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Background : Recent data suggest that beta blockers are associated with increased perioperative risk in hypertensive patients. We investigated whether beta blockers were associated with an increased risk in elderly patients with raised preoperative arterial blood pressure. Methods We conducted a propensity-score-matched cohort study of primary care data from the UK Clinical Practice Research Datalink (2004–13), including 84 633 patients aged 65 yr or over. Conditional logistic regression models, including factors that were significantly associated with the outcome, were constructed for 30-day mortality after elective noncardiac surgery. The effects of beta blockers (primary outcome), renin–angiotensin system (RAS) inhibitors, calcium-channel blockers, thiazides, loop diuretics, and statins were investigated at systolic and diastolic arterial pressure thresholds. Results Beta blockers were associated with increased odds of postoperative 30-day mortality in patients with systolic hypertension (defined as systolic BP >140 mm Hg; adjusted odds ratio [aOR]: 1.92; 95% confidence interval [CI]: 1.05–3.51). After excluding patients for whom prior data suggest benefit from perioperative beta blockade (patients with prior myocardial infarction or heart failure), rather than adjusting for them, the point estimate shifted slightly (aOR: 2.06; 95% CI: 1.09–3.89). Compared with no use, statins (aOR: 0.35; 95% CI: 0.17–0.75) and thiazides (aOR: 0.28; 95% CI: 0.10–0.78) were associated with lower mortality in patients with systolic hypertension. Conclusions These data suggest that the safety of perioperative beta blockers may be influenced by preoperative blood pressure thresholds. A randomised controlled trial of beta-blocker withdrawal, in select populations, is required to identify a causal relationship.

Malcolm Keith Sykes was one of the most prominent British anaesthetists of the second half of the 20th century. His career extended from 1950 to 1991, a period of major advances in anaesthesia and critical care, to which he made considerable contributions. Born in Somerset in 1925, Keith Sykes went to Cambridge University to read natural science tripos before studying clinical medicine at University College Hospital (UCH). He began his professional training as house physician at UCH and house surgeon at Norfolk and Norwich. He then undertook national service in Germany, where in addition to his duties as regimental medical officer he also learnt to administer anaesthetics. Later, at a British military hospital in Hamburg he was the sole anaesthetist. On returning to the UK he sat the Diploma of Anaesthesia, starting his formal training in anaesthetics at UCH. During his training he was awarded a Rickman Godlee travelling scholarship, which allowed him to visit centres in the USA for a year, mostly in Boston at the Massachusetts General Hospital under Professor Henry Beecher, to gain experience in research. This confirmed his wishes to pursue an academic career in anaesthesia. He also visited many …

Methods. A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to b-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes. Results. Neuraxial block was associated with an increased risk of the primary outcome [287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02 –1.49; P¼0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07–1.64; P¼0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44 –1.33; P¼0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65 –1.17; P¼0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99 –1.30; P¼0.08]. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone [86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00 –4.35; P,0.001].

We read the editorial on ‘Preoperative blood pressure measurement: what should GPs be doing?’ with great interest.1 In support of the lack of evidence that reducing blood pressure helps, the authors quote the POISE study,2 stating that beta-blockers were used to reduce blood pressure preoperatively and the data suggested that it did more …

Once considered to confer cardiac protection, perioperative beta-blockade is now regarded as potentially harmful as reduction of cardiac complications is associated with increased all-cause mortality and increased risk of strokes. Over the past decades relatively small studies were not powered enough to detect relatively rare complications, thus all-cause mortality and increased risk of stroke never reached statistical significance, and were discounted. It needed a large randomised controlled trial (RCT) POISE with more than 8,000 patients for these clinically important complications to reach statistical significance. POISE did not address the issue of acute goal-directed administration of beta-blockers when clinically indicated for the management of cardiovascular instability, such as tachycardia, hypertension, myocardial ischaemia, thus practice needs not change. However, initiating beta-blockade for cardiac protection needs to consider the balance of risk and benefits for each individual patient. With considerable caution in respect of beta-blockers, other pharmacological agents need to be considered. While showing promise in previous relatively small studies, clonidine and aspirin have been found in POISE 2, a RCT with over 10,000 patients, to offer no cardiac protection. Clonidine caused hypotension and aspirin increased bleeding. There is limited data and evidence for cardiac protection in respect of calcium channel blockers, ACE inhibitors, angiotensin receptor antagonists and nitroglycerin. However, observational studies and limited RCTs, mostly in cardiac surgery, suggest that statins offer perioperative protection and should be initiated in patients who need them for medical reasons.

