DOI 10.1378/chest.111.1.218 1997;111;218-224Chest

 Daniel T. Layish and Victor F. Tapson in Massive Pulmonary EmbolismPharmacologic Hemodynamic Support

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Copyright1997by the American College of Chest Physicians,Physicians. It has been published monthly since 1935.

is the official journal of the American College of ChestChest

Pharmacologic Hemodynamic Supportin Massive Pulmonary Embolism*Daniel T. Layish, MD; and Victor F. Tapson, MD

(CHEST 1997; 111:218-24)

Key words: inotropes; pulmonary embolism; vasopressors

Abbreviations: CO=cardiac output; LVEDP=left ventricularend-diastolic pressure; NE=norepinephrine; PAP=pulmonaryartery pressure; PE=pulmonary embolism; PVR.pulmonaryvascular resistance; RV=right ventricular, right ventricle;RVEDP=right ventricular end-diastolic pressure; SVR=systemicvascular resistance

Approximately 630,000 patients develop pulmo¬nary embolism (PE) in the United States each

year.1 PE causes or contributes to approximately200,000 deaths per year in the United States alone.1In general, mortality ranges from 6 to 8%, but risesto more than 30% when complicated by hypoten¬sion.12 Of those patients in whom PE is fatal,approximately 67% die within 1 h of onset of symp¬toms.1 Therefore, this subset has been quite difficultto include in studies evaluating management options.Much of our current understanding of the efficacy

of various inotropic and vasopressor agents in hemo-dynamically unstable patients with PE comes fromanimal models, which can be difficult to extrapolateto the clinical treatment of patients. The anestheticagents used in many of the animal studies mayinterfere with the response to the protocol agents,which creates difficulties in generalizing the findingsto a nonanesthetized population. Positive pressureventilation (mandatory in anesthetized animals) hasits own hemodynamic effects that might alter or

obscure those of the experimental PE. Glass beads(used in many of the animal studies to simulate PE)may not liberate vasoactive mediators to the same

extent as fresh clots. The hemodynamic derange¬ments in response to formed thrombus are more

profound than those seen after embolization of freshautologous clot,3 although the latter model is more

commonly used in the studies cited in this review.Microembolization has been shown to produce pul¬monary edema,45 which can worsen hypoxic vaso-

*From the Division of Pulmonary/Critical Care Medicine, De¬partment of Medicine, Duke University Medical Center,Durham, NC.Manuscript received November 17, 1995; revision accepted July22, 1996.Reprint requests: Dr. Tapson, Duke University Medical Center,Box 31175, Durham, NC 27710

constriction, perhaps to a different extent than actualPE. The size ofthe emboli used in the animal modelsinfluences the degree of hypoxemia (and secondaryvasoconstriction) as well as the hemodynamic re¬

sponse seen with protocol medications.46 Concomi¬tant treatment with heparin (used in some but not allstudies) may alter the hemodynamic response to

protocol agents by inhibiting intravascular coagula¬tion and thus preventing the release of vasoactivehumoral factors.7 In addition, there may be impor¬tant differences between species in terms of drugdoses, vital signs, heart rate dependence, and collat¬eral blood flow. For example, acetylcholine producesvasodilation of the pulmonary circulation in man butvasoconstriction in canine species.8 Thus, applyinginformation obtained from experimental models toclinical patient management must be done withutmost caution.

Pathophysiology

The pathophysiology of circulatory failure andshock due to PE is primarily caused by a reducedcross-sectional area of the pulmonary vascular bed.9This occurs because of the mechanical effect of theembolus itself, as well as secondary effects, includinghypoxic/acidotic vasoconstriction and release of va¬

soactive substances.4-7'1011 The resultant increase in

pulmonary artery pressure (PAP) leads to increasedright ventricular (RV) afterload, myocardial walltension, and oxygen consumption.12 The consequentdepression in RV performance reduces cardiac out¬

put (CO) and BP, leading to shock. Indeed, RVfailure may be defined as the point at which CO andBP fall despite increased RV end-diastolic pressure(RVEDP).13 RV distention can also interfere withleft ventricular filling and thus contribute to dimin¬ished CO.14 The reduced CO lowers mixed venous

