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Resveratrol pretreatment can protect the heart by inducing pharmacological preconditioning. Whether resveratrol protects the heart when applied at reperfusion remains unknown. We examined the effect of resveratrol on myocardial infarct size when given at reperfusion and investigated the mechanism underlying the effect. Isolated rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion, and myocardial samples were collected from the risk zone for Western blot analysis. Mitochondrial swelling was spectrophotometrically measured as a decrease in absorbance at 520 nm (A(520)). Resveratrol reduced infarct size and prevented cardiac mitochondrial swelling. Resveratrol enhanced GSK-3beta phosphorylation upon reperfusion, an effect that was mediated by the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway. Resveratrol translocated GSK-3beta from cytosol to mitochondria via the cGMP/PKG pathway. Further studies showed that mitochondrial GSK-3beta was co-immunoprecipitated with cyclophilin D but not with VDAC (voltage dependent anion channel) or ANT (adenine nucleotide translocator). These data suggest that resveratrol prevents myocardial reperfusion injury presumably by targeting the mPTP through translocation of GSK-3beta from cytosol to mitochondria. Translocated GSK-3beta may ultimately interact with cyclophilin D to modulate the mPTP opening.

The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (mTOR) inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta phosphorylation was not altered by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.

Purpose: This study determined the incidence of and identified risk factors for 48 hour (h) and 30 day (d) postoperative mortality after inpatient operations., Methods: A retrospective cohort study was conducted using Anesthesiology's Quality Indicator database as the main data source. The database was queried for data related to the surgical procedure, anesthetic care, perioperative adverse events, and birth/death/operation dates. The 48 h and 30 d cumulative incidence of postoperative mortality was calculated and data were analyzed using Chi-square or Fisher's exact test and generalized estimating equations., Results: The 48 h and 30 d incidence of postoperative mortality was 0.57% and 2.1%, respectively. Higher American Society of Anesthesiologists physical status scores, extremes of age, emergencies, perioperative adverse events and postoperative Intensive Care Unit admission were identified as risk factors. The use of monitored anesthesia care or general anesthesia versus regional or combined anesthesia was a risk factor for 30 d postoperative mortality only. Time under anesthesia care, perioperative hypothermia, trauma, deliberate hypotension and invasive monitoring via arterial, pulmonary artery or cardiovascular catheters were not identified as risk factors., Conclusions: Our findings can be used to track postoperative mortality rates and to test preventative interventions at our institution and elsewhere.

Purpose: This paper aims to determine the one-year incidence of, and risk factors for, perioperative adverse events during in-patient and out-patient anesthesia-assisted procedures., Design/methodology/approach: A quality assurance database was the primary data source. Outcome variables were death and the occurrence of any adverse event. Risk factors were ASA physical status (PS), age, duration and type of anesthesia care, number of operating rooms running, concurrency level and medical staff. Data were stratified by in-patient or out-patient, surgical (e.g. thoracotomy) or non-surgical (e.g. electroconvulsive therapy), and were analyzed using Chi square, Fisher's exact test and generalized estimating equations., Findings: Of 27,970 procedures, 49.8 percent were out-patient and greater than 80 percent were surgical. For surgical procedures, adverse event rates were higher for in-patient than out-patient procedures (2.11 percent vs. 1.45 percent; p < 0.001). For non-surgical procedures, adverse event rates were similar for in-patients and out-patients (0.54 percent vs. 0.36 percent). The types of adverseevents differed for in-patient and out-patient surgical procedures (p < 0.001), but not for non-surgical procedures. ASA PS, age, duration of anesthesia care, anesthesia type and medical staff assigned to the case were each associated with adverse event rates, but the association depended on the type of procedure., Practical Implications: In-patient and out-patient surgical procedures differ in the incidence of perioperative adverse events, and in risk factors, suggesting a need to develop separate monitoring strategies., Originality/value: The paper is the first to assess perioperative adverse events amongst in-patient and out-patient procedures.