Background There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2-5.2), but there was substantial heterogeneity (I(2) = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1-10.9, I(2) = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4-2.3, I(2) = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5-4.0, I(2) = 4%). Conclusions An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

The main antiplatelet agents used in cardiology are salicylates, thienopyridines (e.g. clopidogrel), and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors (such as tirofiban, abciximab, and eptifibatide). Patients with stable angina or known ischaemic heart disease are usually prescribed lifelong low-dose aspirin. For those with a recent acute coronary syndrome or percutaneous coronary intervention (PCI), additional cover with clopidogrel is indicated for a finite period of usually 3–12 months. GPIIb/IIIa inhibitors have even greater antiplatelet activity, as these glycoproteins on the platelet surface represent the final common pathway in platelet activation, leading to platelet aggregation and subsequent thrombus formation (Fig. 1). Both aspirin and clopidogrel inhibit platelet function irreversibly. Aspirin non-selectively acetylates the enzyme cyclooxygenase, permanently inhibiting the ability of the platelet to synthesize the pro-thrombotic eicosanoid thromboxane A2. Endothelial cells instead synthesize the anti-thrombotic prostaglandin PGI2, favouring a balance towards reduced platelet activation. Clopidogrel inhibits the P2Y12 subtype of the ADP receptor, preventing ADPmediated platelet activation. It is a prodrug that must first be metabolized to its active form by the hepatic cytochrome P450 isoenzyme CYP3A4. The lifespan of a platelet is around 10 days; hence, restoration of normal platelet function in patients taking aspirin or clopidogrel takes 5–10 days. GPIIb/IIIa inhibitors are licensed for use in patients with unstable angina or non-ST elevation myocardial infarction (MI) and as an adjunct to PCI. In contrast to salicylates and thienopyridines, they offer reversible platelet inhibition in a doseand concentration-dependent manner. Tirofiban and eptifibatide are the shortest acting of these agents, with half-lives of around 2–5 h. Both are cleared by the kidney largely unchanged, with normal platelet function usually returning within 6–8 h of stopping an infusion.

The number of percutaneous coronary interventions (PCI) performed annually has increased rapidly over the last two decades. Coronary angioplasties are now commonly complemented with the insertion of coronary artery stents. Initially bare metal stents (BMS) were developed with drug-eluting stents (DES) subsequently being introduced. Drug-eluting stents reduce in-stent restenosis at the cost of prolonged anti-platelet therapy. While observational studies suggest that coronary artery bypass graft surgery protects against perioperative cardiac events in non-cardiac surgery, no such evidence exists for PCI. In order to prevent stent thrombosis, patients need to receive dual anti-platelet therapy (generally aspirin and clopidogrel) for four to six weeks with BMS, and at least one year with DES. Patients on dual anti-platelet therapy are at risk of severe bleeding during surgery. However, withdrawal of dual anti-platelet therapy is associated with the risk of stent thrombosis. The risk of cardiac complications seems to exceed the risk of bleeding, and maintenance of dual anti-platelet therapy is advocated whenever possible. Surgery in closed cavities (neurosurgery, intraocular surgery) necessitates the withdrawal of dual anti-platelet therapy. There is a significant risk of perioperative complications in patients who have DES, or recently inserted BMS, and consequently surgery should not be performed without a discussion involving the surgeon, cardiologist, anaesthetist, and the patient.

Objective:Recent growing evidence suggests that beta-blocker treatment could improve cardiovascular dynamics and possibly the outcome of patients admitted to intensive care with severe sepsis or septic shock.Design:Systematic review.Data sources:MEDLINE and EMBASE healthcare databases.Review methods:To investigate this topic, we conducted a systematic review of the above databases up to 31 May 2015. Due to the clinical novelty of the subject, we also included non-randomized clinical studies. We focused on the impact of beta-blocker treatment on mortality, also investigating its effects on cardiovascular, immune and metabolic function. Evidence from experimental studies was reviewed as well.Results:From the initial search we selected 10 relevant clinical studies. Five prospective studies (two randomized) assessed the hemodynamic effects of the beta1-blocker esmolol. Heart rate decreased significantly in all, but the impact on other parameters differed. The imbalance between prospective studies’ size (10 to 144 patients) and the differences in their design disfavor a meta-analysis. One retrospective study showed improved hemodynamics combining metoprolol and milrinone in septic patients, and another retrospective study found no association between beta-blocker administration and mortality. We also found three case series. Twenty-one experimental studies evaluated the hemodynamic, immune and/or metabolic effects of selective and/or non-selective beta-blockers in animal models of sepsis (dogs, mice, pigs, rats, sheep), yielding conflicting results.Conclusions:Whilst there is not enough prospective data to conduct a meta-analysis, the available clinical data are promising. We discuss the ability of beta blockade to modulate sepsis-induced alterations at cardiovascular, metabolic, immunologic and coagulation levels.

