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The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world's population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them. Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow. This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great., Competing Interests: Ben Freedman reports prior fees and advisory board honoraria from Bayer Pharma AG, Boehringer Ingelheim, Daiichi-Sankyo, Omron and Pfizer/BMS, loan devices from Alivecor, and grants to the institution for investigator-initiated studies from BMS/Pfizer, unrelated to the current work. Jeff Healey has held research grants and received speaking fees from BMS/Pfizer, Bayer, Servier, Medtronic, Boston Scientific, Abbott, ARCA biopharma, Cipher pharma, and Myokardia. Lis Neubeck has received honoraria from Pfizer BMS and Daiichi Sankyo (<£2000). Renate Schnabel has received lecture fees from BMS/Pfizer outside this work. Jesper Hastrup Svendsen reports grants, personal fees, and other from Medtronic and grants from Gilead. Isabel Arbelo has received speaker fees from Biosense Webster. FD Richard Hobbs has received occasional fees and or travel expenses reimbursed in the past five years for consultancy, speaking, or advisory meetings from BI and Bayer. Janina Stepinska has received research grants from Bayer and Sanofi; consulting or lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Sanofi, and Servier. Antoni Martínez-Rubio has participated in scientific advisory boards or research projects financed by Bayer, Boehringer Ingelheim, Daichii-Sankyo, and Pfizer., (Copyright: © 2021 The Author(s).)

Although the potential for transcutaneous electronic nerve stimulation (TENS) units to interfere with appropriate function of cardiac pacemakers is well documented, an adverse interaction between a TENS unit and an ICD has never been reported. We describe a patient in whom a TENS unit created an electrical artifact that was interpreted by a transvenous ICD as ventricular fibrillation, leading to the delivery of inappropriate therapy. TENS units should be used with caution in patients with ICDs.

Objectives: We sought to 1) determine the proportion of appropriate elderly patients admitted to the hospital with unstable angina who are treated with aspirin and heparin; 2) identify patient factors associated with the Agency for Health Care Policy and Research (AHCPR) guideline-based use of aspirin and heparin; and 3) compare practice patterns and patient outcomes before and after publication of the AHCPR guidelines., Background: Improving the care of patients with unstable angina may provide immediate opportunities to mitigate the adverse consequences of unstable angina. However, despite the importance of this diagnosis, there is a paucity of information on the patterns of treatment and outcomes across diverse sites and recent trends in practice that have occurred, especially since the publication of the AHCPR practice guidelines., Method: We performed a retrospective cohort study using data created from medical charts and administrative files. The sample included 300 consecutive patients admitted to one of three Connecticut hospitals in the period 1993 to 1994 and 150 consecutive patients admitted in 1995 with a principal discharge diagnosis of unstable angina or chest pain., Results: Of the 384 patients > or =65 years old who had no contraindications to aspirin on hospital admission, 276 (72%) received it. Of the 369 patients > or =65 years old who had no contraindications to heparin on admission, 88 (24%) received it. Among the 321 patients > or =65 years old who had no contraindications to aspirin at hospital discharge, 208 (65%) were prescribed it. When 1995 was compared with 1993 to 1994, the use of aspirin (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3 to 4.0) and heparin (OR 2.8, 95% CI 1.6 to 4.9) on hospital admission significantly increased, and the use of aspirin at discharge (OR 1.4, 95% CI 0.8 to 2.4) increased. Concomitantly, there was a significant reduction in 30-day readmission (OR 0.52, 95% CI 0.27 to 0.99)., Conclusions: Our results indicate an improvement in the care and outcomes of elderly patients with unstable angina, but there remain opportunities for further improvement.

The effects of nitrous oxide on left ventricular diastolic function and its potential interactions with ischemia-induced diastolic dysfunction have not been described. Accordingly, we investigated the effects of nitrous oxide in ischemic and remote nonischemic myocardium during baseline, 90 min severe low-flow myocardial ischemia (systolic bulge), and reperfusion in 11 open-chest dogs. Anesthesia was maintained with fentanyl infusion (2 micrograms.kg-1.min-1), animals were ventilated with 60% nitrogen in oxygen, and hemodynamic variables were recorded prior to and after the replacement of nitrogen by 60% nitrous oxide. During baseline, nitrous oxide moderately increased chamber stiffness (+ 10%), myocardial stiffness (+33%), and unstressed length (+4%) and decreased the peak lengthening rate (-10%). Moreover, nitrous oxide decreased regional contractility during baseline (-12% at apex, -8% at base) as well as in nonischemic myocardium during myocardial ischemia (-9%) and reperfusion (-8%). However, nitrous oxide did not modify ischemia-induced systolic or diastolic dysfunction in ischemic myocardium during ischemia and reperfusion. Myocardial ischemia (+45%) and reperfusion (+57%) were associated with an increase in myocardial stiffness of nonischemic myocardium regardless of the anesthetic technique used. This study is the first to demonstrate that in addition to its well established negative inotropic effect, nitrous oxide affects regional diastolic function.

