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3 Pathophysiology of Lung Damage Following Acute Brain Injury Evolving to Brain Death
Protective Mechanical Ventilation in Brain Dead Organ Donors
The Double-Hit Model
To explain the development of organ failure associated with severe brain injury
evolving to brain death, a “double-hit” model has been proposed integrating the
above-described experimental and clinical evidence [16, 17].
The first hit is represented by the systemic consequences of the sympathetic
storm and the pro-inflammatory environment caused by brain injury eventually
evolving to brain death. Once “primed” the respiratory system is then vulnerable to
further inflammatory insults caused by mechanical stress induced by mechanical
ventilation. A vicious circle may therefore be activated: the deterioration of the
respiratory function may worsen damage of the central nervous system that will
result in distal organ failure. In this prospective, the lungs represent an organ particularly susceptible to receive further insults if mechanical ventilation is not applied
with a protective modality .
In a model of traumatic brain injury, membrane lipid peroxidation, nuclear chromatin degeneration, vacuolar degeneration of subcellular organelles, and downregulation of antiapoptotic genes have been demonstrated in type II alveolar cells [18,
19]. In a rat model of intracerebral hemorrhage, Wu and coworkers showed increased
expression of inflammatory mediators and neutrophil infiltration both in the brain
and lung . In an experimental model of ischemic stroke, lung water content was
significantly increased compared to control . Kalsotra et al. in an experimental
model of cortical impact injury found altered lung permeability, marked migration
of neutrophils, and activated macrophages in the alveolar space .
All these data led to the conclusion that the acute brain injury should induce cellular
changes and function in the lungs. Another line of research has instead focused the
attention on the role of mechanical ventilation after acute brain injury. Quilez and
coworkers demonstrated that an injurious mechanical ventilation may induce neuronal
activation in the amygdala, thalamus, and paraventricular hypothalamic nuclei in intact
animals . Heuer and coworkers showed neuronal shrinkage in the hippocampus
region of previously healthy animals with acid aspiration-induced lung injury.
In addition to these experimental studies on animal models, there are clinical
data that demonstrate the susceptibility of the respiratory system after acute brain
injury. In patients with cerebral hemorrhage, evidence of acute lung edema has been
demonstrated by extravascular lung water accumulation , while in patients
dying at the scene and within 96 h of acute brain injury, evidence of elevations in
lung weights has been shown . More recently, Mascia and coworkers demonstrated that patients with acute brain injury are more susceptible to develop respiratory failure (47 %) than a general population of critically ill patients (38 %) .
The Role of Mechanical Ventilation
The main indication for ventilatory support in patients with severe brain injury is to
treat the respiratory dysfunction consequent to cerebral damage. Under these circumstances, an adequate ventilatory setting to guarantee tight control of blood gas
C. Faggiano et al.
exchange helps in preventing secondary brain insults. However, in patients with a
diagnosis of brain death, mechanical ventilation is used to maintain gas exchange
that ensures homeostasis of the peripheral organs.
There has been increasing evidence that the mechanical forces necessary to
inflate the lung during ventilatory support can cause damage – so-called ventilatorinduced lung injury (VILI) – and this damage may worsen outcomes . This
phenomenon is more evident in pulmonary conditions characterized by a nonhomogeneous distribution of lung damage such as ARDS. In these patients it is well
established that a ventilatory strategy designed to minimize VILI by applying a tidal
volume of 6 ml/kg of predicted body weight (PBW) and plateau pressure <30 cmH2O
improves outcome . Later on, the hypothesis that VILI may occur also in “normal” lungs has been made. This hypothesis has generated some studies on the
effects of protective mechanical ventilation during general anesthesia. The major
goal was to apply the theories “of open lung approach” derived from mechanical
ventilation of patients with ARDS to organ donor lungs ventilated for a short period
To date, all these studies demonstrated that in patients who underwent mechanical ventilation for elective surgery or in the ICU, protective ventilation strategy with
low tidal volume significantly reduced mortality, pulmonary infection, and atelectasis . On the contrary, the level of optimal PEEP is still controversial.
Regarding the relationship of mechanical ventilation with brain damage, recent
experimental studies showed that VILI may also impact brain structure and function. Lung stretch-induced hippocampal apoptosis has been demonstrated in
mechanically ventilated animals with high pressure. Models of coexisting lung and
brain acute injuries show that lung damage is worsened by the copresence of brain
injury. Lopez-Aguilar and coworkers demonstrated that massive brain injury might
increase lung vulnerability to subsequent injurious mechanical or ischemia–reperfusion injuries increasing the risk of posttransplant primary graft failure . Heuer
and coworkers demonstrated that acute intracranial hypertension damaged previously normal lungs and exacerbated the damage in lungs with preexisting lesions
. Krebs and coworkers demonstrated that protective ventilation minimized lung
morpho-functional changes and inflammation in the presence of massive brain
injury compared to conventional ventilation .
Traumatic brain injury has been definitively identified as a predisposing factor
for ARDS . Recently, Rincon et al. reported that the occurrence of this complication carried a higher risk of in-hospital death after brain injury . In a prospective observational study in patients with severe brain injury, Mascia and coworkers
demonstrated that injurious mechanical ventilation was a contributing factor to the
development of ARDS and that patients with this complication were more dependent from ventilatory support and spent more days in the ICU . Similar results
were also demonstrated in potential organ donors. In an observational study conducted in 15 Italian ICUs, after diagnosis of brain death, cardiovascular management was modified to preserve peripheral organ perfusion, while ventilatory
management was not modified from a “cerebral protective” to a “lung protective”
strategy, and no maneuvers for recruiting the lung and preventing mechanical stretch
Protective Mechanical Ventilation in Brain Dead Organ Donors
were performed. Consequently during the 6 h period required by the Italian law for
brain death confirmation, 50 % of potential lung donors became ineligible for lung
donation due to deterioration in oxygenation . These data strongly support the
notion that activation of the innate immune system after brain injury causes distal
organ injury through the release of inflammatory mediators even without macroscopic evidence of organ damage and suggest that mechanical ventilation may
affect lung function of potential organ donors predisposing to posttransplant primary graft failure. Therefore, the lungs primed by an inflammatory response elicited by brain injury could be further injured by sequential noxious stimuli leading to
lung failure and ARDS.