To assess the incidence of major cardiac events in critically ill patients with a high risk of cardiac complications presenting with an elevated heart rate.Observational, retrospective study in a 15-bed medical/surgical Intensive Care Unit (ICU) at a university hospital for a period of 12 months.We studied patients with a high risk of cardiac complications, according to the revised Goldman index, who were treated for at least 36 hrs in the ICU. Patients presenting with prolonged elevated heart rate, defined as a heart rate95 beats/min for12 hrs in at least one 24-hr period of their ICU stay, were investigated. Cardiac high-risk patients not developing this criterion served as controls. Major cardiac events, defined as nonfatal myocardial infarction, nonfatal cardiac arrest, and cardiac related death, were the primary outcome measures.From a total of 791 patients, 69 patients were assessed as cardiac high-risk patients. Of 39 patients with prolonged elevated heart rates, 19 (49%) sustained major cardiac events, whereas in the control group of 30 patients, only four patients (13%) had a major cardiac event (p = .002; odds ratio, 6.2). Patients with elevated heart rate had to be treated 4.5 days longer in the ICU (p = .01), whereas the ICU and 30-day post-ICU discharge survival rates did not differ significantly.In this study, we provide evidence for an increased incidence of major cardiac events in critically ill, cardiac high-risk patients with a prolonged elevated heart rate during their ICU stay. In addition, elevated heart rate was associated with a significantly longer ICU stay.

The aim of this review of the literature was to evaluate the effectiveness of anesthetics in protecting the heart against myocardial ischemia-reperfusion injury.Articles were obtained from the Medline database (1980-, search terms included heart, myocardium, coronary, ischemia, reperfusion injury, infarction, stunning, halothane, enflurane, desflurane, isoflurane, sevoflurane, opioid, morphine, fentanyl, alfentanil sufentanil, pentazocine, buprenorphine, barbiturate, thiopental, ketamine, propofol, preconditioning, neutrophil adhesion, free radical, antioxidant and calcium).Protection by volatile anesthetics, morphine and propofol is relatively well investigated. It is generally agreed that these agents reduce the myocardial damage caused by ischemia and reperfusion. Other anesthetics which are often used in clinical practice, such as fentanyl, ketamine, barbiturates and benzodiazepines have been much less studied, and their potential as cardioprotectors is currently unknown. There are some proposed mechanisms for protection by anesthetic agents: ischemic preconditioning-like effect, interference in the neutrophil/platelet-endothelium interaction, blockade of Ca2+ overload to the cytosolic space and antioxidant-like effect. Different anesthetics appear to have different mechanisms by which protection is exerted. Clinical applicability of anesthetic agent-induced protection has yet to be explored.There is increasing evidence of anesthetic agent-induced protection. At present, isoflurane, sevoflurane and morphine appear to be most promising as preconditioning-inducing agents. After the onset of ischemia, propofol could be selected to reduce ischemia-reperfusion injury. Future clinical application depends on the full elucidation of the underlying mechanisms and on clinical outcome trials.

Myocardial dysfunction may contribute to the haemodynamic instability which accompanies sepsis, and may result in circulatory failure. There is no association between systolic dysfunction (SD) and mortality in septic patients and there is conflicting evidence regarding the effects of diastolic dysfunction (DD) on mortality in septic patients.We conducted a systematic review and meta-analysis to investigate DD and mortality in septic patients. We included studies conducted in this patient population which investigated the association between DD reported according to tissue Doppler imaging (TDI) criteria and mortality, using the longest reported follow-up. As a secondary endpoint, we evaluated the association between SD and mortality according to the results reported by the retrieved studies.We included seven studies in our meta-analysis with 636 septic patients, 48% of them were found to have DD. We found a significant association between DD and mortality (RR 1.82, 95% CI 1.12-2.97, p = 0.02). This finding remained valid in a further analysis which including an older study reporting DD without TDI criteria. Five studies reported data on SD for a total of 581 patients, 29.6% of them with SD. No association was found between SD and mortality (RR 0.93, 95% CI 0.62-1.39, p = 0.73). Looking at subgroups, there was a trend towards higher mortality comparing isolated DD or combined SD-DD vs normal heart function (p = 0.10 and p = 0.05, respectively).Diastolic dysfunction is common in septic patients and it is associated with mortality. Systolic dysfunction is less common and is not associated with mortality in this group of patients.

