TO · 2018. 11. 9. · to hemorrhagic, septic, or cardiogenic shock. The septic shock models. include injection of endotoxin alone, injection of endotoxin and living Escherichia coli

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Report Number V

The Treatment of Shock B9ased Upon1'hysioogical Principles and ImpedancA Method

for Moasuring Cardiac Output in Shock

Annual Progress Report

Richard C. Lillehe., M.D., Ph.D.

July 1 1968 to June 30, 1969

Supported By

U.S. Army Medical Research and Development Cormand

Washington, D.C. 20315

Contract No. DA-49--193- IED-2539

DDC Availability Statement

"This dociument may be further distributed byIaxy holder onulywith specific prior arproval oft'he Co=,,nnME.7 eneral,'U.S. Army Medicial Research

en- ^CM ;nA Af1MMlKY:Washington, D.C. 20315.'

I

FI,

V

ABSTRACT

Using radioactive microspheres, we have found that neitherendbtoxin nor gram negative bacteria or the combination of thetwo, when used to induce shock in dogs, cause arteriovenousshunts to open in the gut or the liver. Shunts cannot bedemonstrated in the lungs under these same conditions. In-flammation in addition to injection of bacteria and/orendotoxin appears necessary before arteriovenoua shunts open.Capillary membrane permeability pressutres in shock have beenmeasured In the forepaw of the dog. Shook is associated witha d6creased capillary presure due to leak of fluid throughdamaged capillary walls. Maesive doses of corticosteroidsor tolerance to shock i.nduced with epinephrine or endotoxinpreserves membrane permeability pressure in the normLl range.Tolerance to epinephrine or endotoxin is also P-seociated withdecreased reactivity of the renal and intestinal microcircula-tion. during ahock. Correlation between laboratory experimentsand clinical treatment of shock has been obtained with aportable shock unit.

FOREWORD

in conducting the research described in this report,the investigator(s) adherea to the "Guide for LaboratoryAnimal Facilities and Care," as prbmulgated by the Committeeon the Guide for Laboratory Animal, Resources, NationalAcademy of Sciences-National Research Council.

Pe

Page 2

TABLE OF Co1ENTS

IDim Number

Title lae I

Abstract 2

Foreword 2Table of Contents 3Body of Report - Outlined report 4I. Experimental studies 4

A. hicrocirculation in septic shookB. Capillary membrane permeability 5C. Tolerance to shonk 5

II. Clinical shock unit patients 6A. General plan of obeervation and 6

treatmentB. Hemodynumic observations in septic 7

shockC. Cardiogenio Shock 7D. 'Impending shook 8

!II. Impedance method for measuring cardiac a

output in shockSelected Bibliography 9Distribution List 10Document Control Data form 1473 (with abstract) 11Key Words 12

Back Cover

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=B

I. Experimental StudiesA. Ilcrocirculation in Septic Shock

Arteriovenous shunting in the viscera of man apparentlyplays a major role in the hmodynamic and metabolic distur-bances occurring in gram negative septic shock. Yet themechanism for shunting is not fully understood and the exls-tence of shunts is difficult to prove. We have studiedshunting in the lung, liver, and intestine of dogs subjectedto hemorrhagic, septic, or cardiogenic shock. The septicshock models. include injection of endotoxin alone, injectionof endotoxin and living Escherichia coli bacteria, and in-Jection of endotoxin, living Escherichia coli bacteria and thecreation of an inflammatory focus in the viscera or subcu-taneous tissues. Shunting in these shock models was studiedby the use of radioactive plastic microspheres (25+5 micra)for the liver and intestine and by the use of arterial andvenous oxygen tensions and Berggren's formula of the lung.

