Medical diagnostic system, apparatus and methods are disclosed. Optical transmitters generate radiation-containing photons having a specific interaction with at least one target chromophore in a target structure, preferably a blood vessel such as the interior jugular vein. The optical transmitters transmit the radiation into at least a first area including a substantial portion of the target structure and into a second area not including a substantial portion of the target structure. Optical receivers detect a portion radiation scattered from at least the first area and the second area. A processor estimates oxygenation, pH or cardiac output based on the scattered radiation detected from the first area, and the scattered radiation from the second area.