Background Both mitochondrial adenosine triphosphate-sensitive potassium (MKATP) channels (selectively blocked by 5-hydroxydecanoate) and stretch-activated channels (blocked by gadolinium) have been involved in the mechanism of ischemic preconditioning. Isoflurane can reproduce the protection afforded by ischemic preconditioning. We sought to determine whether isoflurane-induced preconditioning may involve MKATP and stretch-activated channels. Methods Anesthetized open-chest rabbits underwent 30 min of coronary occlusion followed by 3 h of reperfusion. Before this, rabbits were randomized into one of six groups and underwent a treatment period consisting of either no intervention for 40 min (control group; n = 9) or 15 min of isoflurane inhalation (1.1% end tidal) followed by a 15-min washout period (isoflurane group; n = 9). The two groups received an intravenous bolus dose of either 5-hydroxydecanoate (5 mg/kg) or gadolinium (40 micromol/kg) before coronary occlusion and reperfusion (5-hydroxydecanoate, n = 9; gadolinium, n = 7). Two additional groups received 5-hydroxydecanoate or gadolinium before isoflurane exposure (isoflurane-5-hydroxydecanoate, n = 10; isoflurane-gadolinium, n = 8). Area at risk and infarct size were assessed by blue dye injection and tetrazolium chloride staining. Results Area at risk was comparable among the six groups (29 +/- 7, 30 +/- 5, 27 +/- 6, 35 +/- 7, 31 +/- 7, and 27 +/- 4% of the left ventricle in the control, isoflurane, isoflurane-5-hydroxydecanoate, 5-hydroxydecanoate, isoflurane-gadolinium, and gadolinium groups, respectively). Infarct size averaged 60 +/- 20% (SD) in untreated controls versus 54 +/- 27 and 65 +/- 15% of the risk zone in 5-hydroxydecanoate- and gadolinium-treated controls (P = nonsignificant). In contrast, infarct size in the isoflurane group was significantly reduced to 26 +/- 11% of the risk zone (P < 0.05 vs.control). Both 5-hydroxydecanoate and gadolinium prevented this attenuation: infarct size averaged 68 +/- 23 and 56 +/- 21% of risk zone in the isoflurane-5-hydroxydecanoate and isoflurane-gadolinium groups, respectively (P = nonsignificant vs.control). Conclusion 5-Hydroxydecanoate and gadolinium inhibited pharmacologic preconditioning by isoflurane. This result suggests that MKATP channels and mechanogated channels are probably involved in this protective mechanism.

Cardiovascular complications of anaesthesia and surgery remain frequent and have short- and long-term consequences. Identification of high-risk patients is an essential step in the management of patients with cardiovascular disease who are not always fully investigated before admission for non-cardiac surgery. Clinical risk indices allow the risk of complications to be evaluated. However, many indices are inadequate in vascular surgical patients, and there is a need for objective testing of cardiac function and coronary reserve, as poor left ventricular function and reversible ischaemia during stress test are predictors of increased cardiac risk. These tests allow the patient's condition to be optimized. This may include coronary bypass surgery. Recently, biological markers of left ventricular dysfunction and of myocardial damage have been introduced. Brain natriuretic peptide concentration is inversely correlated with the ejection fraction, while troponins I and T are very valuable markers of myocardial damage.

Myocardial ischaemia occurs frequently during the peri-operative period and is associated with major cardiac events in patients with silent or overt coronary artery disease. Often caused by an imbalance between excessive oxygen demand and limited oxygen supply, ischaemia may also occur as a result of endothelial dysfunction in diseased coronary arteries. Myocardial ischaemia impairs systolic and diastolic ventricular function and facilitates the development of arrhythmias. The effects of myocardial ischaemia may persist after reperfusion (myocardial stunning). When ischaemia is chronic, down-regulation of ventricular function (myocardial hibernation) allows the heart to recover after reperfusion. Peri-operatively myocardial ischaemia is most frequently silent and is caused by haemodynamic aberrations, coagulation disorders and/or hypoxaemia. Prevention of peri-operative silent ischaemia is necessary in order to reduce the risk of adverse cardiac events.

Arterial hypertension is common. It is well established that such hypertension is associated with cardiovascular complications, and that the risk of these complications can be reduced by anti-hypertensive treatment. The pathophysiology of hypertension is complex and not fully elucidated. Many physiological systems influence blood pressure, and the responses of some of these are reset. Changes have been observed both in well-known mechanisms, such as the baroreflex control of blood pressure, and in more recently described systems, such as the production of nitric oxide by the endothelium. Physical changes known as remodelling occur in the intimal and medial layers of blood vessel walls. Target organ damage may be seen in many organs, most notably the heart, the kidneys and the cerebral circulation. It is the experience of most anaesthetists that hypertensives display cardiovascular lability and that this is less marked if the blood pressure is controlled by treatment. There is also considerable evidence for an association between hypertension and major perioperative cardiovascular complications. Patients with hypertension should be carefully assessed prior to anaesthesia. An estimate of the severity of the hypertension should be based, if possible, on several blood pressure readings. Target organ damage should be sought. It is widely accepted that, where possible, surgery should be deferred in patients with poorly controlled or uncontrolled hypertension, and treatment given to lower the blood pressure. There is no evidence to support any particular level of blood pressure as a cut-off for treatment. We suggest that, in patients with a systolic pressure greater than 210 mmHg, a diastolic pressure greater than 115 mmHg, or target organ damage and a diastolic pressure greater than 100 mmHg, anaesthesia and surgery should be deferred if possible. In all patients on anti-hypertensive medication, this should be continued throughout the peri-operative period.

