Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study
© The Author(s). 2017
Received: 19 November 2016
Accepted: 16 March 2017
Published: 23 March 2017
The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of ‘relative hypoxia’ which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients.
In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) ≤0.5 and PaO2/FiO2 ≥ 200 mmHg underwent a 2-hour exposure to hyperoxia (FiO2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24 h and 48 h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2 h of hyperoxia (t1) and 2 h after returning to their baseline FiO2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test.
EPO increased within 48 h in patients exposed to hyperoxia from 16.1 [7.4–20.2] to 22.9 [14.1–37.2] IU/L (p = 0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79–90] of baseline). The response after 2 h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO2.
A two-hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48 h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis.
KeywordsErythropoietin Anemia Normobaric hyperoxia Microcirculation
Anemia is a frequent problem in critically ill intensive care patients . Inhibition of erythropoietin (EPO) production induced by inflammatory cytokines contributes to the etiology of critical illness anemia [2–4]. A diminished oxygen (O2) content due to anemia or hypoxaemia is the physiologic stimulus for EPO synthesis . Reports suggest that a sudden decrease in tissue O2 levels after a short-term exposure to normobaric hyperoxia can stimulate EPO synthesis by producing a state of “relative” hypoxia (normobaric oxygen paradox, NOP) [6, 7]. However, studies are needed to demonstrate the effectiveness of this procedure, to define the optimal dose and frequency of exposure , and to confirm the safety of transient exposure to hyperoxia in ICU patients. Hyperoxia induces oxidative damage to various organs , coronary and systemic vasoconstriction  with a fall in cardiac output , and a possible decrease in regional O2 delivery . Exposure to arterial hyperoxia is also associated with higher mortality in certain ICU patient subsets .
We aimed to test the effectiveness of the NOP on increasing serum EPO levels in critically ill patients. Secondly, we explored the safety of hyperoxia exposure by evaluating the microcirculatory response to hyperoxia and the effects upon circulating levels of nitric oxide (NO), reactive O2 species (ROS) and the antioxidant, glutathione (GSH).
This prospective, non-randomized study was approved by the Institutional Review Board of the Azienda Ospedaliera Universitaria Ospedali Riuniti of Ancona, Italy (Protocol nr. 212638; NCT02481843 www.clinicaltrials.gov). Written informed consent was obtained from the enrolled patients or their next of kin. Adult (≥18-year old) patients admitted to the 12-bed medical-surgical ICU of Azienda Ospedaliera Universitaria Ospedali Riuniti of Ancona, Italy between April 2013 and March 2015 and requiring mechanical ventilation with an inspired O2 fraction (FiO2) ≤0.5 and PaO2/FiO2 ≥ 200 mmHg were eligible to participate. Exclusion criteria were: hemoglobin (Hb) <9 g/dL, acute bleeding or blood transfusion during the study period; surgical interventions during the study period; acute or chronic renal failure; hemodynamic instability; chronic obstructive pulmonary disease; pregnancy; factors impeding evaluation of the sublingual microcirculation (oral surgery or maxillo-facial trauma). In all patients, blood pressure was monitored with an arterial catheter. Sedation and analgesia, fluids and vasopressors were provided according to individual needs.
Forty patients were enrolled in total and were allocated in the hyperoxia or control group using a before-after method. The first 20 patients (hyperoxia group) underwent a 2-hour period of normobaric hyperoxia (FiO2 1.0), according to the protocol applied by Balestra et al. . No variation in FiO2 was applied to the last 20 patients (control group). All patients were enrolled in the morning and hyperoxia was performed between 10.00 and 14.00 h to minimize variability due to the circadian rhythm of EPO production. No variations to sedation or vasopressor dosing or ventilator settings were applied during the study period.
On the study day, measurements were taken at baseline (t0), after 2 h of breathing 1.0 FiO2 (hyperoxia, t1) and 2 h after returning to baseline FiO2 (t2). Measures included body temperature, heart rate (HR), mean arterial pressure (MAP), arterial and central venous blood gases, arterial lactate, evaluation of the sublingual microcirculation and peripheral microvascular (StO2) oxygenation. The same measures were performed in the control group but with no period of hyperoxia. Serum EPO, reticulocyte count, Hb and hematocrit were measured at 8 am in all patients on the study day, and at 24 and 48 h.
