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Effects of Ibuprofen on the Hypoxemia of Established Ethchlorvynol-Induced Unilateral Acute Lung Injury in Anesthetized Dogs
labOratory and animal stUdles Effects of lbuf.rofen on the Hypoxemla of Established Ethchlorvyno -Induced Unilateral Acute Lung Injury In Anesthetized Dogs* Harnly S. Sprague, M.D.;t Alan H. Stephenson, Ph.D.;t Thomas E. Dahms, Ph.D.;§ Nesher G. Asner; and Andrew]. Lonigro, M.D.,
Nonsteroidal anti-inftammatory agents, given prior to induction of unilateral acute lung injury with ethchlorvynol (ECV) in anesthetized dogs, prevent the decreases in systemic oxygen tension (PaOJ which are observed when ECV is given alone. We investigated whether ibuprofen, administered after acute lung injury, would result in improvement in arterial oxygenation. In animals not receiving ibuprofen after unilateral acute lung injury with ECV, Pa01 decreased and venous admixture increased signi&candy from control values at all experimental time-periods. In those animals
receiving ibuprofen, signiflcant decreases in venous admixture were noted. 'Ibe decrease in Pa01 after ECV administration was signi&candy less than that observed in animals that did not receive ibuprofen after acute lung injury (p<0.05~ Ibuprofen had no effect on extravascular lung water. 'Ibese results demonstrate that in an ECV model of acute lung injury the administration of ibuprofen, after the acute lung injury, results in signiflcant decreases in venous admixture.
_Nute lung injury in humans, termed the adult respiratory distress syndrome (ARDS), is characterized clinically by systemic hypoxemia and nonhydrostatic pulmonary edema. 1 The pathophysiologic correlates of ARDS include increased pulmonary capillary permeability, 1 decreased lung compliancel.3 and altered reactivity of the pulmonary vasculature. 4 The sedative-hypnotic drug ethchlorvynol (ECV [Placydyl]), when administered intravenously, produces acute lung injury in humans5 and in experimental animals. a.e Previously we reported that, in anesthetized dogs, ECV, selectively infused into the right pulmonary circulation, resulted in systemic hypoxemia and the rapid furmation of nonhydrostatic pulmonary edema confined to the right lung. 8•7 In addition, we demon-
strated that the administration of the nonsteroidal antiinflammatory agents, ibuprofen or indomethacin, prior to the induction of unilateral acute lung injury with ECV, prevented the development of systemic hypoxemia but had no effect on the accumulation of extravascular lung water (EVLW). 7 Although the latter results provided insights into pathophysiologic mechanisms of the injury, of greater importance in defining a therapeutic role fur these agents would be studies in which nonsteroidal antiinflammatory drugs were administered at some time after acute lung injury had been established. In the present work, we investigated the hypothesis that states that the administration of the nonsteroidal antiinflammatory agent ibuprofen, after the establishment of unilateral acute lung injury with ECV, would correct the defect in oxygenation of the blood but would not affect the accumulation of EVLW.
*From the Medical Service, Veterans Administration Medical Center, and the De~ments of Medicine and Pharmacology, St. Louis University School of Medicine, St. Louis. t Assistant Professor of Medicine. :!:Assistant Research Professor of Pharmacology. §Associate Research Professor of Medicine. •Professor of Medicine and Pharmacology. This work was supported by the Veterans Administration and in part by a National Heart, Lung, and Blood Institute, Adult Respiratory Failure SCOR _grant HL-30572. This project was completed during the tenure of Dr. Sprague as a Buder-Peters Fellow of the St. Louis Heart Association.
1088
METHODS
Preparation of Animals Eighteen microfilaria-free male mongrel dogs (22.5±1.1 kg) were
fasted overnight but allowed free access to water and then anesthetized intravenously with sodium pentobarbital (30 mg/kg). Anesthe-
sia was maintained with continuous intravenous administration of pentobarbital at a rate of 0.05 mglkg/min. The animal preparation has been described in detail previously.'' The right and left lungs UnUateral Acute Lung lf1ury In Aneathellzed Dogs (Sptague et el)
were venti1ated independently but synchronously through a Carlens catheter with room air at 12to15 breaths per minute with a total tidal volume of 15 ml/kg. Individual lung tidal volumes were adjusted to achieve equal peak airway pressures as well as equal end-tidal carbon dioxide tensions (LB-2 C01 analyzer, Beckman). Neither ventilatory rate nor tidal volumes were altered throughout the course of the experiment after initial blood gas stability had been achieved. Airway pressures were monitored continuously. An end-expiratory pressure of 5 cm ffaO was maintained tor each lung throughout the experiment 'lb avoid atelectasis, both lungs were hyperinHated to 20 cm HaO every ten minutes mcept in the periods immediately prior to lung water determination. Adequacy ofdivision of ventilation and the position of the Carlens catheter were con&rmed by collapsing the left lung during continued ventilation ofthe right lung. After total separation of ventilation was verified, the left lung was fully reexpanded. The left main pulmonary artery was isolated and fit with a Statham electromagnetic flow probe (8 to 10 mm, id) with nonocclusive zero feature tor continuous measurement of left pulmonary blood flow. Distal to the flow probe, a hydraulic balloon-type external vascular occluder (model OC-8, IVM) was placed around the left main pulmonary artery. 1Wo flow-directed Swan-Ganz catheters were advanced into the main pulmonary artery via peripheral veins, one tor continuous measurement of mean pulmonary arterial pressure ('Ppa), and the other tor obtaining aliquots of mixed venous blood. Arterial and mixed venous blood samples were collected anaerobically and analyzed within &ve minutes tor pH, partial pressure ofC01 (Pc<>a) and partial pressure of The electrodes were calibrated 0 1 (P<>a) (BMS3-MK2, Radiometer~ with tonometered blood samples (ll.237) that had been equilibrated with standardi7.ed gas mixtures. For measurements of mean left atrial pressure ('Pia) and mean systemic arterial pressure (Psa~ catheters were placed directly into the left atrium via the left atrial appendage and into the aorta via the femoral artery, respectively.