Objectives: The effects of changes in preload on paradoxical myocardial wall motion during ischemia have been previously studied. However, the studies have been performed using slow volume changes. It was decided to study the effects of fast changes in preload, which would occur during caval occlusion, on the regional pressure-length loops during ischemia. Design: Retrospective trial. Setting: Experimental animal laboratory in a university medical center. Participants: Ten anesthetized adult dogs. Interventions: In an open chest preparation, regional ischemia was achieved by occluding the left anterior descending coronary artery for 10 minutes, with sudden caval occlusions being performed to assess the influence of preload on wall motion. Measurements and Main Results: Left ventricular pressure and regional segmental lengths were measured. During caval occlusion, beat by beat, percent postsystolic shortening and percent systolic bulging in the ischemic region, percent isovolumetric shortening in the nonischemic region, and percent systolic shortening in both regions were calculated. Caval occlusion significantly decreased the end-diastolic pressure (12.62 ± 1.02 to 3.39 ± 0.59 mmHg) and length. In the ischemic area, although systolic shortening became more negative (−1.8 ± 0.79% to −9.65 ± 1.08%), postsystolic shortening (9.66 ± 0.73% to 15.53 ± 1.2%) and systolic bulging (4.6 ± 0.49% to 12.67 ± 1.04%) increased. In the nonischemic area, systolic shortening decreased slightly but significantly (18.01 ± 3.24% to 14.93 ± 3.64%) as isovolumetric shortening increased (2.77 ± 0.68 to 7.37 ± 1.29%). Caval occlusion increased the rightward shift and accentuated the distortion of the ischemic loop. The nonischemic loop displayed a leftward shift of the systolic isovolumetric component and a slight decrease in percent total length change. Conclusion: Caval occlusion modifies the shape of the pressure-length loop of the ischemic myocardium. This change in shape may interfere with the assessment of regional systolic indexes obtained by caval occlusion in ischemic hearts.

Objectives. This study sought to explore the separate and combined effects of changes in preload, afterload and contractility on the dynamics of systolic bulging. Background. The extent of ischemic systolic bulging has been shown to be mechanically disadvantageous to left ventricular pump performance. The factors that determine ischemic segmental wall motion have not been systematically studied. Methods. Fourteen beagles were instrumented with sonomicrometers, micromanometer pressure gauges and a balloon in the inferior vena cava. Regional function was evaluated before and after 90 s of proximal left circumflex coronary artery occlusion. Occlusions were repeated after increasing systolic pressure by 5 to 10 (afterload I) and 15 to 20 mm Hg (afterload II) with graded aortic occlusion during inotropic stimulation with dobutamine (2.5 and 5 μg/kg body weight per min intravenously), with simultaneous 5-μg/kg per min dobutamine infusion and afterload II and during 2.5% halothane (negative inotrope) concentration. A 20-min recovery period was allowed between each stage of the experiment so that regional function returned to its preocclusion level. Ischemic wall motion was characterized by percent systolic bulging and its peak positive systolic lengthening rate (+dL/dt). Results. Because bulging is markedly influenced by regional preload, systolic bulging was characterized over a wide range of end-diastolic lengths of the ischemic segment during caval balloon occlusion. During each intervention, a decrease in regional preload increased the extent of percent systolic bulging. This preload dependency was more pronounced with dobutamine infusions. An increase in afterload was not associated with increased percent systolic bulging at any given preload. At a predetermined preload, bulging was not appreciably altered when an increase in left ventricular systolic pressure was not associated with a change in peak positive first derivative of left ventricular pressure (+dP/dt) but was significantly worse when peak +dP/dt increased. Dobutamine caused a dose-dependent increase in percent systolic bulging and peak +dL/dt that was positively correlated with peak +dP/dt. Conclusions. By using different loading and inotropic interventions and analyzing the regional wall motion behavior over a range of regional preloads, we can conclude that preload and rate of pressure (tension) development are the principal determinants of systolic bulging. Increases in left ventricular pressure alone had a minimal effect on systolic bulging. (J Am Coll Cardiol 1997;29:846–55)

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.

In this post hoc subanalysis of the Perioperative Ischemic Evaluation (POISE) trial, we sought to determine whether nitrous oxide was associated with the primary composite outcome of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal cardiac arrest within 30 days of randomization. The POISE trial of perioperative β-blockade was undertaken in 8351 patients. Nitrous oxide anesthesia was defined as the coadministration of nitrous oxide in patients receiving general anesthesia, with or without additional neuraxial blockade or peripheral nerve blockade. Logistic regression, with inverse probability weighting using estimated propensity scores, was used to determine the association of nitrous oxide with the primary outcome, MI, stroke, death, and clinically significant hypotension. Nitrous oxide was administered to 1489 (29%) of the 5133 patients included in this analysis. Nitrous oxide had no significant effect on the risk of the primary outcome (112 [7.5%] vs 248 [6.9%]; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.82-1.44; 99% CI, 0.75-1.57; P = 0.58), MI (89 [6.0] vs 204 [5.6]; OR, 0.99; 95% CI, 0.75-1.31; 99% CI, 0.69-1.42; P = 0.94), stroke (6 [0.4%] vs 28 [0.8%]; OR, 0.85; 95% CI, 0.26-2.82; 99% CI, 0.17-4.11; P = 0.79), death (40 [2.7%] vs 100 [2.8%]; OR, 1.04; 95% CI, 0.6-1.81; 99% CI, 0.51-2.15; P = 0.88) or clinically significant hypotension (219 [14.7%] vs 544 [15.0%]; OR, 0.92; 95% CI, 0.74-1.15; 99% CI, 0.70-1.23; P = 0.48). In this post hoc subanalysis, nitrous oxide was not associated with an increased risk of adverse outcomes in the POISE trial patients. This analysis was limited by the observational nature of the data and the lack of information on the concentration and duration of nitrous oxide administration. Further randomized controlled trial evidence is required.

