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SURGICAL PERSPECTIVES

italin: The Rationale for a Hypothetical Hormone

obert H Bartlett, MD, FACS

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solated brain death causes apnea that results in cardiacrrest in minutes. If apnea is prevented by mechanicalentilation, vital organ function gradually progressesrom normal to failure in a reproducible, identifiable,nd relentless fashion.1,2 This phenomenon has onlyeen of interest in the last few decades because of theossibility of transplanting organs from brain-dead buteart-beating cadavers into recipients with organ failure.he window for harvesting organs for transplantation isnly as long as the period between brain death and organailure—approximately 48 hours.

An isolated organ perfused with blood at 37°C fol-ows an accelerated course of the same pathophysiologicequence: normal function, loss of vasomotor tone,dema, organ failure.3,4 Organ culture (as opposed toissue culture) has never been accomplished, yet an or-an transplanted into a viable recipient functions indef-nitely. What is the cause of organ failure in the absencef a brain, and why should we care?

he pathophysiology of brain deathfter brain death (with mechanical ventilation) and after

he “Cushing response” of hypertension and bradycar-ia, vital organ function remains normal for 6 to 12ours. The first manifestation of organ malfunction is

oss of distal tubular function in the kidney, resulting inrofound diuresis (diabetes insipidus). This is from a

ack of antidiuretic hormone secretion from the brain.ntreated, diabetes insipidus leads to hypovolemia andrgan failure from hypovolemic shock. When diabetesnsipidus is prevented by administration of vasopressinantidiuretic hormone), blood volume is maintainednd vital organ function continues for another 12 to 24ours. The next manifestation of organ failure is loss ofystemic vasomotor tone, resulting in vasodilation, rela-ive hypovolemia, and hypotension. The physiologicicture resembles anaphylaxis. Untreated, this phenom-

eceived February 18, 2004; Revised March 30, 2004; Accepted April 6,004.rom the Department of Surgery, University of Michigan Medical School,nn Arbor, MI.orrespondence address: Robert H Bartlett, MD, University of Michiganedical School, Department of Surgery, 2920 Taubman Health Care Center,

nn Arbor, MI 48109-0331.

2862004 by the American College of Surgeons

ublished by Elsevier Inc.

non results in cardiac arrest from hypovolemic shockithin a few hours. This vascular collapse can be treatedith systemic alpha-adrenergic agents and infusion of

luids. But after about 6 hours of this treatment (24 to 48ours from brain death), increasing dosages of pressorsre required to maintain blood pressure, and generalizedapillary leakage begins, resulting in generalized edema.he capillary leakage predominates the perfusion phys-

ology. Continuous infusion of fluid is required to main-ain the blood volume, and those organs that malfunc-ion while edematous begin to fail. Pulmonary edemaesults in lung dysfunction. Cardiac edema results in aoss of diastolic compliance and decreased cardiac out-ut. Intestinal edema results in profuse diarrhea. Even-ually a combination of hypoxemia, hypercarbia, acido-is, and low cardiac output results in cardiac arrest.1,2 Inome ways, this multiple organ failure (MOF) syndromeesembles an accelerated version of the loss of other hor-ones secreted by the brain (adrenocorticotropic hor-one, thyroid stimulating hormone, and vasopressin).ut administration of these hormones in large doses (ordministration of secondary hormones like thyroidormone and adrenal cortical steroids) has only alight delaying effect on the multiple organ failureyndrome.5,6

The same sequence of loss of vasomotor tone, capil-ary leakage, edema, and organ failure occurs with iso-ated organs perfused with blood or other perfusates.3,4

he physiologic sequence is the same for normothermicsolated perfused kidney, heart, lung, liver, intestine, and

uscle. Isolated perfused organs will respond to alpha-drenergic agents for a period of hours but eventually,ike the intact perfused cadaver, will lose tone, becomedematous, and lose function. If the heart-beating ca-aver is supported with a heart/lung machine, the sameequence of events occurs (Bartlett RH, unpublishedbservations). Reports of prolonged function of isolatederfused organs were from experiments in which theerfused organ was attached to a live-brain donor, eitherirectly7,8 or through dialysis.9 Reports of viable cells inerfused small organs are essentially tissue culture.10 Inhe 1930s Carrel and Lindbergh11 collaborated on anrgan perfusion system and described successful preser-

