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Hyperoxemia and hypoxemia impair cellular oxygenation: a study in healthy volunteers
Intensive Care Medicine Experimental volume 12, Article number: 37 (2024)
Abstract
Introduction
Administration of oxygen therapy is common, yet there is a lack of knowledge on its ability to prevent cellular hypoxia as well as on its potential toxicity. Consequently, the optimal oxygenation targets in clinical practice remain unresolved. The novel PpIX technique measures the mitochondrial oxygen tension in the skin (mitoPO2) which allows for non-invasive investigation on the effect of hypoxemia and hyperoxemia on cellular oxygen availability.
Results
During hypoxemia, SpO2 was 80 (77–83)% and PaO2 45(38–50) mmHg for 15 min. MitoPO2 decreased from 42(35–51) at baseline to 6(4.3–9)mmHg (p < 0.001), despite 16(12–16)% increase in cardiac output which maintained global oxygen delivery (DO2). During hyperoxic breathing, an FiO2 of 40% decreased mitoPO2 to 20 (9–27) mmHg. Cardiac output was unaltered during hyperoxia, but perfused De Backer density was reduced by one-third (p < 0.01). A PaO2 < 100 mmHg and > 200 mmHg were both associated with a reduction in mitoPO2.
Conclusions
Hypoxemia decreases mitoPO2 profoundly, despite complete compensation of global oxygen delivery. In addition, hyperoxemia also decreases mitoPO2, accompanied by a reduction in microcirculatory perfusion. These results suggest that mitoPO2 can be used to titrate oxygen support.
Background
Hypoxemia increases the risk of death in ICU patients by 50% [1, 2]. However, in 10% of all ICU patients, therapy with supplemental oxygen leads to supraphysiological arterial oxygen tensions [3]. As hyperoxemia is also associated with increased mortality [1,2,3,4], careful titration of oxygen therapy is imperative. Clinical trials have attempted to establish optimal oxygen targets but results are contradictory, partly due to the absence of a direct biomarker of oxygen toxicity and oxygen debt. Most likely, determining oxygen dose is complicated by the lack of knowledge of the effects on a cellular level [5,6,7,8].
The rationale for supplemental oxygen therapy is to prevent cellular hypoxia [6]. The effects on a cellular level are unclear due to the variable effects of oxygen on organ perfusion. Hypoxemia increases cardiac output, recruits previously closed capillaries and decreases mitochondrial oxygen consumption, which improve global oxygen delivery and lower oxygen demand [9,10,11,12]. On the other end, hyperoxemia reduces cardiac output and increases ROS production, leading to impairments in microcirculatory perfusion [13, 14]. This could potentially offset the increase in arterial oxygen content and limit oxygen extraction by tissues [1, 2]. Potentially supporting this, multiple analyses have shown an association between hyperoxemia and mortality in critically ill patients [1,2,3]. However, this relationship is not always present in severity-adjusted models [4]. As such, the causality of hyperoxemia-associated harm remains doubtful, also partly due to an incomplete understanding of the cellular and physiological effects of supplemental oxygen [6, 15].
The development of the protoporphyrin IX delayed lifetime technique enables the measurement of mitochondrial oxygen tension non-invasively in the skin (mitoPO2). Mitochondria are the utilizers of oxygen and therefore mitoPO2 reflects the balance between oxygen supply and demand at the most downstream level [16, 17]. Cutaneous mitoPO2 correlates well with organ mitoPO2 and responds accurately to changes in FiO2 or in tissue perfusion [16, 18,19,20,21]. Moreover, it also allows measurement of mitochondrial respiration (mitoVO2) non-invasively [22, 23].
The aim of this study was to investigate the effect of hypoxemia and hyperoxemia on mitoPO2 as marker of cellular oxygen availability in healthy human volunteers.
Methods
Study design and participants
This physiological cross-over intervention study in healthy human volunteers was conducted in the ICU of a teaching hospital (OLVG hospital, Amsterdam, The Netherlands). The study was approved by the institutional review board (MEC-u). Healthy human volunteers > 18 years and with BMI < 25 kg/m2, were screened for eligibility. Participants were excluded if they had an allergy for plaster adhesives, mitochondrial disease, skin lesions, anemia or had a history of smoking or altitude exposure (> 1000 m) in the 3 months previous to inclusion.
