental protocol was approved by the Governmental Animal Care Committee (reference number 35-9185.81/G-24/08).
All animals were handled in accordance with the European Communities Council Directive of November 24th, 1986 (86/609/EEC).
Study design
A setup with one control group and 9 interventional groups was chosen. Experimental time line is shown in Fig. 1.
All animals were anaesthetized by single dose intraperitoneal injection of pentobarbital (50 mg/kg body weight). After intubation of the trachea
Baseline data
All animals were healthy as well as drug- and test naive.
Before induction of CA, physiological parameters including arterial blood gas samples, core body temperature, and mean arterial pressure were in the normal range without differences between the interventional and the control group (see supplementary material, Table S1). Transoesophageal electrical fibrillation caused circulatory arrest within 15 s in all animals. Duration of surgical preparation before induction of CA was comparable in all
Interpretation/scientific implications
As echocardiographic measurements that are routinely used to assess myocardial function are not very reliable and depending on the experience of the investigator especially with regard to stroke volume and left ventricular performance in small laboratory animals such as rats, we performed left ventricular pressure–volume conductance catheter measurement to evaluate EF as a clinically widely used parameter describing myocardial inotropy. Our results demonstrate that the application of
Generalisability/translation
If further targeted studies and studies in larger animals show reproducible beneficial effects clinical studies in humans could be initiated.
Funding
Funding by German Research Community. Reference number: BO 1686/1-4.
References (0)
Cited by (31)
Opportunity Knocks? The Expansion of Volatile Agent Use in New Clinical Settings
2018, Journal of Cardiothoracic and Vascular AnesthesiaCitation Excerpt :Transient exposure to volatile anesthetics either before or after (respectively referred to as preconditioning or postconditioning) an ischemic event followed by reperfusion reduces myocardial injury.54,55 Interestingly, several animal models have shown beneficial cardiac and neurologic properties of exposure to volatiles in the setting of cardiopulmonary resuscitation.56–58 Numerous clinical trials have been conducted in this area, with mixed findings among cardiac surgical patients.
European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015. Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015.
2015, ResuscitationCitation Excerpt :Short-acting drugs (e.g., propofol, alfentanil, remifentanil) will enable more reliable and earlier neurological assessment and prognostication (see Section 7).138 Volatile anaesthetics have been used to sedate post cardiac arrest patients139 but although there are some animal data suggesting myocardial and neurological benefits,140 there are no clinical data showing an advantage with this strategy. Adequate sedation will reduce oxygen consumption.
Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest
2015, ResuscitationCitation Excerpt :Ischemic postconditioning, which utilizes structured pauses in CPR, was shown to improve left ventricular ejection fraction (LVEF) and neurologically intact survival in a porcine model of cardiac arrest including 15 min of untreated VF.12 Sevoflurane has been shown to reduce release of cardiac biomarkers, reduce apoptosis, and improve LVEF; however, no difference in neurologic function was reported.13,14 Poloxamer 188 (P188) is a nonionic copolymer thought to adhere to gaps in the cell membrane, thereby blocking pores caused by severe cellular stress.15
Anaesthetic Postconditioning at the Initiation of CPR Improves Myocardial and Mitochondrial Function in a Pig Model of Prolonged Untreated Ventricular Fibrillation
2014, ResuscitationCitation Excerpt :The use of isoflurane as a general anaesthetic before and after VF and CPR in both the APoC and CON group may have contributed to a smaller APoC effect of the sevoflurane as the CON hearts may also have received some degree of cardioprotection by preconditioning;47,48 in the absence of a negative outcome, however, this is of negligible concern. We did not perform a dose response study in the APoC group as these are more difficult in larger vs smaller animals11 due to the large number of subjects needed. Although our porcine model is the closest before clinical trials, a one-to-one translation into clinical practice may be hampered by species- and organ-dependent differences in sensitivity to IR.49
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The ARRIVE Guidelines. Animal Research: Reporting In Vivo Experiments.
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.04.012.