Transplantation has become universally accepted treatment of end-stage organ failure in patients meeting the criteria of its implementation. Shortage of organs for transplantation is a worldwide problem. The number of patients awaiting transplants continues to increase more rapidly than that of organ retrieval. 

Various initiatives are undertaken to break this stalemate. One of them is aggressive donor management (ADM) [1, 2], which involves early identification of a potential donor, intensive therapy instituted immediately after the brain death has been pronounced, specially trained teams. Procedures should be performed in the multi-profile unit of intensive therapy. Suitable management requires a tremendous amount of effort and expenditure. Its final effect is an increase in the number of transplantations.

The protective ventilatory strategy in potential organ donors (POPS) concerns the guidelines for mechanical lung ventilation of potential donors and involves: small tidal volumes, high PEEP, CPAP and  FIO2 0.6 during apnoea tests, alveolar recruitment manoeuvres after each disconnection of the ventilator and bronchial suctioning of the secretion using a closed system (Table 1).

Moreover, the criteria for potential organ donors have been extended. An ideal donor is often replaced with a borderline donor [3, 4]. As a result, the probability of organ failure in the early post-transplantation period is higher. It is essential to match the organ and the status as well as characteristics of a recipient. The optimal selection increases the chances of success. The final decision accepting the organs for donation is made by the transplant team after analysing the recipient’s status (degree of urgency), quality of organs and estimated time of ischaemia (distance between hospitals, time of organ implantation). The commonest exclusion criterion for hearts and lungs is their impaired function [5].

Pronouncement of brain death and confirmation of potential possibility to collect organs should provoke actions to optimize organ functions and to prepare suitable conditions for their acquisition and transplantation [6].

The causes of organ shortage are complex [7]. The family approval is relevant; the cultural and psychological barriers have to be overcome. In this respect, the effective initiative of artistic circles is worth stressing. The actors of the “Stary” theatre in Krakow supported by clinical psychologists organize national trainings in the field of contacts with donor’s families. Another important element is the presence of an experienced, well-trained coordinator with a team of professionals dealing with the procedure logistics. Each transplantation centre has a specialist in transplant coordination. “Poltransplant” has been carrying out trainings in this field for years. Criteria of organ qualification need to be systematized. They are determined by individual transplantation centres, which base on their own experience. An extremely relevant part of actions aiming at successful transplants is the management of donors; this management also has to be standardized.

The information which should be provided already during the first phone contact between the transplantation centre and the hospital notifying a potential donor is his/her blood group, body weight, height and circumference of the thoracic cavity.  These data are necessary for selection of an appropriate recipient. In heart transplants, the difference between the donor and recipient body weight should not exceed 20%. If a recipient has pulmonary hypertension, the bigger heart from an older donor is selected. The height and chest circumference determine the selection of lung recipients.

A potential donor is a patient in whom brain death has been pronounced. Progressive ischaemia of CNS leads to systemic disturbances [8]. Ischaemia of the mesencephalon causes parasympathetic activation and sinus bradycardia. Ischaemia of the pons results in excessive sympathetic stimulation and hypertension (Cushing’s reflex). Abnormalities in blood supply to the medulla oblongata enhance the tension of the sympathetic system, which coexists with inhibition of baroreceptor reflexes. Sympathetic stimulation results in high concentrations of circulating endogenous catecholamines [9]. The “vegetative storm” is the cause of vasoconstriction, hypertension, tachycardia and negative oxygen balance of the myocardium. The spasm of coronary vessels prevents oxygen supply to the myocardium, which results in subendocardial ischaemia, myocytolysis, necrosis of contractile proteins, subendocardial haemorrhages, oedema, and leucocyte infiltrations.  The excessive amounts of calcium ions accumulate in the myocardial cells, which induces impaired production of ATP and accumulation of active oxygen species. The period of intensive sympathetic activation is followed by decreased tonus of the vegetative system, reduced vascular resistances and hypotonia. The brain death is accompanied by arrhythmia and conduction abnormalities, which result from decreased tonus of the vagus nerve, excessive sympathetic stimulation, myocardial ischaemia, electrolyte disturbances and the therapy used.