During and after an ischemic injury, maintenance and recovery of cardiac function may critically depend on remote nonischemic myocardium. Graded myocardial ischemia is associated with an approximately 50% increase in stiffness of nonischemic myocardium. We determined whether this increase in stiffness is unique to the ischemic period or persists during reperfusion. Ten anesthetized (isoflurane 1.0% vol/vol) open-chest dogs were instrumented to measure left ventricular pressure and dimensions (sonomicrometry) in ischemic and nonischemic myocardium. Regional chamber stiffness and myocardial stiffness were assessed using the end-diastolic pressure-length relationship which was modified by stepwise infusion and withdrawal of 200 mL of the animals' own blood during baseline, 45 min low flow ischemia (systolic bulge), and 60 min after the onset of reperfusion. In remote nonischemic myocardium, regional myocardial ischemia was associated with a significant (P < 0.05) increase in chamber stiffness (+44%) and myocardial stiffness (+48%). Sixty minutes after the onset of reperfusion, chamber stiffness (+54%, P < 0.05 versus baseline) and myocardial stiffness (+55%, P < 0.05 versus baseline) remained increased. Thus, the ischemia-induced increase in stiffness of remote nonischemic myocardium persists for at least 60 min after reperfusion.

We have determined the effects of alterations in preload on ischaemia-induced diastolic dysfunction in anaesthetized beagles instrumented to measure left ventricular pressure and regional dimensions. Low-flow regional ischaemia decreased peak lengthening rates in ischaemic (mean -26 (SEM 6) mm s-1, P < 0.01) and non-ischaemic (-8.6 (3.4) mm s-1, P < 0.05) myocardium. Peak lengthening rates and the time constant of iso-volumic relaxation (tau) were not affected by alterations in preload. Absolute values of tau failed to distinguish between ischaemia and control. The ischaemia-induced decrease in peak negative dP/dt was preload dependent and caused mainly by a concomitant decrease in peak left ventricular pressure. We conclude that indices derived from segmental lengthening are sensitive to ischaemia and insensitive to preload, in contrast with indices derived from left ventricular pressure. It remains to be determined if monitoring of early segmental lengthening will improve detection and assessment of perioperative myocardial ischaemia.

Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA2 activity, with an associated increased TXB2/6-keto-PGF1 alpha ratio.

Though a sustained post-ischemic decrease in contractile function has been clearly established, post-ischemic diastolic function has not been thoroughly investigated. Accordingly, 11 anesthetized (isoflurane 1%) open-chest beagles were instrumented to measure left ventricular pressure and dimensions (circumferential length and wall thickness) in an apicoanterior area supplied by the left anterior descending coronary artery (LAD). Pressure-dimension relations were modified by stepwise infusion and withdrawal of 200 mL of the animals' own blood during baseline, 45 minutes partial occlusion of the LAD (systolic bulging), and 60 minutes after the onset of reperfusion. Stiffness constants were derived from the end-diastolic pressure-length and stress-strain relations, respectively. Myocardial ischemia was associated with significant (P < 0.05) alterations of the following parameters of diastolic function: (1) 47% increase in end-diastolic pressure; (2) 22% decrease in peak negative dP/dt; (3) 9% increase in the time constant of isovolumic relaxation (tau); (4) postcystolic contraction; (5) 6% increase in end-diastolic length and 10% decrease in end-diastolic thickness; (6) 12% increase in unstressed length (creep) and 13% decrease in unstressed thickness; (7) 51% increase in chamber stiffness and a 63% increase in myocardial stiffness; and (8) 40% decrease in the peak lengthening rate. After 60 minutes of reperfusion, only end-diastolic pressure and tau had returned to baseline values whereas systolic shortening fraction, postsystolic contraction, and end-diastolic and unstressed dimensions had only partially recovered. No recovery occurred in peak negative dP/dt, chamber stiffness, myocardial stiffness, and peak lengthening rate. Thus, both myocardial ischemia and reperfusion are associated with complex changes in global and regional left ventricular diastolic function.

The direct effects of nitrous oxide on left ventricular contractility and myocardial oxygen consumption (MVO2) in the ischemic isolated rat heart were studied. The rat heart was isolated and perfused by a Langendorf technique. The aortic stump was cannulated and the heart was perfused with Kumpeis solution bubbled with 95% O2 and 5% CO2 (control phase). A latex balloon was inserted into the left ventricle (LV) to measure LV pressures and dP/dt. Coronary flow was measured and MVO2 was calculated. After the control phase, perfusion pressure was decreased to induce global ischemia (ischemic phase). There were four groups of eight hearts each: control, nitrogen, nitrous oxide, and halothane groups. After 15 min of ischemic phase, the perfusion pressure was increased and the gas mixture was changed to the standard gas mixture (reperfusion phase). Nitrous oxide did not further depress myocardial contractility compared with nitrogen in the ischemic phase, and did not alter MVO2 in the ischemic phase compared with nitrogen. Halothane significantly depressed myocardial contractility and decreased MVO2 in the ischemic phase compared with the control.

