Brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury

Abstract Cerebral ischemia is a well-recognized contributor to high morbidity and mortality after traumatic brain injury (TBI). Standard of care treatment aims to maintain a sufficient oxygen supply to the brain by avoiding increased intracranial pressure (ICP) and ensuring a sufficient cerebral perfusion pressure (CPP). Devices allowing direct assessment of brain tissue oxygenation have showed promising results in clinical studies, and their use was implemented in the Brain Trauma Foundation Guidelines for the treatment of TBI patients in 2007. Results of several studies suggest that a brain tissue oxygen-directed therapy guided by these monitors may contribute to reduced mortality and improved outcome of TBI patients. Whether increasing the oxygen supply to supraphysiological levels has beneficial or detrimental effects on TBI patients has been a matter of debate for decades. The results of trials of hyperbaric oxygenation (HBO) have failed to show a benefit, but renewed interest in normobaric hyperoxia (NBO) in the treatment of TBI patients has emerged in recent years. With the increased availability of advanced neuromonitoring devices such as brain tissue oxygen monitors, it was shown that some patients might benefit from this therapeutic approach. In this article, we review the pathophysiological rationale and technical modalities of brain tissue oxygen monitors, as well as its use in studies of brain tissue oxygen-directed therapy. Furthermore, we analyze hyperoxia as a treatment option in TBI patients, summarize the results of clinical trials, and give insights into the recent findings of hyperoxic effects on cerebral metabolism after TBI.     

Brain tissue oxygenation in patients with cerebral occlusive disease and arteriovenous malformations

It is not clear if ventilation with oxygen increases brain tissue oxygen pressure (PO2) during ischaemia. We have measured brain tissue PO2, carbon dioxide pressure (PCO2) and pH during baseline anaesthesia and oxygen ventilation in non-ischaemic control patients (n = 9), patients with cerebral occlusive disease (n = 11) and patients with arteriovenous malformations (AVM, n = 12). The same anaesthetic treatment was given to all groups and anaesthesia was constant during the study. Arterial pressure, brain temperature and arterial blood-gas tensions were similar between groups. Under baseline conditions, brain tissue PO2 was mean 4.2 (SD 1.4) kPa in the controls and was 70% lower in patients with ischaemia and AVM. Patients with occlusive disease also had elevated tissue PCO2 and acidosis. During oxygen ventilation, PO2 increased to 7.5 (2.9) kPa in controls and this was 50% greater than the increase in the ischaemia and AVM patients. The results showed that baseline tissue oxygenation and increases in PO2 during hyperoxia were attenuated in patients with ischaemia or AVM.      

Pression tissulaire cérébrale en oxygène : pour quoi faire et pour qui ?

The main purpose of neurointensive care is to fight against cerebral ischaemia. Ischaemia is the cell energy failure following inadequacy between supply of glucose and oxygen and demand. Ischemia monitoring starts with a global approach, especially with cerebral perfusion pressure (CPP) determined by mean arterial pressure and intracranial pressure (ICP). However, global monitoring is insufficient to detect “regional” ischaemia, leading to development of local monitoring such as brain oxygen partial pressure (PtiO₂). PtiO₂ is measured on a volume of a few mm³ from a probe implanted in the cerebral tissue. The normal value is classically included between 25 and 35 mmHg and critical ischemic threshold is 10 mmHg. Understanding what exactly is PtiO₂ is still a matter of debate. PtiO₂ is more an indicator of oxygen diffusion depending of oxygen arterial pressure (PaO₂) and local cerebral blood flow (CBF). Increase PaO₂ to treat PtiO₂ would hide information about local CBF. PtiO₂ is useful for the detection of low local CBF even when ICP is low as in hypocapnia-induced vasoconstriction. PtiO₂-guided management could lead to a continuous optimization of arterial oxygen transport for an optimal cerebral tissue oxygenation. Finally, PtiO₂ has probably a global prognostic value because studies showed that hypoxic values for a long period of time lead to an unfavourable neurologic outcome. In conclusion, PtiO₂ provides additional information for regional monitoring of cerebral ischaemia and deserves more intensive use to better understand it and probably improve neurointensive care management.     

Neuromonitoring

The monitoring of critically ill brain-injured patients has become increasingly complex. Several techniques are now available for global and regional brain monitoring that provide early warning of impending brain ischaemia and allow optimization of cerebral haemodynamics and oxygenation. Modern neurointensive care utilizes a combination of monitoring techniques (multimodal monitoring) to identify or predict secondary cerebral insults and guide therapeutic interventions in order to maximize the potential for good outcome after brain injury. Developments in multimodal monitoring have allowed a movement away from rigid physiological target-setting towards an individually tailored, patient-specific approach. This review describes current monitoring techniques used during the intensive care management of brain injury.     

From the macroscopic lesion to cellular ischemia

Traumatic brain injury (TBI) constitutes a major health and economic problem for developed countries, being one of the main causes of mortality and morbidity in children and young adults. Because of the immense importance and future consequences of TBI, the physician who sees a patient soon after brain injury must have a complete understanding of the pathophysiology and develop a practical knowledge of initial management of such patients. TBI may have intracranial and systemic effects that combine to give overall cerebral ischaemia. Injury to the nervous system is characterised by a stereotypic pattern, irrespective of the primary injury. The primary injury initiates a multitude of inflammatory cascades resulting in secondary brain injury, the effect of which is as important as the primary injury. This period of brain inflammation can last up to three weeks and renders the brain more susceptible to the effects of systemic insults such as hypotension, hypoxia and/or pyrexia. It has been shown in postmortem examination of patients dying from severe TBI that more than 90% had evidence of secondary ischaemic damage. The concept of 'cerebral protection' has been extended to encompass pretreatment of secondary injury. Preventing and treating cerebral ischaemia is the main goal of initial management of head-injured patients. Initial care focuses on achieving oxygenation, airway control and treatment of arterial hypotension.     

