Noncardiogenic Pulmonary Edema AfterAbdominal Aortic Aneurysm Surgery

IAN S. PATERSON, M.B., F.R.C.S., JOSEPH M. KLAUSNER, M.D., ROBERT PUGATCH, M.D., PAUL ALLEN, M.D.,JOHN A. MANNICK, M.D., F.A.C.S., DAVID SHEPRO, PH.D.t, and HERBERT B. HECHTMAN, M.D., F.A.C.S.

Limb ischemia in experimental animals leads to white blood cell(WBC) and thromboxane (Tx)A2 dependent pulmonary dys-function. This study examines the pulmonary sequelae of lowertorso ischemia in 20 consecutive patients aged 63 ± 5 years(mean ± SEM) who underwent elective abdominal aortic aneu-rysm surgery. After 30 minutes of aortic cross-clamping, plasmaTxB2 levels had risen from 77 ± 26 pg/ml to 359 ± 165 pg/ml(p < 0.01) and was temporally related to increass in mean pul-monary artery pressure (MPAP) from 18 ± 1 to 23 ± 3 mmHg(p < 0.01), as well as to increases in pulmonary vascular resis-tance (PVR) from 0.07 ± 0.02 to 0.12 ± 0.02 mmHg sec/ml (p< 0.01). Each time that the aortic clamp was repositioned andwith final declamping, after 83 ± 10 minutes, there were furtherincreases in MPAP to a peak of 32 ± 2 mmHg (p < 0.01) andin PVR to 0.26 ± 0.030 mmHg sec/ml (p < 0.01), corrffespondingto a plasma TxB2 level of 406 ± 177 pg/ml (p < 0.01). MPAPand PVR returned to baseline values within 30 minutes of de-clamping. Ten minutes after removal of the aortic clamp, plateletlevels had fallen from 180 ± 41 to 97 ± 17 X 103/mm3 (p < 0.01)and WBC levels from 8900 ± 1100 to 4700 ± 400/mm3 (p <0.01). Both platelets and WBC returnd towards normal levels,but at 24 hours, while WBC was elevated at 13000 ± 900/ mm3(p < 0.01), platelets were 44% of baseline at 135 ± 14X 103/mm3 (p < 0.01). Four to 8 hours after surgery, pulmonarydysfunction was manifest by increases in physiologic shunt from9 ± 2% to 16 ± 2% (p < 0.01), and peak inspiratory pressure(PIP) from 23 ± 2 to 33 ± 2 cmH2O (p < 0.01). Chest radiog-raphyAemonstrated interstitial pulmonary edema in all patients,whereas pulmonary artery wedge pressure was 12 ± 2 mmHg,excluding the possibility of left ventricular failure. After 24 ours,pulmonary edema had resolved, and the PIP and PaO2 had bothreturned to baseline. These data indicate that reperfusion of theischemic lower torso leads to the synthesis of TxA2, an eventtemporally related to pulmonary hypertension and transient leu-kopenia with subsequent pulmonary microvascular iqiury man-ifest by interstitial edema.

Supported in part by The National Institute of Health, Grants No.GM24891-10, GM 35141-03, HL16714-13; The Brigham SurgicalGroup, Inc.; and The Trauma Research Foundation.

Reprint requests and correspondence: Herbert B. Hechtman, M.D.,Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Submitted for publication: June 27, 1988.

From the Department of Surgery, Brigham and Women'sHospital, and Harvard Medical School, and The Biological

Science Center, Boston University,t Boston, Massachusetts

R EPERFUSION OF A LARGE MASS of ischemic tis-sue, such as the lower torso, may induce systemicinflammatory reactions.' Severe and sometimes

fatal cardiopulmonary complications have been described.Previously, these reactions have been attributed to an-aerobic metabolic products and to microaggregates re-leased from the ischemic tissue and then entrapped by thelungs.2" Current information suggests that microaggre-gates are unlikely mediators.5 Furthermore, it is our beliefthat the toxic agents involved are not the result ofanerobicmetabolism, but rather are oxygenation products of ara-chidonic acid released during the reperfusion ofischemic

6tissue.Ischemia of a limb is a stimulus for the synthesis of

thromboxane (Tx)A2.7'8 Studies in experimental animalshave indicated that ischemia-generated Tx leads to a risein mean pulmonary arterial pressure (MPAP), polymor-phonuclear (PMN) entrapment in the lungs,5 and an in-crease in lung microvascular permeability.9 This studywas designed to test the thesis that reperfusion ofthe isch-emic lower torso in humans leads to a similar sequenceof events.

