ii. the role of sympathetic pathways in the elevation of pulmonary

Neurohemodynamics of Pulmonary Edema

II. The Role of Sympathetic Pathways in the Elevation ofPulmonary and Systemic Vascular Pressures following the

Intracisternal Injection of FibrinBy STANLEY J. SARNOFF, M.D., AND L. CHARLOTTE SARNOFF

The authors criticize the concept of "neurogenic pulmonary edema" as resulting from an increasein pulmonary capillary permeability mediated by nerve impulses to those vessels. They show thatone of the methods used to produce "neurogenic pulmonary edema" markedly elevates systemicand pulmonary vascular pressures, the latter to levels high enough to produce pulmonary edema.Vagotomy and/or upper thoracic sympathectomy do not prevent the elevation of pulmonaryvascular pressures. Blockade of the sympathetic innervation to the systemic vascular bed lowersthe systemic vascular pressures and brings the pulmonary vascular pressures back to normal. Thecontrol of pulmonary vascular pressures by sympathetic impulses to the systemic vascular bed isdemonstrated.

T HE CONCEPT of neurogenic pulmo-nary edema, which relates central nervousinjury, irritation, or stimulation to the

pulmonary edema state, has suffered somewhatfrom a lack of observation of those phenomenaconcurrently going on in the cardiovascularsystem.As a result the view has become widespread

that the pulmonary edema state results froman increase in pulmonary capillary permeabilitymediated by nerve impulses, independent ofthat hemodynamic change which might readilybe expected to produce pulmonary edema,namely, an increase in pulmonary capillarypressure.One notable exception to the foregoing has

been the recent study of Campbell, Haddy,Adams and Visscher,' in which these authorsdemonstrated that increased intracranial pres-sure produced acute pulmonary edema whichwas preceded by a rise in both pulmonary ar-terial and venous pressures. This was not, how-ever, accompanied by arterial hypertension,but instead by bradyeardia and a loweredcardiac output. The pathway was demonstratedto be vagal.

From the Department of Physiology, HarvardSchool of Public Health, Boston, Mass.

Aided by a research grant from the NationalHeart Institute, United States Public Health Service.

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In 1949, Cameron and De,2' 3in attemptingto produce chronic hydrocephalus in the rabbit,injected a combination of thrombin and fibrino-gen into the cisterna magna of the rabbit.The rabbit promptly developed massive, over-whelming, lethal pulmonary edema. Theauthors felt that this occurred as a result ofincreased pulmonary capillary permeability re-sulting from nerve impulses, primarily vagal.

These phenomena seemed worthy of closerhemodynamic scrutiny, especially with regardto those pressure changes occurring in the pul-monary vascular bed. Accordingly, the follow-ing study was undertaken.The integration of this work with other pul-

monary edema research by previous investiga-tors will not be done here but will be attemptedin a subsequent communication.

METHODF Eighteen rabbits weighing from 1.6 to 2.9 Kg.were used, and the anesthetic was a 25 per centsolution'of urethane given intravenously in doses of4 cc.0per Kilogram. Ninety mongrel dogs weighingfrom%10.5 to 20.5 Kg. were anesthetized withmorphine sulfate 4 mg. per Kilogram, chloralose 48mg. per Kilogram, and urethane 480 mg. per Kilo-gram. The morphine sulfate was given intramuscularly30 minutes'prior to the intravenous administrationof the latter two agents, which were then givenslowly as a mixed warm solution. The results ofexperiments on these dogs will form the basis of a

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NEUROHEMODYNAMICS OF PULMONARY EDEMA

subsequent report4 as well as this one. Sixty-fiveof these experiments were technically satisfactoryfrom the point of view of yielding significant data.

All pressures studied were obtained by means ofthe electromanometer5 and recorded with direct-writing galvanometers which register in rectilinearcoordinates. The point of zero reference for pres-sure determinations was arbitrarily selected as apoint 4 cm. above the lowest point on the concavedog board. This, of course, introduced some errorin terms of absolute values, since dog size and posi-tion varied somewhat from experiment to experi-ment. This error, however, remained constantthroughout any given experiment. Mean pressureswere obtained by electrical integration of the fullpulse pressures.

In the dog, central systemic venous pressure,pulmonary artery pressure, pulmonary "capillary"pressure,6 left auricular or pulmonary venous pres-sure, and femoral arterial or aortic pressure wereobtained through appropriately placed catheters,utilizing fluoroscopy when needed. Systemic arterialand left auricular or pulmonary venous pressureswere recorded in every dog studied. The pericardiumwas opened for cannulation of the left auricle butwas intact if the pulmonary vein was cannulatedinstead. Other pressures were recorded as indicatedbelow. Carotid artery and left auricular pressureswere measured in four of the rabbits studied.Two types of dog preparations were used, closed

and open chest. When the closed chest preparationwas used, left auricular pressures were obtainedthrough a catheter passed retrograde up the femoralartery and aorta and through the aortic and mitralvalves.6 7 With the open chest preparation directcannulation of either the left auricular appendage ora lobular pulmonary vein was used. In some experi-ments pulmonary artery and pulmonary "capillary"pressures were obtained by means of a twin lumencatheter, one lumen of which opened 6 cm. proximalto the distal lumen orifice. Final positioning of thecatheters was checked by fluoroscopy when in-dicated and by analysis of the pulse contours ob-tained. All experiments were done with a tracheot-omy tube in place, and respiration was maintainedby a modified Starling pump in both the open andclosed chest experiments. Heparin in the catheterswas employed to avoid clotting.When autonomic blockade was desired, 0.04 to

