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Cerebral Oxygen Delivery and Consumption in Brain-Injured Patients

Department of Anaesthesiology and Intensive Care, Medical University in Lublin, 20-954 Lublin, Poland
Department of Anesthesiology and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, 16132 Genoa, Italy
Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy
Department of Anesthesiology and Surgical-Trauma Intensive Care, Hospital Clinic Universitari, University of Valencia, 46010 Valencia, Spain
Author to whom correspondence should be addressed.
J. Pers. Med. 2022, 12(11), 1763;
Submission received: 27 August 2022 / Revised: 12 October 2022 / Accepted: 17 October 2022 / Published: 25 October 2022
(This article belongs to the Special Issue New Paradigms in Anesthesia and Intensive Care)


Organism survival depends on oxygen delivery and utilization to maintain the balance of energy and toxic oxidants production. This regulation is crucial to the brain, especially after acute injuries. Secondary insults after brain damage may include impaired cerebral metabolism, ischemia, intracranial hypertension and oxygen concentration disturbances such as hypoxia or hyperoxia. Recent data highlight the important role of clinical protocols in improving oxygen delivery and resulting in lower mortality in brain-injured patients. Clinical protocols guide the rules for oxygen supplementation based on physiological processes such as elevation of oxygen supply (by mean arterial pressure (MAP) and intracranial pressure (ICP) modulation, cerebral vasoreactivity, oxygen capacity) and reduction of oxygen demand (by pharmacological sedation and coma or hypothermia). The aim of this review is to discuss oxygen metabolism in the brain under different conditions.

1. Introduction

Organism survival depends on oxygen delivery and utilization to maintain the balance of energy and toxic oxidants production [1]. This regulation is crucial to the central nervous system (CNS). Brain tissue presents a peculiarly dynamic consumption of energy. The most productive metabolic process of energy analogs is oxidative phosphorylation, relating to oxygen consumption [2]. Already in 1890, Roy and Sherrington observed that increased neuronal activity elevates energy consumption and compensatory metabolic and vasculature reactions, which in turn improve the functionality of neurons [3]. Therefore, the oxygen level in cerebral tissue is a crucial element that impacts nerve and glial cell functions [2].
Brain injury is a common cause of morbidity and mortality worldwide, especially in the young population [4]. Secondary brain damage occurs in the hours, days or weeks after an event, and is associated with fatal outcomes [5]. Secondary insults may be mediated by impaired cerebral metabolism, ischemia, intracranial hypertension and oxygen concentration disturbances such as hypoxia [6,7]. The combination of hypoxia and hypotension is associated with enormously high mortality rates [8]. Recent data highlight the important role of clinical protocols in improving oxygen delivery and resulting in lower mortality in traumatic and nontraumatic brain-injured patients [9,10]. Clinical protocols guide the rules for oxygen supplementation based on physiological processes such as increased oxygen supply (by monitoring of mean arterial pressure (MAP) and intracranial pressure (ICP), cerebral vasoreactivity and oxygen capacity) and reduction of oxygen demand (by pharmacological sedation and coma or hypothermia) [11]. Therefore, monitoring oxygen concentrations such as brain tissue oxygen (PbtO2) is an important aspect of brain injury clinical practice [12]. In addition, monitoring of mean arterial pressure and oxygenation of both local and global tissues are essential for oxygenation and final outcomes [13].
The aim of this review is to discuss oxygen metabolism in the brain under different conditions.

2. Oxygen Delivery and Autoregulation

The weight of the brain is only 2% of the human body, but cerebral tissue uses 25% of the glucose and about 20% of the oxygen delivered to function normally [14]. Oxygen consumption is 3.5 mL of oxygen/100 g tissue/1 min; therefore, the regulation of blood flow and delivery of oxygen to cerebral tissue is crucial for brain function [15]. Importantly, 75–80% of the energy consumed by neurons is used at the synapses to restore the neuronal membrane potentials lost during depolarization [16]. The continuous supply of oxygen to the brain occurs via arterial blood and is transported to brain tissue by diffusion. Diffusion is linked to the oxygen conductivity of cerebral tissue, determined by the geometry of capillaries (distance and area) and the metabolism of tissue (oxygen gradient from capillary to tissue) [17]. Extraction of oxygen is inversely proportional to blood flow (when metabolism is constant) and directly proportional to metabolism (when flow is constant) and the area between tissue and capillaries. Thus, a reduction in oxygen delivery increases oxygen extraction. It should be noted that when cerebral blood flow (CBF) is reduced by 50–60%, the consequent elevation of oxygen extraction is insufficient to maintain proper cerebral oxygenation and a constant cerebral metabolic rate of oxygen (CMRO2) [18]. Thus, cerebral oxygen delivery is determined by blood oxygen content and cerebral blood flow. In physiological conditions, total blood flow in the brain is constant because of the contribution of the large arteries to vascular resistance, as well as the impact of the parenchymal arterioles on considerable basal tone.
Autoregulation of cerebral blood flow is the mechanism that enables the brain to maintain relatively constant blood flow through changes in perfusion pressure [19]. In a normotensive, physiological state, the ensuing cerebral perfusion pressure (CPP) is in the range of 60 to 160 mmHg, and CBF is maintained at 50 mL per 100 g of brain tissue per minute. Outside of this range, autoregulation is lost, and CBF starts to be dependent on MAP in a linear mode [20]. A drop of CPP below the lower limit of 50 mmHg results in cerebral ischemia [21]. This reduction of CBF is compensated for by elevated oxygen extraction from the blood.
The individualization of care by targeting optimal, near to cerebral autoregulation (CA)-guided CPP is connected with improved outcomes in TBI patients [22]. It is worth remembering that combined brain tissue oxygen with ICP/CCP-guided therapy strongly ameliorates favorable long-term outcomes [23]. In addition, in a recent meta-analysis, Xie et al. documented that this combined therapy did not present any effects on mortality, ICP/CPP and length of stay of patients after TBI [23].
Over a physiological range of partial oxygen pressure (PaO2) (75–100 mmHg; 7–13.33 kPa), PaO2 has little effect on global CBF as long as it does not fall below 50 mmHg (6.67 kPa). This is because CBF is connected to the arterial content of oxygen rather than PaO2. The form of the hemoglobin–oxygen dissociation curve indicates that the arterial content of oxygen is comparatively stable over the discussed PaO2 range [24].
The primary gradient determining the oxygen level in the brain may be enhanced by a gradient-independent mechanism of cerebral vessel tone changes and increases in CBF during functional neural activation (neurovascular coupling) [25,26]. The main role of this mechanism is to transport higher levels of oxygen in advance of the elevated consumption during neuronal activation [27].
Impairment of cerebral perfusion and metabolism following brain injury has been documented repeatedly. Unfavorable outcomes after brain injury are connected with hypoperfusion and decreased glucose metabolism and CMRO2 [28]. Recent data have documented a connection between CMRO2 and Glasgow Coma Score (GCS) after traumatic brain injury [29,30,31,32]. Soustiel et al. demonstrated that in TBI patients, CBF is somewhat reduced during the first 24 h, and greater hypovolemia is observed following poor outcomes. Importantly, a decrease in CMRO2 and the cerebral rate of glucose metabolism (CMRG) correlates with worse outcomes [32].

3. Oxygen Consumption

Oxygen is transported to the cerebral cells by blood diffusion from the capillary to the mitochondria, until it is consumed in the mitochondria as part of oxidative metabolism. CMRO2 is the rate of consumption and energy homeostasis in the brain and in healthy, awake people, averages 3.3 mL/100 g/min [33]. It is related to CBF. Under elevated metabolic demand, the cerebral vasculature dilates to supply an appropriate increase in CBF.
Importantly, with elevated neural activity, CMRO2 also rises [34,35]. In a normal, unstimulated brain, energy is mostly provided by glucose oxidation. Nevertheless, the metabolic rates of the oxygen-to-glucose ratio, CMRO2/CMR(glc), called the oxygen-to-glucose index (OGI), increase during activation and diverge from the textbook value of 6. In addition, the levels of lactates in the brain increase during sensory (e.g., visual) stimulation [34]. This oxidative metabolism yields more energy as compared to glycolysis, but precise measurements of this process are limited [36]. Mitochondria present a high metabolic activity and a critical role in aerobic energy production, and their main function is the production of adenosine triphosphate (ATP) through oxidative phosphorylation.
Mitochondrial dysfunction is a major factor in the occurrence of cell damage. Successful resuscitation during ischemia/reperfusion demands the reestablishment of aerobic metabolism by reperfusion of oxygenated blood. Mitochondria play a fundamental role as effectors of reperfusion injury. Damage to the organelle impairs oxidative phosphorylation and elimination of cytochrome c in the cytosol. The main mechanisms are oxidative stress and Ca2+ overload [36].
Disturbances in oxygen delivery stop electron flow and interrupt the generation of the “proton motive force” important in ATP production mentioned above. Of course, cells may produce ATP anaerobically by glycolysis. However, this process is less effective, insufficient for metabolic demands, and the final products are lactates.

4. Oxygen in the Cells

The role of mitochondria is to maintain maximal levels of ATP in the physiological range of oxygen. It is important to remember that there are also other mechanisms responsible for oxygen consumption. Mostly, O2 is consumed by mitochondria, but 1–2% of oxygen is incompletely reduced to superoxide anion (O2−) (Figure 1).
Organisms develop important adaptation mechanisms [1]. One of these mechanisms is metabolic suppression. Reduction of mitochondrial oxygen consumption in cells is observed in oxygen levels between 1 and 3% in vitro. “Oxygen conformance” occurs when the oxygen (<0.3%) level begins to limit the cytochrome c oxidase (COX) (complex IV) [37]. Hypoxia, as a result of limited oxygen accessibility, results in reduction of oxidative phosphorylation and loss of resynthesized phosphates, ATP and phosphocreatine. The ATP-dependent Na/K pump is also changed and promotes the influx of Na, Ca and water into cells, causing cytotoxic edema. In addition, ischemia impacts catabolism of adenine nucleotides, resulting in the accumulation of hypoxanthine in cells. Cytosolic calcium elevation promotes various pathways, such as activation of phospholipases and importantly the release of prostaglandins, lipases, proteases and endonucleases, which damages structural elements of cells [41]. In addition, after increased expression of proinflammatory gene products in the endothelium (leukocyte adhesion molecules, cytokines, endothelin thromboxane A2) a proinflammatory state is observed. In contrast, prostacyclin and nitric oxide are suppressed.

5. Hyperventilation/Hypoventilation

One of the most powerful factors affecting cerebral perfusion is hyperventilation/hypoventilation, with an effect on CBF and PaCO2. Hyperventilation is a common therapy used to reduce elevated ICP or to relax a tense brain (hypocapnia-reduced CBF and CBV). In traumatic brain injury (TBI) patients, hyperventilation generates a 34% decrease in CBF and a 9% reduction in cerebral blood volume (CBV) when PaCO2 is decreased from 40 to 30 mmHg [42]. However, hyperventilation and hypocapnia, apart from vasoconstriction and decreased CBF, also cause neuronal excitability and a longer duration of seizure elevation, an increase in excitatory amino acids and alkalosis of cerebrospinal fluid with a left shift in the oxygen–hemoglobin dissociation curve (OHDC) [43,44]. All these mechanisms may predispose to reduction in oxygen supply and delivery and a significant increase in oxygen extraction.
It should be noted that carbon dioxide is a common molecule with a physiological range of 35–45 mmHg. Hypocapnia (partial pressure of carbon dioxide <35 mmHg) and mild hypercapnia (>45 mmHg) generate important nervous system disturbances. Recent data have documented that hypercapnia presents neuroprotective mechanisms and may improve CBF through cerebral vasodilatation. Hypercapnia also leads to brain edema, elevated ICP, a right shift in the oxyhemoglobin dissociation curve, reduction of systemic vascular resistance (SVR) and an increase in the tissue oxygen availability [45,46].
Hyperventilation is a double-edged sword with some short-term beneficial effects and longer-term risks. The initial PaCO2 value in TBI in patients with normal ICP should be within the normal range of 38–42 mmHg. Controlled hyperventilation during mechanical ventilation in TBI patients (never below PaCO2 of 30 mmHg) is an approved therapeutic, temporary (during the first 24 h after injury) life-saving intervention in severe intracranial hypertension [46]. However, PaCO2 levels should be regulated and individualized in every patient using multimodal neuromonitoring methods [11,47].

6. A Brief Search for “4-H” Factors Affecting CRMO2 and Cellular Oxygen Balance

Brain cells are especially susceptible to ischemic damage because of several unusual features of their energy metabolism, high metabolic rate, restricted intrinsic energy stores and critical relationship with the aerobic metabolism of glucose. Therefore, cell metabolism and the consumption of crucial compounds can be altered by drugs or clinical status, which can be summarized as “4-H”.