The proconvulsant properties of exogenously administered opioids in man are not established. We prospectively evaluated relationships between epileptiform activity and opioid dose in 20 patients undergoing coronary artery revascularization. Baseline electroencephalograms were performed before surgery. Ten subjects were given fentanyl and 10 sufentanil, at 100 micrograms/kg and 10 micrograms/kg, respectively, in 4 divided doses, 3 min apart. Midazolam (4 mg) was given 3 min after the last dose of narcotic. Serum opioid concentrations were measured by radioimmunoassay. Within 3 min of the first opioid dose, 19 of 20 patients developed epileptiform activity, characterized by generalized single and multiphasic, low-to-moderate voltage spike discharges, similar in appearance to benign epileptiform transients of sleep (BETS). Despite continuously increasing serum concentrations of opioid, the number of spike discharges initially increased during the first and second dose intervals and then declined during the third and fourth dose intervals. This dissociation between epileptiform discharges and measured serum opioid concentration was unexpected and remained unexplained. Spike activity was consistently attenuated (P = 0.000003) within 20 sec of midazolam administration. Abrupt cessation of discharges after administration of the anticonvulsant, midazolam, suggests an epileptogenic mechanism for the opioid-induced activity.

Several varieties of pulmonary artery catheters (PACs) with pacing capabilities are now available. Although specific recommendations for prophylactic perioperative placement of pacemakers have been offered previously, the authors believe that those recommendations warrant further examination, taking into consideration the availability of new pacing modalities. Toward this end, the use of pacing PACs in cardiac surgical patients was prospectively examined. In 600 consecutive adult patients with PACs placed prior to cardiopulmonary bypass (CPB), the cardiac anesthesiologist recorded if a pacing PAC was placed, the indications for placing it, and whether the catheter was used to pace. If a pacing PAC was not chosen, the anesthesiologist indicated whether cardiac pacing was needed prior to CPB. In all patients, the presence and specifics of the following five possible indications were documented: sinus node dysfunction/bradydysrhythmias, atrioventricular heart block, fascicular or bundle branch block, cardiac reoperation, and/or valvular heart disease. PACs with pacing capability were placed in 180 of the 600 patients (30.0%) and were used in 34 of these 180 patients (18.8%). In 4 of 420 patients (0.95%) without pacing PACs, cardiac pacing was needed prior to CPB. The following preoperative diagnoses were significant predictors (P less than .05) for the use or need for pacing catheters: sinus node dysfunction/bradydysrhythmias, a history of transient complete atrioventricular block, aortic stenosis, aortic insufficiency, and reoperation. The majority of adult patients undergoing cardiac surgery do not require the use of a pacing PAC prior to CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Normothermic cardiopulmonary bypass (CPB) is used in cardiac surgery at some institutions. To compare hemodynamic and hormonal responses to hypothermic (29 degrees C) and normothermic nonpulsatile CPB, 20 adults undergoing coronary artery bypass graft and/or aortic valve replacement were studied. Hemodynamic measurements and plasma hormone concentrations were obtained from preinduction to the third postoperative hour. The two groups were given similar amounts of anesthetics and vasodilators. Systemic vascular resistance increased only during hypothermic CPB, and heart rate was higher at the end of hypothermic CPB. Postoperative central venous pressure and pulmonary capillary wedge pressure were lower after hypothermic CPB. Oxygen consumption decreased by 45% during hypothermic CPB, did not change during normothermic CPB, but increased similarly in the two groups after surgery; mixed venous oxygen saturation (SvO2) was significantly lower during normothermic CPB. Urine output and composition were similar in the two groups. In both groups, plasma epinephrine, norepinephrine, renin activity, and arginine vasopressin concentrations increased during and after CPB. However, epinephrine, norepinephrine, and dopamine were 200%, 202%, and 165% higher during normothermic CPB than during hypothermic CPB, respectively. Dopamine and prolactin increased significantly during normothermic but not hypothermic CPB. Atrial natriuretic peptide increased at the end of CPB and total thyroxine decreased during and after CPB, with no difference between groups. This study suggests that higher systemic vascular resistance during hypothermic CPB is not caused by hormonal changes, but might be caused by other factors such as greater blood viscosity. A higher perfusion index during normothermic CPB might have allowed higher SvO2.

