Consequences of the Diaphragm Driven Artificial Heart–Animal Implantation and Mock Circulation Studies

__ I

EXPERIMENTAL APPROACHES

Consequences of the Diaphragm Driven Artificial Heart-Animal Implantation and Mock Circulation Studies" Jeffrey L. Peters, n.o.:: F. M. Donovan, t-; Ph.D./· o and Tun Kawai, M.D. o O

The effects of air-driven diaphragm, artificial hearts implanted with either cardiopulmonary bypass or deep hypothermia were studied in ten calves surviving beyond the initial effects of surgery (beyond 40 bours). Calves were maintained up to ten days with normal aortic blood pressures, but with elevated right ventricular and pulmonary artery pressures and gradually inceasing venous pressure, and symptoms of right artificial heart failure. Smooth, Silicone rubbersurfaced, artificial bearts produced less blood damage than rough-surfaced hearts of Dacron fibrils; however, there was greater evidence of embolization witb the smooth hearts. Mock circulation studies indicate that an asynchronously beating atrium as occurs in the calf experiments can drastically reduce cardiac output. Elimination of the bigh C-wave which occurs with the artificial beart could be demonstrated on the mock circulation witb the use of an active valve. The major problem with the present artificial heart is postulated to be at the inftow. Asynchronously beating atria with bigh pressure pulses and compression of the artificial beart against tbe natural atria and inftow vessels severely decreases cardiac output.

The development of an artificial heart suitable for implantation in man has been the goal of many investigators for the past ten years.! In the last two years, advances in implantation surgery and artificial heart technology have brought this goal within reach for the near future.P" Two-hundred pound calves have been implanted with artificial hearts and have survived beyond ten days.7.g For simplicity and ease of production, these artificial hearts have been air-driven diaphragm hearts with air °From the Division of Artificial Organs, University of Utah, Salt Lake City. Awarded Third Prize, 1972 Alfred A. Richman Essay Contest, American College of Chest Physicians. Supported in part by NHLl (Medical Devices Applications Program), NIH Contract #NIH 69-2181 with Dr. W. ]. Kolff as principal investigator, Division of Artificial Organs, University of Utah, Salt Lake City. ° °Assistant Research Professor of Surgery. Reprint requests: Dr. Peters, Dion. Artificial Organs, Bldg 512, University of Utah, Salt Lake City 84112

CHEST, VOL. 63, NO.4, APRIL, 1973

lines running outside the chest to an external air supply. The rationale has been that once a biocompatible, artificial heart has been perfected, a totally implanted internal power supply, such as an atomic power unit, could be interfaced." The underlying philosophy of artificial heart development has been to use the simplest possible pump and then modify the design according to criteria established from mock circulation and in vivo implantation experiments. This approach has resulted in the current diaphragm artificial heart, without electronics in the chest, which responds to Starling's Law (ie an increase in filling pressure causes an increase in stroke volume ),u'l3 This paper presents the results of in vivo and mock circulation studies of the hemodynamic, physiologic and pathologic consequences of the air-driven diaphragm artificial heart. 589

590

PETERS, DONOVAN, KAWAI MATERIALS AND METHODS

In vivo artificial heart experiments were carried out in ten calves (7I to 91.5 kg), of which seven were preconditioned Holstein calves, the procedures for which have been previously described.w The criterion for this study was survival of a calf with a total artificial heart beyond the immediate effects of surgery (ie calves surviving beyond 40 hours). An air-driven diaphragm, Kwan-Gett, 7 cm diameter hemispherical heart (Fig 1) with either a rough (Dacron materials, seven experiments) or smooth surface (Silicone rubber, three experiments) was used in all experiments. The smooth Silicone rubber hearts were cured in a conventional oven. Silicone rubber flap valves were utilized as inflow valves in all experiments and also as outflow valves in two experiments. Wada-Cutter outflow valves were used in two experiments and Silicone rubber tricuspid outflow valves in five experiments. The stroke volume of each ventricle was 100 mI. Artificial hearts were implanted with cardiopulmonary bypass with the use of a Bentley oxygenator" at normothermia (five experiments) and with surface cooling deep hypothermia, with circulatory and respiratory arrest less than one hour (five experiments). 7.111 The artificial heart was attached to a portion of the natural atria by atrial cuffs which were connected to the right and left artificial ventricles. The artificial aorta and pulmonary artery were attached by quick connects to the natural outflow vessels. The artificial hearts were driven at a fixed rate, usually 120 beats per minute and 30 percent systolic duty cycle. The left ventricular air drive pressure was usually 6 psi and the right ventricular drive pressure was 4 psi. All calves were monitored for venous and arterial pressures after implantation. Some experiments were for hemodynamic evaluation of the artificial heart, which included ventricular, atrial and peripheral blood pressures. The remaining experiments were designed to study changes in blood coagulation factors with a minimum of indwelling catheters to prevent catheter emboli formation. Respiratory (nasal O:! or positive pressure respiration) and fluid support were provided as required by the calf. Blood transfusions were given postoperatively as required for blood loss and thereafter when the hematocrit decreased below 25 percent. Antibiotics (streptomycin, penicillin or gentamicin) were administered as required, and in most experiments, as a prophylactic postoperatively. Pain medication (pentazocine, meperidine) was also administered after surgery. General blood chemistry evaluations included SMA 12/60 (Technicon Corp) scans,

