Reserve-driven flow control for extracorporeal life support: proof of principle.

Extracorporeal life support systems lack volume-buffering capacity. Therefore, any decrease in venous intravascular volume available for drainage may result in acutely reduced support flow. We recently developed a method to quantify drainable volume and now conceived a reserve-driven pump control strategy, which is different from existing pressure or flow servo control schemes. Here, we give an outline of the algorithm and present animal experimental data showing proof of principle. With an acute reduction in circulatory volume (10-15%), pump flow immediately dropped from 4.1 to 1.9 l/min. Our pump control algorithm was able to restore bypass flow to 3.2 l/min (about 80% of the original level) and, thereby, reduced the duration of the low-flow condition. This demonstrates that a reserve-driven pump control strategy, based on the continuous monitoring of drainable volume, may maintain extracorporeal circulatory support flow, despite serious changes in filling conditions.

Hydrodynamic performance and heat generation by centrifugal pumps.

For over a century, centrifugal pumps (CP) have been used in various applications, from large industrial pumps to flow pumps for aquariums. However, the use of CP as blood pumps has a rather short history. Consequently, the hydraulic performance data for a blood CP are limited. The aim of our investigation was to study the hydraulic performance and the heat generation of three commercially available CP: Bio-Medicus Bio-Pump BP80 (Medtronic), Rotaflow (Jostra Medizintechnik), and DeltaStream DP2 (MEDOS Medizintechnik AQ). The study was performed using a circuit primed with a water-glycerin mixture with a dynamic viscosity of 0.00272 pa/s. Pressure-flow curves were obtained by a stepwise stagnation of the pump outlet or inlet. The temperature changes were observed using ThermaCAM SC2000 (Flir Systems). The pumps' performance in close to clinical conditions ('operating region') was analysed in this report. The 'operating region' in the case of the BP80 is positioned around the pressure-flow curve at a pump speed of 3000 rpm. In the case of the Rotaflow, the 'operating region' was between the pump pressure-flow curves at a speed of 3000 and 4000 rpm, and the DP2 was found between 7000 and 8000 rpm. The standard deviation of mean pressure through the pump was used to characterise the stability of the pump. In experiments with outlet stagnation, the BP80 demonstrated high negative association between flow and pressure variability (r = -0.68, p < 0.001). In experiments with the DP2, this association was positive (r = 0.68, p < 0.001). All pumps demonstrated significantly higher variability of pressure in experiments with inlet stagnation in comparison to the experiments with outlet stagnation. The rise of relative temperature in the inlet of a pump was closely related to the flow rate. The heating of fluid was more pronounced in the 'zero-flow' mode, especially in experiments with inlet stagnation. In summary, (1) the 'zero-flow' regime, which is described in the manuals of some commercially-available pumps, is the use of the pump outside the allowable operating region. It is potentially dangerous and should, therefore, never be used in clinical settings. (2) Using centrifugal pumps for kinetic-assisted venous return can only be performed safely when the negative pressure at the inlet of the pump is monitored continuously. The maximum allowable negative pressure has to be defined for each type of pump, and must be based on pump performance.

Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops.

OBJECTIVES: Patients in heart failure with left bundle branch block benefit from cardiac resynchronization therapy. Usually the left ventricular pacing lead is placed by coronary sinus catheterization; however, this procedure is not always successful, and patients may be referred for surgical epicardial lead placement. The objective of this study was to develop a method to guide epicardial lead placement in cardiac resynchronization therapy. METHODS: Eleven patients in heart failure who were eligible for cardiac resynchronization therapy were referred for surgery because of failed coronary sinus left ventricular lead implantation. Minithoracotomy or thoracoscopy was performed, and a temporary epicardial electrode was used for biventricular pacing at various sites on the left ventricle. Pressure-volume loops with the conductance catheter were used to select the best site for each individual patient. RESULTS: Relative to the baseline situation, biventricular pacing with an optimal left ventricular lead position significantly increased stroke volume (+39%, P =.01), maximal left ventricular pressure derivative (+20%, P =.02), ejection fraction (+30%, P =.007), and stroke work (+66%, P =.006) and reduced end-systolic volume (-6%, P =.04). In contrast, biventricular pacing at a suboptimal site did not significantly change left ventricular function and even worsened it in some cases. CONCLUSIONS: To optimize cardiac resynchronization therapy with epicardial leads, mapping to determine the best pace site is a prerequisite. Pressure-volume loops offer real-time guidance for targeting epicardial lead placement during minimal invasive surgery.