Po2 and amplifies the arterial desaturation caused byventilation-perfusion mismatch in PE,15 in turn

worsening myocardial oxygenation and performance.Theoretically, inotropic agents in the setting of PE

might be expected to increase RV work by forcingincreased output into a circulation with fixed vascu¬

lar resistance.16 Unlike the left ventricle, the RVunder normal conditions has high compliance andcan be perfused throughout the cardiac cycle. How-

218 Reviews

ever, when acute pulmonary hypertension causes

increased RV intracavitary pressure, right coronaryblood flow in systole can become dependent on thepressure gradient between the aorta and RV.13The response of the RV to an acute increase in

afterload depends on the prior cardiovascular historyof the patient.917 In a patient without prior cardio¬vascular disease, the thin-walled RV is unable to

generate a mean PAP greater than 40 mm Hg in thesetting of acute PE, whereas PE in a patient with a

chronically hypertrophied RV may result in pulmo¬nary hypertension disproportionate to the degree ofembolic obstruction.9 Thus, the patient with priorcardiopulmonary disease may develop depression ofthe cardiac index with a lesser degree of obstruc¬tion.9To accurately describe the pressure-flow relation¬

ship of the pulmonary vasculature, pressure-flowcoordinates must be determined at several levels ofCO.12 This has been done in a canine model byopening systemic arteriovenous fistulas and varyingthe applied resistance.18 Over the physiologic rangeof blood flow and for constant outflow pressure, theslope of the pressure-flow relationship was con¬

stant.19 Linear extrapolation of the pressure-flow lineto zero defines the mean closing pressure (or effec¬tive vascular outflow pressure) of the pulmonaryvasculature, while the slope of the linear segment(unit pressure change per unit change in flow)represents the incremental pulmonary vascular resis¬tance (PVR)12 (Fig 1). An elevation in mean PAPcould be due to an increase in either mean closingpressure or increased incremental resistance, or

some degree of elevation in both of these factors.Data obtained in dogs suggest that the increase in

PAP after PE is predominantly due to increasedmean pulmonary vascular closing pressure and notincreased incremental vascular resistance.12 Thismay have eventual clinical impact since awareness ofthe particular mechanism producing increased RVafterload may allow pharmacologic therapy to betargeted more specifically, or lead to combinationtherapy designed to achieve synergy through reduc¬tion of both closing pressure and incremental resis¬tance.1219 For instance, in a canine model of pulmo¬nary hypertension, both norepinephrine (NE) andisoproterenol decreased PVR, but only the latteraffected pulmonary vascular tone as defined byincremental resistance.19

320n

4 8 12 16

DRIVING PRESSURE (Ppa"Pa> <cmH20)

124

Figure 1. Rlood flow (Q) is plotted as function of drivingpressure for flow (Ppa-PA) under zone 2 conditions. Solid linerepresents a P-Q relationship in a vascular bed with a criticalclosing pressure. Dotted lines represent P-Q relationship thatshould be assumed if a calculation of pulmonary vascular resis¬tance were made at two ponts (A and R) on that relationship. Seetext for further explanation. P=pulmonary arterial pressure;PA=alveolar (airway) pressure. Reprinted with permission fromGraham et al.55

elevated RV volume, this approach increases RVmyocardial oxygen consumption, worsening oxygensupply-demand ratios and resulting in RV ischemiaand deterioration in RV function.2021 Volume expan¬sion may worsen RV function by causing mechanicaloverstretch (Starling phenomenon) and/or by reflexmechanisms that depress contractility.21 However,Mathru et al22 found a favorable effect of volumeexpansion on myocardial performance in a glass beadembolization model of PE in goats. These authorsspeculated that the conflicting results may be due to

species variation in coronary vascular anatomy and/ordifferent levels of aggressiveness in volume expan¬sion.22 Clearly, the response to volume also dependson factors such as baseline cardiovascular status andextent of RV afterload.12

Volume Expansion

The traditional first-line agent for hypotension isvolume expansion. However, some evidence suggeststhat in the setting of pulmonary hypertension and