Study procedures
Participants had an ALAcare patch placed on the sternum 4 h before start of the experiment and were monitored using ECG and pulse oximetry. An arterial catheter was placed for blood pressure monitoring and blood sampling. In the cross-over design, predetermined hypoxic and hyperoxic gas mixtures were delivered in a fixed order in all participants using high flow nasal cannula. After 30 min of accustoming to the setup, hypoxemia was titrated to an SpO2 of 75–85% for 15 min. The target SpO2 was achieved by titrating the FiO2 of the high-flow nasal cannula between an FiO2 of 9% and 12%. The flow-rate remained equal for all participants at 40L/h to ensure no rebreathing. When participants remained between an SpO2 of 75% and 85% during a complete minute, the FiO2 was set for the remainder of the hypoxic phase. After completion of 15 min, participants had a wash-out period of 45 min of breathing atmospheric air before commencement of hyperoxic gas breathing. Hyperoxic gas mixture was delivered for periods of 15 min with incremental FiO2 of 40%, 60%, 80% and 100%. After each step, clinical data was collected and measurements were done. MitoPO2 was measured using the COMET (Photonics Healthcare, Utrecht, The Netherlands). The non-invasive cardiac output was recorded continuously using pulse wave contour analysis with the volume clamp method. The sublingual microcirculation was imaged using sidestream darkfield imaging (SDF) at baseline, after hypoxemia and after hyperoxemia to prevent the mixing of hyperoxic gas mixture with atmospheric air during the hyperoxic phases [24,25,26].
Measurements
COMET
MitoPO2 was computed from the mean mitoPO2 during the first 30 s of a dynamic measurement (1 Hz). MitoVO2 is defined as the rate of mitochondrial deoxygenation after local occlusion of circulation by applying pressure on the probe. It is calculated by automatic linear fitting of the slope using MATLAB (The Mathworks Inc). The method of performing a dynamic measurement and calculating mitoVO2 is described in detail elsewhere [27].
Non-invasive cardiac output
Cardiac index and systemic vascular resistance index were measured continuously throughout the experiment using the volume clamp method in the Nexfin device (BMEYE, Amsterdam, The Netherlands) as invasive arterial wave-form estimation of cardiac-output was not available in our ICU. The change between two measurements of Nexfin-CO has been shown to have very good agreement with invasive cardiac output and has been used previously to monitor hyperoxemia induced changes in cardiac output [25, 28, 29, 30].
A finger cuff was placed on the index or middle finger according to the manufacturer’s instructions. The mean of the last 2 min of each step was used for analysis. The cardiac index was used to calculate global oxygen delivery (DO2) was calculated using the following formula: DO2 = CO*(10*Hb/dl*SaO2 + PaO2*0.03). Hb, SaO2 and PaO2 were obtained from arterial blood gas analysis.
Sublingual microcirculation
The sublingual microcirculation was recorded using a handheld video microscope with sidestream darkfield imaging (SDF) with the MicroScan (MicroVision Medical, The Netherlands, Amsterdam). Sublingual measurements were done by one researcher trained in microcirculatory image recording. Directly after removal of the high-flow nasal cannula, SDF measurements were performed. Three anatomical sites were recorded: the medial and both lateral parts of the sublingual area. The validated AVA 4.3C software (Microvision Medical, Amsterdam, The Netherlands) was used for quality control and analysis of images [31]. AVA 4.3C automatically assesses the focus, contrast and stability of the images. Additionally, good quality captures required the presence of flow in large vessels, to exclude possible pressure artefacts. Images were only evaluated in case the quality was sufficient. The proportion of perfused vessels (PPV), proportion of perfused small vessels (PPV small), density, and the perfused DeBacker density were determined automatically by the software. The perfused DeBacker Density are all vessels with visible microcirculatory flow. The Percentage of Perfused Vessels (PPV) is calculated as the percentage of perfused vessels in relation to the total number of all vessels and for small vessels in particular (PPV small). Small vessels (capillaries) have a diameter less than 20 µm The mean values of three recordings of each parameter were used for final analysis.
Statistical analysis
Sample size calculation is based on the expected drop in mitoPO2 during hypoxemia as predicted by a mathematical model as there are no previous data available for the expected effect size [32]. Modified Krogh equations predict that a saturation decrease from 98% to 85% results in a mitoPO2 decreases of 40 mmHg. Since we expected that homeostatic mechanisms (cardiac output increase and microcirculatory recruitment) would attenuate this mitoPO2 decrease, we set the minimum detectable difference at 20 mmHg. The standard deviation is expected to be 15 mmHg, corresponding to the sample standard deviation in healthy human volunteers [20]. The calculated sample size for a paired t test with a power of 90%, a significance level of 0.05, an effect size of 1.33 (minimum difference of 20 mmHg divided by the standard deviation of 15 mmHg) is 9 subjects. We also expected to see an increase of 20 mmHg in mitoPO2 in response to hyperoxia, based on previous studies in rats [33, 34].
