Brain tissue respiration in trauma

Brain tissue respiration in trauma: Comparison

Please note this is a comparison between Version 1 by Mario Forcione and Version 4 by Conner Chen.

The passage of oxygen (O

₂

) from vessels into the cells comprises multiple steps in different volumes (e.g., intracellular erythrocytes, plasma, interstitial tissue, intracellular brain cells) and is influenced by multiple physiological factors (e.g., cerebral blood flow, capillary density, concentration of hemoglobin (Hb), O

₂

affinity for Hb). The pathogenesis of brain trauma may alter the mechanisms that regulate these steps.

Tissue Respiration
brain trauma
traumatic brain injury
microcirculation
Oxygen–Hemoglobin Dissociation Curve
Metabolic Dysfunction
Cerebral Blood Flow
Fåhraeus Effect
Microcirculatory Reactivity
interstitial tissue

1. Physiological Tissue Respiration

1.1. Oxygen Forms in the Blood and Oxygen Diffusion

In blood vessels, O

₂

is dissolved in its gaseous form and is in equilibrium with the O

₂ bound to the Hb, which is the main component ^[1][2]. Concentrations of the gas component of O

bound to the Hb, which is the main component [11,12]. Concentrations of the gas component of O

₂

alone are usually given as arterial partial oxygen pressure (PaO

₂

). The O

₂ diffuses across the blood–brain barrier (BBB) in its gaseous form driven by the differences in partial oxygen pressure between the plasma and interstitial tissue ^[3].

diffuses across the blood–brain barrier (BBB) in its gaseous form driven by the differences in partial oxygen pressure between the plasma and interstitial tissue [13].

1.2. Hemoglobin and Oxygen–Hemoglobin Dissociation Curve

In adults, the majority of Hb is a tetramer compounded by two alpha and two beta subunits, each holding a heme group, which is an organic compound (iron–protoporphyrin IX) with an atom of iron in a ferrous oxidative state (Fe

²⁺

), where the O

₂ can be bound ^[1][4]. O

can be bound [11,14]. O

₂ is a homeotropic allosteric modulator to Hb ^[1][4]. O

is a homeotropic allosteric modulator to Hb [11,14]. O

₂ binding presents positive cooperativity, and the oxygen–hemoglobin dissociation curve has a sigmoid shape as a result ^[1][4].

binding presents positive cooperativity, and the oxygen–hemoglobin dissociation curve has a sigmoid shape as a result [11,14].

Hydrogen (H

⁺

), carbon dioxide (CO

₂

), and 2,3-diphosphoglycerate (2,3-DPG) are heterotropic allosteric modulators to Hb, and they can shift the sigmoid-shaped oxygen–hemoglobin dissociation curve to the right, i.e., to higher values of O

₂ pressure ^[5]. Similar results can also be obtained in vitro by increasing temperature.

pressure [15]. Similar results can also be obtained in vitro by increasing temperature.

The Bohr effect is responsible for the shift of the oxygen–hemoglobin dissociation curve caused by changes in H

⁺ concentration ^[5]. CO

concentration [15]. CO

₂ has a two-fold role in the shift of the oxygen–hemoglobin dissociation curve: it directly binds to the N-terminal amino groups of Hb subunits; it influences the blood pH ^[5].

has a two-fold role in the shift of the oxygen–hemoglobin dissociation curve: it directly binds to the N-terminal amino groups of Hb subunits; it influences the blood pH [15].

1.3. Partial Oxygen Pressure Gradients in the Microcirculation and Interstitial Tissue

There is a pressure gradient between the PaO

₂

and PbtO

₂ (i.e., radial gradient) ^[6]. As mentioned in

(i.e., radial gradient) [16]. As mentioned in

Section 2.1.1

, this radial gradient of partial oxygen pressure across the microcirculation’s vessels’ walls drives the diffusion of O

₂ outside the vessels ^[6][7]. The values of PbtO

outside the vessels [16,17]. The values of PbtO

₂

are the net result of the O

₂

inflow into the interstitial tissue from the vessels and the O

₂ outflow from the interstitial tissue into the mitochondria for consumption by the electron transport chain ^[2][7].

outflow from the interstitial tissue into the mitochondria for consumption by the electron transport chain [12,17].

