Advanced therapy in thoracic surgery - part 8 pps

The lessons learned from these early experiences are that studies of lung HAR should be performed with animals models where recipient survival depends on xenograft function.29–32By contr

Lung Retransplantation / 385

15 Novick RJ, Kaye MP, Patterson GA, et al Redo lung

trans-plantation: a North American–European experience J Heart

Lung Transplant 1993;12(Pt 1):5–15; discussion 15–6.

16 Struber M, Wilhelmi M, Harringer W, et al Flush perfusion

with low potassium dextran solution improves early graft

function in clinical lung transplantation Eur J

Cardiothorac Surg 2001;19:190–4.

17 Fischer S, Matte-Martyn A, De Perrot M, et al potassium dextran preservation solution improves lung function after human lung transplantation J Thorac Cardiovasc Surg 2001;121:594–6.

Low-18 Pierre AF, Sekine Y, Hutcheon MA, et al Marginal donor lungs: a reassessment J Thorac Cardiovasc Surg 2002;123:421–7; discussion 427–8.

Success of clinical allotransplantation as a therapeutic

option for end-stage kidney, heart, lung, and liver

disease has resulted in the worldwide diffusion of this

life-saving treatment However, since there are not

enough cadaveric organs to meet the present clinical

demand, it has also actualized the growing problem of

donor organ availability

Despite this shortfall, which affects all organs, the

disparity between the supply and demand for organs is

most acute for the lung According to the 2002 United

Network for Organ Sharing registry, 3,822 patients are

waiting on the recipient list in the United States for lung

transplantation, and only about 1,000 of these patients

will receive transplants The reasons for this frustrating

scenario are the unique susceptibility of lungs to damage

induced by the brain-dead treatment, the marginal yearly

increase of donor lungs, and the growing number of

teams performing lung transplantation As expected,

access to the waiting lists is currently very restricted,

patients in need of lungs are waiting approximately twice

as long today as in 1990 (the median waiting period is 7

months for patients younger than age 16 years and 23

months for those older than age 16 years), and many

patients die while awaiting lungs

One solution to the shortage of donor lungs would be

to increase the supply of lung allografts from human

sources other than cadaveric donors1 or use artificial

organs,2but the benefit of either as a temporary or

permanent alternative to allotransplantation remains to

be proven Xenotransplantation, the transplantation into

humans of organs from other species, is regarded as an

important solution.3The advantages would be obvious

An unrestricted number of donor lungs would be

avail-able for patients currently excluded from the waiting

lists, the procedure could be planned on routine ing lists and not as an emergency procedure, the lungswould be harvested from healthy anesthetized animalsrather than from brain-dead human donors on life-sustaining drugs and mechanical ventilation, theischemic time would be minimized, and donor lungscould be genetically manipulated to minimize recipientrejection responses.4,5

operat-History

The modern era of transplantation began in the earlytwentieth century with the experiments of Alexis Carrel,who transplanted a variety of vascularized organs intodifferent anatomic sites of the same animal (ie, auto-transplantation) and between animals of the same (ie,allotransplantation) and different (ie, xenotransplanta-tion) species The success observed with renal autograftsdemonstrated that transplantation was indeed technicallyfeasible but also that other mechanisms were responsiblefor the disappointing survival results In the late 1950s,the immunological mechanisms of the immune responsebegan to emerge and the subsequent advent of 6-mercap-topurine, azathioprine, and prednisone made kidneyallotransplantation feasible

This success suddenly generated a demand for renaltransplantation exceeding the organ supply and, as aconsequence, renewed attention toward the potential ofanimal organ transplantation in humans As shown inTable 31-1,6–15 pigs and nonhuman primates have beenused as sources of organs, and despite the early failures,the 9 months’ functional survival of a chimpanzee kidneytransplanted into a human recipient6clearly suggested apotential clinical application of xenografts

Basic Immunobiology

Hyperacute Rejection

Experience with experimental lung xenotransplantation

is quite limited in comparison with other organs, and as

a consequence, the pathogenesis of lung HAR has not yet

been clearly defined In other experimental discordant

models,24 the factors initiating and sustaining HAR

involve an antigen–antibody interaction on the

periph-eral endothelium of the xenografts with subsequent

complement activation via the classical pathway Once

activated, the mechanism by which HAR is promoted is

poorly understood; since lysis of xenograft endothelium

is usually not seen, it is most probably that individual

complement components, including C3a, C5a, and the

membrane attack complex, initiate rapid endothelial cell

(EC) activation, resulting in hemorrhage and edema of

interstitial tissues and thrombosis of xenogeneic vessels

The lung was once considered relatively resistant to

HAR25until further investigations proved this to be false.26

In 1995, Kaplon and colleagues reported short-term

survival of baboon into which pig single-lung was

ortho-topically transplanted, with evidence of modest rise in

pulmonary vascular resistance (PVR), acceptable gas

transfers, marginal decline of xenoreactive natural

anti-bodies (XNA), patchy deposition of immunoglobulin (Ig)

M and complement proteins along the pulmonary

endothelium.27 Despite significant xenograft injury (eg,

intra-alveolar hemorrhage), the functional and histological

absence of HAR led the authors to conclude that the lung

was relatively resistant to HAR A plausible explanation of

the lack of HAR would be, however, that their observations

were related to xenograft hypoperfusion, since following

transient occlusion of the contralateral pulmonary artery

or double-lung xenotransplantation,28all xenografts failed

within 3.5 hours as a result of a tenfold increase in PVR

The lessons learned from these early experiences are that

studies of lung HAR should be performed with animals

models where recipient survival depends on xenograft

function.29–32By contrast, Pierson and colleagues, and

others, proved that pig lungs are rapidly damaged by

human blood via a XNA–complement interaction and a

consecutive loss of flow (PVR-related) and function.26,33

In our experimental studies, we defined the functional

and histopathologic hallmarks of lung HAR using an ex

vivo perfusion-and-ventilation pig-to-human lung

model.34,35Pig lungs perfused with unmodified whole

human blood (WHB) showed severe pulmonary

hyper-tension and pulmonary dysfunction as early as 30

minutes into reperfusion, massive hemorrhagic

pul-monary edema, severe interstitial edema, alveolar

hemor-rhage, and several fibrin and platelet thrombi localized in

and obstructing the small vessels (arterioles, capillaries,

and venules) (Figure 31-2) but not the large (segmental

or lobar) pulmonary vessels Upon immunofluorescence,there were diffuse deposits of human IgG and IgM,complement anaphylatoxins (C1q, C3a, C5a, C5b–9),coagulation proteins, and fibrinogen on the alveolarendothelial surfaces (Figure 31-3) All xenografts failed at

115
44.2 minutes into reperfusion These observationsreinforce the paradigm that places the activation ofxenograft endothelium at the center of the HAR process36

and provide evidence that pig lungs are equally ble to HAR as other solid organs upon reperfusion withhuman blood and that the front-line target of the recipi-ent effector system is the EC located in the peripheraland not the proximal28pulmonary vasculature Anothernoteworthy facet of our findings is that the HARobserved in the pig-to-human discordant model differscompletely from the rejection observed in the pig-to-nonhuman primate27,29–32,37 and in clinical allotrans-plantation between human leukocyte antigen (HLA)-incompatible patients.38,39

suscepti-388 / Advanced Therapy in Thoracic Surgery

FIGURE 31-2 Histology of pig lungs perfused with human blood A,

Fibrin and platelet thrombus (arrow) within a peripheral pulmonary arteriole and located next to a terminal bronchiole (white arrow).

Original magnification 360 B, Multiple fibrin and platelet thrombi in

an interalveolar capillary Original magnification 180.

390 / Advanced Therapy in Thoracic Surgery

and anti-Gal IgG (63%) in the human blood within 30

minutes upon reperfusion These findings, not observed

in pig lungs perfused with autologous blood, are in line

with previous observations suggesting that IgM and IgG

XNA bind the Gal epitope on the xenograft’s

endothe-lial cells and initiate HAR.4,21However, the development

of lung HAR depends on the activation of complement

as well, as shown by the diffuse deposition of

comple-ments proteins C1q and C3 along the alveolar capillary

walls of pig lungs and the decrease of total complement

activity in the human blood shortly after reperfusion.34,35

That this step is essential for the development of HAR is

suggested by the observations that inactivation of

complement by cobra venom factor (CVF), soluble

complement receptor ty pe 1 (sCR1), C1 esterase

inhibitor (C1-Inh), or -globulin prevents HAR and

prolongs discordant xenograft survival.46Most evidence

suggests that, in pig-to-primate xenografts, the

comple-ment system becomes activated through the classical

pathway (Figure 31-5) upon the binding of the XNA to

the Gal 1–3Gal epitopes Except for situations in which

the alternative pathway is stimulated by

ischemia-reperfusion injury or ex vivo circuits, the alternativepathway generally does not initiate tissue injury in pig-to-primate models