Data is presented in mean ± SD or median (IQR) if non-normally distributed. Within-group differences over time were analyzed using repeated measures one-way ANOVA. Hypoxemia was compared with baseline. In case of significance, post-hoc tests were done with Mann–Whitney U test and Bonferroni correction for hyperoxia to determine at which FiO2 the changes in variables occurred. For hyperoxemia and hypoxemia, a separate linear regression model was performed for mitoPO2 and mitoVO2. Parameters which differed significantly (p < 0.05) during hyperoxic/hypoxic phases in the ANOVA analysis were entered into the model as independent variables. Statistical analysis was done using Rstudio (Posit, Vienna, Austria).
Results
We enrolled 9 healthy volunteers, of which 6 were female. The median age was 25 (22–25) years and BMI was 21.7 (21.3–23.2)kg/m2. Inhalation of 10% FiO2 resulted in a decrease in PaO2 from 107 (99–113) mmHg to 45(38–50) mmHg and SaO2 from 98 (98–98)% to 80 (77–83)%, (p < 0.0001). Some participants noted feeling drowsy during hypoxic gas breathing, which resolved rapidly during the wash-out step. No other discomfort was noted. Hyperoxic gas breathing increased the PaO2 stepwise, with a plateau from 80% to 100% FiO2, as shown in Fig. 1A.
Macro-hemodynamic and respiratory response
Hypoxic gas mixture breathing resulted in an increase in heart rate from 70 (60–79) bpm to 84 (71–88) bpm (Fig. 2). This paralleled an increase in cardiac output of 16 (12–16)% from baseline and a decrease in systemic vascular resistance index of 21 (17–28)%. Whereas arterial oxygen content (CaO2) decreased with 20 (15–25)% during hypoxemia, DO2 was maintained when compared to baseline (p = 0.62). The wash-out period restored all hemodynamic indices to baseline. Hyperoxia did not induce significant changes in macro hemodynamic parameters compared to baseline. PaCO2 decreased significantly at 100% FiO2. Hypoxic gas breathing did not result in hypocapnia (Table 1). Other arterial blood gas parameters were not significantly altered during hyperoxic or hypoxic breathing.
MitoPO2 and mitoVO2
Hypoxic mixture breathing induced a profound decline in mitoPO2 from 42 (35–51)mmHg to 6 (4.3–9)mmHg (Fig. 3). Concurrently, MitoVO2 decreased from 3.7 (2.9–5.0)mmHg/s to 0.80 (0.50–1.0)mmHg/s (p < 0.01). Wash-out recovered mitoPO2 to 39 (13–52) mmHg and mitoVO2 to 3.2 (0.92–4.8)mmHg/s.
Hyperoxic gas breathing also resulted in a median decrease in mitoPO2 when compared to washout (p = 0.03). In all participants, mitoPO2 decreased to 20 (9.0–27) mmHg when breathing 40% FiO2 (p < 0.05), which remained significantly lower compared to wash-out until 80% FiO2 (p = 0.038) (Fig. 3). Hyperoxia did not result in a significant decrease in mitoVO2 when compared to wash-out (RM ANOVA p = 0.2). However, mitoVO2 was strongly correlated with mitoPO2 ( r = 0.84, p < 0.001) during all experimental phases (Fig. 4). In linear mixed model analysis, mitoPO2 remained the only predictor of mitoVO2 with coefficient of − 0.10 (− 0.8 to − 0.12).
Microcirculation
During hypoxemia, no significant recruitment of the microcirculation was observed (Fig. 5 and Table 1). During hyperoxic gas breathing, parameters of sublingual microcirculation worsened (Fig. 5). Proportion of perfused vessels (PPV) decreased from 96 (95–98)% to 80 (80–89)% at the end of the hyperoxia period. The absolute number of perfused vessels decreased in parallel, from 3.6 (3.2–4.1) to 2.4 (1.4–2.7).
Determinants of mitoPO2
A linear regression model was performed to determine the influencing factors on mitoPO2. PaO2 and Perfused DeBacker density were identified as significant predictors of mitoPO2 during hyperoxia and baseline/wash-out (p < 0.05). During the hyperoxic phase, mitoPO2 was linearly correlated with PaO2 (r = − 0.44, p < 0.01) and the perfused DeBacker Density (r = 0.6, p = 0.023). Figure 6 shows the fitted general model with PaO2 and perfused DeBacker Density as explanatory variables. Inclusion of the hypoxic phase results in a non-significant correlation between perfused DeBacker density and mitoPO2, due to an inability of perfused DeBacker density recruitment to restore mitoPO2 to baseline values (Fig. 5C).
Discussion
We assessed the effect of acute hypoxemia and hyperoxemia on mitoPO2 as a marker of oxygen debt and toxicity. Despite complete compensation of global oxygen delivery during hypoxemia, mitoPO2 decreased in all participants. Also, we demonstrated that hyperoxemia is detrimental to mitoPO2, through reduced microcirculatory perfusion.
