Brian A. Cason

Anesthetic-induced Preconditioning Previous Administration of Isoflurane Decreases Myocardial Infarct Size in Rabbits

Background: Experimental evidence suggests that ATP‐sensitive potassium channels are involved in myocardial ischemic preconditioning. Because some pharmacologic effects of isoflurane are mediated by KATP channels, the authors tested the hypothesis: Isoflurane administration, before myocardial ischemia, can induce or mimic myocardial preconditioning. Methods: Myocardial infarct size was measured in three groups of propofol‐anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed in their pretreatment: Group 1 (control, N = 13) no pretreatment, Group 2 (ischemic preconditioning, N = 8), 5 min of coronary occlusion and 15 min of reperfusion; Group 3 (isoflurane pretreatment; N = 15), 15 min of isoflurane (1.1% end‐tidal) and 15 min of washout. Hemodynamics were monitored serially. Myocardial infarct size and the area at risk were defined using triphenyltetrazolium chloride staining and fluorescent microspheres, respectively, and both were measured using computerized planimetry. Results: Infarct size expressed as a percentage of area at risk was 23.4 +/‐ 8.5% (mean +/‐ SD) in the isoflurane group compared with 33.1 +/‐ 13.3% in controls, and 8.7 +/‐ 6.2% in the ischemia‐preconditioned group. Analysis for coincidental regressions, followed by tests for equality of slope and elevation, showed that the linear relationship between infarct size and area at risk was significantly (P < 0.05) different in all three groups because of differences in line elevation. Minor differences in hemodynamic variables were found between groups, which were unlikely to account for the significant differences in infarct size. Conclusions: Proadministration of isoflurane, before myocardial ischemia, reduces myocardial infarct size, and mimics myocardial preconditioning.

Association of the pattern of use of perioperative β-blockade and postoperative mortality.

Background:The 1996 atenolol study provided evidence that perioperative &bgr;-adrenergic receptor blockade (&bgr;-blockade) reduced postsurgical mortality. In 1998, the indications for perioperative &bgr;-blockade were codified as the Perioperative Cardiac Risk Reduction protocol and implemented at the San Francisco Veterans Administration Medical Center, San Francisco, California. The present study analyzed the association of the pattern of use of perioperative &bgr;-blockade with perioperative mortality since introduction of the Perioperative Cardiac Risk Reduction protocol. Methods:Epidemiologic analysis of the operations undertaken since 1996 at the San Francisco Veterans Administration Medical Center was performed. The pattern of use of perioperative &bgr;-blockade was divided into four groups: None, Addition, Withdrawal, and Continuous. Logistic regression, survival analysis, and propensity analysis were performed. Results:A total of 38,779 operations were performed between 1996 and 2008. In patients meeting Perioperative Cardiac Risk Reduction indications for perioperative &bgr;-blockade, Addition is associated with a reduction in 30-day (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.33 to 0.83; P = 0.006) and 1-yr mortality (OR, 0.64; 95%, CI 0.51 to 0.79; P < 0.0001). Continuous is associated with a reduction in 30-day (OR, 0.68; 95% CI, 0.47 to 0.98; P = 0.04) and 1-yr mortality (OR, 0.82; 95% CI, 0.67 to 1.0; P = 0.05). Withdrawal is associated with an increase in 30-day (OR 3.93, 95% CI, 2.57 to 6.01; P less than 0.0001) and 1-yr mortality (OR, 1.96; 95% CI, 1.49 to 2.58; P < 0.0001). Conclusion:Perioperative &bgr;-blockade administered according to the Perioperative Cardiac Risk Reduction protocol is associated with a reduction in 30-day and 1-yr mortality. Perioperative withdrawal of &bgr;-blockers is associated with increased mortality.

Mechanisms of Isoflurane-induced Myocardial Preconditioning in Rabbits

BACKGROUNDnIsoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways.nnnMETHODSnMyocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance.nnnRESULTSnInfarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P<0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant).nnnCONCLUSIONSnGlyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.