Measurement of EVLW Estimates ofEVLW were made periodically over the course ofthe experiment by repeated measurements of emavascular thermal volume (EVIV). Final estimates of EVLW at the end of the experiment were con&rmed by gravimetric methods. For measurement of EVTY, a 5-French catheter with attached thermistor (model 96020-SF, Edwards Laboratories) was placed into a femoral artery. The EVIV was quantified by a microprocessol'-based system (9310 compute.; Edwards Laboratories), which compares the mean transit times of an indicator confined to the vascular space with one that distributes throughout the entire thermal mass of the lung. A bolus of iced 5 percent dextrose containing 2 mg of indocyanine green dye was injected rapidly into the superior vena cava via a catheter introduced into the right jugular vein. The dye concentration curve was measured by withdrawing blood (Sage pump. model 351) through the cuvette of a dye densitometer (model 0402-A, Waters) via the 5-French catheter with attached thermistor. Thus, the dye concentration curve and the thermal curve were determined simultaneously. Cardiac output was calculated by integration of the area under the thermal curve and EVIV was computed based on the difference between the mean transit times ror each indicator."' Following measurement of total EVTY, right lung EVIV was obtained by occluding the left main pulmonary artery ror one minute with the external balloon occludet during administration of the thermal-dye bolus. Thus, total as well as right EVIV were determined directly, whereas left EVIV was calculated as the difference between total and right Evrv. The EVTY, expressed in milliliters per kilogram of body weight, represents the mean of two to three determinations. Previously we demonstrated that EVIV is not affected by operative intervention or repeated left main pulmonary artery occlusions prior to induction of unilateral acute lung injury in this model.• Howevei; to avoid diverting the entire cardiac output to an injured lung,
unilateral measurements of EVIV were not made after induction of acute lung injury with ECV. Bight lung EVIV fDllowing injury with ECV was calculated as the difference of total EVIV and EVIV in the left lung determined prior to ECV administration. Immediately rollowing the last EVIV determination, an aliquot of systemic arterial blood was withdrawn, the pulmonary hila, pulmonary artery and aorta were clamped and the lungs were removed fOr gravimetric determination ofEVLW. The lungs were homogenized and dried to constant weights individually. Gravimetric determinations ofEVLW were corrected tor the weight of blood in each lung based on measurement of the residual hemoglobin in the lungs according to the method of Pearce et al. u Other Measuremsnts Bight pulmonary blood flow was calculated as the difference between left pulmonary blood flow measured with the electromagnetic flow probe and total pulmonary blood flow (cardiac output) determined by thermal dilution as described above. Venous admixture was calculated from the equation: QvatQt= (Cc'01 -Ca0J/(Cc'01 -CVO.) where QvaJQt refen to venous admixture and Cc'O., Ca01 and CV01 refer to capillary, arterial and mixed venous oxygen contents, respectively. 11 Arterial, mixed venous and capillary 0 1 saturations were calculated by the method of Bossing and Cain. D The alveolar Po. was calculated from the alveolar gas equation. 14 E%p6fimental Protocola
Left pulmonary blood flow, as well as Psa, Ppa and Pia, were recorded continuously throughout the experiment After hemodynamic stability had been achieved fDllowing thoraootomy and instrumentation, measurements of cardiac output, total and right lung EVTY, as well as arterial and mixed venous pH, Pea. and Po. were determined several times during the control period; fe, prior to the induction of lung injury. Following these control measurements, the left main pulmonary artery was occluded tor 90 seconds during which time ECV. 9to15 mw'kg, was administered as a bolus into the superior vena cava. In all animals, measurements of total pulmonary blood flow (cardiac output), total EVIV and arterial and mixed venous blood gases were made at 30, 60, 90 and 120 min after the unilateral administration of ECV. Eight animals did not receive ibuprofen after acute lung injury had been established. This group was included to characterize the changes in pulmonary hemodynamics, blood gas composition and EVLW, which occur in response to unilateral ECV-induced acute lung injury in the absence of cyclooxygenase inhibition. In ten additional animals, ibuprofen was administered immediately after the 60-min post-injury measurement period. This timeperiod was chosen because by 60 min after ECV administration there were signi&cant increases in EVLW and venous admixture indicating that acute lung injury had been established. Ibuprofen (Upjohn, sodium ibuprofenate, 12.5 mg/kg) was administered as an intravenous bolus during a period of &ve minutes. This dose was selected based on the efficacy of ibuprofen as an inhibitor of cyclooxygenase activity. • 11 In all experiments, fDllowing the final (120 min) EVIV determination, the lungs were removed tor measurement of EVLW by gravimetric methods. Staflatfcal AnalyBIB
Statistical significance between control (pre-ECV) and experimental periods within each group was determined with a two-way analysis of variance (ANOVAi If the F ratio indicated that changes had occurred, a Least Signi&cant Difference (LSD) test was used to identify individual differences.• For comparison of gravimetric and thermal-dye estimates of EVLW, a one-way ANOVA was used. 11 Comparisons between control (pre-ECV) periods rot each group of experiments were made using an unpaired Students t test 11 Probability values of0.05 or less were considered statistically significant All results are reported as means ± SEM. CHEST I 92 I 8 I DECEMBER, 1887
1-
REsuCTS Group Comparisons Prior to Induction of Unilateral Acute Lung Injury Hemodynamic, blood gas and EVI'V measurements obtained prior to unilateral ECV administration (control) in both groups of animals are depicted in Tuble 1. There were no significant differences between groups for these control (pre-ECV) measurements.
ECV-Induced Unilateral Acute Lung Injury In the animals not receiving ibuprofen after the induction of unilateral acute lung injury with ECV, arterial Po1 (PaOJ was significantly decreased from control values at all time-periods: viz, 30, 60, 90 and 120 min following the administration ofECV (Tuble 1). The decreases in Pa01 were associated with significant increases in venous admixture compared with control values at all time-periods (Tuble 1). 'Ibtal pulmonary blood flow decreased after ECV administration and there was a small, fractional redistribution of intrapulmonary blood flow away from the injured right lung to the uninjured left lung, which reached statistical significance at the 60-, 90-, and 120-min periods af\:er the induction of lung injury (Tuble 1). Unilateral ECV administration produced no change in Pia; Ppa, however, was increased at both 90 and 120 min afterinjury (Tuble 1).
Effects of Ibuprofen on Established ECV-Induced Unilateral Acute Lung Injury The administration of ibuprofen 60 min after the induction of unilateral acute lung injury with ECV
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Effect of ethchlorvynol (ECV (9 to 15 mg/kg]) introduced Into the right pulmonary circulation on the change In venoua admixture (Qv&JQt) with (n=lO; 0-0) and without (n=8; ......_.) ibuprofen (ll.5 m!Vkg) administered 60 min after the onset of acute lung Injury. Asterisk, p<0.05 compared to animals not receiving ibuprofen. FIGURE 1.
produced an improvement in venous admixture. Within 30 min of ibuprofen administration, venous admixture had decreased to values not different from those observed prior to the induction of acute lung injury (Tuble 1). In contrast, venous admixture was increased at all time-periods in those animals that did not receive ibuprofen after ECV-induced acute lung injury (Tuble 1). The changes in venous admixture from pre-injury control values are represented in Figure 1. The increase in venous admixture at the 3o- and 60min periods after lung injury was similar in both groups. However, the changes in venous admixture observed after ibuprofen administration differed significantly
'IBble 1-Effecta ri' lbupnfen Adrniniatend 60 min AjtBr- EthclJoroynol-lnduced Acute Lung Injury on Hemodynamic,
Blood Flow and Blood Goa Meaaumnenta•
Control
30 min
60min
90min
120 min
15.8±1.4
18.2±1.7 17.1±1.6
20.7±1.9§ 20.3±1.9§
20.0±2.0§ 21.1±2.0§
4.7±0.8 4.0±0.5
5.3±0.8 4.2±0.5
5.4±0.7 4.5±0.5
6.1±0.7 5.2±0. 7§
5.5±0.5 5.5±0. 7§
2.60±0.22 2.40±0.14
2.03±0.19§ 2.04±0.14§
1.89±0.17§ 1.85±0.12§
1.91±0.16§ 1.53±0.09§
1.76±0.14§ 1.43±0.09§
Ppa, mm Hg ECV only ECV/ibuprofen Pia, mm Hg ECVonly ECV/ibuprofen Qt, Umin ECV only ECV/ibuprofen Flowu.. % ECV only ECV/ibuprofen Pa01, mm Hg ECV only ECV/ibuprofen
QwJQt
ECVonly ECV/ibuprofen
16.3±1.8 16.9±1.7 15.7±1.5
35±3 41±2
36±4 42±2
42±5t 46±3
44±6* 53±4:j:
50±6§ 58±5§
84.7±2.3 84.9±1.7
74.9±2.7§ 77.5±1.8§
75.0±3.1§ 77.4±2.3§
74.0±3.8§ 80.7±2.6t
71.9±4.4§ 79.6±2.2*
8.4±1.2 10.0± 1.4
13.0±1.7:1= 14.8± 1.9*
12.4±1.7t 14.3±2.2t
13.7±2.6§ 9.5± 1.5
15.8±3.4§ 9.3± 1.3
•ECV, ethchlorvynol; 'Pt>a. mean pulmonary arterial pressure; Pia, mean left atrial prelsure; Qr, total pulmonary blood flow; Flowu., percentage of total blood flow perfusing the left lung; Pa01, systemic arteri&l oxygen tension; (!VtJQt., venous admixture. tp<0.05 compared to respective pre-injury control values. :j:p<0.01 compared tel respective pre-injury control values. §p<0.001 compared to respective pre-injury control values.
