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Observations done in well managed brain-dead organ donors on ventilatory support, and the fine tuning of the acid-base balance in whom irreversible loss of the brain has occurred, will inevitably lead to a progressive dysfunction of all organs. Ventricular fibrillation will be the terminal event. Once brain death was established, 62% suffered cardiac arrest within 24 hours and 87% by the end of 72 hours.1

Continuous improvement of solid organ transplantation procured from brain-dead beating heart organ donors resulted in an increasing demand of this commodity. The current organ donor pool no longer can meet the continuously expanding demand and approximately 30% of cardiac, liver, lung, heart/lung and 7% of renal patients, will die or deteriorate further. They will be deemed unsuitable for transplantation before a donor organ becomes available.2 The outcome of a transplanted marginal donor organ in a marginal recipient has the worst survival provided the quality of the donor organ is improved before harvesting from the brain-dead organ donor. This is of great relevance for organs from which immediate function is required, such as the heart or liver.

The complexity of brain death induced organ injury is multifactorial. Patients who will become brain-dead and eventual organ donors will undergo a variety of traumatic events such as direct tissue/organ injury, hemorrhagic shock, excessive inotropic support, hypoxia, variety of blood products and crystalloid transfusions, infections, nutritional starvation. etc. These events, and the primary brain injury, may contribute or precipitate the death of the brain. The major source of donor organs will be from patients dying of head injury or spontaneous intracranial

Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience hemorrhage.2 The multiple noxious events may vary in severity and duration. Whatever the precipitating event that leads to brain death, two sets of injury will impact the body as a whole: a) an autonomic storm3 (parasympathetic and sympathetic) lasting from minutes to hours4 and b) a rapid disintegration of the hypothalamic-hypophyseal axis, endocrine collapse3 (cortisol, thyroid hormones, insulin, anti-diuretic hormone and others), which will result in progressive inhibition of cellular metabolic aerobic pathways and diabetes insipidus lasting from hours to days.

Organs such as the heart, procured from unstable brain dead organ donors dependent on dopamine in excess of 20-30 mcg/kg/min, may have poor functional outcome in the recipient. This is due to further cellular injury that will occur during the cold preservation time followed by reperfusion tissue injury in the recipient. The described additive detrimental events may result in an organ requiring further inotropic or mechanical support, or result in primary graft failure thus compromising further a successful outcome of the transplanted organ in the recipient. Understanding the mechanisms of organ injury in the brain dead organ donor and in the recipient will allow timely pharmacological and endocrine intervention, reversal of correctable conditions and prevention of metabolic abnormalities in the potential brain dead organ donor. This will result in a well-functioning organ in the recipient, not only enlarging the donor organ pool but improving the survival following transplantation.

The Autonomic Storm

In experimental animal models of brain death, a sudden increase of the en-docranial pressure3 or acute brain ischemia4 are associated with an Autonomic storm involving the parasympathetic and sympathetic systems (Fig. 3.1). The well recognized Cushing's reflex is part of the initial response as endocranial pressure increases.5

The continuous hemodynamic and electrocardiographic monitoring done in baboons over 24 hours has shown initial significant changes, during which the sympathetic activity impacts the entire body. There is a significant release of endogenous and circulating plasma catecholamines.3 The adrenergic activity is manifested on the cardiovascular system at the level of beta and alpha receptors. The cardiac activity clearly expresses these initial effects of the Autonomic storm,6 and the consequences of calcium-induced injury are observed on light and electron microscopy.

Electrocardiographic Changes

The continuous electrocardiographic (EKG) monitoring done in baboons before, during and following the induction of brain death, clearly shows the various stages of the autonomic activity.3

Initially, there is a marked parasympathetic activity (Stage I). This is characterized by sinus bradycardia, sinus stand still, asystole, junctional escape beats and a combination of A node, bundle of His and fascicular bundle conduction blocks. As this initial period progresses into the next stages, the sympathetic activity pre

Fig. 3.1. Plasma catecholamines in the experimental animal measured prior to induction of brain death (BD). There is a significant increment following induction of endocranial hypertension, by 2 h neoepinephrine plasma levels fell below control values.