Isoflurane Anesthesia and Myocardial Ischemia: Comparative Risk versus Sufentanil Anesthesia in Patients Undergoing Coronary Artery Bypass Graft Surgery

Whether isoflurane has the potential to produce coronary artery steal and associated myocardial ischemia is still controversial. Previous studies addressing this issue in humans did not purposefully control hemodynamics or use continuous measures of myocardial ischemia. The authors used transesophageal echocardiography (TEE) and continuous Holter electrocardiography (ECG) to study the relative risk of myocardial ischemia during isoflurane or sufentanil anesthesia under strict control of hemodynamics in 186 high-risk patients undergoing elective coronary artery bypass graft (CABG) surgery. Overall, hemodynamics were well controlled (increased heart rate = 9.8%; increased systolic blood pressure = 7.1%; decreased systolic blood pressure = 10.8% of total prebypass time compared with preoperative baseline values), with no difference between the two anesthetics. In the 162 patients with interpretable TEE recordings, moderate to severe TEE ischemic episodes (grade change greater than or equal to 2) developed in 33 (21%) during the prebypass period, with no difference between isoflurane (12 of 56 = 21%) and sufentanil (21 of 106 = 20%) (P = 0.97). The duration and severity of TEE episodes were not significantly different between the two groups. No correlation was observed between TEE ischemic episodes and isoflurane concentrations (range 0.47-1.75%). In the 181 patients with interpretable ECG recordings, ECG evidence of ischemia developed in 34 (19%) during the prebypass period, with no difference between isoflurane (12 of 59 = 20%) and sufentanil (22 of 122 = 18%) (P = 0.87). The duration and severity of electrocardiographic ischemic episodes were also similar in patients receiving either isoflurane or sufentanil. Four of the 62 patients (6%) who received isoflurane had an adverse cardiac outcome versus 15 of 124 patients (12%) who received sufentanil (P = 0.34). The authors findings demonstrate that, when hemodynamics are controlled, the incidence of myocardial ischemia (TEE or ECG) during isoflurane and sufentanil anesthesia is similar.

Blockade of Adenosine Triphosphate-sensitive Potassium Channels Eliminates Isoflurane-induced Coronary Artery Vasodilation

BackgroundThe mechanisms by which volatile anesthetics induce vasodilation are unknown. Recent studies of adenosine triphosphate-sensitive potassium channels (KATP channels) in the vascular smooth muscle of the coronary circulation suggest that these channels play a role in the coronary artery dilation produced by hypoxemia, the coronary blood flow (CBF) reactive hyperemic response, and in CBF auto regulation. We therefore conducted this study to determine the role of KATP channels in isoflurane-induced coronary vasodilation. MethodsStudies were conducted in six open-chest, anesthetized swine. The left anterior descending coronary artery was cannulated and perfused by blood passed through a membrane oxygenator. This preparation allowed us to administer drugs and volatile anesthetics regionally to the perfused myocardium, minimizing systemic effects. Regional CBF response to 1.5% and 3.0% isoflurane administered via the membrane oxygenator was measured before and after blockade of KATP channels, and was compared to the vasodilation produced by regional administration of several doses of sodium nitroprusside and adenosine. Blockade of KATP channels was achieved by regional intracoronary administration of glibenclamide (1–22 μg·kg-1·min-1), a specific blocker of these channels. ResultsAdministration of 1.5 and 3.0 percent isoflurane increased regional CBF by 29 ± 29% and by 62 ± 28%, respectively. Under control conditions, blockade of KATP, channels decreased mean CBF by 18%, but did not cause Ischemia. KATP channel blockade totally eliminated the vasodilator response to both doses of isoflurane. During KATP channel blockade the response to 3% isoflurane was converted to net vasoconstriction: mean ΔCBF = −5% ± 6%, P = <0.05 versus control. Negative inotropic effects of isoflurane were not eliminated by glibenclamlde. Because KATP, channel blockade was so effective in eliminating Isoflurane-induced coronary vasodilation, the dose of glibenclamlde was decreased in sequential experiments, but total blockade of isoflurane vasodilation was achieved even at the smallest dose of glibenclamide studied (1 μg·kg-1·min-1). The vasodilator response to nitroprusside was not affected, and the vasodilator response to adenosine was partially inhibited (consistent with their known mechanisms of action). ConclusionsBlockade of KATP, channels by glibenclamide completely inhibits Isoflurane-induced coronary vasodilation in the regionally perfused swine myocardium. The response to sodium nitroprusside, a drug that induces vasodilation via a different mechanism, was unaffected. The response to adenosine, a drug whose vasodilation is partially mediated via KATP channels, was partially inhibited. These results suggest that in vivo isoflurane-induced coronary artery vasodilation is predominantly mediated by KATP channels.

