Post-operative myocardial dysfunction does not affect the physiological response to early mobilization after coronary artery bypass grafting.

BACKGROUND: An acute increase in oxygen demand can be compensated for either by increased cardiac index (CI) or increased oxygen extraction, resulting in reduced mixed venous oxygen saturation (SvO2). We tested the hypothesis that post-operative cardiac dysfunction may explain why oxygen extraction alone is increased during early mobilization after cardiac surgery. METHODS: Twenty patients with a pre-operative ejection fraction > 50% were included in an open prospective observational study comparing the changes in SvO2 and hemodynamics during mobilizations immediately prior to surgery and on the first post-operative morning. RESULTS: Mobilization induced an absolute reduction in SvO2 of 17.7 +/- 7.4% pre- and 19.0 +/- 5.5% post-operatively (NS). ANOVA for a series of measurements throughout the mobilization sequence identified no different effect on SvO2 between pre- and post-operative mobilizations (P = 0.567). The SvO2 level was reduced post-operatively resulting in a SvO2 during standing exercise of 55% before and 49% after the surgery (P < 0.01). Mobilization increased the heart rate (HR) and decreased the stroke volume index (SVI), leaving CI unchanged. This response was similar pre- and post-operatively (NS). Compared with pre-operative measurements, CI and HR increased post-operatively while SVI remained unchanged despite elevated cardiac filling pressures and reduced systemic vascular resistance. The left ventricular stroke work index was reduced, indicating reduced myocardial performance. CONCLUSION: Myocardial function was reduced on the first morning after coronary artery bypass grafting (CABG), but during post-operative mobilization this reduction did not significantly influence the changes in CI or SvO2.

Mixed venous oxygen desaturation during early mobilization after coronary artery bypass surgery.

BACKGROUND: Early postoperative mobilization induces a marked reduction in mixed venous oxygen saturation (S(v)O(2)) after aortic valve replacement. We investigated whether a similar desaturation occurs among coronary artery bypass grafting (CABG) patients, and if the desaturation was related to the preoperative ejection fraction (EF). METHODS: Thirty-one CABG patients with a wide range in EF were included in an open observational study. We recorded hemodynamic and oxygenation variables during mobilization on postoperative day 1 and day 2 using a pulmonary artery catheter. RESULTS: Patients with an EF ranging from 24 to 87% were mobilized without clinical problems. S(v)O(2) at rest was 65.4 +/- 4.9% (mean +/- SD) on day 1 and 64.3 +/- 5.8% on day 2 (NS). During mobilization, cardiac index and oxygen delivery were reduced while oxygen consumption was increased (P-values: 0.000, 0.007 and 0.000, respectively). Consequently, oxygen extraction increased, resulting in a marked reduction in S(v)O(2)-42.9 +/- 8.3% on day 1 and 47.4 +/- 8.5% on day 2 (P = 0.025 between days). Several pre-, intra- and postoperative factors were tested as possible predictors for S(v)O(2) during mobilization. No factor contributed substantially. CONCLUSION: Patients with CABG exhibit a marked desaturation during early postoperative mobilization. Preoperative ejection fraction did not affect S(v)O(2) during exercise. The clinical consequences and underlying mechanism require further investigation.

Beta-adrenergic signalling and threshold adrenaline concentration for induction of fibrillation in the perfused heart pretreated with antihypertensive drugs.

