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Brain tissue respiration in trauma: History
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Subjects: Biochemistry & Molecular Biology
Contributor: Mario Forcione

The passage of oxygen (O2) 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), O2 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, O2 is dissolved in its gaseous form and is in equilibrium with the O2 bound to the Hb, which is the main component [1][2]. Concentrations of the gas component of O2 alone are usually given as arterial partial oxygen pressure (PaO2). The O2 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].

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 (Fe2+), where the O2 can be bound [1][4]. O2 is a homeotropic allosteric modulator to Hb [1][4]. O2 binding presents positive cooperativity, and the oxygen–hemoglobin dissociation curve has a sigmoid shape as a result [1][4].

Hydrogen (H+), carbon dioxide (CO2), 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 O2 pressure [5]. 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]. CO2 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].

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

There is a pressure gradient between the PaO2 and PbtO2 (i.e., radial gradient) [6]. As mentioned in Section 2.1.1, this radial gradient of partial oxygen pressure across the microcirculation’s vessels’ walls drives the diffusion of O2 outside the vessels [6][7]. The values of PbtO2 are the net result of the O2 inflow into the interstitial tissue from the vessels and the O2 outflow from the interstitial tissue into the mitochondria for consumption by the electron transport chain [2][7].

The O2 outflow from the microcirculation starts from the arterioles and leads to a progressive decrease of PaO2 toward the capillaries [7][8][9][10]. Micro-vessels exchange O2 via convective flow and diffusion (when there is a differential PaO2 in nearby micro-vessels) [11][12]. The O2 diffusion includes backflow from areas of the interstitial tissue with higher PbtO2 than PaO2 [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 PaO2 in the venoules compared to that in the capillaries [9][13]. This complex O2 transport across the microcirculation results in a U-shaped PaO2 longitudinal gradient, with the lowest levels in the capillaries [6][9].

The non-uniform PaO2 longitudinal and radial gradients along the microcirculation imply a heterogeneity of the O2 diffusion into the interstitial tissue. The PbtO2 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 O2 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].

In healthy brain tissue, the PaO2 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 PaO2 longitudinal gradient (and consequently a lesser PaO2 radial gradient and differences in O2 diffusion along the microcirculation), as well as the presence of the Virchow–Robin space, the PbtO2 in a healthy brain can be considered approximately uniform [13].

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 O2 carried per unit cross-sectional area by the capillaries decreases compared to the arterioles, which affects the longitudinal gradient along the microcirculation [6].

1.4.2. Plasma Gap

The volume of plasma between the erythrocytes and the vessel wall (i.e., plasma gap) is an obstacle to O2 diffusion, as the O2 has to move across it to diffuse outside the vessels. This means that if there is an increase in the plasma gap, O2 diffusion is reduced. Since the Fåhraeus effect increases the plasma gap along the microcirculation, the O2 diffusion is more profoundly affected in the smallest vessels [6].

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

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 PbtO2 is held constant: the variable radii of the vessels of the microcirculation prevent any change in the amount of O2 delivered [18].

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

Similar to the cerebral autoregulation described in Section 1.5, the brain metabolic status can also influence the radii of the vessels in the microcirculation and so the O2 delivered. This regulation is driven through by-products of the metabolism itself (e.g., CO2), 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].

It should be mentioned that the complexity of the homeostatic mechanism makes it possible to maintain the tissue O2 metabolism constant despite different Hb concentrations in the vessels [20].

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 O2 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 O2 delivered to the tissue and thus a reduction in PbtO2 [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].

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 O2 transported into the tissue and so decreases the PbtO2 by reducing the O2 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 O2 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].

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 PbtO2 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 O2 delivery [32][33].

2.1.3. Response to Therapeutic Hyperoxia

Clinical studies on a TBI population showed that increasing the PaO2 (i.e., hyperoxia) caused the PbtO2 and the brain aerobic metabolism to increase [34][35].

The limited propensity of O2 to diffuse into liquids and the high arterial saturation in the lungs together prohibit all but small increases of total O2 due to hyperoxia [36].

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 PbtO2 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 O2, and the associated hyperglycolysis, decreases the O2 consumption and increases the lactate/pyruvate ratio, respectively [40][41]. Metabolic dysfunction can be unrelated to the tissue perfusion [22][42][43].

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 O2 delivery is elevated via increased hematocrit or hyperoxia, as described in Section 2.1.2, Section 2.1.3, despite an increase in PbtO2 [44][45][46]. The results from the clinical studies described in Section 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 O2 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.

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].

2.3. Microcirculatory Dysfunction

There could be multiple structural impairments to the microcirculation that give rise to abnormal O2 diffusion and significantly alter the PbtO2 [49]. Analogous to abnormal O2 consumption, as explained in Section 2.2.2, abnormal O2 diffusion can also affect the tissue respiration in normally perfused brain regions [50].

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 O2 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 (Section 2.2.3.2) [52].

2.3.2. Reduction of Vascular Density in the Microcirculation

The distance between cells and their nearest vessels affects the rate at which O2 diffuses into the cells, as well as the O2 concentration in the cells and the interstitial tissue: O2 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 O2 [51]. This reduction of vascular density decreases PbtO2 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 PbtO2 and tissue respiration is illustrated by the lack of response in the PbtO2 and O2 extraction in cases of hyperoxia when the vascular density is low [36].

An increase in CPP can reopen occluded capillaries and increase O2 diffusion [9][56].

2.4. Abnormalities in Cerebrovascular Regulation

Cerebrovascular regulation (Section 1.5) can be impaired in some TBI patients, so that changes in CPP translate directly into changes in CBF [57].

2.5. Cerebral Vasospasm

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

2.6. Abnormalities in the Microcirculatory Reactivity to the Metabolic Status

The homeostatic role of microcirculatory regulation in cell metabolism explained in Section 1.6 can be impaired in TBI patients. For example, the compartmentalization of NO by erythrocytes (Section 1.6) could be absent in patients who receive a blood transfusion with consequent vasodilation [32].

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 1.4. This perturbs the physiological oxygen-carrying capacity along the microcirculation described in Section 1.4.1. Furthermore, an increased plasma gap reduces O2 diffusion (Section 1.4) and compartmentalization of NO by erythrocytes (Section 1.6) [19]. Damage to the endothelial glycocalyx (e.g., endotheliopathy (Section 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 PaO2 in the physiological microcirculation are significant because the dissociation curve has a sigmoidal shape, and the PaO2 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 PaO2.

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.

2.8.1. Hydrogen Concentration

The severity of the impairments to tissue metabolism described in Section 2.2 can lower proportionally the pH in the interstitial tissue [61][62]. 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 O2 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].

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 Section 2.8.1, CO2 concentration is related to patients’ prognoses [61].

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].

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].

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).

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.

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].

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].

Therapeutic interventions to lower the temperature in TBI patients could reduce PbtO2 via physiological thermoregulatory responses (e.g., shivering) [79].

This entry is adapted from the peer-reviewed paper 10.3390/ijms22031122

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