Ventilatory Management of Potential Organ Donors
As the number of patients waiting for lung transplantation exceeds the number of
organs available, recently several approaches have been proposed to increase them.
These are protective mechanical ventilation, expansion of donors including patients
who died after cardiac arrest, and pulmonary reconditioning techniques (EVLP)
using marginal lungs .
The technique called EVLP (ex vivo lung perfusion) uses a chamber in which the
lung of the donor to be reconditioned for 4 h during the treatment of perfusion and
ventilation is placed. Also in this case protective mechanical ventilation is proposed
(7 ml/kg PBW of the donor, FiO2 of 0.2, and respiratory rate of 7 breaths/min) with a
recruitment maneuver per hour. The lungs are considered eligible for transplantation if
at the end of four hours the lungs have a P/F ≥ 350 with a tidal volume of 10 ml/kg.
Protective ventilation applied to the donor after brain dead diagnosis is at the
moment the approach proposed mainly to the ideal donors to preserve their function.
The standards for donor lung transplantation are represented by a person with
age <55 years, the PaO2/FiO2 ratio >300, nonsmoker or former smoker for at least
20 years, a negative chest X-ray for pulmonary condensations, absence of purulent
pulmonary secretions, and negative microbiological tests [37, 38].
In donors who meet these criteria at the beginning of the observational period
required for brain death diagnosis, clinicians should avoid the deterioration of lung
function, adopting a protective mechanical ventilation.
Often in potential donors, some conditions of hypoxemic lung injury can be
observed, identified by chest X-ray: pulmonary infiltrates, atelectasis, and pulmonary edema. A recent study has highlighted the potential reversibility of two of the
three types of lung injury. Indeed, if handled properly, edema and atelectasis can not
only be limited in their evolution, but also potentially corrected by appropriate therapeutic interventions.
To understand the ventilatory approach used in the past for organ donors, it is
useful to briefly recall that mechanical ventilation for patients with severe brain
injury is oriented to a “cerebral protective” strategy in order to avoid hypoxemia and
hypercapnia, thus limiting secondary insults to the brain. According to available
guidelines , a PaCO2 between 35 and 40 mmHg is usually obtained with high
C. Faggiano et al.
tidal volumes and low respiratory rates, while a PaO2 > 90 mmHg should be obtained
with high FiO2 and low level of PEEP to avoid interference with cerebral venous
drainage. If patients with severe brain injury evolve to brain death, critical care
management of the potential organ donors suggests that the priority should be
shifted from a “cerebral protective” strategy to an “organ protective” strategy able
to optimize organ donation. In this prospective, the lungs of potential organ donors
may play a double role: the lungs are responsible for maintaining systemic homeostasis (optimal oxygenation and optimal acid–base balance), but the lungs act also
as potential organs to be donated and such as they should be protected by further
“hits” that can impair their function.
Traditionally only the maintenance of systemic homeostasis has been considered
as a therapeutic target; indeed clinical management of potential organ donors is
oriented to guarantee optimal oxygenation and perfusion rather than to primarily
protect the cardiothoracic organs.
Following this approach, the report of Crystal City meeting recommended the
following ventilatory strategy : tidal volume between 8 and 15 mL/kg to maintain PaCO2 between 35 and 40 mmHg and peak pressure lower than 30 cmH2O and
PEEP levels equal to 5 cmH2O and elevated fraction of inspired oxygen (FiO2) in
order to guarantee O2 saturation higher than 95 %. Apnea test for brain death declaration is performed disconnecting the patient from the ventilator with high-flow
oxygen, and besides bronchoscopy, frequent suctioning and aspiration precautions
are also recommended. These guidelines are not substantially different from the
above-quoted Brain Trauma Foundation guidelines for management of traumatic
brain injury patients. Although after brain death declaration the ventilatory strategy
is no more oriented to cerebral protection, the shift proposed is mainly oriented to
guarantee systemic homeostasis. The adherence to the international guidelines for
organ donor management has been verified in a multicenter observational study
which confirmed that the ventilatory and hemodynamic management of potential
organ donors was coherent with published recommendations and might have been
suboptimal in preserving lung function. Therefore a potential conflict of interest
may exist between the priority to maintain systemic homeostasis (optimal gas
exchange and acid–base balance) and the priority to protect the lungs based on the
robust evidence that VILI may occur also in “normal” lungs at risk to develop
ARDS predisposing to posttransplant primary graft failure.
Recently a multicenter randomized controlled trial compared the use of a protective
ventilatory strategy to the conventional strategy proposed by the international guidelines in potential organ donors . The protective strategy included low tidal volume
(6–8 mL/kg of predicted body weight), PEEP equal to 8–10 cm H2O, the use of closed
circuit for tracheal suction, alveolar recruitment maneuvers after any disconnection,
and the use of continuous positive airway pressure during apnea test. The application
of this strategy increased the number of eligible and transplanted lungs, while the number of transplanted hearts, livers, and kidneys was similar in both groups .
In the same prospective, several studies have proposed to extend lung donor criteria and to apply protocols to fully recruit the lungs. Angel and coworkers proposed
the San Antonio Lung Transplant (SALT) protocol applying levels of PEEP up to