Recent investigations have shown that antihypertensive drug treatment leads to enhanced myocardial beta-adrenoceptor sensitivity. This study was therefore conducted to establish whether or not such hypersensitivity might trigger myocardial arrhythmia subsequent to adrenaline exposure. Adult male Wistar rats (n = 6 per group) were treated with either placebo (vehicle), metoprolol (2.40 mg.kg-1.day-1), timolol (0.075 mg.kg-1.day-1), verapamil (5.50 mg.kg-1.day-1) or enalapril (0.50 mg.kg-1.day-1) for 20 consecutive days. Hearts were excised and perfused ad modum Langendorff in the presence of an adrenaline gradient (0-300 nM) for 20 min with either 3.0 mM or 5.9 mM of potassium in the perfusion buffer. Adrenaline threshold concentration (ATC, nanomolar) at myocardial fibrillation was recorded, as well as tissue cAMP contents, beta-adrenoceptor number, G-protein levels and signalling effector enzyme activities. The main findings were: (1) ATC and cAMP levels were affected in hearts perfused with low-concentration potassium buffer only. In terms of ATC, the beneficial effect of each drug regimen appeared to be in the rank order of: placebo = enalapril > verapamil > timolol > metoprolol. There was an inverse correlation between ATC and myocardial cAMP contents at the start of fibrillation; (2) Subsequent to fibrillation, beta-adrenoceptor number, hormone-elicited adenylate cyclase activities and Gs alpha:Gi2 alpha-ratio were no different from preperfusion values; (3) Significant inverse correlations between beta 1-adrenoceptor numbers and ATC were observed. We conclude that alterations in beta-adrenoceptor number, G proteins and cAMP induced by antihypertensive drugs are predictive of the myocardial sensitivity to adrenaline in terms of time to continuous and irrevocable fibrillation.

Enhanced responsiveness of the myocardial beta-adrenoceptor-adenylate cyclase system in the perfused rat heart (I).

Crude myocardial sarcolemmal membrane fractions were prepared from rat hearts subjected to total global ischemia with and without normoxic reperfusion, or global anoxic (N2) perfusion with and without normoxic reperfusion. The direct effects on beta-adrenoceptor number, G-protein levels and stimulation of the adenylate cyclase (AC) complex were assessed. In terms of AC activation, ischemia led to a marked increase (4-fold) in sensitivity to terbutaline (beta2-agonist) and phorbol ester (tetradecanoyl phorbol acetate = TPA) stimulation, whereas the dobutamine (beta1) responsiveness and Gpp(NH)p activation through G(s)alpha/G(i2)alpha remained unaltered. However, forskolin-elicited holoenzyme activity fell markedly during normoxic reperfusion. Ischemia did not change the beta1-adrenoceptor number, while beta2-receptor population increased by approximately 45%. Western blots of myocardial G(s)A and G(i2)alpha contents revealed that ischemia selectively diminished G(i2)alpha levels only by some 50-70%. Contrastingly, anoxia selectively increased the AC sensitivity (2-fold) to beta1-adrenergic stimulation. As subsequent to ischemia, anoxia also increased the sensitivity to TPA stimulation, however, only 2-fold. Gpp(NH)p activation was unchanged, while forskolin-enhanced activity gradually declined, also during ensuing normoxic reperfusion. Anoxia brought about a 75% enhancement in beta1-receptor number, while beta2-receptors remained unaffected. However, altered receptor number normalized on termination of normoxic reperfusion. Finally, anoxia led to a 50-60% decimation of myocardial G(i2)alpha levels, while G(s)alpha was only marginally reduced. Despite the fact that the ischemia and anoxia effectuated a similar deterioration of physiological heart parameters, myocardial contents of energy rich phosphate moieties and loss of G(i2)alpha, ischemia rendered the most profound increase in responsiveness of the sarcolemmal AC system.

Procaine is effective for minimizing postischemic ventricular fibrillation in cardiac surgery.

Procaine hydrochloride was added to cardioplegia and studied for its efficacy in stabilizing the postischemic rhythm after aortic declamping in cardiac surgery. Fifty-six patients scheduled for coronary artery bypass grafting (CABG), were included in a randomized, double-blind study. The patients were anesthetized with isoflurane, low-dose fentanyl, diazepam, and pancuronium. In the study group (28 patients), St. Thomas' Hospital cardioplegic solution II (Plegisol) was prepared with 1 mM procaine. The control group (28 patients) was given the same cardioplegia with saline. Ventricular fibrillation (VF) occurring after declamping was treated with direct current (DC) shock (8-12-12-20 J). There were no significant differences with regard to demographic properties or anesthesiologic and surgical treatment. Two patients (7%) in the procaine group required DC shock for VF, compared to 28 (100%) in the control group (P < 0.001). The amount of lidocaine (mean +/- SEM) given for resistant dysrhythmias was 3.6 mg +/- 3.6 in the procaine group compared to 35.7 mg +/- 9.2 in the control group (P < 0.002). One patient in each group required temporary pacing. The number of synchronized DC shocks for conversion of atrial fibrillation was lower in the procaine group (P < 0.05). The enzyme release the first day after surgery was lower in the procaine group (P < 0.05). Procaine (1 mM) in cardioplegia stabilizes the postischemic rhythm in CABG surgery in humans without any observed adverse effects.

