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associated clotting abnormalities andrenal failure. Significantly, there is usu-

ally hemoglobinuria, denoting hemoly-sis. In fact, the destruction of red cellsunder any circumstances is oftenaccompanied by severe, sometimesfatal, results. It was noted in 1954, thata transfusion reaction frequently result-ed in disseminated intravascular coagu-lation (DIC), and it was postulated thatthe microclots of DIC occluded the

microcirculation, resulting in renal fail-ure.1

All cell membranes, bacterial aswell as mammal, are made up of aninner and an outer layer of phospho-lipids, the hydrophobic tails projectinginto the space between the layers. Itwas found that compounds containingcholine were distributed through the

outer leaflet of the membrane, whileaminophospholipids were found exclu-sively on the cytoplasmic side of theinner leaflet.2 When red blood cellssickle, or lyse as in paroxysmal noc-turnal hemoglobinuria, theseaminophospholipids are translocatedfrom the inner to the outer leaflet andare thus exposed to the surroundingmedium.3 This exposure also occurswhenever red cells or tissue cells arebroken by means such as trauma, heat,cold, anoxia, viruses or plasmodia.Bacterial cell walls demonstrate thesame translocation phenomenon whenbroken by antibodies, antibiotics or

Thrombolytic Drugs as a NewTreatment for Acute RespiratoryDistress Syndrome: A Brief ReportRobert M. Hardaway, MD

Texas Tech University School of Medicine, El Paso, Texas

KEY WO R D S : disseminatedintravascular coagulation, t r a u m a t i cs h o c k , septic shock, multiple organf a i l u r e, acute respiratory distresss y n d r o m e, thrombolytic drugs

ABSTRACT

Hemolysis of red cells has been shownto precede the development of shock-like states. All cell walls, both animal

and bacterial, are composed of a phos-pholipid bilayer. The inner layerincludes an amino component and isthrombogenic when exposed to the cir-culation, as occurs when the cell is frag-mented. This in turn may initiatedisseminated intravascular coagulation(DIC), in which the microclots may tem-porarily occlude the microcirculation,

causing tissue necrosis and multipleorgan failure. Several animal experi-ments are briefly described whichdemonstrate the lethality of this mecha-nism. A clinical trial involving patientswith acute respiratory distress syndrome(ARDS) refractory to traditional treat-ment modalities also demonstrates theeffectiveness of thrombolytic drugs.

INTRODUCTION

It has been recognized for over a centu-ry that a mismatched blood transfusionoften causes a severe, sometimes fatal,reaction, a reaction consisting of theimmediate onset of shock, usually with

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heat. Feola et al4 found that evenextremely small amounts of theseaminophospholipids not only activateintravascular coagulation, (evidenced bya drop in the serum fibrinogen and dep-osition of fibrin in the microcirculationof most organs), but also producesthrombycytopenia, leukopenia, fibrinoly-sis (appearance of fibrin split productsin the plasma), activation of the alter-nate pathway of complement (elevationof factors C3a des Arg and C5a des Arg)and, possibly activation of the kinin-sys-tem (suggested by the development ofcirculatory instability and bron-chospasm). When present in greater

amounts, these compounds can belethal. To demonstrate this, aminophos-pholipids were infused into rabbits overa 30-minute period. They all developedDIC with thrombocytopenia, low fib-rinogen, and appearance of fibrin splitproducts. The lungs were congested andedematous, livers were enlarged andcongested, and spleens contained hem-

orrhagic infarcts. Rabbits are particular-ly sensitive to DIC, perhaps in partbecause their reticulo-endothelial sys-tem (RES) is unable to remove fibrinefficiently from the circulation. This isillustrated by the Shwartzman reaction,in which two injections of endotoxin arerequired to produce a fatality. The firstfills the RES with fibrin; the second

proves fatal, because the RES is alreadyfull of fibrin and cannot remove it fastenough. Pigs and humans have a moreefficient RES and are able to cope withthe excess fibrin.5

Further evidence that the cell wallsthemselves are toxic, not just the intactorganisms, is given by the observation ofElaine Tuomanen,6 who tells how her

friend, Alexander Tomay, accidentallychallenged animals with killed pneumo-cocci, and yet the animals got sick.Dead bacteria seemed as harmful as liv-ing ones. How could this be?