ISSN 1072-7515/04/$30.00doi:10.1016/j.jamcollsurg.2004.04.008

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ation for days to weeks in their classic book The Culturef Organs (1938). The perfusate was fresh serum witharious additives. The results are reported as anecdotalithout denominators, and definitive experiments wereever reported.Much can be deduced about the cause of MOF after

rain death (MOFB) from events in nature and events inlinical practice. Does the presence of a dead brain or thebsence of a live brain cause MOFB? Systemic absorp-ion of the autolytic products of any necrotic tissue willause this syndrome, and absorption of materials from aecrotic brain could account for MOFB. But this isnlikely for the following reasons: Necrosis of the entireortex sparing the midbrain does not cause MOFB, butather a persistent vegetative state with normal organunction. The time sequence of MOFB is too rapid to bexplained by absorption of the necrotic tissue productsthe latter usually requires 3 to 5 days). Most conclu-ively, I (unpublished observations) and Cowley and col-eagues12 have observed that the MOFB syndrome is theame in experimental animals after brain death with anntact brain or removal of the brain by decapitation. Sohe syndrome is caused by the absence of a live brain.

More specifically, the syndrome is caused by absencef a portion of the midbrain. Death of the entire cortexnd subcortical areas, which does not involve the mid-rain or brain stem, results in a persistent vegetative stateanging from stupor to complete loss of response to anytimuli, but organ function remains normal. Death ofhe brain stem, which can occur with basilar artery oc-lusion, resembles C1 quadriplegia, but MOFB does notccur. In the midbrain itself, removal of the pituitaryland or loss of hypothalamic-pituitary secretion of thenown brain hormones causes loss of function of thearget organs (Sheehan’s syndrome), but can be treatedndefinitely with substitution of the appropriate hor-

ones without MOFB. Trauma or ischemia can causeoss of the poorly defined controller of metabolism in theypothalamus, resulting in runaway hypermetabolism

Abbreviations and Acronyms

DDAVP � desmopressin acetate (a synthetic analogue ofvasopressin)

ECLS � extracorporeal life supportMOF � multiple organ failureMOFB � multiple organ failure after brain deathVON � vital organ nucleus

nd hyperthermia, without MOFB. From all of thesebservations we can conclude that MOFB results fromhe loss of a localized part of the midbrain or hypothal-mus. For purposes of this discussion, we will call thisrea the vital organ nucleus (VON). All medical studentsave seen it under the microscope, but we see what we

ook for, and we look for what we know. For example,ould the VON be the paraventricular nucleus of theypothalamus, or some other unexplained collection ofells?

ow does the midbrain prevent multiplergan failure?hat is the function of the vital organ nucleus? By ob-

erving the effects of the loss of the VON, we can deducehat the function is to maintain vasomotor tone andapillary integrity throughout the body, or to remove ornhibit normal substances or events that cause loss ofasomotor tone and capillary leakage. Either or bothctive and inhibitory mechanisms are possible. To sepa-ate these two alternatives it is helpful to consider howhe effects of the VON are mediated.

The VON effects could be mediated by neurogenic orumoral mechanisms. It is unlikely that the mechanism

s neurogenic for the following reasons: Complete tran-ection of the spinal cord does not cause MOFB. To beure, there is an initial loss of vasomotor tone (spinalhock), but this is transient and easily treated by fluidnfusion and alpha-adrenergic drugs. Normal regulatoryontrol of vasomotor tone is permanently impaired afterpinal cord transection, but is always treatable and

OFB does not result. Similarly, transection of bothagus nerves in the neck results in the loss of some car-iac and pulmonary reflexes but not in MOFB. Finally,nd most compelling, excised and reimplanted or trans-lanted organs function normally without any innerva-ion, as long as the host has a normal brain or, moreccurately, a normal VON. From these observations weonclude that the mechanism of action of the VON isumorally mediated.If the active or inhibitory mechanism is blood borne,

s it mediated by an actively secreted substance (by def-nition, a hormone) or by some modification of cells orhemicals as they pass through the VON? Although pos-ible, it is unlikely that the effect is mediated by somehange in circulating cells or platelets. The concentra-ion of white cells and platelets is unchanged after braineath. Patients with essentially no circulating white cells,