MitoPO2 at baseline was 40 mmHg, corresponding to previous studies in healthy volunteers [19, 27]. MitoPO2 decreased sharply in acute hypoxemia. This corroborates predictions from mathematical experimental models which showed significant reductions in mitoPO2 in response to hypoxemia [32, 35]. Although intuitive, this finding is in contrast with some studies in healthy volunteers which show that indirect markers of tissue oxygenation are largely unchanged during acute hypoxemia [11, 15, 36–38]. Accordingly, it was proposed that adaptive mechanisms, such as an increase in CO and recruitment of the microcirculation could maintain oxygen delivery to cells and has led to the speculation that lower SpO2 targets could be beneficial in critically ill patients [15]. Indeed, we found an increase in CO through an increase in heart rate, causing a maintained global DO2 during hypoxemia. Nevertheless, the sharp decrease in mitoPO2 shows that hypoxemia decreases oxygen delivery into the parenchyma. The probable explanation is that in the microcirculation, the augmented blood flow above physiological levels is not beneficial during acute hypoxemia because the time for red blood cells to unload their (limited) oxygen content decreases, thus causing hypoxemic tissue hypoxia [12, 32, 39]. Although systemic DO2 reflects the total oxygen content carried per unit time, it does not reflect the ability of the microcirculation to unload oxygen into the parenchyma. Mathematical models and experimental studies corroborate this disconnection showing a decrease in ScvO2 and increase in oxygen extraction ratio during hypoxemia [32, 40]. An alternative explanation is that despite an increase in CO, the observed decrease in mitoPO2 is mediated by redistribution of blood flow away from the skin, kidneys, GI and liver to the heart and brain during hypoxemia [41–44]. In shock and critical illness, skin blood flow closely resembles visceral organ blood flow. However, it remains unknown whether this close relation remains during a combination of hypoxemia and shock. The detrimental effects of hypoxemia on internal organs is further supported by significant cognitive decline in healthy human volunteers during acute hypoxemia, likely representing slight cerebral oxygen debt [32, 45]. Commonly used markers of tissue oxygenation/perfusion such as NIRS and lactate, may not be suitable to ensure adequate cellular oxygenation in the context of acute hypoxemia [15].
Hyperoxemia also causes a profound decrease in mitoPO2, occurring at a PaO2 level of 200 mmHg. This occurred in parallel with a decrease in sublingual perfused vessel density. Although previous studies have shown a decrease in microcirculatory perfusion [30, 40, 46, 47], it was also shown that oxygen delivery increased with increased PaO2 [48–50]. This combination has led to the accepted hypothesis that an increased tissue oxygen tension induces radical oxygen species mediated damage. However, tissue pO2 measurements were performed using devices that disturb the integrity of the tissue. Also, the SDF technique has been unable to elucidate the downstream effect of hyperoxemia on oxygen toxicity and debt as it is not able to evaluate the oxygen content of capillaries [46, 49, 51, 52]. This study is the first to directly measure cellular oxygen availability in response to hyperoxemia and indeed demonstrates that a PaO2 above 200 mmHg has a detrimental effect on cellular oxygenation, at least in healthy volunteers. Of note, this cutoff value (200 mgHg) corresponds well with PaO2-associated mortality in critically ill patients [1, 2]. Our results show no dose-dependency of decreasing mitoPO2 while increasing PaO2, with the effect plateauing at an FiO2 of 40%. This corresponds to meta-analyses showing that PaO2 has no dose-dependent effect on mortality [1, 5]. Taken together, our findings suggest that a reduction in tissue oxygenation, through reduction in microcirculatory perfusion might account for the observed harm of hyperoxemia in hospitalized patients.
Our study has potential implications for future clinical investigations into hyperoxemia and hypoxemia. Intensivists frequently assess markers of tissue oxygenation (lactate, microcirculation) when hypoxemia is refractory. However, whereas no evidence exists that lactate reflects tissue hypoxia during hypoxemia, we demonstrate that mitoPO2 may be an alternative [11, 15, 37, 53]. Increasing PaO2 during normoxemia to attempt to increase oxygen delivery is done frequently [54]. However, this has never been empirically demonstrated to be effective and guidelines provide contradictory recommendations for supplemental oxygen therapy during normoxemia [55–60]. We show that from a PaO2 of 200 mmHg and above, median mitoPO2 is lower than the 25 mmHg threshold associated with organ failure in critically ill patients. As such, our results suggest that O2-supplementation should probably not exceed an upper PaO2 limit of 200 mmHg, as it is associated with a decrease in tissue oxygenation. However, it remains to be investigated whether a low mitoPO2 reflects adverse effects on cellular integrity and organ function in patients [61]. In addition, the heterogeneous effect of PaO2 on hemodynamics warrants further investigation of mitoPO2 as a biomarker of oxygen toxicity and debt for personalized titration of PaO2 in critically ill patients.
