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J Thorac Cardiovasc Surg 1994;108:495-502
© 1994 Mosby, Inc.

GENERAL THORACIC SURGERY

Influences of nonpulsatile pulmonary flow on pulmonary functionEvaluation in a chronic animal model

Masayuki Sakaki, MD, Yoshiyuki Taenaka, MD, Eisuke Tatsumi, MD, Takeshi Nakatani, MD, Hisateru Takano, MD


Osaka, Japan

From the Department of Artificial Organs, National Cardiovascular Center Research Institute, Osaka, Japan.

Received for publication Nov. 8, 1993. Accepted for publication March 9, 1994. Address for reprints: Masayuki Sakaki, MD, Department of Artificial Organs, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka, 565, Japan.

Abstract

To clarify the influences of nonpulsatile blood flow on the physiologic function of the lung, we established nonpulsatile pulmonary circulation with a centrifugal pump in a chronic animal model (adult goats, n = 6). As the initial phase, a pulsatile right ventricular assist device was implanted to bypass the whole blood supply from both the right atrium and right ventricle to the pulmonary artery. After 2 weeks of pumping, the pulsatile pump was replaced with a centrifugal pump without anesthesia, and nonpulsatile pulmonary circulation was instituted. In this experimental model, no significant change was observed in either mean pulmonary arterial pressure or pulmonary vascular resistance index during the pulsatile pumping compared with that on the fourteenth day of nonpulsatile pumping. Blood gas data, extravascular lung water content, and serum level of angiotensin-converting enzyme were maintained within normal ranges. There was also no significant change in the ventral to dorsal blood perfusion ratio of the lower lobe of the right lung. These results indicate that pulmonary functions are not affected by nonpulsatile pulmonary circulation for a period of 14 days in this animal model. (J THORAC CARDIOVASC SURG 1994;108:495-502)

Recently, the centrifugal pump has been widely applied in assisted circulation for severe heart failure as the pump for right or left heart bypass. In particular, right heart bypass with a centrifugal pump is increasingly applied in the treatment of patients with right heart failure. Go 1 Because centrifugal pumps may become more commonly applied for long-term use, such as for bridging to heart transplantation or for an implantable total artificial heart, the physiologic effects of nonpulsatile pulmonary blood flow on body or organ perfusion may be a major concern in these applications. Although its effect on systemic circulation has been extensively examined, the influence of nonpulsatile pulmonary circulation on the lung has not yet been fully elucidated.

Previous experiments in acute animal models have revealed elevation of pulmonary vascular resistance Go Go 2-6 or increase in lung water content Go Go 6,7 in nonpulsatile pulmonary circulation. Furthermore, in patients, abnormal distribution of pulmonary blood flow has been observed after the Glenn or Fontan operation. Go Go 8-10 Such results suggest that nonpulsatile blood flow may affect the pulmonary microvascular circulation. However, experiments in chronic animal models have demonstrated survival for more than 3 months with nonpulsatile pulmonary circulation. Go Go 11-14 Because the need for prolonged use of such bypass support in patients may increase, a chronic model for the study of nonpulsatile pulmonary blood flow should be established.

In view of the foregoing, we established a chronic animal model to clarify the influence of nonpulsatile blood flow on pulmonary hemodynamics, gas exchange, metabolic functions, and the distribution of lung tissue perfusion in awake animals.

MATERIALS AND METHODS

Six healthy adult goats weighing from 50 to 63 kg (57.5 ± 1.9 kg, mean ± standard error of the mean) were used. Sterile techniques were enforced throughout the experiments.

The experiment was carried out in two stages as follows to analyze the effect of the depulsation itself rather than the effects of the surgical intervention and general anesthesia. Initially, the goats were premedicated intramuscularly with ketamine hydrochloride 10 mg/kg and atropine sulfate 0.01 mg/kg. After intubation of the goats, anesthesia was maintained with halothane (0.5% to 1.5%) with a mixture of nitrous oxide and oxygen. Left thoracotomy was performed through the fourth costal bed. An inflow cannula with multiple side holes was inserted into the right atrium and ventricle through the right atrial appendage, and an outflow cannula was sutured onto the main pulmonary artery to bypass the whole venous return blood. A diaphragm-type ventricular assist device Go 15 (VAD, Toyobo Co., Ltd., Osaka, Japan) was installed between these two cannulas. Right heart bypass was started at a rate of 70 to 80 beats/min in a fixed rate mode, and the bypass flow was maintained the same as the aortic flow. We did not ligate the pulmonary artery to occlude the bypass circuit for a few minutes during switching of the pump. After the chest was closed, the introducer for the lung-water catheter was inserted via the left carotid artery (Fig. 1).



