Sören Häggmark

Cardiotoxicity of ropivacaine – a new amide local anaesthetic agent

Anaesthetically equipotent doses of lidocaine, bupivacaine and a new bupivacaine–like local anaesthetic agent, ropivacaine, were injected into the left anterior descending coronary artery of pentobarbital–anaesthetized pigs. The aim was to study the cardiotoxicity of ropivacaine in relation to the two other drugs. A random, crossover, dose response study design was used. The following doses of the drugs were administered: lidocaine (L): 1,2,4,8 and 16 mg, bupivacaine (B): 0.25, 0.5, 1,2 and 4 mg and ropivacaine (R): 0.33, 0.66 1.33, 2.66 and 5.33 mg. Systemic haemodynamics, left ventricular dP/dT and a 12–lead electrocardiogram were recorded continuously during the study period. The drugs depressed cardiac contractility in relation to their local anaesthetic potency on the isolated nerve–4:3:l(B:R:L). The prolongation of the ECG QRS–interval was regarded as a measure of electrophysiologic toxicity. Comparable prolongation of the QRS–interval was recorded after 2 mg of bupivacaine, 4.5 mg of ropivacaine and 30 mg of lidocaine. Thus, the electrophysiological toxicity ratio was 15:6.7:1 (B:R:L). Provided local anaesthetic potency data can be extrapolated from the isolated nerve preparation to regional anaesthesia in humans, ropivacaine appears to provide a greater margin of safety than bupivacaine, if inadvertently injected into the venous circulation.

Comparison of Hemodynamic, Electrocardiographic, Mechanical, and Metabolic Indicators of Intraoperative Myocardial Ischemia in Vascular Surgical Patients with Coronary Artery Disease

To compare mechanical, electrocardiographic, and metabolic indices of myocardial ischemia, the cardiokymogram (CKG), the V5 ECG, left anterior descending coronary artery territory lactate extraction, and pulmonary capillary wedge pressure (PCWP) were measured in 53 vascular surgical patients with coronary artery disease. Measurements were performed preoperatively and at four specific intraanesthetic intervals: after tracheal intubation, before surgery, and 10 and 30 min after incision. Measurements and sampling sequence took 5-7 min, and therapy for the probable cause of ischemia was instituted following completion of this sequence. Myocardial ischemia was defined as type II or III CKG, 0.1 mV or greater horizontal or downsloping depression of V5 ECG ST segment, 0.2 mV or greater elevation of V5 ECG ST segment, or myocardial lactate production. Thirty-nine patients (74%) had a total of 89 episodes of myocardial ischemia. Seventy-four episodes (83%) were detected by the CKG, 31 (44%) were evident on the ECG, and 13 (15%) by evidence of lactate production. The concordance among the indices of myocardial ischemia was poor. Patients with an abnormal preoperative ECG experienced a greater number of ischemic episodes (P less than 0.001). Elevation of PCWP or the presence of A-C or V-waves greater than 5 mmHg above the mean did not individually reflect ischemia reliably. Intraoperative myocardial ischemia is common in vascular surgical patients and is most sensitively detected by ventricular wall motion abnormality.

Superoxide dismutase and catalase reduce infarct size in a porcine myocardial occlusion-reperfusion model

We investigated if superoxide dismutase and catalase could reduce myocardial infarct size in an open chest occlusion-reperfusion model. Thirty pigs were used for the experiment. The left anterior descending artery was ligated for 60 min followed by a 5 h reperfusion period. After randomisation and blinding the two enzymes or placebo were injected into the left atrium as a bolus immediately before and at the end of the occlusion and as a continuous infusion over the first hour of the reperfusion period. The total dose for each enzyme was 8 mg/kg bw. Tetrazolium staining was used to determine infarct size. The study code was not broken until all calculations and exclusions had been made. Nine animals died from intractable ventricular fibrillation, most commonly during the occlusion. Another three were excluded for technical reasons. We found that superoxide dismutase and catalase reduced infarct size in relation to myocardium at risk from a mean of 89% to 63% (P less than 0.01). Initial plasma half life for the two enzymes after the bolus infusions were calculated to be 30 min.

Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: an experimental study with special reference to lidocaine and bupivacaine.

In 15 pigs lidocaine and bupivacaine were injected into the left anterior descending (LAD) coronary artery to investigate the cardiotoxic effects of these drugs. Anesthesia was maintained by a continuous intravenous pentobarbital infusion and ventilation was controlled. Aortic, pulmonary arterial, right atrial, and left ventricular pressures, a standard 12 lead ECG, cardiac output, and great cardiac venous blood flow were recorded. The local anesthetics were administered at body temperature over approximately 10 sec in a random, crossover fashion at the following equipotent anesthetic doses: bupivacaine, 0.25, 0.5, 1, 2, and 4 mg; lidocaine, 1, 2, 4, 8, and 16 mg. The hemodynamic effects were short-lived, peaking about 5 sec after drug infusion. At the highest dose, both drugs decreased left ventricular dP/dT by 28% (P less than 0.001) and aortic blood pressure by 12% (lidocaine) and 8% (bupivacaine) (P less than 0.001 and P less than 0.01). Heart rate, cardiac output, and coronary venous blood flow did not change. Thus, the cardiodepressant ratio between the two drugs was comparable with their local anesthetic the two drugs was comparable with their local anesthetic potency ratio (bupivacaine/lidocaine, 4:1). Seven animals died in ventricular fibrillation within 1 min after 4 mg bupivacaine dose. All animals given 16 mg lidocaine survived. Ventricular fibrillation was preceded by progressive widening of the QRS complexes recorded over the area perfused by the LAD. The ECG changes after 16 mg lidocaine were of the same magnitude as those recorded after 1 mg bupivacaine. In five of the surviving animals 32 and 64 mg lidocaine were injected intracoronarily after termination of the crossover study.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical effects of the heparin coated surface in cardiopulmonary bypass