Methods

A series of 20 consecutive patients undergoing electiveabdominal aortic aneurysm surgery comprised the studygroup (Table 1). Before surgery, all patients were insertedwith arterial and flow-directed 7 French pulmonary ar-terial catheters (Abbott Critical Care Catheters, Chicago,IL). General anesthesia was used after intramuscular pre-medication with 0.04 mg/kg medazolamTM (Roche, Nut-ley, NJ) or 0.14 mg/kg morphine sulphate. All patients

231

m

PATERSON AND OTHERS

TABLE 1. Patient Profiles

Values (mean± standard

Patient Characteristics No. of Patients error)

Age (years) 63 5Sex

Male 1 5Female 5

Preoperative diseaseHypertension 9Myocardial ischemia 11Obstructive pulmonary 10

Aneurysm classificationSuprarenal 4Infrarenal 16

Aortic cross-clamp (min)Suprarenal 118 ± 25Infrarenal 76 ± 27

Estimated blood loss (1) 2.4 ± 0.5Fluid replacement (1)

Autologous blood 2.2 ± 0.6Homologous blood 0.5 ± 0.2Crystalloid 8.3 ± 1.1

Weight gain at 24 hours(kg) 8.2± 1.2

were paralyzed and mechanically ventilated. They were

maintained with fentanyl, oxygen, and nitrous oxide. Afterinduction of anesthesia, crystalloid was infused to main-tain a high pulmonary artery wedge pressure (PAWP)(> 10 mmHg), which in the past has been shown to pre-vent large falls in cardiac output during aortic aneurysmsurgery.'0 Each patient received 5000 units ofheparin in-travenously just before application of the aortic cross

clamp. Blood transfusions, including cell saver blood(Autotrans, Eletromedics Inc., Englewood, CO) were ad-ministered at the time of wound closure. All blood was

transfused through a 40-ti Pall filter" (Pall Corp., GlennCove, NY). After the operation, all patients were graduallyweaned from the ventilator and were extubated by 24hours.

Studies including some but not all measurements were

conducted at the following time periods: 1) before oper-

ation, 2) 10 minutes after induction of anesthesia andintubation, 3) 30 minutes after skin incision, 4) 30 minutesafter aortic clamping, 5) 3 minutes after each clamp re-

positioning, 6) just before declamping, 7) 3 minutes after

final clamp removal, 8) at the time ofwound closure, and9) hourly for 24 hours after operation. The following sec-

tions discuss the measurements that were performed.

Hemodynamics

Central venous pressure (CVP), MPAP, PAWP, andMAP were measured with strain gauge transducers (Bent-ley, Irvine, CA). The values were taken at end-exhalation.Pulse rate was counted from the arterial wave form. Car-diac outputs (CO) were performed in triplicate using thethermodilution technique.

Hematology

Platelet and WBC counts were assayed on arterial bloodusing phase microscopy.

Prostanoids

Plasma concentrations of TxB2 and 6-keto-PGFI, thestable hydrolysis products of TxA2 and prostacyclin, re-spectively, were measured with a double radioimmu-noassay,12 using an antibody whose cross-reactivity withheterologous prostenoids was less than 1%. Blood wasdrawn into tubes containing ethylene diamine tetraceticacid and aspirin. The blood was centrifuged at 1500 X gfor 20 minutes, and the plasma was separated and storedat -20 C until assayed.

Pulmonary Function

Mixed venous and arterial blood samples were analyzedfor P02, PCO2, and pH using Clark and Severinghauselectrodes (Instrumentation Laboratory, Model 813, Lex-ington, MA). Hemoglobin and per cent saturation were

measured spectrophotometrically (Instrumentation Lab-oratory, Model 282) and the physiologic shunt function(QsQr) calculated from the Berggren equation:'3

Qs-CC CaO2 X 100

OT CcO2 C

where Os is shunt flow, Qr is total flow, CaO2 and C°02are oxygen contents in arterial (a) and pulmonary arterial(v) blood. CcO2 is the oxygen content in capillary bloodderived from the alveolar gas equation assuming a respi-ratory quotient of one. PIP was measured at the end ofan inspiratory pause while the patient was mechanicallyventilated. PVR was calculated from the equation:

PVR = MPAP - PAWPGo

Chest Radiography.

Radiographs were taken before operation, and 4-8hours and 24 hours after operation. All postoperative films

were portable, anteriopostenor exposures taken in inspi-ration with the patient in the sitting position. The x-ray

films were interpreted in a blinded fashion by a singleroentgenologist (Dr. R. Pugatch). The films were assessed

with regard to ten radiologic criteria for edema, and eachfilm was assigned a score between the grades of0-4, witha grade of 0 being nornal.

