Myocardial protection with monophosphoryl lipid-A against aortic cross clamping-induced global stunning.

BACKGROUND: Monophosphoryl lipid-A (MLA) has a late window (24 hours) of cardioprotection against acute myocardial infarction. It is not known whether MLA, administered, 24 hours before surgery, attenuates intraoperative ventricular dysfunction "stunning" associated with aortic cross-clamping and reperfusion during elective cardiac surgery. We determined the dose-response relationship between MLA and ventricular function in a canine model of global myocardial stunning in the absence of necrosis. The role of expression of inducible heat shock protein 70 (HSP 70i) was also investigated. METHODS: Mongrel dogs (n = 32) were intravenously injected with either a vehicle solution or 3, 5, 10, 35 ug/kg MLA. Twenty four hours later, dogs were anesthetized and instrumented, in situ, to monitor the left ventricular performance (the slope of regression between stroke-work and end diastolic length). Tissue samples were obtained to determine HSP70i using immunoblot analysis. After a period of equilibration on cardiopulmonary bypass, the aortic cross-clamp was applied at normothermia for 30 minutes followed by 60 minutes of reperfusion. ATP and catabolites were determined in transmural myocardial biopsies. Triphenyl-tetrazolium chloride (TTC) staining was used to determine myocardial necrosis. RESULTS: MLA treatment did not alter myocardial contractility or ATP metabolism. Global ischemia resulted in about 50% depletion of ATP and remained depressed during reperfusion in all groups. MLA-treated hearts had improved functional recovery in a dose dependent-manner. Significant recovery was observed at the highest dose (35 ug/kg) compared to the control group. Immunoblot analysis demonstrated significant increase in HSP 70i in the MLA-treated hearts. CONCLUSIONS: MLA exhibits a delayed (24 hours) window of protection against myocardial stunning associated with aortic cross-clamping. HSP70i expression may play a role in MLA-mediated cardioprotection.

Unexpected natural death of iatrogenic origin.

The paper deals solely with iatrogenic disaster due to the misuse of therapeutic drugs prescribed or unprescribed, and its main purpose is to encourage a high index of suspicion that an unexpected apparently natural death may be iatrogenic due to the medicines administered before death. Toxic effect, side effect and adverse reaction are defined and particular attention is given to adverse effects induced by drug interaction and to the impact of disease and of the extremes of age on the potency of drugs. The deaths under discussion are "biochemical deaths" and as such are difficult to prove at post mortem examination especially if the forensic pathologist has not been made aware of the identity of drugs administered before death. Examples which are apt to create difficulties, particularly those due to drug interaction, are discussed, including oral hypoglycaemics, anticoagulants, anticonvulsants, antidepressants, hypotensives and cardiac glycosides. The solution to the problem is not to refrain from using necessary drugs, but to use them wisely with full awareness of the mechanisms whereby they can become lethal.