The radioactive microspheres are injected into thesuperior mesenterLc artery of dogs following inaC>uion ofwhatever shock is being studied. Blood flow frrn 'he superior

mesenteric veirs is then collected and the nunbei' of micro-bpheres passing. through the superior meaenteric ricrocircula-tion is estimated by measuring the radioactivity of thecollected blood. The microspheres passing through the hepaticartery distrIbution of dogs in shock from various causes arecaught in the lungs and the radioactivity of the excised lungis then measured.

Berggren's equation has been used to determine thepulmonary arteriovenous shunting in these same shock models.We have f-ond that the number of microspheres as measured byradioactivity passing through the 8uperior mesenteric orhepatic circulation in dogs in shock from endotoxin or fromendotoxin and bacteria, is less than one percent.

The findihgs in the lung are similar to thcee for theliver and gut, with no significant increase in pulmonaryshunting noted from injection of endotoxin or endotoxinsard 1ivhg baoteria. These studies give further evidencethat in sepsis neither endotoxin nor bacteria alone areresponsible for the arteriovenouq p1rni . vhich is socommonly found in mrn suffeing pt.r _r 1.,oJ.

To simulate more closely th- septic -rocl cture of man,we are how dbveloping an" experimental septic s*)crk model inthe dog, pig, ahd monkey, Which combines the i.,,.con ofliving bacteria, endotoxin, and the creation of a focus ofinflammation. In preliminary studies, we have he::- shownfor the first time that we can reproduce the hem~d-Tiamicand metabolic changes which are seen in man suffering gramnegat ve sepsis. Our next step is to study the effects oftreatment, with special emphasis on assive doses of cortico-

-t--ds on thas eseptic shock model in wh1.ch b Q.&h onrdlaoutput and low resistance occurs. Proposals for this studyare detailed in the contract application for the years1969 - 70.

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Im

B. Capilltxy Membrane PermeabilityIWe have studied the capillary membrane permeability

pressure olt the forepaw of dogs suffering shock due to theenidotoxin of Bs3herlchla coli bacteria. This Is anotherattempt to oxamine the microcirculation ih shock atd itsreeponue to tret~tm~nt. Uain~, an ieolated, isogxavimietricforepaw of the dog, we determiniA the capillary permeabilitypresaure to be 17 u-inHg in norual dogs. Tbe cap illarypermeability pressure of the forepaw four houra followingthe induction of endotoxin shock decreauea to 9.5 =4~iindicating that in endotoxin shock the capillary integrityis damaged and fluid is apparently leaking into interstitialspaces more easily than normal,

The isolated forepaw preparation of the shocked dogtreated early with fluids and a massive doae of methylpreenisolone retains a capillary permeability pressure in thenormal range (about 17 mmHg). This indicatea that treatme.has aparently stabilized and preserved the integrity of thecapillary membrane in the forepaw and, by doing so, hasprevented loss of fluid into the interstitial spaces of theforepaw. Thus, these studies show a specific .mechanism forthe lose of volume in septic shock. Moreover, these cnvudiesshow another beneficial effect of massive doses of cortico-steroids in maintaining the integrity of the capillarymembrane. Previously we demonstrated that massive doses ofsteroids slowed nerve impulse transmission in sympatheticnerves which reduces the intensity of vasoconstrictioncharacteristically occurring in shock.

Similar studies on capillaryj permeability pressure arenow being done on the kidney. Here again, these studiesindicate that there ia a loss of capillary integrity asevidenced by lowered capillary permeability pressure afterseptic shock is induced. Treatment with corticosteroidsmaintains the permeability pressure of the microcirculationof the kidliey in the normal range. The model here has beenendutoxin induced shock, but similar changes appear to occurin cardiogenic shock and in hemorrhagic shock when it isprolonged. Similar studies are being planned for the pig andfor the rhesus monkey to obtain data in experimental animalswith a physiology more closely akin to man.

