This article reviews the role of modalities that directly monitor brain parenchyma in patients with severe traumatic brain injury. The physiology monitored involves compartmental and perfusion pressures, tissue oxygenation and metabolism, quantitative blood flow, pressure autoregulation, and electrophysiology. There are several proposed roles for this multimodality monitoring, such as to track, prevent, and treat the cascade of secondary brain injury; monitor the neurologically injured patient; integrate various data into a composite, patient-specific, and dynamic picture; apply protocolized, pathophysiology-driven intensive care; use as a prognostic marker; and understand pathophysiologic mechanisms involved in secondary brain injury to develop preventive and abortive therapies, and to inform future clinical trials.
Key points
- •
Secondary injury is characterized by a cascade of biochemical, cellular, and molecular events, often compounded by the effects of systemic insults, such as hypotension and hypoxemia.
- •
ICP, CPP, PRx, CBF, PbtO 2 , LPR, and electrophysiologic data are parts of an integrated, patient-specific approach.
- •
Incorporation of patient demographics, brain imaging, and multimodality data can lead to the creation of individualized patient trajectories and physiologic latent states.
Introduction
This article reviews the role of modalities that directly monitor the brain parenchyma in patients with severe traumatic brain injury (TBI). The physiology monitored involves compartmental and perfusion pressures, tissue oxygenation and metabolism, quantitative blood flow, pressure autoregulation, and electrophysiology. There are several proposed roles for this multimodality monitoring (MMM):
- •
Track, prevent, and treat the cascade of secondary brain injury (SBI), known to occur after primary TBI at the tissue and cell level.
- •
Monitor the neurologically injured, often heavily sedated, patient who may have no informative clinical examination. This takes into account the idea that irreversible brain injury may have occurred by the time clinical examination changes are noted at the bedside.
- •
Integrate clinical examination, neuroimaging, and MMM data into a composite, patient-specific and dynamic picture. Based on this, aim toward targeted management that optimally balances the timing and the benefit/risk ratio of medical-surgical interventions.
- •
Apply protocolized, pathophysiology-driven intensive care.
- •
Use as a prognostic marker.
- •
Understand the pathophysiologic mechanisms involved in SBI to develop preventive and abortive therapies, and to inform future clinical trials.
Introduction
This article reviews the role of modalities that directly monitor the brain parenchyma in patients with severe traumatic brain injury (TBI). The physiology monitored involves compartmental and perfusion pressures, tissue oxygenation and metabolism, quantitative blood flow, pressure autoregulation, and electrophysiology. There are several proposed roles for this multimodality monitoring (MMM):
- •
Track, prevent, and treat the cascade of secondary brain injury (SBI), known to occur after primary TBI at the tissue and cell level.
- •
Monitor the neurologically injured, often heavily sedated, patient who may have no informative clinical examination. This takes into account the idea that irreversible brain injury may have occurred by the time clinical examination changes are noted at the bedside.
- •
Integrate clinical examination, neuroimaging, and MMM data into a composite, patient-specific and dynamic picture. Based on this, aim toward targeted management that optimally balances the timing and the benefit/risk ratio of medical-surgical interventions.
- •
Apply protocolized, pathophysiology-driven intensive care.
- •
Use as a prognostic marker.
- •
Understand the pathophysiologic mechanisms involved in SBI to develop preventive and abortive therapies, and to inform future clinical trials.
Pathophysiologic rationale
Secondary injury is characterized by a cascade of biochemical, cellular, and molecular events, including the endogenous evolution of cerebral damage and the effects of systemic insults, such as hypotension and hypoxemia. Based on experimental TBI models the mechanisms producing SBI can be grouped as (1) those associated with ischemia, excitotoxicity, energy failure, and resultant cell death cascades; (2) secondary cerebral swelling; (3) axonal injury; and (4) inflammation and regeneration. At the core of these mechanisms a resultant tissue hypoxia and/or dysoxia is believed to underlie a state of cellular energy failure.
