JOURNAL

OF SURGICAL

RESEARCH

Extended

18, 437-445 (1975)

Preservation

of the lschemic

by Ventilation

with

Canine

Lung

PEEP

ERIC W. FONKALSRUD, M.D., MANUEL SANCHEZ, LUIS LASSALETTA, M.D., CHRISTIAN SMEESTERS, M.D. AND ISA0 HIGASHIJIMA, M.D. Division of Pediatric Surgery, UCLA School of Medicine, Los Angeles, California 90024 Submitted for publication December 1I, 1974

MATERIALS AND METHODS Twenty-two conditioned adult mongrel dogs weighing 14-20 kg were anesthetized with sodium pentobarbital and metaphane and ventilated through a modified Carlens double-lumen tube for dogs at 14-18 breaths per minute. A left thoracotomy was performed, and both the right and left main pulmonary arteries (PA), the left pulmonary veins (PV), and the left mainstem bronchus were isolated. Noncrushing vascular occlusion clamps were then placed across the left PA and PV. In five dogs (Group I), the left mainstem bronchus was clamped with the lung in the deflated state for a period of 8 hr, while the right lung was ventilated normally through one segment of the Carlens double-lumen tube. In three dogs (Group IIA), the left bronchus was inflated with a mixture of 60% oxygen, 25% nitrogen, and 5% carbon dioxide at 10 cm water pressure and then clamped. The bronchus was reinflated every hour to maintain the constant intrabronchial pressure. In three additional dogs (Group IIB), the pressure of the continuous inflation was increased to 25 cm of water. In another three dogs, both the ischemic and the normal contralateral lungs were ventilated with the same gas mixture using cyclic respirations at a rate of 18 breaths per minute at a maximum inspiraSupported by USPHS Grant HL14333 and in part by tory pressure of 25 cm water and a slightly Contract AT (04-I) GEN-12 between USAEC and the negative pressure during expiration (Group University of California. Presented at the Eighth Annual Meeting of The III). In eight dogs, cyclic ventilation with the Association for Academic Surgery, Los Angeles, same gas mixture as above with an inspiraCalifornia, November 6-8, 1974. tory pressure of 25 cm of water with a

The extreme sensitivity of the lung to periods of ischemia and nonventilation has been one of the major factors limiting successful lung transplantation. Pulmonary arterial perfusion has been shown to be of little benefit in providing support to the lung during periods of ischemia [3, lo]. On the other hand, ventilation of an ischemic lung has been demonstrated to exert a salutary effect on the preservation of lung function after periods of prolonged ischemia Ill]. Previous studies from this laboratory have shown that pulmonary edema occurs in the unexpanded canine lung that has been made ischemic for more than 2 hr and that death of the animal invariably occurs when the ischemia time is extended to 6 hr [5]. Further studies have demonstrated that continuous lung expansion during the period of ischemia may provide sufficient support to permit subsequent function of the lung after 8 hr of ischemia [6]. Cyclic ventilation has been less successful in achieving lung function after ischemia than has continuous expansion. The present study was undertaken to determine whether cyclic ventilation of the ischemic lung with positive and expiratory pressure (PEEP) might provide additional benefit in extending the safe period of lung ischemia.

437 Copyright @1975by Academic Press, Inc. All rights of reproduction in any form reserved.

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positive end expiratory pressure of 5-7 cm of water was used for a IO-hr period (Group IV). The left lung was not permitted to collapse completely at any time during the period of ischemia. After release of the occlusion clamps, the chest was closed with chest tube drainage. Mechanical ventilation through the Carlens tube was given to each dog for an average of 6 hr after operation. Postoperative sedation with pentobarbital was given to permit prolonged intubation. Each dog was given ampicillin, 250 mg TID, beginning 24 hr prior to operation and continued for 7 days postoperatively. The pressure in the femoral artery was monitored continuously throughout the operative procedure. Single-breath, equilibrium, and washout ventilation scans with xenon 133, and perfusion scans with technetium sulfate ggm-labeledalbumin macroaggregates were performed 2 days, 3 wk, and 3 mo after the period of left-hilar occlusion. Bronchospirometric measurements and blood gas analysis were performed preoperatively, within 3 days postoperatively, 1 mo after the period of lung ischemia, and at 6 mo on representative dogs from each group by means of a Gaensler-Collins 9-liter double bronchospirometer. Bronchograms were performed at various intervals after revascularization in representative dogs from each group. RESULTS The survival of the dogs after periods of left pulmonary ischemia is summarized in