C. Tclerance to ShockHigh doses of epinephrine, norepinephrine, and'endo-

tox-in result in increased sympathetic nervous activity,peripheral vasoconstrictioa, reduced tissue perfusion anddeath of doge. G~ven in sublethal amounts, the dosage oftruese agents can be increased to usually l5thal levels with-

ou aveseeffects if doein- a stpis fashion. The dogis then considered tolerant to one or the other of thesevubstances. Under these conditions, the dogs are relativelyinsensitive to sympathetic stimulation and do not respond byintense peripheral viscerocutaneous vaaoconstriction whichis, apparently, the cardinal response to hemorrhagic, septic,and cardiogenic shock.

Paeh

In tolerant dbgs, rolatively insensitive to vasooon-strictlve stimuli, the induction of usually lethal homorrhagic,septia, or oardiogealc shook 4oes not result in the usualdegree of intensive peripheral vasoconstriction. That is, thealpha adrenergically sensitive viscorooutaneous vascular bedsdo not respond by vasoconstriotibn despite a foll in cardiacoutput and blood pressure. Thus, blood flow remains moreequitably dietributed to all vascular beds. Moreover, oxygenconsumption remains in the normal range and survival is near100 percent.

Capillary permeability studies have been started ontolerant dogs in shock. These indicate that inauced toleranceto shook, like massive doses o! corticceteroids, preserve amore normal capillary pressure, indicating that one means bywhich tolerance to Ahook proteots against doth is throughpreservation of capillary integrity.

We have found that induction of tolerance by' the use ofchronic injections ol epinephrine norepinephrine, or endotoxin,in sublethal amounts, can usually be induced in a minimum oftwo weeks. The' tolerance so induced appears to last for upto three months, but is definitely dissipated by six months.Tolerance studies are now planned for the pig and for therhesus monkey as the next atep in the eventual induction oftolerance to shock in man. This program has great eventualbenefits for the combat soldier as well as to civiliansexposed to military or natural catastrophes.

II. Clinical Shock Unit PatientsA. General Plan of Observat!on ahd Treatment

During the past year, 1968-69, we have studied 85patients in shock at the University of iinnesota Hospitals,with the aid of our clinical shock unit. While these studiesare not directly suppor-ted by the Research and DevelopmentCommand contract, the results of these studies provideevidence of the value of applying the principles learned inthe laboratory to the treatment cf the acutely. ill.

These patiehts who suffered from traumatic cardlogenicor septic shock, or oombinationz of these probiems werestudied with the aid of a mobile shook cart equipped withstrain gauge transducers, a transistorized densitometer, andoihar e pipuc talwi us vsua1l roCnut -rteri -- _venous pressures, cardiac outputs, and other derived datafor immediate use at the bedside. Such data is alob recordedfor future use. In addition to hemodynamic studies, respira-tory and metabolic effects of shock are also recorded.Arterial and venous oxygen and carbon dioxide tensions andsaturations are measured. Most patients are also beingaesistod with one of the various types of respirators sooxygen uptake can be measured nd, ultimately, oxygen con-sumption determined. Moreover, with the aid of Berggren'sformula and the above dat&, arterial venous shunting in thelungs can be estimated. Blood pH, and lactate, and serumelectrolytes are also measured and used as a guide to treat-ment. All patients are also catheterized so that hourly urinevolumes can be accurately recorded. All of the above data,including a careful examination of the patient are availablewithin 30 to 45 minutes after the patient in shock is seen.

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B. Hemodynamic Observations in Septic Shockoonwtant linding in patients suffering actual or

impending sepcio shock is a normal or high cardiac outputalong with a normal o -r low total periph..eral resistance. Thesefitdings occur in the face of clinical signs of poor nutri -tional blood flow buoh a6 aoidoeia, elevated blood lactate,oliguria, and cool, pale, skin.