Oxidative metabolism is based on convective oxygen transport from ambient air to blood capillaries, with hemoglobin and erythrocytes as vehicles; oxygen diffusion from erythrocytes in the capillaries to mitochondria in the cells; and oxygen reduction in the mitochondria via the electron transport chain. Failure in any of these three steps could result in similar clinical manifestations; nevertheless, targeted and differentiated management requires distinguishing the actual mechanisms involved. The main types, causes, and neuromonitoring profiles of tissue hypoxia are summarized in Table 1 . In clinical practice, it is difficult to determine the exact nature of tissue hypoxia without integration of data from MMM and neuroimaging.
| Type | Pathophysiology | Neuromonitoring Profile |
|---|---|---|
| Ischemic | Inadequate CBF | ↓CBF, ↓PbtO 2 , ↑LPR (high lactate/low pyruvate), ↑OEF |
| Low extraction | Low arterial P o 2 (hypoxemic hypoxia) Low hemoglobin concentration (anemic hypoxia) Low half-saturation tension P50 (high-affinity hypoxia) | ≅CBF, ↓PbtO 2 , ↑LPR (high lactate/low pyruvate), ≅OEF |
| Shunt | Arteriovenous shunting (microvascular shunt) | ↑CBF, ≅PbtO 2 , ↑LPR (high lactate/low pyruvate), ↓OEF |
| Dysperfusion | Diffusion barrier (intracellular or interstitial edema) | ≅CBF, ≅PbtO 2 , ↑LPR (high lactate/low pyruvate), ↓OEF |
| Uncoupling | Mitochondrial dysfunction | ≅CBF, ≅PbtO 2 , ↑LPR (high lactate/normal pyruvate), ↓OEF |
| Hypermetabolic | Increased demand | ↑CBF, ↓PbtO 2 , ↑LPR (high lactate/low pyruvate), ↑OEF |
Among the different types of hypoxia, ischemia has long been regarded as the central cause of SBI. Studies in the 1970s demonstrated low cerebral blood flow (CBF) in the first few hours after injury, and postmortem examination of patients with fatal head injuries provided evidence of ischemic necrosis. These findings led to management strategies directed at augmenting cerebral perfusion, blood flow, and oxygen delivery. These strategies, however, have not reliably proven to positively impact clinical outcomes, although they are known to potentially carry significant morbidity. The finding of a high rate of acute respiratory distress syndrome in patients treated with hemodynamic augmentation as an anti-ischemia regimen is a prime example.
There are further mechanistic objections to the current model of ischemic hypoxia as the predominant mechanism. It seems that except for cases of extremely low cerebral perfusion pressure (CPP) the presence of ischemia, using a variety of techniques, has remained elusive. Recent observations have highlighted alternative mechanisms: dysperfusion hypoxia as a result of increased mean diffusion length from erythrocytes to mitochondria caused by intracellular or interstitial edema, uncoupling hypoxia caused by intrinsic mitochondrial dysfunction, and shunt hypoxia in the forms of capillary transit time heterogeneity and thoroughfare channel shunt flow. Increases in capillary transit time heterogeneity were shown to reduce the maximum achievable oxygen extraction fraction (OEF) for a given CBF and tissue oxygen tension. This overview provides the context for the discussion that follows on the different components of MMM.
Modalities
Intracranial Pressure and Derived Indices (Pressure Reactivity Index)
Cerebral swelling and accompanying intracranial hypertension contributes to secondary damage in two ways. Intracranial hypertension can compromise cerebral perfusion leading to secondary ischemia; in addition, it can produce the devastating consequences of deformation through herniation syndromes. Intracranial hypertension has been closely linked to adverse outcomes after TBI. In conjunction with optimization of CPP, the control of raised intracranial pressure (ICP) has formed the cornerstone of brain trauma guidelines, and together these have led to a reduction in mortality from TBI. In the absence of randomized controlled trials (RCTs) directly comparing ICP treatment thresholds, the cutoff for treatment had been traditionally set at 20 mm Hg based on observational data. Nevertheless, the Brain Trauma Foundation guidelines had recognized that rather than accepting a generic, absolute ICP threshold, an attempt should be made to individualize thresholds based on patient characteristics, other critical parameters, and on a risk-benefit consideration of treating ICP values.
The recent BEST-TRIP trial compared two management protocols for treatment of severe TBI: one involving ICP monitoring (with a threshold of 20 mm Hg) and the other involving serial computed tomography imaging and neurologic examination. It is beyond the scope of this article to discuss this study in any detail apart from highlighting some points recently made by an international panel of experts. It should be appreciated that this was not a trial of ICP monitoring or the efficacy of such monitoring, and as a consequence the role of ICP monitoring in directing the treatment of established intracranial hypertension cannot be decided based on the data from the BEST TRIP. The primary impact of the trial should be to promote further investigation into understanding the clinical profile of patients who may actually benefit from monitoring, into determining patient-specific ICP thresholds, and in sharpening therapeutic algorithms.