Limitations
Our study has several limitations. As this was a study in healthy volunteers, results might not apply to the critically ill patient. Patients in the ICU often have disturbed Hb-O2 dissociation curves and impaired vascular reactivity, meaning high/low PaO2 and ROS could have a different effect on the visceral and skin microcirculation in patients with systemic inflammation compared to healthy volunteers. Furthermore, the coupling between skin and visceral mitoPO2, blood flow and microcirculation that is seen in experimental hypoxemia could potentially be absent in critically ill patients with shock.
Also, we did not control for normocapnic hypoxemia. Alkalosis was observed in most participants throughout the experiment. However, we found that decreases in mitoPO2 were not explained by hypocapnia as continuous variable in the mixed model but this may have been due to the limited sample size. Furthermore, gas mixture breathing was not randomized as we used a cross over study setting. It is known that both hyperoxemia and hypoxemia have long lasting effects on the microvasculature and arteriolar tone due to increased sympathetic activity, even after cessation of hypoxic and hyperoxic stimuli [62–64]. As such, we cannot exclude the possibility that exposure to hypoxia may have altered the response during hyperoxemia. However, SVR was restored during wash-out and no significant microcirculatory hypoperfusion was noted during hypoxemia. Finally, it is unknown whether a low mitoPO2 during hypoxemia and hyperoxemia reflects cellular damage and organ function. We call for clinical investigations for mitoPO2 as a marker of organ function during resuscitation.
Conclusion
Acute hypoxemia decreases skin mitoPO2 profoundly, despite complete compensation of global oxygen delivery. Hyperoxemia decreases skin mitoPO2 dose-dependently through decreased microcirculatory perfusion. We identified a maximum PaO2 of 200 mmHg for optimal tissue oxygenation in healthy volunteers. These results suggest that mitoPO2 could be used as a marker of oxygen debt during oxygen therapy.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- CaO2:
-
Arterial oxygen content
- CO:
-
Cardiac output
- DO2:
-
Global oxygen delivery
- FiO2:
-
Fraction of inspired oxygen
- MitoPO2:
-
Mitochondrial oxygen tension
- MitoVO2:
-
Mitochondrial oxygen consumption
- PaCO2:
-
Partial pressure of carbon dioxide in arterial blood gas
- PaO2:
-
Partial pressure of oxygen in arterial blood gas
- PPV:
-
Proportion of perfused vessels
- ROS:
-
Radical oxygen species
- SaO2:
-
Arterial haemoglobin oxygen saturation
- SDF:
-
Sidestream darkfield imaging
- SpO2:
-
Saturation of oxygen measured using plethysmography
- SVRi:
-
Systemic vascular resistance index
References
de Jonge E, Peelen L, Keijzers PJ et al (2008) Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Crit Care 12(6):1–8. https://doi.org/10.1186/cc7150
Eastwood G, Bellomo R, Bailey M et al (2012) Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Med 38(1):91–98. https://doi.org/10.1007/s00134-011-2419-6
Schjørring OL, Jensen AKG, Nielsen CG et al (2020) Arterial oxygen tensions in mechanically ventilated ICU patients and mortality: a retrospective, multicentre, observational cohort study. Br J Anaesth 124(4):420–429. https://doi.org/10.1016/j.bja.2019.12.039
Hochberg CH, Semler MW, Brower RG (2021) Oxygen toxicity in critically ill adults. Am J Respir Crit Care Med 204(6):632–641. https://doi.org/10.1164/rccm.202102-0417CI
Palmer E, Post B, Klapaukh R et al (2019) The association between supraphysiologic arterial oxygen levels and mortality in critically ill patients a multicenter observational cohort study. Am J Respir Crit Care Med 200(11):1373–1380. https://doi.org/10.1164/rccm.201904-0849OC
Singer M, Young PJ, Laffey JG et al (2021) Dangers of hyperoxia. Crit Care 25(1):1–15. https://doi.org/10.1186/s13054-021-03815-y
Schumacker PT (2010) Is enough oxygen too much? Crit Care. https://doi.org/10.1186/cc9201
Jones GAL, Peters MJ (2022) Towards causality with liberal oxygen use?∗. Pediatr Crit Care Med 23(2):135–137. https://doi.org/10.1097/PCC.0000000000002876
Cain SM (1965) Appearance of excess lactate in anesthetized dogs during anemic and hypoxic hypoxia. Am J Physiol 209(3):604–610. https://doi.org/10.1152/ajplegacy.1965.209.3.604