The O

₂

outflow from the microcirculation starts from the arterioles and leads to a progressive decrease of PaO

₂ toward the capillaries ^{[7][8][9][10]}. Micro-vessels exchange O

toward the capillaries [17,18,19,20]. Micro-vessels exchange O

₂

via convective flow and diffusion (when there is a differential PaO

₂ in nearby micro-vessels) ^[11][12]. The O

in nearby micro-vessels) [21,22]. The O

₂

diffusion includes backflow from areas of the interstitial tissue with higher PbtO

₂

than PaO

₂ ^[11][12]. The venoules receive poorly oxygenated blood from the capillaries together with well-oxygenated blood from the arterioles through arteriovenous shunts, resulting in a higher level of PaO

[21,22]. The venoules receive poorly oxygenated blood from the capillaries together with well-oxygenated blood from the arterioles through arteriovenous shunts, resulting in a higher level of PaO

₂ in the venoules compared to that in the capillaries ^[9][13]. This complex O

in the venoules compared to that in the capillaries [19,23]. This complex O

₂

transport across the microcirculation results in a U-shaped PaO

₂ longitudinal gradient, with the lowest levels in the capillaries ^[6][9].

longitudinal gradient, with the lowest levels in the capillaries [16,19].

The non-uniform PaO

₂

longitudinal and radial gradients along the microcirculation imply a heterogeneity of the O

₂

diffusion into the interstitial tissue. The PbtO

₂

changes progressively between the vessels and the cells, according to both the proximity of the interstitial tissue to the vessels of the microcirculation, and to their type (e.g., arterioles, capillaries), as the O

₂ diffuses at different rates between the vessels and the mitochondria ^{[2][7][9][10][14]}. This also implies that the levels of oxygenation in the cell vary with the distance to the vessels ^[2].

diffuses at different rates between the vessels and the mitochondria [12,17,19,20,24]. This also implies that the levels of oxygenation in the cell vary with the distance to the vessels [12].

In healthy brain tissue, the PaO

₂ longitudinal gradient is flatter than in the other tissues (e.g., resting skeletal muscle) due to the high brain metabolism, which drives oxygen passage outside vessels at all stages along the microcirculation; and the high tissue perfusion, which creates a high blood transit velocity along the microcirculation ^[6]. As a result of the lesser PaO

longitudinal gradient is flatter than in the other tissues (e.g., resting skeletal muscle) due to the high brain metabolism, which drives oxygen passage outside vessels at all stages along the microcirculation; and the high tissue perfusion, which creates a high blood transit velocity along the microcirculation [16]. As a result of the lesser PaO

₂

longitudinal gradient (and consequently a lesser PaO

₂

radial gradient and differences in O

₂

diffusion along the microcirculation), as well as the presence of the Virchow–Robin space, the PbtO

₂ in a healthy brain can be considered approximately uniform ^[13].

in a healthy brain can be considered approximately uniform [23].

1.4. Roles of the Fåhraeus Effect and Glycocalyx Layer in Oxygen Diffusion in the Microcirculation

1.4.1. Reduction in Hematocrit Along the Microcirculation

The Fåhraeus effect is the progressive decrease of the hematocrit in the smallest vessels of the microcirculation ^[15][16]. Therefore, the O

The Fåhraeus effect is the progressive decrease of the hematocrit in the smallest vessels of the microcirculation [25,26]. Therefore, the O

₂ carried per unit cross-sectional area by the capillaries decreases compared to the arterioles, which affects the longitudinal gradient along the microcirculation ^[6].

carried per unit cross-sectional area by the capillaries decreases compared to the arterioles, which affects the longitudinal gradient along the microcirculation [16].