Table 1. The average length of survival for dogs in Group I was only 2.9 days even though the period of ischemia was only 8 hr. Severe pulmonary edema developed in the left lung of each dog within 5 min after revascularization. The dogs died with progressive hypotension and generalized bleeding with roentgenographic evidence of consolidation of the left lung despite continued assisted ventilation through the endotracheal tube and administration of blood and electrolyte solutions. Each of the six dogs in Group II died within 3 wk postoperatively. Only a slight difference in average dog survival occurred between the dogs that received continuous inflation at 10 cm of water (av 9.3 days) and those inflated at 25 cm of water (av 6.2 days). One dog from Group IIA survived 22 days; however, each of the other dogs died in less than 12 days after operation with pulmonary edema of the left lung, vascular congestion, refractory hypotension, and in several instances, sepsis. The average survival of the three dogs in Group III was 5.5 days. Two of the dogs died within the first 48 hr after operation with severe bloody pulmonary edema from the left lung and generalized symptoms similar to those described for dogs in Group I. All but one of the eight dogs from Group IV survived for more than 1 wk postoperatively; the average survival was 5 1.4 days. In each of the dogs moderate pulmonary edema developed in the left lung after revascularization, although it was less bloody

TABLE 1 Relationship of Dog Survival to Type of Ventilation Provided to Left Lung During Periods of Ischemia

I IIA

Number dogs 5 3

IIB

3

III IV

3 8

Group

5w of ventilation Lung deflated Continuous inflation (10 cm H,O) Continuous inflation (25 cm H,OJ Cyclic ventilation Cyclic ventilation with PEEP

Length of &hernia (hr)

Average survival (days)

8 10

2.9 9.3

10

6.2

10 10

5.5 51.4

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TABLE 2 Left Pulmonary Isotope Uptake After Periods of Hilar Occlusion (Percent of Total)

Group I HA IIB III IV

Hours of hllar occlnsion 8 10 10 10 10

2 Days postocclusion Perfusion’ 32.2 (1) 28.3 (1) 36.2 (2) 32.4 (1) 39.1 (7)

Ventilation 17.7 23.8 37.8 21.7 47.3

3 Weeks Postocclusion Perfusiona 39 (1) 41.3 (5)

Ventilation 34 48.4

aFigure in parentheses denotes the number of dogs on which the study was performed

than that from dogs in the other groups. One of the dogs lived 6 mo postoperatively, at which time he underwent a contralateral pneumonectomy. This dog resumed spontaneous respiration after the operation but experienced slow, deep respirations with a long pause between expiration and inspiration with the respiratory rate gradually slowing until he died 36 hr postoperatively.

Both ventilatory and perfusion pulmonary scans in dogs from each group showed a decrease in isotope uptake in the left lung from an average preocclusion value for perfusion of 46% uptake to the values shown in Table 2 measured at 2 days and 3 wk postoperatively (Figs. 1 and 2). Only six dogs were alive 3 wk postoperatively for scan studies, five of which were from Group IV. The

FIG. 1. Xenon-133 ventilation scintiphoto (left) and macroaggregated technetium 8orir-labeledperfusion scan (right) from dog from Group I performed 48 hr postoperatively. The left-hand image in each scintiphoto corresponds to the previously occluded left lung. Only 17.7% of the inspired isotope was picked up by the left lung. The left-lung uptake of isotope was 32.2% on the perfusion scan. The increased uptake on perfusion as compared to ventilation suggeststhat intrapulmonary right-to-left shunting is occurring in this poorly preserved lung. This dog died 3 days postoperatively.

