Abstract
Organ transplantation is now an accepted and widespread treatment of otherwise fatal organ failure. Living organ donation is the optimal pathway but with the least capacity to meet needs. Donation after death is the norm, but there are inadequate numbers of available donors. Transplantable organs suffer diverse insults from primary injury, iatrogenic causes, and secondary pathophysiological processes initiated by death. These insults can be mitigated with attentive critical care of oxygenation and perfusion. Hormonal replacement is a specific component of organ donor care with a theoretical and observational basis but which is challenged by inadequate class 1 evidence. New technologies are evolving in organ extracorporeal perfusion, which may allow reconditioning and more selective treatment strategies.
Keywords
Brain death, Catecholamines, Hormonal resuscitation, Living donors, Organ donation, Transplantation
Introduction
Organ donation has matured into a viable therapeutic option within the past 60 years. While initial attempts at transplantation were quickly compromised by rejection, growing understanding of immunological mechanisms facilitated successful transplantation and attenuation of the host versus graft response.
The first durably successful transplant procedure was carried out between living monozygotic twins, but following the development of pharmaceutical agents to suppress and subvert the immune response, donation from individuals to recipients with closely matching (rather than identical) HLA profiles became a reality.
Unfortunately, successful transplants are dwarfed by the numbers of patients awaiting transplantation, as well as the number added to the list annually.
This deficit results in 22 deaths per day in the United States for patients awaiting transplant. Other countries are similarly challenged. The statistic emphasizes the need for education and awareness, to maximize opportunity.
Donation can occur from either living or deceased patients with very distinct and separate processes and requirements.
Living Organ Donation
As mentioned, living organ donation was the means by which transplantation was demonstrated to be a viable therapeutic option, and it remains true that living donor organs provide the greatest efficiency in graft function. Current transplantation practices include:
- 1.
Single kidney
- 2.
Liver—left lateral section—from adult to small child
- 3.
Liver—right lobe—from adult to older child or small adult
- 4.
Liver—left lobe—from adult to another adult
- 5.
Isolated lobe of lung (from 2 separate donors) to single recipient
From the anesthetic perspective, living donation is predominantly an exercise in screening and counseling, with little to make anesthesia for this surgical procedure distinct from anesthetic management for resection of any organ pathology. Given known risks to the donor from the surgical procedure, as well as diminished functional reserve, there should be particular emphasis on fully informed consent. This is keenly relevant in the context of over 75% of living donation occurring between family members.
Donation After Death
Organ transplantation from the dead to the living is the predominant paradigm for organ transplantation worldwide. Common throughout is the need for clear separation of the process of declaration of death from the process of procurement.
All patients dying in the intensive care unit should be considered as possible donor candidates once the circumstance of impending death or its diagnosis have been realized. While there are some key disqualifiers ( Table 53.1 ) based largely on the risks of transmission of malignancy or infectious disease, the responsibility for rejecting a donor should reside with the organ procurement agency charged with evaluation of regional need and placement, rather than with the institutions referring donors.
| Active Tuberculosis and Rabies Aspergillus | Hodgkin Disease, Some Leukemias Multiple Myeloma |
| Human immunodeficiency virus infection | Miscellaneous carcinomas |
| Creutzfeldt–Jakob disease | Aplastic anemia |
| Herpetic septicemia | Agranulocytosis |
| Hepatitis B surface antigen positive | Fungal and viral meningitis |
| Rabies | Viral encephalitis |
| All retrovirus infection | Malignant neoplasms, except primary central nervous system tumors and some skin cancers |
| Melanoma (lifetime history) | Aspergillus |
Two main pathways are recognized for the diagnosis of death with distinct implications for management.
Management of Donation After Declaration by Neurological Criteria (Brain Death)
This concept arose as a consequence of the development of the critical care unit, where the subsequent ability to maintain ventilation and circulatory function after neurological devastation by injury or disease, led to increasing numbers of patients limiting access to scarce resources. At the same time, there was growing recognition of the inherent advantages to transplantation in organ procurement from a donor with heart beating. The essence of the diagnosis of death by neurologic criteria is founded on a state of coma and the direct assay of afferent/efferent reflex loops mediated primarily through the brain stem. This examination also requires the exclusion or correction of confounding physiologic abnormalities of temperature, hypoxia, hypotension, and electrolyte imbalance, which might otherwise obtund or inhibit the response to stimulation of the cranial nerves and respiratory center. The history and presentation must support the diagnosis, supplemented by appropriate imaging of the central nervous system.
The detailed mechanics of diagnosis are well described elsewhere.