Investigations using human subjects were conductedin conformity with the principles embodied in the Helsinlideclaration of 1975, and were approved by the Brighamand Women's Hospital and Harvard Medical School In-stitutional Review Boards for Human Research.

232 Ann. Surg. * February 1989

NONCARDIOGENIC PULMONARY EDEMA

PLASMA

500F TxB,

PN 250H

O0

40

30

20

40

- MEAN PULMONARY ARTERYPRESSUREI

PAW

III-I

III

8 - CARD/ACOUTPUT

4S~~~~~~~d3L

4 8 42"24SU~sRGERY-/1OURHoS POSrTo-OP-"

FIG. 1. Aortic cross-clamping and clamp repositioning led to Tx generationand subsequent increases in MPAP. PAWP rose with volume loadingand aortic cross-clamp application. Four to 8 hours postsurgery, whenpulmonary edema occurred, these variables were within normal limits.

Data are presented as mean ± standard error in tablesand figures. Statistical analysis employed an analysis ofvariance, paired and nonpaired t-tests, and linear regres-

sion. When multiple comparisons were performed, theBonferroni procedure was applied.'4 Significant differencewas accepted if p < 0.05.

Results

After incision, the plasma 6-keto-PGF, level rose from48 ± 20 to 205 ± 43 pg/ml (p < 0.01) andreturned towardbaseline with application of the aortic cross-clamp. Thepreoperative level of TxB2 77 ± 26 pg/ml remained un-

changed until aortic occlusion, when it rose to 359 ± 165pg/ml (p < 0.01) (Fig. 1). Application of the aortic cross-

clamp also led to an increase in: MAP from 77 ± 7 to105 ± 4 mmHg (p < 0.01); MPAP from 18 ± 1 to 23 ± 3mmHg (p < 0.01); and PAWP from 13 ± 1 to 16 ± 1

mmHg (p < 0.01) (Fig. 1). The CO fell from 5.5 < 1.0 to3.9 ± 0.8 L min-' (p < 0.01) (Fig. 2).

During the period of aortic occlusion, sodium nitro-prusside was infused into 15 patients in order to controlsystemic hypertension. The MAP fell to 89 ± 3 mmHg,whereas CO was stable. PAWP and MPAP decreased to

I 0-..P-..

I / -

4 8 12 24-SURGSURGERY- -HOURS POST-OP-O

FIG. 2. Cardiac output fell with application ofthe aortic cross-clamp andreturned to normal after surgery.

baseline values. WBC counts fell from baseline values of8900 ± 1100/mm3 to 6200 ± 700/mm3 (p < 0.01) (Fig.3), and platelets fell from 304 ± 22 X 103/mm3 to 180± 41 X 103/mm3 (p < 0.01). Largely due to crystalloidinfusion, the hematocrit had fallen from preoperative val-ues of 36 ± 3% to 30 ± 3% (p < 0.01).

Each clamp repositioning partially restored perfusion.Thus, after one limb of a bifurcation graft was anasto-mosed, the clamp was repositioned in order to restoreflow to that limb. This led to increases in TxB2 concen-trations and a rise in MPAP (Fig. 1) and PVR. After finaldeclamping, TxB2, MPAP, and CO returned to baselinevalues within 30 minutes. PAWP was not significantlyaltered during the period ofreperfusion. WBC and plateletcounts reached their nadir during the first 10 minutes ofreperfusion with values of 4700 ± 400/mm3 and 97 ± 7X 103, respectively (both with p values of < 0.01). Thehematocrit was unchanged.

Respiratory dysfunction occurred in all patients 4-8

45,000

AORTIC CLAMP

WHITE BLOOD CELLS T

4 I8 42 24~-SURGERY-N---OURS POST-OP--l

FMG. 3. Transient leukopenia occurred with aortic cross-clamping, andwith reperfusion during clamp repositioning. Patients had a leukocytosis24 hours after operation.

Vol. 209 * No. 2

AORTIC CLAMP

233Aortic Ckirrom

.c- 6c-"C',-i

5

234 PATERSON AND OTHERS

AORTIC CLAMP

36

tv 28

20L_

*

I*

I ~~ ~

4 8 42"24-- SURGERY ---- OOURS POST-OP------

FIG. 4. Postoperative pulmonary dysfunction was manifest by increasesin PIP and physiologic shunt four to eight hours postsurgery.

hours after surgery. This dysfunction was manifest by in-creases in QS/QT from 9.3 ± 1.6% to 16.1 ± 1.6% (p< 0.01), and PIP from 23 ± 2 to 33± 2 cm H20 (p < .01)(Fig. 4).Pulmonary edema was noted in 16 patients who had

chest radiographs 4-8 hours after operation; two patientshad a grade of 1, six had a grade of 2, five had a grade of3, and three had a grade of 4 (Fig. 5). PAWP was 12 ± 2mmHg during this period of pulmonary edema. Edemaresolved in all cases within 24 hours after operation, atwhich time PIP had returned to 28 ± 2 cmH20 and theQS/QT to 12 ± 5%. All patients were then extubated.

