Late potentials in a bradycardia-dependent long QT syndrome associated with sudden death during sleep.

The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n = 13). Six (67%) of the 9 family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p less than 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86%; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials. It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardia-dependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.

Isolated hindlimb perfusion in dogs: the effect of perfusion pressures on the oxygen supply (ptO2 histogram) to the skeletal muscle.

During regional isolated perfusion, neoplasms in extremities are treated with high doses of chemotherapeutic drugs by means of an extracorporeal circuit. The question is whether optimal tissue perfusion, which is essential for the therapy, is obtained by regulation of the extracorporeal circuit on an adequate perfusion flow or on an adequate perfusion pressure. To determine which perfusion pressure is needed to maintain adequate tissue perfusion, hindlimbs of six dogs were perfused at perfusion pressures 0, 15, 25, and 50 mm Hg below systemic mean arterial pressure. A multiwire polarographic oxygen electrode placed on the sartorius muscle permitted quantitative evaluation of tissue oxygenation by means of ptO2 histograms. Our results indicated that the perfusion pressure must be equal to or within 15 mm Hg below systemic mean arterial pressure to obtain optimal tissue perfusion. To maintain this perfusion pressure, high perfusion flows of about five to 10 times control femoral flows were needed. At a perfusion pressure 50 mm Hg below systemic mean arterial pressure, perfusion flow was normal, but tissue perfusion was severely impaired.

Clear prime for infant cardiopulmonary bypass: a miniaturized circuit.

The extracorporeal circuit used clinically to perform cardiopulmonary bypass (CPB) in small infants is relatively large requiring blood to prime the circuit to reduce hemodilution. To study the merits of clear prime also in infants, we did experiments in rabbits with two extracorporeal circuits: one employing traditional venous gravity drainage (priming volume 330 ml) and the other employing vacuum drainage (priming volume 90 ml). The first circuit still had to be primed with blood, whereas the second circuit could be primed with a clear solution. Both circuits were automatically controlled to lighten the task of the perfusionist to operate the CPB safely and accurately. We demonstrated that the clear priming solution in the second circuit eliminates the hemodynamic deterioration caused by blood prime in the first circuit. Studying the effect of various modes of regulation, we showed that automatic control of CPB based on venous return is similar to autoregulation of the heart according to Starling's law, and maintains not only normal hemodynamics, but also an optimal microcirculation.

Reduction in adverse effects of mechanical ventilation in rabbits with acute respiratory failure by treatment with extracorporeal CO2 removal and a large fluid volume of diluted surfactant.

The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO2 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO2) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO2 was gradually decreased to 40%. In the experimental group, FiO2 was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO2 of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO2, can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.

Large volume instillation of surfactant during extracorporeal life support improves lung function in lung lavaged rabbits.

The sometimes limited effect of surfactant therapy in neonates might be explained in part by an non homogeneous distribution of the surfactant after endotracheal instillation. This distribution can be improved significantly by increasing the fluid volume. The aim of this study was to evaluate the effect of two methods for gas exchange during a large volume instillation of surfactant on the outcome of this treatment in lung lavaged rabbits. In the control group (n = 6) gas exchange was maintained with continuous positive pressure ventilation (CV), whereas in the other group gas exchange was established with extracorporeal life support (ECLS) (n = 6) and intermittent sighs. Five hours after surfactant administration, an identical weaning procedure was started in both groups. The authors found significantly higher PaO2 values in the ECLS group than in the control group in the normocarbia state. All animals in the ECLS group could be weaned to room air maintaining normal blood gases, whereas all the animals in the control group died in the course of weaning. The ventilator efficiency index was significantly higher during the weaning period in the ECLS group, indicating better lung function, than in the control group. The authors conclude that a large volume instillation of surfactant is feasible by applying ECLS and intermittent sighs. Additional studies are needed to elucidate if this combined treatment will be an improvement over current surfactant therapy.

A new hollow fiber membrane oxygenator with an integral heat exchanger: a hematological evaluation in dogs.

A recently developed hollow fiber membrane oxygenator, made of microporous polypropylene (Capiox, Terumo, 1.6 m2) was tested to evaluate the hemocompatibility and the ease and safety of operation. Two types of this oxygenator were tested: one with and one without an integral heat exchanger. Each type was tested in 6 dogs during a partial bypass of 2 hours at a flow rate of 2 l/min. In addition, gas transfer measurements were carried out. The Terumo oxygenator preserved the blood cells and the platelet function very well. In addition, neither the Wu-Hoak index, a method to measure platelet aggregates, nor inspection of the oxygenator revealed platelet aggregates. Operation and debubbling procedure were easy and safe. The estimated rated blood flow for O2 was 1.5 l/min with a corresponding CO2 removal of 90 ml/min. The integral heat exchanger did not affect the results significantly. Our data show that this oxygenator is easy and safe to use. Clinical evaluation is recommended.