The rapid changes in brain extracellular ion concentrations that occur with anoxia are important in understanding the pathophysiology of anoxic-ischemic brain injury. While previous studies have focused on the ionic changes that occur in gray matter areas of the brain, white matter (WM) is also damaged by anoxia. We describe the changes in extracellular K+ concentration ([K+]o) and extracellular pH (pHo) that accompany anoxia in WM, and present new results indicating that glial cells directly contribute to the observed fluctuations of these ions. Anoxia-induced changes in [K+]o and pHo were measured with ion-selective microelectrodes in the isolated rat optic nerve, a typical WM tract. To assess the contribution of glial cells, recordings were also made in optic nerves that contained only glial cells (produced by neonatal enucleation). Anoxia in WM produced less extreme changes in [K+]o and pHo than are known to occur in gray matter; in WM during anoxia, the average maximum [K+]o was 14 +/- 2.9 mM (bath [K+]o = 3 mM) and the average maximum acid shift was 0.31 +/- 0.07 pH unit. These extracellular ionic changes were accompanied by rapid shrinkage of extracellular space volume. The ability of optic nerve axons to conduct action potentials was lost in temporal association with the increase in [K+]o. Increasing bath glucose concentration from 10 to 20 mM resulted in a much larger acid shift during anoxia (0.58 +/- 0.08 pH unit) and a smaller average increase in [K+]o (9.2 +/- 2.6 mM). The increased glucose concentration presumably enhanced anaerobic metabolism, leading to extracellular lactate accumulation and a greater acid shift.(ABSTRACT TRUNCATED AT 250 WORDS)

Study Objective: To observe the effects of continuous intravenous infusion of diltiazem on the renin-aldosterone system and ACTH-adrenocortical axis responses during surgical stimulation., Design: Randomized study of intravenous diltiazem., Setting: Operating room at the Hyogo Medical College Hospital., Patients: Twenty-three patients undergoing upper abdominal surgery were divided into two groups: the control group (n = 10) and the diltiazem group (n = 13). All the patients were without any complications and classified as ASA physical status I., Interventions: Patients in the diltiazem group received an infusion of 10 micrograms/kg/min for 90 to 120 minutes following skin incision., Measurements and Main Results: Plasma adrenocorticotropic hormone, plasma aldosterone and cortisol concentrations, and plasma renin activity were determined with radioimmunoassay before the induction of anesthesia at 10, 30, 60, and 90 minutes after skin incision and at the end of anesthesia. Renin activity did not change significantly. Maximal increases in plasma adrenocorticotropic hormone, aldosterone, and cortisol observed 90 minutes after skin incision were 355 +/- 95 pg/ml, 118 +/- 30 pg/ml, and 14.2 +/- 2.3 micrograms/dl in the control group versus 246 +/- 41 pg/ml, 119 +/- 25 pg/ml, and 15.0 +/- 1.8 micrograms/dl in the diltiazem group, respectively, and there were no significant differences between these groups. Adrenocorticotropic hormone was significantly lower in the diltiazem group compared with that in the control group 60 minutes after the start of surgery (p less than 0.05). There was marked natriuresis (40 +/- 25 microEq/min vs 470 +/- 147 microEq/min at the 90-minute mark) and diuresis (0.16 +/- 0.13 ml/min vs 2.53 +/- 0.88 ml/min) in the diltiazem group., Conclusions: Diltiazem at this dose increased urine output and sodium excretion without affecting most of these hormonal responses to surgical stimulation. These findings suggest that diltiazem has beneficial renal effects independent of hormonal concentrations.

This study was undertaken to determine if fentanyl and sufentanil could produce dose-related suppression of hemodynamic and hormonal responses to surgical stimulation. Eighty patients scheduled for elective CABG were studied in two consecutive protocols: protocol I was a randomized double-blind study of 40 patients who received a single dose of fentanyl (50 or 100 micrograms/kg) or sufentanil (10, 20, or 30 micrograms/kg). Hemodynamic measurements and hormonal concentrations (renin, aldosterone, cortisol, and catecholamines) were determined before and after induction and after intubation and sternotomy. Protocol II was an open randomized study of 40 patients who received sufentanil in one of four doses: 30 micrograms/kg as a single dose, 10 micrograms/kg plus infusion 0.05 microgram.kg-1.min-1, 20 micrograms/kg plus infusion 0.1 microgram.kg-1.min-1, or 40 micrograms/kg plus infusion 0.2 microgram.kg-1.min-1. Hemodynamic measurements and plasma sufentanil and catecholamine concentrations were determined before and after induction and after intubation, sternotomy, and aortic cannulation. Both protocols defined a hemodynamic response as a 15% or more increase in systolic blood pressure (SBP) from control and a hormonal response 50% or more increase over control. During protocol I, 18 patients had a hemodynamic response (average increase in SBP 22.6 +/- 2%) and 35 patients had a total of 59 hormonal responses. During protocol II, 24 patients had a hemodynamic response (average increase in SBP - 31 +/- 3%) and there were 15 catecholamine responses. There were no differences between dose groups in either protocol. It was concluded that in these dose ranges, suppression of hemodynamic or hormonal stress responses is not related to opioid dose.(ABSTRACT TRUNCATED AT 250 WORDS)

It is concluded that there is good scientific basis for an approach that avoids colloid priming solutions as routine for all adult CPB patients. There may be selected individuals who might benefit from colloid therapy; for instance, patients who are predicted to require high left atrial pressures postbypass, those who are borderline for getting through their surgical experience without a homologous red cell transfusion, and patients coming for surgery with a clinically important lung water elevation. In this time of cost constraints there are many more scientifically worthy therapies that could be made available to patients. We should focus on these and resist "luxury items" like routine colloid CPB priming solutions.