0.05 mg. per Kilogram of d-3,4-(1',3'-dibenzyl-2'-ketoimidazolido)-1,2-trimethylene thiophanium d-camphor sulfonate (Ro 2-2222) were given in-travenously. * This agent has been shown by Randalland co-workers8 to block sympathetic ganglionsand prevent stimulation of the vagus.

* Supplies of this compound were made availablethrough the generosity of Dr. Elmer L. Sevringhausof Hoffmann-La Roche, Inc., Nutley, N. J. This agenthas been given the name Arfonad.

Spinal anesthesia was administered throughpreviously placed subarachnoid catheter accordingto the method of Co Tui.9 When total spinal anes-thesia was desired, 5 cc. of a 4 per cent solution ofprocaine hydrochloride were rapidly injected.

In rabbits the atlanto-occipital membrane wasvisualized and 0.2 to 0.3 cc. thrombin and 1.0 to 2.0cc. fibrinogen were injected through a needle inrapid succession. One rabbit received only thefibrinogen. In the early dog experiments a similartechnic was employed, using 3.0 cc. thrombin and10 to 13 cc. fibrinogen. The solutions were made upby dissolving 0.12 Gm. thrombin (500 units) in 5cc. isotonic saline and by dissolving 0.4 Gm. fibrino-gen in 15 cc. isotonic saline. The combined injec-tion will hereinafter be referred to as fibrin. Inlater dog experiments the atlanto-occipital mem-brane was opened widely (1.5 cm.) and the solu-tions simply sprayed over the dorsal aspect of themedulla with a catheter pointing towards thetentorium. This permitted ready egress of fluid andprevented a rise in cerebrospinal fluid pressure.When the preparatory maneuvers had been

completed, a positive displacement pump wasused to accomplish the intravenous infusion of 10cc. per Kilogram of isotonic saline in one minute.Either one, two, or occasionally three such "stand-ard" infusions were given in the 30-minute periodprior to the injection of fibrin. Prior to the intra-cisternal injection of fibrin, these infusions werenever observed to elevate pulmonary venous pres-sure more than 2 mm. Hg. For purposes of com-parison, in some experiments this "standard"infusion was given one or more times after theintracisternal injection and again after ganglionicblockade.

RESULTSObservations in the Rabbit

1. Response of the Rabbit to the IntracisternalInjection of Fibrin. The response of the rabbitto the intracisternal injection of fibrin was aspreviously described.2' 3 A generalized rigor,usually opisthotonos, defecation and urination,and a variable respiratory pattern ranging fromapnea to intense tachypnea and hyperpneaoccurred. When apnea occurred, positive pres-sure breathing was applied until the death ofthe rabbit. Frequently, pink froth and fluidpoured out of the tracheal cannula or, in thoseinstances where positive pressure breathing wasused, through the escape hole in the trachealcannula just prior to or following death. Thelatter occurred in from 2.5 to 35 minutes follow-ing the intracisternal injection. The lungs ofthe rabbits at postmortem examination were

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STANLEY J. SARNOFF AND L. CHARLOTTE SARNOFF

as described by Cameron and Del" and aspreviously shown.'0 Pulmonary edema, varyingin intensity from moderate to severe, occurred

visualize the left auricle and its response to theintracisternal injection of fibrin. Figure 1 showsphotographs taken just before and 70 and 105

A B C

FIG. 1. Rabbit heart seen through left thoracotomy incision and incised pericardium. Rabbit ison its right side with head to the left in each picture. A. 10 seconds prior to injection. Left auricle isin systole. B. 70 seconds after intracisternal injection of 0.3 cc. thrombin and 3.0 cc. fibrinogen inrapid succession. Note enlargement of left auricle. C. 105 seconds after injection. Auricle almostcovers the ventricles. Auricular pulsations were hardly visible in the grossly distended left auricleshown in C.

FIG. 2. Pressure tracings from left auricle andright carotid artery of rabbit. Pressure in millimetersof mercury at the left. Solid lines are electrically in-tegrated (mean) pressures; others are full pressures inthis and subsequent illustrations. 1 mm. (each finevertical line) = 1 second. Intracisternal injection of0.3 cc. thrombin at first arrow and 3.0 cc. of fibrinogenat second arrow.

in all but one of the rabbits. A systematichemodynamic study was not made in the rab-bit, but several findings.were of interest. Whena left thoracotomy incision and opening of thepericardium was performed, it was possible to

seconds after the fibrin injection. It can beseen that significant enlargement of the leftauricle occurred. The left ventricle also ap-peared to enlarge in this and other experiments,but was not as readily photographed. One rab-bit receiving an intracisternal injection of fibrin-ogen alone without preliminary thrombin alsodeveloped acute pulmonary edema which wasas pronounced and more rapidly lethal (2.5minutes) than the average rabbit receiving bothagents.