The sublingual microcirculation was evaluated at five different sites using sidestream dark field (SDF) videomicroscopy (Microscan, Microvision Medical, Amsterdam, NL), as previously described [14–17]. Three images per time-point were analyzed using the Automated Vascular Analysis software (Microvision Medical BV). Total vessel density (TVD), perfused vessel density (PVD), De Backer score, proportion of perfused vessels (PPV), microcirculatory flow index (MFI), flow heterogeneity index (FHI) and blood flow velocity (BFV) were calculated in small or medium vessels (diameter ≤ or >20 μm, respectively) [16, 18]. Continuous video recording was also performed for ≥2 min on one site during the change in FiO2 (either start or end of hyperoxia) to evaluate the early microcirculatory response. Video clips of 10 s’ duration (two per time point) corresponding to before (baseline or 2 h FiO2 1.0) and after (2 min FiO2 1.0 or 2 min after returning to baseline FiO2) the change in FiO2 were selected and subsequently analyzed.
Near-infrared spectroscopy (NIRS) (InSpectra™ Model 650; Hutchinson Technology Inc., Hutchinson, MN, USA) with a 15 mm-sized probe was used to measure microvascular oxygen saturation (StO2) and tissue Hb index (THI)  on the thenar eminence at baseline and during a vascular occlusion test [16, 20]. The StO2 downslope (%/minute) was calculated as an index of O2 consumption, while the StO2 upslope (%/minute) and the area under the curve (AUC) of the hyperemic response were obtained to assess microvascular reactivity .
In the first 12 patients in each group, arterial blood samples (10 mL) were taken at baseline, t1 and t2 and immediately centrifuged; plasma and serum were stored at −70 °C. A marker of NO production was measured as plasma nitrite/nitrate using a Nitric Oxide Colorimetric Detection Kit (Cat. No. K023-H1, Arbor Assays, Ann Arbor, MI, USA) while GSH levels were measured using a Glutathione Colorimetric Detection Kit (Cat. No. K006-H1 - Arbor Assays) following the manufacturer’s instructions. High Reactive Oxygen Species (hROS) levels were determined by hydroxyphenyl fluorescein (Cell Technology Inc, Mountain View, CA, USA), which selectively detects hydroxyl radical (●OH) and peroxynitrite (ONOO−) . Immunoassays could not be performed in all patients for economic reasons.
This was performed using GraphPad Prism Version 6 (GraphPad Software, La Jolla, CA, USA). Normality of distribution was checked using the Kolmogorov-Smirnov test. The data were expressed as mean ± standard deviation (SD) for normally distributed variables or median [1st-3rd quartiles] for non-normally distributed variables. One-way analysis of variance (ANOVA) for repeated measures with Bonferroni post-hoc testing (or Friedman’s test with Dunn’s multiple comparison test for non-normally distributed variables) was used to evaluate changes over time in the same group. For normally distributed variables, the two-way ANOVA for repeated measures with Bonferroni post-hoc testing was used to evaluate differences between the groups. For non-normally distributed variables, the Mann-Whitney U test was applied to evaluate differences between the two groups at the same time-point. Spearman correlation coefficient was calculated to assess correlations between variables. The alpha level of significance was set a priori at 0.05.
A total of 791 patients was screened during the 2-year study period. Of these, 617 patients were excluded because they did not meet the predefined inclusion criteria or had exclusion criteria; 105 patients were excluded as already enrolled in another study; 24 patients denied consent to participation in the study; 45 patients were not enrolled due to the unavailability of the investigators or SDF/NIRS devices. Median age was 74 [53–81] years in the hyperoxia group and 65 [56–73] years in the control group. The male:female ratio was 10:10 and 14:6 in the hyperoxia and control groups, respectively. Admission diagnoses were neurological (hyperoxia group: 4 patients, controls: 12), polytrauma (hyperoxia: 5, controls: 7), post-cardiac arrest (hyperoxia: 7, controls: 1) and sepsis (hyperoxia: 3, none in the control group). The Sequential Organ Failure Assessment (SOFA) score was 8.5 [6.2–10] and 8 [6–9] in the hyperoxia and control groups, respectively.
