Comment by Schmidt and Byrnes based on erroneous assumptions

The comments raised by Schmidt and Byrnes [1] regarding the paper by Kellenberger [2] seems to stem from erroneous assumptions on how the Detalo device is functioning. As it’s main inventor and responsible manufacturer I shall try to elaborate on this here. Having used and optimized carbon monoxide (CO) rebreathing equipment since the early 2000s, including the laboratory equipment sold by Schmidt, it is rather easy for me to appreciate where the misconception may stem from. What essentially seems to confuse is the linking of the traditional way of administrating CO gas by a measure of volume through a handheld plastic syringe, whereas the Detalo device is based on the application of a very exact amount of CO molecules (n). In order to quantify the number of hemoglobin molecules within the circulation, researchers using the manually operated approach must convert the volume of CO gas held within the syringe to its equivalent mols by integration of ambient/syringe pressure and temperature (n = PV/RT). Knowing the molar weight of hemoglobin, the result can then be expressed as a weight measure (typically gram) for easier conception. Alternatively, and in contrast, Schmidt uses pressure and temperature adjusted volumes and Hüfners number as a constant for his calculations, but the overall principle is the same, i.e. CO is administrated as a volume of gas via a manually operated syringe and which content needs adjustment according to manual measures of pressure and temperature. One of the numerous hallmarks of the Detalo device is that the bolus of CO to be administrated to the investigated patient is not set by an administrated volume of gas contrapped in a syringe, but to an exactly defined number of CO molecules administrated form a fixed volume stainless steel chamber. This has several clear advantages. For example, if manually filling a 100 ml syringe with CO at altitude, the amount of gas within the syringe will obviously be far less than at sea level due to the lower barometric pressure. In a similar manner, daily occurring variations in ambient temperature and pressure at sea level, although only to a lesser extent, the amount of CO held within a plastic syringe will vary. Taking this to the extreme, such approach must be considered suboptimal as it should be clear that the dosing of a medical drug should not be changed due to climatic changes, just as the amount of a toxic gas administrated to a human being should not depend on the weather. Of course one could calculate how much CO gas volume should be filled into the syringe in order to compensate for such changes in pressure and temperature, but adding e.g. 82.52 ml of gas into a syringe is near impossible wherefor the more easy fixed volumes of 50 or 100 ml are typically administrated (which is also not a trivial task) but where the amount of gas is then not what was intended to be administrated. In contrast, no matter the environmental condition, the Detalo device applies exactly the number of CO molecules to the investigated patient as it would under standard conditions (25 C and 1013 mbar). Assuming that an operator aims to apply a dose equivalent to e.g. 82.52 ml (at standard conditions) the device calculates how many mol of CO this corresponds to (at 25 C and 1013 mbar) and then automatically adjusts the application so that this exact number of CO molecules is applied regardless of ambient pressure and temperature. This hence ensures that the exact amount of CO that was intended to be administrated in fact also becomes administrated, and I consider this a very smart feature. The main concern raised by Schmidt and Byrnes [1] seems to be that it is unknown to them how much CO is actually applied by the Detalo device. I thus assume they have never had the opportunity to use the device, and hence they will naturally also be unaware that one of the validated measurement outcomes in the ‘result section’ of the software is indeed the exact applied dose of CO to the patient. As required for medical devices, this is indeed very well documented and traceable, and which ironically is in complete contrast to the Schmidt equipment which lacks any kind of validation or traceability. This may of course be of great concern when applying a potentially very toxic gas to humans and which is also one reason why such unregulated laboratory equipment will likely never find its way into clinical medicine. While Schmidt and his co-workers insist to refer to their 2 min approach as ‘optimal’ it should not be mistaken for a optimization of measurement precision or accuracy, which in