Heparin-coated circuit during cardiopulmonary bypass. A clinical study using closed circuit, centrifugal pump and reduced heparinization.

A prospective randomized study was performed to investigate the effect of surface coating with covalently endpoint-attached heparin (Carmeda Bio Active Surface) and reduced general heparinization on haematological indices and complement C5 activation. Care was taken to optimize the rheological design of the system using centrifugal pump and a closed system without venting or machine suction. Twenty patients scheduled for aortocoronary bypass grafting (EF > 0.5) participated in the study. Ten patients were randomized to be treated with heparin-coated equipment (CBAS) and reduced i.v. heparin (1.5 mg.kg-1) while 10 patients treated with identical but noncoated equipment and full heparinization (3 mg.kg-1) served in a Control group. A vacuum suction was used to collect the blood from the operating field and it was autotransfused at weaning from extracorporeal circulation (ECC). Blood samples were obtained from the venous (precircuit) and arterial (postcircuit) side. We used a new and very specific method for detection of C5a based on monoclonal antibodies. The concentration of C5a was low in both groups during the operation but a significant increase was seen on days 1 and 2. In the Control group there was an increase from 10.2 ng.ml-1 +/- 1.2 to 27.5 ng.ml-1 +/- 4.8 on day 2 and in the CBAS group from 10.7 ng.ml-1 +/- 1.2 to 35.6 ng.ml-1 +/- 11.6 on day 2 (NS between groups). The granulocytes and total leukocyte count increased at the end of ECC and was maintained at the elevated level throughout the study period. The amount of free haemoglobin was high in the autotransfused blood in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Serious complications with dextran-70 despite hapten prophylaxis. Is it best avoided prior to delivery?

Dextran is used clinically for plasma volume expansion, improvement of blood flow and thromboprophylaxis, but has been associated with untoward side effects. Immunoprophylaxis with dextran I (hapten), before the infusion of dextran-70, has reduced the incidence of serious dextran-induced anaphylactoid reactions. We report three cases of severe reactions occurring during anaesthesia in spite of immunoprophylaxis. One patient given dextran-70 before Caesarean section had a mild reaction but gave birth to a child with serious brain damage. One patient with an extremely high titre of dextran-reactive antibodies died from myocardial infarction and another patient recovered without sequelae. From our experience we conclude that dextran-induced anaphylactoid reactions are still a serious problem despite immunoprophylaxis. Dextran-70 should be avoided during pregnancy and should not be given during Caesarean section before delivery of the child. Even in the presence of immunological prophylaxis, vigilant observation of the patient is essential and resuscitation equipment must be available when starting a dextran infusion.

Pharmacokinetics and effects on renal function following cilazapril and hydrochlorothiazide alone and in combination in healthy subjects and hypertensive patients.

1. Possible interactions between cilazapril and hydrochlorothiazide with respect to pharmacokinetics and renal effects were investigated in healthy subjects (single dose) and in hypertensive patients (multiple dosing). 2. No significant pharmacokinetic interaction was found between cilazapril and hydrochlorothiazide. 3. Cilazapril showed weak saluretic properties as compared with hydrochlorothiazide, but increased the saluretic effects of hydrochlorothiazide. 4. Cilazapril attenuated the hypokalaemia observed with hydrochlorothiazide in hypertensive patients. 5. The effect on blood pressure reduction obtained from the combination of cilazapril and hydrochlorothiazide lasted longer than that of cilazapril alone.

Bell-shaped concentration-response curve for myocardial stimulation by glucocorticoids. An experimental study in the rat.