OBJECTIVE In a randomised study of 120 patients, undergoing primary operation for coronary heart decease, two groups were investigated as regards to the effects of heparin coated cardiopulmonary bypass on brain function parameters and general clinical outcome. The study group (n = 56) was perfused using an extra-corporeal circuit treated with covalent bonded heparin; the control group (n = 59) used an identical set-up without heparin treatment. Systemic heparin doses were calculated to achieve ACT levels of 250 and 500 s, respectively. Postoperative course was evaluated by examining a set of clinically relevant parameters including a detailed registry of postoperative deviations. Brain function was assessed by the biochemical marker S-100 and tests of memory performance. RESULTS There were several signs of reduced operative trauma in the study group. Hospital stay was reduced by nearly 1 day (P < 0.05). Time on postoperative ventilatory support was approximately 4 h shorter (P = 0.009). Chest drain blood loss was decreased both at 8 (P = 0.01) and 24 h (P = 0.007) postoperatively. Body temperature was lower after surgery and especially on days 2 (P = 0.03) and 3 (P = 0.01). Perioperative creatinine elevation was significantly reduced (P = 0.03). Neurological deviations were fewer (P = 0.01). Brain function assessment revealed reduced plasma levels of S-100 both at termination of cardiopulmonary bypass (P = 0.008) and 7 h later (P = 0.04). However, no remediation of memory impairment could be demonstrated. CONCLUSIONS Cardiopulmonary bypass with covalent bonded heparin attached to the extra-corporeal circuit in combination with a reduced systemic heparin dose seems to reduce safely and effectively the operative stress to the patient. There were also signs of improved cerebral protection.

Effects of Halothane on Coronary Haemodynamics and Myocardial Metabolism in Patients with Ischaemic Heart Disease and Heart Failure

Halothane was administered at an end‐tidal concentration of 1% to 10 patients with stable ischaemic heart disease and clinical and haemodynamic signs of moderate heart failure. Measurements of central haemodynamic variables, coronary sinus blood flow and oxygen, lactate and hypoxanthine balances over the myocardium were done before and at steady state during halothane anaesthesia. Halothane induced marked haemodynamic changes with decreases in mean arterial pressure; (‐43%), mean pulmonary arteriolar occlusion pressure (‐42%), systemic vascular resistance (‐31%), cardiac index (‐20%), stroke volume index (‐31%) and left and right stroke work indices (‐62% and ‐55%, respectively). Heart rate and pulmonary vascular resistance did not change. Coronary sinus blood flow decreased in parallel with perfusion pressure, and myocardial oxygen consumption decreased (‐40%), as did myocardial oxygen extraction. Rate pressure product and triple product correlated better with changes in myocardial oxygen consumption in the present subset of patients than in healthy volunteers during halothane anaesthesia. The findings suggest that halothane, through its systemic vasodilatory effect, unloads the failing left ventricle and that this peripheral action predominates over the direct cardiodepressant action of the agent. The combined findings of unchanged coronary vascular resistance, decreased myocardial oxygen extraction and absence of increasing or pathological levels of lactate and hypoxanthine in coronary sinus blood imply a direct dilatory effect of halothane on the coronary vasculature.

Limitation of myocardial infarct size by superoxide dismutase as an adjunct to reperfusion after different durations of coronary occlusion in the pig.

Superoxide dismutase (SOD) has been documented to limit myocardial infarct size in the richly collateralized dog heart. This study was designed to explore this concept in a low-collateralized animal model. A blind, randomized, placebo-controlled protocol was used in 65 pentobarbital-anesthetized pigs subjected to closed-chest left anterior descending coronary artery occlusion for 30 (n = 22), 60 (n = 22), and 90 (n = 14) minutes followed by reperfusion up to 24 hours from the start of occlusion. Another seven control pigs were subjected to 24 hours of permanent occlusion. A total dose of 9 mg/kg bovine CuZn SOD was administered as a bolus injection immediately before reperfusion followed by a 1-hour infusion. Infarct size was assessed by tetrazolium staining. Myocardium at risk and collateral flow were determined by using cerium-141-labeled microspheres (15 microns) during the occlusion. After 30 minutes of occlusion, infarct sizes in placebo versus SOD-treated animals were 45.5 +/- 15.7% vs. 23.8 +/- 15.6% of myocardium at risk (p = 0.007). The corresponding values after 60 minutes of occlusion were 78.6 +/- 9.3% vs. 66.9 +/- 14.6% (p = 0.035). SOD administered after 90 minutes of occlusion did not limit infarct size (88.5 +/- 4.8% vs. 92.3 +/- 5.2%). Twenty-four hours of coronary occlusion resulted in infarction of 92.4 +/- 4.2% of myocardium at risk. (All values are mean +/- SD.) Ventricular fibrillation occurred in only nine pigs distributed equally between SOD and placebo. The results indicate that CuZn SOD has the potential to further improve the myocardial salvage established by reperfusion of an ischemic pig heart territory. However, the narrow time window for limiting infarct size in the pig by reperfusion is not much extended by SOD.