The authors, on the basis of the literature and their own studies, envisage the behaviour of the renin-angiotensin system and of ADH during anesthesia. With regard to renin-angiotensin, it would seem that the changes reported in the past are due to the surgical procedure itself or result form haemodynamic changes but that no anesthetic has a direct effect upon the secretion of renin. For ADH, three concepts must be borne in mind: not only is secretion not influenced by anesthetics, but on the contrary anaesthesia decreases the "vasopressin" response to surgical stress. By contrast, the surgical procedure may induce the secretion of ADH responsible for coronary vasoconstriction. Finally, at high doses, ADH would appear to have an inverse antinatriuretic effect resulting in a sodium diuresis.

High doses of morphine produced peripheral vasodilation and frequently significant hypotension. These effects are thought to be due, in part, to the release of histamine. One putative advantage of high-dose fentanyl anesthesia is its relatively small effect on peripheral vascular resistance. In a randomized study, the authors examined the possibility that the hemodynamic differences between morphine and fentanyl might be attributable to histamine release. Fifteen patients were studied prior to coronary artery bypass surgery. Subjects received in infusion of morphine (1 mg . kg-1, iv at 100 micrograms . kg-1 . min-1 [n = 8]) or fentanyl (50 micrograms . kg-1 at 5 micrograms . kg-1 . min-1 [n = 7]). Patients in the morphine group had an average 750 per cent peak increase in plasma histamine accompanied by a significant decrease in mean arterial pressure (-27 mmHg- and systemic vascular resistance (-520 dyne . s . cm-5). The greatest decrease in systemic vascular resistance occurred in those patients with the highest levels of plasma histamine (r = -0.81). Patients in the fentanyl group had no change in plasma histamine and no decrease in arterial pressure or systemic vascular resistance. Cardiac output and heart rate were comparable between the two groups. Differences in the release of histamine account for most, if not all, of the different effects of morphine and fentanyl on the peripheral vasculature.

Hemodynamic effects and histamine release by bolus injection of 0.35 mg/kg of d-tubocurarine were studied in 24 patients. H1- and H2-histamine antagonists or placebo were given before dosing with d-tubocurarine in a randomized double-blind fashion to four groups: group 1--placebo; group 2--cimetidine, 4 mg/kg, plus placebo; group 3--chlorpheniramine, 0.1 mg/kg, plus placebo; and group 4--cimetidine plus chlorpheniramine. Histamine release occurred in most patients, the highest level 2 minutes after d-tubocurarine dosing. Group 1 had a moderate negative correlation between plasma histamine change and systemic vascular resistance (r = 0.58; P less than 0.05) not present in group 4. Prior dosing with antagonists partially prevented the fall in systemic vascular resistance. These data demonstrate that the hemodynamic changes associated with d-tubocurarine dosing are only partially explained by histamine release. Thus prior dosing with H1- and H2-antagonists provides only partial protection.

The use of pulsatile perfusion during bypass should create a more physiological milieu and thus attenuate the vasopressin stress response. To determine this, 20 patients scheduled for elective coronary artery bypass operation were studied in two groups. Group 1 had a standard nonpulsatile perfusion, and in Group 2 a pulsatile pump was used. Measurements were made before and after anesthesia, after surgical incision, and at 15 and 30 minutes during and after cardiopulmonary bypass. In both groups, vasopressin levels were significantly elevated after sternotomy (4.5 +/- 1.5 to 37 +/- 10 pg/ml in Group 1 and 3.1 +/- 1.2 to 33 +/- 9 pg/ml in Group 2, p less than 0.05) and during bypass (198 +/- 19 pg/ml in Group 1 and 113 +/- 16 pg/ml in Group 2) but were higher in Group 1 (p less than 0.05). With comparable perfusion pressures in both groups, Group 2 required higher flow (4.2 +/- 0.2 versus 3.5 +/- 0.3 L/min, p less than 0.05) and had lower resistance (1,351 +/- 182 versus 1,841 +/- 229 dynes sec cm-5, p less than 0.05) and higher urine Na+ (123 +/- 5 versus 101 +/- 8 mEq/L, p less than 0.05). These data demonstrate that pulsatile flow can significantly attentuate the vasopressin stress response to bypass. Since vasopressin, at these concentrations, is a potent vasoconstrictor and is capable of producing a Na+ diuresis, this may partially explain the higher flow requirements and the decrease in Na+ excretion.

