Pulmonary Edema After PGE 1 Infusion

James Lee White, MD, Neal W. Fleming, MD, Timothy A. Burke, MD, Nevin M. Katz, MD,Michael G. Moront, MD, and Young D. Kim, MD

PROSTAGLAN DIN S are among the mostprevalent autacoids found in mammalian

tissue and body fluids. Prostaglandin E, (PGE,)stimulates contraction of gastrointestinal andother smooth muscle, inhibits platelet aggrega­tion, and is also a potent systemic and pulmonaryvasodilator. PGE, is used to maintain the pa­tency of the ductus arteriosus in neonates whohave cardiovascular anomalies that require apatent ductus for survival. It has also been usedin the treatment of pulmonary hypertension wherea vasoactive increase in pulmonary vascular resis­tance exists.' In children, use of PGE, has beenassociated with flushing, hyperpyrexia, bradycar­dia, bronchoconstriction, and depression of venti­lation. Side effects reported in adults includehypotension, nausea, flushing, sinus bradycardia,bronchoconstriction, inhibition of platelet aggre­gation, and "rebound coronary vasoconstriction"following abrupt discontinuation of PGE, inevolving myocardial infarction. A case is re­ported of the development of pulmonary edemaas a complication of the use of PGE, for thetreatment of pulmonary hypertension, which hasnot been previously described.

CASE REPORT

A 70-year-old woman with a history of rheumaticvalvular heart disease was admitted to an outlying hospitalfor evaluation of symptoms of increasing shortness of breath,lower extremity swelling, and a 7-kg weight gain over thepreceding 10 days. Physical examination was remarkable forjugular venous distention, hepatojugular reflux, a distendedabdomen with percussible fluid wave, and 2+ pitting edemaof the lower extremities. Lung fields were clear to ausculta­tion and cardiac examination showed a regular rate andrhythm without a murmur, gallop, or rub. A left and rightheart catheterization was performed and showed the follow­ing hemodynamic data: right atrial pressure (RAP) 13 mmHg, right ventricular pressure 135/20 mm Hg, pulmonaryartery pressure (PAP) 135/60 mm Hg, pulmonary capillarywedge pressure (PCWP) 27 mm Hg, and left ventricular

From the Departments of Anesthesia and Surgery,Georgetown University Hospital, Washington, DC.

Address reprint requests to Young D. Kim, MD,Department ofAnesthesia, Georgetown University Hospital,3800 Reservoir RD NW, Washington, DC 20007.

© 1990 by W.B. Saunders Company.0888-6296/90/0406-0014$03.00/0

pressure 160/5 mm Hg. The mean diastolic pressure gradientacross the mitral valve was 20 mm Hg and calculated mitralvalve area was 0.56 crrr', Pulmonary vascular resistance(PVR) was 1,600dyne. s . cm", Coronary angiography wasnormal.

Initial treatment consisted of fluid restriction anddiuretic therapy. After 7 days, the patient was transferred tothis institution for further evaluation and possible mitralvalve replacement. Medications at the time of transferincluded ethacrynic acid (25 mg orally twice a day), digoxin(0.25 mg orally once a day), dipyridamole (25 mg orally threetimes a day), and allopurinol (300 mg orally once a day).Upon arrival, vital signs were: blood pressure 148/62 mmHg, heart rate 92 beats/min, respiratory rate 18 breaths/min, temperature 38°C, and a weight of 83 kg. The lungswere clear to auscultation and no murmurs were appreciatedon cardiac examination. Jugular venous pressure was normal.Abdominal examination showed no evidence of ascites orhepatomegaly. There was I + pitting edema of the lowerextremities. Chest roentgenogram demonstrated left atrialand left ventricular enlargement, a small right pleural effu­sion, and stage II pulmonary venous hypertension (Fig I).Electrocardiogram (ECO) showed normal sinus rhythm,right-axis deviation, and nonspecific ST segment changes inthe lateral chest leads. Serum creatinine and blood ureanitrogen were 1.2 mg/dl, and 18 mg/dl., respectively. Serumalbumin was 3.3 g/100 mL. Complete blood count andurinalysis were within normal limits. An arterial bloodgas on4 L of O2 by nasal cannula was: pH 7.39, Pa02 81 mm Hg,and PaC02 43 mm Hg.

To assess the patient's preoperative hemodynamicstatus, a pulmonary artery catheter was inserted the eveningprior to surgery and showed a PAP of 115/50 mm Hg and acardiac index (CI) of 1.9 L/min/m2 with a correspondingsystemic pressure of 144/72 mm Hg and heart rate of 82beats/min. A PCWP was unobtainable. Because of theseverity of the pulmonary hypertension, it was felt thatassessment of the degree of reversibility of the pulmonaryvasoconstriction was warranted. If the PVR was fixed due tolong-standing mitral stenosis, mitral valve replacement mightnot benefit this patient. A POE 1 infusion was begun at aninitial rate of 10 ng/kg/min and increased slowly up to 80ng/kg/min in an attempt to reduce PAP. The results of thistreatment are summarized in Tables 1 and 2. Over the nextseveral hours, despite a decrease in PVR as evidenced by anincrease in cardiac output (CO) and a slight decrease in PAP,the patient was noted to become increasingly dyspneic andtachypneic. Vital signs 3 hours after the POE) infusion wasbegun were: blood pressure 130/70 mm Hg, heart rate 99beats/min, and a respiratory rate of 28 breaths/min. Physicalexamination was significant for rales throughout both lungfields.The ECG was unchanged. Chest roentgenogram showedextensive interstitial infiltrates with vascular redistribution(Fig 2), and a diagnosis of pulmonary edema was made.Treatment consisted of discontinuing the POE) infusion,increasing the FP2' and additional diuretic therapy.