Inotropes and Vasopressors

Molloy et al20 used an autologous blood clot modelof PE to produce shock (defined as a systolic BP of

CHEST/111 /1 /JANUARY, 1997 219

70 mm Hg) in 24 anesthetized dogs. The dogs were

heparinized and then randomly treated with (1) no

additional therapy, (2) volume expansion, (3) isopro-terenol, or (4) NE. The dogs treated with NEdemonstrated hemodynamic improvement and re¬

mained in stable condition during 1 h of continuousinfusion, while those in all other groups had progres¬sive hemodynamic deterioration and death within 10min20 (Table 1). In a canine model using balloonocclusion of the main pulmonary artery to simulatemassive PE, dogs treated with isoproterenol hadworse outcome than untreated control animals, whileNE improved hemodynamics (but not survival).23 In

other animal models of PE in which profoundhypotension was induced, NE has proved superior to

isoproterenol.22-24It may be that the positive inotropic and pulmo¬

nary vasodilatory effects of isoproterenol are out¬

weighed by the peripheral vasodilation it causes. Theresultant hypotension leads to decreased RV perfu¬sion and RV ischemia. Mathru et al,22 using a goatmodel, found that isoproterenol increased CO onlyby producing tachycardia, with stroke volume actu¬

ally decreasing. In contrast to isoproterenol, NEappears to improve RV function by a direct positiveinotropic effect, while also improving RV perfusion

Table 1.Summary of Studies*

Study (FirstAuthor, Year,Reference Animal

No.) Model PE ModelHeparinUsed

PretreatmentHemodvnamics Protocol Agents Key Results

Molloy, 198420 Canine

Rosenberg, Canine197123

Angle, 198925 Canine

Molloy, 198527 Canine

Hirsch, 199129 Canine

Vlahakes,198113

Wolfe, 199235 Canine

Tanaka, 199039 Canine

Ducas, 199218 Canine

Mathru, 198622 Goat

McLean,199042

Ghignone,198543

Lee, 198344

Autologous bloodclot

Ralloon occlusionof main PA

Autologous bloodclot

Autologous bloodclot

Autologous bloodclot

Canine PA ligation

Autologous bloodclot

Autologousmuscle cube

Autologous bloodclot

Glass bead

Porcine Glass bead

Canine Glass bead

Yes SBP 70 mm Hg

No MAP 45-50 mm Hg

Yes

Yes

No

No

Yes

Yes

No

No

Canine Autologous blood Yesclot

40% decrease in CO(mean SBP 96 mm

Hg)MAP 73 mm Hg

No MAP 48 mm Hg

No MAP 36 mm Hg

24% reduction in CI, no

significant change inMAP

CO decreased by 34%without change inMAP

36% reduction in CO,MAP 71 mm Hg

30% reduction in MAP

25-30% reduction in

CO, no significantchange in MAP

47% reduction in CO,no significant changein MAP

Control, IV fluids,isoproterenol, NE

Control, isoproterenol,NE

45-75% reduction in CO NE

NE, isoproterenol

Control, phenylephrine,NE

Phenylephrine

Amrinone, control

Dopamine, dobutamine,milrinone, IV fluids

Dopamine, dobutamine

Dopamine, NTG,isoproterenol, NE, IVfluids

PGEl5 NTG,nitroprusside,hydralazine

Nitroprusside,hydralazine

Hydralazine,nitroprusside

NE clearly improvedoutcome (all otherdogs died)

NE improvedhemodynamics but notsurvival

NE increased COthrough increasedstroke volume

Isoproterenol increasedCO, NE did not

Both increased MAP,only NE significantlyincreased CO

Improved CO and RVfunction

All control animals died,dogs treated withamrinone all survived

Milrinone was the onlyagent that did not

produce significantincrease in CI

Both agents raised CO

IV fluids appeared to bethe most effectiveagent

PGE: most selective forpulmonary circulation,but only hydralazineraised CO

Only hydralazineimproved CO

Only hydralazineimproved CO

*CIrrcardiac index; MAP=mean arterial pressure; NTG^nitroglycerin; PA^pulmonary artery; PGE1=prostaglandin Ex; SBP=systolic BP.