hematocrit, platelet count, free plasma hemoglobin, blood gases and pH. Blood volumes were determined in some experiments utilizing the radio-iodinated human serum albumin (RIHSA) dilution method. The experiments were terminated when the calves showed evidence of metabolic failure (eg uremia, uncontrollable acidosis, bacteremia) or required continuous respiratory support (nasal 02 or positive pressure respirator). At the termination of each experiment, gross and microscopic examinations were performed on the major organs. The artificial heart was carefully examined for fit in the thorax and for nature of the inner surface. In some experiments, casts were made of the natural-artificial atrial chambers and of the inflow vessels to evaluate the volume of the atria and the position of the Inflow vessels. MOCK CIRCULATION STUDIES

A volume-sensitive mock circulation with a venous compliance of 25 ml/rnm Hg and an arterial compliance of 1 ml/mm Hg, was used to evaluate the artificial hearts prior to Implantatton.ts The artificial heart function curves were determined at two driving rates with and without vacuum applied during diastole. Filling pressures were varied between 0 and 20 mm Hg, The duty cycle (1 percent systole) was held constant and the characteristics for each heart were determined at constant outflow pressure (eg 100 mm Hg mean pressure for the left ventricle (Fig 2) and 25 mm Hg mean pressure for the right ventricle). Two separate studies were performed on the mock circulation to test: (1) The effects of a synchronous and asynchronous beating atrium on the function curves of the artificial heart. Function curves (cardiac output vs inflow pressure) at constant driving pressure, duty cycle, arterial pressure and two rates (90 and 120 beats per minute) were determined. The artificial heart was attached to: (a) a simulated venous inflow tract (Penrose drain); (b) a passive artificial atrium and simulated inflow tract; and (c) a variable-timed active

FUNCT. CURVES 12

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FIGURE 2. Function curves of the artificial heart (left ventricle) on the mock circulation.

CHEST, VOL. 63, NO.4, APRIL, 1973

CONSEQUENCES OF DIAPHRAGM DRIVEN ARTIFICIAL HEART artificial atrium and simulated inflow tract. Dye was injected into the artificial heart close to the inflow valve to test for regurgitation. (2) The effects of an active inflow valve on inflow pressures of the artificial heart. In this mock circulation study, an active air-driven circular disc valve, which opens completely during diastole and closes prior to systole, was tested in place of a passive flap inflow valve. Function curves were determined at constant heart rate, duration of systole and arterial pressure using four ventricular pressures (125, 150, 175 and 200 mm Hg). Valve inflow pressures were measured in each condition.

591 VP

RESULTS

The mean survival time of ten calves with total artificial hearts was 94.1 hours (range 41.4 to 260 hours). Hemodynamically, the aortic pressures were comparable to the three-month-old calf with a nor-

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mal heart with a range of 125 to 175 mm Hg systolic pressure and 60 to 100 mm Hg diastolic pressure.F'P Right ventricular pressure (above 100 mm Hg peak systolic) and pulmonary artery pressure (above 50 mm Hg peak systolic) were elevated from the normal. Figure 3 illustrates blood pressures in a chronically instrumented artificial heart experiment (TH70 C12). The venous pressures gradually increased in almost all experiments. Figure 4 illustrates a composite of mean femoral venous pressures in four experiments. Atrial pulsatile pressures and mean pressures were abnormally high and at times peak atrial pressures were above 40 mm Hg. The remnant natural atria were functional in calves after implantation. Figure 5 illustrates right atrial pressure in a calf in which the artificial heart was turned off momentarily and the natural remnant right atrium continued to beat. Mock circulation studies with an artificial atrium and artificial heart attached and mmHg

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CHEST, VOL. 63, NO.4, APRil, 1973

FIGURE 5. Right atrial pressure in a calf when the artificial heart was turned off momentarily. Mean circulatory pressure was 15 mm Hg.