Objective: Our aim was to determine if NO prevents mitochondrial oxidant damage by mobilizing intracellular free zinc (Zn(2+))., Methods: Zn(2+) levels were determined by imaging enzymatically isolated adult rat cardiomyocytes loaded with Newport Green DCF. Mitochondrial membrane potential (DeltaPsi(m)) was assessed by imaging cardiomyocytes loaded with tetramethylrhodamine ethyl ester (TMRE)., Results: S-nitroso-N-acetylpenicillamine (SNAP) dramatically increased Zn(2+), which was blocked by both ODQ and NS2028, two specific inhibitors of guanylyl cyclase. The protein kinase G (PKG) inhibitor KT5823 blocked the effect of SNAP while the PKG activator 8-Br-cGMP mimicked the action of SNAP, indicating that the cGMP/PKG pathway is responsible for the effect of SNAP. The increased Zn(2+) was prevented by 5-hydroxydecanoate (5HD) but was mimicked by diazoxide, implying that mitochondrial K(ATP) channel opening may account for this effect. Since chelation of Zn(2+) blocked the preventive effect of SNAP on H(2)O(2)-induced loss of DeltaPsi(m) and exogenous zinc (1 microM ZnCl(2)) prevented dissipation of DeltaPsi(m), Zn(2+) may play a critical role in the protective effect of NO. The MEK (mitogen-activated protein kinase or extracellular signal-regulated kinase) inhibitor PD98059 blocked the preventive effects of SNAP and zinc on DeltaPsi(m), indicating that extracellular signal-regulated kinase (ERK) mediates the protective effect of both these compounds on mitochondrial oxidant damage. A Western blot analysis further showed that ZnCl(2) significantly enhances phosphorylation of ERK, confirming the involvement of ERK in the action of Zn(2+)., Conclusions: In isolated cardiomyocytes, NO mobilizes endogenous zinc by opening mitochondrial K(ATP) channels through the cGMP/PKG pathway. In these cells, Zn(2+) may be an important mediator of the action of NO on the mitochondrial death pathway.

The adenosine A(3) receptor plays an important role in ischemic preconditioning. Activation of the adenosine A(3) receptor with its agonists induces both early and late pharmacological preconditioning through various mechanisms. As the first potent and selective adenosine A(3) receptor agonist, IB-MECA (N(6)-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide) has been demonstrated to induce cardioprotection against myocardial ischemia/reperfusion injury when given before onset of ischemia by triggering pharmacological preconditioning. More importantly, IB-MECA can also protect the heart even when administered at the onset of reperfusion after ischemia, indicating a strong likelihood that the drug may be useful for the treatment of patients with acute myocardial infarction. However, since IB-MECA has been reported to have lethal effects at higher concentrations, and may cause systemic hypertension in some species, further studies are needed to find the best treatment strategy to increase its therapeutic potential.

Compartment syndrome of the extremities is usually associated with direct trauma and often requires surgical fasciotomy to avert potential complications and morbidity. We present a case of upper extremity compartment syndrome resulting from pressurized infusion of autologous whole blood, in which fasciotomy was avoided by the application of a simple and effective technique using an elastic Esmarch bandage. Guidelines for surgical fasciotomy and the hazards associated with pressurized infusion of fluids in the anesthetized patient are discussed., (Copyright 2002 by Elsevier Science Inc.)

A 4-year-old boy with coarctation of the aorta underwent surgical aortic arch repair with general anaesthesia and thoracic epidural analgesia. In the immediate postoperative period, the child developed a unilateral Horner syndrome which appeared to be related to the epidural infusion rate. Management of this patient as well as alternate aetiologies of Horner syndrome are described. Horner syndrome is a rare complication of epidural catheters and is often unrecognized, especially in children.