The desparity betweea clinical signs of shock and hemo-dyunnic measurements of an apparently adequate cardiao outputcan only be ex-plained by the opening of arterovenou~s shunts.These can be moat easily demonstrated in. the lung, where wefind -that oxygen tension of arterial blood is usually belownormal evre though the patient is receivin 100 percent oxygenl.Moreover, the low arterial venous oxygen -dfference suggestethat blood is bypasaing nutritional vascular beds not only inthe lung, but in tht other viscera and skin as well. Theseshunts .can ouset it th lung, in the viscera, in. in~flammedpleura, or peritoneixu, or subcutaneous tissues. Attempts tomeasure shunting directly in septic shock in the kidney havebegun by placiiag catheters in the'renal artery and renal veinof patients i~u ehoCk. Here again, using'the oxygen saturations,and blood flow studies across this organ, we believe we canobtain blood flows across the kidney as well as data to indicatewhether shunting is present in this organ in sepsis.

The living bacterial factors seem responsible for theopening of shunts since endctoxin in the absence of bacterialinflammation in the dog does'not lead to shunting In any organas was noted above, However, when an inflammatory process isinduced by chemicals or bacteria along with endotoxins, we thencan reproduce the picture which is so characteristically seenin mail of a high caidiac output and low total peripheralresistance in the face of a severe decrease i~n nutritionalblood flow to the viscera and skin.

The therapeutic protocol tor the atieuts in septic shockincludes liberal use of blood, plasma, plasma substitutes,low molecular dextran, and balanced salt solutions, combinedwith massive intravenous doses of corticoasteroidn. usuallymethylprednisolone '(30 mg/kg) or dexamethaisonce (6 mg/kg). AlongW4--tFCCMaS,=,.SV4 -- givenc tho bins and a Cogieinrvnul. ~nlytasuc fbceilcntaminaticn. is eliu..nated whenever pciarzible. This combinationof measures has lead to the survival (actual dis'charge fromthe hospital) of over 70 percent of th~f patien . a notableimprovement in our own previous resultf. and in th-e resultsreported by others,

C. Cardiogenic ShockA protocol similar to that outlJtn;:d above for thona

patients suffering septic shock has been uc~v.d with eoci nsin cardiogenic shock in which the increascd pruriphert-. rcr-sstance of cardiogenic shock is dec:ceascE-4 by t'he uee ofmasivedoses of corticooteroids. The use of v; 4opresor

sLLLbutaneva u6 bev a~Lkvoided ia. £iUtt Palta.e

Page 7

D. Impending Shock

In the past year, we have been called earlier to seeatients who are suffering sepsis or cardiovascular problmem.

of these patients still have a nomal blood pressure,alough they manifest signs of a low cardiac output, and highresistance with oliguria if cardiac damage is the problem.Other patients suffering sepsis show the typical signs of highcardiac output and low resistance with oliguria. When thesepatients are seen early and treated early with fluids andmassive dose of corticoateroids, then subsequent hypotenaionhas not occurred and survival is near 100 per cent. It isour hope that the prevention of shook through tb eventualinduction of tolerence in man combined with early treatment'ay virtually eliminate death from 'septio or oardiogenicinsults or following trauma.

III. Impedance Method for Measuring Cardiac Output in ShockA separate report has been submitted on this phase

of our study by Dr. Robert reek.

Page 8-II

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SM.LC TL) BI~jI OG1 '.1iIY

1. Dtetzman, R.H. and Lillehei, R.C.: The treatment ofcardiogenic zh6ok IV. The uee'of phenoxybenz~mina arndchlorpromazine, January, 1968, Aw.Heart J. 75: 136.

2. Dietzman, R.H. and Lil',ehei, B.C..: The treatment bfcardio~anic shook V. The Use of steroids. February,1968,Am Heart J. 751 274.

3. Dietzman, R.HI., Peerster, J.A., Idezuki, Y.,.Bloch, J.H.,anrd Lil2.ehei, R.'.,: Peripheral reeistan'ce changes duringshock in, man. !lay, 1966.Angiolo~y, 19:5, P. 268 .

4. Dietzoan', R,11.., Nordbeg 1 E David, Loken, M.IK. andLillehei, R.C;t Xenonfbmyocardial blood flowdetermination: A eimple new balloon teclhnique.June,l968.Am. J. of Physiol. 124:6.