744 Journal ofCardiothoracic Anesthesia, Vol 4, No 6 (December), 1990: pp 744-747

PULMONARY EDEMA AFTER PGE, INFUSION 745

Fig 1. Admission chestroentgenogram shows left atrialand left ventricular enlargementwith stage II pulmonary venoushypartension and a small right pleu­ral effusion.

Resolution of the pulmonary edema occurred over thenext several hours as noted by improvement on physicalexamination, chest roentgenogram, and arterial blood gases.A decision was made to replace the patient's mitral valve.Surgery was performed 36 hours later and consisted of mitralvalve replacement and tricuspid valveannuloplasty. Postoper­ative PAP was 50 to 60/30 to 40 mm Hg. The remainder ofher hospital course was unremarkable.

DISCUSSION

Von Euler/ coined the term "prostaglandin"in 1936 in his work involving the smooth musclecontracting and vasodepressor activities of semi­nal fluid. However, it was not until 1962 whenPGE l was isolated that a strong interest wasgenerated regarding these compounds. PGE l isderived from the cyclooxygenase pathway ofarachidonic acid metabolism. Its vasodilator prop-

erties are thought to occur via activation of theadenylate cyclase system with a resultant in­crease in intracellular cyclic AMP. PGE l isinactivated by specific enzymes widely distrib­uted throughout the body with subsequent oxida­tion of the intermediate metabolites to dicarbox­ylic acid.

Pulmonary hypertension as a result of mi­tral stenosis is frequently severe enough to war­rant mitral valve replacement. Following valvereplacement there is usually a decrease in leftatrial pressure and subsequent reversal of thepreviously elevated PVR. PGE l can reduce PVRin patients with pulmonary hypertension when anactive or vasospastic component to this elevatedPVR exists.' Szczeklik et aJ3 demonstrated that

Table 1. Effect of PGE, Infusion on Hemodynamics

PGE, HR CO SAP PAP SVRTirne" (ng/kg/min) (beats/min) (L/min) (mmHg) (mmHg) (dyne· s· em- 5)

0 0 80 3.5 136/64 110/50 1.8741 30 88 4.3 130/64 105/43 1,2102 50 82 4.6 143/68 107/44 1,4433 80 99 5.2 131/68 99/53 1,2154 50 99 5.1 129/68 92/52 1,2395 0 98 4.4 128/70 108/60 1,250

Abbreviations: PGE" prostaglandin E,; HR, heart rate; CO, cardiac output; SAP, systemic arterial pressure; PAP, pulmonary arterypressure; SVR, systemic vascular resistance.

• Hours after PGE, infusion started (0 = baseline, 5 = 1 hour after infusion stopped).

746

Table 2. Effect of PGE, Infusion on Arterial Blood Gases

PaD, PaCO, RRTime* pH (mmHg) (mmHg) F,O, (breaths/min)

0 7.39 81 43 4 Lt 18

3 7.40 56 41 4L 28

4 7.39 68 39 1.0 20

5:j: 7.40 70 43 1.0 22

7 7.35 136 45 1.0 20

Abbreviation: RR, respiratory rate.

*Hours after PGE, infusion was started (0 = baseline).

t4 L of O2 by nasal canula.

:j:PGE, discontinued.

PGE1 can significantly reduce PVR in patientswith mitral stenosis and pulmonary hyperten­sion.

However, there may be a population ofpatients with pulmonary hypertension in whomPGE1 therapy is inappropriate. PVR exceeds 800dyne. s· cm ? in approximately 12% of patientswith mitral stenosis." Clinical findings in thesepatients are usually consistent with right-sidedheart failure. In this group of patients, pulmo­nary artery vasoconstriction may limit pulmo­nary arterial blood flow and, thus, minimize theelevation of left atrial pressure. This is thought tobe a protective mechanism for the pulmonarycapillary bed. Therefore, vasodilator therapy inthese patients would be potentially deleterious byremoving this protective adaptation. Conceptu-

WHITE ET AL

ally, this is best explained by examining thehemodynamic effects of such an intervention.