220 Reviews

by peripheral vascular alpha-receptor stimulationand increased systemic BP. Another study using a

canine autologous blood clot model of PE showedthat NE improved ventricular function over a widerange of BP and RV afterloads (suggesting that itsbeneficial effects are not limited to the subset withfrank shock).25 Of note, when NE was titrated to a

moderate increase in BP, ventricular performanceimproved without increasing PVR and without det¬rimental effects on renal flow or function.25 Althoughcalculated PVR (PVR=PAP-LVEDP/CO) may de¬crease with NE, this is based on the assumption thatleft ventricular end-diastolic pressure (LVEDP) isequivalent to pulmonary vascular outflow pressure,19which may not be the case in experimental PE.26When Ducas et al19 examined pressure-flow relation¬ships in a canine autologous blood clot model of PE,NE did not change incremental PVR, while isopro¬terenol decreased this parameter. Thus, the in¬creased PAP seen with NE is due to increased flowand not increased vascular tone.12 This is significantsince one might expect the pressor effects of NE toincrease incremental PVR, which would be counter¬

productive in the treatment of RV failure.The poor outcome noted in animals treated with

isoproterenol may not necessarily be applicablewhen BP prior to treatment is higher. This was

evaluated by Molloy et al27 using an autologousblood clot model in dogs, with an end point of a 40%reduction in CO, which caused mild systemic hypo¬tension (mean systolic BP of 96 mm Hg postembo-lization). Under these circumstances, isoproterenolmore than doubled CO (from 1.3 to 3.0 L/min),while NE increased stroke volume (at constantRVEDP) but not CO (due to a decrease in heartrate). In an uncontrolled series of nine normotensiveor mildly hypotensive patients with PE, responses to

isoproterenol varied considerably but typically in¬cluded increased stroke volume, CO, and heart ratewith only a slight reduction in mean systemic arterialpressure and no significant change in mean PAP or

oxygenation.28 Peripheral vasoconstriction alonedoes not appear to be adequate for hemodynamicsupport in patients with massive PE. Hirsch et al29(using a canine autologous blood clot model) com¬

pared the effects of a pure vasopressor (phenyleph¬rine) to NE, which has combined $r(inotropic) anda-(vasoconstrictor) adrenergic properties. Bothagents were able to restore systemic BP to normal,but only NE produced significant improvement inCO, RV myocardial blood flow, and RV myocardialoxygen consumption.29 This is consistent with theresults of Ducas et al,30 who compared NE withmethoxamine (a direct a1-agonist) in a canine glassbead model of PE. Therefore, the inotropic effect ofNE enhances the ability of the RV to meet the

increased energy demands imposed by the (experi¬mental) PE. It is also possible that the vasopressoragents caused increased coronary vascular resistancethat outweighed the improvement in coronary per¬fusion pressure.12 However, Vlahakes et al13 demon¬strated reversal of ischemia and improved RV func¬tion and CO with phenylephrine (at dosages whichshould have had only a-adrenergic effects) afterpulmonary artery ligation in dogs.13 A vasoconstric-tive effect on the venous circulation (with resultantincreased venous return and preload) may havecontributed to the observed effect. The more pro¬found degree of hypotension (mean arterial pressureof 48 mm Hg) prior to treatment in the study ofVlahakes et al may have allowed an effect on CO tobe seen.12

Epinephrine has a-vasoconstrictive effects compa¬rable to those of NE, a1 effects far greater thandobutamine, but has far less (32 activity. Therefore, itcombines the beneficial properties of NE (vasocon¬striction with increased RV perfusion, positive ino-tropy) and dobutamine (positive inotropy) withoutthe vasodilatory effects of the latter (which can havedetrimental consequences on RV coronary perfusionpressure in the setting of systemic hypotension). Apatient has been described who had shock from PEthat was refractory to volume expansion, dobu¬tamine, urokinase, and NE but responded (by he¬modynamics and oxygenation) to a continuous infu¬sion of epinephrine (1 fxg/kg/min).31 Although this isonly a single case report (and may have been con¬

founded by the concurrent administration of recom-binant tissue plasminogen activator and epineph¬rine), it is of interest because of the theoreticaladvantages of epinephrine.

