The effect of permissive hypotension on cerebral energy metabolism is not well described. The cerebral energy state is completely dependent on oxidative metabolism, which is reflected immediately in the cerebral cytoplasmic redox state. The ratio between interstitial lactate and pyruvate (LP ratio) is shown to be a robust marker of the cellular redox state.
In the present study we demonstrate that a period of 60 min severe hypotension causes a decrease in PbtO2 but only a small increase in the intracerebral LP ratio. This increase along with stable values of glucose, glycerol, and glutamate indicates reversible metabolic perturbation of the cerebral redox state.
Brain tissue oxygenation (PbtO2) and LP ratio
During the induced hemorrhagic shock PbtO2 decreased to levels regarded as near critical [15]. Along with the decrease in PbtO2 the LP ratio increased but remained within normal levels. The elevation was due to an increase in lactate along with a less pronounced increase in pyruvate.
Although the metabolic perturbation is caused by a decrease blood and oxygen supply, the observed pattern is not consistent with cerebral ischemia. Cerebral ischemia is characterized by a significant decrease in PbtO2 and glucose along with a significant increase in LP ratio due to an increase in lactate and decrease in pyruvate [16]. On the other hand, the observed metabolic pattern in the present study is compatible with mitochondrial dysfunction [17]. The concept of mitochondrial dysfunction should be viewed in its broadest term. Mitochondrial dysfunction will obviously exist when mitochondria are damaged, but the metabolic patterns are also seen if the metabolic demands exceed the capacity of the oxidative metabolism, i.e., during seizures [18]. However, yet another mechanism is responsible for the observed metabolic pattern in the present study.
During hemorrhage, numerous compensatory mechanisms are activated on both the cellular, tissue, and whole-organism level. The end goal is to maintain a steady supply of oxygen to end-organ tissues as well as prevent excessive bleeding and ensure hemostasis. As bleeding continues, cardiac output, and eventually blood pressure, drops [19]. To ensure cerebral perfusion pressure and cerebral blood flow (CBF) is adequate, autoregulatory mechanism exists. This autoregulatory mechanism ensures that CPP is regulated within a narrow range. The mechanism has been described as both myogenic, metabolic, and neurogenic [20, 21]. When the blood pressure reaches a point where the delivery of oxygen to peripheral tissue is compromised, transition to anaerobic metabolism occurs. During this gradual decrease in CBF oxygen supply to the brain would be insufficient before the supply of substrate (glucose) is seriously jeopardized. This is because of the difference in concentrations and degree of tissue extraction [22]. This phase between compensated low systemic blood pressure and pronounced cerebral ischemia was characterized as hypoxic hypoxia by Siesjö in the 1970s [22], and is characterized by decreasing PbtO2 and elevation of lactate along with normal values of glucose and pyruvate similar to the observed pattern in the present study. As blood pressure continues to decrease deliverance of both oxygen and glucose is further compromised resulting in a pattern of ischemia and metabolic crisis. We have previously shown in a similar animal model that hemorrhagic shock to a MAP of 40 mmHg and a duration of 90 min caused ischemia and subsequent irreversible cerebral damage evaluated by intracerebral microdialysis, ICP, and PbtO2 [11]. In the present study, 60 min of hypotension resulted in an apparently reversible metabolic perturbation. Accordingly, the metabolic perturbations during hemorrhagic shock represent a continuum from normal cerebral metabolism to jeopardized but potential reversible metabolism similar to hypoxic hypoxia towards irreversible ischemia.
The pattern of pronounced cerebral ischemia was seen in one animal in the present study and was characterized by a marked increase in intracerebral LP ratio and decrease in PbtO2 and glucose. The rise in LP ratio was caused by a steep increase in lactate along with a decrease in pyruvate. This finding underlines the individual differences in each animal regarding cerebral autoregulation and ability to compensate physiological crisis, and that 60 min of severe hypotension is on the edge of how long the autoregulatory mechanisms can compensate for low CBF/systemic blood pressure.
After reinfusion of shed blood, the PbtO2 level increased to levels above baseline values. As PbtO2 primarily is linked to the CBF [23] this increase is likely due a post-hypoperfusion hyperemia.
Parallel to the increase in PbtO2 levels during the observational period, a decrease was seen in LP ratio tending towards baseline levels but not reaching baseline values. Thus, our null hypothesis cannot be rejected. Although the LP ratio did not return to baseline values, the increase in hemisphere LP ration did not exceed normal levels at any point during the experimental protocol, thus supporting reversible metabolic perturbation. This conclusion is supported by the interstitial levels of glutamate and glycerol. Glutamate is regarded as a marker of pending energy failure [24], and glycerol is regarded as a marker of cell membrane degradation and hence cell damage [25]. In the present study glutamate remained stable and within normal values [26]. Glycerol exhibited a slight increase during the observation period but remained within normal values [26].