The effect of CPB on plasma ADH levels, urine flow, and urine osmolality was studied in nine patients. All patients received morphine, 1 mg. per kilogram, and 50 per cent nitrous oxide-50 per cent oxygen for anesthesia. CPB utilized a Travenol disposable bubble oxygenator and the prime consisted of 3 L. of Ringer's lactate. Measurements were made prior to induction of anesthesia , at 30 minutes following surgical incision, and at 15, 30, and 45 minutes during CPB. There were no statistically significant changes in mean arterial BP, cardiac index, serum sodium, or serum osmolality in any period. Urine flow increased from 0.99 +/- 0.3 ml. per minute to a high of 6.13 +/- 2.0 ml. per minute at 30 minute at 30 minutes on CPB (P less than 0.02). Urine osmolality declined from a control value of 691 +/- 142 mOsm. per kilogram to a low of 425 +/- 48 mOsm. per kilogram at 45 minutes on CPB (p less than 0.05). ADH levels rose from a control value of 4.3 +/- 1.5 to 13.0 +/- 3.3 pg. per milliliter with surgical stimulatiion (p less than 0.05). During CPB the ADH levels rose to a peak of 23.7 +/- 3.6 pg. per milliliter at 30 minutes (p less than 0.01) and were declining at 45 minutes. These data suggest that the stress of CPB results in an outpouring of ADH (or vasopressin) to function as a pressor to produce an increase in peripheral resistance. The ADH concentrations far exceed those required for normal physiologic control of water excretion and the urineflow will thus vary more with the hemodynamic changes than with the ADH levels.

Nonpulsatile cardiopulmonary bypass, in patients with coronary artery disease, produces a significant increase in thromboxane, a potent platelet aggregant and putative coronary vasoconstrictor. Pulsatile flow may decrease the incidence of perioperative infarction and the hormonal stress response to bypass. This study assessed the effect of pulsatile blood flow on plasma thromboxane and prostacyclin profiles during cardiopulmonary bypass by serial measurement of their stable metabolites, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Two groups of eight patients each were studied before, during, and after cardiopulmonary bypass. Eight patients had routine (nonpulsatile) bypass and eight had pulsatile flow. In the nonpulsatile group, the TxB2 concentration significantly increased during bypass (65 +/- 39 to 1,224 +/- 306 pg/ml, p less than 0.01) and rapidly returned to control. Prostacyclin also rose (53 +/- 20 to 613 +/- 132 pg/ml, p less than 0.01). In the pulsatile group, TxB2 rose during bypass (53 +/- 18 to 693 +/- 130 pg/ml, p less than 0.01), but peak concentration was significantly lower than in the nonpulsatile group (1,224 +/- 306 versus 693 +/- 130 pg/ml, p less than 0.05). Prostacyclin rose sharply during cardiopulmonary bypass in the pulsatile group (53 +/- 22 to 1,033 +/- 136 pg/ml, p less than 0.01) and was higher than in the nonpulsatile group (1,033 +/- 136 versus 325 +/- 33 pg/ml, p less than 0.01). There were no intragroup differences of plasma hemoglobin, hematocrit, or platelet count. These data demonstrate that pulsatile flow significantly alters prostacyclin and thromboxane profiles during cardiopulmonary bypass and favors production of the coronary vasodilator and platelet disaggregant prostacyclin. This may be an important factor in some of the clinical advantages previously reported with this modality.

Arginine vasopressin, the antidiuretic hormone in man, in low concentrations increases reabsorption of water in the collecting ducts of the kidney, producing a concentrated urine. It is also a potent vasoconstrictor because of its direct effect on arteriolar smooth muscle, particularly the splanchnic, renal, and coronary vascular beds. This appears to be a dose-dependent response. In very high concentrations it is capable of producing a diuresis with increased urinary sodium excretion. The preponderance of evidence today has failed to show any significant increase in antidiuretic hormone levels with anesthesia alone, provided significant hemodynamic changes do not occur. It seems unlikely, then, that the inhalation anesthetics or high-dose narcotic anesthesia are a direct stimulus to ADH release. If a decrease in urine flow does occur, it is more likely caused by either the renal hemodynamic effects of the anesthetic or a secondary release of ADH. Surgical stimulation is capable of significantly increasing ADH levels. This apparently is a stress response that can be attenuated by the depth of anesthesia. Such a response to operation may produce ADH levels that can indeed decrease urinary flow, but more importantly may succeed in achieving levels that can exert a significant vasopressor effect. In unusual circumstances, vasopressin levels can occur that are capable of producing a diuresis and increased urine sodium excretion.