Effects of halothane, enflurane, and isoflurane on coronary blood flow autoregulation and coronary vascular reserve in the canine heart

To investigate the effects of volatile anesthetics on coronary blood flow (CBF) autoregulation and coronary vascular reserve, studies were performed on chronically instrumented dogs, awake and during the administration of 1.0 MAC halothane, enflurane, and isoflurane. Coronary pressure-flow plots were generated by measuring left anterior descending coronary artery blood flow while varying coronary inflow pressure with a hydraulic occluder. Autoregulation was quantitated by two measures: the slope of the horizontal “autoregulated” portion of the pressure-flow relationship and the autoregulation index (ArI) of Norris, Slope values (ml min−1 mmHg−1 SD) were: awake, 0.243 0.043; halothane, 0.414, 0.044; enflurane, 0.587, 0.187; and isoflurane, 0.795 0.246. The increase in slope was statistically significant only for halothane and isoflurane (P < .05). The ArI approaches 1.0 when autoregulation is perfect, and approaches zero or is a negative number when autoregulation is absent. The authors found ArI values of: awake, 0.55; halothane, −0.08; enflurane, −0.01; isoflurane, −0.02. These values indicate good autoregulation while awake, but impaired autoregulation with all three anesthetics (P < .05). Coronary vascular reserve was calculated, at a diastolic coronary pressure of 40 mmHg, as the difference between resting flow and flow during maximal coronary vasodilation induced by intracoronary adenosine. Coronary vascular reserve, maximal coronary conductance, and coronary zero-flow pressure were not significantly altered by these anesthetics. The authors conclude that 1.0 MAC enflurane, halothane, and isoflurane mildly disrupt CBF autoregulation, increasing CBF out of proportion to myocardial demands. Under the conditions of this study, these anesthetics do not affect maximal CBF or coronary vascular reserve.

Perioperative β-blockade: atenolol is associated with reduced mortality when compared to metoprolol.

Background:The Atenolol study of 1996 provided evidence that perioperative &bgr;-blockade reduced postsurgical mortality. In 1998, the indications for perioperative &bgr;-blockade were codified as the Perioperative Cardiac Risk Reduction protocol and implemented at the San Francisco Veterans Affairs Medical Center. The current study tested the following hypothesis: Is there a difference in mortality rates between patients receiving perioperative atenolol and metoprolol? Methods:Epidemiologic analysis of the operations performed at the San Francisco Veterans Affairs Medical Center since 1996 was performed. High-risk inpatients with perioperative &bgr;-blockade were divided into two groups: patients who received perioperative atenolol only and those who received metoprolol only. Patients who switched between the two chronic oral &bgr;-blocker medications were excluded. IV administration of &bgr;-blockers was ignored. Propensity matching analysis was used to correct for population differences in risk factors. Results:There were 38,779 operations performed from 1996 to 2008, with 24,739 inpatient procedures. Based on analysis of inpatient medication use, 3,787 patients received atenolol only (1,011) or metoprolol only (2,776). Thirty-day mortality (atenolol 1% vs. metoprolol 3%, P < 0.0008) and 1-yr mortality (atenolol 7% vs. metoprolol 13%, P < 0.0001) differed between the two &bgr;-blockers. Analysis based on inpatient and outpatient &bgr;-blocker use showed a similar pattern. Propensity matching that corrected for multiple cardiac risk factors found an odds ratio (OR) of 2.1 [95% CI 1.5–2.9], P < 0.0001 for increased 1-yr mortality with metoprolol for inpatient use. Conclusion:Perioperative &bgr;-blockade using atenolol is associated with reduced mortality compared with metoprolol.

Mortality Probability Model III and Simplified Acute Physiology Score II: Assessing Their Value in Predicting Length of Stay and Comparison to APACHE IV

BACKGROUNDnTo develop and compare ICU length-of-stay (LOS) risk-adjustment models using three commonly used mortality or LOS prediction models.nnnMETHODSnBetween 2001 and 2004, we performed a retrospective, observational study of 11,295 ICU patients from 35 hospitals in the California Intensive Care Outcomes Project. We compared the accuracy of the following three LOS models: a recalibrated acute physiology and chronic health evaluation (APACHE) IV-LOS model; and models developed using risk factors in the mortality probability model III at zero hours (MPM(0)) and the simplified acute physiology score (SAPS) II mortality prediction model. We evaluated models by calculating the following: (1) grouped coefficients of determination; (2) differences between observed and predicted LOS across subgroups; and (3) intraclass correlations of observed/expected LOS ratios between models.nnnRESULTSnThe grouped coefficients of determination were APACHE IV with coefficients recalibrated to the LOS values of the study cohort (APACHE IVrecal) [R(2) = 0.422], mortality probability model III at zero hours (MPM(0) III) [R(2) = 0.279], and simplified acute physiology score (SAPS II) [R(2) = 0.008]. For each decile of predicted ICU LOS, the mean predicted LOS vs the observed LOS was significantly different (p <or= 0.05) for three, two, and six deciles using APACHE IVrecal, MPM(0) III, and SAPS II, respectively. Plots of the predicted vs the observed LOS ratios of the hospitals revealed a threefold variation in LOS among hospitals with high model correlations.nnnCONCLUSIONSnAPACHE IV and MPM(0) III were more accurate than SAPS II for the prediction of ICU LOS. APACHE IV is the most accurate and best calibrated model. Although it is less accurate, MPM(0) III may be a reasonable option if the data collection burden or the treatment effect bias is a consideration.