1090
U,...... Acute Lung
l~ury
In Anellhellzed Dogs (Sprague et 81)
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FIGURE 2. Effect of ethchlorvynol (ECV [9 to 15 mg/kg]) introduced into the right pulmonary circulation on extravascular lung water (EVLW) in the injured lung estimated by the indicator dilution technique with (n =10; 0--0) and without (n =8; ._.) ibuprofen (12.5 mglkg) administered 60 min after the onset of acute lung injury; p<0.01 for all experimental periods compared with respective control value.
from those observed in the animals that received ECV only (p<0.05, Fig 1). Although the Pa01 remained lower than the pre-injury control value after ibuprofen administration ('Ikble 1), the decrease in Pa01 of 5 ± 2 mm Hg at 120 min after ECV administration was significantly less than the 13 ± 3 mm Hg decrease observed in the animals that did not receive ibuprofen after the development of acute lung injury (p<0.05). Mean left atrial pressure increased significantly only in the ibuprofen-treated animals, but the magnitude of the change was small and the values did not exceed those measured in the ECV-only group at any timeperiod. The fraction of total pulmonary blood flow, which redistributed from the injured right lung to the uninjured left lung, increased at 90 and 120 min after lung injury in the ibuprofen-treated animals ('Ikble 1). The increase in flow to the uninjured lung at 90and120 min after ECV administration was not different from that observed in the animals that did not receive ibuprofen.
Extravascular Lung Water Accumulation The administration of ibuprofen 60 min after the incluction of acute lung injury with ECV did not attenuate the increases in EVLW in the injured right lung (Fig 2, Tuble 2). Extravascular thermal volume, used as an index of EVLW, increased progressively in both groups (Fig 2). The EVLW, measured gravimetrically at the end of each experiment for the injured right lung and uninjured left lung, did not differ between the groups (Tuble 2). DISCUSSION
Ethchlorvynol, when administered into the pulmonary circulation of experimental animalss.e or humans, 5 results in systemic hypoxemia and nonhydrostatic pulmonary edema. The progressive increases in
EVLW, which begin within 15 min of ECV administration, occur in the absence of sustained increases in mean pulmonary arterial or left atrial pressures, 8•7 and are associated with increased pulmonary vascular permeability to endogenous and exogenous solutes' as well as with increased pulmonary lymph flow without a change in lymph-to-plasma albumin ratio. 11 These findings are, therefore, consistent with the contention that ECV administration results in increased pulmonary capillary permeability. The administration of ECV selectively into the pulmonary circulation of the right lung of dogs results in the rapid formation of nonhydrostatic pulmonary edema confined to the fight lung and systemic hypoxemia.' 7 Previously we reported that administration of either indomethacin or ibuprofen, prior to the induction of acute lung injury with ECV, resulted in protection of Pa01 , whereas the accumulation of EVLW was unaffected. 7 The results presented here extend these observations and suggest that, at least in ECV-induced acute lung injury, the administration of ibuprofen after the induction of lung injury results in attenuation of the decreasing Pa01 and a decrease in venous admixture. These findings contrast with those reported for acute lung injury in sheep induced either by Escherichia colt contamination18 or by E coli endotoxin111 where neither ibuprofen nor meclofenamate, respectively, prevented the fall in Pa01 when administered after lung injury had been established. Our results are, however, consistent with the observations of Kopolovic et al, 11 who reported that, in pigs, application of ibuprofen after acute lung injury had been established with live Pseudomonas aeroginosa infusion protected against failure of oxygenation of the blood. The results presented here do not allow resolution of the differences among the various studies; however, these differences may be related to type, duration or extent of uijury or to species differences. The decrease in venous admixture affi>rded by ibuprofen administered 60 min after the induction of unilateral lung injury occurred without augmented Table 2-Detennination cf E~r Lung Water by the Double Indicator Dilution Technique and the Gravimetric Met~ BO min~ the Induction cf Unilateral Acute Lung Inju,.,, toilh Etltehloror/nol*
Uninjured (left) lung EVLW (ml/kg body weight) Thermal-dye Gravimetric Injured (right) lung EVLW (ml/kg body weight) Thermal-dye Gravimetric
ECV Only (n=8)
ECV/lbuprofen (n= 10)
3.19±0.29 2.96±0.26
2.41±0.23 2.86±0.18
9.27±0.26 8.26±0.40
10.15±0.68 7.99±0.50
*ECV, ethchlorvynol; EVLW. extravascular lung water. CHEST I 92 I 6 I DECE~BER,
1967
1091
redistribution of intrapulmonary blood flow from the injured to the uninjured lung (Table 2). In addition, the decreases in total pulmonary blood flow (cardiac output) were not different from those observed in the animals that did not receive ibuprofen after acute lung injury. These findings suggest that the decrease in venous admixture associated with ibuprofen administration may have been due to improvement in ventilation-perfusion relationships within the injured right lung itsel£ It is likely that the injury to the right lung was not uniform although the entire cardiac output was diverted to the right lung during ECV administration. 8•7•22 If ibuprofen administration resulted in a redistribution of blood flow from injured to uninjured areas within the right lung, then venous admixture could be reduced without diversion of blood flow to the uninjured left lung. It is also possible that ibuprofen might have influenced the distribution of ventilation within the injured lung resulting in improved matching of ventilation and perfusion and, thereby, a reduction in venous admixture. The design of the present study does not permit measurement of individual lung compliance or airway resistance; however, in some experiments, peak airway pressures were determined fur each lung throughout the development of acute lung injury. Peak airway pressures in the injured right lung did not differ from peak airway pressures in the uninjured left lung at any time-period in the animals that received either ECV or ECV fullowed by ibuprofen, suggesting that large alterations in either airway resistance or lung compliance did not occur. It has been suggested by us 7 and others23 that the beneficial effect of ibuprofen on the blood gas response to acute lung injury is due to the ability of ibuprofen to block cyclooxygenase activity, which results in the inhibition of prostaglandin and thromboxane synthesis. However, ibuprofen also has been suggested to alter the responses observed fullowing acute lung injury by inhibition of leukocyte aggregation in response to complement activation, 14 to inhibit neutrophil migration into pulmonary air spaces after endotoxin administration15 and to inhibit thrombininduced increases in pulmonary lymph flow and protein clearance. 18 The latter two effects appear to be independent of inhibition of cyclooxygenase activity. Recently, work from this laboratory suggested that ECV-induced acute lung injury was not associated with increased production of 6-keto-prostaglandin F 1,,, the stable metabolite of prostacyclin, in the blood, bronchoalveolar lavage fluid or in the supernatant of lung slice incubates obtained from injured lungs. 'itT Thus, although the decrease in venous admixture observed after ibuprofen administration in the present study may have been due to inhibition of the furmation of some other product of cyclooxygenase activity, it is also possible that the improvement resulted from 1092
effects of ibuprofen unrelated to its capacity to block cyclooxygenase activity. The administration of ibuprofen 60 min after ECVinduced acute lung injury did not alter the accumulation of EVLW in the injured right lung measured by gravimetric techniques (Tuble 2) or estimated by EVTV (Fig 2). Thus, the decrel1$e in venous admixture that occurred consequent to ibuprofen administration cannot be attributed to an effect on the amount of total EVLW present in the injured lung, a finding consistent with previous studies. 4,7.lls.19 In summary, we have demonstrated that the administration of the nonsteroidal anti-inflammatory drug, ibuprofen, 60 min after the induction of acute lung injury with ECV results in a decrease in venous admixture in the absence of any effect on lung water accumulation. These findings support the hypothesis that ibuprofen, administered after the onset of acute lung injury, results in improvement in ventilationperfusion relationships and that this effect is not related to decreased accumulation of EVLW. ACKNOWLEDGMENTS: The writers wish to express their gratitude to Mrs. Wanda Jo Schreiweis, Mr. Karl F. Olsen and Miss Lori J. Heitmann for their excellent technical effi>rts and to Mrs. Mary Blecha fur her superb assistance in preparation of the manuscript. We thank R. Charles Lenz of the Upjohn Company fur supplying the sodium ibuprofenate.