6.1. Hypoxia

The brain is one of the most sensitive organs to hypoxia, reoxygenation and oxidative stress. As mentioned above, the brain has very high metabolic oxygen requirements, and it is highly susceptible to hypoxic damage (Table 1).
Oxidative stress in mitochondria occurs in the state of redox imbalance and small oxidant patterns such as superoxide radical, hydroxyl radical or nitric oxide radicals are accumulated. It should be noted that both hypoxia and hyperoxia may induce oxidative stress and apoptosis [48,49,50]. Acute hypoxia elevates ROS production in the brain, and reoxygenation promotes this process. A low oxygen level leads to increased lipid peroxidation, protein oxidation and nitric oxide levels and antioxidant defense systems. Superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) and reduced/oxidized glutathione (GSH/GSSG) ratio) are significantly inhibited in brain cells. One of the crucial regulators of oxygen homeostasis and angiogenesis control in a hypoxic state are HIFs (hypoxia-inducible factors). There are three transcription factors, HIF-1, HIF-2 and HIF-3 [51]. These heterodimers are expressed by β subunits (HIF-1β, HIF-2β and HIF-3β) and connected with α subunits, HIF-1α, HIF-2α and HIF-3α, directly influencing hypoxia. The HIF-1 and HIF-2 are transcriptional regulators with unique target genes. HIF-1 regulates the acute response to hypoxia (<24 h), and the network formatted by HIF-1 predisposes to elevated perfusion and an increased oxygen level [52].
PaO2 has little effect on global CBF as long as it does not fall below 50 mmHg [53]. At this point, there is a dramatic increase in blood flow with a further deterioration in PaO2 [53]. Reduction of ATP levels during hypoxia opens KATP channels on smooth muscle and causes hypopolarization and vasodilatation [54]. Importantly, hypoxia further decreases PaO2, and CBF may increase by up to 400% of the baseline level [55]. Changed CBF does not affect metabolism, but hemoglobin saturation decreases from 100% (at PaO2 > 70 mmHg (PaO2 > 9.33 kPa)) to 50% (at <50 mmHg (at <6.66 kPa)) [55]. In addition, the decrease in PaO2 increases the production of local NO and adenosine. Chronic hypoxia increases CBF by affecting capillary density [56,57]. Energy cell failure and delayed apoptosis are connected with NO•, catalyzed by stimulation of nitric oxide synthase (nNOS) by lactic acidosis and disruption of ionic transport [58,59].
In addition, neuronal membrane conversion leads to the release of glutamate, which promotes activation of N-methyl-D-aspartate (NMDA) receptors and calcium influx promoting lipases, proteases and endonucleases, precipitating free radical formation [59,60]. Finally, inflammation, critical mitochondrial dysfunction and ROS (superoxide, hydroxyl, hydrogen peroxide and other) production with oxidation of lipids, proteins, cells and deoxyribonucleic acid (DNA) are observed.
In animal models, oxidative stress parameters and the antioxidant system return to the control system 24 h post brain injury [61]. Coimbra-Costa et al. documented that after 24 h of reoxygenation, oxidative stress is reduced, but apoptosis is preserved, especially in the hippocampus [62]. The apoptotic rate in the hippocampus being higher than in the cortex may be the reason for impairment of brain functions in hypoxic brain damage [63]. One of the crucial regulators of oxygen homeostasis and angiogenesis under a hypoxic state are hypoxia-inducible factors (HIFs) [64]. The HIF-1 binds to hypoxia-responsive elements (HRE) on gene promoters in the nucleus and promotes transcription of target genes such as vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1) and others such as glycolysis enzymes, lactate dehydrogenase or erythropoietin [65,66,67]. HIF-1 is also crucial in glycolysis upregulation in astrocytes and Schwann cells [68]. In contrast, HIF-2 and HIF-3 expressions start under chronic hypoxia in the endothelium. Importantly, the switch from HIF-1 to HIF-2 and HIF-3 is observed during the adaptation of the endothelium to prolonged hypoxia. HIF-1 covers the angiogenesis by formation of a primary and very primitive network, and later expression of HIF-2 and HIF-3 stabilizes and promotes maturation of this vasculature [69]. In addition, the network formatted by HIF-1 predisposes to elevated perfusion and increased oxygen level [52].
Another mechanism under chronic hypoxia, which advances proteasomal degradation, is based on the carboxyl terminus of the Hsp70-interacting protein (Hsp70/CHIP complex) [70]. The receptor for activated kinase C1 (RACK1) also leads to degradation of HIF-1α and promotion of heat shock protein 90 (Hsp90), which secures the α subunit [71,72]. Furthermore, RACK1 generates proteasomal degradation and ubiquitination of HIF-1α [73]. Moreover, Kruppel-like factor 2 (KLF2), expressed in endothelial cells and responsible for physiological vascularity formation, activates HIF-1 hypoxic degradation in “a von Hippel–Lindau-independent, but proteasome-dependent manner” via interruption of the connection Hsp90 with HIF-1 [74,75].
MicroRNA (miRNAs) is a family of noncoding RNA molecules with 18–22 nucleotides [76]. There is growing interest in the critical role of miRNA in the development and functioning of the central nervous system as a gene regulator in “cleaving and silencing the gene expression” [77]. In contrast, atypical levels of miRNA are documented in various neurological disorders [78]. The miRNA 210 is mainly expressed in a hypoxic state and is promoted by HIF1 α and establishes a neuroprotective effect in hypoxia–ischemia damage [79,80].
The miRNA molecules decrease the apoptotic processes of neuronal cells with inhibition of caspases [81,82]. Therefore, with the growing interest in the association of miRNA patterns with hypoxia/ischemia, these molecules may be clinical biomarkers for ischemia and an individual miRNA therapeutics complex [83]. The protective effect of glucocorticoids (GCs) under hypoxia and ischemia/reperfusion has been shown recently [84]. GC administration leads to increased tolerance to hypoxia in the central nervous system [85,86]. Acute hypoxia activates hypothalamic–pituitary–adrenal (HPA) with accumulation of up to 24 h of corticosterone in serum [85]. Recent data have shown that hypoxic tolerance is connected with upregulation of HIF-1 α and increased release of GC [85,87]. Direct crosstalk between GC receptors and HIF-1 is potentially a basis of the biochemical pathways for GC upregulation of HIF-1 target genes [88,89,90].
Clinical implications of hypoxia:
  • Reduced brain tissue oxygenation is a predictor of poor outcome following severe traumatic brain injury.
  • Hypoxic–ischemic brain injury (HIBI) is associated with significant mortality and morbidity [91].
  • The LOCO2 study documented that targeting lower PaO2 improves outcomes in patients with acute respiratory distress syndrome (ARDS) [92].
  • The brain tissue oxygen tension (PbtO2) is crucial, the second monitored variable after ICP, representing multimodality monitoring in TBI patients [11,93].
  • Secondary hypoxia is connected with extended production of cytokines in CSF and superior elevation of serum biomarkers such as myelin-basic protein (MBP) and S100 [94].
  • The MBP, S100 and neuron-specific enolase (NSE) biomarkers are more elevated in patients with hypoxia and unfavorable outcomes (Extended Glasgow Outcome Coma Score (GOSE) 1–4) [94]
  • HIBI, as a two-hit model, is an effect of primary and secondary ischemic/hypoxic damage predisposing to overall devastating severe injury of neurovascular units [91]
  • Secondary brain hypoxia is connected with de novo neuronal and astroglial injury. Importantly, secondary hypoxia is associated with cerebral proinflammatory response but not parallel cerebral endothelial injury [91].
  • Protocols based on PbtO2 and ICP monitoring significantly decrease cerebral hypoxia time after TBI [95].
  • Acute intermittent hypoxia (AIH) and task-specific training (TST) may synergistically improve motor functions after central nervous system injury [96].

6.2. Hyperoxia

The concept of hyperoxia toxicity is defined by endogenous production of ROS [48,97].
Experimental examination of mitochondrial structure after 100% oxygen therapy showed swollen and huge mitochondria and diluted and damaged mitochondria membranes and cristae, which were directly connected with myelin, axonal and cellular organelle injury in the cortical brain [98]. Hyperoxia is connected with inhibition of Akt expression and/or phosphorylation, the reverse of low oxygen levels [99,100]. Experimental research has documented that in rat models of hyperoxia (FiO2 0.4–0.8), p-Akt expression decreases steadily, over time until 12 h, then reverses to baseline value [100,101]. Thus, Akt signaling increases in hypoxia and is depressed in hyperoxia [102].
Mitogen-activated protein kinases (MAPKs) are involved in the PI3K-Akt signaling pathway, an important pathway with a neuroprotective role against hypoxia or oxidative stress [103]. Recent data on rat models showed that hyperoxia (FiO2 0.4–0.8) decreases the p-ERK1/2 activation until 12 h and is followed by recovery in the subsequent 12 h [101]. Furthermore, hyperoxia in rat brain models impacts BDNF and neurotrophins 3 and 4 downregulation, and proceeds with correction in the subsequent 15–20 h, predisposing to hyperoxia-linked apoptotic neurodegeneration [101,104]. Erythropoietin receptor (EpoR) binding, observed in different brain areas, also plays an important role in oxygen metabolism [105]. Under hypoxia, it is upregulated because HIF-1α binds to the Epo, showing a neuroprotective effect contrary to ischemia hypoxia/reoxygenation injury [106,107,108]. Experimental data showed that hyperoxia upregulates Epo in mice treated with FiO2 0.5 for 3 weeks, elevating HIF-2α, but during 4 weeks of treatment with FiO2 = 0.3, only EpoR expression increases [100]. Noteworthy is NO, which ameliorates oxygen delivery by improving cerebral blood flow in the microvasculature [109]. In addition, NOS presents a neuroprotective effect by improving vessel autoregulation [110]. It triggers different mechanisms such as BDNF expression, HIF stabilization, S-nitrosylation of the HIF, blocking HIF-1α degradation, interaction with MAPK and phosphoinositide 3-kinase (PI3K) signaling, and EpoR expression upregulation [111,112,113,114,115,116]. In a nonphysiological state presenting hyperactivity of selected NOS, the NO starts to be neurotoxic as a free radical [109]. High oxygen concentration controls NOS expression and inhibits NO via surplus release of superoxide anions inhibiting NO vasorelaxation and promoting vasoconstriction in the brain [117,118]. Importantly, the connection of superoxide anions with NO promotes peroxynitrite (ONOO−) production with destructive properties [119,120,121]. In animal research, NO is connected with hyperoxia-induced proliferation and proinflammatory responses in astrocytes via cyclooxygenase-2 and prostaglandin E2 suppression [122].
Clinical implications of hyperoxia:
  • Hyperoxia is associated with higher mortality and worse short-term functional outcomes, especially in patients who receive uncontrolled oxygen delivery during the first 24 h after brain injury (probably because of hyperoxia-induced oxygen-free radical toxicity with or without vasoconstriction) [123].
  • Potential toxicity of a high oxygen concentration (patients receiving FiO2 of more than 0.6).
  • Previous studies documented that higher inspired oxygen concentration is associated with acute lung injury, with mild to severe diffuse alveolar damage (DAD) [124].
  • High oxygen levels within 72 h after aneurysmal rupture is an uninfluenced predictor of cerebral vasospasm [125].
  • In addition, liberal oxygen therapy increased 30-day mortality compared with conservative therapy [126].
  • Controversial high-dose oxygen therapy recommendations to reduce surgical site infections (SSIs) by World Health Organization global guidelines for the prevention of surgical site infection [127].
  • Hyperoxemia may reduce cardiac output and increase systemic vascular resistance in patients with cardiovascular failure [128].