Pathophysiology After Brain Death
There are evident inflammatory consequences of neurological injury apparent in the perimortem period, with demonstration of cytokine release and complement activation as a result of both primary injury and secondary ischemia ( Table 53.1 ).
The cardiopulmonary system may initially be challenged by the sympathetic reflex of intracranial hypertension but subsequently takes the brunt of exposure to drainage of cerebrally derived cytokines, with consequent dysfunction.
The active inflammatory process may be coupled with iatrogenic insult induced by treatments for neurologic injury, e.g., osmotherapeutic agents causing circulatory volume depletion, alkalosis consequent to hyperventilation, tachycardia, and hypertension as a result of inotropic augmentation of cerebral perfusion.
These insults are augmented by the deficit in cerebrally mediated homeostatic mechanisms that follows brain death. The summary effect to the potential donor is strikingly similar to the patient with severe shock and multiorgan failure ( Table 53.2 ).
| Component of Brain Death | Physiological Mechanisms | Pathological Consequence |
|---|---|---|
| Damaged brain tissue | Release of IL-1, IL-2, IL-4, IL-8, IL-10, IL-12, IFN- γ , PAF, TNF-α, TGF-β | Platelet malfunction/endothelial activation/inflammation/coagulopathy |
| Hypothalamic/pituitary ischemia and dysfunction | Thermoregulatory dysfunction | Hypothermia |
| Mesencephalic ischemia | Diabetes insipidus | Hypovolemia |
| Spinal cord ischemia | Vasoplegia | Hypotension |
| Pontine ischemia | Oscillating sympathetic/Parasympathetic activity | Arrhythmia |
| Brain stem ischemia | Catecholamine “Storm” | Hypertension/myocardial stunning |
At this stage, successful organ procurement exquisitely depends on the quality of resuscitation, with over 80% of donors requiring active intervention to maintain physiological stability.
Even with intervention, 25% of possible donors are lost prior to procurement as a consequence of hemodynamic instability, reducing organ viability via hypotension and/or hypoxia.
Myocardial injury and dysfunction are common, with 30% of adults demonstrating a significantly reduced ejection fraction. This can improve if given the time. The same phenomenon is observed in up to 38% of pediatric donors, suggesting that the causative mechanism is independent of coexisting ischemic heart disease.
Earlier suggestions that adrenoreceptor polymorphisms were related to myocardial dysfunction have not been validated in larger series.
Lung function is often negatively affected by the primary insult and subsequent death, with a decrease in pulmonary vascular resistance, increased pulmonary blood flow, and an increase in lung water. However, as in any critical care setting, donor lungs may also be affected by passive atelectasis, as well as infection as a consequence of either hypostasis or aspiration at the time of primary injury. One retrospective case series identified a higher incidence of lung infection after the use of hypertonic saline for the treatment of cerebral edema.
Liver function is sensitive to hypoxia, hypotension, and hypernatremia, although some have challenged the last of these conditions. Explanted livers from donors declared by neurologic criteria have increased inflammatory expression and leukocyte infiltration as opposed to those livers from donors after circulatory death.
Kidney injury is also vulnerable to systemic challenges of oxygen delivery but may also be adversely impacted by premortem contrast studies to evaluate cerebral circulation, as well as the dehydration of diabetes insipidus or mannitol administration.
Electrolyte abnormalities are common after brain injury but are usually resolved to exclude confounding during the process of brain death diagnosis. Perimortem stress catabolism induces hyperglycemia, which with accompanying reduced insulin secretion enhances further diuresis and hyperglycosuria. Adrenal function is also depleted in up to 76% of patients after brain death. Free triiodothyronine (T3) and its prohormone thyroxine (T4) also decrease significantly, with consequent increase in anaerobic metabolism and depletion of mitochondrial ATP regeneration. The deficit in high-energy phosphates impairs myocardial contractility.
Management of the Brain Dead Donor
Despite the impact of inflammatory changes on donor physiology, there are no currently credible mechanisms for pharmacologically inhibiting or antagonizing the development of the inflammatory state. Steroid therapy has been suggested to have antiinflammatory effects, but there is increasing acceptance that its effects are more in keeping with facilitation of catecholamine efficacy.
Management is therefore based predominantly on treatment of circulatory volume depletion, maintenance of cardiac contractility, and treatment of vasoplegia, with some consideration of hormonal replacement across these domains.
Having the appropriate skill base involved is crucial. Intervention by physician teams in organ donor management can materially facilitate and improve recovery of organ function, with increased opportunity for successful procurement. Contrary to some expectations, increased critical care time after declaration of death is associated with decreased risks of delayed graft function, especially in donors younger than 55 years.