The isolated perfused rat heart was used to study the myocardial effects of glucocorticoid methylprednisolone sodium succinate (MPSS 0, 100, 500 and 1000 mg/l) in normoxic conditions. Various physiological variables including coronary flow rate (CFR), left ventricular developed pressure (LVDP), dP/dTmax, dP/dTmin and heart rate (HR) were assessed. At the end of the perfusion period the hearts were freeze clamped and analyzed for tissue content of calcium and various metabolites. MPSS (500 mg/l) resulted in vasodilatation and inotropic stimulation. An increase was found in CFR (+17% +/- 4), LVDP (+6% +/- 1), dP/dTmax (+13% +/- 2), dP/dTmin (+9% +/- 3); (P less than 0.05). Heart rate was depressed (-14% +/- 2, P less than 0.05). MPSS (100 mg/l) had no effect on CFR or contractility. MPSS (1000 mg/l) resulted in a transient vasodilatation and a progressive myocardial depression. MPSS perfusion (100 and 500 mg/l) increased the adenine nucleotide pool and at all concentrations MPSS elevated the myocardial content of lactate. We conclude that in normoxic conditions there is a bell-shaped curve of myocardial inotropic stimulation by the glucocorticoid hormone, and also a stimulation of metabolism possibly by increased cellular supply of substrates.

Steroids protect the beta-adrenergic system during reperfusion after ischemia: effects of methylprednisolone on the beta-adrenergic response system.

Methylprednisolone sodium succinate (MPSS) administered during reperfusion may improve myocardial function. These effects have been related to adrenergic stimulation. The present study investigated (1) the effects of ischemia and reperfusion on the beta-adrenergic response system and (2) the ability of MPSS to modify the ischemic effects on the beta-adrenergic system. Isolated perfused rat hearts were used. The ischemic protocol consisted of aerobic perfusion (20 minutes) followed by total, global normothermic (37 degrees C) ischemia (30 minutes) and reperfusion (30 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). The non-ischemic protocol consisted of aerobic perfusion (20 minutes) followed by aerobic perfusion (20 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). At the end of the experiments all hearts were rapidly frozen in liquid nitrogen. Crude sarcolemmal membranes were prepared and stimulated at the beta-receptor, at the coupling (G.- or N-) protein, or directly at the adenylate cyclase enzyme (AC). Results were assessed by cyclic adenosine monophosphate (cAMP) production. Tissue specimens were analyzed for myocardial content of cAMP and methylprednisolone (MP). In the ischemic protocol, the responsiveness of the beta-adrenergic system was significantly reduced at the G.-protein level. The treatment with MPSS (100 or 500 mg/L) during reperfusion preserved the beta-adrenergic response. MPSS (1,000 mg/L) offered no protection. In the non-ischemic protocol, MPSS reduced the response of the beta-adrenergic system in a dose-dependent manner at the same level. The hearts in the ischemic protocol had significantly higher contents of MP than the hearts in the non-ischemic protocol at corresponding concentrations of MPSS. The present study suggests that postischemic cardiac failure may result in part from beta-adrenergic dysfunction. This loss of function, probably at the level of the protein connecting the receptor and AC, can successfully be prevented by an optimal dose of MPSS during reperfusion after ischemia.

Modification of myocardial ischemic injury: a concentration response study of glucocorticoid supplementation during reperfusion.

Reperfusion of the ischemic myocardium is routinely done during cardiac surgery and in the catheterization laboratory after acute regional ischemia. While reperfusion of the ischemic myocardium is necessary in order to regain full functional and biochemical recovery, the reperfusion by itself may aggravate the ischemic damage. Glucocorticoids have been shown to modify the outcome from ischemic injury in various experimental and clinical situations, but the results are conflicting. This protocol was performed using normothermic ischemic (30 minutes) isolated rat hearts, and postischemic reperfusion (30 minutes) with methylprednisolone sodium succinate (MPSS; 100-500-1,000 mg/L) was studied. All indices of myocardial function and all metabolic variables were significantly reduced after ischemia. MPSS (100 mg/L) improved dP/dTmax (recovery 68 +/- 3% v control 48 +/- 7%) and some of the other indices of left ventricular performance studied. MPSS (100 mg/L) also improved the tissue concentration of adenosine triphosphate (ATP) (13.8 +/- 0.5 mumol/g dry weight v control 11.3 +/- 0.8) and the total adenosine pool (16.8 +/- 0.7 mumol/g weight v control 13.9 +/- 0.8 mumol/g dry weight). MPSS (1,000 mg/L) impaired recovery of myocardial function (dP/dTmax, dP/dtmin, rate-pressure product [RPP]), increased tissue lactate (7.2 +/- 2.0 mumol/g dry weight v control 3.6 +/- 0.8), reduced glycogen (30.6 +/- 2.5 mumol/g dry weight v control 49.8 +/- 3.3), and energy charge (0.848 +/- 0.018 v control 0.890 +/- 0.010). It is concluded from the present experiments that modification of an ischemic injury by glucocorticoids given at the onset of reperfusion is possible, and that an optimal concentration of 100 mg/L exists for MPSS supplementation. MPSS in a concentration of 1,000 mg/L aggravated the reperfusion injury, probably by interference with cellular respiration.