Hemodynamic and blood gas data
Variations in hemodynamics and blood gas parameters under hyperoxia and after the return to baseline FiO2
Heart Rate (bpm)
70 ± 20
71 ± 22
77 ± 22##‡
67 ± 19
66 ± 19
72 ± 25
Mean Arterial Pressure (mmHg)
Body temperature (°C)
36.1 ± 1.1
36.3 ± 0.9
36.3 ± 1.1*
36.7 ± 0.8
36.7 ± 0.9
37.1 ± 0.8#‡
108 ± 35
433 ± 109###***
111 ± 26‡‡‡
118 ± 33
119 ± 28
115 ± 33
290 ± 93
435 ± 111###***
287 ± 82‡‡‡
314 ± 108
315 ± 93
303 ± 99
7.48 ± 0.07
7.49 ± 0.07
7.48 ± 0.07
7.45 ± 0.06
7.45 ± 0.05
7.45 ± 0.06
Base excess (mmol/L)
5.0 ± 5.2
5.3 ± 5.3
5.6 ± 4.9
2.9 ± 3.8
3.1 ± 4.1
3.3 ± 3.6
Effects on erythropoiesis
Variations in erythropoietin, reticulocyte count, haemoglobin and haematocrit in the two groups
10.7 ± 1.4
10.2 ± 1.3
10.1 ± 1.3#
11.7 ± 2.0
11.3 ± 1.8
11.3 ± 1.7
32 ± 6
31 ± 6
30 ± 6#*
34 ± 8
34 ± 8
34 ± 8
Effects on the sublingual microcirculation
Sublingual and peripheral microvascular changes after a 2-hour exposure to hyperoxia and 2 h after return to baseline FiO2
TVD small (mm/mm2)
TVD medium (mm/mm2)
PVD small (mm/mm2)
PVD medium (mm/mm2)
0.9 ± 0.6
0.6 ± 0.5*
0.8 ± 0.6
1.2 ± 0.6
1.2 ± 0.6
1.1 ± 0.7
De Backer score (n/mm)
MFI small (AU)
PPV small (%)
96 ± 3
94 ± 4
95 ± 3
94 ± 4
95 ± 3
95 ± 4
FHI small (AU)
497 ± 63
489 ± 81
502 ± 45
520 ± 56
519 ± 54
531 ± 65
80 ± 8
82 ± 8
82 ± 7
81 ± 9
81 ± 8
82 ± 9
StO2 downslope (%/min)
−7.9 [−9.1, −7.0]
−7.7 [−9.3, −6.8]
−9.4 [−11.0, −7.9]‡
−8.1 [−9.7, −6.8]
−7.9 [−10.1, −7.0]
−8.6 [−9.9, −6.9]
StO2 upslope (%/min)
StO2 area under the curve (%*min)
14.6 ± 8.8
18.0 ± 11.8
13.2 ± 7.6
20.3 ± 15.1
19.8 ± 14.7
18.3 ± 13.3
11.0 ± 3.2
11.4 ± 3.8
11.8 ± 3.2
12.6 ± 2.2
12.7 ± 3.5
13.0 ± 3.1
The StO2 value was not affected by changes in FiO2. The gradient of the StO2 downslope was however significantly increased at t2 in the hyperoxia group (p < 0.01 versus t1) implying increased O2 extraction rate, although no significant difference was found with the control group. The StO2 upslope, area under the curve and THI did not show any significant change over time in the hyperoxia group compared to controls. All NIRS parameters remained stable in the control group and no differences were found between the two groups at any time-point (Table 3).
NO, ROS and GSH
Changes in nitrite/nitrate, GSH and ROS after a 2-hour exposure to hyperoxia and 2 h after return to baseline FiO2
Hyperoxia (n = 12)
41 ± 17
45 ± 21
43 ± 18
Controls (n = 12)
51 ± 18
55 ± 16
59 ± 14
Hyperoxia (n = 12)
Controls (n = 12)
Hyperoxia (n = 12)
Controls (n = 12)
In this prospective observational study on 40 critically ill patients within different disease categories, a single 2-hour exposure to normobaric hyperoxia was associated with a slight increase in serum EPO levels over the following 48 h, despite wide inter-individual variability in the response observed. An initial decrease in microvascular perfusion was seen during hyperoxia, followed by normalization on returning to the baseline FiO2. Serum ROS levels were elevated after hyperoxia, while the return to the baseline FiO2 was associated with an increase in GSH and normalization of ROS levels.