Acute and short-term effects of partial left ventriculectomy in dilated cardiomyopathy: assessment by pressure-volume loops.

OBJECTIVES: The aim of this study was to evaluate the short-term effects of partial left ventriculectomy (PLV) on left ventricular (LV) pressure-volume (P-V) loops, wall stress, and the synchrony of LV segmental volume motions in patients with dilated cardiomyopathy. BACKGROUND: Surgical LV volume reduction is under investigation as an alternative for, or bridge to, heart transplantation for patients with end-stage dilated cardiomyopathy. METHODS: We measured P-V loops in eight patients with dilated cardiomyopathy before, during and two to five days after PLV. The conductance catheter technique was used to measure LV volume instantaneously. RESULTS: The PLV reduced end-diastolic volume (EDV) acutely from 141+/-27 to 68+/-16 ml/m2 (p < 0.001) and to 65+/-6 ml/m2 (p < 0.001) at two to five days postoperation (post-op). Cardiac index (CI) increased from 1.5+/-0.5 to 2.6+/-0.6 l/min/m2 (p < 0.002) and was 1.8+/-0.3 l/min/m2 (NS) at two to five days post-op. The LV ejection fraction (EF) increased from 15+/-8% to 35+/-6% (p < 0.001) and to 26+/-3% (p < 0.003) at two to five days post-op. Tau decreased from 54+/-8 to 38+/-6 ms (p < 0.05) and was 38+/-5 ms (NS) at two to five days post-op. Peak wall stress decreased from 254+/-85 to 157+/-49 mm Hg (p < 0.001) and to 184+/-40 mm Hg (p < 0.003) two to five days post-op. The synchrony of LV segmental volume changes increased from 68+/-6% before PLV to 80+/-7% after surgery (p < 0.01) and was 73+/-4% (NS) at two to five days post-op. The LV synchrony index and CI showed a significant (p < 0.0001) correlation. CONCLUSIONS: The acute decrease in LV volume in heart-failure patients following PLV resulted at short-term in unchanged SV, increases in LVEF, and decreases in peak wall stress. The increase in LV synchrony with PLV suggests that the transition to a more uniform LV contraction and relaxation pattern might be a rationale of the working mechanism of PLV.

Hemodynamic effects in acute cardiomyoplasty of different wrapped muscle activation times as measured by pressure-volume relations.

BACKGROUND: Correct timing of mechanical interaction between wrapped latissimus dorsi muscle (LDM) and the heart during cardiac systole has been poorly understood and remains a controversial issue. Therefore, left ventricular pressure-volume relations were analyzed in acute cardiomyoplasty while changing the synchronization delays. METHODS: Effects of different delays between the sensed cardiac R wave and wrapped muscle contraction were studied in goats submitted to acute left cardiomyoplasty. Conductance and micromanometer catheters were used to evaluate hemodynamics. Systolic contribution of the wrapped muscle was studied in preassisted and assisted beats, whereas diastolic effects were studied in assisted and postassisted beats. RESULTS: At best settings, cardiomyoplasty resulted in a significant (p < 0.05) increase in left ventricular ejection fraction (from 42.2 +/- 9.2 to 56.7% +/- 13%), in stroke work (from 2769 +/- 1140 to 4271 +/- 1717 gm/m2), in dP/dt (from 1185 +/- 342 to 1510 +/- 285 mmHg/sec), in end-systolic pressure (from 93.5 +/- 22.5 mmHg to 97.3 +/- 22.3 mmHg), and in peak ejection rate (from 282 +/- 64 to 533 +/- 241 mL/sec). Stroke volume showed a mean increase of 35% (from 42.2 +/- 9.9 mL to 56.9 +/- 20.1 mL) during assisted beats. Diastolic function was not substantially impaired at optimal stimulation delay. Incorrect timing of LD contraction resulted in suboptimal improvement or no change in comparison with unassisted hemodynamics. CONCLUSIONS: Our study documents support of cardiac performance by LDM. Incorrect timing of heart/wrapped muscle interaction led to suboptimal hemodynamic results. Muscle contraction timing is an important factor in cardiomyoplasty outcome.

A new stimulation protocol for cardiac assist using the latissimus dorsi muscle.