Bickler PE, Feiner JR, Lipnick MS, Batchelder P, Macleod DB, Severinghaus JW (2017) Effects of acute, profound hypoxia on healthy humans: implications for safety of tests evaluating pulse oximetry or tissue oximetry performance. Anesth Analg. https://doi.org/10.1213/ANE.0000000000001421
Hobler KE, Carey LC (1973) Effect of acute progressive hypoxemia on cardiac output and plasma excess lactate. Ann Surg. https://doi.org/10.1097/00000658-197302000-00013
Schumacker PT, Samsel RW (1989) Analysis of oxygen delivery and uptake relationships in the Krogh tissue model. J Appl Physiol 67(3):1234–1244. https://doi.org/10.1152/jappl.1989.67.3.1234
Smit B, Smulders YM, van der Wouden JC, Oudemans-van Straaten HM, Spoelstra-de Man AME (2018) Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis. Crit Care 22(1):1–10. https://doi.org/10.1186/s13054-018-1968-2
Spoelstra-De Man AME, Smit B, Oudemans-Van Straaten HM, Smulders YM (2015) Cardiovascular effects of hyperoxia during and after cardiac surgery. Anaesthesia 70(11):1307–1319. https://doi.org/10.1111/anae.13218
Kiers HD, Pickkers P, Kox M (2022) Hypoxemia in the presence or absence of systemic in fl ammation does not increase blood lactate levels in healthy volunteers. J Crit Care 71:154116. https://doi.org/10.1016/j.jcrc.2022.154116
Römers LHL, Bakker C, Dollée N et al (2016) Cutaneous mitochondrial Po2, but not tissue oxygen saturation, is an early indicator of the physiologic limit of hemodilution in the pig. Anesthesiology. https://doi.org/10.1097/ALN.0000000000001156
Ince C, Mik EG (2016) Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol. https://doi.org/10.1152/japplphysiol.00298.2015
Neu C, Baumbach P, Plooij AK et al (2020) Non-invasive assessment of mitochondrial oxygen metabolism in the critically ill patient using the protoporphyrin IX-triplet state lifetime technique—a feasibility study. Front Immunol 11(May):1–9. https://doi.org/10.3389/fimmu.2020.00757
Baumbach P, Neu C, Derlien S et al (2019) A pilot study of exercise-induced changes in mitochondrial oxygen metabolism measured by a cellular oxygen metabolism monitor (PICOMET). Biochim Biophys Acta Mol Basis Dis 1865(4):749–758. https://doi.org/10.1016/j.bbadis.2018.12.003
Baumbach P, Schmidt-Winter C, Hoefer J et al (2020) A pilot study on the association of mitochondrial oxygen metabolism and gas exchange during cardiopulmonary exercise testing: is there a mitochondrial threshold? Front Med. https://doi.org/10.3389/fmed.2020.585462
Harms FA, Ubbink R, de Wijs CJ, Ligtenberg MP, ter Horst M, Mik EG (2022) Mitochondrial oxygenation during cardiopulmonary bypass: a pilot study. Front Med 9:1–13. https://doi.org/10.3389/fmed.2022.785734
Wefers Bettink MA, Harms FA, Dollee N et al (2020) Non-invasive versus ex vivo measurement of mitochondrial function in an endotoxemia model in rat: toward monitoring of mitochondrial therapy. Mitochondrion. https://doi.org/10.1016/j.mito.2019.11.003
Harms FA, Voorbeijtel WJ, Bodmer SIA, Raat NJH, Mik EG (2013) Cutaneous respirometry by dynamic measurement of mitochondrial oxygen tension for monitoring mitochondrial function in vivo. Mitochondrion 13(5):507–514. https://doi.org/10.1016/j.mito.2012.10.005
Ubbink R, Bettink MAW, Janse R et al (2017) A monitor for cellular oxygen METabolism (COMET): monitoring tissue oxygenation at the mitochondrial level. J Clin Monit Comput 31(6):1143–1150. https://doi.org/10.1007/s10877-016-9966-x
Broch O, Renner J, Gruenewald M et al (2012) A comparison of the Nexfin ® and transcardiopulmonary thermodilution to estimate cardiac output during coronary artery surgery. Anaesthesia 67(4):377–383. https://doi.org/10.1111/j.1365-2044.2011.07018.x
Coppel J, Bountziouka V, Martin D, Gilbert-Kawai E (2021) A comparison of the quality of image acquisition between two different sidestream dark field video-microscopes. J Clin Monit Comput 35(3):577–583. https://doi.org/10.1007/s10877-020-00514-x
Harms F, Stolker RJ, Mik E (2016) Cutaneous respirometry as novel technique to monitor mitochondrial function: a feasibility study in healthy volunteers. PLoS ONE 11(7):1–11. https://doi.org/10.1371/journal.pone.0159544
Ameloot K, Van De Vijver K, Broch O et al (2013) Nexfin noninvasive continuous hemodynamic monitoring: Validation against continuous pulse contour and intermittent transpulmonary thermodilution derived cardiac output in critically ill patients. Sci World J 2013:1. https://doi.org/10.1155/2013/519080