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FIG. 2. Ventilation (left) and perfusion (right) scintiphotos performed on dog from Group IV 48 hr after IO-hr period of ischemia and cyclic ventilation with PEEP. The isotope uptake in the left lung with ventilation was 52%, and the radioactive uptake in the left lung with perfusion was 42%. The percentage of total isotope taken up by the left lung was consistently higher on ventilation as compared to perfusion in dogs from Group IV.

percentage uptake of isotope on ventilation scans paralleled the figures for perfusion scans, although in Group IV, the ventilation uptake was somewhat greater than the perfusion. The average uptakes for perfusion and ventilation in the five dogs from Group IV examined 3 wk postoperatively were 41.3% and 48.4%, respectively. This was close to the average preocclusion values (Fig. 3). Scans were not performed on many dogs from Groups I, II, and III because their conditions were critical after the period of hilar occlusion. The results of bronchospirometric evaluation performed on two dogs from Group I in the early postoperative period is shown in Table 3. The VO, in the left lung was only 15.1% of the total (Fig. 4). The percent of total PO, recorded for the left lung in dogs from Group IV was near normal at 72 hr, 1 mo, and 6 mo postoperatively (Figs. 5 and 6).

Bronchograms performed on two dogs

from Group IV showed some narrowing and blunting of the peripheral bronchioles 2 mo postoperatively, with little change seen in a repeat study in one dog performed 4 mo later (Fig. 7). DISCUSSION Pulmonary transplantation, either as an autograft or a homograft, necessarily requires a period in which the lung is without autogenous pulmonary and bronchial arterial blood flow as well as ventilation. Whereas revascularization of acutely ischemit regions of the brain are known to produce hemorrhagic infarction, this phenomenon has not been widely recognized as a hazard of pulmonary revascularization after periods of complete ischemia. After prolonged acute pulmonary ischemia, both capillary and alveolar damage occurs, causing an ischemic infarction to become hemorrhagic when blood flow is reestablished. The severity of the infarction and rapidity of

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FIG. 3. Ventilation (left) and perfusion (right) scintiphotos taken 3 mo postoperatively in dog from Group IV. There was 53% uptake of the isotope by the left lung on ventilation and 44.4% isotope uptake by the left lung on perfusion.

onset of subsequent intrapulmonary hemorrhage with production of bloody pulmonary edema fluid appear to correlate directly with the length of the period of ischemia. When pulmonary ischemia involves obstruction of both pulmonary and bronchial arteries, pulmonary capillary and alveolar injury is much more likely to occur than when the lung is partially protected by collateral circulation through the bronchial vessels. The

validity of this observation originally made in the dog was recently demonstrated in three human patients who were hospitalized with severe pulmonary ischemia (obstructed tricuspid valve prosthesis, obstructed atria1 baffle after repair of transposition of the great vessels, massive pulmonary embolism) and who died from massive tracheobronchial hemorrhage after successful surgical restoration of pulmonary blood flow [2]. In

TABLE 3 Differential Bronchospirometric Studies After Periods of Left Hilar Occlusion Group I Total FO, cc/min FO, left lung (cc/min) VO, right lung (cc/min) VO, percent left lung VO, (only left lung ventilated) cc/min

Group IV

24 hr (2)=

72 hr (5)”

1 mo (4)u

6 mo (1)’

119.1 19.1 100 15.1

135.6 56.6 79 41.7

158.2 66.6 91.6 42.1

141 65 76 46.1

-

‘Number in parentheses indicates number of dogs studied.

-

91

100

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FIG. 4. Difirential bronchospirometric tracing on dog from Group I performed within 24 hr of operation. Both lungs were ventilated with room air. The lower tracing is that of the left lung. The following data are shown from this study: PO,, left = 19.1 cc/min; VO,, right = 100 cc/min; VO,% of totalin left lung = 15.1%.Left lung V, = 1145cc/min, or 19.4%of total.

