Skip to main content

The physiological basis for individualized oxygenation targets in critically ill patients with circulatory shock

Abstract

Background

Circulatory shock, defined as decreased tissue perfusion, leading to inadequate oxygen delivery to meet cellular metabolic demands, remains a common condition with high morbidity and mortality. Rapid restitution and restoration of adequate tissue perfusion are the main treatment goals. To achieve this, current hemodynamic strategies focus on adjusting global physiological variables such as cardiac output (CO), hemoglobin (Hb) concentration, and arterial hemoglobin oxygen saturation (SaO2). However, it remains a challenge to identify optimal targets for these global variables that best support microcirculatory function. Weighting up the risks and benefits is especially difficult for choosing the amount of oxygen supplementation in critically ill patients. This review assesses the physiological basis for oxygen delivery to the tissue and provides an overview of the relevant literature to emphasize the importance of considering risks and benefits and support decision making at the bedside.

Physiological premises

Oxygen must reach the tissue to enable oxidative phosphorylation. The human body timely detects hypoxia via different mechanisms aiming to maintain adequate tissue oxygenation. In contrast to the pulmonary circulation, where the main response to hypoxia is arteriolar vasoconstriction, the regulatory mechanisms of the systemic circulation aim to optimize oxygen availability in the tissues. This is achieved by increasing the capillary density in the microcirculation and the capillary hematocrit thereby increasing the capacity of oxygen diffusion from the red blood cells to the tissue. Hyperoxia, on the other hand, is associated with oxygen radical production, promoting cell death.

Current state of research

Clinical trials in critically ill patients have primarily focused on comparing macrocirculatory endpoints and outcomes based on stroke volume and oxygenation targets. Some earlier studies have indicated potential benefits of conservative oxygenation. Recent trials show contradictory results regarding mortality, organ dysfunction, and ventilatory-free days. Empirical studies comparing various targets for SaO2, or partial pressure of oxygen indicate a U-shaped curve balancing positive and negative effects of oxygen supplementation.

Conclusion and future directions

To optimize risk–benefit ratio of resuscitation measures in critically ill patients with circulatory shock in addition to individual targets for CO and Hb concentration, a primary aim should be to restore tissue perfusion and avoid hyperoxia. In the future, an individualized approach with microcirculatory targets will become increasingly relevant. Further studies are needed to define optimal targets.

Introduction

Circulatory shock, which is defined as a life-threatening state of circulatory system failure associated with decreased tissue perfusion, leading to inadequate oxygen delivery (DO2) to meet cellular metabolic demands, remains a common condition with high morbidity and mortality in the intensive care unit (ICU) [1, 2]. Rapid restitution and maintenance of adequate tissue perfusion and oxygenation is the main treatment goal in critically ill patients in shock [3]. The determinants of global DO2 are the cardiac output (CO), the hemoglobin (Hb) concentration and the oxygen saturation in the arterial blood (SaO2). Hemodynamic management in the ICU thus aims to optimize these three physiological variables (Fig. 1A). However, defining targets for each of these variables to rapidly restore tissue perfusion while avoiding adverse effects associated with over-resuscitation (Fig. 1D), remains a challenge.

Fig. 1
figure 1

Overview of tissue oxygenation. Physiological homeostasis of oxygen delivery to the tissue depends on macrocirculatory (A) and microcirculatory (B) parameters. The macrocirculatory parameters, such as Hb concentration, SaO2, CO and intravascular volume rely on the microcirculatory function. Circulatory shock (D) with insufficient oxygen availability in the tissue is due to reactive oxygen species, inflammation and microcirculatory heterogeneity leading to cell death. The review aims to focus on oxygenation targets, representing a delicate balance between risks and benefits (C). Interventions to influence the different parameters are shown in grey. The measurements options are shown in blue. PiCCO Pulse Contour Cardiac Output, Echo Echocardiography, BGA Blood Gas Analysis, PAC Pulmonary Artery Catheter, HVM Hand-held Vital Microscopy, mitPO2 mitochondrial PO2, NIRS Near-Infrared Spectroscopy

Current resuscitation protocols often emphasize an increase in CO. Interventions are guided by volume or inotrope responsiveness of the stroke volume (SV), a concept based on the Frank-Starling relationship [4, 5] and contractility. They are implemented in various ways in clinical practice [6,7,8]. The focus of the resuscitation is primarily the macrocirculation (Fig. 1A) although in circulatory shock the coherence between the macro- and the microcirculation is often uncoupled. This is shown by an absence of increase in tissue perfusion even though SV might still be responsive to a hemodynamic intervention. Thus, even in presence of persistent fluid responsiveness continued volume resuscitation may be associated with a negative effect on tissue perfusion [9] and with worse outcome [10, 11]. In the case of volume resuscitation, this can be partly explained by a reduction in tissue perfusion with red blood cells through hemodilution related decrease in capillary hematocrit. Without knowledge of the determinants of tissue perfusion and oxygenation, the optimal target for CO remains unknown and may vary from person to person [12]. Additionally, the relationship between DO2 and consumption in sepsis and septic shock has been found to depend on the presence of microcirculatory shunting in addition to mitochondrial dysfunction [13]. Recent technological developments that allow direct bedside assessment of microcirculatory function could open up the possibility of targeting microcirculation [14,15,16] and put individualized, tissue red blood cell perfusion focused therapy within reach [17, 18].