Stolmeijer R, Van Ieperen E, Lameijer H, Van Beest P, Ter Maaten JC, Ter Avest E (2022) Haemodynamic effects of a 10-min treatment with a high inspired oxygen concentration in the emergency department: a prospective observational study. BMJ Open 12(9):1–8. https://doi.org/10.1136/bmjopen-2021-059848
Smit B, Smulders YM, Eringa EC et al (2018) Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion. Microcirculation 25(2):1–8. https://doi.org/10.1111/micc.12433
Dobbe JGG, Streekstra GJ, Atasever B, van Zijderveld R, Ince C (2008) Measurement of functional microcirculatory geometry and velocity distributions using automated image analysis. Med Biol Eng Comput 46(7):659–670. https://doi.org/10.1007/s11517-008-0349-4
Hilderink BN, Crane RF, Baysan M et al (2023) A simulation of skin mitochondrial PO2 in circulatory shock. J Appl Physiol 134:1165–1176. https://doi.org/10.1152/japplphysiol.00621.2022
Mik EG, Van Leeuwen TG, Raat NJ, Ince C (2004) Quantitative determination of localized tissue oxygen concentration in vivo by two-photon excitation phosphorescence lifetime measurements. J Appl Physiol. https://doi.org/10.1152/japplphysiol.01399.2003
Mik EG, Johannes T, Zuurbier CJ et al (2008) In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. Biophys J. https://doi.org/10.1529/biophysj.107.126094
Sharan M, Gupta S, Popel AS (1998) Parametric analysis of the relationship between end-capillary and mean tissue PO2as predicted by a mathematical model. J Theor Biol 195(4):439–449. https://doi.org/10.1006/jtbi.1998.0805
Bickler PE, Feiner JR, Lipnick MS, Batchelder P, MacLeod DB, Severinghaus JW (2017) Effects of acute, profound hypoxia on healthy humans. Anesth Analg. https://doi.org/10.1213/ane.0000000000001421
Lundsgaard-Hansen P, Augustin E, Dawert I, Schülgen C (1966) Regional differences of the lactate/pyruvate response to progressive arterial hypoxemia. Pflugers Arch Gesamte Physiol Menschen Tiere 292(1):60–75. https://doi.org/10.1007/BF00413125
Wolff CB, Richardson N, Kemp O et al (2008) Near infra-red spectroscopy and arterial oxygen extraction at altitude. Adv Exp Med Biol. https://doi.org/10.1007/978-0-387-71764-7_24
Schumacker PT, Cain SM (1987) The concept of a critical oxygen delivery. Intensive Care Med 13(4):223–229. https://doi.org/10.1007/BF00265110
Damiani E, Casarotta E, Orlando F et al (2021) Effects of normoxia, hyperoxia, and mild hypoxia on macro-hemodynamics and the skeletal muscle microcirculation in anesthetised rats. Front Med 8:1–10. https://doi.org/10.3389/fmed.2021.672257
Bernstein D, Teitel D, Sidi D, Heymann MA, Rudolph AM (1987) Redistribution of regional blood flow and oxygen delivery in experimental cyanotic heart disease in newborn lambs. Pediatr Res 22(4):389–393. https://doi.org/10.1203/00006450-198710000-00004
Smit B, Smulders YM, Eringa EC et al (2018) Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis. Crit Care 22(1):1–16. https://doi.org/10.1186/s13054-018-2123-9
Dyess DL, Christenberry DP, Peeples GL et al (1998) Organ blood flow redistribution in response to hypoxemia in neonatal piglets. J Investig Surg 11(6):381–392. https://doi.org/10.3109/08941939809032215
Pinsky MR, Schlichtig R (1990) Regional oxygen delivery in oxygen supply-dependent states. Intensive Care Med 16(2):169–171. https://doi.org/10.1007/BF01785248
Wang L, Sang L, Cui Y et al (2022) Effects of acute high-altitude exposure on working memory: a functional near-infrared spectroscopy study. Brain Behav. https://doi.org/10.1002/brb3.2776
Orbegozo D, Pu F, Donadello K et al (2015) Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microvasc Res 98:23–28. https://doi.org/10.1016/j.mvr.2014.11.006
Fink S, Ray CW, McCartney S, Ehrlich H, Shoemaker WC (1984) Oxygen transport and utilization in hyperoxia and hypoxia: relation of conjunctival and transcutaneous oxygen tensions to hemodynamic and oxygen transport variables. Crit Care Med. https://doi.org/10.1097/00003246-198411000-00004
Hafner S, Beloncle F, Koch A, Radermacher P, Asfar P (2015) Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or Mr. Hyde? A 2015 update. Ann Intensive Care 5(1):1–14. https://doi.org/10.1186/s13613-015-0084-6