1.4.2. Plasma Gap

The volume of plasma between the erythrocytes and the vessel wall (i.e., plasma gap) is an obstacle to O

₂

diffusion, as the O

₂

has to move across it to diffuse outside the vessels. This means that if there is an increase in the plasma gap, O

₂

diffusion is reduced. Since the Fåhraeus effect increases the plasma gap along the microcirculation, the O

₂ diffusion is more profoundly affected in the smallest vessels ^[6].

diffusion is more profoundly affected in the smallest vessels [16].

In addition to the Fåhraeus effect, the glycocalyx layer of the capillary walls can also widen the plasma gap ^[6].

In addition to the Fåhraeus effect, the glycocalyx layer of the capillary walls can also widen the plasma gap [16].

1.5. Cerebral Blood Flow Autoregulation

The autoregulation of cerebral blood flow (CBF) maintains constant perfusion in the microcirculation regardless of changes in cerebral perfusion pressure (CPP), provided that CPP lies within a physiological range, by vasoconstricting or vasodilating the vessels in the microcirculation ^[17]. By regulating the CBF, the PbtO

₂

is held constant: the variable radii of the vessels of the microcirculation prevent any change in the amount of O

₂ delivered ^[18].

delivered [28].

1.6. Vascular Tone of the Microcirculation According to the Tissue Metabolic Status

Similar to the cerebral autoregulation described in

Section 2.1.5

, the brain metabolic status can also influence the radii of the vessels in the microcirculation and so the O

₂

delivered. This regulation is driven through by-products of the metabolism itself (e.g., CO

₂), or molecules released by the endothelium and/or erythrocytes in response to the status of tissue saturation (e.g., nitric oxide (NO), nitrite) ^[12][18][19].

), or molecules released by the endothelium and/or erythrocytes in response to the status of tissue saturation (e.g., nitric oxide (NO), nitrite) [22,28,29].

It should be mentioned that the complexity of the homeostatic mechanism makes it possible to maintain the tissue O

₂ metabolism constant despite different Hb concentrations in the vessels ^[20].

metabolism constant despite different Hb concentrations in the vessels [30].

2. Tissue Respiration in Traumatic Brain Injury

The pathogenetic mechanisms that follow brain trauma can result in several abnormalities in tissue respiration, which exhibit high interpatient and intrapatient variabilities (

Section 1

). Systemic comorbidities (e.g., hemorrhagic shock) and the treatment received can further exacerbate these abnormalities as well as the scale of the divergence between patients.

2.1. Reduction of Circulatory Oxygen Delivery Capacity

The circulatory O

₂ delivery capacity to the brain is the product of the CBF and oxygen-carrying capacity per unit volume ^[21]. A reduction in either means less O

delivery capacity to the brain is the product of the CBF and oxygen-carrying capacity per unit volume [31]. A reduction in either means less O

₂

delivered to the tissue and thus a reduction in PbtO

₂ ^[9]. It should be highlighted that the complexity of brain trauma pathogenesis, and the different effects it has on the physiological mechanisms that maintain brain homeostasis, mean it is not always possible to infer brain ischemia from a certain status of cerebral perfusion or Hb levels alone ^[20][22].

[19]. It should be highlighted that the complexity of brain trauma pathogenesis, and the different effects it has on the physiological mechanisms that maintain brain homeostasis, mean it is not always possible to infer brain ischemia from a certain status of cerebral perfusion or Hb levels alone [30,32].

2.1.1. Reduction of Cerebral Blood Flow

Brain trauma can reduce the CBF: the impairment can be localized to specific regions; its magnitude can vary across the brain; it can be related to the systemic status (e.g., pyrexia) ^[23][24][25]. The decreased cerebral perfusion reduces the O

Brain trauma can reduce the CBF: the impairment can be localized to specific regions; its magnitude can vary across the brain; it can be related to the systemic status (e.g., pyrexia) [33,34,35]. The decreased cerebral perfusion reduces the O

₂

transported into the tissue and so decreases the PbtO

₂

by reducing the O

₂ delivery ^{[26][27][28][29]}. The relevance of CBF to tissue oxygenation post-trauma is demonstrated by the positive effect that fluid replacement and plasma expansion have on the O

delivery [36,37,38,39]. The relevance of CBF to tissue oxygenation post-trauma is demonstrated by the positive effect that fluid replacement and plasma expansion have on the O