Steroids and cardioplegia: effects of glucocorticoids upon vascular resistance during cardioplegic perfusion.

The effects are assessed of methyl prednisolone sodium succinate (MPSS) upon coronary flow rate (CFR) during a 20 minute anoxic, cold (20 degrees C) cardioplegic perfusion with a potassium-enriched (K+ 20 mmol/l) commercially obtained Ringer solution and 15 min of subsequent normothermic aerobic reperfusion without steroid, based on measurements made on the isolated rat heart. Myocardial release of creatine kinase (CK) was obtained during reperfusion and at the end of the experiments the hearts were freezeclamped and analyzed for high energy phosphate compounds and tissue calcium. In the absence of filtering and MPSS the coronary flow rate gradually declined to 32% +/- 4 after 20 min. MPSS presented a bell-shaped concentration response curve with respect to improvement of CFR. An optimal effect (only reduction to 64% +/- 11) was obtained with MPSS 100 mg/l, while no improvement was obtained with 1000 mg/l (reduction to 28% +/- 3). After 15 min of reperfusion with normal medium at 37 degrees the hearts perfused with MPSS 100 mg/l presented with higher values for energy charge and ATP and lower tissue calcium content than the hearts perfused with MPSS 1000 mg/l. Using filtration (0.8 micron) of the cardioplegic solution the CFR was reduced to 45% +/- 4. We therefore conclude that MPSS in an optimal concentration (100 mg/l) may afford effective coronary vasodilation and overcome particle induced vasospasm, and that in higher concentrations (1000 mg/l) the improvement in CFR is lost. This high concentration may also have unfavorable effects upon the myocardium.

Protection of the ischemic myocardium: dose-response relationships with glucocorticoids in filtered cardioplegic solutions.

A concentration-responsive study of supplementation with methyl prednisolone sodium succinate (MPSS: 0-10-100-500-1000 mg/l) to a potassium-based crystalloid cardioplegic solution, administered under hypothermic conditions, has been undertaken in the isolated working rat heart. The solution was filtered through a very fine filter (0.22 micron), thereby excluding particles able to increase vascular resistance and reduce postischemic performance. The solution was administered intermittently at a constant flow rate during 180 min of ischemia at 20 degrees C. The per cent postischemic recovery of aortic flow rate for the following concentrations of MPSS was: 0 mg/l 57%; 10 mg/l 49%; 100 mg/l 52%; 500 mg/l 38%; and 1000 mg/l 28%. MPSS supplementation did not improve upon any of the physiological, enzymatic or metabolic (total tissue high-energy phosphates, lactate, glycogen, Ca++) variables. The highest concentrations (500 and 1000 mg/l) of MPSS decreased postischemic performance. The hearts perfused with sodium succinate in a concentration equimolar to MPSS 1000 mg/l recovered less than the hearts subjected to unmodified cardioplegia. It is concluded that MPSS does not confer any additional protection to a potassium-based, calcium-containing crystalloid cardioplegic solution when it is effectively filtered. High concentrations of MPSS may prove toxic to the ischemic myocardium.

Cardioplegia: mechanisms of protection revisited.

A number of factors may influence the myocardial outcome after cardiac surgery, some of which are related to the actual handling of the patient during the perioperative period, and, in particular, to the absence or presence of protective procedures during periods of aortic occlusion. Cold chemical cardioplegia offers the present best alternative for ischaemic protection. The intermittent coronary infusion of cold cardioplegic solutions provides an effective low cost procedure that proves effective for the majority of surgical corrections. However, increasing knowledge to the ischaemic process and its amelioration and the continuing problem of poor postoperative cardiac function of patients in preoperative heart failure, should encourage further experimental and clinical research into perioperative myocardial protection.