Improved tissue perfusion during pressure regulated hyperthermic regional isolated perfusion. A clinical study.

In previous studies on isolated hindlimb perfusions in dogs, the authors proved that the extracorporeal circuit should be regulated at a delta pressure (systemic mean arterial pressure minus hindlimb mean arterial pressure) of not more than 15 mmHg, to achieve adequate tissue perfusion. To confirm this in patients the authors performed clinical perfusions, divided into three groups. In group I and II the extracorporeal circuit was regulated at a delta pressure of 15 mmHg and 50 mmHg, respectively. In group III perfusions were performed using the common technique of a predetermined fixed flow. Tissue oxygenation, determined by means of a transcutaneous pO2 electrode, was adequate in group I and was severely impaired in group II and III. Although in group I high perfusion flows were needed, leakage was less than 10%. To achieve adequate tissue perfusion during clinical regional perfusions, the extracorporeal circuit must be regulated at a delta pressure of 15 mmHg.

Effects of acute bleeding on oxygen supply to the skeletal muscle in dogs.

To study the effect of acute bleeding on the oxygen supply to the skeletal muscle, heparinized dogs were bled via an arterial cannula until mean arterial pressures of 25 and 50 mm Hg below initial value were reached. The shed blood was retransfused in reverse (50, 25 mm Hg) after correction of the acid-base imbalance in the dogs. Oxygen supply to the skeletal muscle was measured by means of a multiwire polarographic electrode placed on the sartorius muscle and was evaluated by means of ptO2 histograms. The ptO2 histograms showed that the oxygen supply to the skeletal muscle is severely impaired after a decrease in mean arterial pressure of 25 mm Hg. Further impairment was seen after a decrease in pressure of 50 mm Hg. During retransfusion tissue oxygenation was normalized only after all shed blood was retransfused and the initial mean arterial pressure was reached.

High-frequency oscillation affects surfactant phospholipid metabolism in rabbits.

Surfactant phospholipid metabolism was studied in anesthetized rabbits ventilated with high-frequency oscillation at a frequency of 5 Hz and a mean airway pressure of 5 cm H2O. Blood gases were normal although some atelectasis was evident after 1 h. The static compliance of the lungs and amount and composition of surfactant phospholipids of the lamellar body and alveolar lavage fraction were comparable to values found for spontaneously breathing rabbits. The data obtained for the incorporation of radioactively labeled palmitate into phospholipids are compatible with intracellular degradation of newly synthesized surfactant phospholipids. This hypothesis is supported by two observations. First, the rapid initial increase in specific activity of SPC and PC of the lamellar body fraction is not accompanied by a similar rapid increase in specific activity of SPC and PC of the lamellar body fraction is not accompanied by a similar rapid increase in specific activity of the alveolar lavage fraction. Second, a dissociation occurs between the metabolism of PC and SPC for the lamellar body fraction but not for the alveolar lavage fraction. The change in metabolism might be caused by the absence of large pressure swings during this pattern of ventilation.

High-frequency ventilation in rabbits with respiratory insufficiency.

Treatment of respiratory insufficiency using continuous positive pressure ventilation (CPPV) with positive end-expiratory pressure (PEEP) is often associated with high airway pressures and large tidal volumes resulting in parenchymal damage and an exacerbation of ventilation/perfusion mismatch. High-frequency jet ventilation and high-frequency oscillation purportedly provide adequate ventilation and might preclude these harmful side effects. Few data exist comparing these methods in a model of respiratory insufficiency. Respiratory insufficiency was produced in three groups of six rabbits by 15 pulmonary lavages with saline (35 ml kg-1) to remove surfactant, following which ventilation for the subsequent 5 hr was as follows: group I, CPPV with a frequency of 60 bpm, and a minute volume of 400 ml min-1 kg-1; group II, oscillatory ventilation with a loudspeaker system delivering a tidal volume of 6-8 ml at a frequency of 5 Hz; and group III, jet ventilation with volumes of 6-8 ml at a frequency of 5 Hz. All groups were ventilated with a PEEP of 10 cm H2O and a FiO2 of 1.0. Arterial blood samples were taken every hour. All three methods provided adequate oxygenation without important differences. The arterial pCO2 rose in all three groups owing to the seriousness of the respiratory insufficiency created. This rise was the highest with oscillatory ventilation. Three of the six rabbits deteriorated after 3 hr of jet ventilation and died with elevated pCO2S with pO2S with bloody edema coming out of the trachea. Because of this apparent damaging effect of jet ventilation and because oscillatory ventilation achieved the same gas exchange but at lower airway pressures as compared to jet ventilation and CPPV, it is thought that oscillatory ventilation is superior over both jet ventilation and CPPV for application in respiratory insufficiency.