each of these patients, severe pulmonary edema developed while left atria1 pressure was below normal, indicating loss of lung capillary integrity. Continuous perfusion with pulsatile or nonpulsatile techniques with a wide variety of perfusates has not been helpful in providing long-term support to the isolated canine lung. The extreme sensitivity of the pulmonary microvasculature to sudden changes in pressure and flow have made these techniques less helpful than might be anticipated. On the other hand, ventilation of the ischemic lung has been demonstrated to have a very salutary effect on lung preservation [3, 6, 8, 11, 121.The extended benefit of utilizing PEEP with cyclic ventilation to the ischemic lung is demonstrated in the very significantly improved survival of

dogs in this group compared to the other techniques studied. This study corroborates the view that one of the most important factors in the preservation of lung function is oxygenation. Unlike other organs, the lung, which receives blood that is relatively low in oxygen content under normal circumstances, probably receives oxygen for the metabolic requirements of its component cells not as much from blood as from inspired air. Moreover, oxygen from inspired air diffuses as quickly, or even more so, into lung cells than into the red cells traversing the lung vasculature. Cyclic ventilation of the lung with PEEP appears to facilitate oxygenation at the alveolar level, since it prevents alveolar collapse, which, when it occurs, is particularly difficult to reexpand due to a decreasein surfactant caused by the

FONKALSRUD

ET AL.: PRESERVATION

OF ISCHEMIC CANINE LUNG

FIG. 5. Differential bronchospirometric tracing on dog from Group IV performed 1 mo postoperatively. Both lungs are ventilated with room air. The lower tracing is that of the left lung. The following data are shown: I’O,, left = 66.6 cc/mitt; VO,, right = 75 cc/mitt; VO,% of total in left lung = 47%; left lung V, = loo0 cc/mitt, or 44.4% of total.

FIG. 6. Differential bronchospirogram on dog from Group IV 1 mo postoperatively. The left lung has been ventilated with room air with the right bronchus occluded. The left lung VO, = 100 cc/min; the I&, = 3770 cc/min.

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FIG. 7. Bronchogram performed on dog from Group IV 6 mo postoperatively. Although the ventilation scan showed42.5% uptake by the left lung 1 wk prior to the bronchogram, this study shows some narrowing and blunting of the peripheral bronchioles, particularly in the lower lobe.

pulmonary ischemia [ 131.Furthermore, the functional residual capacity is elevated, and right-to-left shunting is reduced with PEEP ventilation. Five centimeters of end expiratory pressure was used since higher pressures have been shown to significantly reduce cardiac output [4]. The revascularized canine lung is, in many respects, analogous to the human lung with idiopathic respiratory distress syndrome and appears to benefit from therapeutic measures that have been helpful in treating this and other pulmonary conditions clinically [ 1, 71. Since pulmonary arterial perfusion is important for the provision of essential nutrients other than oxygen, it is likely that more prolonged periods of pulmonary ischemia may not be tolerated unless some form of perfusion is coordinated with venti-

lation. Recent studies by Kondo and associates [9] have shown that flushing the pulmonary vasculature with Sacks solution, which approximates intracellular electrolyte composition, may extend the period of lung ischemia 2-fold. The Carlens double-lumen tube was an essential feature in preventing edema fluid produced in the left lung from flowing into the contralateral normal lung and causing asphyxia. A period of postoperative respiratory support with repeated endotracheal suction appears essential if maximal dog survival is to be achieved and the preservation techniques are to be validly assessed. Since the mechanical complications of pulmonary autotransplantation and the complex problems of rejection after allo-