2. Response of Left Auricular and CarotidArterial Pressures. Following the intracisternalinjection of fibrin, a rise in carotid arterial andleft auricular pressure developed in the fourrabbits in which these pressures were measured(fig. 2).Observations in the Dog

Characteristically, following the intracis-ternal injection of fibrin, there was a sharpelevation of arterial pressure and, more or lesssimultaneously, a rise in pulmonary artery,

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"capillary," and venous pressures. This wasaccompanied by a transient motor and respira-tory response similar to, but less marked than,that seen in the rabbit. Central systemic venouspressure rose either slightly (3 mm. Hg) ormarkedly (30 mm. Hg). When an elevation ofpulmonary vascular pressures did occur, it usu-ally reached a peak sometime within the firstminute and then either remained elevated, fellslightly to a sustained plateau, or returned tocontrol levels in about five minutes. In thelatter case, they could be readily re-elevated

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quently as: (a) more experience with the in-jection technic was obtained, and (b) the openatlanto-occipital membrane technic describedabove was used, and (c) two or occasionallythree "standard" infusions rather than onewere given prior to intracisternal fibrin injec-tion.

1. The Development of Acute PulmonaryEdema in the Dog after the Intracisternal FibrinInjection. Since the study was concerned withhemodynamic observations and the effect ofsystemic vasodilation on pulmonary vascular

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FIG. 3. Pressure tracings from vena cava, pulmonary artery, left auricle and femoral artery ofdog. A fibrin injection 11 minutes previously had been only partially successful in producing hy-pertension. Solid lines = electrically integrated (mean) pressures; other lines, full pulse pressures.Chart speed is 2.5 mm. per second except for brief portion in A where speed is 25 mm. per second. A.Intracisternal injection of 3 cc. thrombin at first arrow and 11 cc. fibrinogen at second arrow. B.Starts four minutes after end of A. 0.04 mg. per kilogram Ro 2-2222 given intravenously at arrow.

Note return of vena cava, pulmonary artery, and pulmonary venous pressures to normal levels withonly slight fall of femoral arterial pressure.

by the administration of one "standard" in-fusion.

The cardiovascular response of the dogs was

more or less consistent, but not infrequentlydeviations occurred from the pattern describedabove. In one dog a bradyeardia without hyper-tension developed. This was in one of theearlier experiments in which the atlanto-occipi-tal membrane had not been opened and thevagi were intact. In one-fourth of the dogs a

striking systemic arterial hypertension de-veloped, but left auricular pressure rose onlyslightly or not at all. In general, the nonchar-acteristic type of response occurred less fre-

pressure, only two dogs which developed ele-vated left auricle pressures after the fibrinwere left untreated. These showed generalizedpulmonary edema at postmortem examination.

2. Effect of Intracisternal Fibrin on the Ar-terial and Venous Pressures of the Pulmonaryand Systemic Vascular Beds. Figure 3A showsthe hypertension that developed in vena cava,pulmonary artery, left auricle, and femoralartery following the intracisternal injection offibrin. The initial period of bradyeardia wasreplaced by tachycardia. It was assumed thatpulmonary capillary pressure would be slightlyhigher than left auricular pressure, or, in this

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instance, more than 70 mm. Hg. It is note-worthy that the mean pressure gradient be-tween femoral artery and thoracic vena cavawas markedly widened, whereas the pressuregradient between pulmonary artery and veinwas hardly altered following the fibrin injection.The highest left auricular pressure obtainedafter the fibrin injection is shown in figure 3.In those dogs in which a significant pulmonaryvascular hypertension developed, the post-fibrin increment of pulmonary venous pressurevaried between 10 and 64 mm. Hg.

3. Effect of the Autonomic Blocking Agent,Ro 2-2222, on Elevated Pulmonary and SystemicVascular Pressures. Since the pathways were

jection of fibrin, the administration of Ro2-2222 was followed by a fall of these pressuresto control levels or below.

4. Effect of Vagotomy on Elevated Left Auricu-lar Pressure. It was important to find out if thecausal pathway was vagal (fig. 4). Followingthe intracisternal fibrin injection and the de-velopment of arterial hypertension and tachy-cardia, left auricular pressure rose from acontrol level of 11 mm. Hg to 51 mm. Hg.This then gradually fell to the sustained plateauof 30 mm. Hg as seen at the beginning of thetracing in figure 4. Bilateral cervical vagotomywas followed by a further slight elevation ofleft auricular pressure. Partial ganglionic block-

FIG. 4. Pressure tracings from left auricle and femoral artery of dog. Chart speed = 1 mm. persecond. 3 cc. thrombin and 11 cc. fibrinogen given into cisterna magna previously (see text). Vagusnerves cut at first arrow. 0.04 per kilogram Ro 2-2222 given intravenously at second arrow.