Intermittent hyperoxia can stimulate erythropoiesis in healthy volunteers and in various patient categories [6, 7, 22, 23], although other reports have questioned the existence of a NOP . Mechanisms underlying the NOP may involve regulation of Hypoxia-Inducible Factor 1-alpha (HIF-1α) expression. During normoxia, HIF-1α undergoes ubiquitination by the Von Hippel Lindau tumor suppressor and degradation into the proteasome. This process is mediated by the oxidized form of glutathione (GSSG). Under hypoxia, the GSH-GSSG ratio increases, thus limiting the inactivation of HIF-1α, which can induce expression of the EPO gene. The increase in ROS during hyperoxia induces de novo synthesis of GSH. When returning to normoxia, the increased production of GSH, together with the reduction of GSSG to GSH, creates a “surplus” of GSH that enhances the inactivation of HIF-1α . Our findings are consistent with this theory: serum ROS levels increased after 2 h of hyperoxia, while GSH levels were elevated 2 h after returning to the baseline FiO2. This variation in GSH levels may be able to modulate the activity of HIF-1α and EPO production.
Several factors may account for the inter-individual variability observed in the NOP response. Arterial hyperoxia (PaO2 > 100 mmHg) was present at baseline in 60% of patients in the hyperoxia group; this may have had either a positive (enhanced induction of GSH synthesis) or negative (higher ROS levels) impact on the EPO response. The two groups were also unbalanced for admission diagnosis so definitive conclusions cannot be drawn. Importantly, baseline Hb levels tended to be lower in the hyperoxia group: this could in itself act as a stimulus for EPO synthesis independent of exposure to hyperoxia.
As EPO secretion normally follows an individual circadian rhythm of production, individual matching of the circadian rhythm is needed to detect an increase in EPO levels at a specific time of the day . This could be particularly important in ICU patients where the normal circadian rhythm of hormone production is frequently abolished due to their underlying illness as well as sedation and disturbances in the sleep-wake cycle . We measured EPO levels at 08.00 h each morning in all patients to limit the impact of this source of variability.
The ideal “dose” of O2 for triggering the NOP is poorly described. An excessive increase in ROS (such as that induced by hyperbaric hyperoxia) may suppress rather than stimulate EPO production . An FiO2 of 1.0 may not represent optimal dosing for all patients and could have produced varying effects. Repeated rather than single exposures may perhaps be more effective .
Arterial hyperoxia causes vasoconstriction, thus reducing tissue perfusion [11, 26]. This cannot be part of an evolutionary innate response as exposure to high concentrations of inspired oxygen can only be traced back to the relatively modern era. Arterial hyperoxia must therefore represent a purely iatrogenic ‘insult’; the ensuing physiological response (vasoconstriction) to the resulting tissue hyperoxia may reproduce adaptive efforts to match O2 supply to reduced cellular metabolic needs seen in pathological states such as sepsis where tissue oxygen tensions rise . The corollary of reducing oxygen supply in conditions of relative tissue oxygen excess is a blunting of the increase in ROS production, thereby attenuating toxicity.
Mechanisms underlying this response may involve a down-regulation of the adenosine pathway  or modulation of the ROS-mediated prostaglandin and NO pathways  with reduced NO bioavailability . In our study, hyperoxia led to an early decrease in microcirculatory vessel density and perfusion after 2 min of exposure. These alterations persisted after 2 h in some patients, while others showed similar or even increased vessel densities as compared with baseline levels. No reduction in plasma NO levels was seen after 2 h hyperoxia, which may reflect the variability observed in microvascular perfusion. An undetected short-lived derangement in the NO pathway may at least partly explain the early microcirculatory alterations observed. Our results suggest that the vasoconstrictor response was more pronounced during an acute increase in arterial PaO2 rather than after a more sustained exposure. Of note, continuous monitoring of the microcirculation in the same region of sublingual mucosa is likely to be more sensitive in detecting even minute variations in vessel density compared to intermittent measurements, as it excludes any variability related to the random selection of different areas, albeit averaged over three samples [31, 32].