6.3. Hyperthermia

Increased body temperature is frequently observed in patients following brain damage due to direct hypothalamic injury, cerebral inflammation or secondary infection indicating fever.
Systemic hyperthermia is common after brain damage. In patients with brain injury, it is associated with poor neurological outcomes because it predisposes to worse secondary damage [129] (Figure 2).
It should be noted that hyperthermia is not always connected with fever. Fever is an adaptive reaction with, e.g., elevated neutrophil migration, activation of T-lymphocytes and increased interleukin-1 and interferon production [130]. Temperature changes lead to elevated cytokine release, higher neutrophil activity and elevated metabolic expenditure, elevated white blood cell accumulation, increased vascular permeability, and axonal damage [129]. Temperature changes also lead to cerebral blood flow conversion and hence cause changes to cerebral oxygenation. Recent animal research has documented that hyperthermia is associated with CD18 and intercellular adhesion molecule-1 (ICAM-1) activation, as well as with an increase in ionized calcium-binding adapter protein-1 (IBA-1) reactive microglia in the cortex [131]. Hyperthermia also increases ROS generation and apoptosis, for example by c-Jun N-terminal kinase (JNK) activation [132,133]. Wettervik et al. documented that hyperthermia leads to energy metabolism disturbances with no associations with higher ICP and lower CPP [134]. Importantly, higher temperature was connected with lower glucose concentration in cerebral tissue and a higher percentage of the lactate-pyruvate ratio >25 after 5 days [134]. In addition, the authors did not show a connection between hyperthermia and worse clinical outcomes.
The metabolic rate rises by around 20–25% during increased baseline core temperature of over 1.5–2 °C [135]. Recent data have shown that rising core temperature impacts increased cerebral glucose utilization and CMRO2 by 5 to 10% per degree Celsius [136]. Nunneley et al. observed that a temperature elevated by more than 2 °C is associated with a higher glucose metabolic rate in the hypothalamus, thalamus, corpus callosum, cingulate gyrus and cerebellum and lower in the caudate, putamen, insula and posterior cingulum [137]. In addition, an increase in brain metabolism by 10% following a 2 °C higher temperature may be connected with an important reduction of blood flow to support oxygenation [137]. Further, Spiotta et al. documented that hyperthermia did not reduce brain tissue oxygen [138]. It should be noted that higher body temperature leads to a better ability to maintain O2 uptake (VO2) because a higher fraction of the delivered O2 is extracted before the beginning of O2 supply subjection [139]. Cardiovascular adjustments, as well as sympathetic nerve activity during hyperthermia, also impact coupling between CMRO2 and CBF. The activity of sympathetic nerves increases under hyperthermia. Adrenergic nerves surround the vascular system, especially cerebral arteries [140]. Some authors suggest that vasoconstriction under hyperthermia causes decreased CBF [141]. However, there are a few doubts. First, in a hypermetabolic state under hyperthermia, different agents such as histamine, nitric oxide or prostanoids may counteract vasoconstriction [142]. Second, blood pressure significantly influences the cerebral vascular system. Third, the heterogenous response of cerebral vascularity may be modified by hyperthermia and changes in the density of alpha- and beta-adrenergic receptors [143]. Elevated body temperature impairs blood–brain barrier (BBB) integrity, especially with dehydration [144,145]. Finally, Bein et al. documented that the normalization of PaCO2 to eucapnia leads CBF to recuperate to a physiological state [18].
Clinical implications of hyperthermia:
  • Systemic complications such as fever frequently occur in the early phase after brain damage and worsen secondary brain injury [134,146].
  • Up to 50% of patients after acute brain injury experience fever during hospitalization [147].
  • Brain temperature variations (>1 °C) are associated with poor functional outcomes [148].
  • In sum, higher body temperature is associated with elevated metabolic demand and endogenous stress levels, blood pressure level changes, increases in cardiac output and heart rate, hyperventilation, the synaptic release of excitatory amino acids, increased ICP levels, ischemic cortical depolarizations, and BBB breakdown [146,149,150,151,152,153,154].
  • Hyperthermia without oxygen delivery mismatch does not seem to induce significant neurochemical alterations such as glucose, lactate, pyruvate and glutamate levels [151].
  • PbtO2 may be an important element to be monitored during a high body temperature episode to provide a view into oxygen metabolism in the brain [155].
  • PbtO2 variations are observed under increased temperature increases in severe TBI patients. PbtO2 may rise on average in every third and decrease in every sixth episode of high temperature. Recent data have documented that the PbtO2 slope may occur simultaneously with CPP and MAP reduction [156].
  • Temperature management to prevent fever is crucial for patients with severe traumatic brain injury. The international guidelines for severe brain injury highlight the importance of core temperature measurement and treatment above 38 °C [11,46].

6.4. Hypothermia

The main objective of current international clinical guidelines is to ameliorate final outcomes by inhibiting secondary injury, especially in the acute phase after damage. These protocols also include correction of temperature and therapeutic hypothermia. Moderate to deep hypothermia suppresses inflammation and decreases excitotoxicity and the production of free radicals, which is one of the mechanisms of neuroprotection [157]. Different levels of hypothermia improve neuronal tolerance to ischemia and inhibited neuronal death [158,159]. Cerebral hypothermia decreases ICP, maintains BBB function and ameliorates glucose utilization [160,161,162,163]. In addition, lower temperature suppresses hypoxic brain depolarization, releases neurotransmitters and decreases metabolism by protease activation and a high energy phosphate depletion rate [164,165]. Authors have even noted that deep hypothermia affects cerebral ATP production and improves survival after cardiac arrest by three to four times [164]. Importantly, hypothermia during ischemia reduces lipid peroxidation and essentially decreases ROS production [159,166]. Hypothermia reduces JNK activation and the apoptotic rate [132]. Hypothermia also activates a cascade of neuroinflammation and may improve M1/M2 macrophage polarization to a favorable phenotype [167].
Lower temperature improves cerebral metabolism after TBI and cerebral ischemia. In animal models, the metabolic rate for glucose (CMRglc) and CMRO2 is decreased, but significantly, ATP distribution is decreased more than synthesis is [168]. Furthermore, under a normoxic state, hypothermia decreases oxygen consumption in the brain as well as collateral depletion of CBF and delivery of oxygen (elevated cerebrovascular resistance and trace changes in oxygen extraction in the brain) [169]. Temperate hypoxia causes elevated CBF and oxygen extraction, followed by reduced cerebrovascular resistance [170]. Chihara et al., in an animal model of reduction in cerebral temperature by 1.6° ± 0.1° and hypoxia, documented that hypothermia results in decreased oxygen delivery, oxygen consumption and CBF. In addition, a significant improvement in cerebral vascular resistance is observed as well as no oxygen extraction shift [171]. Recent data by Hashem et al., using near-infrared spectroscopy (NIRS) and magnetic resonance imaging (MRI) methods, presented a significant decrease of CMRO2 in the cortex of around 37 and 32% of hypothermic mice and rats, respectively [172]. Therefore, targeting brain tissue oxygenation by different methods such as an NIRS device may be an important aspect of brain damage treatment guidelines for improving cerebral oxygenation, monitoring cerebrovascular reactivity (CVR) and final outcomes [173,174].
Clinical implications of hypothermia
  • Therapeutic hypothermia is a crucial component of current clinical practice guidelines.
  • Therapeutic hypothermia uses different cooling methods to maintain brain temperature at target levels.
  • Therapeutic hypothermia improves neurological outcomes [175]. In contrast, accidental hypothermia at admission after TBI results in higher hospital mortality [176].
  • Recently published data do not promote early prophylactic hypothermia within the first 6 h after damage in TBI patients [177].
  • Body temperature of 35 to 35.5 °C after TBI reduces intracranial hypertension and preserves adequate CPP without cardiac dysfunction and oxygen debt [178]. In addition, hypothermia reduces high ICP [177].
  • Recent meta-analyses have documented the importance of temperature measurement to avoid hypothermia in prehospital management [176].

7. Future Therapies

The oxygen-related mechanisms discussed have been a target for therapy in brain injuries. One crucial element in the management of patients with various forms of cerebral damage is the maintenance of oxygen homeostasis, supply and consumption, translating into normal mitochondrial metabolism. Both hypoxia and hyperoxia may present a negative effect on the final neurological outcome. Recent findings have shown the role of oxygen therapy in neuroprotection, related to normobaric hyperoxia (NBHO). Patients with acute brain injury treated with high oxygen levels (FiO2 0.6–1.0) for two hours presented with improved redox balance and reduced lactate/pyruvate ratio (ΔLPR −3.07 p = 0.015) [179]. The NBHO method is based on continuous administration of oxygen in normal atmospheric pressure. Experimental data have documented the benefits of NBHO in ischemic stroke, hemorrhagic strokes and brain trauma [180,181].
Yang et al. in an animal model experimentally documented the effect of normobaric oxygen therapy (60%) on neurological functions, edema and HIF-1α, aquaporin 4 (AQP4) and Na+/H+ exchanger 1 (NHE1) expression (p < 0.05, respectively). These authors showed that therapy inhibits NHE1 expression and Na+ influx. These effects result in the reduction of brain edema following the movement of water by AQP4 [180]. Hyperbaric oxygen therapy (HBOT) is another therapy proposed in TBI. HBOT is 100% oxygen inhalation under a pressure greater than 1 absolute atmosphere. HBOT suppresses inflammation and defends BBB integrity and supports angiogenesis and neurogenesis [182,183]. Recent data in an animal model documented that oxygen therapy at an early stage after brain damage significantly decreased NF -κB and extracellular histones H1, H2A and H4 expression [184]. Histones are structural proteins in nuclei, an important factor in inflammation caused by hypoxia and ischemia [185]. In addition, HBOT inhibits the apoptotic mechanisms in neuronal cells and preserves the properties of mitochondrial membranes, reducing secondary damage [186,187]. Of course, the clinical effectiveness of HBOT is still controversial. Rockswold et al. documented in a small study that HBOT did not improve outcomes in a group of patients with closed head injury [188]. However, in other phase II clinical trials in 2013, Roackswold et al. demonstrated that combined HBOT with normobaric hyperoxia (NBHT) therapy improves oxidative metabolism and oxygen brain tissue partial pressure levels [189]. In addition, this therapy decreased intracranial hypertension, mortality and improved outcomes (measured by GOSE) [189]. Another study showed that HBOT significantly improved post-traumatic stress disorder symptoms, cognitive functions and decreased depression and anxiety [190].
The controversial effects of HBOT may be explained by the hyperoxic–hypoxic paradox (HHP). Recent research has shown that repetitive and periodic hyperoxia may induce molecular mechanisms and activate mediators similarly to hypoxia [191]. Activation of HIF, VEGF, SIRT, mitochondrial biogenesis and stem cell proliferation is observed during intermittent hyperoxia.
Another therapeutic option is the significant role of lactate in cerebral energy metabolism [192]. Experimental lactate supplementation in ischemic brain damage impacts decreased glutamate- and gamma-aminobutyric acid (GABA) release with improvement in electroencephalogram (EEG) [193]. Furthermore, Berthet et al. documented that lactate supplementation inhibits neuronal death in oxygen and glucose delivery disturbances [194]. The same treatment in middle cerebral artery occlusion and ischemia models also presents a significant neuroprotective effect [195,196]. Ichai et al., in randomized controlled trials, presented that hypertonic sodium lactate (HSL) treatment is more potent in reducing elevated ICP than mannitol in a group of TBI patients [197]. In addition, this effect lasts longer and is connected with improvement in jugular venous O2 saturation, glucose and lactate levels in plasma and pH. Patients also presented better neurological final outcomes [197]. The infusion of HSL for 3 h impacts extracellular metabolites. One theory is that these solutions contain metabolizable lactate and Na ions. Lactate in the brain induces an imbalance between anions and positive charges and counteracts the harmful cellular swelling by compensation of anion efflux [197] (Supplementary Materials).
Recent data have shown elevated lactate, pyruvate and glucose levels in the brain with associated lower glutamate and PbtO2 values as well as ICP. Bouzat et al. documented that these effects may be the result of a brain metabolism shift to elevated lactate utilization, sparing the effect of glucose. In addition, the inhibition of cerebral oxygenation may be secondary to alkalosis, which increases the affinity of oxygen to hemoglobin and suggests a beneficial effect [198]. In summary, hypertonic sodium lactate infusion reduces glutamate-related excitotoxicity, improves cerebral perfusion, buffers metabolic acidosis, decreases cerebral edema and ICP and improves cardiac performance [199,200,201].

8. Conclusions

Oxygen is crucial for the functionality of cerebral cells. Therefore, the mechanisms leading to disruption of oxygen supply and consumption are the subject of continuous intensive research. There is a growing need for novel therapeutic methods to reduce the cascade of pathological cellular processes.

Supplementary Materials

The following supporting information can be downloaded at:, Table S1: Novel therapy approaches.