Objective: To determine whether selective aortic arch perfusion (SAAP) using serial infusions of oxygenated perflubron emulsion combined with aortic epinephrine (AoE) administration is more effective than conventional therapy in treating cardiac arrest., Methods: An experimental cardiac arrest model (10 min ventricular fibrillation and 2 min CPR) was used with 12 mixed-breed canines, randomized into 2 groups: control (n = 6), CPR and IV epinephrine, 0.01 mg/kg, at 12 min and then every 3 min; or AoE-SAAP (n = 6), CPR and aortic epinephrine, 0.01 mg/kg, at 12 min and then every 3 min, and serial SAAP with oxygenated 60% weight/volume (w/v) perflubron emulsion as follows: 300 mL over 30 sec at 12 min as continuous SAAP without CPR; 150 mL over 20-30 sec at 15 min and 18 min as pulsed diastolic SAAP during CPR., Results: AoE-SAAP resulted in increased coronary perfusion pressure (CPP) and return of spontaneous circulation (ROSC) compared with control. CPR-diastolic (release phase) CPP during pulsed diastolic SAAP was similar to or greater in magnitude than the CPP generated during the initial SAAP infusion without CPR. ROSC for control was 0/6 and for AoE-SAAP was 4/6 (p < 0.05, Fisher's exact test). Time from initiation of CPR to ROSC with a sustained systolic aortic pressure > 60 mm Hg was 8.0 +/- 1.2 min in the 4 resuscitated AoE-SAAP animals., Conclusion: The combination of AoE with SAAP infusions of oxygenated perflubron emulsion was more effective than conventional resuscitation therapy. Pulsed diastolic SAAP is a promising method for performing SAAP.

Study Objective: To evaluate selective aortic arch perfusion (SAAP) with an oxygenated fluorocarbon emulsion, with and without aortic arch epinephrine during cardiac arrest., Methods: This randomized, controlled study, undertaken at a university research laboratory, involved 15 mixed-breed dogs. After 10 minutes of ventricular fibrillation and 30 seconds of CPR, the dogs were randomized to three groups, each comprising five dogs. Group 1 (controls) dogs were given CPR and intravenous epinephrine, .01 mg/kg, at 10.5 minutes and then every 3 minutes. Group 2 dogs (IVE-SAAP) were treated with CPR and intravenous epinephrine (IVE) in the same fashion as the control group but were also subjected to SAAP with 275 mL of oxygenated 60% wt/vol perflubron emulsion over 30 seconds. Group 3 dogs (AoE-SAAP) received the same treatment as the IVE-SAAP group, except that the first epinephrine dose was given intraaortically., Results: Coronary perfusion pressure (CPP) increased during SAAP in both the IVE-SAAP and AoE-SAAP groups but was greater in the AoE-SAAP group. CPR diastolic CPP after SAAP was significantly greater in the AoE-SAAP group than in the control group. Return of spontaneous circulation (ROSC) occurred in two control dogs, all five IVE-SAAP dogs, and all five AoE-SAAP dogs. The time elapsed from the initiation of CPR to ROSC was 6.1 +/- 1.9 minutes in the AoE-SAAP group, compared with 11.0 +/- 5.8 minutes in the IVE-SAAP group., Conclusion: SAAP with oxygenated perflubron emulsion improved ROSC, both with and without aortic arch epinephrine. The combination of SAAP with perflubron emulsion and aortic arch epinephrine resulted in higher CPP and more rapid ROSC.