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  		Fig. 1. Schematic view of the right heart bypass circuit. Blood was diverted from the right atrium and right ventricle and sent to the pulmonary artery. After 2 weeks, the VAD was replaced with a centrifugal pump (Blood pump). Right atrial pressure (RAP), left atrial pressure (LAP), pulmonary artery pressure (PAP), and right ventricular pressure (RVP) were continuously monitored. A lung-water catheter was inserted from the left carotid artery into the descending aorta for measurement of extravascular lung water.

 
Pulmonary circulation was maintained as pulsatile flow with the VAD for 2 weeks, after which the effects of the operation and anesthesia had become negligible. The pulsatile pump was then quickly replaced with a centrifugal pump (modified MD-10, Iwaki Pump Co. Ltd., Tokyo, Japan) without anesthesia. The bypass flow through the centrifugal pump was set to maintain the nonpulsatile pulmonary arterial pressure wave form and to maintain the same mean aortic pressure as before the replacement. Systemic anticoagulation was attained with continuous infusion of heparin to maintain the activated coagulation time between 200 and 300 seconds.

Measurements
Hemodynamic parameters.
Fluid-filled pressure-monitoring catheters were inserted into the main pulmonary artery, internal thoracic artery and vein, left atrium, and right ventricle. An electromagnetic flow probe (MFV-2100, Nihon Koden Co., Tokyo, Japan) was placed on the aortic root to measure the cardiac output. Pulmonary vascular resistance (PVR) and PVR index (PVRI) were calculated by the following equations:

PVR = (PAP - LAP)/Flow x 79.9 dyne · sec · cm-5

PVRI = PVR x Body weight dyne · sec · cm-5·kg

where PAP is pulmonary artery pressure and LAP is left atrial pressure.

Blood gases.
Arterial and mixed venous blood samples were obtained from the pressure-monitoring lines for the aorta and pulmonary artery, and the partial pressures of oxygen and carbon dioxide were measured with a blood gas analyzer (Radiometer ABL-2, Copenhagen, Denmark).

Extravascular lung water.
A lung-water catheter for measuring extravascular lung water, (HE-2900, 5F, Electro-Catheter Corp., Rahway, N.J.) was inserted via the introducer in the left carotid artery into the descending aorta 3 days before pump replacement. As the index of extravascular lung water, extravascular thermal volume was measured with a lung water computer by means of a heat-sodium double indicator dilution method Go 16 (MTV-1100, Nihon Koden Co., Tokyo, Japan). Then, 10 ml of ice-cold 5% saline solution was rapidly injected into the right atrium through the catheter, and the thermal dilution and electrical conductivity curves in the aortic arch were obtained. Each measurement of extravascular thermal volume was carried out three times, and the mean value was used for statistical analysis.

Angiotensin-converting enzyme (ACE).
Blood samples were taken from the aortic line for the measurement of angiotensin-converting enzyme (ACE). The serum ACE level was measured by the Kasahara method. Go 17

Pulmonary blood distribution (ventral/dorsal perfusion ratio).
Pulmonary blood flow distribution was evaluated by a colored microsphere method. Go 18 Microspheres (diameter 20 µm, 3 million, E-Z Trac, Los Angeles, Calif.) were injected into the right atrium through the pressure-monitoring line just before the depulsation and on the first and fourteenth days after depulsation. Microspheres of different colors were used for each measurement. They were distributed to the lung tissue and lodged in the microvasculature. After the goats were killed, the microspheres were extracted from tissue samples (2 to 3 gm) of the lower lobe of the right lung, which was contralateral to the side of the thoracotomy and was not affected, and the number of microspheres of each color was counted. Seven samples from the ventral portion of the right lower lobe and seven from the dorsal portion were obtained in each goat to calculate the blood perfusion ratio of the mean values of the ventral to dorsal lung portions.