Author Contributions

Conceptualization, C.R. and D.S.-G.; methodology, D.S.-G. and C.R.; validation, C.R., W.D. and D.S.-G.; formal analysis, D.S.-G.; writing—original draft preparation, D.S.-G.; writing—review and editing, C.R., D.S.-G., W.D., J.G. and R.B.; visualization, D.S.-G., W.D., C.R. and J.G.; supervision, D.S.-G., C.R., W.D. and R.B.; project administration, D.S.-G. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Semenza, G.L. Life with Oxygen. Science 2007, 318, 62–64. [Google Scholar] [CrossRef] [PubMed]
  2. Özugur, S.; Kunz, L.; Straka, H. Relationship between oxygen consumption and neuronal activity in a defined neural circuit. BMC Biol. 2020, 18, 76. [Google Scholar] [CrossRef] [PubMed]
  3. Roy, C.S.; Sherrington, C.S. On the Regulation of the Blood-supply of the Brain. J. Physiol. 1890, 11, 85–158. [Google Scholar] [CrossRef]
  4. Maas, A.I.R.; Menon, D.K.; Adelson, P.D.; Andelic, N.; Bell, M.J.; Belli, A.; Bragge, P.; Brazinova, A.; Büki, A.; Chesnut, R.M.; et al. Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017, 16, 987–1048. [Google Scholar] [CrossRef] [Green Version]
  5. Chesnut, R.M.; Marshall, L.F.; Klauber, M.R.; Blunt, B.A.; Baldwin, N.; Eisenberg, H.M.; Jane, J.A.; Marmarou, A.; Foulkes, M.A. The Role of Secondary Brain Injury in Determining Outcome from Severe Head Injury. J. Trauma Inj. Infect. Crit. Care 1993, 34, 216–222. [Google Scholar] [CrossRef] [PubMed]
  6. Volpi, P.C.; Robba, C.; Rota, M.; Vargiolu, A.; Citerio, G. Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: Results from a large, single centre, observational study. BMC Emerg. Med. 2018, 18, 52. [Google Scholar] [CrossRef]
  7. Maloney-Wilensky, E.; Gracias, V.; Itkin, A.; Hoffman, K.; Bloom, S.; Yang, W.; Christian, S.; Leroux, P.D. Brain tissue oxygen and outcome after severe traumatic brain injury: A systematic review. Crit. Care Med. 2009, 37, 2057–2063. [Google Scholar] [CrossRef]
  8. Jeremitsky, E.; Omert, L.; Dunham, C.M.; Protetch, J.; Rodriguez, A. Harbingers of Poor Outcome the Day after Severe Brain Injury: Hypothermia, Hypoxia, and Hypoperfusion. J. Trauma Inj. Infect. Crit. Care 2003, 54, 312–319. [Google Scholar] [CrossRef]
  9. Bogossian, E.G.; Diaferia, D.; Djangang, N.N.; Menozzi, M.; Vincent, J.-L.; Talamonti, M.; Dewitte, O.; Peluso, L.; Barrit, S.; Al Barajraji, M.; et al. Brain tissue oxygenation guided therapy and outcome in non-traumatic subarachnoid hemorrhage. Sci. Rep. 2021, 11, 16235. [Google Scholar] [CrossRef]
  10. Martini, R.P.; Deem, S.; Treggiari, M.M. Targeting Brain Tissue Oxygenation in Traumatic Brain Injury. Respir. Care 2012, 58, 162–172. [Google Scholar] [CrossRef]
  11. Chesnut, R.; Aguilera, S.; Buki, A.; Bulger, E.; Citerio, G.; Cooper, D.J.; Arrastia, R.D.; Diringer, M.; Figaji, A.; Gao, G.; et al. A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: The Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensiv. Care Med. 2020, 46, 919–929. [Google Scholar] [CrossRef] [Green Version]
  12. Rakhit, S.; Nordness, M.F.; Lombardo, S.R.; Cook, M.; Smith, L.; Patel, M.B. Management and Challenges of Severe Traumatic Brain Injury. Semin. Respir. Crit. Care Med. 2021, 42, 127–144. [Google Scholar] [CrossRef]
  13. Sekhon, M.S.; Gooderham, P.; Menon, D.K.; Brasher, P.M.A.; Foster, D.; Cardim, D.; Czosnyka, M.; Smielewski, P.; Gupta, A.K.; Ainslie, P.N.; et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit. Care Med. 2019, 47, 960–969. [Google Scholar] [CrossRef]
  14. Hyder, F.; Rothman, D.L.; Bennett, M.R. Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels. Proc. Natl. Acad. Sci. USA 2013, 110, 3549–3554. [Google Scholar] [CrossRef] [Green Version]
  15. Rink, C.; Khanna, S. Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke. Antioxid. Redox Signal 2011, 14, 1889–1903. [Google Scholar] [CrossRef] [Green Version]
  16. Harris, J.J.; Jolivet, R.; Attwell, D. Synaptic Energy Use and Supply. Neuron 2012, 75, 762–777. [Google Scholar] [CrossRef] [Green Version]
  17. Gjedde, A. The pathways of oxygen in brain. I. Delivery and metabolism of oxygen. In Advances in Experimental Medicine and Biology; Springer: Boston, MA, USA, 2005; p. 566. [Google Scholar]
  18. Bain, A.R.; Morrison, S.; Ainslie, P.N. Cerebral oxygenation and hyperthermia. Front. Physiol. 2014, 5, 92. [Google Scholar] [CrossRef] [Green Version]
  19. Paulson, O.B.; Strandgaard, S.; Edvinsson, L. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 1990, 2, 161–192. [Google Scholar]
  20. Cipolla, M.J.; Osol, G. Vascular Smooth Muscle Actin Cytoskeleton in Cerebral Artery Forced Dilatation. Stroke 1998, 29, 1223–1228. [Google Scholar] [CrossRef] [Green Version]
  21. Baron, J.-C. Perfusion Thresholds in Human Cerebral Ischemia: Historical Perspective and Therapeutic Implications. Cerebrovasc. Dis. 2001, 11 (Suppl. 1), 2–8. [Google Scholar] [CrossRef]
  22. Tas, J.; Beqiri, E.; van Kaam, R.C.; Czosnyka, M.; Donnelly, J.; Haeren, R.H.; van der Horst, I.C.; Hutchinson, P.J.; van Kuijk, S.M.; Liberti, A.L.; et al. Targeting Autoregulation-Guided Cerebral Perfusion Pressure after Traumatic Brain Injury (COGiTATE): A Feasibility Randomized Controlled Clinical Trial. J. Neurotrauma 2021, 38, 2790–2800. [Google Scholar] [CrossRef] [PubMed]
  23. Xie, Q.; Wu, H.-B.; Yan, Y.-F.; Liu, M.; Wang, E.-S. Mortality and Outcome Comparison Between Brain Tissue Oxygen Combined with Intracranial Pressure/Cerebral Perfusion Pressure–Guided Therapy and Intracranial Pressure/Cerebral Perfusion Pressure–Guided Therapy in Traumatic Brain Injury: A Meta-Analysis. World Neurosurg. 2017, 100, 118–127. [Google Scholar] [CrossRef] [PubMed]
  24. McDowall, D.G. Interrelationships between blood oxygen tensions and cerebral blood flow. Oxyg. Meas. Blood Tissues 1966, 4, 205–219. [Google Scholar]
  25. Attwell, D.; Buchan, A.M.; Charpak, S.; Lauritzen, M.J.; MacVicar, B.A.; Newman, E.A. Glial and neuronal control of brain blood flow. Nature 2010, 468, 232–243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Muoio, V.; Persson, P.B.; Sendeski, M.M. The neurovascular unit—concept review. Acta Physiol. 2014, 210, 790–798. [Google Scholar] [CrossRef]
  27. Sokoloff, L. Energetics of Functional Activation in Neural Tissues. Neurochem. Res. 1999, 24, 321–329. [Google Scholar] [CrossRef]
  28. Hattori, N.; Huang, S.-C.; Wu, H.-M.; Yeh, E.; Glenn, T.C.; Vespa, P.M.; McArthur, D.; E Phelps, M.; A Hovda, D.; Bergsneider, M. Correlation of regional metabolic rates of glucose with glasgow coma scale after traumatic brain injury. J. Nucl. Med. 2003, 44, 1709. [Google Scholar]
  29. Bergsneider, M.; Hovda, D.A.; Lee, S.M.; Kelly, D.F.; McArthur, D.; Vespa, P.M.; Lee, J.H.; Huang, S.-C.; Martin, N.; Phelps, M.E.; et al. Dissociation of Cerebral Glucose Metabolism and Level of Consciousness During the Period of Metabolic Depression Following Human Traumatic Brain Injury. J. Neurotrauma 2000, 17, 389–401. [Google Scholar] [CrossRef]
  30. Bergsneider, M.; Hovda, D.A.; Shalmon, E.; Kelly, D.F.; Vespa, P.M.; Martin, N.A.; Phelps, M.E.; McArthur, D.L.; Caron, M.J.; Kraus, J.F.; et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: A positron emission tomography study. J. Neurosurg. 1997, 86, 241–251. [Google Scholar] [CrossRef]
  31. Obrist, W.D.; Langfitt, T.W.; Jaggi, J.L.; Cruz, J.; Gennarelli, T.A. Cerebral blood flow and metabolism in comatose patients with acute head injury: Relationship to intracranial hypertension. J. Neurosurg. 1984, 61, 241–253. [Google Scholar] [CrossRef]
  32. Soustiel, J.F.; Glenn, T.C.; Shik, V.; Boscardin, J.; Mahamid, E.; Zaaroor, M. Monitoring of Cerebral Blood Flow and Metabolism in Traumatic Brain Injury. J. Neurotrauma 2005, 22, 955–965. [Google Scholar] [CrossRef]
  33. Cold, G.E. Cerebral Metabolic Rate of Oxygen (CMRO2) in the Acute Phase of Brain Injury. Acta Anaesthesiol. Scand. 1978, 22, 249–256. [Google Scholar] [CrossRef]
  34. Shulman, R.G.; Hyder, F.; Rothman, D.L. Lactate efflux and the neuroenergetic basis of brain function. NMR Biomed. 2001, 14, 389–396. [Google Scholar] [CrossRef]
  35. Thompson Jeffrey, K.; Peterson Matthew, R.; Freeman Ralph, D. Single-Neuron Activity and Tissue Oxygenation in the Cerebral Cortex. Science 2003, 299, 1070–1072. [Google Scholar] [CrossRef] [Green Version]
  36. Hyder, F.; Kida, I.; Behar, K.L.; Kennan, R.P.; Maciejewski, P.K.; Rothman, D.L. Quantitative functional imaging of the brain: Towards mapping neuronal activity by BOLD fMRI. NMR Biomed. 2001, 14, 413–431. [Google Scholar] [CrossRef]
  37. Hochachka, P.W.; Buck, L.T.; Doll, C.J.; Land, S.C. Unifying theory of hypoxia tolerance: Molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc. Natl. Acad. Sci. USA 1996, 93, 9493–9498. [Google Scholar] [CrossRef] [Green Version]
  38. Boyer, P.D. The Atp Synthase—A Splendid Molecular Machine. Annu. Rev. Biochem. 1997, 66, 717–749. [Google Scholar] [CrossRef] [Green Version]
  39. Wu, I.C.; Ohsawa, I.; Fuku, N.; Tanaka, M. Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann. N. Y. Acad. Sci. 2010, 1201, 111–120. [Google Scholar] [CrossRef]
  40. Wellen, K.E.; Thompson, C.B. Cellular metabolic stress: Considering how cells respond to nutrient excess. Mol. Cell 2010, 40, 323–332. [Google Scholar] [CrossRef] [Green Version]
  41. Sas, K.; Robotka, H.; Toldi, J.; Vécsei, L. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J. Neurol. Sci. 2007, 257, 221–239. [Google Scholar] [CrossRef]
  42. Diringer, M.N.; Yundt, K.; Videen, T.O.; Adams, R.E.; Zazulia, A.R.; Deibert, E.; Aiyagari, V.; Dacey, R.G.; Grubb, R.L.; Powers, W.J. No reduction in cerebral metabolism as a result of early moderate hyperventilation following severe traumatic brain injury. J. Neurosurg. 2000, 92, 7–13. [Google Scholar] [CrossRef] [PubMed]
  43. Zhang, Z.; Guo, Q.; Wang, E. Hyperventilation in neurological patients: From physiology to outcome evidence. Curr. Opin. Anesthesiol. 2019, 32, 568–573. [Google Scholar] [CrossRef] [PubMed]
  44. Mas, A.; Saura, P.; Joseph, D.; Blanch, L.; Baigorri, F.; Artigas, A.; Fernandez, R. Effect of acute moderate changes in PaCO2 on global hemodynamics and gastric perfusion. Crit. Care Med. 2000, 28, 360–365. [Google Scholar] [CrossRef] [PubMed]
  45. Howarth, C.; Sutherland, B.A.; Choi, H.B.; Martin, C.; Lind, B.L.; Khennouf, L.; LeDue, J.M.; Pakan, J.M.; Ko, R.W.; Ellis-Davies, G.; et al. A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. J. Neurosci. 2017, 37, 2403–2414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Carney, N.; Totten, A.M.; O’Reilly, C.; Ullman, J.S.; Hawryluk, G.W.; Bell, M.J.; Bratton, S.L.; Chesnut, R.; Harris, O.A.; Kissoon, N.; et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017, 80, 6–15. [Google Scholar] [CrossRef]