PETERS, DONOVAN, KAWAI

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driven independently revealed that an asynchronously beating atrium dramatically reduced the output of the artificial heart. Dye injections into the artificial heart regurgitated back into the atrium. Conversely, an optimally timed atrium shifted the function curve to increase the cardiac output at lower input pressures (Fig 6). A component of the high pulsatile pressure due to regurgitation during

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closure of the passive inflow valves (C waves, Fig 7) could be eliminated by substitution of an active valve which closed prior to systole of the ventricle. Inflow pressure with the passive valve and active valve optimally timed at a heart rate of 60 beats per minute (ventricular pressure of 150 mm Hg, and filling pressure of 20 mm Hg) are illustrated in figures 8 and 9. The passive valve demonstrated a high atrial pressure pulse when compared to the active valve on the mock circulation. Instantaneous measurements of the venous volume illustrated no valvular regurgitation when the active valve was optimally timed. However when the active valve was purposely timed out of phase, 40 ml regurgitation was measured. The effect of the artificial heart on red cell damage is summarized in Table 1 of the calf experiments. When cardiopulmonary bypass was utilized to implant the artificial heart, free plasma hemoglobin at the start of pumping ranged from 6 mg percent to 132 mg percent. When deep hypothermia was used for implantation, no free plasma hemoglobin was detected at the initiation of pumping of the artificial heart. The rough surface hearts (Dacron materials) had significantly more hemolysis than the smooth surface hearts, as illustrated by the maximum and minimum values in Table 1. The increase in plasma lactic dehydrogenase concentration correlated with the rise of free plasma hemoglobin.P For example, in a calf (TH71 C4) which was pumped for 102 hours with a smooth surface heart, the maximum plasma hemoglobin was 10.8 mg percent with a maximum LDH value of 828 mU/ ml (control value of 612 mU/ ml). In a calf pumped 260 hours (TH72 C13) with a rough surface heart, the maximum free plasma hemoglobin was 45.5 mg percent and the maximum LDH was 5,470 mU/mI. The calves with the high hemolysis all had hemoglobinuria. Despite the surface of the heart, the hematocrit gradually decreased in all experiments and blood transfusions were required. Total bilirubin gradually increased in all experiments from control levels of less than 0.5 to above 5 mg percent in the longer experiments. Platelets decreased in all experiments independent of the type of surface of the artificial heart (Table 1). Respiratory support was required at some time in all experiments. This usually consisted of two liters per minute of nasal O 2 , One calf required no respiratory support for eight days. Most of the calves could stand, eat, drink and pass urine and stools. Blood volume measurements indicated a gradual increase with the time of pumping in the range of a control value of 7.5 liters to over 10 liters after approximately four days. Terminally in all experiCHEST, VOL. 63, NO.4, APRIL, 1973

593

CONSEQUENCES OF DIAPHRAGM DRIVEN ARTIFICIAL HEART CLOSE Ifl:PLOW V~LV

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ments except one, uric acid (three times control value), blood urea nitrogen (two times control value), and serum glutamic oxaloacetic transaminase (ten times control value) were elevated. Gross examination of organs after each experiment showed icterus in the loose connective tissue of the vessels of the thorax and in the mesentery of the intestines. Evidence of embolization could be readily detected in the lungs, kidneys and occasionally in the intestinal vasculature and brains of calves that had been maintained by smooth surface hearts. An average of 1.2 liters of ascites fluid was found in ten experiments. One calf had no ascites at autopsy. The lungs in most experiments were atelectatic in 200. A R

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the anterior lobes. Table 1 summarizes the microscopic changes which in the lungs consisted of atelectasis, hemorrhage, thrombosis and congestion. The kidneys showed a higher incidence of infarction with the smooth surface hearts; however, the rough surface produced hemoglobin casts in the kidneys. There was microscopic evidence of acute tubular necrosis. The liver in eight experiments was congested and most calves had central lobular necrosis and biliary retention. The spleen was either normal or congested (three experiments) microscopically. In five experiments there were microhemorrhages in the brain. Microhemorrhages were diffuse in the

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9. Pressure pulses on the mock circulation with a passive valve in the artificial heart. ( 1) Arterial pressure; ( 2 ) intraventricular pressure; (3) filling pressure-peak pressure wave 64 mm Hg above mean filling pressure during early systole. Other waves during diastole thought to be due to the movement of the diaphragm and resonance waves in the mock circulation. FIGURE