We performed a retrospective case-control study to investigate hypertension and admission blood pressure as risk factors for postoperative cardiovascular death. We identified records of 76 patients who had died of a cardiovascular cause within 30 days of anaesthesia and elective surgery and 76 matched controls. From the records of each patient (case and control) we recorded the admission blood pressure and details of any history of hypertension. A pre-operative history of hypertension was strongly associated with perioperative cardiovascular death (p < 0.001 with one degree of freedom: odds ratio 4.14, 95% confidence intervals 1.63-11.69). There was no association between systolic or diastolic pressure at admission for operation and perioperative cardiovascular death. The mean admission systolic pressure of the cases was 145.5 mmHg (range 90-250 mmHg) and that of the controls was 146.5 mmHg (range 100-200 mmHg). The mean admission diastolic pressure of the cases was 83.2 mmHg (range 60-130 mmHg), and that of the controls was 84.5 mmHg (range 60-110 mmHg).

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, P0.01) and non-ischaemic (-8.6 (3.4) mm s-1, P0.05) 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.

Patients with coronary artery disease are particularly at risk perioperatively, as myocardial infarction, unstable angina, severe arrhythmia and cardiac death may occur. These events are often preceded by prolonged silent myocardial ischaemia (MI). Moreover, perioperative MI predicts long-term adverse cardiac outcome. Therefore, it is logical to prevent and treat MI. However, the detection of perioperative MI is difficult because of low sensitivity of ST-segment monitoring, low specificity of echocardiography and insufficient availability of equipment for its monitoring. A pragmatic approach is described, including preoperative consideration of myocardial revascularization prior to non-cardiac surgery and perioperative administration of antianginal agents; the effects of clonidine are discussed as well. The role of anaesthetic techniques and normovolaemic haemodilution is considered. MI episodes may be prevented or their duration may be shortened by treating tachycardia, hypotension and, possibly, hypertension. The risks of MI are particularly high during the postoperative period because increased global oxygen consumption associated with recovery, ventilator weaning, shivering and pain may lead to tachycardia and increased ventricular load. These factors must be taken into account in order to prevent MI and improve postoperative cardiac outcome.

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.

We studied 325 patients undergoing elective noncardiac surgery who had preoperative ambulatory ECG monitoring performed for a duration of 5130 h (range 8-24 h; mean 15.8 h). Sixty-four subjects (20%) had one or more episodes of ST segment depression consistent with myocardial ischaemia. Of all preoperative cardiovascular variables measured, the presence of elevated arterial pressure, despite patients being maintained on long term antihypertensive therapy, was the only factor associated significantly with the presence of preoperative silent myocardial ischaemia (P0.002). This correlation was confirmed when arterial hypertension was defined in four separate ways. The incidence of silent ischaemia in these patients was 33-55%. We suggest that admission arterial pressure may therefore be a useful screening test to identify patients at risk of preoperative myocardial ischaemia.

Although end-systolic pressure length and thickness relationships (ESPLR, ESPTR) are now widely used as substitutes for the end-systolic pressure volume relationships, there are some reservations about their use as an index of left ventricular (LV) performance. This study addressed three issues, namely: (1) which loading technique (decreasing preload by inferior vena cava (IVC) balloon occlusion or increasing systolic pressure by aortic constriction) is the most likely to yield usable data; (2) reproducibility of these relationships over a 30 min period; and (3) whether by using end-ejection (zero aortic flow) as a definition of end-systole, ESPLR and ESPTR can be used to characterize myocardial performance independent of load. Thirteen anesthetized beagles, weighing 16–25 kg, were used for this study, and were instrumented with sonomicrometers. We found that when ESPLR and ESPTR were constructed from data derived during aortic constriction, the slopes of these relationships were steeper and more curvilinear than when they were constructed from data recorded during IVC occlusion. In addition, the mean difference between ESPLR, ESPTR obtained 30 min apart was small, although there was a fair degree of variability between the first and second measurements. Using end-ejection to define end-systole, both ESPLR and ESPTR were relatively insensitive to loading conditions (LV end-diastolic pressure of 8–12 mmHg and 14–18 mmHg, aortic systolic pressure of 7–10 mmHg and 20–25 mmHg above baseline (in terms of the slope and shift (leftward or rightward) in these relationships, but were sensitive to inotropic interventions (dobutamine 2.5 μg/kg per min and 5 μg/kg per min). We conclude that, ESPLR and ESPTR, defined from measurements at end-ejection, can be used as adequate descriptors of regional myocardial performance if they were constructed from data over a similar pressure range during IVC balloon occlusion.