How can the main criticisms against the traditional approach to intracranial hypertension be summarized? (1) The ICP threshold set at 20 to 25 mm Hg has resulted from an overall low level of evidence, making the validity of the chosen value questionable. Furthermore, the methods used have not allowed for differentiation between a potentially modifiable therapeutic target and a mere surrogate of injury severity. (2) Absolute thresholds ignore the variability of brain injury types and host characteristics and responses. They also mandate the same unvarying goal throughout a patient’s course. (3) SBI insults, under current paradigms, are treated as unidimensional excursions over a certain number, whereas degree and time range of excursion are not considered. (4) A range of potentially important pathophysiologic variables that describe the relationships among CBF, perfusion pressure, and oxygen delivery/use, and cellular metabolism and mitochondrial state remain unaccounted. (5) The therapeutic interventions that are used carry a price that potentially outweighs the benefits of achieving a fixed ICP goal.
However, continuous ICP monitoring offers the ability to investigate waveform morphology and metrics, potentially expanding the available information from a single number to evaluation of intracranial compliance and pressure-volume compensatory reserve. Continuous ICP can also be used as a surrogate of cerebral blood volume (CBV) (under conditions of a steep pressure-volume curve) and thus when correlated to spontaneous blood pressure fluctuations, offers a window into cerebrovascular pressure autoregulation and reactivity. Cerebrovascular pressure reactivity is defined as the ability of vascular smooth muscle to respond to changes in transmural pressure, and is determined by observing the response of ICP to changes in arterial blood pressure (ABP) ; in pressure-reactive conditions, a rise in ABP leads within 5 to 15 seconds to vasoconstriction with reduction of CBV, and ICP decreases; if defective, CBV increases passively and ICP rises. The opposite applies to a reduction in ABP. A computer-aided method has been developed at Cambridge University to calculate and monitor the moving coherence/correlation index between spontaneous slow waves (20–200 seconds) of ABP and ICP. This method derives a pressure reactivity index (PRx) that has values in the range between −1 and +1. A negative or zero value reflects a normally reactive vascular bed, whereas positive values reflect passive, nonreactive vessels. Previous studies have established a significant correlation between PRx and outcome after head injury, including a time-dependent element: if PRx persisted above 0.2 for more than 6 hours, this was usually associated with a fatal outcome.
Steiner and colleagues and more recently Aries and colleagues have demonstrated the value of using the PRx in identifying an optimal CPP, under and above which clinical outcome worsens. However, the PRx has also been recently used in defining individualized ICP thresholds. When these patient-specific thresholds were used to quantify individualized intracranial hypertension burden, in the form of ICP dose, were shown to be stronger predictors of 6-month clinical outcome as compared with doses derived from the conventional thresholds of 20 and 25 mm Hg. It is furthermore of note that the absolute doses based on the standard thresholds were larger than the individualized ones. This work suggests that the impact of ICP on clinical outcome is critically linked with the state of cerebrovascular pressure reactivity ; pressure-passive conditions add vulnerability in the presence of intracranial hypertension.
Partial Brain Tissue Oxygen Tension
In 1956, Clark described the principles of an electrode that could measure oxygen tension polarographically in blood or tissue. The diffusion of oxygen molecules through an oxygen-permeable membrane into an electrolyte solution causes depolarization at the nearby cathode, starting an electrical current related to the amount of oxygen. These measurements today are performed via the Licox catheter (Integra Neurosciences, San Diego, CA). The probe has a diameter of 0.5 mm, and the measurement area is 5 mm long; clinical experience has shown a run-in time before stable measurements are obtained of less than 2 hours. The catheter requires temperature correction by means of core temperature or, preferably, measurement of brain temperature.
The more interesting question is what is actually measured by the Licox probe? Is partial brain tissue oxygen tension (PbtO 2 ) simply a CBF surrogate? Can it be used as an indicator of the balance between oxygen delivery, demand, and consumption? Although the physiologic significance of PbtO 2 is still not fully understood, our working model is as follows: PbtO 2 (and the lactate-pyruvate ratio [LPR] for that matter, as discussed later) should not be simplistically viewed as a marker of ischemic hypoxia but rather as a complex measure resulting from the various mechanisms involved in the oxygen delivery-utilization pathway. Gupta and colleagues demonstrated that PbtO 2 does not represent end-capillary oxygen tension. Subsequently, Menon and colleagues highlighted the importance of diffusion barriers in the oxygen pathway from blood to the mitochondrial respiratory chain; this barrier is localized in the microvasculature with structural substrates of vascular collapse, endothelial swelling, and perivascular edema. Diringer and colleagues found no improvement in the cerebral metabolic rate for oxygen (CMRO 2 ) after normobaric hyperoxia, ‘‘disconnecting’’ PbtO 2 , and CMRO 2 . Finally, Rosenthal and colleagues reinforced the idea that PbtO 2 is not closely related to total oxygen delivery or to cerebral oxygen metabolism, and instead identified a parabolic relationship between PbtO 2 and the product of CBF and arteriovenous oxygen tension.