Pathologic assessment
At the time of chest closure and at autopsy, small tissue fragments were excised from the left lower lobe of the lung. All samples were fixed in 10% formalin solution and stained with hematoxylin and eosin.

Control data and statistical analysis
Fluid-filled pressure-monitoring catheters and an electromagnetic flow probe were inserted, and the ventral/dorsal blood flow ratio was measured by the colored microsphere method in three adult goats to obtain control data. The serum ACE level was also measured in 10 control goats to determine the normal range.

All data were expressed as mean value and standard error of the mean and analyzed by paired t test or analysis of variance for repeated measures. A probability value of less than 0.05 was considered statistically significant.

All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).

RESULTS

All of the goats tolerated the operation well. They could be extubated within 1 hour after the operation and could stand on the day of the operation. After 2 weeks, the conversion from pulsatile VAD to nonpulsatile pump was performed smoothly, and the behavior of the goats, including respiratory pattern, activity, and appetite, remained unchanged after the replacement. Two of the six goats died suddenly between 10 and 14 days after the operation.

Hemodynamics
Fig. 2 shows the wave forms of PAP during VAD pumping and centrifugal pumping. The pulse pressure of PAP ranged from 8 to 12 mm Hg during VAD pumping. On the other hand, pulsatility was successfully obliterated by centrifugal pumping except for periodic fluctuations corresponding to the respiratory cycle, and nonpulsatile pulmonary blood flow was considered to have been obtained. The cardiac index during VAD and centrifugal pumping was maintained at 109 ± 4.7 and 115 ± 7.6 ml/kg per minute, respectively, and no significant difference was observed.



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  		Fig. 2. Wave forms of electrocardiogram (ECG) and pulmonary artery pressure (PAP) during right ventricular assist device (RVAD) pumping and centrifugal pumping. The wave forms of PAP became almost flat when the centrifugal pump was installed.

 
Changes in mean PAP and calculated PVRI are shown in Figs. 3 and 4, respectively. The mean PAP and PVRI during pulsatile pumping were 14.0 ± 0.7 mm Hg and 6800 ± 140 dyne · sec · cm -5 · kg, respectively, and those on the fourteenth day of nonpulsatile pumping were 13.5 ± 0.3 mm Hg and 6000 ± 1600 dyne · sec · cm -5 · kg, respectively. Although PVRI decreased slightly after conversion, all values were considered to be within the normal range of physiologic fluctuation, and no significant change was observed in either mean PAP or PVRI.



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  		Fig. 3. Mean pulmonary arterial pressure (mPAP) during pulsatile and nonpulsatile pulmonary circulation. No significant change in mPAP was observed after depulsation (dotted line). P, Pulsatile pulmonary circulation with a VAD on each of the last 3 days before conversion; NP, nonpulsatile pulmonary circulation with a centrifugal pump; C, control data from three adult goats.*n = 4.

 


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  		Fig. 4. Pulmonary vascular resistance index (PVRI) during pulsatile and nonpulsatile pulmonary circulation. No significant change in PVRI was observed after depulsation (dotted line). P, Pulsatile pulmonary circulation with a VAD on each of the last 3 days before conversion; NP, nonpulsatile pulmonary circulation witha centrifugal pump; C, control data from three goats.*n = 4 (79.9 dyne · sec · cm-5 = 1 unit).

 
Gas exchange data and extravascular thermal volume
The values of arterial oxygen tension, carbon dioxide tension, oxygen transfer rate, and extravascular thermal volume are shown in GoTable I. Because of occlusion of the introducer and unreliability of long-term electrode measurement with the lung-water catheter, extravascular thermal volume could be measured until the tenth day after depulsation in only three goats. Although arterial carbon dioxide tension and extravascular thermal volume were slightly increased on the fourteenth and tenth days, respectively, no significant difference from the value observed during pulsatile flow was observed during nonpulsatile circulation.


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  		Table I. Effect of nonpulsatile flow on gas exchange and extravascular lung water
 
Serum level of ACE
The serum level of ACE remained within the normal range (8.5 ± 2.6 IU/L, n = 10) during both pulsatile and nonpulsatile pulmonary circulation (GoTable II).