REFERENCES 1 Petty TL. Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233-39 2 Anderson RR, Holliday RL, Priedger AA, Lefcoe M. Reid B, Sibbald WJ. Documentation of pulmonary capillary permeability in the adult respiratory distress syndrome llJ.'C()mpanying human Dis 1979: 119:869-77 sepsis. Am Rev ~esplr 3 Ashbaugh DG, Bigelo DB, Petty TC, Levine BE. Acute respU.tory distress in adults. Lancet 1967; 2:319-.23 4 Brigham KL. Mechanisms of lung injury. Clinics Chest Med 1982; 3:9-24 5 Glauser FL, Smith WR, Caldwell A, Hoshiko M, Dolan GS, B~r H, et al. Ethchlorvynol (Placidyl)-induced pulmonary edema. Ann Intern Med 1976; 84:46-48 6 Stephenson AH, Sprague RS, Dahms TE, Lonigro AJ. Unilateral aclite lung injury induced by ethchl1>rvynol in anesthetized dogs. J Appl Physiol: Respirat Environ Exercise Physiol 1984; 56:1252-59 7 Sprague RS, Stephenson AH, Dahms TE, Lonigro AJ. Effect of Cyc)Qoxygenase inhibition on ethchlorvynol induced acute lung injury in dogs. J Appl Physiol 1986; 61:1053-64 8 Fischer P, Glauser FL, Millen JE, Lewis J, Egan P. The effects of ethchlorvynol on pulmonary alveolar membrane permeability. Am Rev Respir Dis 1977; 116:901-06 9 Fairman RP, Glauser FL, Falls R. Increases in lung lymph and albumin clearance with ethchlorvynol. J Appl Physiol: Respirat Environ Exercise Physiol 1981; 50:1151-55 10 Lewis FR, Elings VB. Microprocessor determination of lung water using thermal-green dye double indicator dilution. Surg Forum 1978; 29:182-84 11 Pearce ML, Yamashita J. Beazell J. Measurement of pulmonary edema. Circ Res 1965; 16:482-88 12 Fletcher EC, Gray BA, LevQi DC. Nonapneic mechanisms of Unilateral Acute Lung Injury In Anelthellzed Dogs (Sprague
et el)
arterial oxygen desaturation during rapid-eye-movement sleep. J Appl Physiol 1983; 54:632-39 13 Rossing RG, Cain SM. A nomogram relating P01, pH, temperature, and hemoglobin saturation in the dog. J Appl Physiol 1966; 21:195-201 14 Comroe JH. Physiology of respiration. Chicago: Year Book Medical Ptiblishers, 1974 15 Adams SS, McCullough KF, Nicholson JS. The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch Int Pharmacodyn Ther 1969;178:115-29 16 Flower RJ, Vane JR. Inhibition of prostag)andin biosynthesis. Biochem Pharmacol 1974; 23:1439-50 17 O'Brien JR. Effect of anti-inflammatory agents on platelets. Lancet 1968; 1:894-95 18 Snedecor GW, Cochran WG. Statistical methods, ed 6. Ames, Iowa: Iowa State University Press, 1967 19 Qarke RA, Dunn DL, Dalmasso AP, Johnson JA, Orser M, Simmons R, et al. Effect of ibuprofen tle!ltment on pulmonary microv~lar permeability and pulmonary function fullowing £scherichia coU peritoneal contamination. Surg Forum 1983; 34:144-46 20 Hutchison AA, Olgetree ML, Snapper JR, Brigham KJ,.. Effect of endotoxemia on hypoxic pulmonary vasoconstriction in unanesthetized sheep. J Appl Physiol 1985; 58:1463-68 21 Kopolovic R, Thrailkill KM, Martin DT, Ambrose T, Vento M, Carey LC, et al. Effects of ibuprofen on a PQrcine model of acute respiratory failure. J Surg Res 1984; 36:300-05 22 Staub NC, Nagano H, Pearce ML. Pulmonary edema in dogs,
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24
25
26
27
28
29
especially the sequence of fluid accumulation in lungs. J Appl Physiol 1967; 22:227-40 Snapper JR, Hutchison AA, Ogletree ML, Brigham KL. Effect of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep. J Clin Invest 1983; 72:63-76 JllCOb HS, Moldow CF, Flynn PJ, Weisdorf DF, Vercellotti GM, Hammerschmidt DE. Therapeutic ramifications of the interaction of complement, granulocytes and platelets in the production of acute lung injµry. Ann NY Acad Sci 1982; 384:489-95 Rinaldo JE, Dauber J, Rogers RM. Effect of ibuprofen on neutrophil emigration into air spaces fullowing endotoxemia in rats (abstract). Am Rev Respir Dis 1983; 127:71 Johnson A, Malik AB. Pulmonary transvascular fluid and protein exchange after thrombin-induced microembolism. Am Rev Respir Dis 1985; 132:70-76 Sprague RS, Stephenson AH, Ovetsky R, Dahms TE, Lonigro AJ. PGI. is not responsible fur the hypoxemia of ethchlorvynolinduced acute lung injury. Am Rev Respir Dis 1986; 133:A389 Sibbald WJ, Warshawski FJ, Short AK, Harris J, Lefcoe MS, Holliday RL. Clinical studies of measuring extravascular lung in critically ill patients. water by the thermal dye t~que Chest 1983; 85:725-31 Brigham KL, Kariman K, Harris TR, Snapper JR, Bernard GR, Young SL. Correlation of oxygenation with vascular permeability-surface area but not with lung water in huml!Jls with acute respiratory failure and pulmonary edema. J Clin Invest 1983; 72:339-49
CHEST I 92 I 8 I DECEMBER, 1987
1093
Nonsteroidal anti-inftammatory agents, given prior to induction of unilateral acute lung injury with ethchlorvynol (ECV) in anesthetized dogs, prevent the decreases in systemic oxygen tension (PaOJ which are observed when ECV is given alone. We investigated whether ibuprofen, administered after acute lung injury, would result in improvement in arterial oxygenation. In animals not receiving ibuprofen after unilateral acute lung injury with ECV, Pa01 decreased and venous admixture increased signi&candy from control values at all experimental time-periods. In those animals
receiving ibuprofen, signiflcant decreases in venous admixture were noted. 'Ibe decrease in Pa01 after ECV administration was signi&candy less than that observed in animals that did not receive ibuprofen after acute lung injury (p<0.05~ Ibuprofen had no effect on extravascular lung water. 'Ibese results demonstrate that in an ECV model of acute lung injury the administration of ibuprofen, after the acute lung injury, results in signiflcant decreases in venous admixture.