Lung dysfunction is also associated with brain death, often preceded by its severe trauma. The causes of lung dysfunction involve inflammatory infiltrations, aspiration of gastric content, neurogenic oedema or trauma. The “vegetative storm” stimulates an increase in pulmonary bed pressure and damage to the vascular endothelium. The circulating mediators of the inflammatory reaction increase the permeability of lung capillary endothelial cells. Excessive fluids due to the therapy administered enhance pulmonary oedema.

Moreover, brain death induces hormonal disturbances involving hypophysis failure, which leads to diabetes insipidus developing in 80% of donors. Furthermore, triiodothyronine deficiency develops due to abnormal TSH secretion and thyroxin metabolism (T4). The decreasing concentrations of insulin and cortisone are observed, which prevents physiological reactions to trauma. The dysfunction of hypothalamus leads to hypothermia enhanced by dilation of peripheral vessels.

The actions to prepare organs for transplantation focus on restoration of homeostasis under brain death conditions. The therapy involves mainly supplementation of intravascular volume, maintenance of heart function and vascular tension in order to provide optimal blood supply to the organs.

In short, the management of multi-organ donors should involve:

1 – haemodynamic monitoring and correction of therapy stabilizing the cardiovascular system,

2 – hormonal therapy,

3 – mechanical lung ventilation together with procedures to prevent pneumonia.

Standard monitoring includes 12-lead ECG, direct measurements of arterial pressure and central venous pressure. The goal is to maintain MAP >70 mm Hg, SAP > 100 mm Hg, HR 60-120 min-1 and CVP 6-10 mm Hg. To stabilize haemodynamic parameters, dopamine or dobutamine should be used in the dose < 10 µg kg-1 min-1.

Initial assessment of myocardial blood supply is based on ECG findings. Each multi-organ donor should undergo 2D echocardiography. If the ejection fraction of the left ventricle is found to be ≤45%, monitoring should be widened with invasive measurements of haemodynamic profile. The Swan-Ganz catheter should be placed in the pulmonary artery.

Further management of the donor is to normalize the following parameters:

• PAWP – 812 mm Hg,

• CI >2.4 L m-2,

• SVR- 800 – 1200 dynes s cm-5.

The first line drug in cases of low vascular resistances is vasopressin. Before the drug is popularized in our country, vasoconstricting effects of noradrenalin may be used. Moreover, adrenaline in the dose < 0.2 µg kg-1 min-1 can be administered. Optimal vascular bed filling enables the reduction in the catecholamine doses. An extremely relevant element of management is active superficial warming (duvets with regulated airflow temperature) and warming of infusion fluids. In lung donors, the intravascular volume is supplemented with albumins (5% or 20% depending on filling parameters). The electrolyte balance should be maintained. Hypernatraemia (>155 mmol L-1) causes liver dysfunction after transplantation. The concentration of haemoglobin should be maintained within the range of 5.6-6.2 mmol dL-1 the minimal acceptable value is 4.3 mmol L-1. The additional parameters to assess the donor’s preparation is the concentration of lactates and saturation of mixed venous blood (>60%) [10].

While planning the heart retrieval, repeated determinations of troponin levels are recommended [11]. Its elevated levels evidence myocardial damage and result in its dysfunction after transplantation. The concentration of troponin should be known during the selection of recipients (information for the transplantation team). The value significantly exceeding the norm is the risk factor of postoperative cardiac failure, especially if it coexists with long-term ischaemia (> 4 h).

Mild hypertrophy of the left ventricular muscle is not a contraindication for heart donation. If electrographic features of the left ventricular hypertrophy are observed, heart retrieval is not recommended [12]. If coexisting coronary atherosclerosis is suspected and coronarography decided, acetylcysteine and sodium bicarbonate should be administered to prevent post-contrast renal failure [8]. This kind of management does not exclude the possibility of kidney transplants.