₂ delivery by re-establishing the CBF without increasing (and theoretically decreasing) the oxygen‑carrying capacity per unit volume ^[21]. However, the pathogenesis of tissue respiration in TBI and the treatments to prevent ischemic episodes cannot be limited to abnormalities in CBF and efforts to prevent/normalize it respectively ^[30].

delivery by re-establishing the CBF without increasing (and theoretically decreasing) the oxygen‑carrying capacity per unit volume [31]. However, the pathogenesis of tissue respiration in TBI and the treatments to prevent ischemic episodes cannot be limited to abnormalities in CBF and efforts to prevent/normalize it respectively [40].

2.1.2. Reduction of Hematocrit

Reduced hematocrit means reduced Hb concentration and in turn a reduced oxygen‑carrying capacity per unit volume.

As expected, red blood cell transfusion in TBI patients increases the oxygen‑carrying capacity, and so the PbtO

₂ the same ^[31]. However, it should be mentioned that increasing the hematocrit yields also an undesirable increase in viscosity, which lowers CBF and thus hampers the positive effects that the increased oxygen-carrying capacity may have otherwise had on O

the same [41]. However, it should be mentioned that increasing the hematocrit yields also an undesirable increase in viscosity, which lowers CBF and thus hampers the positive effects that the increased oxygen-carrying capacity may have otherwise had on O

₂ delivery ^[32][33].

delivery [42,43].

2.1.3. Response to Therapeutic Hyperoxia

Clinical studies on a TBI population showed that increasing the PaO

₂

(i.e., hyperoxia) caused the PbtO

₂ and the brain aerobic metabolism to increase ^[34][35].

and the brain aerobic metabolism to increase [44,45].

The limited propensity of O

₂

to diffuse into liquids and the high arterial saturation in the lungs together prohibit all but small increases of total O

₂ due to hyperoxia ^[36].

due to hyperoxia [46].

2.2. Metabolic Dysfunction

Following brain trauma, there can be a metabolic dysfunction characterized by impairment in the aerobic metabolism (i.e., cytopathic hypoxia) due to mitochondrial damage. Even at non‑pathological levels of PbtO

₂ and CPP, this impairment can result in anaerobic energy production (i.e., hyperglycolysis) as a compensatory mechanism ^{[37][38][39][40]}. The inability of the mitochondria to use O

and CPP, this impairment can result in anaerobic energy production (i.e., hyperglycolysis) as a compensatory mechanism [47,48,49,50]. The inability of the mitochondria to use O

₂

, and the associated hyperglycolysis, decreases the O

₂ consumption and increases the lactate/pyruvate ratio, respectively ^[40][41]. Metabolic dysfunction can be unrelated to the tissue perfusion ^[22][42][43].

consumption and increases the lactate/pyruvate ratio, respectively [50,51]. Metabolic dysfunction can be unrelated to the tissue perfusion [32,52,53].

The relevance of metabolic dysfunction to tissue respiration can be appreciated in the absence of a metabolic response (e.g., normalization of the lactate/pyruvate ratio) when O

₂

delivery is elevated via increased hematocrit or hyperoxia, as described in

Section 2.2.1.2

Section 2.2.1.3

, despite an increase in PbtO

₂ ^[44][45][46]. The results from the clinical studies described in

[54,55,56]. The results from the clinical studies described in

Section 2.2.1.3

, which reported a reduction in the lactate/pyruvate ratio as a response to hyperoxia, were attributed to the progressive deterioration of the metabolic dysfunction, which made the hyperoxia most effective in the early hours from injury, and to O

₂ extraction by a percentage of surviving mitochondria ^[34][35]. The different responses to hyperoxia across clinical studies highlight the interpatient variability of the brain metabolic dysfunction after trauma and the significance of the time since injury.

extraction by a percentage of surviving mitochondria [44,45]. The different responses to hyperoxia across clinical studies highlight the interpatient variability of the brain metabolic dysfunction after trauma and the significance of the time since injury.