Both dopamine and dobutamine have been shownto raise CO in a canine autologous blood clot modelof PE, without dilation of the pulmonary vascula¬ture.18 Only high doses of dopamine (34.3±4.1jJLg/kg/min) improved CO and RV ejection fraction ina glass bead embolization model of PE in goats, butat these doses, profound tachycardia resulted.22 In a

small series of patients requiring ICU admission forPE, dobutamine raised CO and improved oxygentransport and tissue oxygenation at a constant arterialPo2.17 Another study yielded similar results in ten

patients with circulatory failure due to massive PE.32In some cases, arterial Po2 actually fell (presumablydue to worsened ventilation-perfusion mismatchcaused by dobutamine), but even in these patients,arterial oxygen transport improved because the in¬crease in CO was more than compensatory.17 Thevaried effects of dobutamine on gas exchange in thisstudy were believed to be related to differences ininitial CO and degree of hypoxemia, so that furtherinvestigation will be needed to clarify the role of this

CHEST 7111/1/ JANUARY, 1997 221

agent. There is currently controversy concerning theuse of inotropes to raise CO to supraphysiologicvalues to improve oxygen transport in critical ill¬ness.33-34 As suggested above, in the setting of acutePE, raising CO may worsen ventilation-perfusionmatching by redistribution of flow from obstructedto nonobstructed vessels.17

Despite poor results with isoproterenol, amrinone(which also has both inotropic as well as pulmonaryand systemic vasodilating properties and may haveanticoagulant effects) has shown excellent results in a

canine autologous blood clot model.35 The mode ofaction of amrinone is not precisely known, but it isbelieved to involve both inhibition of phosphodies-terase and altered calcium transport.35 In contrast totwo untreated control dogs who died within minutes,the eight dogs treated with amrinone were all resus¬

citated from profound hypotension (three from elec¬tromechanical dissociation). Treated animals demon¬strated a significant increase in mean arterialpressure and CO, and decreased mean PAP. How¬ever, the effects of amrinone on oxygenation were

not reported. This must be examined carefully be¬fore this agent is used in the setting of PE, since ithas previously been noted to worsen oxygenation dueto pulmonary shunting36 and inhibition of hypoxicpulmonary vasoconstriction.37 A single patient hasbeen described with PE (complicated by pulmonaryhypertension and diminished CO) who had hemody¬namic improvement (as well as improved oxygen¬ation) after treatment with amrinone.38 Like amri¬none, milrinone inhibits phosphodiesterase andalters calcium transport.39 It has been studied in a

canine autologous muscle cube model of PE.39 Ox¬ygenation did not worsen with this agent, but im¬

proved slightly. In contrast to dopamine and dobut¬amine, milrinone demonstrated relatively selectivepulmonary vasodilatation, along with its inotropiceffects. The inotropic and pulmonary vasodilatoreffects of milrinone have also been demonstrated in

patients with multiple organ dysfunction40 and sep¬sis41 (at doses that did not cause an increase in heartrate). While these data are intriguing, much workremains to be done before the routine clinical use ofamrinone or milrinone in the setting of massive PEcan be recommended.

Vasodilators

Various vasodilators have been used in experimen¬tal PE in an attempt to improve RV function throughafterload reduction. Nitroglycerin has been adminis¬tered to normovolemic goats after glass bead embo-lization to simulate PE.22 In this study, systemicvascular resistance (SVR) and PVR decreased, while

RV ejection fraction, CO, and oxygen delivery in¬creased. Afterload reduction was believed to be themechanism of improved myocardial performance,although improved myocardial perfusion via coro¬

nary vasodilation is also possible. Of note, volumeloading was required during nitroglycerin infusion to

compensate for its vasodilator effect.22 McLean etal42 used a porcine glass bead embolization model,and titrated each of four vasodilators (prostaglandinEjl, nitroglycerin, sodium nitroprusside, and hydral¬azine) to produce a 30% reduction in mean systemicarterial pressure. Prostaglandin Ex produced thegreatest decrease in PVR and PAP, and was the onlyagent of the four that did not adversely affect thePVR/SVR ratio. Both nitroglycerin and sodium nitro¬

prusside produced moderate decreases in PVR andPAP, but significantly increased the PVR/SVR ratio.