suspected of being autonomic, an autonomicblocking agent was used to ascertain whetherthe elevated pulmonary vascular pressurescould be lowered by ganglionic blockade. Figure3B is a record from the same experiment asshown in Figure 3A and starts four minutesafter the end of that tracing. Vena cava, pul-monary artery, and pulmonary venous pres-sures promptly fell to control levels after theintravenous injection of 0.05 mg. per kilogramof Ro 2-2222. It is important to note that thereturn to normal levels of central venous andpulmonary vascular pressures occurred simul-taneously with a relatively slight fall insystemic arterial pressure. In all instanceswhere elevated pulmonary arterial and venouspressures developed after the intracisternal in-

ade with Ro 2-2222 then produced a slight fallof arterial pressure and a prompt return ofleft auricular pressure to the control level.Bilateral cervical vagotomy was performedeither prior to or during the elvation of pul-monary venous pressure resulting from theintracisternal injection of fibrin in 20 dogs.Prior vagotomy did not protect against theelevation of pulmonary venous pressure. Va-gotomy performed during the period of elevatedpulmonary venous pressure either did notchange this value or, as happened more fre-quently, caused a further elevation.

5. Effect of Preliminary Bilateral Removal ofthe Sympathetic Chain from the Stellate to theFifth Thoracic Ganglion. The possible role ofsympathetic impulses directly to the lung itself

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was investigated by making the fibrin injectionin dogs from which the sympathetic chainsfrom the stellate through the fifth thoracicganglions on both sides had been removedintact. This type of experiment was carriedout in four dogs, and elevations of pulmonaryvascular pressures were obtained in all of them,although the average rise was about one-thirdless than in those with intact sympathetic gan-glions.

6. Effect of Bilateral Upper Thoracic Sym-pathectomy and Midcervical and Upper Thoracic

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7. Effect of "Standard" Infusion on Pul-monary Venous Pressure before and afterIntracisternal Fibrin and after Partial GanglionicBlockade. It was thought worthwhile to ascer-tain the effect of a "standard" infusion onpulmonary venous pressure before, during, andafter the induction of peripheral vasoconstric-tion in a dog from which the pulmonary sym-pathetics had been removed. Figure 5 showsthe record of dog 38, in which a bilateral upperthoracic sympathectomy had been performedas described above. Prior to the injection of

A BFIG. 5. Pressure tracings from vena cava, pulmonary vein, and femoral artery of dog from which

the sympathetic ganglions had been removed on both sides from the stellate through the fifth gan-glion. Chart speed = 1 mm. per second. Prior to the intracisternal injection of thrombin and fibrin-ogen a "standard" saline infusion elevated pulmonary venous pressure 1 mm. Hg. The injection ofthrombin and fibrinogen elevated pulmonary venous pressure from 5 to 21 mm. Hg as seen at thebeginning of A. A "standard" saline infusion was administered between the first and second arrowsin A. The vagus nerves were cut at the third arrow and at the fourth arrow 0.05 mg. per kilogramRo 2-2222 was given intravenously. B starts 14 minutes after end of A. A "standard" saline infusionwas given between the first and second arrows.

Vagotomy and Bilateral Phrenicectomy. Profes-sor I. de Burgh Daly was kind enough to con-

sider this material. He suggested that the abovecombination of denervation procedures wouldstrengthen somewhat the position in regard tocomplete pulmonary denervation and his sug-

gested type of denervation was done in one

dog. The intracisternal injection of fibrin was

followed in one minute by a rise of vena cava

pressure from 4 to 9 mm. Hg, of pulmonaryartery pressure from 18 to 38 mm. Hg, ofpulmonary "capillary" pressure from 9 to 31mm. Hg, and of femoral artery pressure from145/95 to 295/180 mm. Hg.

fibrin, a standard intravenous infusion (10 cc.normal saline per kilogram in one minute) hadlittle effect on pulmonary venous pressure, thatis, a rise of 1 mm. Hg. After the fibrin injectionpulmonary venous pressure was 21 mm. Hg(start of fig. 5A). At that time a "standard"infusion caused a marked rise in pulmonaryvenous pressure, that is, from 20 to 42 mm. Hg(between first and second arrows). At the thirdarrow a bilateral cervical vagotomy was doneand was followed promptly by a further sig-nificant rise of pulmonary venous pressure.Partial blockade of the remaining intact gan-glions (those which supply the splanchnic bed

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and vascular areas from D-6 and below) wasfollowed by a prompt fall to normal levels ofthe elevated pulmonary venous pressure. Four-teen minutes later (fig. 5B) while the dog wasstill partially under the influence of the gangli-onic blockade, the effect on pulmonary venouspressure of another "standard" infusion wassimilar to that obtained prior to intracisternalfibrin, namely, a negligible rise. The same result

with Ro 2-2222. It was, however, more gradualin onset. This time factor was presumablyrelated to the slower development of the sub-arachnoid chemical sympathectomy.