The second determinant of global DO2, Hb concentration, directly facilitates oxygen transport in the blood as oxygen is very poorly soluble in blood plasma (< 3%). Anemia due to various causes is common in critically ill patients. However the transfusion thresholds for these patients are mainly based on two trials, the TRICC [19] and TRISS [20] trial. The trials showed a similar 90-day mortality comparing a Hb of 7 g per deciliter (g/dl) and of 9 g/dl. In patients with septic shock, mortality at 90 days, rates of ischemic events and use of life support were similar in those with a higher Hb target and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions [20]. Following these trials Hb targets between 7 and 8 g/dl were defined for most patients, depending on some general additional factors, such as hemodynamic instability, acute bleeding, or risk factors such as previous surgery or coronary artery conditions [21,22,23]. However, these studies do not fully represent the heterogeneous population of critically ill patients suffering from different types of circulatory shock. Nevertheless, the commonly used Hb concentration targets provide little individualization and often do not consider its role in the restoration of tissue perfusion and organ function (e.g., kidney) in patients with circulatory shock [24].

In terms of optimizing the risk–benefit ratio of hemodynamic stabilization of patients with circulatory shock, oxygen supplementation to increase oxygen content per blood volume, in absence of lung disease, may be the most important to consider (Fig. 1C). A stronger focus on the risks associated with the intervention is desirable, because on the one hand, changes in blood oxygenation within the physiological range of oxygen saturation, according to the dissociation curve, only marginally influence global oxygen supply. On the other hand, supramaximal pulmonary and blood oxygenation can be associated with an increased potential for negative effects. However, increasing acidosis due to tissue hypoperfusion may result in increased DO2 due to the Bohr effect on the dissociation curve. Previous studies have demonstrated that critically ill patients often show high SaO2 values even though there are indications that the relationship between SaO2 and mortality likely is U-shaped [25]. The difficulty in defining SaO2 targets may thus represent a risk for hyperoxia based on fear of hypoxia and avoiding hyperoxia could represent a promising strategy to improve patient management.

This narrative review aims to explore the factors influencing decision-making regarding oxygenation targets in critically ill patients with circulatory shock. It examines the risks and benefits of oxygen supplementation by assessing the physiological basis for DO2 and the regulatory mechanisms designed to counteract deficiencies. By providing an overview of the relevant literature, we aim to support decision making at the bedside and provide an outlook on future trends.

Oxygen delivery to the tissues is the basis for all processes of life

To reach the current understanding of the role of oxygen in sustaining life has taken many centuries of research. Oxygen is essential for modern metazoan organisms, which emerged around 300 million years ago, coinciding with the significant rise of oxygen levels in Earth’s atmosphere [26]. Oxygen was independently discovered by the English chemist Joseph Priestley and Carl Wilhelm Scheel around 1774 [27], and was named by Antoine Lavoisier in 1778. The “Pneumatic Institution”, founded 1798 in Bristol, was one of the first places where the effects of oxygen on the human organism were examined in the setting of different illnesses. In collaboration with James Watt and Humphry Davy many new methods to deliver oxygen to patients were developed. The research was accelerated at the beginning of the twentieth century with the discovery of oxygen tensions as partial pressure by Adolf Fick and Paul Bert. But it was not until 1917 that John Scott Haldane, following a coal mine explosion, developed the first face mask with a possibility to adjust the administration of oxygen [28]. However, the administration of supplemental oxygen is only the first step, as the oxygen must find its way to the tissue, where oxidative phosphorylation takes place. Oxygen rich blood travels through a network of branching vasculature and is distributed in the tissue by the microcirculation, consisting of arterioles, capillaries, and post-capillary venules with a diameter below 20 µm. The red blood cells, which measure between 3 and 6 µm, travel through the capillaries in a single file fashion and provide oxygen via convection and diffusion [15]. The former occurs through the movement of Hb-bound oxygen molecules from the red blood cells in the capillary network to the mitochondria to fulfil their metabolic function [29]. In this process, the high affinity of the cytochrome c oxidase, the enzyme that reduces oxygen to water, to oxygen plays an important role in maintaining homeostasis by binding oxygen over a wide range of local oxygen pressures in the mitochondria, as low as 0.3–1.0 kPa. This remarkable property forms the basis for the oxygen conformance theory, which states that only at the extremely low end of tissue oxygenation, oxygen demand becomes dependent on supply. In other words, the functionality of oxidative phosphorylation as the basis of all life, can be maintained in the most extreme of conditions [30, 31].

Physiologic adaptation to hypoxemia demonstrates the adaptability of the pulmonary and systemic microcirculation