Bredle DL, Bradley WE, Chapler CK, Cain SM (1988) Muscle perfusion and oxygenation during local hyperoxia. J Appl Physiol 65(5):2057–2062. https://doi.org/10.1152/jappl.1988.65.5.2057
Shykoff BE, Lee LR, Gallo M, Griswold CA (2021) Transcutaneous and end-tidal CO2 measurements in hypoxia and hyperoxia. Aerosp Med Hum Perform. https://doi.org/10.3357/AMHP.5856.2021
Bredle DL, Petrini MF, Norman JR, Schuller D, Tuchschmidt JA (1993) Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest. https://doi.org/10.1378/chest.103.4.1311c
Popel AS, Gross JF (1979) Analysis of oxygen diffusion from arteriolar networks. Am J Physiol Heart Circ Physiol. https://doi.org/10.1152/ajpheart.1979.237.6.h681
Huckabee WE (1961) Abnormal resting blood lactate. I. The significance of hyperlactatemia in hospitalized patients. Am J Med. https://doi.org/10.1016/0002-9343(61)90171-1
Helmerhorst HJF, Schultz MJ, van der Voort PHJ et al (2014) Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses. Ann Intensive Care 4(1):1–9. https://doi.org/10.1186/s13613-014-0023-y
Beasley R, Chien J, Douglas J et al (2015) Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults: swimming between the flags. Respirology 20(8):1182–1191. https://doi.org/10.1111/resp.12620
Kallstrom TJ (2002) AARC Clinical Practice Guideline: oxygen therapy for adults in the acute care facility—2002 revision and update. Respir Care 47:717
Mugo C, Chojecki D (2016) Oxygen therapy in acute care settings. Institute Health Economics, Alberta, pp 1–10
Casaubon LK, Boulanger JM, Blacquiere D et al (2015) Canadian stroke best practice recommendations: hyperacute stroke care guidelines, update 2015. Int J Stroke 10(6):924–940. https://doi.org/10.1111/ijs.12551
Nikolaou NI, Welsford M, Beygui F et al (2015) Part 5: Acute coronary syndromes. 2015 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Resuscitation 95:e121–e146. https://doi.org/10.1016/j.resuscitation.2015.07.043
Soar J, Nolan JP, Böttiger BW, et al. (2015) European resuscitation council guidelines for resuscitation 2015. Section 3. Adult advanced life support. Resuscitation 95:100–147. https://doi.org/10.1016/j.resuscitation.2015.07.016
Favaron E, Ince C, Hilty MP et al (2021) Capillary leukocytes, microaggregates, and the response to hypoxemia in the microcirculation of Coronavirus disease 2019 patients. Crit Care Med. https://doi.org/10.1097/CCM.0000000000004862
Bertuglia S, Colantuoni A, Coppini G, Intaglietta M (1991) Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol 260(2):29–32. https://doi.org/10.1152/ajpheart.1991.260.2.h362
Davies T, Gilbert-Kawai E, Wythe S et al (2018) Sustained vasomotor control of skin microcirculation in Sherpas versus altitude-naive lowlanders: experimental evidence from Xtreme Everest 2. Exp Physiol 103(11):1494–1504. https://doi.org/10.1113/EP087236
Milstein DMJ, Helmers R, Hackmann S, Belterman CNW, van Hulst RA, de Lange J (2016) Sublingual microvascular perfusion is altered during normobaric and hyperbaric hyperoxia. Microvasc Res 105:93–102. https://doi.org/10.1016/j.mvr.2016.02.001
Acknowledgements
We would like to thank all volunteers for their participation. We would like to thank Nico Hilderink and Richard Petersen for their excellent technical support of construction of the gas-delivery system.
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BH, JP and NJ conceived and designed the study. BH performed study interventions and measurements. BH and NJ drafted the first version of the manuscript. All authors critically read and reviewed the manuscript.
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The MEC-u approved this study protocol with title “The effect of arterial oxygen content on mitoPO2 in healthy human volunteers” and number NL79079.100.21. Informed consent was obtained from all participants prior to enrollment and study procedures were performed in concordance with the Declaration of Helsinki.
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NJ is editor-in-chief of Intensive Care Medicine Experimental.
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Hilderink, B.N., Crane, R.F., van den Bogaard, B. et al. Hyperoxemia and hypoxemia impair cellular oxygenation: a study in healthy volunteers. ICMx 12, 37 (2024). https://doi.org/10.1186/s40635-024-00619-6
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DOI: https://doi.org/10.1186/s40635-024-00619-6