9. Effect of Curare Administered Prior to theIntracisternal Fibrin. Because it was thoughtthat the diffuse motor activity that follows theintracisternal injection of fibrin might play arole in this phenomenon, curarization with de-

FIG. 6. Pressure tracings from vena cava, pulmonary artery, left auricle and root of aorta in dog.Chart speed = 1 mm. per second. Signal at the bottom. Vagus nerves cut. Aortic occlusion at thqbeginning of each signal and release at the end. A, B, C, D, and E are six minutes apart. Two min-utes after each aortic occlusion, 0.5 per cent of dog's weight of isotonic saline given. Ro 2-2222, 0.05mg. per kilogram, given intravenously two minuts prior to B.

with regard to the effects of a "standard"infusion were obtained in dogs from which thepulmonary sympathetics had not been re-moved.

8. Effect of Spinal Anesthesia after the Intra-cisternal Injection of Fibrin. In three dogs thesubarachnoid injection of procaine hydrochlo-ride during the phase of elevated pulmonaryvenous pressure was followed by a fall in thisvalue comparable in extent to that obtained

camethonium was carried out to the point ofapnea in order to prevent muscular contrac-tions. The subsequent fibrin injection was, ofcourse, not accompanied by a motor response,but vena cava pressure rose from 5 to 9 mm.Hg; pulmonary artery pressure from 15 to 36mm. Hg; pulmonary "capillary" pressure from8 to 32 mm. Hg; and femoral arterial pressurefrom 140/60 (m = 90) to 300/220 (m = 250)mm. Hg. In another type experiment curariza-

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tion with decamethonium did not lower previ-ously elevated pulmonary vascular pressures.

10. Effect of Total Aortic Occlusion on Pul-monary Vascular Pressures before and duringGanglionic Blockade. Another type of experi-ment, in addition to those cited above, wasperformed with the hope of throwing some lighton the role of changes in peripheral vascularblood volume as well as changes in peripheralvascular resistance when peripheral vasocon-striction occurs. After bilateral vagotomy, theleft subclavian artery was tied off at its pointof emergence from the aorta. Subsequently, thesimultaneous clamping of the arch of the aortaand the brachycephalic artery for precisely 30seconds stopped the output of the left ventricleexcept for the blood going through the coronaryarteries. The carotid sinuses were subjected tolowered pressure during the aortic occlusion.The elevation of pressure in vena cava, pul-monary artery, left auricle, and aorta werefound to be more or less constant if the aorticocclusion was done at six-minute intervals andif 0.5 per cent of the dog's body weight ofisotonic saline was injected in the second minuteafter each aortic occlusion. Figure 6 shows theresults of this type of experiment. Before gan-glionic blockade when the aortic occlusion pro-duced peripheral vasoconstriction because ofthe lowered carotid sinus pressure, pulmonaryvascular pressures rose sharply (fig. 6A). Afterganglionic blockade the same aortic occlusionproduced less of a rise in pulmonary vascularpressures (fig. 6B). As the ganglionic blockadewore off, the response approximated its previ-ous magnitude (figs. 6C, D, and E).

DIscUSSIONNone of the above data exclude the possi-

bility that nerve impulses may influence pul-monary capillary permeability. However, it isclear from the experiments we have describedthat there is an alternative explanation to thatput forth by Cameron and De.2 3 That is tosay, the activity of nerve impulses consequentupon the intracisternal injection of fibrin insome way brings about an elevation of pul-monary capillary pressure of such an extentas to be reasonably expected to account forthe edema that occurs.

Just what occurs locally when the medullais bathed in fibrin is not readily apparent. Thereis evidence to support the view that this is anonspecific irritative or locally stimulating phe-nomenon, since Jarisch and associates" reportedthat veratrine introduced into the cisternamagna of rabbits also produced pulmonaryedema. This was confirmed by Horst and co-workers."2

In other experiments not described aboveintracisternal protoveratrine was also followedby marked elevations of pulmonary vascularpressures but not as immediate in onset. Furtherevidence that the clotting process is not es-sential to this phenomenon is also indicatedby the rapidity with which the changes developand, also, by the observation that fibrinogenalone produced acute pulmonary edema in theone rabbit to which it was given.

In view of the striking changes in heart rateand systemic and pulmonary arterial and ve-nous pressures, it seems that some pronouncedstimulation, either direct or indirect, is beingbrought to bear upon the cardiovascular regu-latory centers of the brain. This is about asfar as our understanding of this part of thesequence goes.

Since bilateral cervical vaogtomy neither pre-vents the rise in pulmonary vascular pressuresnor lowers elevated pressures when done afterthe fibrin injection, vagal impulses do not ap-pear to play a causative role in the productionof these elevated pressures in the dog. In themajority of instances when vagotomy was per-formed after the elevation of pulmonary vascu-lar pressures, it was followed by a further riseindicating that vagal activity was, if anything,conferring a partial protective effect.