When treating severe cardiac failure with dynamic cardiomyoplasty, knowledge about the optimal way of stimulating the latissimus dorsi (LD) muscle is of obvious importance. We evaluated a new stimulation protocol in four goats using in situ electrical stimulation of the left LD muscle. Stimulation was started using a burst of two pulses with an interpulse interval of 100 msec for 50 bursts/min. The number of pulses was increased every 2 weeks concomitant with a decrease in interpulse interval. This resulted after 12 weeks in 60 bursts/min using bursts of six pulses with an interpulse interval of 20 msec after 12 weeks. Force measurements, which were done every 2 weeks, showed an early decrease in contraction and relaxation speed as reflected in the ripple (= interstimulus amplitude/peak force amplitude measured at 10 Hz). Fatigue resistance increased significantly within 4 weeks of conditioning as indicated by preservation of force, positive dF/dt, and negative dF/dt. Full preservation of these variables was seen even during a 1-hour fatigue test at the end of the conditioning period. Skeletal muscle enzyme activity as an indicator of muscle damage showed a significant rise in creatine kinase enzyme activity only on the first day following the start of LD stimulation. LD muscle biopsies revealed almost complete transformation to type I muscle fibers with a significant increase in capillary/fiber ratio when compared to the nonstimulated LD muscle. However, some biopsies, in particular near the electrodes, did show some signs of skeletal muscle damage. Contraction characteristics of the fully transformed LD muscles were tested by increasing the number of bursts of six pulses from 50/min to 100/min. Interpulse intervals of 20 and 33 msec were used. These tests revealed that maximal force, positive dF/dt, and negative dF/dt was reached with 50 bursts/min using a six pulse burst with interpulse intervals of 20 msec.

Imipramine induced heart failure in the dog: a model to study the effect of cardiac assist devices.

OBJECTIVE: The value of intravenous imipramine in creating a reversible model of short term heart failure was evaluated in anaesthetised dogs. METHODS: Acute effects of imipramine were studied in 11 dogs using invasive haemodynamic pressure measurements and two dimensional echo evaluation. RESULTS: After a 30 min imipramine infusion (7.5 mg.kg-1.h-1), positive left ventricular dP/dtmax decreased from 1368(SEM 108) to 909(119) mm Hg.s-1 (p < 0.05), left ventricular end diastolic pressure increased from 8(1) to 12(2) mm Hg (p < 0.05), while left ventricular pressure decreased from 106(4) to 87(6) mm Hg (p < 0.05). Cessation of imipramine administration resulted within 60 min in partial restoration of cardiac function. This deterioration and subsequent recovery was also demonstrated with echocardiographic measurements, which showed a decrease in ejection fraction from 54(3)% to 28(2)% (p < 0.05). During administration of imipramine neither significant electrophysiological changes nor supraventricular/ventricular arrhythmias were seen. Repeated infusions of imipramine in three anaesthetised dogs with a two week interval showed the reproducibility of the haemodynamic effects and the recovery of ventricular function. Since the model was developed to evaluate the use of cardiomyoplasty in heart failure, the effect of imipramine was also evaluated on latissimus dorsi muscle contraction. Administration of imipramine did not affect skeletal muscle force development at the dosage used to create heart failure. CONCLUSIONS: This model can be used to produce short term reversible heart failure in anaesthetised animals to test the efficacy of supportive interventions like dynamic cardiomyoplasty, intra-aortic balloon pumping, and mechanical cardiac assist devices.

Further observations to confirm the arrhythmia mechanism-specific effects of flunarizine.

In conscious dogs with chronic atrioventricular (AV) block, we recently demonstrated that flunarizine is effective against ouabain-induced arrhythmias (triggered activity resulting from delayed afterdepolarizations, DADs) but fails to suppress spontaneous ventricular tachycardias (VT) occurring 24 h after left anterior descending coronary artery occlusion (abnormal automaticity). Neither does flunarizine affect normal automaticity, which suggests that flunarizine could be used as a clinical tool to recognize cardiac arrhythmias based on triggered activity. To elucidate further the arrhythmia mechanism-specific action of flunarizine, we investigated (a) its hemodynamic and electrophysiologic effects in 6 anesthetized dogs, (b) its ability to prevent pacing-induced VT 7 days after myocardial infarction (reentry) in 9 anesthetized animals, and (c) its effect on premature escape beats (PEBs) in 9 conscious dogs with chronic AV block. PEBs are probably caused by DADs. Flunarizine decreased systemic blood pressure (p less than 0.01), and left ventricular dP/dt (p less than 0.01), but did not affect AH or HV internal, QRS duration, QT time, or the effective refractory period of either AV node or right ventricle over a wide range of (paced) cycle lengths. Flunarizine decreased the inducibility of PEBs by 42% (p less than 0.01), but not that of the reentrant VT in any of the 6 inducible dogs. Therefore, we conclude that although flunarizine has no electrophysiologic effects in normal heart, it prevents induction of PEBs. The inability of flunarizine to prevent induction of reentrant VT confirms the mechanism-specific action of flunarizine against triggered activity.