XNA and complement activate pig EC, a proteinsynthesis–independent phase of the immune response,referred to as type I EC activation, and hypothesized to

be the underlying cause of HAR.22 Once ECs are vated, they retract from one other, leading to changes intheir physical and biologic characteristics with subse-quent loss of the barrier function and normal anticoagu-lant property of the vascular surface This processinvolves the occurrence of hemorrhage and edema andexposure of the underlying collagen and subendothelialmolecules Platelets adhere to and spread on the suben-dothelial matrix by the interaction of platelets receptorsand von Willebrand’s factor (vWF), and this process isaccompanied by recruitment of cells facilitating coagula-tion and vascular injury, such as P-selectin, platelet-activating factor, thrombin, and leukotrienes The endresult will thus be recruitment of platelets and promo-tion of platelet thrombi and deposition of fibrin alongthe surface of the activated ECs

acti-Vascular Rejection

If HAR can be overcome either by preventing the tion between XNA and epitopes on xenogeneic endothe-lium or by interfering with the activation of complement,

interac-a xenogrinterac-aft is subject over the ensuing dinterac-ays to weeks to interac-arejection process characterized by EC dysfunction, inter-stitial hemorrhage, focal necrosis, fibrin deposition, andeventually thrombosis of the xenograft vessels Thisphenomenon, named “acute vascular xenograftrejection”47 or “delayed xenograft rejection,”48is alsoobserved in concordant xenografts and sometimes inallografts and differs from HAR not only in the kinetics

of graft loss but also in the molecular and cellular nisms leading to thrombosis

mecha-That the vascular rejection is initiated by the binding

of XNA to the xenograft ECs has been established beyonddoubt First, the onset of acute vascular rejection coin-cides temporally with an increase in the synthesis of XNA

in subjects whose circulation is temporarily connected to

a pig organ Second, XNA are diffusely deposited alongthe xenograft endothelium Third, removal of XNA from

a xenograft recipient delays the onset of acute vascularrejection from days to weeks, and treatment of recipientswith agents suppressing XNA may delay rejection formonths or indefinitely

On the binding of XNA to the ECs, there is a type II

EC activation that involves transcriptional induction ofgenes and protein synthesis resulting in the expression ofadhesion molecules, cytokines, procoagulant molecules,and complement components.48 The main mechanisms

FIGURE 31-5 In pig-to-primate xenografts, complement becomes

activated through the classical pathway, and the cascade necessary

to the development of hyperacute rejection is the assembly of the

terminal components (C5b67, C5b-8, C5b-9) A key role is the

forma-tion of C3 convertase because it mediates opsonizaforma-tion and cell lysis

leading to loss of endothelial cell function Under physiologic

condi-tions, regulators of complement activity (RCA) such as decay

acceler-ating factor (DAF) and membrane cofactor protein (MCP) regulate

complement activation by dissociating and degrading C3 convertase.

CD59 prevents formation of the membrane attack complex (MAC) by

blocking C9 binding to C8.

Lung Xenotransplantation: Lessons Learned and Future Perspectives / 391

that underlie xenograft loss caused by acute vascular

rejection are thus the donor–organ EC activation and

infiltration into the graft of host monocytes, natural

killer cells, and the products of their activation, which

collectively promote intragraft inflammation and

throm-bosis.48Whether the total inhibition of XNA and

comple-ment would allow survival of discordant xenografts, if

the putative T cell response is suppressed, is questioned

This suggests that other factors may potentially lead to

acute vascular rejection Because HAR can now be

prevented in nearly all cases, vascular rejection is

consid-ered the major hurdle to the successful clinical

applica-tion of lung xenotransplantaapplica-tion

Accommodation

Early attempts to transplant ABO-incompatible renal

allografts showed that temporary depletion of anti-A or

anti-B antibodies from the recipient in the

pretransplan-tation period allowed prolonged graft survival in some

patients even after the return of the antigraft antibodies

to the circulation and despite the presence of a functional

complement system This process, called

“accommoda-tion,” denotes a sort of graft resistance to humoral injury

under conditions that would otherwise result in HAR or

vascular rejection A similar phenomenon has been also

observed in xenografts, albeit infrequently.49The possible

causes for accommodation include morphologic and

functional differences between the XNA that return after

depletion and the preexisting XNA, alterations in antigen

expression or, more likely, an acquired resistance by

xenogeneic ECs to humoral immune injury after the

return of the XNA in the recipient’s circulation

Cellular or Chronic Rejection

To date, no reports have been published where HAR or

vascular rejection have been indisputably overcome It is

therefore uncertain as to whether these immune

re-sponses play an important role in xenotransplantation as

they do in lung allotransplantation However,

experi-ments with murine skin and pancreatic-islet grafts,

which are not subject to HAR or vascular rejection, have

shown that T cell–mediated xenograft rejection is often

as vigorous, or more so, than T cell–mediated allograft

rejection and that conventional immunosuppressive

agents may be less effective in prolonging xenograft than

allograft survival.25

Strategies to Overcome HAR

With the increasing understanding of its

physiopathol-ogy, four basic strategies to overcome HAR have

emerged, namely (1) prevention of the XNA–xenograft

endothelium interaction, (2) blockage of the early steps

of complement activation, (3) adhesive interactions inthe coagulation pathway, and (4) pig-donor genetic engi-neering (Figure 31-6)

Prevention of XNA–Xenograft Endothelium

Interaction

This can be afforded either by depleting or inhibiting thehuman XNA or by injecting soluble carbohydrate, satu-rating the XNA binding sites before engrafting Therationale for depleting XNA from the circulation of apotential xenograft recipient is the accommodationwhereby discordant or ABO-incompatible graftscontinue to survive despite a functional complementsystem and in the presence of antidonor antibody if therecipient has undergone a pretransplant depletion ofantidonor antibodies Pretransplant removal of circulat-ing XNA from potential xenotransplant recipients can beobtained by (1) plasmapheresis, (2) perfusion of humanblood through pig donor organs, or (3) columnimmunoabsorption

The first two techniques prolong pig-to-primatexenograft survival from minutes to many days.50Duringplasmapheresis, red and white blood cells are isolated andreturned to the primate, but all other blood elements,including the plasma containing XNA, are discarded.During pig organ perfusion, the entire blood volume of aprimate is pumped into the pig organ vasculature, andthe XNA are removed because they adhere to the pig’sendothelium The major limitations of these techniques,however, are that they remove also the primate’simmunoglobulins and complement and coagulationproteins, thus increasing the susceptibility to infectionand thrombogenic disorders Moreover, neither tech-nique can be continued indefinitely, and the ultimate risk

of immunological reactions once XNA reappear is stillthere

Specific depletion of human XNA has been obtained

by Rieben and colleagues with extracorporeal munoabsorption (EIA) of human plasma through animmunoaffinity column of a newly developed, syntheticGal1–3Gal disaccharide.51Based on these in vitro stud-ies, 50 to 60% of the anti-Gal IgM and IgA were specifi-cally absorbed and the cytotoxic effect of human serum

im-on pig kidney (PK15) cells was almost totally inhibitedafter EIA; other plasma proteins were normal throughthe process Similarly, in vivo studies by Taniguchi andcolleagues suggested that in immunosuppressed, splenec-tomized baboons, repeated EIA using the sameimmunoaffinity column may reduce XNA levels andserum cytotoxicity significantly for several days.52

To test the validity of the above-mentioned techniques

in the pig-to-human lung combination, we have oped in our laboratory an in vivo pig organ perfusion

devel-colleagues.57,58 They created a large polymer with several

Gal epitopes incorporated (1–3 galactose

trisaccharide-polyethylene glycol conjugate) This drug given

intra-venously before, during, and throughout a xenogenic

pig-to-baboon transplant diminished the Gal-antibodies

to undetectable levels The influence of Gal-antibodies

could be controlled, but the remaining non-

Gal-antibodies were still present and played their role in

vascular rejection The new substances seem capable to

overcome HAR and may lead to accommodation (not yet

shown) So far, none of these results are shown in lung

xenotransplantation, since there are major organ-specific

differences

Prevention of the Early Steps of Complement

Activation

Although CVF prevents HAR following pig-to-baboon

heart transplantation,59it is unlikely that these strategies

will have clinical application since it is associated with

unacceptable morbidity and production of CVF

anti-bodies Since these antibodies have a Gal oligosaccharide

as a terminal structure, there might be some anti-Gal

antibodies, which may preclude further therapy with CVF

and favor rapid xenograft rejection.60Other soluble

complement inhibitors injectable in the pretransplant

period are C1 Inh, which prevents the activation of C1 by

human XNA binding to pig EC and sCR1, which showed

marked inhibited total and alternative pathway serum

complement activity and prolonged xenograft survival in

an in vivo pig-to-primate cardiac xenotransplantation

model.46 In addition, the lung is particularly sensitive to

ischemia and reperfusion, which is mediated in part

through activation of the complement cascade.61,62 Since

the lung is particularly susceptible to complement injury,

and antibody-driven activation of the classical pathway is

the principle mediator of HAR in other organs,63we

reasoned that effective regulation of complement

activa-tion should be particularly effective for preventing HAR

To date, there are no studies on the use of pharmacologic

complement inhibitors in discordant lung xenografting,

but one major disadvantage is that they must be given

systemically, and in addition to preventing

complement-mediated xenograft injury, they may also inhibit

appro-priate destruction of infectious pathogens.64,65

Adhesive Interactions in the Coagulation Pathway

Adhesion molecules play a critical role in

ischemia-reperfusion injury and mediate the lung injury seen with

systemic complement activation,66,67Where they have

been examined, the interaction between most pig and

human integrin and selectin ligands appears to occur

under circumstances analogous to those described within

either species and may thus be considered to occur in an

appropriate “physiologic” manner P-selectin and cellular adhesion molecule 1 (ICAM-1) are examples ofadhesion molecules whose function has been well char-acterized in this species combination and found to func-tion physiologically.68,69In the xenogeneic situation, other

inter-“nonphysiologic” molecular interactions may also triggerpathogenic adhesive interactions between porcineendothelium and primate platelets and neutrophils.Like complement activation, activation of the coagula-tion cascade occurs most efficiently on activated cellsurfaces Interestingly, coagulation pathway dysregulationwas recently shown to play a central role in clinical acutelung injury, in that administration of activated protein Cwas associated with decreased morbidity and mortalityfrom acute respiratory distress syndrome (ARDS)/systemicinflammatory response syndrome (SIRS).70–73