It is well to emphasize the basic differencebetween the experimental syndrome describedabove and that used by Campbell, Haddy,Adams and Visscher.' These authors observedthat increasing intracranial pressure by theinflation of a subdural balloon over the dog'scerebrum was followed by a moderate elevationof pulmonary arterial and venous pressures andeventually pulmonary edema. However, sys-temic arterial pressure either fell or remainedat control levels and the pulse rate was slowed.Vagal blockade with atropine returned pul-

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monary vascular pressures to normal, elevatedcardiac output, and averted the developmentof pulmonary edema. There is a reasonablysatisfying comparison to be made between theexperimental syndrome produced by these au-thors and that which is seen clinically in thepostoperative neurosurgical patient or one withbrain injury from other causes.The experimental pulmonary edema syn-

drome, which has been the subject of this com-munication, more closely resembles the cardio-vascular type of pulmonary edema, since it isaccompanied by hypertension, tachycardia, andmarkedly elevated pulmonary arterial andvenous pressures. As will also be seen froma subsequent communication,4 cardiac outputis restricted in relation to the rise in left auriclepressure. It may be argued that the hyperten-sion seen in these experiments is more severethan that seen clinically and that the condi-tions are "nphysiologic." It should be remem-bered, however, that the experimental syn-drome described in the above experiments isone in which an attempt was made to producea cardiovascular type of pulmonary edema inan organism with a normal heart. Clinical pul-monary edema of the cardiovascular typegenerally occurs in an organism in which diseasehas significantly diminished the work capacityof the heart as a pump. The diseased humanheart may reasonably be expected to fail at alower challenge threshold than that of thenormal dog.The elevation of pulmonary vascular pres-

sures apparently does not depend upon theintegrity of the sympathetic nerve supply tothe lung, since these pressures rose with intra-cisternal fibrin even after a bilateral upperthoracic sympathectomy had been performed.The combined denervation procedure suggestedby Prof. 1. de Burgh Daly likewise did notprevent the elevation of pulmonary vascularpressures following intracisternal fibrin. Theaverage elevation of pulmonary venous pressurewas less than that seen in dogs with intactsympathetic ganglions. It must be remembered,however, that the sympathectomy performedalso deprived a significant portion of theperipheral -vascular bed of the possibility ofparticipating in the constrictor response.

From flow data to be presented elsewhere,4it will be clear, as might be anticipated, thatthe elevation of systemic arterial pressure islargely the result of increased peripheral vascu-lar resistance. Further evidence that centrallymediated nerve impulses to the lung are notan important factor in the rise of pulmonaryvascular pressures will be found in the fact thatthe pulmonary vascular resistance is not ele-vated following the intracisternal fibrin. In anycase, it would be difficult to hold pulmonaryvasoconstriction responsible for the marked ele-vations of left auricular pressure observedabove.The administration of a "standard" infusion

uniformly produced a significant rise in pul-monary venous pressure after peripheral vaso-constriction had been induced by intracisternalfibrin. Contrariwise, the same infusion had littleor no effect on pulmonary vascular pressuresif it was administered either prior to the in-tracisternal fibrin or after pulmonary vascularpressures had been returned to normal bymeans of ganglionic blockade.

Of considerable interest in the interpretationof the above data is the fact that pulmonaryvascular pressures may be elevated by impulsestravelling over sympathetic fibers to the periph-eral vascular bed, and conversely, they may bereturned to normal by sympathetic blockadeof the peripheral vascular bed. This relationshipmay help to reconcile in some measure theopposing views of those who do and those whodo not believe that there is significant nervouscontrol of the volume and pressure of the bloodin the pulmonary vascular bed.

It was clear from gross observation of theleft auricle (fig. 1) and pulmonary veins aswell as consideration of the pressure elevationsin the pulmonary vascular bed that a markedincrease in the volume of blood between thepulmonic and mitral valves takes place aftermedullary stimulation with fibrin. That thereis a striking increase in peripheral vascularresistance and apparent left ventricular failurewill be shown in a subsequent publication.4However, to consider this the complete explana-tion of the observed phenomena would be anoversimplification of the problem, for general-ized peripheral vasocoiistriction, in addition to

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NEUROHEIMODYNAMIJCS OF PULMONARYER\1DEM'IA

increasing peripheral vascular resistaice, alsodecreases the volume of blood which can beheld in the peripheral vascular bed. This extravolume of blood must then be shifted to someother area, presumably to a vascular bed withlittle or no constrictor potential, the lung.As seen in figure 6A when the aorta was oc-

cluded for 30 seconds, left auricular pressurerose sharply. During the period of aortic oc-clusion it is to be expected that the low pressurein the carotid sinuses induced peripheral vaso-constriction. In figure GB, two minutes afterganglionic blockade, aortic occlusion resultedin a much smaller elevation of left auricularpressure. As the ganglionic blockade wore off,the rise in left auricular pressure graduallyregained its previous level (fig. 6C, I), and E).Leaving aside the effect of Ro 2-2222 on thecoronary vessels, it is reasonable to assume thatthe aortic occlusion produced a similar im-pedance effect whenever it was applied. Withconstrictor impulses to the peripheral vascularbed intact, left auricular pressure rose sharply,and when these were blocked, the rise was muchless pronounced. It would seem that peripheralvasoconstriction should be thought of as pro-ducing a blood shift from periphery to lung aswell as increasing the resistance against whichthe left ventricle works, insofar as the effecton pulmonary capillary pressure is concerned.This has recently been confirmed in otherstudies utilizing a technic for the continuousregistration of changes in pulmonary bloodvolume."3The therapeutic implications of the principle