Brain death induces dysfunction of the distal pituitary lobe, whose clinical symptom is diabetes insipidus. Hypoactivity of the frontal pituitary lobe causes deficiencies in TSH, ACTH and growth hormone. The clinical consequences are low concentrations of thyroid hormones and cortisol. In the hormonal therapy of donors, steroids, thyroid hormone and desmopressin (analogue of vasopressin stimulating V2 receptors) are used.

Steroids inhibit the release of cytokines in brain death. Their beneficial kidney, heart and lung effects were documented based on observations of the function of transplanted organs during the first post-transplant year. Methylprednisolone is recommended in the dose of 15 mg kg-1 every 24 h [9, 13].

The administration of thyroid hormones enables to reduce the doses of catecholamines, stabilize the systemic pressure, decrease CVP and improve CO. Haemodynamic stabilization improves oxygen balance of organs prepared for transplantation [9, 10]. Triiodothyronine (T3) is characterized by quick onset of action; its availability does not change with the donor status. Thyroxine (T4) requires conversion into its active form. The reaction is unpredictable in time due to altered environment (e.g. catecholaminaemia). The infusion of triiodothyronine 3 µg h-1 should be preceded by the initial dose of 4 µg. Doses of T4 should be respectively higher - 10 µg h-1 and 20 µg [10].

Vasopressin acts through three types of receptors. V1 are located in the blood vessels. Their stimulation results in increased tension of vascular walls and elevated pressure. Antidiuretic effects of vasopressin are regulated by V2 receptors. The stimulation of V3 receptors leads to the release of ACTH. The vasopressin analogue (arginine vasopressin) selectively activates V2 receptors; its action lasts 6-20 h. It is used intravenously in the doses 2-6 µg every 6-8 h. Its administration is likely to prevent diabetes insipidus, which may destabilize the haemodynamic status of the donor. Vasopressin is used in a wide range of doses (0.5-15 U h-1); the consequences of its use, i.e. coronary, renal, visceral vasoconstriction should be taken into consideration [8].

A common symptom accompanying brain death is elevated concentration of blood glucose resulting from insulin resistance. The level of glucose should be maintained at 4-8 mmol L-1 [12].

If haemodynamically unstable donors improve after the institution of hormonal therapy, filling of vascular bed, restoration of proper body temperature and morphology, the doses of catecholamines may be reduced.

The decision of organ retrieval should be preceded by observation of the donor status for about 2 h followed by haemodynamic tests (full profile) and echocardiography. CO and contractility are adequately assessed if SVR values (800-1200 dynes s cm-5) and cardiac index are normal (Fig. 1).

It is worth stressing that kidneys from multi-organ donors (including the heart) are characterized by markedly lower percentage of their dysfunction in the remote post-implantation periods [14].  Normal function of the organ is likely to result from optimal haemodynamic status of the donor and proper perfusion of organs for transplants.

Due to shortage of lungs for transplantation and increased mortality rates among patients awaiting transplants – borderline donors are accepted - aged above 55 years, those addicted to tobacco for more than 20 years or treated with ventilators for > 5 days [15, 16]. The guidelines of potential donor lung ventilation were presented in Table 1. The mixture of respiratory gases should be moistened and warmed. Ventilator-associated lung damage is more common when the peak inspiratory pressures exceed 30 cm H2O. The management of lungs for retrieval requires a series of arterial blood gasometry, lung X-ray films and bronchoscopy. To prevent aspiration, the donor is positioned with the bed head elevated (30-45o); frequent aspiration of oral secretion is recommended. The pressure in the tightly inflated cuff should be higher than 25 cm H2O. The respiratory secretion should be aspirated using a closed system. Regular manoeuvres of alveolar recruitment and body position changes (lateral recumbent position) are recommended. Alveolar recruitment involves periodic use of PEEP, 15 cm H2O or 30-60-second lung ventilation with peak pressures of 30 cm H2O [10]. According to some pulmonologists, in cases of low oxygenation ratios (PaO2:FIO2) and presence of X-ray lung infiltrations, pressure-controlled ventilation 25 cm H2O should be applied combined with PEEP 15 cm H2O over 2 h [17]. After such a recruitment, they use typical ventilation; after further 30 min, lung X-ray and gasometry are repeated. The therapy is accompanied by restricted intravenous supply of crystalloids and attempts to achieve negative fluid balance (diuretics may be used in well-documented cases). The vascular bed volume is supplemented with colloids (albumins 20%). It is obligatory to perform microbiological tests of the tracheal aspirates and to administer target antibiotics. Bronchoscopy should be carried out early and samples from bronchial lavage sent for bacteriological tests. Empiric broad-spectrum antibiotic therapy ought to be instituted in donors at high risk of pneumonia.