Several “nonphysiologic” interactions in the tion pathway between porcine endothelium, humanplatelets, and coagulation factors have been identifiedthat are potentially important to HAR.74–78Whereasquiescent human platelets do not bind to human vWF,porcine vWF binds to human platelets through anonphysiologic interaction via GP1b and the alpha1domain of vWF.79Human thrombin activation is activelyinhibited by regulatory proteins on human endothelium,but constitutive activation of human thrombin occurswhen human plasma is exposed to quiescent porcineendothelium.8 0 Thrombomodulin and ectoadeno-sinediphosphatase, potent anticoagulant moleculesexpressed by normal endothelium, are rapidly down-regulated or lost after exposure of porcine endothelium

coagula-to human blood constituents, leading coagula-to a procoagulantendothelial phenotype.81,82Porcine vWF appears to bindhuman complement even in the absence of antipig anti-body,83suggesting that pig vWF itself may serve as aprimary nidus for inflammation In addition, high shearstress, which occurs at sites of vasoconstriction, causesplatelet aggregation to vWF and shedding of procoagu-lant microparticles.84Finally, aggregated platelets coatedwith vWF, or vWF multimers released from the surface ofinjured or activated ECs, may thus activate complement

in soluble phase, triggering productions of ins in the blood as well as where they are expressed in theorgan.85Thus even if pig endothelium is not activated byother interactions, platelet adhesion and binding ofcomplement are likely to occur and to trigger prothrom-botic and proinflammatory events in the graft and else-where in the organ recipient

anaphylatox-Genetically Engineered Donor Pigs

The recent development of genetically engineered miceand pigs has opened several alternative approaches forthe prevention of HAR.17One large step forward to xeno-

Lung Xenotransplantation: Lessons Learned and Future Perspectives / 393

transplantation has been taken by generating transgenic

pigs that do not express the Gal antigens on their ECs.5

The expression of these antigens depends on the function

of a single gene encoding for the enzyme

1,3galactosyl-transferase This gene was “knocked out” by homologous

recombination, and the frontline targets for the human

XNA disappeared Unfortunately, there are no data yet

published about these newly designed piglets This very

promising news is hopefully not overestimated because it

is known from mouse Gal-knockout strains that there is

still a remaining Gal-epitope production (about 10%)

driven by an additional intracellular

1,3galactosyltrans-ferase, which was recently discovered Even though some

Gal-epitope will still be present in theses donor pigs an

important influence on HAR and vascular rejection will

be seen

The most promising way appeared in the past to be

the development of genetically engineered pigs

express-ing one or more of the human C-reactive protein

(CRP).17 They include (1) decay accelerating factor

(DAF), a phosphatidylinositol-linked integ ral

membrane protein that prevents assembly of the

classi-cal pathway C3 convertase, (2) membrane cofactor

protein (MCP), a membrane associate protein that

serves as a cofactor for factor I-mediated cleavage and

inactivation of C3b, (3) C4bBP, a soluble binding

protein with decay accelerating activity for the

inactiva-tion of C3 convertase, (4) CD59 or membrane inhibitor

of reactive lyses (MIRL), which prevents formation of

the membrane attack complex by blocking C9 binding

to C8 Because of the species-restricted molecular

incompatibilities, the membrane-associated CRPs

expressed on the surface of a given donor animal organ

are unable to effectively control the human complement

cascade, and this accounts for most of the inflammatory

response observed in HAR By incorporating human

complement regulatory transgenes into the germline of

donor pigs, several groups have recently achieved

considerable prolongation of pig heart function after

heterotopic transplantation into primates.86 Parallel

experience using lungs from animals transgenic for

human DAF (hDAF) or CD59 (hCD59) have produced

controversial results Pierson and associates found

incomplete physiologic and histologic protection from

HAR using transgenic pigs expressing hDAF perfused ex

vivo with fresh human blood, except in two pigs

expressing very high levels of hDAF on their pulmonary

endothelium.8 7 By contrast, Dagget and colleagues

found that pig lungs expressing hDAF and hCD59

func-tioned better than nontransgenic pig lungs when

perfused (for 2 hours) with human plasma.37 However,

in an earlier experience, Pierson and associates

demon-strated that by depleting the recipient’s complement

with CVF, profound pulmonary hypertension and HARstill occurred, even when human XNA depletion wasadded.8 8 These and other8 9 preliminary experiencessuggest that although transgenic pigs expressing CRPs

at physiologically appropriate levels may prolongxenograft survival, other efforts directed to abrogate theeffects of the humoral and cellular response need to bedone

Comment

Xenotransplantation has the potential to address theacute problem of lung allograft shortage and may haveadditional advantages over allotransplantation AlthoughHAR has so far prevented the clinical use of pig lungs, acombination of the outlined strategies and the new Gal-knockout pigs offer a realistic hope that lung xenograftsmay survive in humans beyond the hurdle of HAR.Unfortunately, while clinical trials are currently proposed

or underway to address whether pig kidneys, livers, andhearts are suitable organs in humans, lung xenotrans-plantation is still in its experimental childhood

However, some clues are available; anatomic andphysiologic similarities between humans and pigs indi-cate that pig lungs may function adequately, at least inthe short term Pig lungs are hyperacutely rejected in asimilar fashion to other pig organs when perfused withuntreated human blood, and despite the fact that they donot have the synthetic functional problems of pig kidneys

or livers, they are more prone to other nonxenogeneicinjuries (eg, ischemia-reperfusion injury) than are otherpig organs There are several strategies that prevent lungHAR, and there is optimism that the simplest one will beuseful in a future clinical setting

Nevertheless, to be of significant clinical impact and

to solve the actual allograft shortage, lung xenograftsurvival must be at least as good as allograft survival Inthis sense, major areas of consideration for laboratoryinvestigations beyond HAR need to be explored toaddress the long-term xenograft survival

Acknowledgment

This work was supported by the Immunology ConcertedAction (#3026PL950004) of the ImmunologyBiotechnology Program from the European Union, anEast-West INSERM contract and the German Researchfoundation (Deutsche Forschungsgemeinschaft, DFG)

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38 Frost AE, Jammal CT, Cagle PT Hyperacute rejection

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39 Pierson RN III, Loyd JE, Goodwin A, et al Successful

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40 Cooper DKC Clinical survey of heart transplantation

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41 Galili U, Rachmilewitz EA, Peleg A, Flechner I A unique

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42 Galili U Interaction of the natural anti-Gal antibody with

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43 Oriol R, Ye Y, Koren E, Cooper DKC Carbohydrate antigens

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44 Galili U, Clark MR, Shohet SB, et al Evolutionary

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45 Galili U The natural anti-gal antibody: evolution and

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46 Pruitt SK, Kirk AD, Bollinger RR, et al The effect of soluble

complement receptor type 1 on hyperacute rejection of

porcine xenografts Transplantation 1994;57:363–70.

47 Leventhal JR, Matas AJ, Sun LH The immunopathology of

cardiac xenograft rejection in the guinea pig-to-rat model.

Transplantation 1993;56:1–8.

48 Bach FH, Winkler H, Ferran C, et al Delayed xenograft

rejection Review Immunol Today 1996;17:379–84.

49 Winkler H, Ferran C, Bach FH Accommodation of

xenografts: a concept revisited Xenotransplantation

1995;2:53–6.

50 Cooper DKC, Human PA, Lexer G Effects of cyclosporin

and antibody adsorption on pig cardiac xenograft survival

in the baboon J Heart Transplant 1988;7:238–46.

51 Rieben R, van Allmen E, Korchagina EY, et al Detection,

immunoabsorption, and inhibition of cytotoxic activity of

anti- Gal antibodies using newly developed substances

with synthetic Gal 1–3Gal disaccharide epitopes.

54 Ghanekar A, Luo Y, Yang H, et al The alpha-Gal analog GAS914 ameliorates delayed rejection of hDAF transgenic pig-to-baboon renal xenografts Transplant Proc 2001;33:3853–4.

55 Cairns T, Lee J, Goldberg L, et al Inhibition of the pig to human xenograft reaction using soluble Gal 1–3Gal and Gal1–3Gal1–4GlcNac Transplantation 1995;60:1202–7.

56 Galili U The alpha-gal epitope (Gal alpha 1–3Gal beta 1–4GlcNAc-R) in xenotransplantation Biochimie 2001;83:557–63.

57 Diamond LE, Byrne GW, Schwarz A, et al Analysis of the control of the anti-gal immune response in a non-human primate by galactose alpha1–3 galactose trisaccharide- polyethylene glycol conjugate Transplantation 2002;73:1780–7.

58 Byrne GW, Schwarz A, Fesi JR, et al Evaluation of different alpha-galactosyl glycoconjugates for use in xenotransplan- tation Bioconjug Chem 2002;13:571–81.

59 Leventhal JR, Dalmasso AP, Cromwell JW Prolongation of cardiac xenograft by depletion of complement Transplantation 1993;55:857–66.

60 Cooper DKC, Koren E, Oriol R Manipulation of the aGal antibody-aGal epitope system in experimental discor- dant xenotransplantation Xenotransplantation 1996;3:102–11.

anti-61 Heller T, Hennecke M, Baumann U, et al Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia/reperfusion injury J Immunol 1999;163:985–94.

