**2. Brain death-related pathophysiological systemic disorders**

Brain death is a complete cessation of all brain functions, including the brain stem, when the etiology of brain dysfunction is known and considered irreversible. All reversible causes must be examined and excluded. The essential criteria for brain death, according to the American Academy of Neurology (AAN), are coma or unresponsiveness, absence of brain stem reflexes, and apnea. A patient determined to be brain dead is legally and clinically dead, and can be considered as organ donor in agreement with his own and his next of kin's choice [5]. Loss of central regulation leads to severe pathophysiological alterations in haemodynamics and the respiratory, inflammatory and endocrine systems [7, 8].

## **2.1 Cardiovascular changes**

The increased intracranial pressure following cerebral trauma, infarction or hemorrhage causes increased arterial blood pressure as an attempt to restore adequate cerebral perfusion. In case this fails, ischemia of pons generates a reflex response, known as Cushing reflex, with bradycardia and hypertension. The ischemic damage then progresses through the entire brain and results in sympathetic stimulation and a catecholamine storm characterized by hypertension, tachycardia, and severe peripheral vasoconstriction. A more explosive increase of intracranial brain pressure correlates with a higher increase in catecholamine concentrations. Consequently, a significant reduction in blood flow prevails despite increased systemic perfusion pressure, and leads to visceral and myocardial ischemia [8, 9]. Observations in brain-dead donors show evidence of myocardial ischemia on echocardiographic exam [10, 11].

The initial phase of a catecholamine storm is followed by a loss of sympathetic tonus and profound vasodilation due to ischemia of the brain stem vasomotor nuclei. Many factors contribute to hypotension, including vasodilatation, catecholamine depletion, myocardial dysfunction, relative hypovolemia, and endocrine dysfunction. Hypoperfusion further deteriorates organ integrity and, together with a catecholamine explosion, leads to deleterious consequences for potential grafts if left untreated.

### **2.2 Pulmonary changes**

Two main complications related to brain death-induced lung injury and dysfunction are neurogenic pulmonary edema and inflammatory acute lung injury. Donors may also have specific pulmonary damage, including aspiration, atelectasis, contusion, chest trauma, or infection [12]. Volume overload after fluid resuscitation, also due to profound hypotension, increases the risk of pulmonary edema [8].