Persistently depressed PbtO 2 has been linked with poor neurologic outcomes; similarly to the situation with ICP, it is to date unclear if it represents a mere surrogate of injury severity or if it could be a modifiable treatment target with outcome implications. The preliminary step toward answering this question was undertaken in a phase II RCT of the safety and efficacy of brain tissue oxygen monitoring. In the Brain Tissue Oxygen Monitoring in Traumatic Brain Injury (BOOST-2) trial, 110 patients were randomized to treatment based on ICP monitoring alone (goal ICP <20 mm Hg) versus treatment based on ICP (goal <20 mm Hg) and PbtO 2 (goal >20 mm Hg). The primary outcome was achieved with a median fraction of time with PbtO 2 less than 20 mm Hg of 0.44 in the ICP group and 0.14 in the ICP + PbtO 2 group ( P <.00001). There was no significant difference between adverse events and protocol violations were infrequent. The nonfutility outcome measure was also met, with a nonstatistical trend toward lower mortality and poor outcome at 6-months in the ICP + PbtO 2 group. The investigators therefore concluded that a treatment protocol guided by both ICP and PbtO 2 reduces the duration of measured brain tissue hypoxia. The findings of this study will help determine the sample size for a phase III RCT.
Microdialysis
Microdialysis is used clinically to estimate extracellular interstitial concentrations of small molecules (a standard 20-kDa nominal molecular weight cutoff membrane recovers glucose, pyruvate, lactate, glycerol, and glutamate), but can also be used to recover much larger molecules, such as inflammatory mediators from the interstitial fluid. The physiologic premise for obtaining tissue metabolic data rests on the assumption that it is critical to know when there is a transition from aerobic to anaerobic metabolism as a sine qua non of energy failure. This is signified by a biochemical pattern of increased lactate production and pyruvate consumption, leading to an increased LPR (thresholds of >25 or >40 have been used). Consequently, the LPR is thought of as a sensitive marker of brain redox state and secondary ischemic injury, and when raised has been associated with unfavorable clinical outcomes.
PET studies have found variable relationships among CMRO 2 , OEF, and LPR based on the thresholds for ischemia used, timing of monitoring, and probe location. Type of tissue hypoxia is also expected to affect the OEF-LPR relationship, because OEF is expected to increase in ischemic and decrease in shunt or diffusion barrier hypoxia. Recent works further demonstrate that an increased LPR may have a wide differential diagnosis. Importantly, energy crisis has been demonstrated to occur in the absence of ischemia or defects in oxygen delivery and on the basis of primary mitochondrial dysfunction. A pattern of increased lactate with near normal pyruvate may indicate mitochondrial failure rather than ischemia. Knowledge of the functional status of mitochondria and of the presence of oxygen diffusion barriers is critical in the interpretation of an increased LPR.
Cerebral Blood Flow
Historically, methods measuring CBF involved “one-time” measurements with the use of administered tracer gases and dyes, or thermodilution. Modern neuromonitoring paradigms require that the measurements be continuous and applicable at the bedside. One such technique uses thermal diffusion to measure local CBF; it uses an intraparenchymal probe with a thermistor and a temperature sensor and measures the thermal gradient between the distal thermistor that is heated by 2°C and the proximal temperature sensor and provides a quantified regional CBF measurement in mL/100 g/min. Preliminary small studies have been done to assess its usefulness and reliability in measuring autoregulation combined with ICP, CPP, and PRx and found it to be safe with minimal complications and able to provide assessment of local vascular resistance changes in response to blood pressure and hyperventilation challenges.
A mean value of 18 to 25 mL/100 g/min is considered normal; however, serial changes or trends rather than absolute values may better detect early neurologic deterioration or vasospasm or help assess a response to therapy. Limitations include effects of temperature and hyperthermia, and there are no data correlating with clinical outcomes at this time. Also the limitation of interpreting absolute CBF numbers, outside of extremes, without local oxygenation and metabolic data should be kept in mind. Technical limitations, such as measurement drift, have also been recently described. Examples of MMM in regional ischemia, transient intracranial hypertension, and systemic hypotension are demonstrated in Figs. 1–3 , respectively.
Related posts:
Traumatic Brain Injury
Concussion—Mild Traumatic Brain Injury
Cerebral Metabolism and the Role of Glucose Control in Acute Traumatic Brain Injury
Cerebral Edema in Traumatic Brain Injury
Past, Present, and Future of Traumatic Brain Injury Research
Role of Metabolomics in Traumatic Brain Injury Research
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