62 Stammberger U, Hamacher J, Hillinger S, Schmid RA sCR1sLe ameliorates ischemia/reperfusion injury in experi- mental lung transplantation J Thorac Cardiovasc Surg 2000;120:1078–84.

63 Dalmasso AP, Vercellotti GM, Fischel RJ, et al Mechanism

of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients Am J Pathol 1992;140:1157–66.

64 Lu CY, Khaireldin TA, Dawidson IA, et al transplantation FASEB J 1994;8:1122–30.

Xeno-65 Hecker JM, Lorenz R, Appiah R, et al C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation Transplantation 2002;73:688–94.

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66 Mulligan MS, Warner RL, Rittershaus CW, et al Endothelial

targeting and enhanced antiinflammatory effects of

complement inhibitors possessing sialyl Lewisx moieties J

Immunol 1999;162:4952–9.

67 Mulligan MS, Schmid E, Till GO, et al C5a-dependent

up-regulation in vivo of lung vascular P-selectin J Immunol

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68 Simon AR, Warrens AN, Sykes M Efficacy of adhesive

interactions in pig-to-human xenotransplantation.

Immunol Today 1999;20:323–30.

69 Warrens AN, Simon AR, Theodore PR, Sykes M

Human-porcine receptor-ligand compatibility within the immune

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Xenotrans-plantation 1999;6:75–8.

70 Bernard GR, Vincent JL, Laterre PF, et al Recombinant

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recombi-nant human activated protein C for severe sepsis N Engl J

Med 2001;344:699–709.

71 Grey ST, Tsuchida A, Hau H, et al Selective inhibitory

effects of the anticoagulant activated protein C on the

responses of human mononuclear phagocytes to LPS,

IFN-gamma, or phorbol ester J Immunol 1994;153:3664–72.

72 Hirose K, Okajima K, Taoka Y, et al Activated protein C

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injury in rats by inhibiting neutrophil activation Ann Surg

2000;232:272–80.

73 Grinnell BW, Hermann RB, Yan SB Human protein C

inhibits selectin-mediated cell adhesion: role of unique

fucosylated oligosaccharide Glycobiology 1994;4:221–5.

74 Robson SC, Young VK, Cook NS, et al Thrombin

inhibi-tion in an ex vivo model of porcine heart xenograft

hypera-cute rejection Transplantation 1996;61:862–8.

75 Robson SC, Kaczmarek E, Seigel JB, et al Loss of ATP

diphosphohydrolase activity with endothelial activation J

Exp Med 1997;185:153–63.

76 Nagayasu T, Saadi S, Holzknecht RA, et al Expression of

tissue factor mRNA in cardiac xenografts: clues to the

pathogenesis of acute vascular rejection Transplantation

2000;69:475–82.

77 Alwayn IP, Appel JZ, Goepfert C, et al Inhibition of platelet

aggregation in baboons: therapeutic implications for

xeno-transplantation Xenotransplantation 2000;7:247–57.

78 Bustos M, Saadi S, Platt JL Platelet-mediated activation of endothelial cells: implications for the pathogenesis of trans- plant rejection Transplantation 2001;72:509–15.

79 Schulte am Esch J II, Cruz MA, Siegel JB, et al Activation of human platelets by the membrane-expressed A1 domain of von Willebrand factor Blood 1997;90:4425–37.

80 Siegel JB, Grey ST, Lesnikoski BA, et al Xenogeneic endothelial cells activate human prothrombin Transplantation 1997;64:888–96.

81 Kalady MF, Lawson JH, Sorrell RD, Platt JL Decreased fibrinolytic activity in porcine-to-primate cardiac xeno- transplantation Mol Med 1998;4:629–37.

82 Saadi S, Holzknecht RA, Patte CP, et al mediated regulation of tissue factor activity in endothe- lium J Exp Med 1995;182:1807–14.

Complement-83 Holzknecht ZE, Coombes S, Blocher BA, et al Identification of antigens on porcine pulmonary microvas- cular endothelial cells recognized by human xenoreactive natural antibodies Lab Invest 1999;79:763–73.

84 Miyazake Y, Momura S, Miyake T, et al High shear stress can initiate both platelet aggregation and shedding of procoagulant containing microparticles Blood; 88:3456–64.

85 Holzknecht ZE, Coombes S, Blocher BA, et al Immune complex formation after xenotransplantation: evidence of type III as well as type II immune reactions provides clues

to pathophysiology Am J Pathol 2001;158:627–37.

86 McCurry KR, Kooyman DL, Alvarado CG, et al Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injur y Nat Med 1995;1:423–7.

87 Pierson RN, Pino-Chavez G, Young VK, et al Expression of human decay accellerating factor may protect pig lung from hyperacute rejection by human blood J Heart Lung Tranplant 1997;16:231–9.

88 Pierson RN, Kaspar-Konig W, Tew DN, et al Profound pulmonary hypertension characteristic of pig lung rejec- tion by blood is mediated by xenoreactive antibodies inde- pendent of complement Transpl Proc 1995;27:274.

89 Hoopes CW, Platt JL Molecular strategies for clinical transplantation in cardiothoracic surgery Sem Thorac Cardiovasc Surg 1996;8:156–74.

xeno-CHAPTER 32

ROBERT H BARTLETT,MD

JONATHAN W HAFT,MD

Chronic respiratory failure represents a heterogeneous

group of diseases affecting millions of people worldwide

and is the third leading cause of death in the United

States, accounting for more than 350,000 deaths annually.1

In addition, both the death rate and prevalence of lung

disease appear to be increasing, in large part related to the

rapid expansion of the aging population Chronic

respira-tory failure includes, but is not limited to, chronic

obstructive pulmonary disease (COPD), idiopathic

pulmonary fibrosis, pulmonary sarcoidosis, cystic fibrosis,

and primary pulmonary hypertension Emphysema and

chronic bronchitis affect approximately 16 million

Americans and has been steadily rising over the last

several decades, with nearly 120,000 deaths in 1999

attrib-uted to COPD.1Idiopathic pulmonary fibrosis is a

progressively disabling illness characterized histologically

by fibrosis and architectural distortion Its prevalence is

estimated to be around 13 to 20 per 100,000 in the United

States, and median survival from the time of diagnosis is

less than 3 years.2Pulmonary sarcoidosis is often

asymp-tomatic and associated with spontaneous regression, but

approximately 5% of affected individuals develop

relent-less pulmonary dysfunction leading to inevitable death

from respiratory failure.3Cystic fibrosis, a genetic

condi-tion with an autosomal recessive mode of transmission,

affects approximately 30,000 Americans,4with median

survival steadily rising but presently at approximately 30

years of age.5Primary pulmonary hypertension is a rare

and uniformly fatal disorder of unknown etiology

Survival from the time of diagnosis remains less than 3

years.6Patients suffering from these diseases, as well as

several other less common conditions, typically progress

to end-stage respiratory failure Long-term invasive

mechanical ventilation is often the only treatment strategy

as patients deteriorate Lung transplant currently offersthe only hope for prolonged survival and reasonable qual-ity of life under most circumstances

Lung transplant has enjoyed increasing success overthe last 20 years, with 1- and 3-year survival rates of 76and 56%.7However, transplant is necessarily limited bythe finite pool of suitable cadaveric organs Between 1996and 2002, the number of patients listed more thandoubled from 1,900 to nearly 4,000, while the number oftransplants performed has plateaued near 1,000 As aresult, the wait list time now exceeds 2 years at most busycenters with a mortality rate for listed patients of over20% Because of the scarcity of this resource, relativelystrict criteria have been established for lung transplanteligibility, thus excluding patients greater than 65 years ofage, obese or malnourished patients, and those in chronicrenal failure and strongly discouraging transplant inpatients who require temporary or permanent mechani-cal ventilatory support.8Unfortunately, previously eligi-ble patients who decompensate or those with end-stagerespiratory failure excluded from eligibility for transplantbecause of age or underlying medical conditions cur-rently have no treatment options There clearly is a needfor new therapeutic strategies designed either as a bridge

to lung transplant for listed but acutely worseningpatients or as a transplant alternative, possibly servingthose individuals currently considered unsuitable fortransplant