Study Objective: To determine if delivery of epinephrine to the peripheral arterial system by an aortic arch catheter is more effective than central venous epinephrine administration during cardiac resuscitation., Design: Randomized, nonblinded, controlled trial., Type of Participants: Sixteen mongrel canines (25 to 31 kg)., Interventions: Animals had aortic arch pressure, and right atrial pressure, superior vena cava infusion, and descending aortic arch infusion catheters placed using fluoroscopy. After ten minutes of ventricular fibrillation, three DC countershocks were delivered over one minute. If unsuccessful, CPR at 120 compressions per minute was begun, and at 60 seconds of CPR, epinephrine (1 mg/50 mL normal saline) was administered either through the superior vena cava or the aortic arch catheter followed by one more minute of CPR. Defibrillation then was attempted and, if unsuccessful, further resuscitative efforts followed advanced cardiac life support guidelines, except route and dose of epinephrine remained the same., Measurements and Main Results: Aortic arch pressure, right atrial pressure, and coronary perfusion pressure (diastolic aortic arch pressure minus diastolic right atrial pressure) were recorded continuously. Aortic arch pressure and coronary perfusion pressure increased more rapidly and to a greater magnitude with aortic arch-epinephrine than superior vena cava-epinephrine. Coronary perfusion pressure doubled by ten seconds in seven of eight in the aortic arch-epinephrine group versus none in the superior vena cava-epinephrine group. Aortic arch pressure and coronary perfusion pressure increases consistently plateaued within 60 seconds after aortic arch-epinephrine but not after superior vena cava-epinephrine. Return of spontaneous circulation was faster (P < .05) in the aortic arch-epinephrine group. Maximal coronary perfusion pressure after epinephrine correlated with the coronary perfusion pressure immediately before epinephrine administration in both groups, but more strongly in the aortic arch-epinephrine group (P = .0001)., Conclusion: For an equivalent dose of epinephrine, aortic arch administration produces a more rapid response and more rapid peak effect than central venous administration. The combination of aortic arch-epinephrine administration and aortic pressure monitoring may be useful when initial standard resuscitative measures have not been successful.

Study Objectives: To demonstrate the technique of selective aortic arch perfusion during cardiac arrest and to observe the hemodynamic effects of volume infusion and aortic epinephrine administration., Design: Sequential series, nonrandomized, noncontrolled., Type of Participants: Fourteen mongrel dogs weighing 21 to 36 kg., Interventions: Animals had midaortic arch pressure, right atrial pressure, and descending aortic arch balloon occlusion catheters placed. After ten minutes of ventricular fibrillation, balloon inflation and aortic arch infusions were initiated as follows: group 1 (six), 30 mL/kg/min of 0.9% NaCl for two minutes; group 2 (four), 30 mL/kg/min of oxygenated lactated Ringer's with 2 mg/L epinephrine for two minutes, followed by CPR; and group 3 (four), 20 mL/kg/min of oxygenated perfluorochemicals with 4 mg/L epinephrine for one minute, then CPR., Measurements and Main Results: Midaortic arch pressure, right atrial pressure, and coronary perfusion pressure each rose significantly in all groups. Midaortic arch pressure and coronary perfusion pressure increases were greater in groups 2 and 3 than in group 1. In groups 1 and 2, right atrial pressure increases at end-selective aortic arch perfusion were excessive as midaortic arch pressure and right atrial pressure increased linearly and similarly after 20 to 30 seconds. In groups 2 and 3, CPR-diastolic midaortic arch pressure and coronary perfusion pressure after selective aortic arch perfusion were good and similar to midaortic arch pressure and coronary perfusion pressure at end-selective aortic arch perfusion., Conclusion: Selective aortic arch perfusion is technically feasible, but excessive right atrial pressure increases limit maximal infusion rates and volumes. Selective aortic arch perfusion infusates with epinephrine produce greater midaortic arch pressure and coronary perfusion pressure during infusion than infusate without epinephrine. Controlled studies are needed to determine if selective aortic arch perfusion improves resuscitation outcome.

Changes in plasma adenosine and inosine were measured during high-dose narcotic anesthesia and surgery for coronary artery bypass grafting (CABG), and mitral or aortic valve replacement (V). Arterial and mixed venous blood samples were obtained for measurement of adenosine and inosine at eight sampling intervals ranging from preanesthesia induction to discontinuation of cardiopulmonary bypass (CPB). Arterial but not mixed venous adenosine was markedly elevated in blood samples 10 minutes after intubation, but the fourfold elevation was significant only in the CABG patient group. Mixed venous inosine and adenosine were most consistently elevated in post-CPB samples. In a separate study of arterial adenosine changes during induction, a uniform drug administration protocol was used, and again adenosine was significantly increased immediately after intubation. It is possible that adenosine and perhaps inosine may contribute to cardiovascular responses following induction-intubation and also after discontinuing CPB.