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o circulating platelets, or both (following chemother-py, for example) live for days or weeks without MOFntil infection supervenes. The known mechanisms byhich circulating cells are activated to cause a systemic

ffect are responses to abnormal events, not normal con-rol mechanisms. For example, cell-mediated andntibody-mediated immunity require a stimulus thatauses lymphocytes or dendritic cells to carry a chemicalessage to reticuloendothelial tissue, which, in turn,

esults in effector cellular response. The only other cir-ulating particle, the erythrocyte, is an unlikely candi-ate to carry a cell-based message to other body tissues.rom these observations we can conclude that the effectf the VON is mediated through the plasma. Experi-ents on isolated organs in which the perfusate in-

luded plasma or dialysate from a viable animal supporthis observation.7-9

If the effect requires blood perfusion and is mediatedhrough the plasma, does it involve active secretion of aubstance, or could it be that a normal circulating sub-tance is deactivated in the VON? Local deactivation isossible but unlikely for the following reasons: the VONs physically a small area that receives only a small frac-ion of the cardiac output. Inactivation or other modifi-ation of known vasoactive molecules takes place in areasf high blood flow such as the kidney, liver, or reticu-oendothelial tissue. (Inactivation of nitric oxide takeslace by hemoglobin binding throughout the vascularpace.) In other circumstances in which a very small bitf tissue influences systemic organ function, the effectors either neurogenic (as in the carotid and aortic bodies),r active secretion of a substance (pituitary, adrenal, thy-oid, and gonadal hormones, for example). From thesebservations, we conclude that the mechanism of actionf the VON is most likely mediated by an actively se-reted chemical that has distant effects, so is a hormone.his is the mechanism by which the midbrain controlsther organ functions. The secretion and feedbackechanisms are well known for growth hormone, adre-

ocorticotropic hormone, thyroid stimulating hor-one, follicle stimulating hormone, luteinizing hor-one, vasopressin, and oxytocin. We have named this

ypothetical hormone vitalin.

haracterizing the hormonef there is an area in the midbrain identifiable as theON, and if the VON secretes vitalin, how is the effectf vitalin mediated? The target tissue seems to be the

ndothelium, vascular smooth muscle, or both. Doesitalin cause a direct effect on this systemic “organ” (likentidiuretic hormone or oxytocin), or is a secondaryndocrine organ involved (like adrenocorticotropic hor-one or thyroid stimulating hormone)? Could it be that

here is an endocrine organ the size of the thyroid ordrenal that has a hormonal function that has never beeniscovered? The answer is yes. There are many areas ofhe body where neuroendocrine tissue exists that couldave secretory endocrine activity. The lung, for example,as a glomus pulmonale at the pulmonary artery bifur-ation that is very similar to the carotid body, and theung itself is full of nests of neuroendocrine cells, theunctions of which are unknown. Remnants of neuralrest tissue reside all along the midline, from the organ ofuckerkandl to isolated neuroendocrine cells residing in

he retroperitoneum and posterior mediastinum. Neo-lasms made of or including such cells can secrete hor-ones normally secreted by the brain or by other endo-

rine organs. Some neoplasms of these neural cells, suchs certain ganglioneuromas, neuroblastomas, and adre-al tumors, are said to be nonfunctional, but whatould be the physiologic effect of increased plasma lev-

ls of vitalin? If a secondary endocrine organ mediateshe effect of vitalin, we would expect to see an ablationffect if disease or dissection (such as loss of the adrenals,arathyroids, or islets of Langerhans) removes that or-an. Inadvertent surgical removal of such a secondaryrgan would require complete dissection of neural crestemnant tissue or complete removal of the lungs andulmonary artery. Of course, the latter occurs in com-ined heart/lung transplantation, but a putative second-ry endocrine organ would be included in the trans-lant. So it is possible but unlikely that vitalin from theON acts by stimulating a secondary endocrine organ.The brain hormone vasopressin has effects similar to

he theoretical effects of vitalin. The effect of vasopressins on the distal renal tubule as ADH, and directly onndothelium and smooth muscle cells rather than on aecondary endocrine organ. One Japanese group re-orted that MOFB in brain-dead humans was preventedy administration of large amounts of vasopressin.13 Iunpublished observations) and other investigators14

ave not been able to corroborate this report. Perhapshe Japanese preparation of vasopressin included someitalin, a possibility that will be discussed later.