The effects of enflurane on myocardial oxygen consumption, metabolism and coronary blood flow (argon washin) were studied in 10 patients with 2- or 3-vessel coronary artery disease undergoing coronary artery bypass surgery. All patients were men with stable angina and normal left ventricular function and were on maintenance doses of beta-receptor- or calcium-antagonists. Anaesthesia consisted of enflurane and 50% nitrous oxide in oxygen. Measurements were performed and blood samples were taken with the patient awake, 30 min after induction of anaesthesia without any surgical stimulation and during sternotomy. End-tidal enflurane concentrations averaged 0.9% after induction and 2.5% during sternotomy. Enflurane decreased coronary blood flow significantly by 36% after induction, while sternotomy increased coronary blood flow by 29%. Myocardial oxygen uptake was decreased by 33% and was increased by 37% during sternotomy. Coronary vascular resistance did not change significantly during the entire observation period, while coronary sinus oxygen saturation significantly increased after induction by 20% followed by a decrease to preinduction levels during sternotomy. Myocardial glucose, free fatty acids, lactate and pyruvate uptake were significantly reduced after induction and increased to preinduction levels during sternotomy. Myocardial lactate production could not be demonstrated at any time during the observation period.

The use of buprenorphine-diazepam-N2O (60%)-O2 anesthesia in open heart surgery was investigated. The authors examined the hemodynamic changes produced and the response of stress hormones. Twenty adult patients with atrial septal defects undergoing surgical correction were studied in two groups of 10, receiving either 6 micrograms/kg of buprenorphine (B6) or 12 micrograms/kg of buprenorphine (B12) for the induction of anesthesia. Both groups received a subsequent dose of 6 micrograms/kg of buprenorphine with the commencement of extracorporeal circulation (ECC). With surgery, mean arterial pressure showed a transient increase in both groups and thereafter was stable. Heart rate in the B6 group was increased from the onset of surgery to the day after, while the B12 group showed no significant change. Filling pressures showed no change in either group. Plasma catecholamine concentrations in the B6 group, in contrast to the B12 group, increased significantly from midoperation to after completion of the operation (ECC 10 minutes, B6 group v B12 group: plasma norepinephrine 616 +/- 231 v 195 +/- 38 pg/mL, plasma epinephrine 1385 +/- 392 v 572 +/- 132 pg/mL, P less than 0.05). Plasma ADH levels in both groups rose with the commencement of surgery, reaching a peak at ECC 10 minutes (B6 group 88.1 +/- 8.4 v B12 group 124.4 +/- 27.2 pg/mL). However, in contrast to plasma catecholamines, the antidiuretic hormone (ADH) levels in the B12 group remained higher until the first postoperative day. Therefore, patients who received the larger dose of buprenorphine had better control of hemodynamics and catecholamines, but a greater elevation of plasma ADH levels.

The effect of substituting 66% nitrous oxide for nitrogen on global and regional myocardial function before and after critical constriction of the left anterior descending coronary artery (LAD) was studied in six open-chested dogs anesthetized with 1% halothane (inspired). Regional myocardial function was measured in the region of the LAD and in the region of the left circumflex artery using sonomicrometry, and LAD blood flow was measured. Administration of nitrous oxide produced moderate depression of global performance. Regional shortening in both myocardial segments was reduced, and dysfunction also appeared in the LAD segment. This dysfunction was observed in the presence of both normal coronary blood flow, and after critical constriction. The appearance of dysfunction when coronary blood flow was unimpaired suggests that ischemia may not be the only cause of regional myocardial dysfunction.

The effects of isoflurane on myocardial oxygen uptake, metabolism and coronary blood flow (argon washin-technique) were studied in 10 patients undergoing three-vessel coronary artery bypass surgery. All patients were men with stable angina and normal left ventricular function and were receiving maintenance doses of beta-receptor antagonists or calcium channel blocking drugs. Anaesthesia consisted of isoflurane and 50% nitrous oxide in oxygen. Measurements were performed and blood samples were taken with the patients awake, 20 min after induction of anaesthesia without surgical stimulation, and during sternotomy and sternal spread. End-tidal isoflurane concentrations averaged 0.4% after induction of anaesthesia and 1.5% during sternotomy. Isoflurane significantly decreased myocardial blood flow by 18% following induction of anaesthesia, while sternotomy increased myocardial blood flow to pre-induction levels. Induction decreased myocardial oxygen uptake by 32%, while sternotomy increased oxygen uptake by 21% vs post-induction values. Myocardial uptake of glucose, lactate, free fatty acids and pyruvate significantly decreased after induction and increased to pre-induction levels during sternotomy. Myocardial lactate production, indicating myocardial ischaemia, was observed in 1 patient after induction and in three patients during sternotomy; three additional patients demonstrated a marked reduction in myocardial lactate uptake after induction and during sternotomy. It is concluded that all changes in myocardial metabolism, oxygen uptake and coronary blood flow were the result of a decrease in haemodynamic load on the myocardium and reduced contractility, while the increase in these parameters during sternotomy was due to an increase in myocardial work.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulsatile perfusion during cardiopulmonary bypass (CPB) has been reported to have a number of beneficial effects, including attenuation of hormonal stress responses and improved organ blood flow and function. To determine the effect of pulsatile perfusion on temperature gradients and the time required for cooling and rewarming during CPB, we studied 21 patients scheduled for elective coronary artery operations. The patients were divided into two comparable groups: Group 1 (N = 11) had standard nonpulsatile perfusion, while in Group 2 (N = 10), a pulsatile pump was used. Rectal and esophageal temperatures were monitored, as were deltoid muscle temperatures and upper arm and finger skin temperatures in the same extremity. Ambient temperature, bypass flow and pressure, and bypass time were similar in both groups. Time required to cool to the lowest esophageal temperature was virtually identical for both groups (Group 1, 17 +/- 3 min; Group 2, 17.6 +/- 5 min), as was rewarming time (Group 1, 26.8 +/- 11 min; Group 2, 27.2 +/- 6 min). There were no significant differences in temperature measurements between groups except briefly during rewarming when finger skin temperature rose more rapidly in Group 1 (p less than 0.05). Temperature changes following CPB were the same for both groups, with rectal and esophageal temperatures showing an inverse relationships. These data demonstrate that pulsatile flow does not substantially alter rewarming time or temperature gradients during hypothermic CPB.

