Positive end-expiratory pressure (PEEP) can cause numerous physiologic changes. These changes may take place in the lungs, with respect to intrathoracic pressures and lung compliance, and in cardiac output. Clinical observation has also demonstrated for more than 30 years that PEEP can increase intracranial pressure (ICP). Animal and some human data have supported two theories about how this increase in ICP takes place. By increasing intrathoracic pressure, venous return is compromised. As a result, cerebral venous blood volume increases and causes elevation in ICP. Alternatively, in a case where increased PEEP reduces cardiac output, the mean arterial pressure (MAP) may go down and necessarily lower the cerebral perfusion pressure (CPP) and if the injured brain maintains autoregulation, a decreased CPP will result in arteriodilatation, which increases total cerebral blood volume (CBV). With increased CBV comes increased ICP.

It is important to note that increased PEEP does not always translate into increased ICP. Body position can interfere with the transmission of central venous pressure. For example, in patients sitting upright (at an angle of close to 90° degrees), the jugular vein will collapse in systole and fail to transmit increased intrathoracic pressure. Alternatively, for cases of brain injuries in which autoregulation is lost, decreased CPP may not alter ICP; however, decreased CPP may lead to other problems, such as ischemia. Some evidence has shown that in lungs with normal compliance, increased PEEP transmits to increased ICP, but in lungs with low compliance, it does not.