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  		Table II. Effect of nonpulsatile flow on serum ACE level
 
Blood flow distribution
In five of the six goats, blood flow distribution could be measured by the colored microsphere method; the microspheres could not be extracted in the remaining goat. Fig. 5 shows the blood perfusion ratio of the ventral to dorsal lung segments of the right lower lobe during pulsatile pumping and on the first and fourteenth days of nonpulsatile pumping in each goat. All values were within the normal range, and ventral/dorsal perfusion ratio during pulsatile pumping (1.8 ± 0.3) was not significantly different from that (1.5 ± 0.1) on the fourteenth day of nonpulsatile pulmonary circulation.



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  		Fig. 5. Ventral/dorsal blood perfusion ratio of the lower lobe of the right lung (Qv/Qd) during pulsatile pumping and on the first and fourteenth days of the nonpulsatile pumping. The different symbols correspond to individual goats. P, Pulsatile pulmonary circulation with a VAD; NP, nonpulsatile pulmonary circulation with a centrifugal pump; C, control data from three goats.

 
Histologic findings
Microscopic evaluation of the samples obtained on the fourteenth day of nonpulsatile pumping revealed no significant changes in the thickness of the alveolar wall compared with that at the time of chest closure, and no perivascular interstitial edema was noted (Fig. 6).



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  		Fig. 6. Microscopic appearance of the lung on the fourteenth day of nonpulsatile pumping. No perivascular interstitial edema or alveolar wall thickening was evident. (Hematoxylin and eosin stain; original magnification x200.)

 
DISCUSSION

Several types of centrifugal pumps have recently been developed for assisted circulation. Go 19 These pumps have been widely applied in not only left but also right heart bypass. Go 1 On the other hand, since Lee and DuBois Go 20 demonstrated in 1955 that the pulmonary capillary bed has pulsatile flow under normal conditions, several studies in which the effects of pulsatile and nonpulsatile pulmonary blood flow were compared have been reported. Go Go 2-14 However, the question of whether the lung requires pulsatile blood flow has not yet been resolved. One reason for the difficulty in concluding the meaning of pulsatile flow in these studies is that they were performed under unphysiologic conditions. Reactions of the pulmonary vasomoter system to the autonomic nervous system Go Go 21-24 and to vasoactive agents Go 25 in the isolated perfused lung or in an animal model under general anesthesia may not be comparable with those under normal physiologic conditions.

To resolve this issue, we designed a two-stage experimental model. By using a VAD as the pulsatile pump and a centrifugal pump as the nonpulsatile pump in the right heart bypass circuit, we could immediately convert the pulmonary blood flow pattern from pulsatile to nonpulsatile in an awake animal. Regarding the influence of surgical intervention, we Go 26 have previously observed in a similar model that the systemic influence of surgery can be ignored after about 2 weeks after the operation.

Influence of depulsation on hemodynamics
Many investigators have found an increase in pulmonary arterial pressure and vascular resistance with nonpulsatile blood flow in ex vivo or acute animal experiments. Go Go Go 2-6,27 However, we speculated that the behavior of the regulatory system of pulmonary vascular resistance in an ex vivo or acute animal model would differ from that in a chronic awake animal model. The Cleveland Clinic group Go Go 11-14 has performed long-term evaluations of the nonpulsatile systemic and pulmonary circulations with centrifugal pumps in awake animals during ventricular fibrillation. They reported that PAP and PVR in nonpulsatile pulmonary circulation were stable during the experiment, but that both parameters were higher than those observed in normal circulation. We considered that these changes might have been caused by deleterious effects derived from the surgical intervention or from the four conduits placed in the thoracic cavity for the biventricular bypass, including possible atelectasis and effusion of the lung. In our experimental model, we could observe the reaction of the pulmonary vascular system in the absence of the influence of these factors, and we observed no significant changes in PAP and PVRI after depulsation. The results may indicate that the pulmonary vasomotor system in an awake animal can accommodate the immediate change of pulsatile blood flow to nonpulsatile flow, with stable maintenance of pulmonary circulation comparable with that in the pulsatile state.