It should be stressed that the metabolic dysfunction is a significant component in TBI pathogenesis, and an increase in lactate/pyruvate ratio is linked to poorer clinical outcomes ^[47][48].

It should be stressed that the metabolic dysfunction is a significant component in TBI pathogenesis, and an increase in lactate/pyruvate ratio is linked to poorer clinical outcomes [57,58].

2.3. Microcirculatory Dysfunction

There could be multiple structural impairments to the microcirculation that give rise to abnormal O

₂

diffusion and significantly alter the PbtO

₂ ^[49]. Analogous to abnormal O

[59]. Analogous to abnormal O

₂

consumption, as explained in

Section 2.2.2

, abnormal O

₂ diffusion can also affect the tissue respiration in normally perfused brain regions ^[50].

diffusion can also affect the tissue respiration in normally perfused brain regions [9].

2.3.1. Anatomical Damage to the Vessels in the Microcirculation

The end organ impairment in TBI patients can be influenced by multiple systemic and local structural injury factors, which results in an impairment in the O

₂ diffusion: after brain trauma, there can be endothelium swelling, BBB damage, and perivascular edema ^[51]. A recent study reported that hemorrhagic shock trauma patients may have a systemic endotheliopathy in the early hours after injury, which is characterized by endothelial cell damage and glycocalyx shedding, and which leads to a reduction of blood flow and vascular density in the microcirculation (

diffusion: after brain trauma, there can be endothelium swelling, BBB damage, and perivascular edema [60]. A recent study reported that hemorrhagic shock trauma patients may have a systemic endotheliopathy in the early hours after injury, which is characterized by endothelial cell damage and glycocalyx shedding, and which leads to a reduction of blood flow and vascular density in the microcirculation (

Section 2.2.3.2) ^[52].

) [61].

2.3.2. Reduction of Vascular Density in the Microcirculation

The distance between cells and their nearest vessels affects the rate at which O

₂

diffuses into the cells, as well as the O

₂

concentration in the cells and the interstitial tissue: O

₂ must travel this distances and progressively diffuse across various tissue sizes ^[1][53]. After brain trauma, some vessels in the microcirculation become occluded or collapse, increasing the distance between the center of the perfused capillaries and the farthest cells that receive their O

must travel this distances and progressively diffuse across various tissue sizes [11,62]. After brain trauma, some vessels in the microcirculation become occluded or collapse, increasing the distance between the center of the perfused capillaries and the farthest cells that receive their O

₂ ^[51]. This reduction of vascular density decreases PbtO

[60]. This reduction of vascular density decreases PbtO

₂ and lowers aerobic metabolism, with the greatest impact in the tissue farthest from the perfused capillaries ^[51][54][55]. The relevance of vascular density to PbtO

and lowers aerobic metabolism, with the greatest impact in the tissue farthest from the perfused capillaries [60,63,64]. The relevance of vascular density to PbtO

₂

and tissue respiration is illustrated by the lack of response in the PbtO

₂

and O

₂ extraction in cases of hyperoxia when the vascular density is low ^[36].

extraction in cases of hyperoxia when the vascular density is low [46].

An increase in CPP can reopen occluded capillaries and increase O

₂ diffusion ^[9][56].

diffusion [19,65].

2.4. Abnormalities in Cerebrovascular Regulation

Cerebrovascular regulation (

Section 2.1.5) can be impaired in some TBI patients, so that changes in CPP translate directly into changes in CBF ^[57].

) can be impaired in some TBI patients, so that changes in CPP translate directly into changes in CBF [66].

2.5. Cerebral Vasospasm

Cerebral perfusion in TBI patients can be impaired by episodes of vasospasm caused by a secondary injury ^[58].

Cerebral perfusion in TBI patients can be impaired by episodes of vasospasm caused by a secondary injury [67].