Use of heparin-bonded circuits in cardiopulmonary bypass improves clinical outcome.

Objective : The use of heparin-coated surfaces in cardiopulmonary bypass has been shown to decrease the inflammatory response imposed by the contact between blood and artificial surfaces. One would expect this reaction to improve clinical outcome. However, this has been difficult to verify. This investigation is based on an aggregation of two randomized studies from our institution and highlights possible effects of heparin coating on a number of clinically oriented parameters. Design : Departmental analysis of patients subjected to coronary artery bypass surgery using heparin-coated circuits. Cardiopulmonary bypass was employed using either the Carmeda or Duraflo heparin coatings compared with a control. The systemic heparin dose was reduced in the heparin-coated groups (ACT > 250 s) vs control group patients (ACT > 480 s). The effects of heparin coating related to clinical outcome were studied. Results : The use of heparin-coated circuits reduced the mean length of stay in hospital from 7.8 - 2.5 to 7.3 - 1.8 days ( p = 0.040) and postoperative ventilation time from 9.7 - 9.2 to 8.2 - 8.5 h ( p = 0.018), blood loss 8 h post surgery from 676 - 385 to 540 - 245 ml ( p = 0.001), individual perioperative change of haemoglobin loss ( p = 0.001), leukocyte count ( p = 0.000) and creatinine elevation ( p = 0.000), proportion of patients exposed to allogenous blood transfusions 39.2 vs 23.9% ( p = 0.001), postoperative coagulation disturbances 4.4 vs 0.4% ( p = 0.006), postoperative deviations from the normal postoperative course 47.2 vs 36.7% ( p = 0.035), neurological deviations 9.4 vs 3.9% ( p = 0.021) and atrial fibrillation 26.4 vs 18.0% ( p = 0.041). No effects were found with respect to perioperative platelet count, postoperative fever reaction and 5-year survival. Conclusion : Based on several indicators, the use of heparin coating in cardiopulmonary bypass is associated with improved clinical results.

Neurological and general outcome in low-risk coronary artery bypass patients using heparin coated circuits

OBJECTIVE The clinical significance of heparin coating in cardiopulmonary bypass has previously been investigated. However, few studies have addressed the possible influence on brain function and memory disturbances. METHODS Three hundred low-risk patients exposed to coronary bypass surgery were randomised into three groups according to type of heparin coating: Carmeda Bioactive Surface, Baxter Duraflo II and a control group. Outcome was determined from a number of clinically oriented parameters, including a detailed registry of postoperative deviations from the normal postoperative course. Brain damage was assessed through S100 release and memory tests, including a questionnaire follow-up. RESULTS Clinical outcome was similar for all groups. Blood loss (Duraflo only), transfusion requirements and postoperative creatinine elevation were reduced in the heparin-coated groups. A lower incidence of atrial fibrillation was noted in the Duraflo group. Heparin coating did not uniformly attenuate the release of S100 or the degree of memory impairment. CONCLUSIONS Cardiopulmonary bypass (CPB) with heparin coating and a reduced dose of heparin seems to be safe. Clinical outcome and neurological injury seem not to be associated with type of heparin coating used for CPB. However, blood loss and transfusion requirements may be reduced.

On-Line Computerized Vectorcardiography: Influence of Body Position, Heart Rate, Radiographic Contrast Fluid and Myocardial Ischemia

UNLABELLED On-line computerized vectorcardiography (cVCG) is increasingly being used for continuous monitoring of myocardial ischemia, however, little is known about factors other than ischemia causing electrocardiographic abnormalities. This paper describes how three important cVCG parameters, STC-VM, ST-VM and QRS-VD, are affected by different body positions, myocardial ischemia, contrast injection and increasing heart rate in patients with and without coronary artery disease. The main findings of the study are: contrast injection and different body positions caused major changes in QRS-VD but affected ST-VM and STC-VM to a minor degree. Increasing heart rate by atrial pacing produced substantial changes in all three parameters. Ischemia during angioplasty also produced changes in all three parameters, STC-VM being the most sensitive parameter. IN CONCLUSION (1) STC-VM (> or = 50 microV) is the most valuable parameter for monitoring ischemia; (2) we propose ST-VM > or = 50 microV as criterion instead of previously used 25 microV; (3) QRS-VD cannot be used as a single marker of ischemia, and (4) electrocardiographic changes induced by increased heart rate should be taken into account during interpretation.