Post-conditioning: Promising answers and more questions

Volatile anesthetic agents have been used for decades in the peri-operative setting. Data from the past 15 years have shown that pre-injury administration of volatile anesthetic can decrease the impact of ischemia-reperfusion injury on the heart, brain, and kidney. Recent data demonstrated that volatile agents administered shortly after injury can decrease the ischemia-reperfusion injury. Several questions need to be answered to optimize this therapeutic target, but this is a promising era of secondary injury mitigation.

damage [8]. Th e mechanisms of volatile agent postconditioning are being explored by several laboratories around the world [9,10]. Lemoine and colleagues [11] showed on in vitro right atrial appendages that the human heart is sensitive to desfl urane-associated postconditioning. Th e data from Steurer and colleagues [1] off er the 'fi rst in man' evidence of post-conditioning and potential myocardial protection in a clinical setting: sevofl urane administered in the intensive care unit (ICU) arrival for 4 hours. Th ey showed a decreased troponin release in the sevofl urane group. Interestingly, there was still an eff ect even with a 2-to 3-hour gap after the onset of ischemia (aortic clamping) and a 1-to 2-hour gap between the start of reperfusion (aortic cross-clamp release) and the administration of sevofl urane (upon arrival to the ICU). Th is investigation opens a new fi eld and new potential therapeutic opportunities. Further questions remain to be answered to optimize and assess the clinical magnitude of myocardial protection provided by post-conditioning (Table 1).
Sevofl urane and isofl urane are very fl exible generic anesthetic drugs administered daily by numerous anesthetists around the world. Th e demon stration of cardioor neuroprotective eff ects (or both) when applied after the ischemia will make them interesting in myocardial ischemia, cardiogenic shock, or even traumatic brain injuries. Sevofl urane administration in the ICU has been done previously [12,13]. It has been shown to be associated with fast awakening/weaning times after the drug is stopped [12]. Th e anesthesia-conserving device has made the delivery simple and adaptable on 'regular' ICU-type ventilators. However, technical aspects such as gas analyzers, concentration measurement, and exhausted gas scavenging (most ICU-type ventilators release the exhaust gases into the environment) need to be taken into account. Educational aspects must include nurse training, dosage, availability of dantrolene, and training for the unlikely event of a malignant hyperthermia reaction. In addition, data show plasma fl uoride concentration (39 ± 25 μmol/L) close to safety limits (50 μmol/L) at 24 and 48 hours after 9 hours of sevofl urane [14]. Sevofl urane administration beyond 12 to 24 hours needs to be assessed in terms of fl uoride plasma concentration and nephrotoxicity. Environmental eff ects of widespread anesthetic gas use need to be taken into account [15]. Most cardiac surgery patients require a maximum of a few hours of mechanical ventilation (if any). In these circumstances, sevofl urane sedation in the cardiac ICU may be a very fl exible option with an additional myocardial protection benefi t.

Conclusions
Sevofl urane and possibly other volatile anesthetic agents show promising post-conditioning properties after cardiac surgery. Th is opens a new fi eld of investigations and potential therapies aiming at mitigating secondary myocardial injury after the primary injury is done. More data are necessary to assess the magnitude conferred by this protection, its clinical relevance, the window of opportunity, and the collateral protection on other organs. Very promising answers, and more questions, are to come. Abbreviation ICU, intensive care unit.

Table 1. Some research questions regarding sevofl urane post-conditioning
Is the post-conditioning eff ect related to the "dose" of sevofl urane? Is there a minimum duration or minimum alveolar concentration to obtain post-conditioning? Is there a dose response curve on sevofl urane post-conditioning? Do all volatile anesthetic agents (isofl urane or desfl urane) provide the same post-conditioning organ protection?
Does the lower release in cardiac damage markers shown by Steurer et al. [1] translate into outcome diff erences? Lower myocardial infarction rates? Lower inotropic support? Better cardiac output? Shorter intensive care unit/hospital stays? Lower mortality? Lower resource utilization?
How long is the therapeutic window after reperfusion to exhibit a post-conditioning organ protection? That is, how long after cardiopulmonary bypass or injury does sevofl urane have to be started to induce post-conditioning?
Is there an additional cardioprotective eff ect when sevofl urane is used intraoperatively (pre-conditioning)?
Is there a protective eff ect on other organs such as the brain or the kidney?
Animal data suggest that post-conditioning is better in males [16] and inhibited by hyperglycemia [17]: Is post-conditioning benefi cial only in males or in the context of tight glucose control (or both)?
Sevofl urane administration is associated with plasma fl uoride levels above upper limit. How long can we use sevofl urane for sedation/post-conditioning in terms of fl uoride toxicity?