There are several examples of the

toxicity of inner cell walls. TheHerxheimer reaction may be due to thebroken cell walls of the spirochete.Ascitic fluid contains many broken cells,which when reinjected into the circula-tion by the Leveen shunt results in DIC.If one injects human amniotic fluid(which contains many broken cells)intravenously into a dog, DIC results.7

The pulmonary artery pressure rises,blood may become incoagulable, andmultiple organ failure may result. If onefilters the amniotic fluid before injectingit, the fluid is harmless. The dead fetussyndrome and the reperfusion syndromemay be due to absorption of damaged

cellular debris.

EXPERIMENTS

Several experiments done over the last40 years elucidate the problem.8-10

Experiment I

Sixteen healthy pigs were divided intotwo groups, control and treated.8 All 16

pigs were injected with an identical doseof heat-killed culture of E. coli organ-isms. Eight of the pigs were also given250,000 units of urokinase (Abbokinase,a plasminogen activator) diluted in 20mL saline and injected over a 20-minuteperiod starting 20 minutes after the E.coli injection. The 8 untreated pigs weregiven 20 mL of saline. These untreated

pigs all developed extremely low arterialPO2 and severe acidosis and died within24 hours. At autopsy, they showed con-gested, edematous lungs and congestedliver and bowel mucosa. The 8 pigstreated with plasminogen activator allsurvived 24 hours. They were sacrificedand at autopsy showed minimal lesions.

Experiment IIFour healthy pigs were injected with aheat-killed culture of pneumococcusorganisms in the same dose as the E.coli. Four other pigs were injected witha killed culture of pneumococcus except

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that the culture was diluted to 0.1 of theabove. All eight pigs died within 24hours, most before 6 hours, and autopsyshowed congested edematous lungs.

Experiment III

Nine pigs were given 60 standard blowsto each thigh with a carpenters hammer(under anesthesia), being careful not todamage skin, bone or vessels.9 Bloodvolume was kept in a normal range withnormal saline IV. Nine other pigs simi-larly traumatized were given 250,000units of urokinase (Abbokinase) IV,starting 4 hours after the trauma. The 9untreated pigs all died within 48 hours,

and at autopsy showed congested, hem-orrhagic lungs. The 9 treated pigs allsurvived 48 hours and were sacrificed.At autopsy, their lungs showed minimallesions. The blood of all pigs, treatedand untreated, showed hemolysis.

Experiment IV

Twenty-two dogs were bled to a mean

arterial pressure of 40 mm Hg, andmaintained in a state of hemorrhagicshock for 4 hours. The removed bloodwas treated carefully, allowed to come incontact only with plastic, never air orglass.10 Seven dogs were subjected to thesame hemorrhagic shock and were given10 mL of their own blood which hadbeen frozen and thawed (producing

hemolysis). The 22 dogs subjected onlyto hemorrhagic shock had a 9% mortali-ty. The seven dogs subjected to thesame hemorrhagic shock and given 10mL of their own hemolyzed blood alldied within 24 hours. The administra-tion of fibrinolysin (an activated plasminno longer manufactured) in a separateseries of this same study, this time utiliz-

ing 13 dogs subjected to hemorrhagicshock and hemolyzed blood, significant-ly lowered mortality from 100% to38%.10

Experiment V

A clinical trial of treatment of severeARDS with thrombolytics was conduct-ed. Twenty patients suffering fromARDS secondary to trauma or sepsiswere treated with thrombolytics aftertreatment with respiratory support,including positive end expiratory pres-sure (PEEP), had failed to bring Pao

2up

to 60 mmHg Treatment consisted of1000 units of Urokinase (Abbokinase.Abbott) per pound of body weight intra-venously in saline as a bolus in 10 min-utes followed by 1000 units per pound ofbody weight per hour for 24 hours.Every case responded favorably, the

average Pao2 rising from 47.7 mmHg to231.5 mmHg, P=0.0001. There was nobleeding or changes in clotting parame-ters, which were normal both before andafter treatment.11

Patients were not included in theprotocol until 48 hours after injury orsurgery, if they had a head injury or ifthey had a history of a clotting defect or

stroke.