2.6. Abnormalities in the Microcirculatory Reactivity to the Metabolic Status

The homeostatic role of microcirculatory regulation in cell metabolism explained in

Section 2.1.6

can be impaired in TBI patients. For example, the compartmentalization of NO by erythrocytes (

Section 2.1.6) could be absent in patients who receive a blood transfusion with consequent vasodilation ^[32].

) could be absent in patients who receive a blood transfusion with consequent vasodilation [42].

The relevance of CBF regulation in the microcirculation by molecules indicative of metabolic status is demonstrated during therapeutic hyperventilation to reduce ICP: prolonged hyperventilation can significantly reduce levels of CO2, which leads to ischemia by vasoconstriction ^[59].

2.7. Fåhraeus Effect and the Role of Endotheliopathy in Brain Trauma Microcirculation

The pathophysiological mechanism of brain trauma can act via the Fåhraeus effect to change the physiology of tissue respiration. Impaired regulation of the vessels’ radii in the microcirculation due to brain trauma, and/or a reduction of hematocrit due to hemorrhage, can both theoretically induce sooner and exacerbate the physiological decrease in hematocrit along the microcirculation described in

Section 2.1.4

. This perturbs the physiological oxygen-carrying capacity along the microcirculation described in

Section 2.1.4.1

. Furthermore, an increased plasma gap reduces O2 diffusion (

Section 2.1.4

) and compartmentalization of NO by erythrocytes (

Section 2.1.6) ^[19]. Damage to the endothelial glycocalyx (e.g., endotheliopathy (

) [29]. Damage to the endothelial glycocalyx (e.g., endotheliopathy (

Section 2.2.3.1

)) can also affect the plasma gap.

2.8. Shifts in the Oxygen–Hemoglobin Dissociation Curve in the Tissue Microcirculation

The heterotropic allosteric modulators shift the oxygen–hemoglobin dissociation curve to the right to different degrees, depending on the changes in their concentrations after brain trauma. The resulting modulations of PaO

₂

in the physiological microcirculation are significant because the dissociation curve has a sigmoidal shape, and the PaO

₂

approaches the steepest region of the curve. In brain trauma, the modulators are even more relevant to the tissue respiration, because they regulate the curve at even steeper segments due to further reductions in PaO

₂

Systemic changes related to systemic comorbidities, such as respiratory acidosis or sepsis, could further compound locally abnormal modulator concentrations ^[60]. Akin to the clinical status, different treatments and/or the response to treatments can alter the modulators’ concentrations and therefore contribute to the interpatient variability.

Systemic changes related to systemic comorbidities, such as respiratory acidosis or sepsis, could further compound locally abnormal modulator concentrations [69]. Akin to the clinical status, different treatments and/or the response to treatments can alter the modulators’ concentrations and therefore contribute to the interpatient variability.

2.8.1. Hydrogen Concentration

The severity of the impairments to tissue metabolism described in

Section 2.2.2 can lower proportionally the pH in the interstitial tissue ^[61][62]. The H

can lower proportionally the pH in the interstitial tissue [70,71]. The H

⁺ concentration in the erythrocytes, which regulates the oxygen–hemoglobin dissociation curve, is in equilibrium with that of the plasma and, in turn, that of the interstitial tissue ^[63]. Therefore, the lowered pH in the interstitial tissue facilitates the Hb dissociation to O

concentration in the erythrocytes, which regulates the oxygen–hemoglobin dissociation curve, is in equilibrium with that of the plasma and, in turn, that of the interstitial tissue [72]. Therefore, the lowered pH in the interstitial tissue facilitates the Hb dissociation to O

₂

in the erythrocytes. Decreased Hb concentration due to hemorrhage after trauma can further increase the H

⁺

concentration via reduced Hb buffering.

Similar to the metabolic impairment in TBI, the interstitial tissue pH is associated with the patient’s prognosis, as the two phenomena are linked ^[64][65].

Similar to the metabolic impairment in TBI, the interstitial tissue pH is associated with the patient’s prognosis, as the two phenomena are linked [73,74].