Simply providing physiologic stability can allow significant improvement of ejection fraction over serially performed echocardiograms. Inotropic support may be necessary to maintain oxygen delivery over this recovery time. Cardiac output–guided optimization improves donor stability and may indeed increase the retrieval rate of hearts. Hearts may even be transplanted following cardiac arrest, provided there is adequate quality of management.
The vasoplegic state is a function of the sympathectomy of brain death, together with inflammatory dilation in response to cerebral cytokines. The consequent use of vasopressors and inotropes to mitigate those effects has demonstrated benefit with an increase in the number of organs transplanted per donor (OTPD) and graft function. Alternatively, there is evidence suggesting that a reduction in the use of pressors was also associated with improved OTPD numbers.
The ability to remove pressors may simply reflect a more stable donor; however, it seems appropriate to avoid unnecessary treatment and exposure to undesirable side effects by adopting treatment to physiological targets.
Certainly, dopamine and epinephrine are associated with more arrhythmias in the critically ill than norepinephrine or vasopressin.
Vasopressin has diverse effects via different receptors, with the V1 receptor stimulating vasoconstriction and platelet aggregation, while the V2 receptor increasing water reabsorption in the distal collecting duct, as well as increasing the release of Factor VIII and von Willebrand factor.
Used on its own, it increases the mean arterial pressure and is associated with reduced catecholamine requirement in unstable organ donors. However, systematic reviews of its efficacy in the treatment of vasodilatory shock show conflicting results. There are concerns of intestinal ischemia with higher doses, and it seems appropriate to be cautious in cases of critical visceral perfusion.
Its effective combination with glucocorticoid and thyroid hormone was first postulated by Novitzky and then popularized as part of the “Papworth Cocktail” where its use was associated with improved cardiac function and successful transplantation of hearts initially deemed unsuitable. Subsequent large case series have demonstrated increased function in transplanted hearts, lungs, livers, and kidneys, although the treatment group had less incidence of diabetes, hypertension, and death from cerebrovascular accident, and was younger with lower serum creatinines.
Glucocorticoids have biochemical effects both inducing and facilitating vasoconstriction, via a reduction in prostacyclin production, increased α-adrenoreceptor numbers, and inhibition of nitric oxide synthase. They increase catecholamine effect by upregulating β-adrenoreceptors and promoting cyclic AMP signaling within the cell.
After brain death, steroid use is associated with reduced catecholamine requirements. However, in a systematic review of effect in brain dead potential donors, 14 observational studies demonstrated improved donor hemodynamics and oxygenation status, with increased OTPD, and improved recipient and graft survival, while 10 of 11 randomized controlled trials gave only neutral results.
T3 and T4 exert affects protein transcription to increase calcium entry into the sarcoplasmic reticulum, while also directly affecting membrane ion channels. Increased heart rate and contractility result.
Similar to glucocorticoids, a systematic review listed 16 case series or retrospective audits, all of which reported beneficial effects, but failed to account for possible confounders. Conversely the seven randomized trials (four with placebo controls) reported no benefit from thyroid hormones, either alone or in combination with other therapies, although the proportion of hemodynamically unstable donors (who may be the ideal target group) was too small to exclude benefit. The authors concluded that there was no role for routine administration.
Resuscitation also requires fluid replacement to restore the volume losses previously described.
There is little to support definitive choices of fluid, apart from a strong recommendation to avoid hydroxethyl starch, which has been repetitively associated with adverse renal effects in the critically ill. Crystalloid choices should take account of an association between high serum chloride levels and increased dialysis requirements, again in critically ill patients, while the use of hypertonic saline to treat premortem cerebral edema has been associated with increased infection. There are no other clear indications to aid choice.
Transfusion to correct obvious coagulopathy can aid resuscitation, but lung injury is associated with red cell transfusion, and at this stage, it would seem appropriate to limit correction targets to that of general critical care. There are theoretical concerns on albumin disposition in transplanted lungs, given possible hyperpermeability via caveolin-1-mediated effects, but no current evidence of clinical significance.
Attention should rather be paid to balancing the effects of adequate volume resuscitation on other systems, e.g., the effect of fluid volume on lungs, and there have been increased numbers of organs procured when using treatment algorithms focused on “donor management goals,” even in older and more marginal donors.
The use of an algorithm following pulse pressure variability to optimize fluid loading did not result in any reduction in procured organs. Treating to predefined targets should reduce any inappropriate administration, while ensuring at least a basic minimum of resuscitation. Target variables are shown in Tables 53.3 and 53.4 .
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