of peripheral vasodilation in the managementof acute pulmonary edema are apparent, es-pecially in view of previous data from patientsin acute pulmonary edema who were treatedwith spinal anesthesia.'4 That a significant low-ering of pulmonary venous pressure can beachieved with only a slight lowering of arterialpressure gives rise to the hope that this prin-ciple may prove useful in the treatment of thepulmonary edema accompanying coronary in-sufficiency as well as that accompanying hyper-tension. Moreover, closer scrutiny of the abovefigures reveals that left auricular or pulmonaryvenous pressure began to fall at a time whensystemic arterial pressure had fallen hardly at

all. Theoretically, at least, if it is possible toadjust the degree of peripheral vasodilationdelicately, it should be possible to diminishsignificantly elevated pulmonary venous pres-sures with only a slight fall ill arterial pressure.Preliminary clinical results with Ro 2-2222suggest that delicate adjustment of peripheralvascular resistance is possible."The authors are keenly aware of the pitfalls

to be encountered in the casual application ofStarling's law to the patient or intact animalwith acute heart failure. And yet, even takinginto account the fact that there may be a whole"family" of curves instead of a single curve toexpress the relationship between end diastolicpressure and stroke work, it seems reasonableto conclude that in at least some of the experi-merits shown above, the left ventricle was work-ing at a more advantageous point on the Star-ling curve after peripheral vasodilation hadproduced a lowering of left auricular pressure.

Horst and (o-w-orkers'2 using intracisternalveratrine found that the development of pul-monary edema in the rabbit was prevented bythe prior administration of the hydrogenatedderivatives of ergotamine. Cruchaud and Vermeill6 using intracisternal fibrin in rabbits foundthat the pulmonary edema was prevented byDibenamine in three rabbits and by dihydro-ergotamine in five. Neither group measuredleft auricular or pulmonary venous pressuresbut their data suggested that the sympatho-adrenal system was in some way involved.

In experiments not described above Ro 2-2222 did not prevent the pressor response toepinephrine and also did not lowser arterialpressure which was previously elevated by epi-nephrine. This makes it unlikely thatendogenously secreted epinephrine was a deci-sive factor either ill the elevation of pulmonaryvascular pressures or in their return to normalwith ganglionic blockade. It does iot, howevrer,preclude the possibility that endogenously se-creted epinephrine may have contributed to theover-all response.

Lastly, the authors are obliged to justify theuse of a new term ill (conn1lectioin with acutepulmonary edema. The term "neurogenic pul-monary edema" has been used by many authorsto (convey a variety of meanings. In the minds

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of some it represents an influence on pulmonarycapillary permeability in the absence of anincrease in pulmonary capillary pressure. Inthe view of others it represents any pulmonaryedema in which nerve impulses have a primarycausal role without special consideration ofwhether or not they cause a significant eleva-tion of pulmonary capillary pressure. In recentyears the authors have come to feel that itsusefulness as a means of explicit communicationis far outweighed by the confusion it engenders.It was thought that a more causally specificterm would be helpful. The phrase "neuro-hemodynamic pulmonary edema" has beenfound useful in our laboratory and is herewithdefined.Neurohemodynamic pulmonary edema is that

state wherein an increase in the rate of transferof fluid from pulmonary capillary to the extra-vascular space of the lung is brought about byan increase in pulmonary capillary pressure,which in turn is brought about either directlyor indirectly by nerve impulses.

SUMMARY AND CONCLUSIONS1. The intracisternal injection of thrombin

and fibrinogen (fibrin) is followed by stimula-tion of the cardiovascular centers. This pro-duces an elevation of pulmonary and systemicarterial and venous pressures in the dog andcarotid and left auricular pressures in the rab-bit. It also produces a grossly observable in-crease in the blood volume of the left auricleand pulmonary veins.

2. Bilateral vagotomy prior to the fibrin in-jection does not prevent this elevation, nordoes intercurrent vagotomy lower the elevatedpulmonary vascular pressures in the dog.

3. Bilateral upper thoracic sympathectomy(stellate to fifth thoracic ganglion) performedprior to the fibrin injection does not preventthe elevation of pulmonary vascular pressures,nor does total pulmonary denervation.

4. Elevated pulmonary vascular pressures re-turn to normal promptly after ganglionicblockade with Ro 2-2222.

5. It is felt that nerve impulses causingperipheral vasoconstriction can create a sub-stantial increase in the volume and pressure ofblood in the pulmonary vascular bed. Con-

versely, effective blockade of these impulsescan reverse these phenomena.

6. It is noteworthy that only a small decreasein peripheral arterial pressure may be requiredto return markedly elevated pulmonary vascu-lar pressures to normal.