Microvascular density and perfusion normalized after the return to the baseline FiO2. This was associated with a decrease in MAP and an increase in HR after 2 h , suggesting a decrease in systemic vascular resistance. The increased gradient in the StO2 downslope at 2 h after returning to baseline FiO2 indicates a higher regional O2 extraction rate. This likely reflects an increase in local perfusion and O2 consumption in this phase. Notably, the microvascular response at 2 h after return to normoxia was inversely related to the variations observed after 2 h of hyperoxia. In other words, those patients who did not demonstrate hyperoxia-induced vasoconstriction tended to show an unaltered or even decreased vessel density at return to baseline FiO2. Several factors including baseline PaO2 and ROS levels, factors affecting vascular tone, or an underlying microvascular/endothelial dysfunction may determine this “non-physiological” response. In healthy volunteers normobaric hyperoxia induced a reduction in the estimated muscle O2 consumption with slower StO2 drop during the VOT . In our study, the StO2 downslope was unaltered after 2 h of hyperoxia, suggesting no apparent effect on muscle O2 consumption, which seems in contrast to the increased ScvO2. It should be taken into account that the response of the peripheral skeletal muscle circulation may not always reflect the response of other organs in the critically ill. Microvascular mechanisms of regulation and adaptation may vary between different capillary beds and may be impaired in a heterogeneous manner during critical illness. Sedation or vasopressors in ICU patients may influence tissue O2 requirements and extraction rate in the peripheral skeletal muscle circulation. Differences in the study protocol and time of exposure to hyperoxia may also contribute to the discrepant results.
Our study has several limitations. First, the non-randomized, non-blinded design of the study, together with the relatively small sample size, precludes drawing definitive conclusions. Second, we studied a necessarily heterogenous critically ill patient population, although we tried to standardize both the patients and their status (e.g. cardiorespiratory stability) as much as possible. Third, baseline differences in Hb between the two groups may be responsible for different changes in EPO levels, irrespective of the exposure to hyperoxia. In addition, we cannot exclude that differences in other parameters between the two groups (e.g. lower body temperature in the hyperoxia group) influenced microvascular perfusion and the changes detected. Fourth, the observed increase in EPO levels may not have been sufficient to induce a significant increase in erythropoiesis. The 48-hour observational period may have been too short to detect an increase in reticulocyte count and Hb after the exposure to hyperoxia. We focussed upon EPO production as numerous confounding factors may have influenced Hb levels over this time period including hemodilution due to fluid infusion, anemia of inflammation, repeated blood sampling, and other blood losses. Fifth, NO, ROS and GSH were measured only in 60% of the study population. Lastly, cardiac output and systemic vascular resistance were not measured in this stable population. As MAP was stable over the course of our study despite the local vasoconstrictor response, we speculate that cardiac output was reduced after 2 h of hyperoxia.
A two-hour exposure to normobaric hyperoxia was associated with a slight increase in serum EPO levels within 48 h in critically ill patients. Mechanisms responsible for the stimulation of erythropoiesis may include an enhanced production of GSH induced by an increase in ROS. This enhanced oxidative stress was followed by normalization 2 h after returning to baseline levels of FiO2. An early vasoconstrictor response was observed at the microcirculatory level under hyperoxia. After 2 h , the response was heterogeneous between different patients, but normalized on returning to the baseline FiO2.
The findings of this pilot study encourage further exploration of the NOP as a means of stimulating erythropoiesis during critical illness. However, adequately controlled studies are needed to isolate the effect of short-term hyperoxia on EPO production independently of possible confounding factors such as baseline Hb levels or the patient’s underlying disease. Potential dangers of excessive O2 exposure must also be considered, specifically enhanced oxidative stress and short-term alterations in microvascular perfusion. Further investigations should clarify the time course of the microvascular response and recovery under hyperoxia in critically ill patients and identify any factors potentially influencing this response.