CHEST, VOL. 63, NO.4, APRIL, 1973

594

PETERS, DONOVAN, KAWAI HEMODYN. CONSEQ. OF 11£ AIR DRIVEN DIAPHRAGM ART. t£ART WITH FLAP INFLOW VALVES

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brain of the calf in which the left ventricle exploded when the pressure regulator failed. The fit of the artificial heart was variable in these experiments. If the heart fit correctly in the thorax, there was no kinking of the major vessels and the lungs were only minimally compromised. The most frequent area of poor fit was at the junction of the natural right atrium and atrial cuff. When observed, kinking caused only partial occlusion of the inflow tract of the right ventricle. Plaster casts of the natural atrium, superior and inferior vena and atrial cuff indicated atrial volumes in the range of 42 to 64 ml. The artificial heart in all experiments had a fibrin ring at the housing-diaphragm junction. The smooth surface hearts had fibrin clots behind the inflow valves and behind the cusps of the outflow valves. The cusps of the outflow valve also had clots in them. The rough surface hearts had a fibrin coagulum membrane on the pumping diaphragm which was not firmly attached. In one experiment the fibrin-coagulum membrane was separated from the diaphragm and was infected with Pseudomonas bacteria which was cultured from the major organs at autopsy. DISCUSSION

As a result of the longer survivals, hemodynamic and metabolic consequences have elucidated new problem areas that have to be solved in order to have an artificial heart suitable for total heart replacement in man. Currently, the venous pressure increases with the time of pumping of the artificial heart. High pulsatile atrial pressures have also been measured which have been demonstrated on the mock circulation to be partially eliminated (C-wave component) with an active inflow valve that closes prior to systole." Figure 10 is a schematic of the hemodynamic consequences of the air-driven diaphragm, artificial heart with Hap inflow valves.

Pulsatile atrial pressures have been shown to dramatically decrease the inflow to the natural atrium, a phenomenon Guyton and associates" refer to as venous rectification. Synchronized atrial relaxation has been shown to induce a flow of blood from the venous system into the atrium, which provides a reservoir of blood immediately available for rapid filling of the ventricle.P It has also been demonstrated with the natural heart that the phasic pattern of instantaneous thoracic vena caval How is determined by right atrial pressure events which predominate over the "ventricular suction action."23 Synchronized attial contractions, which are absent when the artificial heart is implanted because cardiac output is optimized on the basis of maximum ventricular output, have been demonstrated on the mock circulation to shift the function curve of the artificial heart to increase cardiac output at lower filling pressures." Conversely, asynchronous atrial contractions have been shown to dramatically decrease the output of the artificial heart. Most probably in the calf with an artificial heart the effects of asynchronously beating natural atria on cardiac output are somewhere between the two extremes of synchronous and asynchronous atrial contractions. The natural atrium and atrial cuff have been shown to have a volume in the range of 42 to 64 ml, which in the presence of asynchronous contractions and slight kinking of the great veins when the artificial heart is compressed up against the atria (as may occur when the calf lies on his sternum), may further limit the filling of the artificial heart. Since the stroke volume of one ventricle of the artificial heart is 100 ml, incomplete filling and inflow obstruction may be producing the symptoms of artificial right heart failure. These symptoms have been demonstrated in the calf with the acutely increasing central venous pressures above 10 mm CHEST, VOL. 63, NO.4, APRIL, 1973

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36.8/1.9

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«0/10

K. G. Hemis, Silieone rubber with nylon velour housing, rough

230/30

K. G. Hemis, Silieone rubber amoath

1070/130

K. G. Hemis, Silieone rubber treated with Dacron fibrils. rougb

760/207 (.fter 24 hrs)

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34/1.9

400/200

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Central lobular neerosia, biliary retention

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Slight inf_

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Atelectasia, bemorrhages

Central lobular necr
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Elperiment electiv=r terminated because of sepsia• pulmonary failure. Artificial heart membrane infected (Peeudomonse)

Hypereellu1ar glomerular witb eon~e!lted glomular cap; Iaries, eortical medullary