  47. Oddo, M.; Bösel, J. Monitoring of brain and systemic oxygenation in neurocritical care patients. Neurocritical Care 2014, 21, 103–120. [Google Scholar] [CrossRef]
  48. Chen, R.; Lai, U.H.; Zhu, L.; Singh, A.; Ahmed, M.; Forsyth, N.R. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front. Cell Dev. Biol. 2018, 6, 132. [Google Scholar] [CrossRef] [Green Version]
  49. Banasiak, K.J.; Xia, Y.; Haddad, G.G. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog. Neurobiol. 2000, 62, 215–249. [Google Scholar] [CrossRef]
  50. Chang, E.; Hornick, K.; Fritz, K.I.; Mishra, O.P.; Delivoria-Papadopoulos, M. Effect of Hyperoxia on Cortical Neuronal Nuclear Function and Programmed Cell Death Mechanisms. Neurochem. Res. 2007, 32, 1142–1149. [Google Scholar] [CrossRef]
  51. Serocki, M.; Bartoszewska, S.; Janaszak-Jasiecka, A.; Ochocka, R.J.; Collawn, J.F.; Bartoszewski, R. miRNAs regulate the HIF switch during hypoxia: A novel therapeutic target. Angiogenesis 2018, 21, 183–202. [Google Scholar] [CrossRef] [Green Version]
  52. Koh, M.Y.; Lemos, R.; Liu, X.; Powis, G. The hypoxia-associated factor switches cells from HIF-1α-to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011, 71, 4015–4027. [Google Scholar] [CrossRef] [Green Version]
  53. Masamoto, K.; Tanishita, K. Oxygen Transport in Brain Tissue. J. Biomech. Eng. 2009, 131, 074002. [Google Scholar] [CrossRef]
  54. Taguchi, H.; Heistad, D.D.; Kitazono, T.; Faraci, F.M. ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia. Circ. Res. 1994, 74, 1005–1008. [Google Scholar] [CrossRef]
  55. Johnston, A.J.; Steiner, L.A.; Gupta, A.K.; Menon, D.K. Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity. Br. J. Anaesth. 2003, 90, 774–786. [Google Scholar] [CrossRef] [Green Version]
  56. Xu, K.; LaManna, J.C. Chronic hypoxia and the cerebral circulation. J. Appl. Physiol. 2006, 100, 725–730. [Google Scholar] [CrossRef]
  57. Boero, J.A.; Ascher, J.; Arregui, A.; Rovainen, C.; Woolsey, T.A. Increased brain capillaries in chronic hypoxia. J. Appl. Physiol. 1999, 86, 1211–1219. [Google Scholar] [CrossRef]
  58. Torres-Cuevas, I.; Parra-Llorca, A.; Sánchez-Illana, Á.; Nuñez-Ramiro, A.; Kuligowski, J.; Cháfer-Pericás, C.; Cernada, M.; Escobar, J.; Vento, M. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017, 12, 674–681. [Google Scholar] [CrossRef]
  59. Rocha-Ferreira, E.; Hristova, M. Plasticity in the Neonatal Brain following Hypoxic-Ischaemic Injury. Neural Plast. 2016, 2016, 4901014. [Google Scholar] [CrossRef] [Green Version]
  60. Sekhon, M.S.; Ainslie, P.N.; Griesdale, D.E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: A “two-hit” model. Crit. Care 2017, 21, 90. [Google Scholar] [CrossRef] [Green Version]
  61. Chen, H.; Yoshioka, H.; Kim, G.S.; Jung, J.E.; Okami, N.; Sakata, H.; Maier, C.M.; Narasimhan, P.; Goeders, C.E.; Chan, P.H. Oxidative Stress in Ischemic Brain Damage: Mechanisms of Cell Death and Potential Molecular Targets for Neuroprotection. Antioxid. Redox Signal. 2011, 14, 1505–1517. [Google Scholar] [CrossRef] [Green Version]
  62. Coimbra-Costa, D.; Alva, N.; Duran, M.; Carbonell, T.; Rama, R. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol. 2017, 12, 216–225. [Google Scholar] [CrossRef] [PubMed]
  63. Peña, F.; Ramirez, J.-M. Hypoxia-induced changes in neuronal network properties. Mol. Neurobiol. 2005, 32, 251–283. [Google Scholar] [CrossRef]
  64. Majmundar, A.J.; Wong, W.J.; Simon, M.C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 2010, 40, 294–309. [Google Scholar] [CrossRef] [PubMed]
  65. Dengler, V.L.; Galbraith, M.D.; Espinosa, J.M. Transcriptional regulation by hypoxia inducible factors. Crit. Rev. Biochem. Mol. Biol. 2014, 49, 1–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Chávez, J.C.; Agani, F.; Pichiule, P.; LaManna, J.C. Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia. J. Appl. Physiol. 2000, 89, 1937–1942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Lukyanova, L.D.; Kirova, Y.I. Mitochondria-controlled signaling mechanisms of brain protection in hypoxia. Front. Neurosci. 2015, 9, 320. [Google Scholar] [CrossRef] [Green Version]
  68. Brix, B.; Mesters, J.R.; Pellerin, L.; Jöhren, O. Endothelial cell-derived nitric oxide enhances aerobic glycolysis in astrocytes via HIF-1α-mediated target gene activation. J. Neurosci. 2012, 32, 9727–9735. [Google Scholar] [CrossRef]
  69. Koh, M.Y.; Powis, G. Passing the baton: The HIF switch. Trends Biochem. Sci. 2012, 37, 364–372. [Google Scholar] [CrossRef] [Green Version]
  70. Luo, W.; Zhong, J.; Chang, R.; Hu, H.; Pandey, A.; Semenza, G.L. Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α 2. J. Biol. Chem. 2010, 285, 3651–3663. [Google Scholar] [CrossRef] [Green Version]
  71. Liu, Y.V.; Semenza, G.L. RACK1 vs. HSP90: Competition for HIF-1α degradation vs. stabilization. Cell Cycle 2007, 6, 656–659. [Google Scholar] [CrossRef]
  72. Liu, Y.V.; Baek, J.H.; Zhang, H.; Diez, R.; Cole, R.N.; Semenza, G.L. RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α. Mol. Cell 2007, 25, 207–217. [Google Scholar] [CrossRef] [Green Version]
  73. Ravi, R.; Mookerjee, B.; Bhujwalla, Z.M.; Sutter, C.H.; Artemov, D.; Zeng, Q.; Dillehay, L.E.; Madan, A.; Semenza, G.L.; Bedi, A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 2000, 14, 34–44. [Google Scholar] [CrossRef]
  74. Bhattacharya, R.; SenBanerjee, S.; Lin, Z.; Mir, S.; Hamik, A.; Wang, P.; Mukherjee, P.; Mukhopadhyay, D.; Jain, M.K. Inhibition of Vascular Permeability Factor/Vascular Endothelial Growth Factor-mediated Angiogenesis by the Kruppel-like Factor KLF2. J. Biol. Chem. 2005, 280, 28848–28851. [Google Scholar] [CrossRef]
  75. Kawanami, D.; Mahabeleshwar, G.H.; Lin, Z.; Atkins, G.B.; Hamik, A.; Haldar, S.M.; Maemura, K.; LaManna, J.C.; Jain, M.K. Kruppel-like Factor 2 Inhibits Hypoxia-inducible Factor 1α Expression and Function in the Endothelium. J. Biol. Chem. 2009, 284, 20522–20530. [Google Scholar] [CrossRef] [Green Version]
  76. Lee, Y.; Ahn, C.; Han, J.; Choi, H.; Kim, J.; Yim, J.; Lee, J.; Provost, P.; Rådmark, O.; Kim, S.; et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003, 425, 415–419. [Google Scholar] [CrossRef]
  77. Davis, G.M.; Haas, M.A.; Pocock, R. MicroRNAs: Not “fine-tuners” but key regulators of neuronal development and function. Front. Neurol. 2015, 6, 245. [Google Scholar] [CrossRef] [Green Version]
  78. Xiao, S.; Ma, Y.; Zhu, H.; Sun, H.; Yin, Y.; Feng, G. miRNA functional synergistic network analysis of mice with ischemic stroke. Neurol. Sci. 2015, 36, 143–148. [Google Scholar] [CrossRef]
  79. Chan, S.Y.; Loscalzo, J. MicroRNA-210: A unique and pleiotropic hypoxamir. Cell Cycle 2010, 9, 1072–1083. [Google Scholar] [CrossRef] [Green Version]
  80. Yang, G.-Y.; Zeng, L.; Liu, J.; Wang, Y.; Wang, L.; Weng, S.; Tang, Y.; Zheng, C.; Cheng, Q.; Chen, S. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front. Biosci. 2011, E3, 1265–1272. [Google Scholar] [CrossRef] [Green Version]
  81. Qiu, J.; Zhou, X.-Y.; Zhou, X.-G.; Cheng, R.; Liu, H.-Y.; Li, Y. Neuroprotective effects of microRNA-210 on hypoxic-ischemic encephalopathy. BioMed Res. Int. 2013, 2013, 350419. [Google Scholar] [CrossRef] [Green Version]
  82. Tan, K.S.; Armugam, A.; Sepramaniam, S.; Lim, K.Y.; Setyowati, K.D.; Wang, C.W.; Jeyaseelan, K. Expression Profile of MicroRNAs in Young Stroke Patients. PLoS ONE 2009, 4, e7689. [Google Scholar] [CrossRef] [Green Version]
  83. Minhas, G.; Mathur, D.; Ragavendrasamy, B.; Sharma, N.K.; Paanu, V.; Anand, A. Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies. Front. Neurosci. 2017, 11, 386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Bobryshev, P.; Bagaeva, T.; Filaretova, L. Ischemic preconditioning attenuates gastric ischemia-reperfusion injury through involvement of glucocorticoids. J. Physiol. Pharmacol. 2009, 60 (Suppl. 7), 155–160. [Google Scholar]
  85. Rybnikova, E.A.; Mironova, V.I.; Pivina, S.G.; Ordyan, N.E.; Tulkova, E.I.; Samoilov, M.O. Hormonal Mechanisms of Neuroprotective Effects of the Mild Hypoxic Preconditioning in Rats, 1st ed.; Springer Nature BV: Berlin/Heidelberg, Germany, 2008; p. 239. [Google Scholar]
  86. Davis, C.; Hackett, P. Advances in the prevention and treatment of high altitude illness. Emerg. Med. Clin. 2017, 35, 241–260. [Google Scholar] [CrossRef] [PubMed]
  87. Rybnikova, E.; Mironova, V.; Pivina, S.; Tulkova, E.; Ordyan, N.; Nalivaeva, N.; Turner, A.; Samoilov, M. Involvement of the hypothalamic-pituitary-adrenal axis in the antidepressant-like effects of mild hypoxic preconditioning in rats. Psychoneuroendocrinology 2007, 32, 813–823. [Google Scholar] [CrossRef] [PubMed]
  88. Vanderhaeghen, T.; Beyaert, R.; Libert, C. Bidirectional Crosstalk Between Hypoxia Inducible Factors and Glucocorticoid Signalling in Health and Disease. Front. Immunol. 2021, 12, 684085. [Google Scholar] [CrossRef]
  89. Kodama, T.; Shimizu, N.; Yoshikawa, N.; Makino, Y.; Ouchida, R.; Okamoto, K.; Hisada, T.; Nakamura, H.; Morimoto, C.; Tanaka, H. Role of the Glucocorticoid Receptor for Regulation of Hypoxia-dependent Gene Expression. J. Biol. Chem. 2003, 278, 33384–33391. [Google Scholar] [CrossRef] [Green Version]
  90. Lim, W.; Park, C.; Shim, M.K.; Lee, Y.H.; Lee, Y.M.; Lee, Y. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper. Br. J. Pharmacol. 2014, 171, 735–745. [Google Scholar] [CrossRef] [Green Version]
  91. Hoiland, R.L.; Ainslie, P.N.; Wellington, C.L.; Cooper, J.; Stukas, S.; Thiara, S.; Foster, D.; Fergusson, N.A.; Conway, E.M.; Menon, D.K.; et al. Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post–Cardiac Arrest. Circ. Res. 2021, 129, 583–597. [Google Scholar] [CrossRef]
  92. Barrot, L.; Asfar, P.; Mauny, F.; Winiszewski, H.; Montini, F.; Badie, J.; Quenot, J.-P.; Pili-Floury, S.; Bouhemad, B.; Louis, G.; et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N. Engl. J. Med. 2020, 382, 999–1008. [Google Scholar] [CrossRef]
  93. Bardt, T.F.; Unterberg, A.W.; Härtl, R.; Kiening, K.L.; Schneider, G.H.; Lanksch, W.R. Monitoring of brain tissue PO2 in traumatic brain injury: Effect of cerebral hypoxia on outcome. In Intracranial Pressure and Neuromonitoring in Brain Injury; Marmarou, A., Bullock, R., Avezaat, C., Baethmann, A., Becker, D., Brock, M., Hoff, J., Nagai, H., Reulen, H.-J., Teasdale, G., Eds.; Springer: Vienna, Austria, 1998; pp. 153–156. [Google Scholar]