Recent successes have allowed mechanical cardiacsupport to become standard practice in bridging patientswith severe heart failure to cardiac transplant Since theapproval of ventricular assist devices by the Food andDrug Administration as a bridge to transplant, more than70% of patients have undergone successful implantation

and have survived until a suitable cadaveric organ could

be found.9In addition, there is increasing evidence

suggesting that the use of these devices allows

rehabilita-tion of the decompensated patient, thus improving

outcomes after transplant.10In fact, many patients have

elected to forgo transplant because their quality of life

while supported with a ventricular assist device was so

dramatically improved In addition, mechanical cardiac

support may have a role in treating patients deemed

inel-igible for transplant by age or medical comorbidity, as

demonstrated by the much publicized and impressive

Rematch1 1 trial and the anticipated Intrepid1 2 trial

Groups invested in the development and testing of

artifi-cial lungs hope to draw many parallels from the success

of mechanical cardiac support as they look for innovative

alternative treatment strategies for patients with

end-stage respiratory failure

History

Attempts to treat respiratory failure with artificial lungs

have appeared since the 1970s.13,14These initial devices

also relied upon thin membranes to provide gas transfer,

but were limited by the quality and reproducibility of

these materials As a result, oxygen transfer and carbon

dioxide elimination were highly variable and incapable of

providing meaningful support In addition, several of the

initial prototypes attempted to avoid external

communi-cation with a continuous gas source by directly

connect-ing gas lines to the bronchial tree Animal experiments

were fraught with ventilation problems as fluid and

fibrosis obstructed gas flow

Nonetheless, these early reports demonstrate the need

and the feasibility of an implantable long-term artificial

respiratory support As the use of extracorporeal

oxy-genation became more widespread in the setting of open

heart surgery on mechanical bypass, materials and

tech-niques improved dramatically Hollow fiber oxygenating

membranes used today demonstrate improved

gas-exchange efficiency and are lower in profile, renewing

enthusiasm in the development of an artificial lung

Current Designs

Features of a support device that can serve either as a

bridge or alternative to lung transplant in the treatment

of end-stage respiratory failure should include the

capac-ity to satisfy the necessary gas-exchange requirements,

eliminating or treating right heart failure, and to

mini-mize trauma to other organ systems Furthermore, these

devices should be conceptually simple and reliable so as

to be capable of providing long-term support on an

ambulatory basis Extracorporeal membrane oxygenation

(ECMO) involves percutaneous or surgical cannulation

of large peripheral or central vessels, circulation withblood flow powered by servoregulated roller or centrifu-gal blood pumps, and gas exchange delivered via microp-orous hollow fiber or solid silicone oxygenators.Extracorporeal life support (ECLS) has been used exten-sively in the treatment of acute cardiac or respiratory fail-ure both in children and adults, primarily successful as ashort-term bridge to recovery.15 However, the cost andcomplexity associated with ECLS using current systems,

in addition to the blood element trauma and inherentinfectious risks, make this modality unsuitable forprolonged support Furthermore, the need for continu-ous monitoring by trained personnel in an intensive careunit setting makes ambulatory support and physicalrehabilitation prohibitive

Intravascular oxygenation has been used in severalclinical trials in the setting of acute respiratory failure as

an adjunct to conventional mechanical ventilation.16–18

These devices consist of a network of hollow fiber genating membranes connected by a manifold to thesweep gas inflow and outflow lines and inserted into theinferior vena cava percutaneously via the femoral vein.Unfortunately, the effectiveness of these early devices waslimited largely because they could demonstrate beingcapable of transferring only up to one-half of the totalgas-exchange requirements of an adult patient Newertechnology has resurrected intravascular oxygenation,with current efforts focusing on improving blood mixingand thus the creation of secondary flows at the boundarylayer where blood and the gas exchange membranesinterface.19 The most significant advances include theincorporation of a mechanical balloon pump and asystem of fixed fiber matting, with in vivo testingcurrently underway Initial trials will again focus onpatients suffering from acute respiratory failure, serving

oxy-as a bridge to recovery Whether this tactic hoxy-as potential

in the treatment of chronic respiratory failure and isfeasible as a long-term ambulatory treatment remains to

be seen

Several groups have focused their attention on apumpless implantable or wearable oxygenator because ofseveral theoretical advantages using this approach.Advances in the efficiency of newer gas exchange mem-branes have allowed the development of oxygenatorswith low blood flow resistance An example is the proto-type device manufactured by Michigan Critical CareConsultants, MC3 (Ann Arbor, MI).20–26Using a centrallypositioned inlet, this device takes advantage of radialblood flow through a series of parallel wound micro-porous hollow fibers potted at both ends into a manifoldfor the sweep gas inlet and outlet (Figure 32-1) Thecommercially available hollow fibers (Celgard Inc,Charlotte, NC) that serve as the gas exchange substrate have

Artificial Lungs / 399

Artificial Lungs / 401

cific pathologic situation, such as the relative importance

of chronic right heart failure, deficiencies in oxygenation

or carbon dioxide removal, and infectious concerns

The effect on right ventricular load under each of these

configurations has been investigated using a theoretical

lumped parameter model, taking into account the

differ-ences in outflow impedance.2 8 Although the terms

pulmonary and systemic vascular resistances are most

commonly used to describe afterload, “input impedance”

defines cardiac load in a pulsatile system Impedance is

the opposition to pulsatile flow and considers thecombined effect of vessel caliber, compliance, and pulsewave reflections.29Pulse wave reflections occur in anypulsatile system and primarily originate at locationswhere there is a significant change in the flow path geom-etry, such as narrowings or branch points These pressurewave reflections directly counter flow and affect imped-ance Determining input impedance involves mathemati-cally reducing the instantaneous pressure and flowwaveforms in the aortic or PA into a mean term and aseries of sine waves using Fourier transformation(Figure 32-3) These sine waves each have a characteristicamplitude, or height, relative to the X-axis, a frequency,and phase angle, or its position relative to the Y-axis Eachsine wave represents a harmonic; the frequency at eachharmonic is an integer multiple of the fundamentalfrequency, or the frequency of the pressure and flow wave-forms For example, when the heart rate is 60, a frequency

of 1 Hz, the frequency of the pressure and flow sine waves

at the first harmonic is 1 Hz, the frequency at the secondharmonic is 2 Hz, and so on Impedance (Z) is the ratio ofthe amplitudes of pressure and flow expressed as a func-tion of harmonic Although the zero harmonic imped-ance (Z0) is the ratio of mean pressure to mean flow andthus is analogous to resistance, impedance at the integerharmonics represents the opposition to flow pulsations.First harmonic impedance (Z1) is probably the mostimportant single indicator of pulsatile load because themajority of flow occurs within the first harmonic.Impedance is particularly important to consider in thepotential use of an artificial lung perfused by the rightventricle Although these devices have resistances thatapproximate pulmonary vascular resistance, their geome-try and compliance are drastically different from thenormal circulation Therefore, the characteristics of thedevice and its mode of attachment will have an enormousimpact on the impedance seen by the right ventricle, asdemonstrated by the theoretical lumped parameter study.However, certain configurations may offer other advan-tages despite significant increases in right ventricularinput impedance Any mode of attachment may be moreappropriate under specific clinical scenarios and should

be considered for all its merits and shortcomings

When the return of oxygenated blood is directed intothe left atrium, blood flow can be competitive with thepulmonary circulation (see Figure 32-2A) or exclusivelythrough the device (see Figure 32-2B) The competitive

flow approach allows blood flow to travel in parallel, with

a fraction of the cardiac output shunted into the artificiallung, and the remainder continuing through the nativepulmonary circulation The magnitude of diverted blood

is dependent on the comparative impedance of the native

FIGURE 32-2 Schematics representing potential applications of a

pumpless artificial lung perfused by the right ventricle A, Partial

respiratory support, with blood flow in parallel with the native

pulmonary circulation B, Pulmonary replacement, diverting the entire

right sided cardiac output through the artificial lung C, Total

respira-tory support, with flow in series with the native pulmonary circulation.

Artificial Lungs / 403

demonstrated the consequences of high impedance in

the context of normal resistance on right ventricular load

and function Although there was no change in cardiac

output or mean PA pressure, right ventricular ejection

flow patterns were severely altered, with persistent

dias-tolic flow and reduced peak and sustained sysdias-tolic flow

(Figure 32-4) Whether these abnormalities will progress

to right heart failure and the effect on left ventricular

performance remain unclear but are under current active

investigation We have also developed a prototype

compliance chamber, applying variable pneumatic

compression to the compliance reservoir (Figure 32-5),

which appears to reduce impedance and restore normal

cardiac function (see Figure 32-4).31

The next potential mode of attachment involves

creat-ing a support circulation in series with the native lungs

(see Figure 32-2C) By creating inflow and outflow

conduit anastamoses to the proximal and distal main PA,

respectively, a snare placed around the intervening

seg-ment of PA can divert the entire right ventricular cardiac

output through the artificial lung for gas exchange This

approach is capable of supporting all of the oxygenation

requirements of large animals, as demonstrated in acute

studies by clamping the endotracheal tube of

anes-thetized sheep,22and in chronic experiments using a

smoke inhalational model of respiratory failure.24,25The

PA-to-PA configuration has several inherent advantages,

other than its ability to provide total respiratory support

First, directing the outflow of the artificial lung into the

distal PA, the diseased lungs can serve as an embolic trap

to prevent the inevitable microthrombi formed within

the extensive foreign surface from ejecting into the

systemic circulation In addition, preserving native

pulmonar y blood flow retains the metabolic and

endocrine lung functions Lastly, delivering oxygenated

blood to chronically diseased lungs may allow some

recovery or slow the deterioration Unfortunately, there

are several drawbacks to the PA-to-PA approach Despite

its low resistance, application of the artificial lung in

series necessarily increases the total resistive load against

the right ventricle As predicted by the theoretical

lumped parameter model, this application of a pumpless

artificial lung perfused by the right ventricle generates

the greatest magnitude of right heart strain.28Although

the incidence of right ventricular failure in large animal

series has been reduced with newer generations of

devices,25the in-series application will likely be

prohibi-tive in patients with respiratory failure associated with

cor pulmonale Furthermore, anatomic considerations

may limit feasibility The unusual length of the main PA

of sheep allows room for two large caliber anastamoses

with a flow occluder.32It is unclear if human anatomy

will be amenable to a similar construct

Hematologic Compatibility

Flow through extracorporeal systems is associated withproblems involving various hematological componentsand can be generalized into three major impediments:(1) red cell hemolysis, (2) platelet activation andconsumption, and (3) activation of the coagulation

Pulmonary artery flow: native circulation

-5 0 5 10 15 20 25 30

Pulmonary artery flow: pulmonary replacement

-5 0 5 10 15 20 25 30

Pulmonary artery flow: pulmonary replacement with compliant device

-5 0 5 10 15 20 25 30

FIGURE 32-4 Pulmonary artery flow versus time A, Normal

circula-tion, with rapid systolic upstroke and absent diastolic flow B,

Pulmonary replacement with noncompliant artificial lung

demonstrat-ing arrested systolic upstroke with persistent diastolic flow C,

Pulmonary replacement with artificial lung in series with a prototype compliance chamber.