Effects of bradykinin on inducible sustained ventricular tachycardia two weeks after myocardial infarction in pigs.

We studied the in vivo effect of bradykinin infusion on inducible sustained ventricular tachycardia (VT) 2 weeks after myocardial infarction in pigs, based on the assumption that the antiarrhythmic effect of angiotensin-converting enzyme (ACE) inhibitors may, apart from their angiotensin-II lowering effect, also be due to elevation of endogenous bradykinin levels. Of the six pigs with inducible VT in the control state, four were noninducible during subsequent bradykinin infusion (p less than 0.05). The ventricular effective refractory period (VERP) did not change during bradykinin infusion (from 237 +/- 37 to 239 +/- 42 ms), nor did intraventricular conduction change (filtered QRS duration was 45 +/- 17 ms before and 43 +/- 19 ms during infusion). Bradykinin caused both a significant systolic blood pressure (SBP) decrease (from 79 +/- 14 to 49 +/- 4 mm Hg, p less than 0.001) and diastolic BP (DBP) decrease (from 41 +/- 10 to 27 +/- 4 mm Hg, p less than 0.01). In conclusion, exogenous bradykinin reduced the inducibility of sustained VT 2 weeks after myocardial infarction. Because refractory periods or conduction velocity were not affected, the mechanism of action might be associated with the BP decrease, which can decrease wall stress. The previously reported antiarrhythmic effect of ACE inhibitors may be due in part to elevation of endogenous bradykinin levels.

In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig.

In this study, the effect of bradykinin or saline infusion during ischemia and reperfusion on electrical stability, 2 weeks after myocardial infarction, was assessed. Acute myocardial infarction was induced in 21 pigs by a transluminal occlusion of the left coronary artery with a catheter balloon, inflated for 45 min. Bradykinin was administered by a 30-min infusion that started after 30 min of coronary occlusion and was continued until 15 min after reperfusion. Although creatine kinase levels in bradykinin-treated animals were significantly lower (p less than 0.001), 2 week survival was not different between groups. In survivors, the filtered QRS (ventricular deflection) duration (detected using signal-averaged electrocardiography) was significantly prolonged in saline-treated pigs, whereas in bradykinin-treated pigs this prolongation was prevented. The terminal voltage of the QRS complex was significantly lower in saline-treated pigs than in bradykinin-treated pigs. These two parameters signify an improved electrical stability after bradykinin treatment. Refractory periods in saline-treated hearts were longer than in bradykinin-treated hearts (106 +/- 10% vs. 95 +/- 13%, p less than 0.05). Also, current thresholds in the infarct border zones showed a greater variance in saline-treated hearts (p less than 0.001), pointing toward more tissue heterogeneity of the infarct border zone. Programmed electrical stimulation showed a trend toward reduced inducibility of sustained ventricular tachycardia in bradykinin-treated hearts. Therefore, bradykinin improves electrical stability weeks after experimental myocardial infarction.

Electrophysiological, rate dependent, and autonomic effects of the class III antiarrhythmic almokalant after myocardial infarction in the pig.

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mumol.kg-1.min-1, continuous infusion: 0.0025 mumol.kg-1.min-1) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 18 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms (P < 0.05) and at PCL 300 ms: from 150 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed stimulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.

Improved tissue perfusion during pressure-regulated hyperthermic regional isolated perfusion in dogs.

To achieve adequate tissue perfusion during regional isolated perfusion, hind limbs of dogs were perfused for 60 min, regulating the extracorporeal circuit on pressure. The dogs were divided into three groups. In groups I and II perfusions were performed at a delta pressure (systemic mean arterial pressure minus hind limb mean arterial pressure) of respectively 50 and 15 mm Hg; in group III delta pressure was also 15 mm Hg but the cytostatic drug Melphalan was added. Tissue perfusion was determined by means of a multiwire polarographic oxygen electrode. Adequate tissue perfusion was obtained only at subnormal perfusion pressures (groups II and III), although in all groups perfusion flow was higher than preoperative flow. At low perfusion pressures (group I), tissue perfusion was severely impaired. In all groups leakage remained less than 10%. During regional isolated perfusion the extracorporeal circuit must be regulated at a delta pressure of 15 mm Hg to achieve adequate tissue perfusion.

Late potentials in a porcine model of anterior wall myocardial infarction and their relation to inducible ventricular tachycardia.