Changes in canine latissimus dorsi muscle during 24 wk of continuous electrical stimulation.

To study functional, structural, and biochemical adaptations to electrical stimulation of striated muscle in a large animal, the canine latissimus dorsi (LD) muscle was conditioned continuously for 24 wk with an increasing number of pulse bursts (burst duration 250 ms, burst frequency 30 Hz). Force measurements in vivo after 12 wk showed a significant decrease in the ripple, the ratio of interstimulus to peak force amplitude, from 0.94 +/- 0.03 to 0.13 +/- 0.08 (SE; n = 8, P less than 0.05), indicating reduction in contractile speed. Also the steep part of the force-frequency relation shifted to lower frequencies. A significant change in fiber-type composition was seen with both enzyme- and immunohistochemistry, manifested by an increase of type I fibers from 29.5 +/- 2.9 to 83 +/- 8% (SE; n = 8, P less than 0.05). During this period a transient rise in the number of type IIc/Ic fibers (from 3 to 10%) was seen. In the stimulated muscle, capillary-to-fiber ratio increased from 1.9 +/- 0.4 to 2.7 +/- 0.1 (P less than 0.05). A significant increase in mitochondrial volume was also seen, especially in the peripheral part of the fiber. Both creatine kinase and lactate dehydrogenase revealed a significant decline in activity within 12 wk. At the same time a shift in lactate dehydrogenase-isozyme pattern was observed toward the cardiac composition. No additional changes occurred after 12 wk of stimulation, indicating that conversion of the canine LD muscle was complete within this period.

A new method to select stimulus strength after cardiomyoplasty.

At present, there is no technique available for the determination of optimal stimulus strength in patients after cardiomyoplasty. To stimulate the latissimus dorsi (LD) muscle, we implanted Itrel stimulators in two goats and cardiomyostimulators in three goats following the routine cardiomyoplasty procedure. During the following 3 months, these LD muscles were conditioned at 2.5-4.0 volts (V). After conditioning, LD muscle shortening was measured on x-ray films using the distance between two stimulation electrodes as references. LD muscle shortening increased rapidly at higher stimulus strength and reached 13% +/- 2% at 2.0 V. Shortening was calculated in one patient at 4, 6, and 9 weeks following surgery. The increase in the number of pulses per burst (2, 3, and 6, respectively) had a positive effect on muscle shortening between the two stimulation electrodes (10%, 14%, and 20%, respectively). Also, muscle shortening was measured between two clips attached to the distal part of the LD muscle. Muscle shortening in the area wrapped around the left ventricle was 15% after 9 weeks. In a second patient, shortening between the electrodes was 16% at 14 months after surgery, and distal muscle shortening was 11%. We concluded that optimal stimulation after cardiomyoplasty could be detected more accurately by measurement of LD muscle shortening using the stimulation electrodes or surgical clips as markers.

Changes in myocardial high-energy phosphate stores and carbohydrate metabolism during intermittent aortic crossclamping in dogs on cardiopulmonary bypass at 34 degrees and 25 degrees C.

The effect of cooling to 25 degrees C on myocardial metabolism was studied during four periods of global ischemia (10 minutes each) followed by 15 minutes of reperfusion in dogs on cardiopulmonary bypass. Systemic and heart temperature at normothermia (group N, 34 degrees C; n = 15) was compared with general hypothermia (group H, 25 degrees C; n = 16). Before and at the end of each aortic crossclamp period in small myocardial biopsy specimens the adenosine triphosphate, creatine phosphate, inorganic phosphate, glycogen, and lactate content was analyzed. Also, lactate and inorganic phosphate were measured in the coronary effluents during the repetitive periods of reperfusion. Hemodynamic function was not different at 60 minutes after cardiopulmonary bypass compared with pre-cardiopulmonary bypass values, and was not different between the groups N and H. The tissue content of adenosine triphosphate and glycogen decreased progressively during the experimental period, resulting in slightly depressed values in both groups at the end of cardiopulmonary bypass. Pronounced effects of ischemia and reperfusion on tissue content of creatine phosphate, inorganic phosphate, and lactate were observed after each period of ischemia. The net decrease in tissue creatine phosphate content was not different between groups N and H (41 +/- 4 versus 38 +/- 4 mumol.gm-1 dry weight; mean +/- standard error of the mean) after 10 minutes of ischemia. However, during ischemia the net inorganic phosphate increase in myocardial tissue was significantly higher in group H (70 +/- 7 mumol.gm-1) than in group N (44 +/- 3 mumol.gm-1). These findings do not support the notion that myocardial protection is improved during hypothermia. Moreover, quantitatively the release of inorganic phosphate and lactate did not correlate with the amount accumulated in the myocardial tissue during the preceding periods of ischemia. The release appeared to be temperature dependent, that is, significantly reduced at 25 degrees C. The present data demonstrate why clinical outcome is satisfactory in both surgical procedures, when in general the periods of aortic crossclamping do not exceed 10 minutes each and the reperfusion periods in between the ischemic episodes last about 15 minutes. Besides, the findings indicate that hypothermia is not strictly necessary under these circumstances.