Membrane oxygenation using microporous hollow fibers

is associated with plasma leakage through the individual

micropores and eventual oxygenator failure

Mech-anistically, plasma leakage results from the progressive

deposition and adsorption of phospholipids onto the

surface of the individual fibers.38These hydrophobic

lipids reduce the surface tension directly at the blood–gas

interface, allowing leakage to occur The rate of

progres-sion towards device failure appears to be related to the

content and character of circulating bloodstream lipids

Future prototypes will incorporate either solid silicone

fibers or microporous fibers coated with a nonporous

but gas-diffusible material, and oxygenators using such

nonporous membranes as the gas exchange substrate are

currently under study.39

Clinical Trial Design

As with any clinical trial, success is largely dependent

upon patient selection As the technology improves and

the potential for clinical utilization rapidly approaches,

planning the most appropriate clinical trial becomes

imperative This includes not only patient selection, but

also trial size, the planned duration of support, and

iden-tifying achievable and meaningful outcomes Several

bioengineering laboratories recently surveyed the nation’s

largest lung transplant centers to provide feedback in trial

design, in anticipation of future clinical application.40Not

surprisingly, 97% of all responding programs, including

70% of the high-volume centers, supported and would

actively participate in a clinical trial using an artificial

lung as a bridge to lung transplant This degree of

wide-spread support is largely a result of the rising mortality on

the transplant wait list, the lack of alternatives for

decom-pensating patients, and the recently demonstrated success

of ventricular support as a bridge to cardiac transplant

However, in order for the artificial lung to demonstrate

capability as a bridge to transplant, patients must receive

some degree of priority on the transplant wait list, as was

done during the initial trials of ventricular assist devices

Current standing United Network for Organ Sharing

(UNOS) policy regarding the allocation of cadaveric lung

graft allografts relies entirely upon waiting time among

candidates of similar size and ABO blood type It is

prob-ably unlikely to envision successful initial artificial lung

trials if expected to provide event-free support for as long

as 1 year It is encouraging to the developers of artificial

lungs that more than one-half of lung transplant program

directors supported restructuring of the UNOS allocation

policy to allow priority allocation to patients enrolled in

an artificial lung trial These changes must be enacted

before any clinical trial can be initiated

In terms of patient selection, ideal candidates arelikely individuals currently awaiting transplant but wors-ening to the point where they are unlikely to survive until

a suitable organ will become available Patients with pathic pulmonary fibrosis and primary pulmonaryhypertension have the highest mortality on the wait listand are typically younger and with fewer associatedcomorbidities The benefit of artificial lung supportwould likely outweigh the risk of surgical implantation.Cystic fibrosis patients also have high wait list mortality;however, the risk of infectious complications leaves mostcenters reluctant to include this group, at least in initialtrials Patients with emphysema, although the mostfrequent indication for transplant, are probably not ideal,

idio-as it would be difficult to clearly demonstrate a survivalbenefit, given their typically protracted and unpre-dictable course

Summary

Significant progress has been achieved in the ment of artificial lungs, capable of providing full orpartial gas-exchange support, for prolonged periods oftime, and on an ambulatory basis These devices may becapable of serving as a bridge to lung transplant forpatients with end-stage respiratory failure, a problemthat currently has no alternative remedy With severalimpending modifications and long-term animal testing,along with support from the lung transplant community,this technology will soon be available to satisfy a much-needed solution to a difficult clinical problem

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extra-28 Boschetti F, Perlman CE, Cook KE, Mockros LF Hemodynamic effects of attachment modes and device design of a thoracic artificial lung ASAIO J 2000;46:42–8.

29 Milnor WR Pulsatile blood flow N Engl J Med 1972;287:27–34.

30 Cook KE, Makarewicz AJ, Backer CL, et al Testing of an intrathoracic artificial lung in a pig model ASAIO J 1996;42:M604–9.

31 Haft JW, Bull JL, Rose R, et al Design of an artificial lung compliance chamber for pulmonary replacement ASAIO J 2003;49:35–40.

32 Harper DD, Alpard SK, Deyo DJ, et al Anatomic study of the pulmonary artery as a conduit for an artificial lung ASAIO J 2000;46:184.

33 Hennessy VL, Hicks RE, Nierwiarowski S, et al Function of human platelets during extracorporeal circulation Am J Physiol 1977;232:H622–8.

34 Annich GM, Meinhardt JP, Mowery KA, et al Reduced platelet activation and thrombosis in extracorporeal circuits coated with nitric oxide release polymers Crit Care Med 2000;28:915–20.

35 Miskulin J, Annich G, Gillian C, et al NO flux determines thromboresistance in NO-releasing extracorporeal circuits ASAIO J 2002;48:145.

36 Gorman RC, Ziats NP, Rao AK, et al Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass J Thorac Cardiovasc Surg 1996;111:1–12.

37 Gartner MJ, Wilhelm CR, Gage KL, et al Modeling flow effects on thrombotic deposition in a membrane oxygena- tor Artif Organs 2000;24:29–36.

38 Montoya JP, Shanley CJ, Merz SJ, Bartlett RH Plasma age through microporous membranes ASAIO J 1992;38:M399–405.

leak-39 Funakubo A, Higami T, Sakuma I, et al Development of a membrane oxygenator for ECMO using a novel fine sili- cone hollow fiber ASAIO J 1996;42:M837–40.

40 Haft JW, Griffith BP, Hirschl RB, Bartlett RH Results of an artificial-lung survey to lung transplant program directors.

J Heart Lung Transplant 2002;21:467–3.

406 / Advanced Therapy in Thoracic Surgery

Clinical evidence continues to support the role of surgery

in the management of patients with myasthenia gravis

The goal of surgery is complete thymectomy along with

resection of associated thymoma, if present Successful

management of patients with myasthenia gravis depends

on multidisciplinary care involving neurology, surgery,

anesthesia, and critical care medicine Diagnosis,

preop-erative preparation, intraoppreop-erative management, and

postoperative care are covered in this chapter Since the

first edition of this text, staging criteria have been added,

new surgical techniques included, and surgical and

anes-thesia results updated Predictors of treatment outcome

are also discussed

Myasthenia gravis is a disorder characterized by

neuromuscular weakness and fatigue of voluntary

muscles It is generally believed to be an autoimmune

disease that targets the postsynaptic acetylcholine

recep-tor, resulting in interference of signal transmission at the

neuromuscular junction Supporting this theory is the

fact that circulating acetylcholine receptor antibodies are

identified in over 90% of patients with myasthenia

gravis On the other hand, antibody levels do not change

or correlate with clinical response to therapy Therefore,

the pathophysiology of this disease remains incompletely

worked out Muscles supplied by the cranial nerves are

preferentially affected The disease is twice as common in

women as in men, and the clinical course is variable The

relationship of thymic abnormalities to myasthenia

gravis has long been appreciated and far antedated

successful thymectomy for this disease Early surgical

management of patients with myasthenia involved

attempts at thymic gland devascularization or excision,

invariably without clinical improvement, and at the price

of exceedingly high mortality Acceptance of thymectomy

for patients with myasthenia gravis is attributed toBlalock and colleagues, who in 1939 reported successfulthymectomy in a 19-year-old woman with myastheniagravis and a 6
5
3 cm benign thymoma.1Over half acentury later, although the benefits of thymectomyremain undisputed, the indications for thymectomy andthe specific surgical approach that should be used remainunresolved

Diagnosis and Staging

The diagnostic tests available to establish the diagnosis ofmyasthenia gravis are well established and are onlybriefly covered in this chapter Diagnostic tests include(1) administration of anticholinesterase agents (eg,Tensilon test), (2) electrophysiology studies, (3) detection

of serum anticholine receptor antibodies, and (4) clinicalexamination Computed tomography of the chest isrecommended to detect occult thymic neoplasms Oncethe diagnosis is established, the disease is staged Stagingclassifies the severity of the disease and determines treat-ment options The most commonly used staging system

is that advocated by Osserman, or a variant of it, whichstages patients based on whether symptoms are ocular orgeneral, and on their severity (Table 33-1).2