Fig. 3.1. Plasma catecholamines in the experimental animal measured prior to induction of brain death (BD). There is a significant increment following induction of endocranial hypertension, by 2 h neoepinephrine plasma levels fell below control values.

dominates resulting initially in sinus tachycardia without ischemic changes (stage II). Stage III is characterized by the development of unifocal and multifocal ventricular ectopic activity and runs of ventricular tachycardia. During stage IV, sinus rhythm resumes again manifesting now marked acute ischemic changes (Fig. 3.2), ST segment abnormalities and development of Q waves. Stage V starts at the time of recovery of the ST segments and the phase out of the sympathetic overactivity. The heart is in sinus rhythm. Nonspecific ST changes, QRS abnormalities, and flattening or biphasic T waves are noted.7

The autonomic overactivity is initially vagus-mediated, followed by endogenous catecholamine release from sympathetic nerve endings. In baboons, bilateral surgical vagotomy performed before induction of brain death prevents all EKG changes observed in stage I. The bilateral surgical ablation of the sympathetic ganglia abolishes the tachycardia, the EKG ischemic changes observed during stages II-IV, as well as the final QRS and ST-T changes previously described in stage V.8 Animal pretreatment with beta blockers and calcium blockers prior to the induction of brain death9 also resulted in complete prevention of the EKG stages II-V. This obviously will have relevance in the pharmacological management of potential organ donors.

Hemodynamic Changes

Systemic and pulmonary hemodynamic monitoring correlate well with the autonomic overactivity.3 At the systemic level, the initial parasympathetic activity

Fig. 3.2. Transient electrocardiographic acute ischemic changes during the induction of brain death in the baboon observed at the peak of the systemic vascular resistance (SVR), resembling an acute myocardial infarction. As the SVR normalizes the Q waves and ST changes recover.

is short lived. This is mainly manifested by hypotension. As the massive catechola-mine release occurs, the muscular arterioles constrict, the arterial blood pressure (BP) significantly rises as well as the systemic vascular resistance (SVR), and the observed acute increment of the heart rate results in a marked increment of the heart work. The left ventricle (LV) is unable to overcome the acute work load and global LV failure occurs which is manifested by a drop of the cardiac output (CO), elevation of the end-diastolic pressure (LVEDP), pulmonary wedge pressure (PCWP) and dilatation of the LV cavity10 (Fig. 3.3).

In the pulmonary circulation, the consequences of acute LV failure are manifested by rapid elevation of the pulmonary artery (PAP) pressure. However, this does not exceed the left atrial pressure. The large compliance of the pulmonary circulation rapidly accommodates and pools the systemic blood returning to the right atrium. Thus, there is a temporary increase of the PA flows while the systemic CO is transiently reduced. These systemic and pulmonary changes are observed at the peak of the SVR. Furthermore, the rapid work increment induced by the excessive sympathetic activity induces inadequate subendocardial oxygen delivery to match the demand. This is clearly evident during EKG stages III-IV. Furthermore, the acute subendocardial ischemia and LV dilatation may induce acute mitral valve regurgitation, which may explain the significant elevation of the LA pressure. Recovery of this abnormal hemodynamic status is rapid and may well explain one of the possible mechanisms of neurogenic pulmonary edema observed in head injury, in which the PCWP is normal at the time of the patient examination.10

Fig. 3.3. Systemic and pulmonary hemodynamic response to induction of experimental BD. There is a significant increment of the systemic vascular resistance (SVR) and of the arterial pressure (MAP), resulting in the left ventricular failure. The aortic (AO) flow falls markedly while the pulmonary artery blood flow recovers rapidly and exceeds the AO flows. This results in blood pooling in the lungs. At the peak of the SVR, the left atrial pressure exceeds the pulmonary artery pressure, possibly as a result of LV failure and mitral valve regurgitation inducing pulmonary capillary disruption.

Fig. 3.3. Systemic and pulmonary hemodynamic response to induction of experimental BD. There is a significant increment of the systemic vascular resistance (SVR) and of the arterial pressure (MAP), resulting in the left ventricular failure. The aortic (AO) flow falls markedly while the pulmonary artery blood flow recovers rapidly and exceeds the AO flows. This results in blood pooling in the lungs. At the peak of the SVR, the left atrial pressure exceeds the pulmonary artery pressure, possibly as a result of LV failure and mitral valve regurgitation inducing pulmonary capillary disruption.

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