_Nute lung injury in humans, termed the adult respiratory distress syndrome (ARDS), is characterized clinically by systemic hypoxemia and nonhydrostatic pulmonary edema. 1 The pathophysiologic correlates of ARDS include increased pulmonary capillary permeability, 1 decreased lung compliancel.3 and altered reactivity of the pulmonary vasculature. 4 The sedative-hypnotic drug ethchlorvynol (ECV [Placydyl]), when administered intravenously, produces acute lung injury in humans5 and in experimental animals. a.e Previously we reported that, in anesthetized dogs, ECV, selectively infused into the right pulmonary circulation, resulted in systemic hypoxemia and the rapid furmation of nonhydrostatic pulmonary edema confined to the right lung. 8•7 In addition, we demon-
strated that the administration of the nonsteroidal antiinflammatory agents, ibuprofen or indomethacin, prior to the induction of unilateral acute lung injury with ECV, prevented the development of systemic hypoxemia but had no effect on the accumulation of extravascular lung water (EVLW). 7 Although the latter results provided insights into pathophysiologic mechanisms of the injury, of greater importance in defining a therapeutic role fur these agents would be studies in which nonsteroidal antiinflammatory drugs were administered at some time after acute lung injury had been established. In the present work, we investigated the hypothesis that states that the administration of the nonsteroidal antiinflammatory agent ibuprofen, after the establishment of unilateral acute lung injury with ECV, would correct the defect in oxygenation of the blood but would not affect the accumulation of EVLW.
*From the Medical Service, Veterans Administration Medical Center, and the De~ments of Medicine and Pharmacology, St. Louis University School of Medicine, St. Louis. t Assistant Professor of Medicine. :!:Assistant Research Professor of Pharmacology. §Associate Research Professor of Medicine. •Professor of Medicine and Pharmacology. This work was supported by the Veterans Administration and in part by a National Heart, Lung, and Blood Institute, Adult Respiratory Failure SCOR _grant HL-30572. This project was completed during the tenure of Dr. Sprague as a Buder-Peters Fellow of the St. Louis Heart Association.
1088
METHODS
Preparation of Animals Eighteen microfilaria-free male mongrel dogs (22.5±1.1 kg) were
fasted overnight but allowed free access to water and then anesthetized intravenously with sodium pentobarbital (30 mg/kg). Anesthe-
sia was maintained with continuous intravenous administration of pentobarbital at a rate of 0.05 mglkg/min. The animal preparation has been described in detail previously.'' The right and left lungs UnUateral Acute Lung lf1ury In Aneathellzed Dogs (Sptague et el)
were venti1ated independently but synchronously through a Carlens catheter with room air at 12to15 breaths per minute with a total tidal volume of 15 ml/kg. Individual lung tidal volumes were adjusted to achieve equal peak airway pressures as well as equal end-tidal carbon dioxide tensions (LB-2 C01 analyzer, Beckman). Neither ventilatory rate nor tidal volumes were altered throughout the course of the experiment after initial blood gas stability had been achieved. Airway pressures were monitored continuously. An end-expiratory pressure of 5 cm ffaO was maintained tor each lung throughout the experiment 'lb avoid atelectasis, both lungs were hyperinHated to 20 cm HaO every ten minutes mcept in the periods immediately prior to lung water determination. Adequacy ofdivision of ventilation and the position of the Carlens catheter were con&rmed by collapsing the left lung during continued ventilation ofthe right lung. After total separation of ventilation was verified, the left lung was fully reexpanded. The left main pulmonary artery was isolated and fit with a Statham electromagnetic flow probe (8 to 10 mm, id) with nonocclusive zero feature tor continuous measurement of left pulmonary blood flow. Distal to the flow probe, a hydraulic balloon-type external vascular occluder (model OC-8, IVM) was placed around the left main pulmonary artery. 1Wo flow-directed Swan-Ganz catheters were advanced into the main pulmonary artery via peripheral veins, one tor continuous measurement of mean pulmonary arterial pressure ('Ppa), and the other tor obtaining aliquots of mixed venous blood. Arterial and mixed venous blood samples were collected anaerobically and analyzed within &ve minutes tor pH, partial pressure ofC01 (Pc<>a) and partial pressure of The electrodes were calibrated 0 1 (P<>a) (BMS3-MK2, Radiometer~ with tonometered blood samples (ll.237) that had been equilibrated with standardi7.ed gas mixtures. For measurements of mean left atrial pressure ('Pia) and mean systemic arterial pressure (Psa~ catheters were placed directly into the left atrium via the left atrial appendage and into the aorta via the femoral artery, respectively.