TABLE 33-1 Staging of Myasthenia Gravis

II Mild to moderate generalized symptoms only III Severe generalized disease

Treatment: The Case for Thymectomy

The importance of thymectomy in the management of

patients with myasthenia gravis continues to be

supported by clinical results, and is no longer the

contro-versial issue it was in the past It is still essential to

under-stand the evidence supporting the use of surgery in the

management of myasthenia patients

There are no prospective treatment trials for patients

with myasthenia gravis from which to define practice

guidelines The reasons for this are the variations in

clini-cal presentation of myasthenic patients with regard to

age, sex, muscle group involvement, degree of weakness,

and antireceptor antibodies These variations have led

Drachman to question whether myasthenia gravis, in

fact, represents a homogeneous entity.3As a result,

treat-ment practice varies widely Treattreat-ment options include

anticholinesterase agents, steroids, plasmapheresis,

immunosuppressive agents, and thymectomy Only

surgi-cal therapy is covered in this chapter

The evidence in favor of the safety and effectiveness of

thymectomy for myasthenia gravis is now extensive

Operative mortality ranges from 0 to 2.7%,4–10with

clini-cal improvement in 62 to 100% of patients.4,6–10Remission,

defined as being symptom-free and off medication, is

achieved in 8 to 69% of patients.4,6–10The favorable

surgi-cal results appear to be a durable response Crucitti and

coworkers reported a postsurgical 10-year survival rate of

78%.11 Buckingham and colleagues used a

computer-assisted match in lieu of prospective randomized data to

compare medical and surgical therapy for myasthenia

gravis.12They found that overall improvement rate and

5-and 10-year survival rates were all significantly better with

surgical therapy than with medical therapy alone

(Figure 33-1) Further, they showed that the surgical

advantages were not age-dependent

The degree of acceptance of surgical therapy is

reflected in a report by Lanska,13who surveyed a group of

board-certified neurologists with an interest in

myasthe-nia to evaluate their referral practice with regard to

thymectomy He found that 8% advocated the procedure

in less than one-third of their patients, 57% advocated it

for one-third to two-thirds of patients, and 35%

advo-cated it for more than two-thirds of their patients

Among these physicians, there was general agreement

that thymectomy was indicated for (1) patients with

thymoma, (2) generalized disease unresponsive to

medical management, and (3) a small subset of patients

with ocular symptoms who fail nonoperative

manage-ment The timing of surgery, preoperative preparation,

and recommended surgical technique are controversial,

but most accept the indications listed above Further, the

trend in therapy is toward earlier surgical intervention

Anatomy of the Thymus Gland

The mechanism by which the thymus gland affects toms in patients with myasthenia gravis is not known.However, the principle of complete thymectomy in thesurgical management of myasthenic patients is widelyaccepted Therefore, an understanding of thymicanatomy is essential to successful, complete thymectomy.The gross anatomy of the thymus gland is well known

symp-to thoracic surgeons as an H-shaped, gray-pink, lated gland in the anterior superior mediastinum with avariable arterial blood supply from branches of the inter-nal mammary vessels and venous drainage throughlarger, recognizable veins into the innominate vein One

lobu-of the most common anatomic variations is for one lobu-ofthe superior thymic limbs to pass posterior to theinnominate vein Remarkably, Jaretzki and Wolff haveshown that thymic tissue is confined to the thymiccapsule in only 2% of patients.14As a result of a complexembryologic migratory pattern, thymic tissue has beenidentified widely throughout the neck and mediastinum.Masaoka and colleagues reported ectopic thymic tissue in

“normal” anterior mediastinal fat.15 Jaretzki and Wolfffound ectopic thymic tissue in the cervical and mediasti-nal region in 32 and 98% of patients, respectively.14Theyreported detailed “mapping” of sites where extracapsularthymic tissue had been found, and on the basis of thesefindings, they advocated a combined cervical andtranssternal approach to thymectomy, which they termedmaximal thymectomy Fukai and colleagues identifiedectopic thymic tissue in the anterior mediastinal fat,retrocarinal fat, and preaortic fat in 44%, 7.4%, and 0%

of patients, respectively.16Most recently, in a review of theclinical significance of ectopic thymus, Ashour foundectopic thymic tissue in 39.5% of patients.17In contrast

408 / Advanced Therapy in Thoracic Surgery

FIGURE 33-1 Comparison of survival between myasthenic patients

treated surgically (thymectomy) and those treated medically From Buckingham JM et al 12

to Jaretzki’s findings, the ectopic thymus was found

pref-erentially in the neck (63.2%) Proponents of complete

thymectomy have drawn on this data in support of their

respective operative techniques

Preoperative Preparation

Although disagreement exists regarding the specifics of

preoperative preparation, there is general agreement that

a planned, systematic approach to stabilize patients

neurologically prior to surgery is important and yields

the best results Wechsler has long been one of the

strongest advocates of a prospective management plan

for myasthenia patients.18 The planned approach that he

advocates, which was developed at Duke University, uses

thymectomy as the sole therapy whenever possible

Medications are used only if needed and not as a matter

of routine

Plasmapheresis is used to stabilize the more acutely ill

patient with respirator y compromise Goti and

colleagues showed that plasmaphersis improved forced

expiratory volume in 1 second (FEV1) and mean

expira-tory force and reduced functional residual capacity

(FRC), while pyridostigmine did not have these effects.19

Plasmapheresis (4 to 8 exchanges) leads to remission of

myasthenia gravis in 45% of cases and lasts 1 to 2 weeks.20

Plasmapheresis has been recommended for myasthenic

patients with vital capacity < 2 L.21 The use of

plasma-pheresis has been shown to reduce postoperative

mechanical ventialtion and intensive care unit stay.22

Preoperative infections, even those that may normally

seem clinically insignificant, are treated to resolution

prior to thymectomy This is done for the theoretic

concern that a localized infection may affect systemic

immune function, which could therefore affect

myas-thenic symptoms and therapeutic outcome

Several studies have examined preoperative risk

factors for postoperative respiratory failure Leventhal

and colleagues proposed a scoring system to predict the

anesthetic risk in patients with myasthenia, assigning

points based on duration of disease, dose of

pyridostig-mine, presence of respiratory disease, and preoperative

vital capacity < 2.9 L.23However, subsequent studies by

other investigators attempting to validate this scoring

system found it to be of only limited value in patients

undergoing thymectomy via sternotomy.24,25The current

experience with myasthenics indicates that the risk

factors associated with the need for mechanical

ventila-tion after surger y are the severity of disease (ie,

Ostermann stage 3 or 4), borderline preoperative

respira-tory function, and the transsternal approach for

of surgery The rationale for decreasing or withholdingthe anticholinesterase is to prevent overdosing, since theanticholinesterase requirement is usually decreased aftersurgery However, if the dose is withheld, the patient may

be weak on arrival to the operating room The practice atour institution and others is to have the patients taketheir usual doses of anticholinesterase up to the time ofsurgery.20Patients receiving chronic steroid therapyusually receive additional coverage of hydrocortisone,

100 mg intravenously, prior to anesthetic induction andthen every 8 hours for an additional three doses

Intraoperative Management

Standard basic monitoring (noninvasive blood pressure,electrocardiographic monitoring, pulse oximetry, end-tidal carbon dioxide, temperature, neuromuscular block-ade, and oxygen concentration) is used for all patientsundergoing thymectomy A precordial stethoscope usedduring induction may need to be exchanged for anesophageal stethoscope so as not to interfere with thesurgical field An arterial catheter for hemodynamic andarterial blood gas monitoring is placed in patients under-going transsternal thymectomy or in patients who havesignificant cardiovascular or respiratory disease A single-lumen endotracheal tube is appropriate unless a thoraco-scopic approach is used, in which case a double-lumenendotracheal tube may be required

Anesthesia is usually induced using an intravenousagent (such as thiopental, propofol, or etomidate) incombination with an inhalational agent Some anesthesi-ologists avoid muscle relaxants, because the patient’sbaseline muscle weakness and the muscle-relaxing effect

of the volatile anesthetic are usually adequate for trachealintubation and anesthetic maintenance However, otheranesthesiologists prefer to use a balanced technique withcarefully titrated muscle relaxants.26Neuromuscularmonitoring should be performed using the obicularisoculi muscle, based on a study by Itoh and colleaguesthat showed the obicularis oculi muscle to be more sensi-tive than the adductor pollicis to neuromuscular block-ing agents in myasthenic patients.27

Patients receiving anticholinesterase drugs may have

an abnormal response to the depolarizing muscle ant, succinylcholine A prolonged block can occurbecause anticholinesterase therapy inhibits the activity oftrue cholinesterase as well as plasma cholinesterase,

relax-Surgery for Myasthenia Gravis / 409

which is responsible for succinylcholine hydrolysis.

Resistance to succinylcholine has also been reported and

is most likely due to the decreased number of

acetyl-choline receptors in patients with active disease.28This

response to succinylcholine is usually normal in patients

who are in remission.29 Patients who undergo

plasma-pheresis have reduced cholinesterase and will have a

delay in metabolism of succinylcholine as well as other

drugs metabolized by plasma cholinesterase such as

mivacurium and remifentanil.20

Patients with active myasthenia gravis are usually

sensitive to the effects of nondepolarizing muscle

relax-ants (eg, vecuronium, rocuronium, and atracurium)

There may be both an increased response and a

pro-longed effect Atracurium has been a recommended

nondepolarizer because of its short elimination half-life

and rapid breakdown independent of plasma

cholinesterase.30A study by Mann and colleagues showed

that patients with a preanesthetic fading after

train-of-four stimulation had a significantly decreased median

effective dose for atracurium while myasthenic patients

without fading had an median effective dose similar to

that of nonmyasthenic patients (0.24 mg/kg).3 1

Vecuronium has also been successfully used in

myas-thenic patients Incremental vecuronium doses of

0.005 mg/kg (one-tenth the normal dose), titrated to

effect with careful neuromuscular blocker monitoring is

the recommendation for these patients.32

Neuromuscular blockade is reversed with neostigmine

or edrophonium ( Tensilon) Using these

anti-cholinesterases for reversal has the theoretic potential of

producing a cholinergic crisis in a patient receiving

anti-cholinesterase therapy, but this is not commonly seen in

clinical practice Caution is used in administering drugs

that have neuromuscular blocking properties as a side

effect These include the aminoglycoside antibiotics,

calcium channel blockers, and antiarrhythmics such as

quinidine and procainamide

An anticholinesterase infusion, usually neostigmine,

may be used during the perioperative period The

patient’s daily dose of pyridostigmine is divided by 60,

and that amount of neostigmine is infused over 24 hours

(usually achieved by adding the dose of neostigmine to

1 L of Ringer’s lactate or normal saline, which is then

infused at 42 cc/h) When the patient is able to take oral

medications, the infusion is discontinued, and an oral

dose of pyridostigmine is restarted

Postoperative Pain Relief

Thoracic epidural anesthesia in combination with light

general anesthesia has been reported to give excellent

postoperative pain relief after transsternal thymectomy.33

In a study by Kirsch and colleagues, lumbar epidural

morphine administered preoperatively provided superiorpostoperative pain relief and better respiratory mechan-ics when compared with intravenous narcotics inpatients undergoing transsternal thymectomy.3 4 Nodifference was found between the groups for the duration

of postoperative intubation or ventilation

Intrathecal (spinal) opioids are also frequently usedfor postoperative pain relief Intrathecal morphineadministered before incision reduces the amount ofparenteral narcotics needed for pain relief after surgery.Patients who are not candidates for either intrathecal orepidural analgesia are given reduced doses of parenteralnarcotics for postoperative pain relief