  94. Yan, E.B.; Satgunaseelan, L.; Paul, E.; Bye, N.; Nguyen, P.; Agyapomaa, D.; Kossmann, T.; Rosenfeld, J.V.; Morganti-Kossmann, C. Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury. J. Neurotrauma 2013, 31, 618–629. [Google Scholar] [CrossRef] [Green Version]
  95. Okonkwo, D.O.; Shutter, L.; Moore, C.; Temkin, N.R.; Puccio, A.M.; Madden, C.J.; Andaluz, N.; Chesnut, R.; Bullock, M.R.; Grant, G.A.; et al. Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II. Crit. Care Med. 2017, 45, 1907–1914. [Google Scholar] [CrossRef]
  96. Welch, J.F.; Sutor, T.W.; Vose, A.K.; Perim, R.R.; Fox, E.J.; Mitchell, G.S. Synergy between Acute Intermittent Hypoxia and Task-Specific Training. Exerc. Sport Sci. Rev. 2020, 48, 125–132. [Google Scholar] [CrossRef]
  97. Gore, A.; Muralidhar, M.; Espey, M.G.; Degenhardt, K.; Mantell, L.L. Hyperoxia sensing: From molecular mechanisms to significance in disease. J. Immunotoxicol. 2010, 7, 239–254. [Google Scholar] [CrossRef]
  98. Bin-Jaliah, I.; Haffor, A.-S. Ultrastructural Morphological Alterations during Hyperoxia Exposure in Relation to Glutathione Peroxidase Activity and Free Radicals Productions in the Mitochondria of the Cortical Brain. Int. J. Morphol. 2018, 36, 1310–1315. [Google Scholar] [CrossRef] [Green Version]
  99. Chong, Z.-Z.; Lin, S.H.; Li, F.; Maiese, K. The Sirtuin Inhibitor Nicotinamide Enhances Neuronal Cell Survival During Acute Anoxic Injury Through AKT, BAD, PARP, and Mitochondrial Associated. Curr. Neurovascular Res. 2005, 2, 271–285. [Google Scholar] [CrossRef]
  100. Terraneo, L.; Paroni, R.; Bianciardi, P.; Giallongo, T.; Carelli, S.; Gorio, A.; Samaja, M. Brain adaptation to hypoxia and hyperoxia in mice. Redox Biol. 2017, 11, 12–20. [Google Scholar] [CrossRef] [Green Version]
  101. Felderhoff-Mueser, U.; Bittigau, P.; Sifringer, M.; Jarosz, B.; Korobowicz, E.; Mahler, L.; Piening, T.; Moysich, A.; Grune, T.; Thor, F.; et al. Oxygen causes cell death in the developing brain. Neurobiol. Dis. 2004, 17, 273–282. [Google Scholar] [CrossRef]
  102. Zhang, Y.; Park, T.S.; Gidday, J.M. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am. J. Physiol. Heart Circ. Physiol. 2007, 292, H2573–H2581. [Google Scholar] [CrossRef] [Green Version]
  103. Nayak, G.H.; Prentice, H.M.; Milton, S.L. Neuroprotective signaling pathways are modulated by adenosine in the anoxia tolerant turtle. J. Cereb. Blood Flow Metab. 2011, 31, 467–475. [Google Scholar] [CrossRef] [Green Version]
  104. Mao, M.; Zhiling, W.; Hui, Z.; Shengfu, L.; Dan, Y.; Jiping, H. Cellular levels of TrkB and MAPK in the neuroprotective role of BDNF for embryonic rat cortical neurons against hypoxia in vitro. Int. J. Dev. Neurosci. 2005, 23, 515–521. [Google Scholar]
  105. Digicaylioglu, M.; Bichet, S.; Marti, H.H.; Wenger, R.H.; Rivas, L.A.; Bauer, C.; Gassmann, M. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl. Acad. Sci. USA 1995, 92, 3717–3720. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Sanchez, P.E.; Fares, R.P.; Risso, J.-J.; Bonnet, C.; Bouvard, S.; Le-Cavorsin, M.; Georges, B.; Moulin, C.; Belmeguenai, A.; Bodennec, J.; et al. Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons. Proc. Natl. Acad. Sci. USA 2009, 106, 9848–9853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Sakanaka, M.; Wen, T.-C.; Matsuda, S.; Masuda, S.; Morishita, E.; Nagao, M.; Sasaki, R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. USA 1998, 95, 4635–4640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Kato, S.; Aoyama, M.; Kakita, H.; Hida, H.; Kato, I.; Ito, T.; Goto, T.; Hussein, M.H.; Sawamoto, K.; Togari, H.; et al. Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury. J. Neurosci. Res. 2011, 89, 1566–1574. [Google Scholar] [CrossRef] [PubMed]
  109. Brown, G.C. Nitric oxide and neuronal death. Nitric Oxide 2010, 23, 153–165. [Google Scholar] [CrossRef]
  110. Garry, P.S.; Ezra, M.; Rowland, M.J.; Westbrook, J.; Pattinson, K.T.S. The role of the nitric oxide pathway in brain injury and its treatment—From bench to bedside. Exp. Neurol. 2015, 263, 235–243. [Google Scholar] [CrossRef] [Green Version]
  111. Cheng, A.; Wang, S.; Cai, J.; Rao, M.S.; Mattson, M.P. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev. Biol. 2003, 258, 319–333. [Google Scholar] [CrossRef] [Green Version]
  112. Li, S.-T.; Pan, J.; Hua, X.-M.; Liu, H.; Shen, S.; Liu, J.-F.; Li, B.; Tao, B.-B.; Ge, X.-L.; Wang, X.-H.; et al. Endothelial Nitric Oxide Synthase Protects Neurons against Ischemic Injury through Regulation of Brain-Derived Neurotrophic Factor Expression. CNS Neurosci. Ther. 2014, 20, 154–164. [Google Scholar] [CrossRef]
  113. Brune, B.; Zhou, J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor-1α (HIF-1α). Curr. Med. Chem. 2003, 10, 845–855. [Google Scholar] [CrossRef]
  114. Chen, Z.Y.; Wang, L.; Asavaritkrai, P.; Noguchi, C.T. Up-regulation of erythropoietin receptor by nitric oxide mediates hypoxia preconditioning. J. Neurosci. Res. 2010, 88, 3180–3188. [Google Scholar] [CrossRef]
  115. Kasuno, K.; Takabuchi, S.; Fukuda, K.; Kizaka-Kondoh, S.; Yodoi, J.; Adachi, T.; Semenza, G.L.; Hirota, K. Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling. J. Biol. Chem. 2004, 279, 2550–2558. [Google Scholar] [CrossRef] [Green Version]
  116. Haase, V.H. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int. 2006, 69, 1302–1307. [Google Scholar] [CrossRef] [Green Version]
  117. Hoehn, T.; Felderhoff-Mueser, U.; Maschewski, K.; Stadelmann, C.; Sifringer, M.; Bittigau, P.; Koehne, P.; Hoppenz, M.; Obladen, M.; Bührer, C. Hyperoxia Causes Inducible Nitric Oxide Synthase-Mediated Cellular Damage to the Immature Rat Brain. Pediatr. Res. 2003, 54, 179–184. [Google Scholar] [CrossRef] [Green Version]
  118. Zhilyaev, S.Y.; Moskvin, A.N.; Platonova, T.F.; Gutsaeva, D.R.; Churilina, I.V.; Demchenko, I.T. Hyperoxic Vasoconstriction in the Brain Is Mediated by Inactivation of Nitric Oxide by Superoxide Anions. Neurosci. Behav. Physiol. 2003, 33, 783–787. [Google Scholar] [CrossRef]
  119. Rocha-Ferreira, E.; Rudge, B.; Hughes, M.P.; Rahim, A.A.; Hristova, M.; Robertson, N.J. Immediate Remote Ischemic Postconditioning Reduces Brain Nitrotyrosine Formation in a Piglet Asphyxia Model. Oxidative Med. Cell. Longev. 2016, 2016, 5763743. [Google Scholar] [CrossRef] [Green Version]
  120. Attaye, I.; Smulders, Y.M.; De Waard, M.C.; Straaten, H.M.O.-V.; Smit, B.; Van Wijhe, M.H.; Musters, R.J.; Koolwijk, P.; Man, A.M.E.S. The effects of hyperoxia on microvascular endothelial cell proliferation and production of vaso-active substances. Intensiv. Care Med. Exp. 2017, 5, 22. [Google Scholar] [CrossRef]
  121. Demchenko, I.T.; Oury, T.D.; Crapo, J.D.; Piantadosi, C.A. Regulation of the Brain’s Vascular Responses to Oxygen. Circ. Res. 2002, 91, 1031–1037. [Google Scholar] [CrossRef] [Green Version]
  122. Pham, H.; Vottier, G.; Pansiot, J.; Duong-Quy, S.; Bollen, B.; Dalous, J.; Gallego, J.; Mercier, J.-C.; Dinh-Xuan, A.T.; Bonnin, P.; et al. Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats. Exp. Neurol. 2014, 252, 114–123. [Google Scholar] [CrossRef]
  123. Brenner, M.; Stein, D.; Hu, P.; Kufera, J.; Wooford, M.; Scalea, T. Association Between Early Hyperoxia and Worse Outcomes After Traumatic Brain Injury. Arch. Surg. 2012, 147, 1042–1046. [Google Scholar] [CrossRef] [Green Version]
  124. Davis, W.B.; Rennard, S.I.; Bitterman, P.B.; Crystal, R.G. Pulmonary oxygen toxicity: Early reversible changes in human alveolar structures induced by hyperoxia. N. Engl. J. Med. 1983, 309, 878–883. [Google Scholar] [CrossRef] [PubMed]
  125. Reynolds, R.A.; Amin, S.N.; Jonathan, S.V.; Tang, A.R.; Lan, M.; Wang, C.; Bastarache, J.A.; Ware, L.B.; Thompson, R.C. Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage. Neurocritical Care 2021, 35, 30–38. [Google Scholar] [CrossRef] [PubMed]
  126. Chu, D.K.; Kim, L.H.-Y.; Young, P.J.; Zamiri, N.; Almenawer, S.A.; Jaeschke, R.; Szczeklik, W.; Schünemann, H.J.; Neary, J.D.; Alhazzani, W. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): A systematic review and meta-analysis. Lancet 2018, 391, 1693–1705. [Google Scholar] [CrossRef]
  127. Suzuki, S. Oxygen administration for postoperative surgical patients: A narrative review. J. Intensive Care 2020, 8, 79. [Google Scholar] [CrossRef] [PubMed]
  128. Smit, B.; Smulders, Y.M.; van der Wouden, J.C.; Oudemans-van Straaten, H.M.; Spoelstra-de Man, A.M.E. Hemodynamic effects of acute hyperoxia: Systematic review and meta-analysis. Crit. Care 2018, 22, 45. [Google Scholar] [CrossRef] [PubMed]
  129. Chatzipanteli, K.; Alonso, O.F.; Kraydieh, S.; Dietrich, W.D. Importance of Posttraumatic Hypothermia and Hyperthermia on the Inflammatory Response after Fluid Percussion Brain Injury: Biochemical and Immunocytochemical Studies. J. Cereb. Blood Flow Metab. 2000, 20, 531–542. [Google Scholar] [CrossRef]
  130. Thompson, H.J.; Tkacs, N.C.; Saatman, K.E.; Raghupathi, R.; McIntosh, T.K. Hyperthermia following traumatic brain injury: A critical evaluation. Neurobiol. Dis. 2003, 12, 163–173. [Google Scholar] [CrossRef]
  131. Truettner, J.S.; Bramlett, H.M.; Dietrich, W.D. Hyperthermia and Mild Traumatic Brain Injury: Effects on Inflammation and the Cerebral Vasculature. J. Neurotrauma 2017, 35, 940–952. [Google Scholar] [CrossRef]
  132. Huang, T.; Solano, J.; He, D.; Loutfi, M.; Dietrich, W.D.; Kuluz, J.W. Traumatic Injury Activates MAP Kinases in Astrocytes: Mechanisms of Hypothermia and Hyperthermia. J. Neurotrauma 2009, 26, 1535–1545. [Google Scholar] [CrossRef]
  133. Kurokawa, H.; Ito, H.; Terasaki, M.; Matsui, H. Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation. Sci. Rep. 2019, 9, 1638. [Google Scholar] [CrossRef] [Green Version]
  134. Svedung Wettervik, T.M.; Engquist, H.; Lenell, S.; Howells, T.; Hillered, L.; Rostami, E.; Lewén, A.; Enblad, P. Systemic Hyperthermia in Traumatic Brain Injury—Relation to Intracranial Pressure Dynamics, Cerebral Energy Metabolism, and Clinical Outcome. J. Neurosurg. Anesthesiol. 2021, 33, 329–336. [Google Scholar] [CrossRef]
  135. Saxton, C. Effects of severe heat stress on respiration and metabolic rate in resting man. Aviat. Space Environ. Med. 1981, 52, 281–286. [Google Scholar]
  136. Mickley, G.A.; Cobb, B.L.; Farrell, S.T. Brain hyperthermia alters local cerebral glucose utilization: A comparison of hyperthermic agents. Int. J. Hyperth. 1997, 13, 99–114. [Google Scholar] [CrossRef]