In line with the importance of maintaining oxidative phosphorylation, the physiological processes along the oxygen supply chain are aimed at avoiding hypoxemia and hypoxia, the former referring to low blood oxygen content, and the latter, to low oxygen levels in the tissue. Genetic and physiological adaptation mechanisms to hypoxia ensure the maintenance of the homeostasis in states of external limitation of oxygen supply, and internal causes of tissue mal perfusion due to systemic disease. However, before understanding the role of hypoxia in disease, isolated models of tissue hypoxia were needed to examine these intrinsic mechanisms. Early research on adaptation to hypoxia was performed by Paul Bert in his compression chamber at the University of Sorbonne in Paris in the nineteenth century. In the following twentieth century subsequent field research was extended to high altitude locations around the world [32]. As partial pressure of oxygen decreases with ascent to high altitudes, the human body relies on an intricate system to detect the lower oxygen availability and react to it to maintain adequate tissue oxygenation. Some of these mechanisms focus on the functioning of the lungs, others on the systemic organs. In general, all animals express hypoxia-inducible factor (HIF) 1, composed of HIF-1α and HIF-1β, and vertebrates also produce HIF-2 and HIF-3. HIF-1 and HIF-2 can activate gene transcription which in turn regulates systemic DO2 and utilization, the role of HIF-3 is less well known. HIF-1 is regulated by oxygen-dependent hydroxylation by the von Hippel-Lindau protein. The O2-dependent binding is inhibited during hypoxic conditions and the HIF-1 activates some and inhibits other genes. At the tissue level, hypoxia leads to angiogenesis via the regulation of vascular endothelial growth factor and to a shift to anaerobic metabolism via the induction of glycolysis and glucose transporters. At the same time HIF-2 regulates several genes that control erythropoiesis [33]. Moreover, HIF are crucial in a multitude of mechanisms protecting cells from oxidative stress by increasing antioxidant production and decreasing oxidant production [34]. While HIF effectively regulates medium- and long-term responses on a cellular level, immediate physiological adaptation is needed to provide acute adaptation to hypoxia.

In order to regulate the function of the cardio-respiratory system during hypoxia, oxygen levels are sensed rapidly at the glomus caroticum, which is located at the bifurcation of the internal and external carotid arteries. The chemoreceptor tissue, which contains type I neuronal glomus cells and type II sustentacular, glia-like cells, is sensory innervated by the carotid sinus nerve. The exact mechanism to detect hypoxia in these cells is not yet found and still under debate. It is assumed that hypoxia depolarizes the glomus cells through a inhibition of K + cannels and that the subsequent calcium-dependent release of excitatory neurotransmitters increases the neuronal activity [35]. In this way, cardiovascular and respiratory responses are triggered and / or modulated. In addition, different parts of the circulatory system have intrinsic regulation mechanisms. The pulmonary circulation responds with vasoconstriction of the pre-alveolar arterioles to a decrease of alveolar oxygen partial pressure. The effect was first described by Bradford and Dean in 1889 and was subsequently named Euler–Liljestrand-reflex [36]. Its rapid onset results from constriction of the small intrapulmonary arteries, mainly the pre-capillary vessels but also, to some extent, the post-capillary venules [37]. The sensory mechanism to detect alveolar hypoxia seems to be within the mitochondria of the smooth muscle cells of the pulmonary arteries [38]. Thanks to this mechanism, a ventilation-perfusion mismatch can be avoided. In global hypoxia, such as at high altitude or with diffuse lung damage, a diffuse Euler-Liljestrand-reflex leads to an increase of pulmonary artery pressure [39]. In the systemic circulation, on the other hand, the focus is to optimize oxygen availability in the tissues (Fig. 1B). Autoregulation of arterial tone plays an important role in the regional distribution of blood flow [40]. An increase in the activity of the sympathetic nervous system during acute hypoxemia, and above all a reduction of the activity of the parasympathetic nervous system in the following weeks, appears to be responsible for an increase in heart rate [41]. Simultaneously changes in plasma volume appear to cause a decrease in SV which ultimately leads to a constant CO [32]. These changes are often confounded by additional factors such as exercise or hypovolemia. Furthermore, systemic vascular tone and systemic vascular hindrance have been found to remain unaffected during ascent to high altitude. Recent observations have led to a deeper understanding of the mechanisms to increase DO2 to the tissue during hypoxic exposure. In a large study of healthy volunteers ascending to 7124 m, recruitment of pre-existing capillaries was identified as the main physiological response to increase microcirculatory oxygen extraction capacity at high altitude [42]. A variability in the response of the microcirculation has been described in different organs [43, 44]. Dark field microscopy images of the sublingual microcirculation recorded in healthy volunteers at sea level and after 2 weeks at 7042 m, representative for the response mechanisms to hypoxia, are shown in Fig. 2A, B.

Fig. 2
figure 2

Sublingual microcirculation images. Representative images of the sublingual microcirculation before and after the topical application of nitroglycerin, during exposure to extreme altitude, and in critically ill COVID-19 patients. The sublingual microcirculation shows a similarly reaction to hypoxia in healthy volunteers at high altitudes, and critically ill COVID-19 patients. The application of a topical nitroglycerin in healthy volunteers leads to an increase of capillary density that is similar to adaptation to high altitude. Adapted from [42, 45]