Measurement of EVLW Estimates ofEVLW were made periodically over the course ofthe experiment by repeated measurements of emavascular thermal volume (EVIV). Final estimates of EVLW at the end of the experiment were con&rmed by gravimetric methods. For measurement of EVTY, a 5-French catheter with attached thermistor (model 96020-SF, Edwards Laboratories) was placed into a femoral artery. The EVIV was quantified by a microprocessol'-based system (9310 compute.; Edwards Laboratories), which compares the mean transit times of an indicator confined to the vascular space with one that distributes throughout the entire thermal mass of the lung. A bolus of iced 5 percent dextrose containing 2 mg of indocyanine green dye was injected rapidly into the superior vena cava via a catheter introduced into the right jugular vein. The dye concentration curve was measured by withdrawing blood (Sage pump. model 351) through the cuvette of a dye densitometer (model 0402-A, Waters) via the 5-French catheter with attached thermistor. Thus, the dye concentration curve and the thermal curve were determined simultaneously. Cardiac output was calculated by integration of the area under the thermal curve and EVIV was computed based on the difference between the mean transit times ror each indicator."' Following measurement of total EVTY, right lung EVIV was obtained by occluding the left main pulmonary artery ror one minute with the external balloon occludet during administration of the thermal-dye bolus. Thus, total as well as right EVIV were determined directly, whereas left EVIV was calculated as the difference between total and right Evrv. The EVTY, expressed in milliliters per kilogram of body weight, represents the mean of two to three determinations. Previously we demonstrated that EVIV is not affected by operative intervention or repeated left main pulmonary artery occlusions prior to induction of unilateral acute lung injury in this model.• Howevei; to avoid diverting the entire cardiac output to an injured lung,
unilateral measurements of EVIV were not made after induction of acute lung injury with ECV. Bight lung EVIV fDllowing injury with ECV was calculated as the difference of total EVIV and EVIV in the left lung determined prior to ECV administration. Immediately rollowing the last EVIV determination, an aliquot of systemic arterial blood was withdrawn, the pulmonary hila, pulmonary artery and aorta were clamped and the lungs were removed fOr gravimetric determination ofEVLW. The lungs were homogenized and dried to constant weights individually. Gravimetric determinations ofEVLW were corrected tor the weight of blood in each lung based on measurement of the residual hemoglobin in the lungs according to the method of Pearce et al. u Other Measuremsnts Bight pulmonary blood flow was calculated as the difference between left pulmonary blood flow measured with the electromagnetic flow probe and total pulmonary blood flow (cardiac output) determined by thermal dilution as described above. Venous admixture was calculated from the equation: QvatQt= (Cc'01 -Ca0J/(Cc'01 -CVO.) where QvaJQt refen to venous admixture and Cc'O., Ca01 and CV01 refer to capillary, arterial and mixed venous oxygen contents, respectively. 11 Arterial, mixed venous and capillary 0 1 saturations were calculated by the method of Bossing and Cain. D The alveolar Po. was calculated from the alveolar gas equation. 14 E%p6fimental Protocola
Left pulmonary blood flow, as well as Psa, Ppa and Pia, were recorded continuously throughout the experiment After hemodynamic stability had been achieved fDllowing thoraootomy and instrumentation, measurements of cardiac output, total and right lung EVTY, as well as arterial and mixed venous pH, Pea. and Po. were determined several times during the control period; fe, prior to the induction of lung injury. Following these control measurements, the left main pulmonary artery was occluded tor 90 seconds during which time ECV. 9to15 mw'kg, was administered as a bolus into the superior vena cava. In all animals, measurements of total pulmonary blood flow (cardiac output), total EVIV and arterial and mixed venous blood gases were made at 30, 60, 90 and 120 min after the unilateral administration of ECV. Eight animals did not receive ibuprofen after acute lung injury had been established. This group was included to characterize the changes in pulmonary hemodynamics, blood gas composition and EVLW, which occur in response to unilateral ECV-induced acute lung injury in the absence of cyclooxygenase inhibition. In ten additional animals, ibuprofen was administered immediately after the 60-min post-injury measurement period. This timeperiod was chosen because by 60 min after ECV administration there were signi&cant increases in EVLW and venous admixture indicating that acute lung injury had been established. Ibuprofen (Upjohn, sodium ibuprofenate, 12.5 mg/kg) was administered as an intravenous bolus during a period of &ve minutes. This dose was selected based on the efficacy of ibuprofen as an inhibitor of cyclooxygenase activity. • 11 In all experiments, fDllowing the final (120 min) EVIV determination, the lungs were removed tor measurement of EVLW by gravimetric methods. Staflatfcal AnalyBIB
Statistical significance between control (pre-ECV) and experimental periods within each group was determined with a two-way analysis of variance (ANOVAi If the F ratio indicated that changes had occurred, a Least Signi&cant Difference (LSD) test was used to identify individual differences.• For comparison of gravimetric and thermal-dye estimates of EVLW, a one-way ANOVA was used. 11 Comparisons between control (pre-ECV) periods rot each group of experiments were made using an unpaired Students t test 11 Probability values of0.05 or less were considered statistically significant All results are reported as means ± SEM. CHEST I 92 I 8 I DECEMBER, 1887
1-
REsuCTS Group Comparisons Prior to Induction of Unilateral Acute Lung Injury Hemodynamic, blood gas and EVI'V measurements obtained prior to unilateral ECV administration (control) in both groups of animals are depicted in Tuble 1. There were no significant differences between groups for these control (pre-ECV) measurements.
ECV-Induced Unilateral Acute Lung Injury In the animals not receiving ibuprofen after the induction of unilateral acute lung injury with ECV, arterial Po1 (PaOJ was significantly decreased from control values at all time-periods: viz, 30, 60, 90 and 120 min following the administration ofECV (Tuble 1). The decreases in Pa01 were associated with significant increases in venous admixture compared with control values at all time-periods (Tuble 1). 'Ibtal pulmonary blood flow decreased after ECV administration and there was a small, fractional redistribution of intrapulmonary blood flow away from the injured right lung to the uninjured left lung, which reached statistical significance at the 60-, 90-, and 120-min periods af\:er the induction of lung injury (Tuble 1). Unilateral ECV administration produced no change in Pia; Ppa, however, was increased at both 90 and 120 min afterinjury (Tuble 1).
Effects of Ibuprofen on Established ECV-Induced Unilateral Acute Lung Injury The administration of ibuprofen 60 min after the induction of unilateral acute lung injury with ECV
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30
90
120
~POSTECV
Effect of ethchlorvynol (ECV (9 to 15 mg/kg]) introduced Into the right pulmonary circulation on the change In venoua admixture (Qv&JQt) with (n=lO; 0-0) and without (n=8; ......_.) ibuprofen (ll.5 m!Vkg) administered 60 min after the onset of acute lung Injury. Asterisk, p<0.05 compared to animals not receiving ibuprofen. FIGURE 1.
produced an improvement in venous admixture. Within 30 min of ibuprofen administration, venous admixture had decreased to values not different from those observed prior to the induction of acute lung injury (Tuble 1). In contrast, venous admixture was increased at all time-periods in those animals that did not receive ibuprofen after ECV-induced acute lung injury (Tuble 1). The changes in venous admixture from pre-injury control values are represented in Figure 1. The increase in venous admixture at the 3o- and 60min periods after lung injury was similar in both groups. However, the changes in venous admixture observed after ibuprofen administration differed significantly
'IBble 1-Effecta ri' lbupnfen Adrniniatend 60 min AjtBr- EthclJoroynol-lnduced Acute Lung Injury on Hemodynamic,
Blood Flow and Blood Goa Meaaumnenta•
Control
30 min
60min
90min
120 min
15.8±1.4
18.2±1.7 17.1±1.6
20.7±1.9§ 20.3±1.9§
20.0±2.0§ 21.1±2.0§
4.7±0.8 4.0±0.5
5.3±0.8 4.2±0.5
5.4±0.7 4.5±0.5
6.1±0.7 5.2±0. 7§
5.5±0.5 5.5±0. 7§
2.60±0.22 2.40±0.14
2.03±0.19§ 2.04±0.14§
1.89±0.17§ 1.85±0.12§
1.91±0.16§ 1.53±0.09§
1.76±0.14§ 1.43±0.09§
Ppa, mm Hg ECV only ECV/ibuprofen Pia, mm Hg ECVonly ECV/ibuprofen Qt, Umin ECV only ECV/ibuprofen Flowu.. % ECV only ECV/ibuprofen Pa01, mm Hg ECV only ECV/ibuprofen
QwJQt
ECVonly ECV/ibuprofen
16.3±1.8 16.9±1.7 15.7±1.5
35±3 41±2
36±4 42±2
42±5t 46±3
44±6* 53±4:j:
50±6§ 58±5§
84.7±2.3 84.9±1.7
74.9±2.7§ 77.5±1.8§
75.0±3.1§ 77.4±2.3§
74.0±3.8§ 80.7±2.6t
71.9±4.4§ 79.6±2.2*
8.4±1.2 10.0± 1.4
13.0±1.7:1= 14.8± 1.9*
12.4±1.7t 14.3±2.2t
13.7±2.6§ 9.5± 1.5
15.8±3.4§ 9.3± 1.3
•ECV, ethchlorvynol; 'Pt>a. mean pulmonary arterial pressure; Pia, mean left atrial prelsure; Qr, total pulmonary blood flow; Flowu., percentage of total blood flow perfusing the left lung; Pa01, systemic arteri&l oxygen tension; (!VtJQt., venous admixture. tp<0.05 compared to respective pre-injury control values. :j:p<0.01 compared tel respective pre-injury control values. §p<0.001 compared to respective pre-injury control values.