  137. Nunneley, S.A.; Martin, C.C.; Slauson, J.W.; Hearon, C.M.; Nickerson, L.D.H.; Mason, P.A. Changes in regional cerebral metabolism during systemic hyperthermia in humans. J. Appl. Physiol. 2002, 92, 846–851. [Google Scholar] [CrossRef] [Green Version]
  138. Spiotta, A.M.; Stiefel, M.F.; Heuer, G.G.; Bloom, S.; Maloney-Wilensky, E.; Yang, W.; Grady, M.S.; Le Roux, P.D. Brain Hyperthermia After Traumatic Brain Injury Does Not Reduce Brain Oxygen. Neurosurgery 2008, 62, 864–872. [Google Scholar] [CrossRef]
  139. Schumacker, P.T.; Rowland, J.; Saltz, S.; Nelson, D.P.; Wood, L.D. Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia. J. Appl. Physiol. 1987, 63, 1246–1252. [Google Scholar] [CrossRef]
  140. Edvinsson, L.; MacKenzie, E.T.; McCulloch, J. Cerebral Blood Flow and Metabolism; Raven Press: New York, NY, USA, 1993. [Google Scholar]
  141. Crandall, C.G.; Gonzalez-Alonso, J. Cardiovascular function in the heat-stressed human. Acta Physiol. 2010, 199, 407–423. [Google Scholar] [CrossRef] [Green Version]
  142. Gross, P.M.; Harper, A.M.; Teasdale, G.M. Interaction of histamine with noradrenergic constrictory mechanisms in cat cerebral arteries and veins. Can. J. Physiol. Pharmacol. 1983, 61, 756–763. [Google Scholar] [CrossRef]
  143. Edvinsson, L. Sympathetic control of cerebral circulation. Trends Neurosci. 1982, 5, 425–429. [Google Scholar] [CrossRef]
  144. Watson, P.; Black, K.E.; Clark, S.C.; Maughan, R.J. Exercise in the heat: Effect of fluid ingestion on blood-brain barrier permeability. Med. Sci. Sport. Exerc. 2006, 38, 2118–2124. [Google Scholar] [CrossRef]
  145. Watson, P.; Shirreffs, S.M.; Maughan, R.J. Blood-brain barrier integrity may be threatened by exercise in a warm environment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 288, R1689–R1694. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Walter, E.J.; Hanna-Jumma, S.; Carraretto, M.; Forni, L. The pathophysiological basis and consequences of fever. Crit. Care 2016, 20, 200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Kilpatrick, M.M.; Lowry, D.W.; Firlik, A.D.; Yonas, H.; Marion, D.W. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery 2000, 47, 850–856. [Google Scholar] [CrossRef] [PubMed]
  148. Weng, W.-J.; Yang, C.; Huang, X.-J.; Zhang, Y.-M.; Liu, J.-F.; Yao, J.-M.; Zi Zhang, Z.; Wu, X.; Mei, T.; Zhang, C.; et al. Effects of brain temperature on the outcome of patients with traumatic brain injury: A prospective observational study. J. Neurotrauma 2019, 36, 1168–1174. [Google Scholar] [CrossRef] [PubMed]
  149. Holtzclaw, B.J. The febrile response in critical care: State of the science. Heart Lung J. Crit. Care 1992, 21, 482–501. [Google Scholar]
  150. Bain, A.R.; Smith, K.J.; Lewis, N.C.; Foster, G.E.; Wildfong, K.W.; Willie, C.K.; Hartley, G.L.; Cheung, S.S.; Ainslie, P.N. Regional changes in brain blood flow during severe passive hyperthermia: Effects of PaCO2 and extracranial blood flow. J. Appl. Physiol. 2013, 115, 653–659. [Google Scholar] [CrossRef] [Green Version]
  151. Stocchetti, N.; Protti, A.; Lattuada, M.; Magnoni, S.; Longhi, L.; Ghisoni, L.; Egidi, M.; Zanier, E. Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury. J. Neurol. Neurosurg. Psychiatry 2005, 76, 1135–1139. [Google Scholar] [CrossRef]
  152. Rossi, S.; Zanier, E.R.; Mauri, I.; Columbo, A.; Stocchetti, N. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J. Neurol. Neurosurg. Psychiatry 2001, 71, 448–454. [Google Scholar] [CrossRef] [Green Version]
  153. Nyholm, L.; Howells, T.; Lewén, A.; Hillered, L.; Enblad, P. The influence of hyperthermia on intracranial pressure, cerebral oximetry and cerebral metabolism in traumatic brain injury. Upsala J. Med. Sci. 2017, 122, 177–184. [Google Scholar] [CrossRef] [Green Version]
  154. Wang, H.; Wang, B.; Normoyle, K.P.; Jackson, K.; Spitler, K.; Sharrock, M.F.; Miller, C.M.; Best, C.; Llano, D.; Du, R. Brain temperature and its fundamental properties: A review for clinical neuroscientists. Front. Neurosci. 2014, 8, 307. [Google Scholar] [CrossRef]
  155. Le Roux, P.; Menon, D.K.; Citerio, G.; Vespa, P.; Bader, M.K.; Brophy, G.M.; Diringer, M.N.; Stocchetti, N.; Videtta, W.; Armonda, R.; et al. Consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care. Neurocritical Care 2014, 21, 1–26. [Google Scholar] [CrossRef]
  156. Rass, V.; Huber, L.; Ianosi, B.-A.; Kofler, M.; Lindner, A.; Picetti, E.; Ortolano, F.; Beer, R.; Rossi, S.; Smielewski, P.; et al. The Effect of Temperature Increases on Brain Tissue Oxygen Tension in Patients with Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Substudy. Ther. Hypothermia Temp. Manag. 2020, 11, 122–131. [Google Scholar] [CrossRef]
  157. Kil, H.Y.; Zhang, J.; Piantadosi, C.A. Brain Temperature Alters Hydroxyl Radical Production during Cerebral Ischemia/Reperfusion in Rats. J. Cereb. Blood Flow Metab. 1996, 16, 100–106. [Google Scholar] [CrossRef] [Green Version]
  158. Dempsey, R.J.; Combs, D.J.; Maley, M.E.; Cowen, D.E.; Roy, M.W.; Donaldson, D.L. Moderate hypothermia reduces postischemic edema development and leukotriene production. Neurosurgery 1987, 21, 177–181. [Google Scholar] [CrossRef]
  159. Haba, K.; Ogawa, N.; Mizukawa, K.; Mori, A. Time course of changes in lipid peroxidation, pre-and postsynaptic cholinergic indices, NMDA receptor binding and neuronal death in the gerbil hippocampus following transient ischemia. Brain Res. 1991, 540, 116–122. [Google Scholar] [CrossRef]
  160. Wells, C.E. The Cerebral Circulation: The Clinical Significance of Current Concepts. Arch. Neurol. 1960, 3, 319–331. [Google Scholar] [CrossRef]
  161. Choi, H.A.; Badjatia, N.; Mayer, S.A. Hypothermia for acute brain injury—mechanisms and practical aspects. Nat. Rev. Neurol. 2012, 8, 214–222. [Google Scholar] [CrossRef]
  162. Dietrich, W.D.; Halley, M.; Valdes, I.; Busto, R. Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol. 1991, 81, 615–625. [Google Scholar] [CrossRef]
  163. Ginsberg, M.D.; Sternau, L.L.; Globus, M.Y.; Dietrich, W.D.; Busto, R. Therapeutic modulation of brain temperature: Relevance to ischemic brain injury. Cerebrovasc. Brain Metab. Rev. 1992, 4, 189–225. [Google Scholar]
  164. Kramer, R.S.; Sanders, A.P.; Lesage, A.M.; Woodhall, B.; Sealy, W.C. The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J. Thorac. Cardiovasc. Surg. 1968, 56, 699–709. [Google Scholar] [CrossRef]
  165. Taft, W.C.; Yang, K.; Dixon, C.E.; Clifton, G.L.; Hayes, R.L. Hypothermia attenuates the loss of hippocampal microtubule-associated protein 2 (MAP2) following traumatic brain injury. J. Cereb. Blood Flow Metab. 1993, 13, 796–802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Dede, S.; Deger, Y.; Meral, I. Effect of Short-term Hypothermia on Lipid Peroxidation and Antioxidant Enzyme Activity in Rats. J. Vet. Med. Ser. A 2002, 49, 286–288. [Google Scholar] [CrossRef] [PubMed]
  167. Truettner, J.S.; Bramlett, H.M.; Dietrich, W.D. Posttraumatic therapeutic hypothermia alters microglial and macrophage polarization toward a beneficial phenotype. J. Cereb. Blood Flow Metab. 2017, 37, 2952–2962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Erecinska, M.; Thoresen, M.; Silver, I.A. Effects of Hypothermia on Energy Metabolism in Mammalian Central Nervous System. J. Cereb. Blood Flow Metab. 2003, 23, 513–530. [Google Scholar] [CrossRef] [PubMed]
  169. Walter, B.; Bauer, R.; Kuhnen, G.; Fritz, H.; Zwiener, U. Coupling of cerebral blood flow and oxygen metabolism in infant pigs during selective brain hypothermia. J. Cereb. Blood Flow Metab. 2000, 20, 1215–1224. [Google Scholar] [CrossRef]
  170. Jensen, A.; Garnier, Y.; Berger, R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur. J. Obstet. Gynecol. Reprod. Biol. 1999, 84, 155–172. [Google Scholar] [CrossRef]
  171. Chihara, H.; Blood, A.B.; Hunter, C.J.; Power, G.G. Effect of Mild Hypothermia and Hypoxia on Blood Flow and Oxygen Consumption of the Fetal Sheep Brain. Pediatr. Res. 2003, 54, 665–671. [Google Scholar] [CrossRef] [Green Version]
  172. Hashem, M.; Zhang, Q.; Wu, Y.; Johnson, T.W.; Dunn, J.F. Using a multimodal near-infrared spectroscopy and MRI to quantify gray matter metabolic rate for oxygen: A hypothermia validation study. NeuroImage 2020, 206, 116315. [Google Scholar] [CrossRef]
  173. Pichler, G.; Baumgartner, S.; Biermayr, M.; Dempsey, E.; Fuchs, H.; Goos, T.G.; Lista, G.; Lorenz, L.; Karpinski, L.; Mitra, S.; et al. Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth (COSGOD III): An investigator-initiated, randomized, multi-center, multi-national, clinical trial on additional cerebral tissue oxygen saturation monitoring combined with defined treatment guidelines versus standard monitoring and treatment as usual in premature infants during immediate transition: Study protocol for a randomized controlled trial. Trials 2019, 20, 178. [Google Scholar] [CrossRef]
  174. Laurikkala, J.; Aneman, A.; Peng, A.; Reinikainen, M.; Pham, P.; Jakkula, P.; Hästbacka, J.; Wilkman, E.; Loisa, P.; Toppila, J.; et al. Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: A post-hoc analysis of the COMACARE trial. Crit. Care 2021, 25, 350. [Google Scholar] [CrossRef]
  175. Clifton, G.L.; Allen, S.; Barrodale, P.; Plenger, P.; Berry, J.; Koch, S.; Fletcher, J.; Hayes, R.L.; Choi, S.C. A Phase II Study of Moderate Hypothermia in Severe Brain Injury. J. Neurotrauma 1993, 10, 263–271. [Google Scholar] [CrossRef]
  176. Rösli, D.; Schnüriger, B.; Candinas, D.; Haltmeier, T. The Impact of Accidental Hypothermia on Mortality in Trauma Patients Overall and Patients with Traumatic Brain Injury Specifically: A Systematic Review and Meta-Analysis. World J. Surg. 2020, 44, 4106–4117. [Google Scholar] [CrossRef]
  177. Wu, X.; Tao, Y.; Marsons, L.; Dee, P.; Yu, D.; Guan, Y.; Zhou, X. The effectiveness of early prophylactic hypothermia in adult patients with traumatic brain injury: A systematic review and meta-analysis. Aust. Crit. Care 2021, 34, 83–91. [Google Scholar] [CrossRef]
  178. Tokutomi, T.; Morimoto, K.; Miyagi, T.; Yamaguchi, S.; Ishikawa, K.; Shigemori, M. Optimal Temperature For The Management Of Severe Traumatic Brain Injury: Effect Of Hypothermia On Intracranial Pressure, Systemic And Intracranial Hemodynamics, And Metabolism. Neurosurgery 2007, 61 (Suppl. 1), 102–112. [Google Scholar] [CrossRef]