Effects and adaptation to hypoxemia in critically ill patients

Different to volunteers at high altitude, critically ill patients in circulatory shock often present with insufficient tissue oxygenation due to impaired microcirculation. In sepsis and septic shock, the microcirculatory alterations also include primary damage to the microcirculation caused by the inflammatory processes and changes to the coagulation system, resulting in a reduced functional capillary density, more non-perfused and intermittently perfused capillaries and an increase in perfusion heterogeneity [3] (Fig. 1D). Other forms of circulatory shock can lead to similar alterations due to secondary damage to the endothelial cells and the tissue [18]. In critically ill patients, altered microcirculation without improvement in disease progression has been shown to be a strong predictor for poor outcome with higher mortality [46]. Measurement of microcirculatory function in critically ill patients with severe hypoxemia and higher SOFA scores due to COVID-19 ARDS showed increased microcirculatory diffusion and convection capacity this in contrast to other viral disease [45, 47, 48]. Representative dark-field microscopy of this population is shown alongside healthy volunteers adapted to high altitude in Fig. 2C. In these patients with isolated lung failure, it was thus possible to study the effects of hypoxemia on an otherwise functionally intact systemic microcirculation and it was shown that adaptation mechanisms to tissue hypoxia are similar to the adaption of healthy volunteers at high altitude. These findings confirm a physiological link between high altitude physiology and critical illness, where in both conditions tissue hypoxia is present. Furthermore, experimental data indicate protective effects associated with adaptation to hypoxia in states of disease, such as a reduced myocardial infarction size in mice when subjected to continuous normobaric hypoxia [49, 50]. These effects show that the intrinsic mechanisms of microcirculation can help the tissue to cope with hypoxemia, provided a sufficient global blood flow and availability of Hb as oxygen carrier.

Hyperoxia may promote microcirculatory dysfunction and cell death through reactive oxygen species (ROS) production

In contrast to hypoxemia, hyperoxia, defined as excess of oxygen in the tissue and hyperoxemia, being a high blood oxygen content, are often caused by medical staff administering an overabundance of oxygen to the patient. Compared to the macro- and microhemodynamic effects of CO and Hb availability, the effect of differences in oxygen saturation achieved by oxygen supplementation is more difficult to quantify. Hyperoxia induced in the clinical setting by lack of awareness [51] can harm patients through production of ROS and induction of inflammation. At the time of discovery, Joseph Priestley was already discussing possible negative effects of oxygen. Shortly thereafter, Antoine Lavoisier discovered the presence of lung damage in guinea pigs after inhalation of pure oxygen [52]. In 1958, a first report was published on lung damage in humans detected after and possibly related to long-term oxygen therapy [53]. Later research located the main source of ROS within the respiratory chain of the mitochondria in the pulmonary vascular endothelial cells, where the precursor superoxide anion originates at complex III at the inner membrane of mitochondria. The superoxide anion in turn changes into hydrogen peroxide and further turns into water or hydroxyl radicals, which are the main ROS [54]. They are responsible for the adverse effects in tissues across the body. The primary effects of hyperoxia in the lung occur in the form of damage to pulmonary capillary endothelial cells, followed by destruction of pulmonary epithelial cells. Hyperoxia and associated high levels of ROS destroy cellular macro-molecules leading to cell death or initiating apoptosis (Fig. 1D). The effect on remote tissues depends on the inflammatory response with the secretion of chemo-attractants and pro-inflammatory cytokines attracting leukocytes. The leukocytes are thus indirect effectors and at the same time another source of ROS with consecutive inflammation and further destruction of lung and other tissue [55]. High levels of superoxide anions can lead to specific organ damage and ultimately, promote multi-organ failure [56]. The hyperoxic microcirculation primarily shows a decrease in capillary density, that may be accompanied by an increased heterogeneity of capillary perfusion as normally seen in septic patients [13, 57, 58]. Additionally, the mitochondrial oxygen tension (mitPO2) decreased over a level of 26.6 kPa PaO2 [59]. In the systemic vascular bed, hyperoxemia can increase vascular resistance and mean arterial pressure and may decrease CO [60, 61]. Despite this in ovine models of acute peritonitis hyperoxia lead to better macro- and microcirculatory parameters [62]. Whereas a systematic review of hyperoxia in sepsis and septic shock in humans showed in 6 out of 10 included studies an increased mortality [63]. A recent study with mechanically ventilated mice could show time- and dose-dependent immune response of hyperoxia with raised cytokines, neutrophils and chemokines [64]. Knowledge of the relationship between the fraction of inspired oxygen (FiO2) and the formation of ROS particularly above a threshold FiO2 of 0.6 [65], and the mechanisms leading to the adverse effects have increased awareness with oxygen supplementation.