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Normal

Normal

Elperiment electively terminated because of pulmonary failure. Calf stood IIJlIIUpported

congestion

Chronie thickening 01 alveolar walls, inflammation and fibroustiasue deP
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596 Hg and high pulsatile venous pressures. Postmortem evidence of central lobular necrosis of the liver and ascites are analogous to cardiac cirrhosis and right heart failure in man. Similarly, high mean and pulsatile left atrial pressures can affect the pulmonary vasculature and can cause morphologic change in the lungs with resultant decreased oxygen transport. An analogous situation of high left atrial pulses in man because of mitral insufficiency can cause an increase in pulmonary blood volume and increase the impedance to right ventricular output. This phenomenon has been referred to as "right ventricular afterload" due to mitral insufficiency which causes an increase in pulmonary blood mass and inertia at the time of right ventricular systole." The extent that left ventricular dynamics of the artificial heart affects right ventricular dynamics is not known at this time. Right ventricular pressure is higher than normal and is related to the mild pulmonary hypertension in the calf. Contributing to the pulmonary hypertension may be the effects of hemolyzed red cells and adenosine diphosphate which have been suggested to have a pulmonary vasoconstrictor effect.26 It is known that the young calf is susceptible to pulmonary hypertension due to pulmonary vasoconstriction from hypoxia'" and can have spontaneous pulmonary hypertension." Progressive pulmonary arterial hypertension after pulmonary venous constriction has been reported by Silove and eo-workers" in Jersey bull calves over a three-month period. TIlls may be occurring acutely in the calf with a total artificial heart when the artificial ventricles compress the atria which then could compress the pulmonary veins, and reduce inflow to the left artificial ventricle. Current efforts in artificial heart research are being directed to replacing the natural atria with artificial atria. They would have the capability of presenting a large volume of blood to the artificial right ventricles, being driven optimally with the ventricles, damping regurgitation pressure and preventing inflow compression. The effect and amount of dp/ dt of the artificial ventricles in the calf has not been studied. Weber and colleagues" have shown in 14 Holstein and Hereford calves that the mean maximum rate of rise of left ventricular pressure of the natural heart is 1,719 mm Hg per second. The blood damage measured in these artificial heart experiments consists of high hemolysis with rough surface hearts and hemoglobinuria when compared to the smooth surface hearts. It appears that hemolysis is a function of the artificial heart since the use of deep hypothermia for implantation eliminated the hemolysis caused by cardiopulmo-

PETERS, DONOVAN, KAWAI

nary bypass. Since serum bilirubin increased in all experiments, there is most probably continuing red cell destruction with pumping of the artificial heart. Further studies are needed to clarify the factors of the artificial heart that cause hemolysis. These experiments indicate that the rough surfaces had less evidence of embolization and suggest that the rough surface allows a fibrin coagulum to be attached to the intima of the artificial heart. However, the possibility of contamination of the smooth Silicone rubber surface of the artificial heart exists in these experiments as the surfaces were cured in a standard oven. Akutsu and eo-workers." however, have had similar long-surviving calves with a smooth Silicone rubber surface but with a different artificial heart design. The fibrin clots behind the inflow valves and at the housing-diaphragm junction of the hemispherical artificial heart found at autopsy indicate possible areas of inadequate washing or blood How stasis. The platelet count decrease in all experiments may be a function of damage by the heart or part of the phenomenon of disseminated intravascular coagulation. It is currently believed that the coagulation system is in a state of eompensation.v-" Blood damage and fibrin deposition on the intima of the artificial heart indicate that driving modes, material-blood interface or How patterns or both (artificial heart design) may have to be altered. Future experiments should clarify the role of the How patterns and shear in the artificial heart on the blood coagulation system.

REFERENCES 1 Nose Y: Advances in biomedical engineering and medical physics. In Cardiac Engineering vol 3. New York, Interscience Publishers, John Wiley and Sons, Inc., 1970, 384 2 Kessler TR, Foote JL, Andrade JE, et al: Methods to construct artificial organs. ASAIO XVII:36-40, 1971 3 KoIH WJ: Removing limiting factors for total cardiac replacement. Transplant Proc III( 4): 1449-1457, 1971 4 Kwan-Gett CS, Van Kampen KR, Kawai J, et al: Results of total artificial heart implantation in calves. J Thorne Cardiovasc Surg 62:880-889, 1971 5 Kwan-Gett CS, Kawai J, Peters JL, et al: Consumption coagulopathy as a limiting factor for the total prosthetic heart. American College of Cardiology meeting, February,I971 6 Kwan-Gett CS, Backman DK, Donovan FM jr, et al: Artificial heart with hemispherical ventricles II and disseminated intravascular coagulation. ASAIO XVII:474480,1971 7 Kawai J, Peters JL, Donovan FM Jr, et al: Implantation of a total artificial heart in calves under hypothermia with 10-day survival. J Thorne Cardiovasc Surg 64:45-60, 1972 8 Kawai J, Donovan FM Jr, Peters JL, et al: Physiologic effects of artificial heart in calves surviving up to ten days. Am Physiol Soc meeting, Lawrence, Kansas, Aug 16-19, 1971 and published in The Physiologist 14:170, 1971

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