Discussion

Ischemia of the arm, leg, or kidney has been shown tobe a stimulus for TxB2 synthesis.7'8"15 This phenomenonhas also been observed in previous studies of abdominalaortic aneurysm surgery8 and is again confirmed by thepresent data (Fig. 1). Tx is most likely the cause of theobserved pulmonary hypertension because it is a potentsmooth muscle constrictor and, temporally, the rise inTxB2 and MPAP are related. In animals, the causal re-

lationship is documented by the observations that pre-

treatment with a Tx synthetase inhibitor prevents the pul-monary hypertension that follows ischemia,9 and infusionof a Tx mimic produces a rise in MPAP.'6 Further, thereis a direct relationship between the amount of Tx syn-

thesized during reperfusion and the magnitude of thesubsequent increase in MPAP (Fig. 6).

In experimental animals where ischemia was producedwith hindlimb tourniquets, plasma TxB2 levels rose onlyafter tourniquet removal when reperfusion was possible.5

Ann. Surg. * February 1989

In the present study, TxB2 levels rose significantly duringthe period of aortic clamping, reflecting collateral perfu-sion which, albeit limited, allowed the expression of theischemic stimulus. Each clamp repositioning that stepwisere-established flow to the ischemic bed led to transientincreases in plasma TxB2 and MPAP (Fig. 1).

Generally the duration of ischemia relates to theamount of Tx synthesized.6' It is likely that with longerperiods ofischemia a point will be reached where Tx syn-thesis is near maximum and further ischemia will nolonger stimulate Tx production. Thus, with suprarenalaneurysms where the ischemic period was 118 minutes(longer than the 76 minutes for infrarenal aneurysms),there was only a modest and insignificant increase inplasma TxB2 (Table 2). Other changes such as the fall incirculating WBC and the postoperative rise in PIP are inaccord with a small increase in TxB2 and also do notachieve significance.

In addition to the pulmonary vasoconstrictive actionofTxA2, it is possible that other events contributed to theproduction ofpulmonary hypertension. Thus, the rise inMAP with the initial application ofthe aortic cross-clampcould have produced an increase in MPAP by virtue ofthe increased left ventricular afterload and rise in PAWP.However, the fact that the MPAP later fluctuated inde-pendently of the MAP or PAWP makes these pressuresunlikely determinants of the pulmonary hypertension.Secondly, the 8.3 1 of crystalloid infused into patients un-dergoing aneurysm repair may be an important factor inproducing a rise in MPAP. Pulmonary hypertension wasnot observed in previous studies from this laboratorypublished 8 years ago, when only 3.0 1 of crystalloid wereinfused. This may simply reflect a failure to monitorMPAP at periods other than 30 minutes after applicationof the aortic clamp.'7 It may also be due to the smallervolume of crystalloid infusion.Two additional causes ofTx generation and pulmonary

hypertension need to be considered. The neutralizationof heparin with protamine sulphate can trigger Tx syn-thesis.'8"9 This mechanism was not operative becauseprotamine was not administered until after final aorticdeclamping, at which time TxB2 levels fell. Finally, thecomplement system could have been activated by the cellsaver used for autologous blood preparation. Theoreti-cally, this could have led to WBC activation and Tx gen-eration. This mechanism was also not operative in ourstudy because the rise in TxB2 occurred before use ofthecell saver. In addition, levels of TxB2 and MPAP werenormal during transfusion.

