New dangers of anesthesia: isoflurane induced opening of the blood–brain barrier (Commentary on Tétrault et al.)



Isoflurane is a widely used anesthetic for inducing well-controlled narcosis during surgical interventions. It can also be employed to cause a coma-like state with burst suppression patterns in the electroenecephalogram (EEG). Deep anesthesia is thought to protect the brain after trauma, during infections and also during drug refractory status epilepticus. Burst suppression patterns in the EEG are, on the other hand, signs of a very severe condition with danger for neuronal integrity.

In this issue, Tétrault et al. report that isoflurane causes a dose-dependent opening of the blood–brain barrier that is initiated in the thalamus and following higher concentrations also involves cortical structures. The opening of the blood–brain barrier was indicated by a shift in the DC component of the EEG, by extravasation of Evans Blue bound to albumin and by an increase in brain volume. The latter is due to the vasogenic edema caused by the extravasation of plasma proteins, leading to increased oncotic pressure in the interstitial space and subsequent increase in intracranial pressure. These acute effects might alter blood flow in the brain and potentially cause neuronal damage. On the other hand, short and controlled opening of the blood–brain barrier may provide a window for brain delivery of drugs that normally not pass the blood–brain barrier. While these results may appear unexpected given the widespread use of isoflurane anesthesia, other drugs with anesthetic properties, most notably ethanol, are known to affect the integrity of the blood–brain barrier as well.

While the blood–brain barrier lies ‘outside the brain’, it is attracting increasing attention from neuroscientists, because it is compromised in many neurological disorders such as brain tumors, trauma, stroke, convulsive status epilepticus, and inflammation. Focal blood–brain barrier opening occurs also around amyloid plaques in Alzheimer’s disease. Opening of the blood–brain barrier in patients with epilepsy can aggravate seizures (Van Vliet et al., 2007). Importantly, opening of the blood–brain barrier can have outlasting consequences on brain function, as recently described in a series of papers by Alon Friedman’s lab in Beersheva, Israel. They demonstrated that a lasting opening of the blood–brain barrier led to albumin uptake into astrocytes, affecting their functional properties, with detrimental consequences for the regulation of extracellular potassium and probably also for glutamate clearance. With a delay of some days, a hyperexcitable focus could develop and seizures emerged in a subgroup of animals (Seiffert et al., 2004; Ivens et al., 2007). Considering this evidence, the work by Tétrault et al. should come as a warning that isoflurane anesthesia should be employed with care. Future research needs to determine whether other anesthetics likewise are capable of opening the blood–brain barrier. Furthermore, it will be important to determine the time period during which isoflurane anesthesia produces lasting effects on brain homeostasis and on the integrity of neurons and circuits.