A complex pattern of hemodynamic changes can occur, which can rapidly progress to cardiac arrest, if untreated. Not all changes; however, are seen with every donor and factors associated with etiology of brain death, time course of the process of death and duration of support after brain death can alter the hemodynamic responses.

Cardiac dysfunction occurs after brain death due to a combination of catecholamine-mediated subendocardial ischemia during the sympathetic surge; increased intracellular calcium concentration inducing oxygen-free radicals; myocardial gene expression; and thyroid hormone depletion. Eight-nine percent of patients with no preexisting heart disease have been found to develop cardiac dysfunction following brain death [5, 6]. The role of thyroid hormone depletion remains an area of controversy; however, rapid loss of free triiodothyronine seen after brain death has been associated with depletion of ATP, increased anaerobic metabolism, and impaired cardiac contractility.

Loss of spinal sympathetic tone, cytokine, and inflammatory mediator release, and cortisol deficiency contribute to vasodilatory shock following brain stem death. Circulating cytokines and inflammatory mediators are released through three mechanisms: the sympathetic outflow surge during medullary death, necrotic brain tissue and ischemia-reperfusion injury from the hypertensive-vasoconstrictive crisis followed by a loss of vasomotor tone [7–9]. Brain death has been associated with more than 100-fold increased in concentrations of IL-6 and other inflammatory markers such as TNF and IL-10. Higher concentrations of IL-6 just prior to organ procurement has been associated with lower number of organs procured for transplantation and lower six-month hospital-free survival in recipients [10].

In addition, recruitment of leukocytes, oxygen-free radicals, and capillary leak are seen [11]. Central cortisol deficiency that results from loss of adrenocroticotropic hormone release can further potentiate the loss of vasomotor tone through down-regulation of catecholamine receptors.

Regardless of blood pressure, patients are often volume depleted. Unrecognized intravascular volume depletion due to factors before death is not uncommon and is often not manifested until loss of vasomotor tone. Blood loss associated with trauma, hyperosmotic therapy such as mannitol and third spacing of fluid in the setting of inflammatory mediators can all contribute to volume depletion. This is further exacerbated by the development of diabetes insipidus with loss of the posterior pituitary function and is seen in over 80 % of brain dead patients [3]. To further exacerbate this, hyperglycemia (from insulin deficiency or attempts to correct hypernatremia with a dextrose solution) can also result in a free water diuresis. Careful attention to volume status during donor management is crucial.

Anterior and posterior pituitary failure renders the clinical picture susceptible to further imbalances that potentiate instability. The degree of hormonal deficiency present has been a significant area of controversy and while largely supported in animal studies, has not consistently been seen in human studies [12–17].

A state of cortisol deficiency occurs after loss of release of adrenocorticotropic hormone from the anterior pituitary. Impairment in the donor’s stress response and sensitivity to catecholamines ensues following brain death. Activated inflammation leads to pro-inflammatory mediators and expression of their receptors on organs which make them more susceptible to immune-mediated injury [18] putting them at higher risk of acute rejection compared to living donors. Modulation of the immune response at the level of the donor is an area of much interest [19–23].

Diabetes insipidus occurs in over 80 % of brain dead donors [24]. The resulting inappropriate diuresis, hyperosmolality, and hypernatremia can affect the viability of potential organs. If the etiology of the shock is unrecognized, aggressive resuscitation with normal saline has the potential to worsen the hypernatremic state.

Impaired inotropy, depletion of ATP, and the development of lactic acidosis may stem from a rapid drop in free triiodothyronine levels. Impaired secretion of thyroid stimulating hormone and loss of peripheral conversion is thought to be the mechanism for depletion of free triiodothyronine.

A drop in insulin secretion results in systemic hyperglycemia, intracellular hypoglycemia, and a resulting energy deficit. This can result in a transition to anaerobic metabolism, further exacerbating a lactic acidosis that may be present from tissue hypoperfusion and thyroid depletion.

Disseminated intravascular coagulopathy and platelet dysfunction are common causes of coagulopathy seen after brain death. Necrotic tissue induces the release of thromboplastin and plasminogen activator leading to DIC in 28 % of donors [25]. In addition, microthrombus formation can be seen from stasis resulting from vasoconstriction during the sympathetic surge.