FONKALSRUD

ET AL.: PRESERVATION

transplantation make evaluation of preservation techniques exceedingly difficult, the present study was undertaken to provide a comparison of several preservation techniques using a standard dog preparation with reproducible results. Studies are currently underway to use PEEP ventilation technique for lung allotransplantation between closely matched beagles. SUMMARY To determine the technique most helpful in reducing the severity of pulmonary injury and consequent edema and congestion that follows revascularization, 22 dogs were subjected to left pulmonary hilar occlusion with the lung either in the deflated state or expanded by continuous or intermittent positive pressure. Cyclic ventilation of the ischemic canine left lung with 5 cm PEEP increased the length of survival more than 5fold when compared to dogs treated by continuous expansion or cyclic ventilation without PEEP. Decreases occurred in isotope uptake on ventilation and perfusion scans and in left lung VO, and V, during the first 48 hr after hilar occlusion in all dogs. Uptake returned to near normal values 3 mo later in dogs ventilated with PEEP. Lung expansion by means of cyclic ventilation with PEEP appears to prevent alveolar collapse and thus facilitates oxygenation during periods of ischemia. In contrast to other organs, the lung appears to receive oxygen for the metabolic requirements of its cells from the inspired air as well as from arterial blood flow and thus probably is capable of being preserved for periods of at least 10 hr by ventilation alone. The good long-term pulmonary function in seven of eight dogs ventilated with PEEP during 10 hr of left pulmonary ischemia suggests that this technique may be beneficial in obtaining grafts for lung transplantation. REFERENCES 1. Ashbaugh, D. G., and Petty, T. L. Positive endexpiratory pressure: Physiology, indications, and

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contraindications. J. Thoruc. Cardiov. Surg. 65:165,1973. 2. Brown, S., Mulder, D., and Buckberg, G. Massive pulmonary hemorrhagic infarction following revascularization of ischemic lung. Arch. Surg. 108:795, 1974. 3. Castagna, J. T., Shors, E., and Benfield, J. R. The role of perfusion in lung preservation. J. Thoruc. Cardiov. Surg. 63:521, 1972. 4. Elkins, R. C., Peyton, M. D., Hinshaw, L. B., and Greenfield, L. J. Clinical hemodynamic and respiratory responses to graded positive end-expiratory pressure. Surg. Forum 25~226, 1974. 5. Fonkalsrud, E. W., Sarwat, A. K., Higashijima, I., Arima, E., and Sanchez, M. Evaluation of pulmonary function in the ischemic, nonventilated canine lung. Surgery 76:527, 1974. 6. Fonkalsrud, E. W., Sanchez, M., Higashijima, I., Gyepes, M., and Arima, E.: Evaluation of pulmonary function in the ischemic, expanded canine lung. Surg. Gynecol. Obsret. (in press). I. Gregory, G. A., Kitterman, J. A., Phibbs, R., Tooley, W. H., and Hamilton, W. K. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. N. Engl. J. Med. 284:1333, 1971. 8. Joseph, W. L., Morton, D. L., and Adkins, P. C. Influence of ischemia and hypothermia on the ability of the transplanted primate lung to provide immediate and total respiratory support. J. Thorac. Cardiov. Surg. 62:752, 1971. 9. Kondo, Y., Turner, M. D., Cockrell, J. V., and Hardy, J. D. Ischemic tolerance of the canine autotransplanted lung. Surgery 76:447, 1974. 10. Stevens, G. H., Rangel, D., Joseph, W. L., Yakeishi, Y., Sanchez, M., and Fonkalsrud, E. W. Evaluation in dogs of various techniques of perfusion to preserve the lung. In J. S. Norman (Ed.), Organ Perfusion and Preservation, p. 229. Ap pleton-Century-Crofts, New York, 1968. II. Stevens, G. H., Rangel, D. M., Yakeishi, Y., Sanchez, M., and Fonkalsrud, E. W. The relationship of ventilation to preservation of the ischemic canine lung graft. In G. Zuidema and D. Skinner (Eds.), Current Topics in Surgical Research, p. 5 1. Academic Press, New York, 1969. 12. Veith, F. J., Sinha, S. B. P., Graves, J. S., Boley, S. J., and Dougherty, J. C. Ischemia tolerance of the lung. J. Thorac. Cardiov. Surg. 61:804,1971. 13. Yakeishi, Y ., Nozaki, N., Rangel, D. N., Stevens, G. H., Adams, F. H., and Fonkalsrud, E. W. Effect of allotransplantation of the canine lung on pulmonary surfactant. Surg. Gynecol. Obsret. 128:1264, 1969.

Extended preservation of the ischemic canine lung by ventilation with PEEP.

JOURNAL OF SURGICAL RESEARCH Extended 18, 437-445 (1975) Preservation of the lschemic by Ventilation with Canine Lung PEEP ERIC W. FONKALS...
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