Metabolic and haemodynamic changes in the heart during the early phase of cardiopulmonary bypass: II. Animal experiments.

A significant release of lactate instead of uptake was observed during the first 10 min of cardiopulmonary bypass preceding aorto-coronary bypass surgery in human patients. To clarify these findings in more detail, myocardial lactate and oxygen metabolism was studied in healthy dog hearts subjected to a protocol similar to the clinical situation. In one group (n = 11) normothermia at 34 degrees C was used with an empty beating heart, and in the other group (n = 11) hypothermia with ventricular fibrillation was applied. Within the first 10 min of bypass no significant changes in high energy phosphates were observed in myocardial biopsies. However, a marked decrease in mean aortic blood pressure and a simultaneous lowering in oxygen consumption was observed in both groups after instalment of bypass. An initial shift from lactate uptake to lactate release occurred while on bypass in the normothermia group. After 10 min of bypass, lactate uptake was restored in hearts of both groups. Therefore, the lactate release during the initial phase of bypass in patients originates both from the instalment of the bypass and from (local) inadequate perfusion, which is most likely to be due to stenosed coronary arteries.

Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischaemia.

Isolated working hearts of 16 month old spontaneously hypertensive rats (SHR, n = 8) and age matched Wistar-Kyoto (WKY, n = 8) rats were exposed to 30 min global normothermic ischaemia followed by 60 min reperfusion. The hearts were routinely perfused at an afterload level of 13.3 kPa and a preload level of 1.0 kPa. The control values of left ventricular pressure, its maximal positive first derivative (dP1v/dtmax), coronary flow per gram heart tissue, and release of lactate and enzymes such as lactate dehydrogenase and aspartate aminotransferase were comparable in both groups. WKY rat hearts ejected almost twice as much perfusate per gram heart weight as the SHR hearts. In pressure-flow curves, obtained during the control period in SHR hearts, cardiac output was independent of changes in afterload, varying between 10.7 and 18.7 kPa. In contrast, in WKY rat hearts increases in afterload resulted in a progressive decrease in cardiac output. Reperfusion of the SHR hearts after 30 min of global normothermic ischaemia resulted in a poor recovery of cardiac output (13% of the control values) and dP1v/dtmax (32%) compared with the values in the WKY rat hearts (66% and 91% of the control values respectively). Reactive hyperaemia was prominent in the WKY rat hearts but completely absent in the SHR hearts. During one hour reperfusion, SHR hearts lost 3.5 times more lactate dehydrogenase and 2.5 times more aspartate aminotransferase than the WKY rat hearts. Pressure-flow curves, obtained during the reperfusion period, showed modest recovery of myocardial function of the WKY rat hearts at the lowest afterload level tested but completely depressed myocardial function of the SHR hearts at all afterload levels. Heart tissue contents of adenosine triphosphate and creatine phosphate after one hour of reperfusion were lower in the SHR than in the WKY rats, but compared with native values a comparable percentage decrease was seen in both groups of rats.

A microcomputer system for haemodynamic measurements in isolated, working rat hearts.

This study describes the application of an Apple IIe microcomputer in combination with a pre-processor in the on-line calculation of haemodynamic variables of the isolated working rat heart and of relative rapid changes in these variables, induced by variations in left atrial filling pressure (preload) and end-diastolic aortic pressure (afterload). Variables such as heart rate, systolic and diastolic left ventricular pressure, the maximal positive and negative first derivative of the left ventricular pressure, systolic and diastolic aortic pressure and aortic flow were continuously calculated and printed at minimal intervals of 6 s. A newly designed procedure to detect the activation of the electrogram, which was necessary to start the detection of a new cardiac cycle, is described.