Lower versus higher oxygenation targets in critically ill patients

The recent advances in our understanding of the effects of both tissue hypoxia and hyperoxia, have underlined the importance of the level of oxygen supplementation not only in terms of a risk–benefit ratio in critically ill patients, but also because of potential protective effects of adaptation mechanisms to hypoxia. Based on the investigation of these pathophysiological mechanisms related to tissue oxygen availability, several clinical studies have been conducted in critically ill patients (Table 1). A trial published in 2014 compared different oxygen saturation (SpO2) targets (SpO2 90–92% versus higher SpO2) and showed only a decrease in lactate levels but no other difference [66]. Another study comparing liberal targets SpO2 above 96% with a conservative group target (SpO2 88–92%) pointed toward a slightly lower 90-mortality in the conservative group [67]. The Oxygen-ICU randomized clinical trial, published in 2016, showed lower ICU-mortality with less episodes of shock, liver failure and bacteremia in the conservative group with an SpO2 target of 94–97% (PaO2 9.3–13.3 kPa) compared to the conventional group with SpO2 of 97–100% (PaO2 up to 20 kPa) [68]. The HYPERS2S-Trial was stopped prematurely when no benefit of hyperoxia with a FiO2 of 1.0 for 24 h compared to a conservative group with SpO2 88–95% could be found [69]. The IOTA review and meta-analysis revealed a dose-dependent increased risk of short- and long-term mortality of patients treated with liberal oxygen [70]. The ICU-ROX investigators found no significant difference in mortality comparing a conservative group with SpO2 < 97% and an usual-oxygen group with no upper limits [71]. On the contrary the LOCO2 Trial was stopped early because of suspicion of an increased risk for serious adverse events and higher 90-day mortality in the conservative group [72]. The biggest prospective study of the HOT-ICU investigators comparing a lower-oxygenation group with PaO2 target of 8 kPa and a higher-oxygenation group with PaO2 of 12 kPa with a total of 2928 patients showed no difference in the 28-day mortality or serious adverse effects [73]. A post hoc subgroup analysis of the cohort did not show any difference in the 90-day mortality between the two groups [74]. Nevertheless, the lower oxygenation group had a significantly higher percentage of days alive without life support. Further a study from the Netherlands with 574 patients (low-normal group PaO2 8–12 kPa, high-normal 14–18 kPa) also found no significant difference in organ dysfunction at 14 days, nor significant differences in 90-day mortality, duration of mechanical ventilation and ICU length of stay [75]. The US PILOT trial, involving 2541 patients, did now show any difference in the number of ventilatory-free days by day 28 between a lower (SpO2 90%), intermediate (SpO2 94%) and a higher (SpO2 98%) oxygenation target group [76]. However, despite the set oxygenation targets, each group in the study experienced substantial periods of hyperoxia (SpO2 of 99–100%), accounting for 12.3% of the total measurements time in the lower group, 14.7% in the intermediate group, and 32.7% in the higher group. The ICONIC-trial, involving 664 patients, did not find any reduction of the 28-day mortality between a low-oxygenation target (PaO2 6.6–10.6 kPa, SaO2 91–94%) or a high-oxygenation target (PaO2 14.6–20 kPa, SaO2 96–100%) [77]. The recently published HOT-COVID-trial did show more days alive without life support at 90 days in the lower oxygenation group (PaO2 8 kPa) compared to the higher oxygenation group (PaO2 12 kPa) [78] but the mortality at 90 days did not differ between the two target groups. Furthermore a literature review with a meta-analysis of 16 trials could not point out a significant difference in mortality in higher or lower oxygenation target at maximum follow-up [79]. The effect of the distinct oxygenation targets in these studies are summarized in Supplementary Table 1. Currently there are two big pending studies, the UK-ROX trial with 16′500 patients and the MEGA-ROX trial with 40,000 patients.

Table 1 Study setting, comparisons and findings in the 12 original studies and the two meta-analyses on the effect of distinct oxygenation targets

These clinical trials show that oxygenation targets might be an important determinant of outcome, but the balance between risks and benefits may lie close together. This leads to an even greater challenge to define targets for oxygenation. Further studies should focus on exploring oxygenation targets in subpopulations of critically ill patients.

Integration of microcirculation measurements in resuscitation of critically ill patients

Currently, the resuscitation of patients with circulatory shock is primarily focused on the macrocirculation. Tissue perfusion is restored by using crystalloids, inotropes, vasopressors and/or blood transfusions [8, 24]. For the primary assessment as well as the assessment of treatment response pulse contour analysis, the pulmonary artery catheter (PAC) and echocardiography are used. However, as the microcirculation determines the oxygen availability for the organs it should be assessed and restored in parallel to the macrocirculation [16] (Fig. 3). Bedside assessment of microcirculation is not well established today but there are different methods used in experimental settings which could also be used in the clinic. One promising option is the hand-held vital microscopy (HVM) that uses dark field imaging technique and can be performed sublingually. HVM enables to measure tissue red blood cell perfusion allowing differentiation of the effect of resuscitation measures on diffusion and convection capacity of oxygen carriers in the capillaries independently. New developments are underway to add two-wavelength measurements and ability to measure hemoglobin oxygen saturation in individual oxygen carriers as they move through the tissue. Another interesting tool is the non-invasively cellular oxygen metabolism measurement monitor (COMET), that measures mitochondrial oxygen tension (mitoPO2), being the real endpoint of the oxygen cascade. [59, 80]. Further, Near-Infrared Spectroscopy (NIRS) can give insight into red blood cell oxygenation and laser Doppler measures red blood cell velocity. It would be welcome if in the future there were a combined tool to measure the mitochondrial oxygen tension and other determinants of the microcirculation. The microcirculation can be influenced by conventional measures such as the manipulation of FiO2, the administration of fluids, RBC transfusions or vasoactiva but also modulation of the NO and the arachidonic pathways as well as the endothelium are discussed. Under certain conditions, the necessary measures for resuscitation of the macro- and microcirculation may be contradictory, for example a desired vasodilatation in the periphery with a need for vasopressors to maintain sufficient organ perfusion. It is important to develop appropriate schemes and test them in the clinic to determine appropriate cut-off values for determinates of the microcirculation. The goal would be a simple assessment of the microcirculation bedside with a corresponding algorithm for optimization.

Fig. 3
figure 3

Resuscitation pathway. The oxygen availability in critically ill patients with circulatory shock should be assessed promptly. The macro- and microcirculation should be evaluated and addressed in parallel and the effect of resuscitation interventions should be re-assessed

Conclusion

The three main determinants of the global DO2 are the CO, the Hb concentration and SaO2. Although it remains challenging to define targets for all three variables and these must be individually adjusted, the emerging literature shows that avoiding hyperoxia is essential to improve the risk–benefit ratio of hemodynamic stabilization in critically ill patients with circulatory shock. In absence of pulmonary disease, oxygen supplementation to increase SaO2 may be one of the least effective means to increase oxygen availability in the tissue. Limiting oxygen supplementation may provide a promising approach to reduce adverse effects of oxygen and even promote protective adaptation mechanisms. Advances in the direct measurement of tissue perfusion and mitochondrial oxygen tension could provide a novel approach to bring tissue-centric, individualized resuscitation at the bedside, increase awareness of the interplay of the SaO2, the CO and the Hb concentration and improve the risk–benefit ratio of hemodynamic interventions.