1090
U,...... Acute Lung
l~ury
In Anellhellzed Dogs (Sprague et 81)
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60
90
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FIGURE 2. Effect of ethchlorvynol (ECV [9 to 15 mg/kg]) introduced into the right pulmonary circulation on extravascular lung water (EVLW) in the injured lung estimated by the indicator dilution technique with (n =10; 0--0) and without (n =8; ._.) ibuprofen (12.5 mglkg) administered 60 min after the onset of acute lung injury; p<0.01 for all experimental periods compared with respective control value.
from those observed in the animals that received ECV only (p<0.05, Fig 1). Although the Pa01 remained lower than the pre-injury control value after ibuprofen administration ('Ikble 1), the decrease in Pa01 of 5 ± 2 mm Hg at 120 min after ECV administration was significantly less than the 13 ± 3 mm Hg decrease observed in the animals that did not receive ibuprofen after the development of acute lung injury (p<0.05). Mean left atrial pressure increased significantly only in the ibuprofen-treated animals, but the magnitude of the change was small and the values did not exceed those measured in the ECV-only group at any timeperiod. The fraction of total pulmonary blood flow, which redistributed from the injured right lung to the uninjured left lung, increased at 90 and 120 min after lung injury in the ibuprofen-treated animals ('Ikble 1). The increase in flow to the uninjured lung at 90and120 min after ECV administration was not different from that observed in the animals that did not receive ibuprofen.
Extravascular Lung Water Accumulation The administration of ibuprofen 60 min after the incluction of acute lung injury with ECV did not attenuate the increases in EVLW in the injured right lung (Fig 2, Tuble 2). Extravascular thermal volume, used as an index of EVLW, increased progressively in both groups (Fig 2). The EVLW, measured gravimetrically at the end of each experiment for the injured right lung and uninjured left lung, did not differ between the groups (Tuble 2). DISCUSSION
Ethchlorvynol, when administered into the pulmonary circulation of experimental animalss.e or humans, 5 results in systemic hypoxemia and nonhydrostatic pulmonary edema. The progressive increases in
EVLW, which begin within 15 min of ECV administration, occur in the absence of sustained increases in mean pulmonary arterial or left atrial pressures, 8•7 and are associated with increased pulmonary vascular permeability to endogenous and exogenous solutes' as well as with increased pulmonary lymph flow without a change in lymph-to-plasma albumin ratio. 11 These findings are, therefore, consistent with the contention that ECV administration results in increased pulmonary capillary permeability. The administration of ECV selectively into the pulmonary circulation of the right lung of dogs results in the rapid formation of nonhydrostatic pulmonary edema confined to the fight lung and systemic hypoxemia.' 7 Previously we reported that administration of either indomethacin or ibuprofen, prior to the induction of acute lung injury with ECV, resulted in protection of Pa01 , whereas the accumulation of EVLW was unaffected. 7 The results presented here extend these observations and suggest that, at least in ECV-induced acute lung injury, the administration of ibuprofen after the induction of lung injury results in attenuation of the decreasing Pa01 and a decrease in venous admixture. These findings contrast with those reported for acute lung injury in sheep induced either by Escherichia colt contamination18 or by E coli endotoxin111 where neither ibuprofen nor meclofenamate, respectively, prevented the fall in Pa01 when administered after lung injury had been established. Our results are, however, consistent with the observations of Kopolovic et al, 11 who reported that, in pigs, application of ibuprofen after acute lung injury had been established with live Pseudomonas aeroginosa infusion protected against failure of oxygenation of the blood. The results presented here do not allow resolution of the differences among the various studies; however, these differences may be related to type, duration or extent of uijury or to species differences. The decrease in venous admixture affi>rded by ibuprofen administered 60 min after the induction of unilateral lung injury occurred without augmented Table 2-Detennination cf E~r Lung Water by the Double Indicator Dilution Technique and the Gravimetric Met~ BO min~ the Induction cf Unilateral Acute Lung Inju,.,, toilh Etltehloror/nol*
Uninjured (left) lung EVLW (ml/kg body weight) Thermal-dye Gravimetric Injured (right) lung EVLW (ml/kg body weight) Thermal-dye Gravimetric
ECV Only (n=8)
ECV/lbuprofen (n= 10)
3.19±0.29 2.96±0.26
2.41±0.23 2.86±0.18
9.27±0.26 8.26±0.40
10.15±0.68 7.99±0.50
*ECV, ethchlorvynol; EVLW. extravascular lung water. CHEST I 92 I 6 I DECE~BER,
1967
1091
redistribution of intrapulmonary blood flow from the injured to the uninjured lung (Table 2). In addition, the decreases in total pulmonary blood flow (cardiac output) were not different from those observed in the animals that did not receive ibuprofen after acute lung injury. These findings suggest that the decrease in venous admixture associated with ibuprofen administration may have been due to improvement in ventilation-perfusion relationships within the injured right lung itsel£ It is likely that the injury to the right lung was not uniform although the entire cardiac output was diverted to the right lung during ECV administration. 8•7•22 If ibuprofen administration resulted in a redistribution of blood flow from injured to uninjured areas within the right lung, then venous admixture could be reduced without diversion of blood flow to the uninjured left lung. It is also possible that ibuprofen might have influenced the distribution of ventilation within the injured lung resulting in improved matching of ventilation and perfusion and, thereby, a reduction in venous admixture. The design of the present study does not permit measurement of individual lung compliance or airway resistance; however, in some experiments, peak airway pressures were determined fur each lung throughout the development of acute lung injury. Peak airway pressures in the injured right lung did not differ from peak airway pressures in the uninjured left lung at any time-period in the animals that received either ECV or ECV fullowed by ibuprofen, suggesting that large alterations in either airway resistance or lung compliance did not occur. It has been suggested by us 7 and others23 that the beneficial effect of ibuprofen on the blood gas response to acute lung injury is due to the ability of ibuprofen to block cyclooxygenase activity, which results in the inhibition of prostaglandin and thromboxane synthesis. However, ibuprofen also has been suggested to alter the responses observed fullowing acute lung injury by inhibition of leukocyte aggregation in response to complement activation, 14 to inhibit neutrophil migration into pulmonary air spaces after endotoxin administration15 and to inhibit thrombininduced increases in pulmonary lymph flow and protein clearance. 18 The latter two effects appear to be independent of inhibition of cyclooxygenase activity. Recently, work from this laboratory suggested that ECV-induced acute lung injury was not associated with increased production of 6-keto-prostaglandin F 1,,, the stable metabolite of prostacyclin, in the blood, bronchoalveolar lavage fluid or in the supernatant of lung slice incubates obtained from injured lungs. 'itT Thus, although the decrease in venous admixture observed after ibuprofen administration in the present study may have been due to inhibition of the furmation of some other product of cyclooxygenase activity, it is also possible that the improvement resulted from 1092
effects of ibuprofen unrelated to its capacity to block cyclooxygenase activity. The administration of ibuprofen 60 min after ECVinduced acute lung injury did not alter the accumulation of EVLW in the injured right lung measured by gravimetric techniques (Tuble 2) or estimated by EVTV (Fig 2). Thus, the decrel1$e in venous admixture that occurred consequent to ibuprofen administration cannot be attributed to an effect on the amount of total EVLW present in the injured lung, a finding consistent with previous studies. 4,7.lls.19 In summary, we have demonstrated that the administration of the nonsteroidal anti-inflammatory drug, ibuprofen, 60 min after the induction of acute lung injury with ECV results in a decrease in venous admixture in the absence of any effect on lung water accumulation. These findings support the hypothesis that ibuprofen, administered after the onset of acute lung injury, results in improvement in ventilationperfusion relationships and that this effect is not related to decreased accumulation of EVLW. ACKNOWLEDGMENTS: The writers wish to express their gratitude to Mrs. Wanda Jo Schreiweis, Mr. Karl F. Olsen and Miss Lori J. Heitmann for their excellent technical effi>rts and to Mrs. Mary Blecha fur her superb assistance in preparation of the manuscript. We thank R. Charles Lenz of the Upjohn Company fur supplying the sodium ibuprofenate.