7. On a theoretic basis peripheral vasodila-tion, by lowering left auricular pressure frommarkedly elevated levels, alters hemodynamicsin such a way that the left ventricle works at amore advantageous point on Starling's curve.

8. The intravenous infusion of 10 cc. of iso-tonic saline per kilogram in one minute haslittle effect on pulmonary venous pressure (<2mm. Hg) in the normal anesthetized dog. In thepresence of marked peripheral vasoconstriction,however, a similar infusion produces strikingelevations of pulmonary venous pressure.

9. The shift of blood from periphery to lungis probably not only a matter of left ventricularfailure but also dependent in part upon thefact that a vascular bed of high constrictorpotential (systemic) can shift blood into anarea of low constrictor potential (pulmonary)and thereby elevate the pressure in the latter.Conversely, peripheral vasodilation can shiftblood from lung to periphery.

10. The use of the term "neurogenic pul-monary edema" has, in the authors' opinion,ceased to be a useful means of explicit com-munication. The suggestion is made that it bediscarded in favor of what, under appropriatecircumstances, is felt to be a more meaningfulterm, namely, "neurohemodynamic pulmonaryedema." A definition of this term has beensuggested.

REFERENCES1CAMPBELL, G. S., HADDY, F. J., ADAMS, W. L.,AND VISSCHER, M. B.: Circulatory changes andpulmonary lesions in dogs following increasedintracranial pressure and the effect of atropineupon such changes. Am. J. Physiol. 158: 98, 1949.

2 CAMERON, G. R., AND DE, S. N.: Experimentalpulmonary oedema of nervous origin. J. Path. &Bact. 61: 375, 1949.

3 -: Pulmonary oedema. Brit. M. J. 1: 965, 1948.4 SARNOFF, S. J., AND BERGLUND, E.: Neurohemo-

dynamics of pulmonary edema. IV. The effectof systemic vasoconstriction and subsequentvasodilation on flow and pressures in the sys-temic and pulmonary vascular beds. Submittedfor publication.

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5RAPPAPORT, M., AND SARNOFF, S. J.: An elec-tronic, multi-range, multi-channel, direct-writingpressure recorder. Federation Proc. 8: 130, 1949.

6HELLEMS, H. K., HAYNES, F. W., DEXTER, L.,AND KINNEY, T. D.: Pulmonary capillary pres-sure in animals estimated by venous and arterialcatheterization. Am. J. Ph3 siol. 155: 98, 1948.HADDY, F. J., CAMPBELL, G. S., ADAMS, W. L.,AND VISSCHER, M. B.: A study of pulmonaryvenous and arterial pressures and other variablesin the anesthetized dog by flexible cathetertechniques. Am. J. Physiol. 168: 89, 1949.

*8RANDALL, L. 0., PETERSON, W. G., AND LEH-MANN, G.: The ganglionic Hlocking action ofthiophanium derivatives. J. Pharmacol. &Exper. Therap. 97: 48, 1949.

9 Co Tui, BURSTEIN, C. L., AND RUGGIERO, W. F.:Total spinal block: A preliminary report. An-esthesiology 1: 280, 1940.

'1SARNOFF, S. J., AND SARNOFF, L. C.: Neurohemo-dynamics of pulmonary edema. I. Autonomicinfluence on pulmonary vascular pressures andthe acute pulmonary edema state. A prelimin-ary report. Dis. Chest. In press.

11 JARISCH, A., RICHTER, H., AND THOMA, H.:

Zentrogenes Lungenodem. Klin. Wchnschr. 18:1440, 1939.

1 HORST, H. G., LEGLER, H., AND WEIJGENER, F.:Hemmung des veratrinlungenbdems des kanin-chens durch dihYdrierte mutterkornalkaloide(hydergin). Ztschr. ges. exper. Med. 116: 179,1950.

1 SARNOFF, S. J., BERGLUND, E., AND SARNOFF, L.C.: Neurohemodynamics of pulmonary edema.III. Estimated changes of pulmonary bloodvolume accompanying systemic vasoconstrictionand vasodilation. Submitted for publication.

14 - , AND FARR, H. W.: Spinal anesthesia in thetherapy of pulmonary edema: A preliminaryreport. Anesthesiology 5: 69, 1944.

D GOODALE, MW. T., AND SARNOFF, L. C.: Gradedreduction of arterial pressure in man by meansof a thiophanium derivative (Ro 2-2222). Itseffect in acute pulmonary edema. Circulati n 6:63, 1952.

16 CRUCHAUD, S., VERMEIL, G., AND HALPERN, B. N.:Action de sympatholytiques sur 1o'edeme aigudu poumon provoqu6 chez le lapin par l'injectionintra-cisternale d'un melange coagulant. Compt.rend. Soc. biol. 144: 181, 1950.

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STANLEY J. SARNOFF and L. CHARLOTTE SARNOFFIntracisternal Injection of Fibrin

the Elevation of Pulmonary and Systemic Vascular Pressures following the Neurohemodynamics of Pulmonary Edema: II. The Role of Sympathetic Pathways in

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