Influence of depulsation on pulmonary microvascular circulation
The results of several studies of the effects of pulsatile and nonpulsatile perfusion on gas exchange Go Go Go Go 6,7,28-30 suggest that nonpulsatile pulmonary blood flow does not affect gas exchange. Our results are consistent with this observation. However, Taguchi and colleagues Go 7 observed a tendency for lung water to accumulate when nonpulsatile pulmonary circulation with right heart bypass was maintained for 10 hours. Wilkens, Regelson, and Hoffmeister Go 31 suggested that the pulsation of blood flow has an important effect on lymphatic return from isolated organs. In addition, they indicated the possibility of relatively mild edematous changes that do not affect gas exchange. These reports suggest that nonpulsatile pulmonary circulation may change the permeability of the pulmonary capillary wall. In contrast with these results, however, we found no accumulation of extravascular lung water or evidence of perivascular or interstitial edema in histologic examinations performed after 2 weeks of nonpulsatile pulmonary circulation in the present study. Although the reason for this discrepancy between our results and those obtained in previous studies is not clear, we consider that anesthesia or surgical manipulation of the lung tissue or unbalanced intravenous fluid infusion may have affected the permeability of the lung in the acute models.

ACE, which converts angiotensin I to angiotensin II, is located on the luminal surface of endothelial cells, especially those of the pulmonary capillaries. To our knowledge, no study has been conducted concerning the relation between pulsatility and release of cellular ACE. Several studies Go Go 32-35 have demonstrated changes in serum ACE activity when pulmonary vascular endothelial cell injury or lung disease, including bronchial asthma or chronic lung disease, is present. Although the causes of such change are still unclear, we consider that the change in serum ACE level may be influenced under nonpulsatile pulmonary circulation, in which an insufficiency of microvascular blood flow can be present. However, our data indicate that the serum level of ACE remains stable and within the normal range during both pulsatile and nonpulsatile pulmonary circulation. We therefore consider the microvascular pulmonary blood flow to be well maintained in nonpulsatile pulmonary circulation.

Distribution of pulmonary blood flow
Clinical studies Go Go 8-10 of the distribution of regional blood flow in lung tissue after the Glenn or Fontan procedure have suggested that nonpulsatile pulmonary blood flow is one of the factors associated with abnormal distribution of pulmonary blood flow. The abnormal distribution of pulmonary blood flow observed in these clinical studies may have been magnified by the compromised condition of the patients. We considered that the design of the present experiment would clarify the influence of nonpulsatile flow on pulmonary blood flow distribution. Rather than the upper/lower perfusion ratio, we measured the ventral/dorsal perfusion ratio to examine the effect of gravitation on the blood distribution. Go Go 36,37 We observed no significant difference in this ratio during pulsatile compared with nonpulsatile pulmonary blood flow. In the present study, a centrifugal pump was used to provide pulmonary blood flow, and the experiment did not last long enough to allow comparison with the Fontan/Glenn circulation. However, these data suggest that nonpulsatile pulmonary flow with a right ventricular assist device does not acutely affect the blood distribution of the lung.

The limitations of our experiment were the absence of a control group, the small number of animals, which reduces the power of analysis, and the short experimental period. With regard to the lack of a control group, we assumed that the measurements would not change as a result of pulsatile assistance during the remainder of the support period. The other limitations cannot presently be resolved, because the present experimental method is technically demanding and the centrifugal pump cannot be driven for a longer period. The development of a centrifugal pump with the capacity for long-term use would be of use in performing more detailed studies.

In summary, we established nonpulsatile pulmonary flow with a centrifugal pump in a chronic animal model. No significant effects on basic hemodynamics, gas exchange performance, extravascular lung water content, serum levels of vasoactive agents, or the microscopic appearance or blood flow distribution of the lung were observed during 14 days of pumping of pulmonary blood flow under the nonpulsatile condition. These results suggest that nonpulsatile flow can maintain pulmonary circulation within physiologic limits without appreciable adverse effects on lung function in awake animals.

Acknowledgments

We thank Dr. T. Kasugai, the Department of Pathology, Osaka University, for pathologic comments, and the other members of the Department of Artificial Organs, National Cardiovascular Center Research Institute, for their assistance. We also acknowledge Professor H. Matsuda, the First Department of Surgery, Osaka University, for relevant discussions and reviewing the manuscript.

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