Subcutaneous emphysema can occur as the result of trauma, surgery, and anesthesia. A case is presented of extensive subcutaneous emphysema after anesthesia for oral surgical reduction of a mandibular fracture. A discussion of the diagnosis, pathophysiology, and treatment of subcutaneous emphysema follows.

Plasma atrial natriuretic peptide immunoreactivity (IrANP) was measured before, during, and after cardiopulmonary bypass for coronary artery bypass graft placement. Eight subjects scheduled for elective operation had in the premedicated preoperative state slightly elevated IrANP compared to controls. Neither induction of anesthesia with a high dose narcotic/non-depolarising relaxant/diazepam technique nor cardiopulmonary bypass changed IrANP significantly. Mixed venous and arterial IrANP increased immediately after discontinuing bypass, and remained elevated 1 h later. Because ANPs affect peripheral resistance as well as urinary sodium loss, the post-bypass elevations in these peptides may contribute to cardiovascular and diuretic effects after cardiopulmonary bypass.

Isolated perfused paced hearts from rats rendered hypothyroid by chronic administration of propylthiouracil have a delayed onset of ischemia-induced myocardial contracture in contrast to hearts from control rats. In addition, the time to reach maximum contracture is delayed, and the magnitude of the contracture pressure is reduced. Preischemia myocardial adenosine triphosphate (ATP) values in the hypothyroid rat hearts are similar to those of control, but the rate of decrease in ATP is slower in the hearts of hypothyroid rats. Thus, it appears that in the hypothyroid state the development of ischemic contracture is associated with a slower fall of ATP.

This article presents basic anesthetic management problems and procedures together with newer anesthetic drugs and monitoring techniques that are likely to be encountered by intensive care physicians. The author's goal is to familiarize all critical care unit based members of the resuscitation team with current aspects of anesthetic management of the trauma patient.

Development of the flow-directed pulmonary artery catheter in combination with reflective fiberoptic oximetry techniques allows the clinician to continuously measure mixed venous oxygen saturation (SvO2). A brief review of the determinants of oxygen balance, the Fick principle, and the technology of continuous SvO2 monitoring is preliminary to a debate between two clinicians on the usefulness of SvO2 monitoring. One clinician highly recommends use of the flow-directed pulmonary artery catheter in patients who require pulmonary artery catheterization. Monitoring of SvO2 is described as a safe, convenient, and reliable option that is cost-effective. Continuous availability of this dynamic physiologic monitor is of great value in improving understanding of serious disturbances in oxygen balance, providing information for rapid diagnosis, and guiding therapeutic interventions. Another clinician suggests a less enthusiastic approach to SvO2 monitoring and argues that SvO2 is a nonspecific index of the matching of oxygen delivery with supply. Although it is a useful adjunct in specific clinical situations, it provides uncertain information in the presence of a number of diseases. Major mistakes in patient management could follow from overreliance upon either absolute SvO2 measurements or analysis of trends over time. Use of the SvO2 monitor has not been proven cost-effective and may actually increase monitoring costs. Both clinicians agree that continuous SvO2 monitoring is valuable in many clinical circumstances, provided the limitations of the measurement are understood.

A 48-year-old man receiving maintenance hemodialysis underwent coronary artery bypass surgery with good results for intractable angina. No complications were observed that could be attributed to the hemodialysis treatment. There appear to be no cogent reasons to arbitrarily exclude this population of patients from consideration for coronary artery bypass surgery.

Intra-aortic balloon pump therapy is often life-saving in patients with refractory cardiac failure following cardiopulmonary bypass, in the peri-infarct period, or in treating complications of coronary artery angioplasty. Anesthesiologists are intimately involved in the care of the majority of IABP patients and require a thorough understanding of the equipment, its physiologic effects, and potential complications.