The microdialysis findings of the present study support the notion that not only the depth but also the duration of the hypotensive period determines if the alterations in brain redox state are reversible or irreversible.
Our findings are supported by an animal study by Wan et al. who reported that intracerebral microcirculation was unaffected by deep and long hemorrhagic hypotension [27]. These findings are also supported in two studies investigating the effect of prolonged and severe hemorrhagic hypotension in rats. The authors found that MAP 40 mmHg for 60–75 min did not cause cognitive damage to the rat, nor was it possible to detect apoptotic areas in the hippocampal area of the brain [28, 29]. However, the abovementioned studies only examined the microcirculatory flow and not the presence of oxygen and nutrients in the interstitial space. Although the authors reported that microcirculation was unaffected, and no structural brain damage was found, deliverance and uptake of oxygen and nutrients might be affected.
Global microdialysis
Our secondary objective was to verify our earlier findings that venous (superior sagittal sinus) microdialysis can be used as a measure for the hemisphere redox state. During the experimental protocol an increase in hemisphere LP was paralleled by an increase in venous (sagittal sinus) LP ratio, but this rise is not distinguishable from the systemic LP rise. Thus, our secondary null hypothesis cannot be rejected. We have previously demonstrated that global changes in cerebral lactate and pyruvate are reflected in the cerebral venous outflow and distinguished from systemic (i.e., arterial blood) perturbations [11, 30]. However, in the present study a similar increase in lactate and pyruvate was observed in arterial blood. Less pronounced shock leads to less pronounced global metabolic crisis and thus less pronounced alterations in venous LP ratio. During hemorrhagic shock an increase in anaerobic metabolism is present on a whole-organism level. The systemic arterial values of lactate and pyruvate would increase, and thus, an increase in systemic LP ratio would be seen. This systemic increase in LP ratio can mask an increase in global cerebral LP ratio measured in venous blood. After e.g. cardiac arrest where the systemic anaerobe metabolism has normalized to aerobic metabolism, the brain may still be suffering after a metabolic ischemic crisis. During supportive venous-arterial extracorporeal membrane oxygenation, venous microdialysis may also be able to detect unfavorable distribution of watershed line to the cerebrum which is not detected by bifrontal near-infrared spectroscopy (NIRS) [30, 31].
Clinical implications
The present study demonstrates an increase in hemisphere LP ratio during moderately long and severe shock. By comparing present findings with earlier finding in a study with 90-min duration of shock, this indicates that there is an upper limit for how long the cerebral autoregulatory mechanisms can compensate for a low systemic blood pressure. As demonstrated by one animal which experienced severe cerebral metabolic changes, not only time but also individual differences between each animal affect how long the autoregulatory mechanisms are able to maintain an adequate cerebral perfusion pressure. During damage control resuscitation and permissive hypotension, all is being done to ensure control of hemorrhage and secure the patient’s survival. Although this is being done as fast as possible it is wise to bear in mind that there might be an upper limit in which autoregulatory mechanisms exist. The rise in hemisphere LP ratio during hemorrhagic shock was followed by a rise in the sagittal sinus LP ratio, but this rise is not distinguishable from the systemic LP rise. In a clinical context, the less invasive technique with jugular bulb microdialysis might have a place in advanced monitoring where global cerebral ischemia or isolated cerebral pathologies might be present. When viewing the results from the present and earlier study [11] together this indicates that reversible metabolic crises might not be detected, but as soon as metabolic crises reach a level where the irreversible injury is imminent, it would be detected.
Limitations
In the present study, we use a fixed-pressure experimental model of hemorrhagic shock. The advantages of this model are its reproducibility as well as the ability of maintaining of a desired target MAP. It also mimics the clinical context where ongoing blood loss is replaced by transfusion with whole blood until a certain target MAP. One disadvantage of the model is the use of heparin to maintain the patency of intravascular catheters before, during, and after hemorrhage. Some studies have shown a possible effect on microcirculation after hemorrhagic shock. However, these studies use substantial higher doses, than in the present study [32]. The use of anesthetics also depresses the animal’s cardiovascular ability to compensate for a decreasing blood pressure. The anesthetized animals also mimic patients undergoing DCS, while utilizing the concepts of DCR. Many of the data collected showed a visual trend towards normalizing, and one might wonder if the values had returned to baseline values if the observation period had been longer. Obviously, the definition of each of the three intervals might affect the statistical test. The definition of each interval, when it starts, and when it ends could also influence the results. Intuitively a rise in LP ratio after a reversible metabolic crisis needs time to return to baseline values after the hypotensive period has ended. In our study we have defined the end of interval B when PbtO2 has normalized indicating a non-critical deliverance of oxygen and nutrients to the brain. Although this does not account for the time the brain’s redox status to return to normal, we consider it to be safer to overestimate the effect of injury.