In this study, normal values for signal averaged electrocardiographic parameters were assessed in healthy pigs (n = 100) and the development of late potentials after myocardial infarction (n = 41) in relation to inducible ventricular tachycardia was investigated. Normal values are: filtered QRS duration (QRS) < or = 78 msec; root mean square voltage of the averaged QRS complex (V(tot)) > or = 51 microV, and duration of terminal activity below 30 microV (D30) < or = 37 msec. The distribution of the root mean square voltage in the last 30 msec (V30) was biphasic. Two weeks after myocardial infarction, QRS was prolonged from 55 +/- 10 to 66 +/- 19 msec (P < 0.002). D30 was prolonged from 19 +/- 6 msec to 28 +/- 13 (P < 0.002). V30 was decreased from 107 +/- 135 microV to 45 +/- 77 (P < 0.02). The total voltage (V(tot)) was decreased from 195 +/- 78 to 123 +/- 61 microV (P < 0.002). In four pigs (19%) late potentials developed. Sustained ventricular tachycardia was inducible in 11 pigs (52%), ventricular fibrillation in two pigs (10%) and eight pigs (38%) were noninducible. Three of 11 inducible pigs and one of the noninducible pigs had a late potential. The incidence of late potentials and their relation to inducible sustained ventricular tachycardia is comparable to the situation in man. Therefore, this pig model is an attractive alternative to the commonly used dog models.

Neurohumoral changes and the inducibility of ventricular tachycardias: effect of early reperfusion on the ischemic porcine myocardium.

The effects of early reperfusion were studied in closed-chest pigs subjected to either 45 min or 3 hr of regional ischemia. Myocardial enzyme release during early reperfusion and electrophysiological stability after two weeks were assessed. Coronary artery occlusion durations of 3 hr and early reperfusion after 45 min were compared. The creatine phosphokinase levels in the coronary effluent were lower after early reperfusion (p less than 0.001). Moreover, in the early reperfusion group, the coronary sinus catecholamine and purine levels rose to higher values than in the 3 hr group. The plasma levels of catecholamines and the plasma renin activity increased rapidly but transiently at reperfusion in the 45 min group. Both the rate-pressure product and the heart rate were elevated at the end of the reperfusion period (p less than 0.001) in the 45 min group. Survival for two weeks was 3 out of 6 animals in the 3 hr group and 5 out of 8 in the 45 min group. In all but one surviving animal, sustained ventricular tachycardias were inducible by programmed stimulation. Abnormally low QRS amplitudes and delayed potentials were found in the signal-averaged electrocardiogram in the early reperfusion group only. In conclusion, early reperfusion causes a reduction of myocardial tissue damage, but simultaneously, neurohumoral parameters showed a greater activation of the sympathetic nervous system and the renin-angiotensin system apparently causing a deleterious increase in oxygen consumption. Therefore, this injurious component of early reperfusion might prevent the potentially beneficial effects of a reduced tissue damage on survival or late arrhythmias.

The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig.

The effects of oral zofenopril pretreatment were investigated in a chronic closed-chest pig model of ischemia and reperfusion. Pigs (25-35 kg) were pretreated orally with zofenopril (15 mg/day) on the 2 days prior to ischemia, which was evoked by the inflation of a catheter balloon in the left anterior descending coronary artery over 45 minutes. The catheter was then removed and the myocardium was reperfused. After 2 weeks, infarct properties were assessed by signal averaging of the body surface electrocardiogram and the inducibility of malignant ventricular tachyarrhythmias was tested with a programmed electrical stimulation protocol. A significant increase in the pressure-rate product (43 +/- 11%, mean +/- SEM), indicating the oxygen demand of the heart, was prevented by zofenopril (19 +/- 8%, p less than 0.05). Zofenopril reduced the peak efflux of adrenaline (1302 +/- 213 vs. 3201 +/- 760 pg/ml; p less than 0.05), noradrenaline (402 +/- 54 vs. 902 +/- 282 pg/ml; p less than 0.05), and of the adenosine catabolites inosine and hypoxanthine (56 +/- 4 vs. 78 +/- 9, pg/ml; p less than 0.05) in the coronary venous effluent. The efflux of the cytoplasmatic enzyme creatine phosphokinase was not significantly reduced after zofenopril (p = 0.08). No difference in plasma renin levels between the groups were found. After 2 weeks, late potentials were found only in the surviving animals from the untreated group, i.e., the voltage vector magnitude was more reduced, and a prolongation of the QRS duration and of the terminal low-amplitude part of the high-frequency QRS were found.(ABSTRACT TRUNCATED AT 250 WORDS)