The cardiovascular effects of the calcium channel blockers verapamil (V), nifedipine (N) and diltiazem (D) were compared in halothane-anesthetized swine. Equipotent hypotensive doses of the three calcium channel blocking drugs were administered randomly by continuous infusion to three groups of six animals each to produce a uniform 25-30% reduction in mean systemic arterial blood pressure (BP). An additional group of six animals received sodium nitroprusside (S) to demonstrate the effects of lowering blood pressure with a pure vasodilator on this experimental preparation. Hemodynamic indices monitored before and after drug administration included ECG, mean systemic and pulmonary artery blood pressure, mean central venous and pulmonary capillary wedge pressure, thermodilution cardiac output, left ventricular pressure, and left ventricular dP/dt. All four study drug infusions reduced BP an average of 28%. V and D reduced BP by decreasing cardiac output (41% and 42%, respectively) without affecting systemic vascular resistance. N and S produced hypotension by decreasing systemic vascular resistance (36% and 21%, respectively) without affecting cardiac output. D reduced heart rate (18%) and both D and V increased the PR interval (60% and 40%, respectively). Calcium chloride (20 mg X kg-1 intravenous bolus) improved indices of myocardial contractility but did not affect drug-induced changes in cardiac electrophysiology. These data demonstrate that in this halothane-anesthetized swine model the administration of equihypotensive doses of verapamil or diltiazem has a more pronounced affect on cardiac conduction and myocardial contractility than does nifedipine, which predominantly reduces systemic vascular resistance with minimal effects on cardiac function.

Electrocardiogram lead CB5 was compared with lead V5 kin 27 patients undergoing coronary artery bypass graft surgery. Lead CB5 is a bipolar lead consisting of a negative electrode over the center of the right scapula and the positive electrode over the fifth interspace in the anterior axillary line. Comparison of CB5 and V5 tracings made while the chest was closed showed the ventricular deflections to be 20% larger in the CB5 lead. The ventricular deflections were highly correlated (r = 0.95 to 0.98). The average P wave voltage was 90% greater in the CB5 lead, and the relative increase in P wave voltage was greater (p less than 0.01) than the 20% increase in the RS deflection. Tracings made while the chest was open gave similar results. The CB5 lead is simple to apply and provides tracings equivalent to the V5 when monitoring for ischemia while allowing easier recognition of P waves.

The cardiovascular and neuromuscular interactions of verapamil and dantrolene were evaluated in 20 chloralose-anesthetized swine. The animals were randomly divided into three groups. Group I, ten animals, received a bolus intravenous injection of 0.1 mg . kg-1 of verapamil followed by the continuous infusion of 5 micrograms . kg-1 . min-1. This group was then randomly divided into two equal subgroups. Five of these animals, Group Ia, continued to receive the verapamil infusion alone. The other five animals, Group Ib, received dantrolene in incremental doses of 1.0, 3.3, and 5.6 mg . kg-1 while the verapamil infusion was continued. An additional group of five animals, Group II, received the same incremental doses of dantrolene but did not receive verapamil. Five control animals, Group III, received the alpha-chloralose anesthetic without dantrolene or verapamil. Neuromuscular function, as measured by twitch height, was affected only by dantrolene, which produced a dose-dependent depression. Verapamil resulted in initial decreases in heart rate, arterial blood pressure, cardiac output, left ventricular dP/dt, and an increase in PR interval. Dantrolene alone produced a mild increase in arterial blood pressure. Dantrolene administration to verapamil-pretreated animals resulted in a profound depression in cardiac function, marked elevation in serum K+ (8.0 +/- 0.7 mEq . l-1), and no change in arterial pH (7.39 +/- 0.02). Cardiac arrest preceded by complete atrioventricular heart block occurred in one animal before and in four animals after the final dantrolene dose was given to animals pretreated with verapamil. Although we cannot extrapolate data from our porcine model to humans, further studies are indicated to help evaluate a possible fatal drug interaction before verapamil and dantrolene are used concomitantly in a clinical setting.