DISCUSSION

The fact that death could be preventedby a plasminogen activator is evidencethat the problem was due primarily tointravascular coagulation (DIC), occlud-ing the microcirculation of the organs,especially the lungs, liver, and kidneys.

The administration of a thrombolyticlysed these microclots, restoring circula-tion to the organs and saving the ani-mals or humans life.

It is postulated that the rupture ofcell membranes (bacterial or mammal)by any means (cold, heat, trauma, antibi-otics, antibodies, viruses, plasmodia, sick-ling or incompatible blood) may result

in intravascular clotting (DIC). Ofcourse most infections are managed suc-cessfully by the bodys own immune sys-tem or by antibiotics without resulting inDIC. Small amounts of broken cell

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walls are easily dealt with in individualswith a functioning reticuloendothelialsystem and adequate circulation. It isonly when other factors, such as severehemorrhage or extensive trauma, arepresent that the possibility of DICbecomes a problem. This occurs in bothtraumatic and septic shock. The DICmay in turn cause acute respiratory dis-tress syndrome and multiple organ fail-ure by obstructing the microcirculationin any and all organs, including lung,liver, kidney, and brain.11 These types ofshock have a high mortality rate but canbe treated effectively and safely withthrombolytics after normovolemia is

achieved. This same process may beinvolved in some cases of coronarythrombosis, pulmonary embolism, andstroke.

REFERENCES

1. Hardaway RM, McKay DG, Williams JH.Lower nephron nephrosis with special refer-ence to hemorrhagic diathesis followingincompatible blood transfusion reaction.Am

J Surg. 1954;87:41-49.

2. Schwartz RS, Chiu DTY, Lubin B. Studies onthe organization of plasma membrane phos-pholipids in human erythrocytes. In:Krucheber WE, Eaton JW, Aster J, et al, eds.Erythrocyte Membranes,Vol 3, Recent Clinicaland Experimental Advances. New York, NY:AR Liss; 1984:89-122.

3. Chiu D, Lubin B, Shobet SB. Erythrocytemembrane lipid organization during sicklingprocess. Br J Hematol. 1973;41:223-234.

4. Feola M, Simoni J, Conigardo PC, et al.Toxicity of polymerized hemoglobin solution.Surg Gynecol Obstet. 1988;166:211-222.

5. Hardaway RM. Syndromes of DisseminatedIntravascular Coagulation with Special

Reference to Shock and Hemorrhage.Springfield, Ill: Charles Thomas Publisher;1966:148.

6. Tuomanen E. Breaching the blood-brain bar-rier. Sci Am. 1993;268:80-84.

7. Hardaway RM, Johnson O. Clotting mecha-nisms in endotoxic shock, a manifestation ofintravascular coagulation.Ann Surg.1961;154:791-802.

8. Hardaway RM. A review of septic shock.Am

Surg. 2000;66:22-29.9. Hardaway RM, Williams CH, Marvasti M, et

al. Prevention of adult respiratory distresssyndrome with plasminogen activator in pigs.Crit Care Med. 1990;18:1413-1318.

10. Hardaway RM, Burns VW. Mechanism ofaction of fibrinolysin in the prevention ofirreversible hemorrhagic shock. Ann Surg.1963;157:305-309.

11. Hardaway RM. Traumatic and septic shockalias post-trauma critical illness. Br J Surg.

1998;85:1473-1479.