REFERENCES 1 Petty TL. Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233-39 2 Anderson RR, Holliday RL, Priedger AA, Lefcoe M. Reid B, Sibbald WJ. Documentation of pulmonary capillary permeability in the adult respiratory distress syndrome llJ.'C()mpanying human Dis 1979: 119:869-77 sepsis. Am Rev ~esplr 3 Ashbaugh DG, Bigelo DB, Petty TC, Levine BE. Acute respU.tory distress in adults. Lancet 1967; 2:319-.23 4 Brigham KL. Mechanisms of lung injury. Clinics Chest Med 1982; 3:9-24 5 Glauser FL, Smith WR, Caldwell A, Hoshiko M, Dolan GS, B~r H, et al. Ethchlorvynol (Placidyl)-induced pulmonary edema. Ann Intern Med 1976; 84:46-48 6 Stephenson AH, Sprague RS, Dahms TE, Lonigro AJ. Unilateral aclite lung injury induced by ethchl1>rvynol in anesthetized dogs. J Appl Physiol: Respirat Environ Exercise Physiol 1984; 56:1252-59 7 Sprague RS, Stephenson AH, Dahms TE, Lonigro AJ. Effect of Cyc)Qoxygenase inhibition on ethchlorvynol induced acute lung injury in dogs. J Appl Physiol 1986; 61:1053-64 8 Fischer P, Glauser FL, Millen JE, Lewis J, Egan P. The effects of ethchlorvynol on pulmonary alveolar membrane permeability. Am Rev Respir Dis 1977; 116:901-06 9 Fairman RP, Glauser FL, Falls R. Increases in lung lymph and albumin clearance with ethchlorvynol. J Appl Physiol: Respirat Environ Exercise Physiol 1981; 50:1151-55 10 Lewis FR, Elings VB. Microprocessor determination of lung water using thermal-green dye double indicator dilution. Surg Forum 1978; 29:182-84 11 Pearce ML, Yamashita J. Beazell J. Measurement of pulmonary edema. Circ Res 1965; 16:482-88 12 Fletcher EC, Gray BA, LevQi DC. Nonapneic mechanisms of Unilateral Acute Lung Injury In Anelthellzed Dogs (Sprague
et el)
arterial oxygen desaturation during rapid-eye-movement sleep. J Appl Physiol 1983; 54:632-39 13 Rossing RG, Cain SM. A nomogram relating P01, pH, temperature, and hemoglobin saturation in the dog. J Appl Physiol 1966; 21:195-201 14 Comroe JH. Physiology of respiration. Chicago: Year Book Medical Ptiblishers, 1974 15 Adams SS, McCullough KF, Nicholson JS. The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch Int Pharmacodyn Ther 1969;178:115-29 16 Flower RJ, Vane JR. Inhibition of prostag)andin biosynthesis. Biochem Pharmacol 1974; 23:1439-50 17 O'Brien JR. Effect of anti-inflammatory agents on platelets. Lancet 1968; 1:894-95 18 Snedecor GW, Cochran WG. Statistical methods, ed 6. Ames, Iowa: Iowa State University Press, 1967 19 Qarke RA, Dunn DL, Dalmasso AP, Johnson JA, Orser M, Simmons R, et al. Effect of ibuprofen tle!ltment on pulmonary microv~lar permeability and pulmonary function fullowing £scherichia coU peritoneal contamination. Surg Forum 1983; 34:144-46 20 Hutchison AA, Olgetree ML, Snapper JR, Brigham KJ,.. Effect of endotoxemia on hypoxic pulmonary vasoconstriction in unanesthetized sheep. J Appl Physiol 1985; 58:1463-68 21 Kopolovic R, Thrailkill KM, Martin DT, Ambrose T, Vento M, Carey LC, et al. Effects of ibuprofen on a PQrcine model of acute respiratory failure. J Surg Res 1984; 36:300-05 22 Staub NC, Nagano H, Pearce ML. Pulmonary edema in dogs,
23
24
25
26
27
28
29
especially the sequence of fluid accumulation in lungs. J Appl Physiol 1967; 22:227-40 Snapper JR, Hutchison AA, Ogletree ML, Brigham KL. Effect of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep. J Clin Invest 1983; 72:63-76 JllCOb HS, Moldow CF, Flynn PJ, Weisdorf DF, Vercellotti GM, Hammerschmidt DE. Therapeutic ramifications of the interaction of complement, granulocytes and platelets in the production of acute lung injµry. Ann NY Acad Sci 1982; 384:489-95 Rinaldo JE, Dauber J, Rogers RM. Effect of ibuprofen on neutrophil emigration into air spaces fullowing endotoxemia in rats (abstract). Am Rev Respir Dis 1983; 127:71 Johnson A, Malik AB. Pulmonary transvascular fluid and protein exchange after thrombin-induced microembolism. Am Rev Respir Dis 1985; 132:70-76 Sprague RS, Stephenson AH, Ovetsky R, Dahms TE, Lonigro AJ. PGI. is not responsible fur the hypoxemia of ethchlorvynolinduced acute lung injury. Am Rev Respir Dis 1986; 133:A389 Sibbald WJ, Warshawski FJ, Short AK, Harris J, Lefcoe MS, Holliday RL. Clinical studies of measuring extravascular lung in critically ill patients. water by the thermal dye t~que Chest 1983; 85:725-31 Brigham KL, Kariman K, Harris TR, Snapper JR, Bernard GR, Young SL. Correlation of oxygenation with vascular permeability-surface area but not with lung water in huml!Jls with acute respiratory failure and pulmonary edema. J Clin Invest 1983; 72:339-49
CHEST I 92 I 8 I DECEMBER, 1987
1093