For the definition of clear targets in critically ill patients further studies are needed. Based on the current literature, we recommend a conservative approach providing only the minimum necessary FiO2 to effectively prevent hyperoxemia and hyperoxia.

Availability of data and materials

Not applicable.

References

  1. Kolte D, Khera S, Aronow WS et al (2014) Trends in incidence, management, and outcomes of cardiogenic shock complicating ST-elevation myocardial infarction in the United States. J Am Heart Assoc 3:e000590

    Article  PubMed  PubMed Central  Google Scholar 

  2. Holler JG, Henriksen DP, Mikkelsen S et al (2016) Shock in the emergency department; a 12 year population based cohort study. Scand J Trauma Resusc Emerg Med 24:87

    Article  PubMed  PubMed Central  Google Scholar 

  3. De Backer D, Donadello K, Sakr Y et al (2013) Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med 41:791–799

    Article  PubMed  Google Scholar 

  4. De Backer D, Aissaoui N, Cecconi M et al (2022) How can assessing hemodynamics help to assess volume status? Intensive Care Med 48:1482–1494

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bakker J, Kattan E, Annane D et al (2022) Current practice and evolving concepts in septic shock resuscitation. Intensive Care Med 48:148–163

    Article  PubMed  Google Scholar 

  6. Jentzer JC, Hollenberg SM (2021) Vasopressor and inotrope therapy in cardiac critical care. J Intensive Care Med 36:843–856

    Article  PubMed  Google Scholar 

  7. Evans L, Rhodes A, Alhazzani W et al (2021) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med 49:e1063

    Article  PubMed  Google Scholar 

  8. Arabi YM, Belley-Cote E, Carsetti A et al (2024) European Society of Intensive Care Medicine clinical practice guideline on fluid therapy in adult critically ill patients. Part 1: the choice of resuscitation fluids. Intensive Care Med 50:813–831

    Article  PubMed  Google Scholar 

  9. Siam J, Kadan M, Flaishon R et al (2015) Blood flow versus hematocrit in optimization of oxygen transfer to tissue during fluid resuscitation. Cardiovasc Eng Technol 6:474–484

    Article  PubMed  Google Scholar 

  10. Gavelli F, Shi R, Teboul J-L et al (2022) Extravascular lung water levels are associated with mortality: a systematic review and meta-analysis. Crit Care Lond Engl 26:202

    Article  Google Scholar 

  11. Tigabu BM, Davari M, Kebriaeezadeh A et al (2018) Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: a systematic review. J Crit Care 48:153–159

    Article  PubMed  Google Scholar 

  12. Ince C (2015) Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 19:S8

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ince C, Sinaasappel M (1999) Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27:1369–1377

    Article  CAS  PubMed  Google Scholar 

  14. Hilty MP, Ince C (2020) Automated quantification of tissue red blood cell perfusion as a new resuscitation target. Curr Opin Crit Care 26:273–280

    Article  PubMed  Google Scholar 

  15. Guven G, Hilty MP, Ince C (2020) Microcirculation: physiology, pathophysiology, and clinical application. Blood Purif 49:143–150

    Article  CAS  PubMed  Google Scholar 

  16. Duranteau J, De Backer D, Donadello K et al (2023) The future of intensive care: the study of the microcirculation will help to guide our therapies. Crit Care 27:190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hilty MP, Guerci P, Ince Y et al (2019) MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy. Commun Biol 2:217

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hilty MP, Akin S, Boerma C et al (2020) Automated algorithm analysis of sublingual microcirculation in an international multicentral database identifies alterations associated with disease and mechanism of resuscitation. Crit Care Med 48:e864–e875

    Article  CAS  PubMed  Google Scholar 

  19. Hébert PC, Wells G, Blajchman MA et al (1999) A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 340:409–417

    Article  PubMed  Google Scholar 

  20. Holst LB, Haase N, Wetterslev J et al (2014) Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 371:1381–1391

    Article  PubMed  Google Scholar 

  21. Mueller MM, Van Remoortel H, Meybohm P et al (2019) Patient blood management: recommendations from the 2018 Frankfurt Consensus Conference. JAMA 321:983–997

    Article  PubMed  Google Scholar 

  22. Cable CA, Razavi SA, Roback JD et al (2019) RBC transfusion strategies in the ICU: a concise review. Crit Care Med 47:1637–1644

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ducrocq G, Gonzalez-Juanatey JR, Puymirat E et al (2021) Effect of a restrictive vs liberal blood transfusion strategy on major cardiovascular events among patients with acute myocardial infarction and anemia: the REALITY randomized clinical trial. JAMA 325:552–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vlaar APJ, Dionne JC, de Bruin S et al (2021) Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med 47:1368–1392

    Article  PubMed  PubMed Central  Google Scholar 

  25. 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 Lond Engl 12:R156

    Article  Google Scholar 

  26. Lyons TW, Reinhard CT, Planavsky NJ (2014) The rise of oxygen in Earth’s early ocean and atmosphere. Nature 506:307–315