If vitalin is a hormone, what is its chemical nature?ther brain hormones are primarily polypeptides. One

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289Vol. 199, No. 2, August 2004 Bartlett Hypothetical Hormone

it of evidence that supports a small molecule hypothesiss the cross-circulation that occurs between a pregnantoman and a fetus. An anencephalic fetus, which devel-ps without a brain, indeed even without a head, willave normal growth, development, and physiologicunction immediately after delivery. An anencephalic fe-us, in which the midbrain has not developed, if resus-itated and ventilated will follow the typical course of

OFB after delivery. Growth, development, and phys-ologic function of the fetus were presumably sustainedy maternal vitalin crossing the placenta. An anence-halic newborn in whom the midbrain and brainstemre present does not develop MOFB.15 Conversely, onare occasions a pregnant woman sustains brain death,ut does not develop MOFB when supported by a me-hanical ventilator. There are 17 case reports of pregnantomen who had all the characteristics of brain death butid not develop MOFB as long as the pregnancy wasaintained (5 days to 17 weeks).16 Most are published as

ase reports.17-19 When the fetus was delivered, maternalardiac arrest occurred from 20 minutes to 2 days laterusually because the ventilator was discontinued). Pre-umably, fetal vitalin crossing the placenta prevented

OFB (although at least seven of these women requiredreatment for diabetic insipidus, suggesting that fetalntidiuretic hormone was insufficient).

Another bit of evidence supporting a small moleculeypothesis is an anecdotal case worth reporting. In975, Dr Alan Gazzaniga and I established cross-irculation between a young man in stage 4 hepaticoma with acute fulminant hepatic failure from viralepatitis and a brain-dead, heart-beating cadaver on me-hanical ventilation. The cadaver was hypotensive anddematous in the final stages of MOFB, so was not aandidate for organ donation. Blood matched betweenhe two without reaction. With informed consent of theamilies, cross-circulation was established with the hopef providing temporary liver function for the patient inepatic coma. This was carried out for 36 hours. Theoung man awoke quickly and eventually recoveredompletely. Of more interest for this discussion was theate of the brain-dead donor. During the cross-irculation, vasomotor tone improved quickly; vasopres-or drugs were stopped; and renal, cardiac, and pulmo-ary functions returned to normal within hours. Whenross-circulation was stopped, MOFB and cardiac arrestccurred. This anecdote is presented without documen-ation because the records have been discarded, but the

ase offers some evidence that a hormone from the VONf the hepatitis patient had a physiologic effect on theonor beyond the effect expected for the knownormones.

lternative explanations for MOFBt has been postulated that the progressive organ failurefter brain death is primarily a result of the Cushing reflex,n which systemic vasomotor tone increases abruptly,training the left ventricle to the point of causing myocar-ial failure, perhaps followed by poor perfusion related toardiogenic shock, and organ failure related to a low flowtate. These phenomena occur after experimental and clin-cal brain death, but experimental animals and patientsho experience the Cushing reflex recover to normal car-iac function in many cases, but progress to MOFB evenith adequate perfusion. If the Cushing reflex is prevented

fter brain death in experimental animals, MOFB occurs athe same rate as it does after the Cushing response.3,20 Anlternate explanation for MOFB is the lack of the knownypothalamic/pituitary brain hormones with subsequentypofunction of the adrenal and thyroid glands. The onsetnd course of MOFB can, indeed, be slowed by adminis-ration of thyroid and adrenal hormones,5,6 but MOFB stillccurs despite continuous or intermittent hormone re-lacement. The MOFB syndrome resembles endotoxemiar systemic sepsis. Is it possible that brain death leads tonusual intestinal mucosal permeability with absorption ofndotoxins or intact bacteria? This is unlikely, becauserain-dead bodies maintained for organ donation do notave septicemia or endotoxemia, despite the early onset ofOFB. Fluctuations of plasma cytokines and other in-

lammatory mediators have been reported after braineath, but these are likely from progressive organ failureather than the cause of progressive organ failure.21,22