Hydralazine produced the most systemic vasodila¬tion for a given amount of pulmonary vasodilation,but was the only agent that significantly increasedCO. After glass bead43 and autologous blood clot44embolization in dogs, hydralazine (but not nitroprus¬side) increased CO and decreased PVR. In theMcLean et al42 study, central venous pressure was

reduced with the agents other than hydralazine andthus reduced venous return may have prevented theincrease in CO one would expect from a reduction inafterload. Future studies should address the role ofconcomitant administration of IV fluids with thevasoactive agent. A patient has been described withPE complicated by low CO (refractory to volumeexpansion and dopamine) who had improved cardiacindex and PVR (without significant hypotension) on

two separate trials of oral hydralazine therapy.45Clearly, the risk of systemic hypotension with result¬ant RV ischemia is the primary concern with the use

of vasodilators in the setting of hemodynamicallysignificant PE. Inhaled nitric oxide has recently beendemonstrated to achieve selective pulmonary vaso¬

dilation in a porcine microembolization model ofmassive PE46 Further study of this agent as well as

other inhaled vasodilators (such as prostacylin) ap¬pears warranted.

Conclusions

The available data seem to support the admin¬istration of NE to ensure adequate RV coronaryperfusion pressure in patients with PE and pro¬found decrease in CO and systemic BP. However,dobutamine may be more appropriate in patientswith moderate systemic hypotension, providedclose monitoring of SVR and mean arterial pres¬sure ensures that adequate RV coronary perfusionpressure is maintained.47 The combined use of

222 Reviews

various vasoactive agents to achieve optimal hemo¬dynamic response deserves further evaluation. For

example, the combined use of dobutamine (for its

inotropic effects) and a vasoconstrictor (such as

NE) to ensure adequate RV perfusion offers the¬oretical merit and warrants investigation. Prelimi¬nary data and theoretical considerations suggestthat epinephrine might be a useful agent in pa¬tients with massive PE. Preliminary data on amri¬none is also encouraging, but this agent cannot

currently be recommended routinely for use inthis setting. Based on the available data, we do notendorse the use of isoproterenol for managementof hemodynamically significant PE. Volume ex¬

pansion must be undertaken cautiously in thesepatients, because of the possibility of worseningRV function. Since RV function can deterioratewith volume even at a relatively low RVEDP, RVfilling pressure may not predict the response tovolume expansion when an increase in RV after-load causes a low CO state.21 Clearly, individualpatient management should be guided by follow¬ing objective hemodynamic and physiologic pa¬rameters. However, the precise role and optimaltype of invasive monitoring in patients with hemo¬dynamic compromise from PE remain to be clar¬ified. Thrombolytic agents have been shown to

improve RV function after PE and are appropriate(in the absence of contraindications) when PE is

accompanied by hypotension.1248 The possibleinteractions of fibrinolytic therapy with the phar¬macologic agents discussed in this review and therole for concomitant administration merit furtherinvestigation.49 Surgical or catheter embolectomymay be appropriate in specific circumstances.50-52Percutaneous pulmonary artery balloon counter-

pulsation is a technique that has theoretical appealfor the treatment of RV failure, and initial animaldata are encouraging.5354 Of course, supplementaloxygen, by ameliorating hypoxic vasoconstriction,is vital to the hemodynamic support of patientswith massive PE.The limitations of animal models outlined above

must be taken into account when extrapolating thesedata to bedside management. Many of the studiescited in this review used different end points in theirexperimental pulmonary hypertension models (Ta¬ble 1, "pretreatment hemodynamics") making directcomparison difficult. Multicenter, randomized, con¬

trolled trials in clinically relevant scenarios in humanbeings would be useful to clarify these importantpatient management issues, but the very nature ofthis patient population presents difficult issues in

study design.

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DOI 10.1378/chest.111.1.218 1997;111; 218-224Chest

Daniel T. Layish and Victor F. TapsonEmbolism

Pharmacologic Hemodynamic Support in Massive Pulmonary

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