Gorlin and Gorlin5 developed a formula forcalculating the area of the mitral valve usinghemodynamic measurements, as follows:

COMitral Valve Area = K x OFT! X (PG)O.5 (1)

where CO = cardiac output; K = hydraulicconstant; OFT! = diastolic filling time interval;and PG = pressure gradient across the mitralvalve. With a fixed mitral valve orifice, thisformula can be arranged to approximate thepressure gradient across the mitral valve asfollows:

Pressure Gradient = (COjOFTI)2 (2)

In this particular patient, by infusing PGE1to decrease PVR and afterload on the rightventricle, there was an increase in CO of 48%(3.5 Ljmin to 5.2 Ljmin), which represents agreater than twofold increase in the pressuregradient across the mitral valve according toequation 2. Although it was not possible todirectly calculate the decrease in the diastolicfilling time interval associated with the increasein heart rate, a conservative estimate of a 15% to25% decrease in the duration of diastole would,

Fig 2. Chest roentgeno­gram taken approximately 4 hoursafter the PGE, infusion was begunshows extensive interstitial infil­trates along with vascular redistri­bution.

PULMONARY EDEMA AFTER PGE, INFUSION

when factored into equation 2 along with theincrease in CO , result in an increase in thevalvular gradient between threefold and four­fold. It is thought that this increased pressuregradient across the mitral valve resulted in pulmo­nary venous hypertension that then led to thesubsequent development of pulmonary edema inthis patient.

As noted above, Szczeklik et al, duringobservations made under stimultaneous left andright heart catheterization, demonstrated signifi­cant reductions in PAP and PVR during a30-minute intravenous infusion of PGE\ in dosesranging from 10 to 20 ng/kg/min in 20 patientswith mitral stenosis.' Significant side effects werenot reported. Demographic examination of Szc­zeklik's study shows an average age of 36.7 years,mean PAP of 38.5 ± 15.2 mm Hg, and PVR of808 ± 387 dyne. s . cm " before PGE\ therapy.The present patient was 70 years old, had a meanPAP as high as 88 mm Hg, and a PVR as high as1,600 dyne· s . em"? before PGE\ infusion wasbegun. Also, the PGE\ dose in this patient waslarger, ranging from 10 to 80 ng/kg/rnin, andwas administered over a longer time period (4hours) .

Before concluding PGE1 caused the pulmo­nary edema observed in this patient, other possi­ble etiologies in the differential diagnosis must beconsidered, including volume overload, ischemicmyocardial dysfunction, and dysrhythmias. Vol­ume overload was not likely the cause of pulmo­nary edema in this patient because hourly urineoutput exceeded fluid input and her body weightwas several kilograms below her initial admissionweight.

Coronary artery disease was not evident byhistory or prior catheterization data and, in theface of an increasing CO, ischemia-induced ven­tricular dysfunction would be unlikely. However,

747

ischemic myocardial dysfunction may occur inthe absence of coronary artery disease. In pa­tients with stenotic valvular disease and a fixedCO, excessive systemic vasodilation may result ina vicious cycle of decreased coronary arteryperfusion pressure and subsequent ventriculardysfunction. Blood pressure was maintained inthis patient despite relatively large doses ofPGE\, and there was no other evidence ofmyocar­dial dysfunction.

Tachyarrhythmias can produce decompen­sation in patients with mitral stenosis. Althoughsinus rhythm was present, an increase in heartrate was observed resulting in a potential de­crease in the diastolic filling time interval. Thismay have been a contributing factor to thedevelopment of pulmonary edema by aggravat­ing the preexisting large gradient across herstenotic mitral valve.

In summary, PGE\ infusion for the treat­ment of pulmonary hypertension induced life­threatening pulmonary edema in this patientwith severe mitral stenosis. As explained previ­ously, the proposed mechanism responsible in­volved a PGE]-induced reduction in PVR thatled to a decrease in right ventricular afterloadand a subsequent increase in CO. This increasein CO along with an increase in heart rate and,therefore, a decrease in the diastolic time intervalof the cardiac cycle, resulted in a large increasein the pressure gradient across the stenotic mitralvalve. This increased pressure gradient was re­flected in the resultant development of pulmo­nary edema. Presently, there is no definitivemethod of distinguishing susceptible patientswith mitral stenosis who may develop this compli­cation based on pretreatment hemodynamic data.Therefore, caution must be urged in the use ofPGE] in the treatment of pulmonary hyperten­sion in patients with mitral stenosis.

REFERENCES

I. Long WA, Rubin LJ: Prostacyclin and PGE 1

treatment of pulmonary hypertension. Am Rev Respir Dis136:173-776, 1987

2. Von Euler US: On the specific vasodilating andplain muscle stimulating substance from accessory genitalglands in man and certain animals (prostaglandin andvesiglandin). J PhysioI88:213-234, 1936

3. Szczeklik J, Dubiel JS, Mysik M, et al: Effects of

prostaglandin E1 on pulmonary circulation in patients withpulmonary hypertension. Br Heart J 40:1397-1401,1978

4. Wood P: Vasoconstrictive factor in pulmonaryhypertension, in Wright Adams , Ilza Veith (eds) : PulmonaryCirculation: An International Symposium, 1958. Philadel­phia, PA, Grune & Stratton, 1959, pp 294-301

5. Gorlin R, Gorlin SG: Hydraulic formula for calcu­lation of the area of the stenotic mitral valve, other cardiacvalves, and central circulatory shunts . Am Heart J 41:1-29,1951