Effects of Isoflurane and Halothane on Coronary Vascular Resistance and Collateral Myocardial Blood Flow: Their Capacity to Induce Coronary Steal

Some coronary vasodilators, paradoxically, may endanger patients with coronary artery disease by causing “coronary steal.” To determine the capacity of isoflurane and halothane to cause coronary steal, the authors studied their effects on coronary vascular resistance (CVR), diastolic coronary artery pressure, and collateral myocardial blood flow. Using ameroid constrictors, chronic occlusions of the left anterior descending (LAD) coronary artery were created in ten dogs. Six to eight weeks after implantation, the dogs were anesthetized with fentanyl and pentobarbital, and a stenosis was created on the circumflex (Cx) coronary artery. Isoflurane and halothane were each administered in doses of 0.5 and 1.5 MAC. Diastolic aortic pressure was held constant. Using small catheters in the circumflex and LAD coronary arteries, the authors measured diastolic coronary artery pressures. Collateral myocardial blood flow was measured by the microsphere method. In this model, halothane and isoflurane minimally affect CVR. The maximum change in CVR, which was found during 1.5 MAC isoflurane, was −8% (not significant). Diastolic coronary pressures distal to the Cx stenosis (54.5 ± 11.5 mmHg) and distal to the LAD occlusion (44.5 ± 5.2 mmHg) did not change significantly with either isoflurane or halothane. Transmural collateral blood flow distal to the LAD occlusion (0.51 ± 0.11 cc.g−1.min−1) was unaltered by either drug. There was no evidence of coronary steal. Epicardial ECG S-T segments showed no evidence of ischemia. The finding of minimal direct effects of halothane and isoflurane on CVR, diastolic coronary pressure, and collateral myocardial blood flow suggest that, under the conditions of this study, neither agent, when used as an adjuvant to high-dose narcotic anesthesia, is likely to cause myocardial ischemia by a coronary “steal” mechanism.

Original ResearchCritical Care MedicineMortality Probability Model III and Simplified Acute Physiology Score II: Assessing Their Value in Predicting Length of Stay and Comparison to APACHE IV

BACKGROUNDnTo develop and compare ICU length-of-stay (LOS) risk-adjustment models using three commonly used mortality or LOS prediction models.nnnMETHODSnBetween 2001 and 2004, we performed a retrospective, observational study of 11,295 ICU patients from 35 hospitals in the California Intensive Care Outcomes Project. We compared the accuracy of the following three LOS models: a recalibrated acute physiology and chronic health evaluation (APACHE) IV-LOS model; and models developed using risk factors in the mortality probability model III at zero hours (MPM(0)) and the simplified acute physiology score (SAPS) II mortality prediction model. We evaluated models by calculating the following: (1) grouped coefficients of determination; (2) differences between observed and predicted LOS across subgroups; and (3) intraclass correlations of observed/expected LOS ratios between models.nnnRESULTSnThe grouped coefficients of determination were APACHE IV with coefficients recalibrated to the LOS values of the study cohort (APACHE IVrecal) [R(2) = 0.422], mortality probability model III at zero hours (MPM(0) III) [R(2) = 0.279], and simplified acute physiology score (SAPS II) [R(2) = 0.008]. For each decile of predicted ICU LOS, the mean predicted LOS vs the observed LOS was significantly different (p <or= 0.05) for three, two, and six deciles using APACHE IVrecal, MPM(0) III, and SAPS II, respectively. Plots of the predicted vs the observed LOS ratios of the hospitals revealed a threefold variation in LOS among hospitals with high model correlations.nnnCONCLUSIONSnAPACHE IV and MPM(0) III were more accurate than SAPS II for the prediction of ICU LOS. APACHE IV is the most accurate and best calibrated model. Although it is less accurate, MPM(0) III may be a reasonable option if the data collection burden or the treatment effect bias is a consideration.