Search

An acute reduction in plasma osmolality causes rapid uptake of water by astrocytes but not by neurons, whereas both cell types swell as a consequence of lost blood flow (ischemia). Either hypoosmolality or ischemia can displace the brain downwards, potentially causing death. However, these disorders are fundamentally different at the cellular level. Astrocytes osmotically swell or shrink because they express functional water channels (aquaporins), whereas neurons lack functional aquaporins and thus maintain their volume. Yet both neurons and astrocytes immediately swell when blood flow to the brain is compromised (cytotoxic edema) as following stroke onset, sudden cardiac arrest, or traumatic brain injury. In each situation, neuronal swelling is the direct result of spreading depolarization (SD) generated when the ATP-dependent sodium/potassium ATPase (the Na+/K+ pump) is compromised. The simple, and incorrect, textbook explanation for neuronal swelling is that increased Na+ influx passively draws Cl− into the cell, with water following by osmosis via some unknown conduit. We first review the strong evidence that mammalian neurons resist volume change during acute osmotic stress. We then contrast this with their dramatic swelling during ischemia. Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia.

Background Spreading depolarization (SD) and the initial, still reversible phase of neuronal cytotoxic edema in the cerebral gray matter are two modalities of the same process. SD may thus serve as a real-time mechanistic biomarker for impending parenchyma damage in patients during neurocritical care. Using subdural platinum/iridium (Pt/Ir) electrodes, SD is observed as a large negative direct current (DC) shift. Besides SD, there are other causes of DC shifts that are not to be confused with SD. Here, we systematically analyzed DC artifacts in ventilated patients by observing changes in the fraction of inspired oxygen. For the same change in blood oxygenation, we found that negative and positive DC shifts can simultaneously occur at adjacent Pt/Ir electrodes. Methods Nurses and intensivists typically increase blood oxygenation by increasing the fraction of inspired oxygen at the ventilator before performing manipulations on the patient. We retrospectively identified 20 such episodes in six patients via tissue partial pressure of oxygen (ptiO2) measurements with an intracortical O2 sensor and analyzed the associated DC shifts. In vitro, we compared Pt/Ir with silver/silver chloride (Ag/AgCl) to assess DC responses to changes in pO2, pH, or 5-min square voltage pulses and investigated the effect of electrode polarization on pO2-induced DC artifacts. Results Hyperoxygenation episodes started from a ptiO2 of 37 (30–40) mmHg (median and interquartile range) reaching 71 (50–97) mmHg. During a total of 20 episodes on each of six subdural Pt/Ir electrodes in six patients, we observed 95 predominantly negative responses in six patients, 25 predominantly positive responses in four patients, and no brain activity changes. Adjacent electrodes could show positive and negative responses simultaneously. In vitro, Pt/Ir in contrast with Ag/AgCl responded to changes in either pO2 or pH with large DC shifts. In response to square voltage pulses, Pt/Ir falsely showed smaller DC shifts than Ag/AgCl, with the worst performance under anoxia. In response to pO2 increase, Pt/Ir showed DC positivity when positively polarized and DC negativity when negatively polarized. Conclusions The magnitude of pO2-induced subdural DC shifts by approximately 6 mV was similar to that of SDs, but they did not show a sequential onset at adjacent recording sites, could be either predominantly negative or positive in contrast with the always negative DC shifts of SD, and were not accompanied by brain activity depression. Opposing polarities of pO2-induced DC artifacts may result from differences in baseline electrode polarization or subdural ptiO2 inhomogeneities relative to subdermal ptiO2 at the quasi-reference.