    Article  CAS  PubMed  Google Scholar 

  27. Priestley J (1776) Experiments and observations on different kinds of air, 2nd edn. Cambridge University Press, Cambridge

    Google Scholar 

  28. Haldane JS (1917) The therapeutic administration of oxygen. Br Med J 1:181–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pias SC (2021) How does oxygen diffuse from capillaries to tissue mitochondria? Barriers and pathways. J Physiol 599:1769–1782

    Article  CAS  PubMed  Google Scholar 

  30. Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39–55

    Article  CAS  PubMed  Google Scholar 

  31. Poole DC, Musch TI, Colburn TD (2022) Oxygen flux from capillary to mitochondria: integration of contemporary discoveries. Eur J Appl Physiol 122:7–28

    Article  CAS  PubMed  Google Scholar 

  32. West JB (2016) Early history of high-altitude physiology. Ann N Y Acad Sci 1365:33–42

    Article  CAS  PubMed  Google Scholar 

  33. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Samanta D, Prabhakar NR, Semenza GL (2017) Systems biology of oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. https://doi.org/10.1002/wsbm.1382

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zoccal DB, Vieira BN, Mendes LR et al (2024) Hypoxia sensing in the body: an update on the peripheral and central mechanisms. Exp Physiol 109:461–469

    Article  CAS  PubMed  Google Scholar 

  36. Euler USV, Liljestrand G (1946) Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 12:301–320

    Article  Google Scholar 

  37. Hillier SC, Graham JA, Hanger CC et al (1985) Hypoxic vasoconstriction in pulmonary arterioles and venules. J Appl Physiol Bethesda Md 1997(82):1084–1090

    Google Scholar 

  38. Sommer N, Alebrahimdehkordi N, Pak O et al (2020) Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing. Sci Adv 6:eaba0694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hilty MP, Müller A, Flück D et al (2016) Effect of increased blood flow on pulmonary circulation before and during high altitude acclimatization. High Alt Med Biol 17:305–314

    Article  PubMed  Google Scholar 

  40. Jansen GFA, Krins A, Basnyat B et al (1985) Role of the altitude level on cerebral autoregulation in residents at high altitude. J Appl Physiol Bethesda Md 2007(103):518–523

    Google Scholar 

  41. Siebenmann C, Rasmussen P, Hug M et al (2017) Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude. J Physiol 595:1619–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hilty MP, Merz TM, Hefti U et al (2019) Recruitment of non-perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m. J Physiol 597:2623–2638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tavy AL, de Bruin AF, Boerma EC et al (2021) Association between serosal intestinal microcirculation and blood pressure during major abdominal surgery. J Intensive Med 1:59–64

    Article  PubMed  PubMed Central  Google Scholar 

  44. Uz Z, Shen L, Milstein DMJ et al (2020) Intraoperative imaging techniques to visualize hepatic (micro)perfusion: an overview. Eur Surg Res 61:2–13

    Article  PubMed  Google Scholar 

  45. 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 49:661–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Trzeciak S, Dellinger RP, Parrillo JE et al (2007) Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med 49(88–98):98.e1–2

    Google Scholar 

  47. Salgado DR, Ortiz JA, Favory R et al (2010) Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection. Can J Anesth Can Anesth 57:940–946

    Article  Google Scholar 

  48. Abou-Arab O, Beyls C, Khalipha A et al (2021) Microvascular flow alterations in critically ill COVID-19 patients: a prospective study. PLoS ONE 16:e0246636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Prokudina ES, Naryzhnaya NV, Mukhomedzyanov AV et al (2019) Effect of chronic continuous normobaric hypoxia on functional state of cardiac mitochondria and tolerance of isolated rat heart to ischemia and reperfusion: role of µ and delta2 opioid receptors. Physiol Res 68:909–920

    Article  CAS  PubMed  Google Scholar 

  50. Maslov LN, Sementsov AS, Naryzhnaya NV et al (2022) The role of mitochondrial KATP channels in the infarct-reducing effect of normobaric hypoxia. Bull Exp Biol Med 174:190–193

    Article  CAS  PubMed  Google Scholar 

  51. Cornet AD, Kooter AJ, Peters MJL et al (2013) The potential harm of oxygen therapy in medical emergencies. Crit Care Lond Engl 17:313

    Article  Google Scholar 

  52. Bean JW (1945) Effects of oxygen at increased pressure. Physiol Rev Am Physiol Soc 25:1–147

    CAS  Google Scholar 

  53. Pratt PC (1958) Pulmonary capillary proliferation induced by oxygen inhalation. Am J Pathol 34:1033–1049

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kallet RH, Matthay MA (2013) Hyperoxic acute lung injury. Respir Care 58:123–141

    Article  PubMed  Google Scholar 

  56. Damiani E, Adrario E, Girardis M et al (2014) Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care Lond Engl 18:711

    Article  Google Scholar 

  57. Edul VSK, Enrico C, Laviolle B et al (2012) Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock. Crit Care Med 40:1443–1448

    Article  PubMed  Google Scholar 

  58. Valenzuela Espinoza ED, Pozo MO, Kanoore Edul VS et al (2019) Effects of short-term hyperoxia on systemic hemodynamics, oxygen transport, and microcirculation: an observational study in patients with septic shock and healthy volunteers. J Crit Care 53:62–68