Analysis of variance
Area under the curve
Blood flow velocity
Flow heterogeneity index
- FiO2 :
Inspired oxygen fraction
Glutathione (reduced form)
Glutathione (oxidized form)
Hypoxia-inducible factor-1 alpha
Intensive care unit
Mean arterial pressure
Microvascular flow index
Normobaric oxygen paradox
- O2 :
Proportion of perfused vessels
Perfused vessel density
Reactive oxygen species
Sidestream dark field
- StO2 :
Tissue oxygen saturation
Tissue hemoglobin index
Total vessel density
The authors wish to thank the patients for their participation in this study and the medical and nurse staff for its support and contribution to the realization of this work.
Availability of data and materials
The data that support the findings of this study are available from the corresponding author upon reasonable request.
AD, MG, EA, RR, LM, PP, MS contributed to the study conception and design and revised the manuscript for important intellectual content. ED, SZ, RD, AG, AV collected and analysed the data, contributed to the interpretation of the results and drafted the manuscript. All authors read and approved the final version of the manuscript. All authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any of its parts are appropriately investigated and resolved.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study protocol was approved by our local ethical committee of Azienda Ospedaliera Universitaria “Ospedali Riuniti” of Ancona, Italy (protocol number 212638). Written informed consent was obtained from all patients or their next of kin.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499–507.View ArticlePubMedGoogle Scholar
- Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555–9.View ArticlePubMedGoogle Scholar
- Van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med. 2000;28:2773–8.View ArticlePubMedGoogle Scholar
- DeAngelo AJ, Bell DG, Quinn MW, Long DE, Ouellette DR. Erythropoietin response in critically ill mechanically ventilated patients: a prospective observational study. Crit Care. 2005;9:R172–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol. 1989;66:1785–8.PubMedGoogle Scholar
- Balestra C, Germonpré P, Poortmans JR, Marroni A. Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the “normobaric oxygen paradox”. J Appl Physiol. 2006;100:512–8.View ArticlePubMedGoogle Scholar
- Lafère P, Schubert T, De Bels D, Germonpré P, Balestra C. Can the normobaric oxygen paradox (NOP) increase reticulocyte count after traumatic hip surgery? J Clin Anesth. 2013;25:129–34.View ArticlePubMedGoogle Scholar
- Rocco M, D’Itri L, De Bels D, Corazza F, Balestra C. The “normobaric oxygen paradox”: a new tool for the anesthetist? Minerva Anestesiol. 2014;80:366–72.PubMedGoogle Scholar
- Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001;21:2–14.View ArticlePubMedGoogle Scholar
- Orbegozo Cortés D, Puflea F, Donadello K, Taccone FS, Gottin L, Creteur J, et al. Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microv Res. 2015;98:23–8.View ArticleGoogle Scholar
- Harten JM, Anderson KJ, Angerson WJ, Booth MG, Kinsella J. The effect of normobaric hyperoxia on cardiac index in healthy awake volunteers. Anesthesia. 2003;58:885–8.View ArticleGoogle Scholar
- Lodato RF. Decreased O2 consumption and cardiac output during normobaric hyperoxia in conscious dogs. J Appl Physiol. 1989;67:1551–9.PubMedGoogle Scholar
- Damiani E, Adrario E, Girardis M, Romano R, Pelaia P, Singer M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care. 2014;18:711.View ArticlePubMedPubMed CentralGoogle Scholar
- Goedhart PT, Khalilzada M, Bezemer R, Merza J, Ince C. Sidestream dark field (SDF) imaging: a novel stroboscopic LED ring-based imaging modality for clinical assessment of the microcirculation. Opt Express. 2007;15:15101–14.View ArticlePubMedGoogle Scholar
