We read with considerable interest the letter of Dr. D'Attellis concerning our recent editorial about anesthetic preconditioning (APC) 1. Importantly, Dr. D'Attellis correctly notes that volatile anesthetics have been used for decades, but have never been shown to reduce morbidity, mortality, or adverse cardiac events, especially in patients undergoing coronary artery bypass graft (CABG) surgery. He emphasizes that many variables affect the extent of ischemia during cardiac surgery, and these factors may confound interpretation of results of studies conducted in this patient population. He further suggests that clinical investigations to assess the impact of APC in high-risk patients undergoing noncardiac surgery may be preferable to studies conducted on patients undergoing CABG.

Dr. D'Attellis’ comments certainly have merit. The array of cardioplegia cocktails, the adequacy of myocardial protection, the presence or absence of cardiopulmonary bypass, the duration of aortic cross-clamping, and, of course, the technical success of the surgical anastomoses all represent factors that may diminish the relative impact of APC. This complex picture may represent a potential reason why previous studies of CABG patients have been unable to demonstrate the clear benefits of volatile anesthetics. However, there may be several other reasons as well. The use of sulfonylurea oral hypoglycemic agents for the treatment of adult-onset diabetes mellitus is common in patients with coronary artery disease. These drugs are known to inhibit the ATP-dependent potassium channel, an important component of the signal transduction cascade responsible for APC. 2Recently, results from our laboratory 3have also shown that the adequacy of control of blood glucose concentration affects APC. High blood glucose concentrations antagonize APC in the presence and absence of diabetes. To complicate matters further, morphine was often used as an anesthetic adjuvant for patients undergoing CABG surgery before the widespread use of synthetic opioids. Morphine also exerts direct cardioprotective effects that are potentiated by volatile anesthetics. 4Factors such as these may be controlled in a prospective clinical trial to determine if volatile anesthetics are truly beneficial in patients with coronary artery disease but are difficult to even assess in retrospective studies.

The use of patients with coronary artery disease undergoing noncardiac surgery for future clinical studies of APC in humans certainly deserves consideration, but is also potentially problematic. The perioperative use of (beta1-adrenoceptor antagonists is a new standard of care, and coronary revascularization before other surgical procedures may limit or completely eliminate the frequency and extent of subsequent ischemic events. Thus, the classic “patient with coronary artery disease undergoing noncardiac surgery” population described in older studies is dwindling as a result of aggressive perioperative management of ischemic heart disease. Myocardial protection produced by volatile anesthetics should ideally be assessed by mortality related to cardiac events. Such outcome data would require a large number of patients but such difficulties are not insurmountable. Clinical investigation of APC in a large patient population with or at risk for coronary artery disease should be undertaken.

Warltier DC, Kersten JR, Pagel PS, Gross GJ: Anesthetic preconditioning: Serendipity and science. A nesthesiology 2002; 97 ( 1): 1–3
Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC: Isoflurane mimics ischemic preconditioning via activation of KATPchannels: Reduction of myocardial infarct size with an acute memory phase. A nesthesiology 1997; 87: 361–70
Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR: Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction. A nesthesiology 2002; 96: 183–8
Ludwig LM, Gross GJ, Kersten JR, Pagel PS, Warltier DC: Morphine enhances pharmacological preconditioning by isoflurane: Role of mitochondrial KATPchannels and opioid receptors. A nesthesiology 2003; 98: 705–11