    Article  PubMed  Google Scholar 

  59. Hilderink BN, Crane RF, van den Bogaard B et al (2024) Hyperoxemia and hypoxemia impair cellular oxygenation: a study in healthy volunteers. Intensive Care Med Exp 12:37

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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 8:672257

    Article  Google Scholar 

  61. Smit B, Smulders YM, van der Wouden JC et al (2018) Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis. Crit Care Lond Engl 22:45

    Article  Google Scholar 

  62. He X, Su F, Xie K et al (2017) Should hyperoxia be avoided during sepsis? An experimental study in ovine peritonitis. Crit Care Med 45:e1060–e1067

    Article  PubMed  Google Scholar 

  63. Catalanotto FR, Ippolito M, Mirasola A et al (2023) Hyperoxia in critically ill patients with sepsis and septic shock: a systematic review. J Anesth Analg Crit Care 3:12

    Article  PubMed  PubMed Central  Google Scholar 

  64. Helmerhorst HJF, Schouten LRA, Wagenaar GTM et al (2017) Hyperoxia provokes a time- and dose-dependent inflammatory response in mechanically ventilated mice, irrespective of tidal volumes. Intensive Care Med Exp 5:27

    Article  PubMed  PubMed Central  Google Scholar 

  65. Turrens JF, Freeman BA, Crapo JD (1982) Hyperoxia increases H2O2 release by lung mitochondria and microsomes. Arch Biochem Biophys 217:411–421

    Article  CAS  PubMed  Google Scholar 

  66. Suzuki S, Eastwood GM, Glassford NJ et al (2014) Conservative oxygen therapy in mechanically ventilated patients: a pilot before-and-after trial*. Crit Care Med 42:1414–1422

    Article  CAS  PubMed  Google Scholar 

  67. Panwar R, Hardie M, Bellomo R et al (2016) Conservative versus liberal oxygenation targets for mechanically ventilated patients. a pilot multicenter randomized controlled trial. Am J Respir Crit Care Med 193:43–51

    Article  CAS  PubMed  Google Scholar 

  68. Girardis M, Busani S, Damiani E et al (2016) Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. JAMA 316:1583–1589

    Article  CAS  PubMed  Google Scholar 

  69. Asfar P, Schortgen F, Boisramé-Helms J et al (2017) Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med 5:180–190

    Article  CAS  PubMed  Google Scholar 

  70. Chu DK, Kim LH-Y, Young PJ et al (2018) Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet Lond Engl 391:1693–1705

    Article  Google Scholar 

  71. ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Mackle D, Bellomo R et al (2020) Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med 382:989–998

    Article  Google Scholar 

  72. Barrot L, Asfar P, Mauny F et al (2020) Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med 382:999–1008

    Article  CAS  PubMed  Google Scholar 

  73. Schjørring OL, Klitgaard TL, Perner A et al (2021) Lower or higher oxygenation targets for acute hypoxemic respiratory failure. N Engl J Med 384:1301–1311

    Article  PubMed  Google Scholar 

  74. Rasmussen BS, Klitgaard TL, Perner A et al (2022) Oxygenation targets in ICU patients with COVID-19: a post hoc subgroup analysis of the HOT-ICU trial. Acta Anaesthesiol Scand 66:76–84

    Article  CAS  PubMed  Google Scholar 

  75. Gelissen H, de Grooth H-J, Smulders Y et al (2021) Effect of low-normal vs high-normal oxygenation targets on organ dysfunction in critically ill patients: a randomized clinical trial. JAMA 326:940–948

    Article  CAS  PubMed  Google Scholar 

  76. Semler MW, Casey JD, Lloyd BD et al (2022) Oxygen-saturation targets for critically ill adults receiving mechanical ventilation. N Engl J Med 387:1759–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. van der Wal LI, Grim CCA, Del Prado MR et al (2023) Conservative versus liberal oxygenation targets in intensive care unit patients (ICONIC): a randomized clinical trial. Am J Respir Crit Care Med 208:770–779

    Article  PubMed  PubMed Central  Google Scholar 

  78. Nielsen FM, Klitgaard TL, Siegemund M et al (2024) Lower vs higher oxygenation target and days alive without life support in COVID-19: the HOT-COVID randomized clinical trial. JAMA 331:1185–1194

    Article  CAS  PubMed  Google Scholar 

  79. Klitgaard TL, Schjørring OL, Nielsen FM et al (2023) Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit. Cochrane Database Syst Rev 9:CD12631

    Google Scholar 

  80. Baysan M, Broere M, Wille ME et al (2024) Description of mitochondrial oxygen tension and its variability in healthy volunteers. PLoS ONE 19:e0300602

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

AS, VZ, JB, RAS, CI and MPH: writing and editing the manuscript.

Corresponding author

Correspondence to Anne-Aylin Sigg.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

CI and MPH hold a patent on the use of AI to analyze microcirculatory images, have developed an automated microcirculatory analysis software platform, and hold shares in Active Medical BV (Leiden, The Netherlands). JB holds shares of DeepMed Zurich GmbH (Zurich, Switzerland). The other authors declare that there are no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sigg, AA., Zivkovic, V., Bartussek, J. et al. The physiological basis for individualized oxygenation targets in critically ill patients with circulatory shock. ICMx 12, 72 (2024). https://doi.org/10.1186/s40635-024-00651-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40635-024-00651-6

Keywords