Carboxyhemoglobin half-life toxicokinetic profiles during and after normobaric oxygen therapy: On a swine model

Abstract

Investigations on acute carbon monoxide (CO) poisoning struggle to highlight a relevant discriminant criterion related to CO poisoning severity for predicting complications, such as delayed neurological syndromes. In this context, it remains difficult to demonstrate the superiority of one method of oxygen (O₂) administration over others or to identify the optimal duration of normobaric 100% oxygen (NBO) treatment. Myoglobin, as hemoglobin, are a potential binding site for CO, which could be a source of extravascular CO storage that impacts the severity of CO poisoning. It is not possible in routine clinical practice to estimate this potential extravascular CO storage. Indirect means of doing so that are available in the first few hours of poisoning could include, for example, the carboxyhemoglobin half-life (COHb_t1/2), which seems to be influenced itself by the level and duration of CO exposure affecting this store of CO within the body. However, before the elimination of CO can be assessed, the COHb_t1/2 toxicokinetic model must be confirmed: research still debates whether this model mono- or bi-compartmental. The second indirect mean could be the assessment of a potential COHb rebound after COHb has returned to 5% and NBO treatment has stopped. Moreover, a COHb rebound could be considered to justify the duration of NBO treatment. On an experimental swine model exposed to moderate CO poisoning (940 ppm for ±118 min until COHb reached 30%), we first confirm that the COHb half-life follows a bi-compartmental model. Secondly, we observe for the first time a slight COHb rebound when COHb returns to 5% and oxygen therapy is stopped. On the basis of these two toxicokinetic characteristics in favor of extravascular CO storage, we recommend that COHb_t1/2 is considered using the bi-compartmental model in future clinical studies that compare treatment effectiveness as a potential severity criterion to homogenize cohorts of the same severity. Moreover, from a general toxicokinetic point of view, we confirm that a treatment lasting less than 6 hours appears to be insufficient for treating moderate CO poisoning.

Keywords: Carbon monoxide; Carbon monoxide poisoning management; Carboxyhemoglobin (COHb); Carboxyhemoglobin half-life (COHbt1/2); Swine; Toxicokinetics.

Graphical abstract

Fig. 1

COHb blood concentration vs time profiles during CO elimination on semi-logarithmic scale for CO which would exhibit a mono- or bi-compartmental model. Inspired by , , where ‘α’ is the distribution constant, ‘β’ is the terminal elimination constant. ‘A’ is the y-axis intercept for the α-phase and ‘B’ the y-axis intercept for the β-phase; ‘t’ is the time after the end of intoxication. COHb_t1/2-α=0.693/α and COHb_t1/2-β=0.693/β.

Fig. 2

COHb samples during CO exposure and the NRM treatment arm on eight swine. For the example, the curve for one of the eight experiments on NRM (in bold) is split into the four phases of the protocol (dashed black horizontal lines). Phase I: Median CO exposure time to reach COHb at 30% being 118 min [±10.4]; Phase II: no treatment (AA) for 10 min; Phase III (treatment): Median time needed to reach COHb at 5% on NRM being 163.2 min [±15.3]. This time varied on other oxygenation/ventilation modalities (not included in Fig. 2; see Table 1); Phase IV: last hour only on AA to verify occurrence of a percentage COHb rebound. From.

Fig. 3

Bi-compartmental COHb_t1/2 elimination observed during ‘treatment phase III’ with all treatments; AA; NiPPV-V; CPAP; NRM; NiPPV-L. COHb elimination curves for each treatment suggest individually that the distribution and elimination of CO from the blood are best explained by a bi-compartmental model, with the exception of the two experiments marked with arrows.

Fig. 4

After treatment phase III on NRM, CPAP, NiPPV-V or NiPPV-L: %COHb evolution during phase IV, the additional hour without any treatment with blood samples taken every 6 min (11 samples for each) (n=19).

Fig. 5

Phase IV. COHb expressed in percentage from last measured value of Phase III (range 4.5–5.2% considered individually as 100%) according to time post-phase III (min). This phase IV is the last hour without any intervention (on AA). Data are expressed as means ± SD. The lines represent the quadratic regression model according to each treatment. This allows us, firstly, to homogenize the starting values, to compare curves and to better visualize the evolution of %COHb if it continues to fall as in treatment during phase III or if it stabilizes or even rises in phase IV.

Fig. 6

Global overview of the impact of CO exposure criteria (duration x level) on the peak %COHb and COHb_t1/2 expected. This could approximate severity CO poisoning in relation to potential CO storage. Pending future studies, the two reference thresholds that could be considered as severity criteria are COHb peak >25% and COHb_t1/2 > 74 min, , .