5. 1)ietzmai, R.andLillehei, R..:Natu'-e. and tamnof shock. Di)cembe, 1968. Ho~pital M~edicine ZPub'Jications,Ltd. london, England, 1: 300-304.

6. Dietzman, R.1., Eroek, R.A., Idezuki, Y. and Lillehei,R.C.:Plasma norepinephrine levels during crkrdi~genic shock intormal and endotoxin tolerant dogs. May 6,1968 (abstract).JJJ4.A 204: 530-531.

7. Lillehef, R.C., Break, R.A., Castaneda, A.R, andDietzman, R.H.,: Treatment of low output eynidrome withmethyipreciniso'lone and isoproterenol. May, 1968(abstract). JAAMA 204:530.

8. Diet~zian, R.H., Dreek, R.,.., Idezuki, Y. and Lillcheij'F.C.:Increased sympathetic nervous system activitv--The lethalfacto-- in experimental cardlogenic shock. I-larch.-April,1968 (abstract). ved..Proc..27:448.

A.Rl. and Liliehel, B.C .: L&w output syndrome: Recogni-tior- and treatment. Janu y-7, 1969. J.Thor-ac. and Cartiov.Surg. 57:#1,.

10. Motsay, G.J., fliatzuan, R.H. azid 1,lllehei, P.C.: StudyCf thoC -4 C-0,4 CUl1ntio^n i n jip -1 i V"-t pm~j t 1'J J2il-tao

tine&of"endotoxin hcked dogs. Katcch-April, 1969(abstract No.74). Fed. Proc. 284#2, p.271.

11. Dietzman, R.H. and Lillehel, R.C.: Clrculatbry Collihpseand Shock. 1969. Tice's Practice of Medicine, Vol.VI,Chapter 2, Hoeber Medicz~l Division - publihers.

12. Dietzman, P.11., Bloch, 3.11., Lyons, G.W. and Lillehei,R.C..:Prevention of lethal bardiogenic shock in epinephrine-tolerant dos. Apr-Il, 1969, Surgery 65:4 pp. 623-628.

13. Lillbhei, R.%".: Pressor agents in cardiogenic shock.June, 1969. Am. J. of Cardiology 23:# 6 ,p.. 900.

14. Motcay, G.0J., Dietzman, R.11. and Lillehel. R.C.:'Treatment of endotoxin sho0c, to be pub.Ilovember,l969,Review of Surgezy

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Medical Researh and Development

13 DTATCommand ICIIUsing radioactive microspheres, we have found that neither endotr '.n

nor gram negative bacteria or the combination of the two, when usedto induce shock in dogs, cause arteriovenous shunts to open in the gutor the liver. Shunts cannot be demonstrated in the lungs under thesesame conditions. Inflammation, in addition to injection of bacteriaand/or endotoxin appears necessary before arteriovenous shunts open.Capillary membrane permeability pressures in shock have been measuredin the forepaw of the dog. Shock is associated withdecreased capillarypressure due to'leak of fluid through damaged capillary walls.Miassivedoses of corticosteroids or tolerance to shock induced with epinephrineor endotoxin preserves membrane permeability pressure in the normalrange. Tolerance to epinephrine or endotoxin is also associated withdecreased reactivity of the renal and intestinal microcirculationduring shock. Correlation between laboratory experiments and clinicaltreatment of shock has been obtained with a portable shock unit.

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Tolerance to Shock

Vasocontric tl on

Vas o d i1aLa t.io()nCorLticovteroids in Shock

Capill~ary Permeabil]ity in Shock

Art a!Jovenou S; Shunts

Impodance Cardli ograpli

Cardiogenic Shock

Sopt Lic ShockEndotoxin Shock

Hemorrhagic Shock

Radioactive I-icrosheres

Page 1 2SculyCifeti

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