Does multiple organ failure after brain death reallyccur? Although we have made the case that the MOFByndrome is inevitable and relentless, the late course af-er human brain death has been very rarely character-zed. Somatic survival depends on mechanical ventila-ion, and when brain death is verified, mechanicalentilation is stopped, and cardiac arrest results. Thenly exceptions are prolongation of somatic survival forurposes of organ donation. Once donor organs areaken, the ventilator is discontinued and cardiac arrestccurs. So there are very few reported cases in whichttempts were made to sustain somatic survival foronger than a day or two, but there are at least 56 such

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290 Bartlett Hypothetical Hormone J Am Coll Surg

ases. We are indebted to Dr DA Sheumon of UCLA foris very thorough review of the reported cases.16 Stimu-

ated by the lack of MOFB in one of his patients, in 1998r Sheumon collected and published a series of 175

ases of prolonged somatic survival without MOFB afterpparent brain death. Some of these reports were anec-otal and not substantiated and some were reports in the

ay press, but 56 of these patients had enough documen-ation to meet the standard criteria for brain death. Drheumon kindly shared his detailed archive with me.entilator support was withdrawn in 19 of these patientsut 37 maintained somatic function with mechanicalentilation for periods up to 1 month (22), 6 months11), or more than 1 year (4). One of these patients stillas normal growth and somatic function 141

2 years afterhe onset of brain death. All patients with somatic func-ion for more than 6 months were children at the time ofhe neurologic event (2 were newborns). Interestingly,7 of these patients were pregnant women in whomomatic function was intentionally maintained in ordero allow the fetus to mature and be delivered. These casesre important because it could be that the developingetus may have secreted vitalin, which crossed the pla-enta and prevented MOFB in the mother. In all cases,

OFB occurred after delivery, but usually the mechan-cal ventilator was discontinued, leading to cardiacrrest.

Did these 56 patients actually have total brain death?heumon summarizes the evidence including autopsyindings in detail, and the evidence is very convincing.ut some patients did not have diabetes insipidus orther signs of pituitary insufficiency. In these patients,e believe that the deep hypothalamus and pituitary

emained viable, presumably secreting vitalin and otheridbrain hormones. To test the vitalin hypothesis, dia-

etes insipidus and hypopituitarism must be present toiagnose total brain death, and there are such cases. Onef the patients in this series was a 49-year-old man whoustained brain injury after cardiac arrest, deteriorated,nd met brain death criteria over 90 hours. Diabetesnsipidus and hypopituitarism occurred, but somaticunction remained stable on a ventilator for 71 days.utopsy showed extensive brain necrosis. How do theseases of somatic survival without MOFB relate to theormone hypothesis? Perhaps the theory is wrong and aiable midbrain is not necessary to maintain somaticunction, although there is ample evidence to supporthe theory. As an alternative explanation, all of these

atients are given biologic or synthetic brain hormones,ncluding vasopressin. Are they being given small dosesf vitalin?

s vitalin vasopressin?f, by definition, diabetes insipidus is essential for theiagnosis of brain death, then treatment with antidi-retic hormone (and other pituitary hormones) is essen-ial to maintain somatic function. Indeed, these hor-ones are routinely given to potential organ donors and

elay the onset of MOFB. All of the patients with pro-onged somatic function after brain death (except forome of the pregnant women) were treated with antidi-retic hormone to control diabetes insipidus. Until quiteecently, the preparation used for antidiuretic hormoneas posterior pituitary extract manufactured by Parkeavis Pharmaceutical (later Warner Lambert and later

et Pfizer). This was a biologic preparation made byrinding up pituitary glands and extracting the smallroteins by chemical means. Could it be that these bio-

ogic preparations contained enough vitalin to preventOFB in some subjects? Or could some vitalin be in-

luded in preparations of adrenocorticotropic hormoner other drugs given to these patients?

More recently, diabetes insipidus has been treated by aynthetic analogue of vasopressin and desmopressin ac-tate (DDAVP). Some of the patients with prolongedomatic survival after brain death have been maintainedith DDAVP.13,16 Is it possible that the hypothetical hor-one we have characterized as vitalin is in fact vasopres-

in or a hormone closely related to it? Certainly theroperties of vasopressin resemble the putative proper-ies of vitalin in many respects. Is it possible that theypothetical hormone is a metabolite of vasopressin orDAVP? That MOFB always occurs despite DDAVP

peaks against this possibility, but it certainly deservesnvestigation.