Although calcium channel blockers may preserve function in ischemic myocardium, they may also produce myocardial depression and dysfunction in the presence of decreased coronary flow. This study was designed to examine the issue of possible protection afforded by diltiazem against ischemia-induced myocardial dysfunction during propofol anesthesia. In eight anesthetized and ventilated dogs, regional myocardial (ultrasonic crystals in both left anterior descending [LAD] and left circumflex [LC] perfusion areas) and global ventricular function were evaluated during progressively severe degrees of myocardial ischemia (LAD constriction) before and after intravenous diltiazem (150 μg/kg). As coronary flow decreased, heart rate increased, and arterial and coronary perfusion pressures, left ventricular dP dt , and cardiac output decreased. Systemic vascular resistance was unaffected. Diltiazem without coronary constriction increased heart rate, and decreased diastolic arterial pressures, left ventricular (LV) end-diastolic, coronary perfusion pressures, LV dP dt max, LAD coronary blood flow, stroke volume, and cardiac output. At all levels of coronary constriction following diltiazem, there were decreases in systolic and diastolic arterial pressures, stroke volume, cardiac output, LV dP dt , and coronary perfusion pressure. Heart rate increased at critical coronary constriction, and then remained constant relative to the prediltiazem state. The regional muscle effects of the reductions in coronary flow in the LAD perfusion territory included decreased systolic shortening and increased postsystolic shortening before and after diltiazem. Diltiazem did not alter the magnitude of the alterations in systolic or postsystolic shortening brought about by coronary constriction. No changes occurred in the LC area. In conclusion, diltiazem depressed global ventricular performance in the presence of propofol anesthesia, but did not worsen or protect regional myocardial function of the compromised LAD segment.

Objectives . This study was designed to investigate the changes in regional distensibility of the ischemic segment and of a remote nonischemic segment brought about by graded myocardial ischemia. Background . Ventricular distensibility is a major determinant of left ventricular end-diastolic pressure. The effects of graded myocardial ischemia on the regional distensibility of the ischemic area have not been studied. Moreover, there are few data on the effects of myocardial ischemia on the regional distensibility of the nonischemic myocardium. Methods . Nine anesthetized open chest mongrel dogs were fitted with instruments to measure left ventricular pressure and circumferential length (sonomicrometry) in the ischemic segment and in a nonischemic segment. The pressure-length relation was modified by stepwise infusion and withdrawal of 200 ml of each dog's own blood over 30 min in five consecutive stages of regional ischemia. Unstressed dimensions were obtained by repeated inferior vena cava occlusions. In both segments, regional distensibility was assessed at end-diastole by means of the constants of the pressure-length (chamber stiffness), the pressure-strain and the force-strain (myocardial stiffness) relations. Results . In the ischemic segment, partial and complete coronary occlusions were associated with a twofold increase in the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant, whereas in the nonischemic segment the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant increased by 50%. Conclusions . Regional myocardial ischemia is associated with a decrease in distensibility of both the ischemic and the remote nonischemic myocardium.

We sought to determine the influence of nitrous oxide on the compromised heart during propofol anesthesia. This study investigated the cardiovascular effects of the combination propofol and nitrous oxide (N2O). Seven beagles were monitored to measure global and regional left ventricular function. Recordings both before and after critical constriction (CC) of the left anterior descending coronary artery (LAD) were performed after propofol, 300 μg·kg−1·min−1, and 10 min after exposure to and discontinuation of 67% N2O. Data were analyzed with ANOVA for repeated measures at 95% confidence level. In the absence of CC, N2O caused moderate, reversible hemodynamic depression (LVdP/dtmax, −13.8%; cardiac output, −17.2%; LAD coronary blood flow, −10.9%) and no regional dysfunction. After CC global hemodynamic depression was of similar magnitude (LVdP/dtmax, −19.9%; cardiac output, −9.2%; stroke volume, −9.2%) but did not recover completely. Systolic shortening in the compromised area decreased (−30.3%) and postsystolic shortening developed to represent 20.3% of total shortening. Despite only moderate hemodynamic depression, 67% N2O causes substantial regional dysfunction in compromised myocardium when added to propofol. (Anesth Analg 1993;76:1322-6)

We have studied the effects of graded infusion rates of propofol (0.2-0.5 mg kg-1 min-1) on left ventricular global and regional function, in eight acutely instrumented dogs. Global function was assessed by measurement of aortic and left ventricular pressure, LV dP/dtmax, aortic blood acceleration and stroke volume. Regional function was assessed by measurement of systolic shortening and the end-systolic pressure-length relationship. The response of the coronary circulation to short periods of occlusion was also assessed. Administration of propofol significantly reduced left ventricular preload, as indicated by reductions in end-diastolic pressure and length; contractility was depressed, the depression being greater in the apex than in the base of the left ventricle. High infusion rates impaired relaxation. Regulation of coronary blood flow was not disrupted. Reductions in preload and contractility contributed to the propofol-induced hypotension. After 60 min, recovery from the greatest infusion rate was incomplete.