The presence of purulent secretion in the airways is not an absolute contraindication for organ collection. Abundant purulent secretion in the bronchial tree, which cannot be completely removed on bronchoscopy, or aspiration features determine the disqualification of lungs. The contraindications for lung retrieval include bilateral infiltrations in the thorax found on X-ray examinations, which persist despite intensive therapy. Unilateral infiltration enables the retrieval of the other lung (Fig. 2).

Lungs unsuitable for transplantation on notification, respond to intensive therapy procedures administered to the donor (ventilation, steroids, dehydration, physiotherapy); the parameters, which decide about the change of qualification improve. The prerequisite on decision taking is PaO2:FIO2  ratio > 300 [16]. The final decision is made by the surgeon retrieving the organ after direct assessment of lungs in the surgical field.

ATYPICAL SITUATIONS

The disseminated intravascular coagulation (DIC) syndrome develops in 23-41% of donors whose brain death resulted from cerebro-cranial trauma [18]. DIC following severe injuries is likely to self-limit and does not induce damage to the organs. Patients with the history of DIC and normal clotting parameters on organ acquisition may be the donors of the heart and lungs. The extended criteria also include bacteraemia. There is no evidence that pathogens permeate into the recipient’s organism [19]. Our experience shows that in such situations, the recipient should immediately receive a targeted antibiotic effective against the pathogen detected in the blood culture of the donor.

The introduction of intensive therapy of the donor may markedly decrease the number of organs disqualified for retrieval. The number of transplants may also be increased by administration of therapy according to accepted standards of management. The team of specialists managing the donor may limit the mortality of recipients awaiting transplantation and prevent an increase in disproportion between availability and demands for transplantation organs. The national crisis in the field of transplantology is likely to be obviated thanks to systematized actions.

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REFERENCES

1.    Salim A, Martin M, Bron C, Rhee P, Demetriades D, Belzberg H: The effect of a protocol of aggressive donor management: implications for the national Organ Donor Shortage. J Trauma 2006; 61: 429-435.

2.    Salim A, Velmahos GC, Brown C, Belzberg H, Demetriades D: Aggressive organ management significantly increases the number of organs available for transplantation. J Trauma 2005; 58: 991-994.

3.    Rosengard BR, Feng S, Alfrey EJ, Zaroff JG, Emond JC, Henry ML, Garrity ER, Roberts JP, Wynn JJ, Metzger RA, Freeman RB, Port FK, Merion RM, Love RB, Busuttil RW, Delmonico FL: Report of the Cristal City Meeting to maximize the use of organs recovered from the cadaver donor. Meeting report. Am J Transplant 2002; 2: 701-711.

4.    Bhorade SM, Vigneswaren W, McCabe MA, Garrity ER: Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart Lung Transplant 2000; 19: 1199-1204.

5.    Hornby K, Ross H, Keshavjee S, Rao V, Shemie SD: Non-utilization of hearts and lungs after consent for donation: a Canadian multicenter study. Can J Anesth 2006; 53: 831-837.

