General anaesthetics as 'awakening agents'? Re-appraising the evidence for suggested 'pressure reversal' of anaesthesia.

Increasing ambient pressure has been suggested to reverse general anaesthesia and provides support for the 'lipid theory'. Anaesthetic dissolution into cell membranes is said to cause their expansion to a critical volume. This triggers a sequence of events as basis of a unitary theory of anaesthestic mechanism. Pressure is argued to restore membrane volume to below critical level, reversing this process. We wished to review the original literature to assess internal consistency within and across papers, and to consider if alternative interpretations were possible. A literature search yielded 31 relevant 'pressure reversal' papers for narrative review, and 8 papers that allowed us to re-plot original data more consistently as 'dose-response' curves for the anaesthetics examined. Original studies were heterogenous for end-points, pressure ranges, species, and agents. Pressure effects were inconsistent, with narcosis at certain pressures and excitation at others, influenced by carrier gas (e.g., nitrogen vs helium). Pressure reversal (a right- or downward-shift on the re-plotted dose-response curves) was evident, but only in some species and at certain pressures and anaesthetic concentrations. However, even more striking was a novel 'awakening' effect of anaesthetics: i.e., anaesthetics reversed the narcotic effect of pressure, but this was limited to certain pressures at generally low anaesthetic concentrations. Contrary to the established view, 'pressure reversal' is not a universal phenomenon. The awakening effect of anaesthetics - described here for the first time - has equal evidence to support it, within the same literature, and is something that cannot be fully explained. Pressure cannot meaningfully be used to gain insight into anaesthetic mechanisms because of its heterogenous, non-specific and unpredictable effects on biological systems.