Surgical Technique

Once a patient is stabilized, surgery may be considered.The goals of surgery are to completely remove thethymus gland and, if present, an associated thymoma.Numerous incisional strategies have been developed toaccomplish this objective Each has its advocates Surgicalapproaches include combined cervical exploration andmedian sternotomy (maximal thymectomy), mediansternotomy (transsternal approach), partial sternotomy,transcervical, infrasternal mediastinoscopy, and thora-coscopy To date, the evidence suggests that, as long as theprinciple of complete thymectomy (with thymoma ifpresent) is adhered to, comparable results can beobtained with the different approaches

Combined Cervical Exploration and Transsternal

General single-lumen endotracheal anesthesia is usedwith the patient positioned supine A separate generouscollar cervical incision and median sternotomy areemployed (Figure 33-2) The two incisions may be joined

as a “T,” for additional exposure for thymomas or forreoperations The cervical dissection extends from theinnominate vein inferiorly to the thyroid isthmus superi-orly; the recurrent laryngeal nerve marks the lateralborders Jaretzki states that this incision provides expo-sure superior to that provided with a cervical incision,while avoiding the impact of a full sternotomy.Contraindications include extensive thymic tumors,especially those involving the lower mediastinum and

410 / Advanced Therapy in Thoracic Surgery

the thymus to the inferior aspect of the thyroid gland are

identified These are then ligated and divided This

inci-sion does not need to be modified for thymoma Again,

more aggressive resection may be required if local

inva-sion by thymoma is encountered

Transcervical Thymectomy

Historically, there has been concern about the safety of

transsternal thymectomy in patients with myasthenia

gravis because of incisional pain and associated

respira-tory compromise, possible phrenic nerve injury, and

mediastinitis In order to circumvent these possible

complications, Crile revived the technique, which

ante-dated open thoracic surgery, of transcervical

thymec-tomy.35 Others, including Kark and Kirschner,36 Cooper

and colleagues,10Ferguson,37and Deeb and colleagues,38

also deserve credit for their contributions to the

descrip-tion of this technique

Patients are positioned supine with the arms tucked at

the side and the neck extended General endotracheal

anesthesia is used, and a collar cer vical incision

employed The superior thymic poles are identified and

dissected free Dissection of the thymus continues

inferi-orly using upward traction on the superior poles

(Figure 33-4) A right-angled retractor is used to lift the

sternum anteriorly, enhancing exposure of the anterior

mediastinum A fiberoptic headlight also helps The

thymic veins are identified during the dissection and

clipped or ligated Some find it easier to remove the

ante-rior mediastinal fat along with the thymus, others

remove the fatty tissue separately The phrenic nerves are

protected and preserved If additional exposure isneeded, a partial or complete sternotomy is added.Most consider the presence of thymoma to be acontraindication to using this approach However, Deeband colleagues,38on the basis of their clinical experience,concluded that the indications for intranscervicalthymectomy can safely be extended to include patientswith thymoma

Infrasternal Mediastinoscopic Thymectomy

A recent report by Uchiyama and colleagues describing anovel use of mediastinoscopy to accomplish thymectomyunderscores the variety of methods available to thesurgeon managing patients with myasthenia gravis.39Theprocedure is performed under general anesthesia Patientsare positioned supine with the neck extended as withstandard mediastinoscopy For the first 18 patients, amidline cervical incision was employed, the anteriorcervical muscles divided in the midline and the thymusidentified in the anterior mediastinal space Using upwardtraction, the thymus was dissected out and removed Forthe last five patients, the thymus was removed using asubxiphoid, or infrasternal, mediastinoscopic thymec-tomy The sternum is retracted upward, video viewingand fiberoptic lighting assist The authors state that expo-sure is adequate for control of thymic vessels and removal

of thymus and anterior mediastinal fat Following tion, a mediastinal drain is left in place

dissec-The authors report one phrenic nerve injury andsuccessful thymectomy in 21 of 23 (91%) patients Theremaining two patients were converted to open ster-notomy There were no deaths, and all patients showedclinical improvement in their myasthenia gravis symp-toms

Partial Sternotomy with or without Cervical Incision

Cervicomediastinal exposure can be attained using apartial sternotomy with or without a cervical incision.This approach facilitates exposure of the anterior-superior mediastinum without subjecting the patient to acomplete sternotomy Patients are positioned as for astandard sternotomy A vertical midline incision isemployed down to the level of the second or third inter-costal space The upper sternum is split with a Lebscheknife or oscillating saw, and the divided sternum spreadwith a pediatric thoracotomy retractor to expose theupper mediastinum (Figure 33-5) If needed, a collarincision is added, resulting in a T-shaped incision Thisapproach gives excellent exposure and avoids a full ster-notomy; however, it is cosmetically unappealing

LoCicero describes a modified approach to partialsternotomy that has much more cosmetic appeal.4 0

Contraindications to this approach include extensive

412 / Advanced Therapy in Thoracic Surgery

FIGURE 33-4 Surgeon’s view of the operative field during

transcervi-cal thymectomy The superior thymic lobes have been mobilized From

Kark AE and Kirschner PA 36

deaths, and complication rates were low (0 to 21%) At

least some improvement in clinical staging and decrease

in medication requirement was noted in 78 to 96% of

patients Remission, defined as being asymptomatic and

off medication, occurred in 18 to 69% of patients

Crucitti and colleagues reported a dramatic decrease

in operative mortality associated with thymectomy

during the study period 1969 to 1989.11This finding and

the recent low reported morbidity and mortality with

thymectomy are a tribute to a multidisciplinary approach

to this disease and advancements in care on all specialty

fronts

Whereas the safety and effectiveness of thymectomy

for myasthenia are well established, the recommended

surgical approach remains controversial There is general

agreement that successful surgical management of

pa-tients with myasthenia gravis requires complete

thymec-tomy There is disagreement as to what surgical approach

is needed to achieve this goal On one end of the

spec-trum, Jaretzki and coworkers, on the basis of studies

showing the incidence and wide cervicomediastinal

distribution of ectopic thymus and comparing

postsurgi-cal results by surgipostsurgi-cal technique (Figure 33-6) believe that

complete thymectomy can be accomplished only by a

combined cervical and median sternotomy incision

(maximal thymectomy).4At the other end of the surgical

spectrum are those who, citing the potential

complica-tions of median sternotomy in patients with myasthenia

who are often on immunosuppressive medications,

believe that complete thymectomy can be performed,

equally effectively and more safely, using transcervical or

videothoracoscopic approaches The lack of prospective

controlled trials, the variation in clinical stage, and the

wide range of treatment plans used have prevented

reso-lution of the controversy regarding surgical approach As

Table 33-2 clearly shows, there are excellent results

reported regardless of the surgical technique used The

favorable effect of thymectomy on patients with

general-ized symptoms of myasthenia gravis has led some to

recommend surgery for patients with stage I (ocularsymptoms) disease Roberts and colleagues have demon-strated that ocular myathenia symptoms were cured orimproved in 70% if no thymoma was present and 67% inpatients with assciated thymoma.47

Clinical improvement following surgery appears to bedurable Jaretzki and colleagues showed postoperativeremission rates of 81% at 89 months of follow-up fornonthymoma patients.4Frist and coworkers reported a 5-year postsurgical survival of 100%,9and Crucitti andcolleagues reported a 10-year survival of 78% with arecurrence rate of 3%.11

There is disagreement as to which clinical factors arepredictive of favorable outcome to thymectomy Jaretzkiand colleagues have shown that more severe preoperativesymptoms, thymoma, and the need for reoperativethymectomy were factors predictive of a less favorableoutcome to surgical therapy.4On the other hand, multi-variate analysis failed to show predictive effect of age, sex,duration of symptoms, use of steriods, preoperativeplasmapheresis, thymic pathology (aside from thymoma),

or anticholinesterase antibody levels Ashour found thatthe presence or absence of ectopic thymic tissue was

414 / Advanced Therapy in Thoracic Surgery

TABLE 33-2 Surgery for Myasthenia Gravis: Results

CX = cervical; MS = median sternotomy; ns = not significant; VATS = video-assisted thoracoscopy.

*Improvement and remission rates for thymectomy without thymoma, reoperation, and with thymoma, respectively.

†Remission rates are shown for patients with mild and severe disease, respectively.

FIGURE 33-6 Comparison of remission rates after thymectomy

according to surgical technique Thymoma patients are excluded From Jaretzki A et al 4