esting the hypothesisur laboratory and clinical research has focused on extra-

orporeal life support (ECLS) in acute cardiac and pulmo-ary failure. Prolonged ECLS is not only possible, but re-ults in successful recovery as long as the brain is viable. Weave studied ECLS in brain-dead animals and patients withhe hope of maintaining organ function for transplanta-ion, but ECLS does not prevent MOFB. Finally, we askhe question “Why?” leading to the theory presented here.ur failure to prevent MOFB with ECLS becomes the

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ontrol for experiments to test the hypothesis. Vasopressins the most attractive candidate for the critical hormone ande have studied it in brain-dead animals (Bartlett RH, un-ublished observations) and patients. There was not a sig-ificant effect using the doses reported by Iwai and col-

eagues13 and Blaine and associates.14 We are now doingther experiments to test the hypothesis.

There are many ways to approach this problem; allequire complex experiments involving chronic brain-ead animals or isolated perfused organs. Models ofrain death may involve the spinal cord and elicit theushing reflex. Decapitation is the best model, but itay induce other physiologic changes. Selective abla-

ion of the pituitary and hypothalamus is another possi-ility. With any model of brain death the hormone hy-othesis can be tested by infusion of agents likeasopressin, brain extracts, plasma from a live donor, orross-circulation of blood plasma or dialysate. Physio-ogic study of isolated perfused organs is another ap-roach. The controls are easily documented, but includell the variables of mechanical perfusion. The isolatederfused organ lacks interorgan relationships, includinguch simple functions as nutrition and excretion, whichust be substituted in this preparation. Drugs, brain

xtracts, plasma, and cross-circulation studies can be ap-lied to the isolated perfused organ. Because organ cul-ure is the ultimate goal of this project, we are currentlyocusing on the isolated perfused organ system to test theypothesis. We will report these experiments as theyroceed, but this will take years in our laboratory. We areaking the unusual step of describing the hypothesis it-elf in this article, with hopes that other laboratories willonsider similar experiments or develop other explana-ions to evaluate the phenomenon of MOFB.

hy is this important?uppose the hypothesis is correct and a hypothalamicormone or vasopressin metabolite is identified that pre-ents multiple organ failure after brain death. Adminis-ration of this hormone to potential organ donors wouldncrease the availability and quality of organs for trans-lantation to some extent. But the real importance ofiscovering such a hormone would not be in organ do-ation, but rather in organ perfusion and preservationorgan culture). All experiments in organ perfusion andreservation show the same physiologic pattern as thateen in the intact body after brain death. Specifically thisncludes normal function for a period of time followed

y loss of vasomotor tone, capillary leakage, and gener-lized edema and organ failure despite all interventions.he only exceptions are experiments in which the per-

usate includes plasma from a live animal.7-9 Althoughells can be grown and maintained in tissue culture forecades, it is impossible to maintain a single organ on alife support system” despite maintaining normal phys-ologic and nutritional status in the circulating perfus-te. We hypothesize that this phenomenon is from thebsence of vitalin in the isolated perfused organ.

If, with the addition of vitalin, organs could be per-used and maintained viable for weeks or months, theossibilities are fascinating. Organ banking for trans-lantation would be possible. Immunomodulation ofonor organs and precise matching to recipients woulde possible. Evaluation and treatment of perfused organsould ensure transplantation of organs with perfect

unction. Without the need for immunosuppression,ransplantation would be not only feasible but also anveryday treatment for genetic conditions such as hemo-hilia or diabetes mellitus by spleen or pancreas trans-lantation. Autologous organs could be removed forreatment until the organ returned to normal, then re-mplanted (in isolated kidney or lung cancer, for exam-le). Neoplasms could be grown in organ culture tovaluate responsiveness to therapeutic intervention. Thehysiology, metabolism, biochemistry, and moleculariology of specific organs and cells could be studied andharacterized at leisure and in human tissue without theeed for animal subjects for these experiments. Organanks could be used to produce the products of normalrgans in great quantities with no infection or other riskssuch as the production of all the components of humanlood, for example). So the pursuit of this hypotheticalormone is a worthwhile endeavor.In conclusion, in the absence of a live brain, organs in

ventilated heart-beating cadaver or in an isolated per-usion system follow an unpreventable sequence of dys-unction and failure. We propose that evidence and the-ry suggest that this phenomenon is caused by the lackf a hormone secreted in the midbrain, which we havealled vitalin.

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