Coincident with Tx synthesis was the observed fall incirculating WBC (Fig. 3). In animals, this appeared to berelated to neutrophil entrapment in the lungs and couldbe prevented by pretreatment with a Tx synthetase inhib-itor.5 The mechanism whereby Tx induces leukoseques-tration is unclear. Tx can directly affect WBC by acting

NONCARDIOGENIC PULMONARY EDEMA

as a chemoattractant.202' In any case, experimental studiesshow that the presence of circulating WBC and active Txsynthesis are central to the pathophysiologic sequence ofevents that follow ischemia and reperfusion. Thus, ani-mals rendered neutropenic do not exhibit elevations inplasma or lung lymph TxB2 upon reperfusion.9 Further,either neutropenia or Tx inhibition prevents increases inpermeability. Neutrophils are likely involved by virtue oftheir ability to release a variety of vasotoxic agents in-cluding proteases, oxygen-free radicals, and eicosanoids.TxA2 can directly moderate microvascular permeabilityby alterations in the endothelial cell cytoskeleton. Thistakes place via a disassembly of actin microfilamentswhich leads to widening ofinterendothelial junctions andreduction in barrier function.22 The same Tx-induced

FIGS. 5A-C. In this patient with bronchitis and emphysema, the pre-operative chest x-ray (A) showed hyperinflated lungs. The marked pul-monary edema noted 6 hours after operation, receiving a score ofGrade4 (B), had largely resolved within 24 hours (C).

cytoskeletal changes appear to allow increased WBC dia-pedesis.20The postoperative observation ofpulmonary edema in

our patients was in accord with the experimental findingsof increased pulmonary microvascular permeability insheep after hindlimb ischemia.9 Although injury to thepulmonary microvascular endothelium with increasedpermeability most likely occurs immediately upon reper-fusion, pulmonary edema that represents a transvascularfluid efflux exceeding lymphatic clearance develops grad-ually. It is not surprising that chest x-ray evidence ofedema may not be noted for several hours.

Evidence of left ventricular failure was not found inpatients undergoing aneursmectomy or in sheep subjectedto hindlimb ischemia. However, the modest increase in

235Vol. 209 x No. 2

236 PATERSON AND OTHERS Ann. Surg February 1989

50

r 0.82

40-0

E30 0

0~~~i20 *

10_

OL ~ ~~I II200 400

PLASMA Tx82 (pg/mi)FMG. 6. There was a direct relationship between plasma levels of TxB2and the mean pulmonary artery pressure. The data represent mean valuesbefore, during, and after ischemia.

postoperative PAWP to 12 mmHg, probably related tothe large fluid infusion, would tend to promote the move-ment of fluid into the lungs if there were increased per-meability. By contrast, in our study of 8 years ago,'7 theaverage postoperative PAWP was 9 mmHg. This reducedpressure would have diminished the amount of edema.Indeed, it was not noted in that study, perhaps becauseof the lower PAWP or perhaps because chest films werenot routinely obtained 4-8 hours after operation.The other postoperative abnormalities in pulmonary

function-that is, the rise in PIP and increase in Qs/Q(T-are most likely related to alveolar collapse and/or distalairway closure.23 These functional abnormalities wereshort-lived and were temporally related to the period whenpulmonary edema was documented. At 24 hours afteroperation, the mechanics of breathing and blood gaseshad improved so that all patients were extubated un-eventfully.

In summary, reperfusion of ischemic tissue during ab-dominal aortic aneurysmectomy results in tx generationwith subsequent pulmonary hypertension, and later, pul-monary edema.

TABLE 2. Comparison ofSupra- and Infrarenal Aneurysms

Variable Measured Suprarenal Infrarenal pvalue

Ischemic time (min) 118 ± 25 76 ± 27 <0.02MPAP maximum (mmHg) 34.3 ± 2.0 33.1 ± 1.6 NSTxB2maximum (pg/ml) 372 ± 111 349 ± 87 NSWBC Decrease(%) 49.0 ± 4.8 37.7 ± 5.2 NSPIP (cm H2O) 35 ± 9 31 ± 6 NS

The rise in MPAP and TxB2 and the fall in WBC were noted withreperfusion. The rise in PIP occurred after operation.

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19. Morel DR, Kitain E, Purcell MH. Clinical pulmonary vasoconstric-tion related to acute pulmonary production ofthromboxane afterprotamine reversal of heparin. Am Rev Respir Dis 1985; 131:405.

20. Doukas J, Hechtman HB, Shepro D. Endothelial-secreted arachi-donic acid metabolites modulate polymorpho-nuclear leukocytechemotaxis and diapedesis in vitro. Blood 1988; 71:771-779.

21. Shasby DM, Shasby SS, Peach MJ. Polymorphonuclear leukocyte:arachidonate edema. J Appl Physiol 1985; 59:47-55.

22. Welles SL, Shepro D, Hechtman HB. Eicosanoid modulation ofstress fibers in cultured bovine endothelial cells. Inflammation1985; 9:439-450.

23. Hogg JC, Agarwal JB, Gardiner AJ, et al. Distribution of airwayresistance with developing pulmonary edema in dogs. J ApplPhysiol 1972; 32:20.