  179. Ghosh, A.; Highton, D.; Kolyva, C.; Tachtsidis, I.; Elwell, C.E.; Smith, M. Hyperoxia results in increased aerobic metabolism following acute brain injury. J. Cereb. Blood Flow Metab. 2017, 37, 2910–2920. [Google Scholar] [CrossRef]
  180. Yang, D.; Ma, L.; Wang, P.; Yang, D.; Zhang, Y.; Zhao, X.; Lv, J.; Zhang, J.; Zhang, Z.; Gao, F. Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. Int. J. Mol. Med. 2019, 43, 1193–1202. [Google Scholar] [CrossRef]
  181. Liang, J.; Qi, Z.; Liu, W.; Wang, P.; Shi, W.; Dong, W.; Ji, X.; Luo, Y.; Liu, K.J. Normobaric Hyperoxia Slows Blood–Brain Barrier Damage and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in Cerebral Ischemia. Stroke 2015, 46, 1344–1351. [Google Scholar] [CrossRef] [Green Version]
  182. Braswell, C.; Crowe, D.T. Hyperbaric oxygen therapy. Compend. Contin. Educ. Vet. 2012, 34, E1–E6. [Google Scholar]
  183. Sanchez, E.C. Mechanisms of action of hyperbaric oxygenation in stroke: A review. Crit. Care Nurs. Q. 2013, 36, 290–298. [Google Scholar] [CrossRef]
  184. Liang, F.; Sun, L.; Yang, J.; Liu, X.-H.; Zhang, J.; Zhu, W.-Q.; Yang, L.; Nan, D. The effect of different atmosphere absolute hyperbaric oxygen on the expression of extracellular histones after traumatic brain injury in rats. Cell Stress Chaperones 2020, 25, 1013–1024. [Google Scholar] [CrossRef]
  185. Xu, Z.; Huang, Y.; Mao, P.; Zhang, J.; Li, Y. Sepsis and ARDS: The dark side of histones. Mediat. Inflamm. 2015, 2015, 205054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Palzur, E.; Vlodavsky, E.; Mulla, H.; Arieli, R.; Feinsod, M.; Soustiel, J.F. Hyperbaric oxygen therapy for reduction of secondary brain damage in head injury: An animal model of brain contusion. J. Neurotrauma 2004, 21, 41–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Palzur, E.; Zaaroor, M.; Vlodavsky, E.; Milman, F.; Soustiel, J.F. Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties. Brain Res. 2008, 1221, 126–133. [Google Scholar] [CrossRef] [PubMed]
  188. Rockswold, G.L.; Ford, S.E.; Anderson, D.C.; Bergman, T.A.; Sherman, R.E. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J. Neurosurg. 1992, 76, 929–934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  189. Rockswold, S.B.; Rockswold, G.L.; Zaun, D.A.; Liu, J. A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. J. Neurosurg. 2013, 118, 1317–1328. [Google Scholar] [CrossRef] [Green Version]
  190. Harch, P.G.; Andrews, S.R.; Rowe, C.J.; Lischka, J.R.; Townsend, M.H.; Yu, Q.; E Mercante, D. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: A randomized controlled trial. Med. Gas Res. 2020, 10, 8–20. [Google Scholar] [CrossRef]
  191. Amir, H.; Shai, E. The Hyperoxic-Hypoxic Paradox. Biomolecules 2020, 10, 958. [Google Scholar] [CrossRef]
  192. Annoni, F.; Peluso, L.; Bogossian, E.G.; Creteur, J.; Zanier, E.; Taccone, F. Brain Protection after Anoxic Brain Injury: Is Lactate Supplementation Helpful? Cells 2021, 10, 1714. [Google Scholar] [CrossRef]
  193. Phillis, J.W.; Song, D.; Guyot, L.L.; O’Regan, M.H. Lactate reduces amino acid release and fuels recovery of function in the ischemic brain. Neurosci. Lett. 1999, 272, 195–198. [Google Scholar] [CrossRef]
  194. Berthet, C.; Lei, H.; Thevenet, J.; Gruetter, R.; Magistretti, P.J.; Hirt, L. Neuroprotective role of lactate after cerebral ischemia. J. Cereb. Blood Flow Metab. 2009, 29, 1780–1789. [Google Scholar] [CrossRef]
  195. Horn, T.; Klein, J. Neuroprotective effects of lactate in brain ischemia: Dependence on anesthetic drugs. Neurochem. Int. 2013, 62, 251–257. [Google Scholar] [CrossRef]
  196. Berthet, C.; Castillo, X.; Magistretti, P.J.; Hirt, L. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: Extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Cerebrovasc. Dis. 2012, 34, 329–335. [Google Scholar] [CrossRef]
  197. Ichai, C.; Armando, G.; Orban, J.-C.; Berthier, F.; Rami, L.; Samat-Long, C.; Grimaud, D.; Leverve, X. Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensiv. Care Med. 2009, 35, 471–479. [Google Scholar] [CrossRef]
  198. Bouzat, P.; Sala, N.; Suys, T.; Zerlauth, J.-B.; Marques-Vidal, P.; Feihl, F.; Bloch, J.; Messerer, M.; Levivier, M.; Meuli, R.; et al. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensiv. Care Med. 2014, 40, 412–421. [Google Scholar] [CrossRef] [Green Version]
  199. Krep, H.; Breil, M.; Sinn, D.; Hagendorff, A.; Hoeft, A.; Fischer, M. Effects of hypertonic versus isotonic infusion therapy on regional cerebral blood flow after experimental cardiac arrest cardiopulmonary resuscitation in pigs. Resuscitation 2004, 63, 73–83. [Google Scholar] [CrossRef]
  200. Ros, J.; Pecinska, N.; Alessandri, B.; Landolt, H.; Fillenz, M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J. Neurosci. Res. 2001, 66, 790–794. [Google Scholar] [CrossRef]
  201. Sørensen, A.T.; Ledri, M.; Melis, M.; Nikitidou Ledri, L.; Andersson, M.; Kokaia, M. Altered Chloride Homeo-stasis Decreases the Action Potential Threshold and Increases Hyperexcitability in Hippocampal Neu-rons. eNeuro 2018, 4. [Google Scholar] [CrossRef]
Figure 1. “Mitochondrial respiration” benefits when reducing nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) components are created by the tricarboxylic acid (TCA) cycle. In the inner mitochondrial membrane, electrons generated from NADH and FADH2 are oxidized to NAD+ and FAD+ by complexes I and II. Afterward, these electrons are transferred successively to complex III, cytochrome c and complex IV. Cytochrome c oxidase (COX, complex IV) transmits electrons to molecular oxygen. This is an important enzyme in the mitochondrial electron transport chain (ETC) connecting oxygen with oxidative phosphorylation [37]. The transmission of electrons through the ETC is connected with proton transfer from the mitochondrial matrix, across the inner membrane to the intermitochondrial membrane space. This translocation develops an electrochemical gradient of protons (pH gradient and membrane potential). These molecules may drift through the F1Fo-ATP synthase (complex V) or back to the mitochondrial matrix [38]. Importantly, complex V connect protons transfer to the production of ATP from adenosine diphosphate (ADP) and phosphate. Under normal oxygen levels, pyruvate, as a product of glycolysis, is transported into the mitochondria, and is transformed into acetyl-CoA by the pyruvate dehydrogenase (PDH) complex [39]. Afterward, acetyl-CoA connects with oxaloacetate and creates citrate—the first step in the tricarboxylic acid cycle. Reducing equivalents in this cycle impacts ETC to production of ATP and reactive oxygen species (ROS) for signaling, and the intermediates of TCA are used for biosynthetic processes such as lipid synthesis [40].
Figure 1. “Mitochondrial respiration” benefits when reducing nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) components are created by the tricarboxylic acid (TCA) cycle. In the inner mitochondrial membrane, electrons generated from NADH and FADH2 are oxidized to NAD+ and FAD+ by complexes I and II. Afterward, these electrons are transferred successively to complex III, cytochrome c and complex IV. Cytochrome c oxidase (COX, complex IV) transmits electrons to molecular oxygen. This is an important enzyme in the mitochondrial electron transport chain (ETC) connecting oxygen with oxidative phosphorylation [37]. The transmission of electrons through the ETC is connected with proton transfer from the mitochondrial matrix, across the inner membrane to the intermitochondrial membrane space. This translocation develops an electrochemical gradient of protons (pH gradient and membrane potential). These molecules may drift through the F1Fo-ATP synthase (complex V) or back to the mitochondrial matrix [38]. Importantly, complex V connect protons transfer to the production of ATP from adenosine diphosphate (ADP) and phosphate. Under normal oxygen levels, pyruvate, as a product of glycolysis, is transported into the mitochondria, and is transformed into acetyl-CoA by the pyruvate dehydrogenase (PDH) complex [39]. Afterward, acetyl-CoA connects with oxaloacetate and creates citrate—the first step in the tricarboxylic acid cycle. Reducing equivalents in this cycle impacts ETC to production of ATP and reactive oxygen species (ROS) for signaling, and the intermediates of TCA are used for biosynthetic processes such as lipid synthesis [40].
Jpm 12 01763 g001
Figure 2. Hyperthermia is associated with poor neurological outcomes because it predisposes to greater secondary damage. Temperature changes lead to elevation of cytokine release, higher neutrophil activity and elevated metabolic expenditure. Hyperthermia also increases ROS generation and apoptosis.
Figure 2. Hyperthermia is associated with poor neurological outcomes because it predisposes to greater secondary damage. Temperature changes lead to elevation of cytokine release, higher neutrophil activity and elevated metabolic expenditure. Hyperthermia also increases ROS generation and apoptosis.
Jpm 12 01763 g002
Table 1. Potentially effect of disorders in oxygen delivery to the brain on selected pathways and factors. Up arrows indicate the direction of the mechanism that may be intensified to varying degrees, depending on the causative factor. The number of arrows defines the intensity of the processes.
Table 1. Potentially effect of disorders in oxygen delivery to the brain on selected pathways and factors. Up arrows indicate the direction of the mechanism that may be intensified to varying degrees, depending on the causative factor. The number of arrows defines the intensity of the processes.
Jpm 12 01763 i001
Oxidative stress↑↑↑↑↑
Hypoxia-inducible factor (HIF)↑↑↑↑
Protein kinase B
Extracellular signal-regulated kinase
Brain-derived neurotrophic factor
Nitric oxide (NO)↑↑↑↑
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Siwicka-Gieroba, D.; Robba, C.; Gołacki, J.; Badenes, R.; Dabrowski, W. Cerebral Oxygen Delivery and Consumption in Brain-Injured Patients. J. Pers. Med. 2022, 12, 1763.

AMA Style

Siwicka-Gieroba D, Robba C, Gołacki J, Badenes R, Dabrowski W. Cerebral Oxygen Delivery and Consumption in Brain-Injured Patients. Journal of Personalized Medicine. 2022; 12(11):1763.

Chicago/Turabian Style

Siwicka-Gieroba, Dorota, Chiara Robba, Jakub Gołacki, Rafael Badenes, and Wojciech Dabrowski. 2022. "Cerebral Oxygen Delivery and Consumption in Brain-Injured Patients" Journal of Personalized Medicine 12, no. 11: 1763.

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