6.    Ullah S, Zabala B, Watkins B, Schmitz ML: Cardiac organ donor management. Perfusion 2006; 21: 93-98.

7.    Mascia L, Bosma K, Pasero D, Galli T, Cortese G, Donadio P, Bosco R: Ventilatory and hemodynamic management of potential organ donors: an observational survey. Crit Care Med 2006; 34: 321-327.

8.    Kutsogiannis DJ, Pagliarello, Doig Ch, Ross H, Shemie SD: Medical management to optimize donor organ potential: review of the literature. Can J Anesth 2006; 53: 820-830.

9.    Smith M: Physiologic changes during brain stem death – lessons for management of the organ donor. J Heart Lung Transplant 2004; 23: 217-222.

10.    Shemie SD, Ross H, Pagliarello J, Baker AJ, Grieg PD, Brand T, Cockfield S, Keshavjee S, Nickerson P, Rao V, Guest C, Young K, Doig Ch: Organ donor management in Canada: recomendations of the forum on medical management to optimize donor organ potential. CMAJ 2006; 174: 13-30.

11.    Potapov EV, Ivanitskaja EA, Loebe M, Mockel M, Muller Ch, Sodian R, Meyer R, Hetzer R: Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure. Transplantation 2001; 71: 1394-1400.

12.    Zaroff JG, Rosengard BR, Armstrong WF, Babcock WD, D Alessandro A, Dec GW, Edwards NM, Higgins RS, Jeevanandum V, Kauffman M, Kirklin JK, Large SR, Marelli D, Peterson TS, Ring WS, Robbins RC, Russell SD, Taylor DO, Van Bakel A, Wallwork J, Young JB: Consensus Conference Report. Maximizing use of organs recovered from the cadaver donor: cardiac recommendations. Circulation 2002; 106: 836-841.

13.    Rosendale JD, Kaufman HM, McBride MA, Chabalewski FL, Zaroff JG, Garrity ER, Delmonico FL, Rosengard BR: Aggressive pharmacologic donor management results in more transplanted organs. Transplantation 2003; 75: 482-487.

14.    Rosendale JD, Chabalewski FL, McBride MA, Garrity ER, Rosengard BR, Delmonico FL, Kauffman HM: Increased transplanted organs from the use of a standardized donor management protocol. A J Transplant 2002; 2: 761-768.

15.    Straznicka M, Follette DM, Eisner MD, Roberts PF, Menza RL, Babcock WD: Aggressive management of lung donors classified as unacceptable: exellent recipient survival one year after transplantation. J Thorac Cardiovasc Surg 2002; 124: 250-258.

16.    Aigner C, Winkler G, Jaksch P, Seebacher G, Lang G, Taghavi S, Wisser W, Klepetko W: Extended donor criteria for lung transplantation – a clinical reality. Eur J Cardiothorac Surg 2005; 27: 757-761.

17.    Angel LF, Levine DJ, Restrepo MI, Johnson S, Sako E, Carpenter A, Calhoon J, Cornell JE, Adams SG, Chisholm GB, Nespral J, Roberson A, Levine SM: Impact of a lung transplantation donor-management protocol on lung donation and recipient outcome. Am J Respir Crit Care Med 2006; 174: 710-716.

18.    Valdivia M, Chamorro C, Romera MA, Balandin B, Perez M: Effect of posttraumatic donors disseminated intravascular coagulation in intrathoracic organ donation and transplantation. Transplant Proceedings 2007; 39: 2427-2428.

19.    Teperman LW: Transplantation. J Am Coll Surg 1999; 188: 184-190.

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Address:

*Ewa Kucewicz-Czech
Oddział Kliniczny Kardioanestezji
 i Intensywnej Terapii Śląskiego UM
ul. Szpitalna 2, 41-800 Zabrze
tel.: 0-32 3733724, tel./fax 0-32 273 27 31
e-mail kardanest@sum.edu.pl

Received: 25.03.2009
Accepted:15.05.2009