Given the central role of hypothalamus in temperature regulation, this process is disrupted following brain death. In addition, the loss of muscular activity leads to an impairment in heat production and this is process is exacerbated by the vasodilated state that ensures following spinal sympathetic outflow cessation.

Arterial hypertension occurs early during brain ischemia but is often self limited. Treatment with short acting agents such as sodium nitroprusside or esmolol are recommended in these cases [26] to keep systolic blood pressure <160 mmHg and mean arterial pressure <90 mmHg.

There has been substantial debate surrounding whether hormonal dysfunction occurs during brain death, its impact on hemodynamics and whether exogenous replacement is beneficial. The largest review to date involved a retrospective analysis of hormonal resuscitation of brain dead donors that demonstrated a greater yield in suitable organs; however, results from subsequent studies and meta-analysis call into question their role [47, 48].

Insulin administration is currently the standard of care for brain dead donors in the setting of hyperglycemia. Recommended targets vary from institution to institution with some that are more intensive than other (<180 mg/dl vs. <108 mg/dl) given the results of the more recent critical care trial evaluating intensive insulin therapy [52]. This study, which evaluated intensive vs. conservative insulin protocol found that the intensive arm was associated with a higher mortality. Interestingly; however, the primary cause of death was cardiovascular suggesting a relationship between intensive insulin therapy and cardiovascular harm. The results of a randomized controlled trial of intensive vs. conservative insulin therapy for brain dead donors to improve renal allograft function is currently underway and could better inform the optimal threshold for the care of the brain dead donor (NCT01140035, Niemann C).

To date, no directive evidence based guidelines exist on coagulopathy management specific to donor management; however, some centers aim for a platelet count of >50,000 μ1⁻¹ and an international normalized ratio <1.5. Administration of platelets and fresh frozen plasma may be warranted prior to retrieval. Alternatively, other centers will only transfuse to reverse coagulopathy in the setting of hemorrhage given the risks associated with transfusion [26, 53].

While hypothermia has the potential to be associated with adverse hemodynamic consequences including arrhythmias, myocardial suppression, cold-induced diuresis and potassium shifts, mild hypothermia may have a beneficial effect on organ preservation in the pre-retrieval phase and pilot trials are underway to examine the feasibility of therapeutic hypothermia as an-in-vivo organ preservation strategy initiated soon after brain death (NCT01680744, Niemann, C).

Ventilatory management for the brain dead donor has undergone significant evolution over the past few years as there had been a lag in the adoption of lung protective ventilatory strategies in the management of the multiorgan donor. A landmark trial by Mascia and colleagues in 2010 demonstrated a significant increase in the number of lung eligible for donation after employment of a lung protective strategy. They ventilated brain dead donors with 6–8 cc/kg, performed recruitment maneuvers after any disconnection from the ventilator, performed the apnea test on continuous positive airway pressure, and used higher positive end expiratory pressures (PEEP) over 6 h. This was compared to standard ventilatory management with tidal volumes in the range of 10–12 cc/kg. Low tidal volume and high PEEP resulted in a significant increase in donor lung eligibility and procurement [1]. The major limitations of this study; however, included that it remains unclear which particular intervention in their strategy has the greatest impact and the implication for retrieval of other organs other than lungs. If we were to extrapolate from studies of ventilator associated lung injury and its potential to worsen end organ function, one could postulate that this strategy would have the potential to improve all organs (Fig. 5.2).

Unfortunately , lungs are the most fragile organs in the multiorgan donor and most susceptible to the hostile environment of the brain dead donor. Less than 10 % of lungs are procured for transplantation. Therefore, meticulous attention to prevent iatrogenic lung injury is crucial to increase lung procurement. Fluid administration and atelectasis are two crucial reversible factors that have the potential to impair lung function. Previous studies have demonstrated that maintaining a more restrictive fluid balance, whether it be by titrating fluids to a more conservative central venous pressure measurement or extravascular lung water threshold, improve the number of organs that are eligible [43, 54].