- Donati A, Damiani E, Botticelli L, Adrario E, Lombrano MR, Domizi R, et al. The aPC treatment improves microcirculation in severe sepsis/septic shock syndrome. BMC Anesthesiol. 2013;13:25.View ArticlePubMedPubMed CentralGoogle Scholar
- Donati A, Damiani E, Luchetti M, Domizi R, Scorcella C, Carsetti A, et al. Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study. Crit Care. 2014;18:R33.View ArticlePubMedPubMed CentralGoogle Scholar
- Damiani E, Adrario E, Luchetti MM, Scorcella C, Carsetti A, Mininno N, et al. Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis. PLoS One. 2015;10:e0122655.View ArticlePubMedPubMed CentralGoogle Scholar
- De Backer D, Hollenberg S, Boerma C, Goedhart P, Büchele G, Ospina-Tascon G, et al. How to evaluate the microcirculation: report of a round table conference. Crit Care. 2007;11:R101.View ArticlePubMedPubMed CentralGoogle Scholar
- Myers D, McGraw M, George M, Mulier K, Beilman G. Tissue hemoglobin index: a non-invasive optical measure of total tissue hemoglobin. Crit Care. 2009;13 Suppl 5:S2.View ArticlePubMedPubMed CentralGoogle Scholar
- Gómez H, Mesquida J, Simon P, Kim HK, Puyana JC, Ince C, et al. Characterization of tissue oxygen saturation and the vascular occlusion test: influence of measurement sites, probe sizes and deflation thresholds. Crit Care. 2009;13 Suppl 5:S3.View ArticlePubMedPubMed CentralGoogle Scholar
- Setsukinai KI, Urano Y, Kakinuma K, Majima HJ, Nagano T. Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem. 2003;278:3170–5.View ArticlePubMedGoogle Scholar
- Cimino F, Balestra C, Germonpré P, De Bels D, Tillmans F, Saija A, et al. Pulsed high oxygen induces a hypoxic-like response in human umbilical endothelial cells and in humans. J Appl Physiol. 2012;113:1684–9.View ArticlePubMedGoogle Scholar
- Ciccarella Y, Balestra C, Valsamis J, Van der Linden P. Increase in endogenous erythropoietin synthesis through the normobaric oxygen paradox in cardiac surgery patients. Br J Anaesth. 2011;106:752–3.View ArticlePubMedGoogle Scholar
- Debevec T, Keramidas ME, Norman B, Gustaffson T, Eiken O, Mekjavic IB. Acute short-term hyperoxia followed by mild hypoxia does not increase EPO production: resolving the “normobaric oxygen paradox”. Eur J Appl Physiol. 2012;112:1059–65.View ArticlePubMedGoogle Scholar
- Paul T, Lemmer B. Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury. Chronobiol Int. 2007;24:45–61.View ArticlePubMedGoogle Scholar
- Crawford P, Good PA, Gutierrez E, Feinberg JH, Boehmer JP, Silber DH, et al. Effects of supplemental oxygen on forearm vasodilation in humans. J Appl Physiol. 1997;82:1601–6.PubMedGoogle Scholar
- Rosser DM, Stidwill RP, Jacobson D, Singer M. Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis. J Appl Physiol. 1995;79:1878–82.PubMedGoogle Scholar
- Bruzzese L, Rostain JC, Née L, Condo J, Mottola G, Adjriou N, et al. Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26-expression in rat. J Appl Physiol. 2015;119:140–7.View ArticlePubMedGoogle Scholar
- Rousseau A, Tesselaar E, Henricson J, Sjoberg F. Prostaglandins and radical oxygen species are involved in microvascular effects of hyperoxia. J Vasc Res. 2010;47:441–50.View ArticlePubMedGoogle Scholar
- Modun D, Krnic M, Vukovic J, Kokic V, Kukoc-Modun L, Tsikas D, et al. Plasma nitrite concentration decreases after hyperoxia-induced oxidative stress in healthy humans. Clin Physiol Funct Imaging. 2012;32:404–8.View ArticlePubMedGoogle Scholar
- Tytgat SH, van der Zee DC, Ince C, Milstein DM. Carbon dioxide gas pneumoperitoneum induces minimal microcirculatory changes in neonates during laparoscopic pyloromyotomy. Surg Endosc. 2013;27:3465–73.View ArticlePubMedGoogle Scholar
- Milstein DM, Helmers R, Hackmann S, Belterman CN, van Hulst RA, de Lange J. Sublingual microvascular perfusion is altered during normobaric and hyperbaric hyperoxia. Microvasc Res. 2016;105:93–102.View ArticlePubMedGoogle Scholar