This study was designed to determine whether the end-systolic pressure-length relationship (ESPLR) reflects changes in regional contractility during the imposition of graded ischemia, and whether it is modified by diltiazem during propofol anesthesia. Seven beagles were anesthetized and instrumented to measure left ventricular pressure and subendocardial segment lengths (sonomicrometry) in the region of the left anterior descending (LAD) and circumflex (LC) arteries. Afterload was increased by the tightening of a snare around the descending thoracic aorta. Pressure-length loops were constructed and the slope of the ESPLR and the x-axis intercept, Lo, were calculated. Graded ischemia of the apical myocardium only was accomplished by the tightening of a micrometer-controlled snare around the LAD to produce Critical Constriction (CC), Ischemia 1 and 2 (I1, I2), and Total Occlusion (TO). In the basal LC region, LAD ischemia had no effect on either the ESPLR slope or Lo. In contrast, the ESPLR slope in the LAD area was decreased by ischemia at I1 (-40%), increased at TO (+69%), and unchanged at CC and I2, and was reduced by diltiazem at CC and I2 (-31% and -36%, respectively). The LAD ESPLR Lo was increased by ischemia by 64% and 61% at I2, and 91% and 122% at TO, before and after diltiazem, respectively. In the LC region, diltiazem decreased systolic shortening and the ESPLR slope. These results indicate that diltiazem has negative inotropic properties in both ischemic and nonischemic areas. Also, Lo is not a constant and must always be redetermined for every intervention. In the absence of ischemia, the ESPLR may be a reliable measure of myocardial contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The aim was to examine the effect of asynchrony and regional myocardial interaction on the pattern of segmental contraction and relaxation. Methods: Three models of asynchrony were produced. Firstly the left anterior descending artery was abruptly occluded for 60 s. Secondly, the same artery was gradually occluded to produce four degrees of ischaemia based on the severity of the mechanical dysfunction. Finally, asynchrony was created by infusing isoprenaline (0.04 μg·ml−1) into the left circumflex artery. Twelve anaesthetised beagles, weighing 16-21 kg, were used for the study. Results: The patterns of contraction and relaxation were characterised by analysing the phases of shortening and lengthening, the peak lengthening rate (dL/dt), and the timing from the onset of systole to minimum systolic length. A consistent pattern of shortening and lengthening was evident during all three models of asynchrony. There were reciprocal relations between the extent of isovolumetric shortening in the normal segment and in the abnormal segment, and on occasion between the extent of isovolumetric shortening in the normal segment and the extent of isovolumetric lengthening in the same segment. Normal segments that showed minimal shortening or even some lengthening during isovolumetric systole tended to shorten beyond ejection, while segments that shortened significantly during isovolumetric contraction, lengthened earlier. Despite no change in isovolumetric shortening, segments also shortened after ejection when the opposite segment lengthened in late systole and early diastole. Conclusions: The pattern of shortening and lengthening depends on the path of contraction or on its entire loading pattern throughout systole. It is also possible that during early isovolumetric systole a segment can either be unloaded or preloaded by an opposing segment.

Study objective – The aim was to investigate the effects of regional myocardial ischaemia, calcium, and verapamil on (a) the hysteresis and (b) slope and length axis intercept of the left ventricular end systolic pressure-length relationship. Design – Segment length in myocardium supplied by the left anterior descending coronary artery was measured in anaesthetised dogs using sonomic-rometry. Three levels of regional myocardial ischaemia were produced by stenosis and occlusion of the left anterior descending artery (ischaemia 1, ischaemia 2, and occlusion). A snare placed around the descending thoracic aorta was used to obtain temporary aortic occlusions. Subjects – Seven open chested mongrel dogs were used, weight 17 kg (range 16–20). Measurements and main results – After abrupt release of temporary aortic occlusions, end systolic lengths were greater than before the occlusion in the normal myocardium. This hysteresis was abolished by regional myocardial ischaemia. However, hysteresis was insensitive to calcium and verapamil. The length axis intercept of the end systolic pressure-length relationship was increased during ischaemia 2, during coronary occlusion, and after administration of verapamil; its slope was increased after coronary occlusion. Conclusions – (1) Viscoelastic properties of the myocardium make a major contribution to hysteresis of the end systolic pressure-length relationship; and (2) the length axis intercept of this relationship is not constant and its slope does not appear to be a sensitive indicator of regional myocardial contractility during regional ischaemia.

Verapamil was the first calcium-channel blocker (CCB). It has been used since 1962 in Europe then in Japan for its antiarrhythmic and coronary vasodilator effects. The CCB have become prominent cardiovascular drugs during the last 15 years. Many experimental and clinical studies have defined their mechanism of action, the effects of new drugs in this therapeutic class, and their indications and interactions with other drugs. Due to the large number of patients treated with CCB it is important for the anaesthetist to know the general and specific problems involved during the perioperative period, the interactions with anaesthetics and the practical use of these drugs.