Patients undergoing mitral valve replacement, particularly those with severe pulmonary hypertension and/or congestive heart failure, may develop life-threatening right heart failure in the immediate postbypass period. We have observed that such patients have intense pulmonary vasoconstriction. The markedly increased pulmonary impedance may aggravate the right heart failure and prevent recovery of right ventricular function in this setting. Therefore, we studied the effects of high-dose prostaglandin E1 (30 to 150 ng/kg/min), a potent pulmonary vasodilator, in combination with massive infusion of norepinephrine (up to 1 microgram/kg/min) into the left atrium in five consecutive patients with refractory right heart failure and pulmonary hypertension after mitral valve replacement. This pharmacologic approach takes advantage of the pulmonary vasodilating effects of prostaglandin E1, while offsetting associated systemic vasodilation and resulting hypotension. All five patients had rapid pulmonary vasodilator responses followed by marked improvement in right ventricular function. All survived the operation and none had right ventricular infarction or chronic right heart failure postoperatively.

Narcotics and potent inhalation anesthetics have different effects on thermoregulation and the distribution of body heat. This study was designed to compare the effect of halothane vs fentanyl anesthesia on temperature gradients developed during and after hypothermic cardiopulmonary bypass. Twenty-two adult patients undergoing coronary artery surgery were given either fentanyl (100 micrograms/kg) or halothane (0.5-1.5%) and oxygen. Thermistor probes were inserted in rectum, esophagus, and deltoid muscle. Surface temperatures were measured on the ring finger and upper arm. All patients were cooled during cardiopulmonary bypass to 28 degrees C, and ambient temperature was maintained at 22-23 degrees C. The times to cool and rewarm were comparable in both groups. Rectal, esophageal, and skin temperatures had not reached equilibrium by 60 min after bypass, but changes in temperature were virtually identical at all sites in both groups. Regardless of differences in the effects of halothane and fentanyl on hormonal responses, blood flow, or central thermoregulation, their net effects on body temperature were the same.

Several experimental and clinical studies have suggested that histamine is released following the administration of neuromuscular blocking agents, and that the histamine release is an important aspect in the hemodynamic response to the drug. We have measured plasma histamine following the administration of a series of neuromuscular blocking agents in man. Our data suggests that members of this class of drugs can cause a dose dependent release histamine release in man and that this release is hemodynamically significant. We have also evaluated the roles of rate of administration, of pretreatment with H1 and H2 antagonists and alterations in drug design as clinical strategies in attenuating the adverse reactions. The data obtained in humans can be shown to validate the cat model as a means of screening novel neuromuscular blocking agents.

Antidiuretic hormone (ADH), growth hormone (GH), and cardiovascular responses to large (anesthetic) doses of alfentanil (1.2 +/- 0.02 mg/kg) and oxygen and sufentanil (13.1 +/- 0.4 microgram/kg) and oxygen were measured before and during surgery (including cardiopulmonary bypass) and at the end of surgery in 29 patients undergoing coronary artery bypass surgery. The data demonstrate that alfentanil-O2 and sufentanil-O2 result in little change in cardiovascular dynamics throughout anesthesia and surgery, and also prevent changes in plasma levels of ADH and GH at all times during the study. Our findings contrast with previous studies with other anesthetics, including fentanyl, in which plasma levels of ADH and GH become markedly elevated during bypass. The results suggest that alfentanil and sufentanil may block hormonal stress responses to surgical stimulus better than fentanyl does. The clinical significance of the difference in ADH and GH responses during fentanyl and during alfentanil or sulfentanil anesthesia remains to be determined. However, this difference may provide part of the explanation why alfentanil and sufentanil-O2 anesthesia require less frequent employment of other anesthetic adjuvants and are easier to use than fentanyl during coronary artery surgery.