2.8.2. Carbon Dioxide Concentration

Tissue acidosis due to metabolic impairment and the reduction of CO2 clearance owing to low perfusion increase the tissue CO2 concentration (or partial pressure) ^[61]. As discussed in

Tissue acidosis due to metabolic impairment and the reduction of CO2 clearance owing to low perfusion increase the tissue CO2 concentration (or partial pressure) [70]. As discussed in

Section 2.2.8.1, CO2 concentration is related to patients’ prognoses ^[61].

, CO2 concentration is related to patients’ prognoses [70].

2.8.3. -Diphosphoglycerate Concentration

Pathogenetic and therapeutic components can modify the concentration of 2,3-DPG in TBI patients: systemic inflammatory response syndrome and/or nutritional support in severely ill patients (e.g., malnutrition; a history of drug abuse) can lead to hypophosphatemia, which reduces levels of 2,3-DPG ^[60][66][67]; the transfusion of stored red blood cells can result in lower levels of 2,3-DPG than of fresh red blood cells ^[68].

Pathogenetic and therapeutic components can modify the concentration of 2,3-DPG in TBI patients: systemic inflammatory response syndrome and/or nutritional support in severely ill patients (e.g., malnutrition; a history of drug abuse) can lead to hypophosphatemia, which reduces levels of 2,3-DPG [69,75,76]; the transfusion of stored red blood cells can result in lower levels of 2,3-DPG than of fresh red blood cells [77].

High levels of 2,3-DPG were reported in the plasma after brain trauma ^[69]. However, the relationship between the plasma—and erythrocytes—2,3-DPG after brain trauma and their combined effect on cerebral tissue respiration are still under investigation ^[69].

High levels of 2,3-DPG were reported in the plasma after brain trauma [78]. However, the relationship between the plasma—and erythrocytes—2,3-DPG after brain trauma and their combined effect on cerebral tissue respiration are still under investigation [78].

2.8.4. Chloride Concentration

Significant infusion of saline 0.9% to resuscitate shocked trauma patients can result in hyperchloremic acidosis ^[70][71]; this condition can shift the oxygen–hemoglobin dissociation curve by changing the blood pH and/or by allosteric modulation (with the former mechanism more profound than the latter).

Significant infusion of saline 0.9% to resuscitate shocked trauma patients can result in hyperchloremic acidosis [79,80]; this condition can shift the oxygen–hemoglobin dissociation curve by changing the blood pH and/or by allosteric modulation (with the former mechanism more profound than the latter).

The use of other drugs to resuscitate patients can avoid hyperchloremic acidosis ^[72][73]. This highlights the interpatient variability of tissue respiration due to the systemic status and the treatment applied.

The use of other drugs to resuscitate patients can avoid hyperchloremic acidosis [81,82]. This highlights the interpatient variability of tissue respiration due to the systemic status and the treatment applied.

2.8.5. Temperature

After brain trauma, there is generally an increase in the brain temperature, which can exceed that of the core, which can be already in a pyretic status ^[74]. The temperature delta between the brain and the core further decreases oxygen–hemoglobin affinity (already changed by the high core temperature), when blood perfuses into the brain tissue ^[74][75].

After brain trauma, there is generally an increase in the brain temperature, which can exceed that of the core, which can be already in a pyretic status [83]. The temperature delta between the brain and the core further decreases oxygen–hemoglobin affinity (already changed by the high core temperature), when blood perfuses into the brain tissue [83,84].

Hyperthermia is associated with poor outcomes and brain damage, including to the BBB and endothelial cells, and metabolic dysfunction ^[75][76][77]. The extent of this damage in a conserved cerebral perfused status can be limited ^[78].

Hyperthermia is associated with poor outcomes and brain damage, including to the BBB and endothelial cells, and metabolic dysfunction [84,85,86]. The extent of this damage in a conserved cerebral perfused status can be limited [87].

Therapeutic interventions to lower the temperature in TBI patients could reduce PbtO

₂ via physiological thermoregulatory responses (e.g., shivering) ^[79].

via physiological thermoregulatory responses (e.g., shivering) [88].