Neurosédation en réanimation

The objectives for using sedation in neurointensive care unit (neuroICU) are somewhat different from those used for patients without severe brain injuries. One goal is to clinically reassess the neurological function following the initial brain insult in order to define subsequent strategies for diagnosis and treatment. Another goal is to prevent severely injured brain from additional aggravation of cerebral blood perfusion and intracranial pressure. Depending on these situations is the choice of sedatives and analgesics: short-term agents, e.g., remifentanil, if a timely neurological reassessment is required, long-term agents, e.g., midazolam and sufentanil, as part of the treatment for elevated intracranial pressure. In that situation, a multimodal monitoring is needed to overcome the lack of clinical monitoring, including repeated measurements of intracranial pressure, blood flow velocities (transcranial Doppler), cerebral oxygenation (brain tissue oxygen tension), and brain imaging. The ultimate stop of neurosedation can distinguish between no consciousness and an alteration of arousing in brain-injured patients. During this period, an elevation of intracranial pressure is usual, and should not always result in reintroducing the neurosedation.     

Alcohol and traumatic brain damage

Many head-injured patients have been drinking alcohol, and it has been suggested that the effect of a raised blood alcohol may be to potentiate brain damage after head injury. To investigate this, a study was carried out on 38 consecutive, recently head-injured patients admitted to the Glasgow Neurosurgical Unit. Conscious level, blood alcohol and serum creatine kinase BB (CKBB) were measured on admission (the latter by radioimmunoassay). Conscious level related strongly to outcome (chi 2 = 11.678, P less than 0.001), and serum CKBB (chi 2 = 8.333, P less than 0.01) but not to blood alcohol level. In patients with severe head injury admitted to a neurosurgical unit, coma is more likely to be due to the injury than to the blood alcohol level, and alcohol does not adversely affect outcome in such patients.     

Brain tissue oxygen tension response to induced hyperoxia reduced in hypoperfused brain

OBJECTIVES: Increasing PaO2 can increase brain tissue PO2 (PbtO2). Nevertheless, the small increase in arterial O2 content induced by hyperoxia does not increase O2 delivery much, especially when cerebral blood flow (CBF) is low, and the effectiveness of hyperoxia as a therapeutic intervention remains controversial. The purpose of this study was to examine the role of regional (r)CBF at the site of the PO2 probe in determining the response of PbtO2 to induced hyperoxia. METHODS: The authors measured PaO2 and PbtO2 at baseline normoxic conditions and after increasing inspired O2 concentration to 100% on 111 occasions in 83 patients with severe traumatic brain injury in whom a stable xenon-enhanced computed tomography measurement of CBF was available. The O2 reactivity was calculated as the change in PbtO2 x 100/change in PaO2. RESULTS: The O2 reactivity was significantly different (p < 0.001) at the 5 levels of rCBF (<10, 11-15, 16-20, 21-40, and > 40 ml/100 g/min). When rCBF was < 20 ml/100 g/min, the increase in PbtO2 induced by hyperoxia was very small compared with the increase that occurred when rCBF was > 20 ml/100 g/min. CONCLUSIONS: Although the level of CBF is probably only one of the factors that determines the PbtO2 response to hyperoxia, it is apparent from these results that the areas of the brain that would most likely benefit from improved oxygenation are the areas that are the least likely to have increased PbtO2.     

Hypothermie et protection cérébrale après traumatisme crânien. Influence des gaz du sang

The usefulness of therapeutic hypothermia is highly debated after traumatic brain injury. A neuroprotective effect has been demonstrated only in experimental studies: decrease in cerebral metabolism, restoration of ATP level, better control of cerebral edema and cellular effects. Despite negative multicenter clinical studies, therapeutic hypothermia is still used to a better control of intracranial pressure. However, important issues need to be clarified, particularly the level and duration of hypothermia, the depth and modalities of sedation. A clear understanding of blood gases variations induced by hypothermia is needed to understand the cerebral perfusion and oxygenation changes. It is essential to recognize and to use hypothermia-induced physiological hypocapnia and alkalosis under strict control of cerebral oxygen balance (jugular venous saturation or tissue PO₂) and also to take into account the increased affinity of hemoglobin for oxygen. Management of post-traumatic intracranial hypertension using hypothermia, directed by intracranial pressure level, and consequently for long duration, is potentially beneficial but needs further clarification.     

Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure.

Early impaired cerebral blood flow (CBF) after severe head injury (SHI) leads to poor brain tissue oxygen delivery and lactate accumulation. The purpose of this investigation was to elucidate the relationship between CBF, local dialysate lactate (lact(md)) and dialysate glucose (gluc(md)), and brain tissue oxygen levels (PtiO2) under arterial normoxia. The effect of increased brain tissue oxygenation due to high fractions of inspired oxygen (FiO2) on lact(md) and CBF was explored. A total of 47 patients with SHI were enrolled in this studies (Glasgow Coma Score [GCS] < 8). CBF was first assessed in 40 patients at one time point in the first 96 hours (27 +/- 28 hours) after SHI using stable xenon computed tomography (Xe-CT) (30% inspired xenon [FiXe] and 35% FiO2). In a second study, sequential double CBF measurements were performed in 7 patients with 35% FiO2 and 60% FiO2, respectively, with an interval of 30 minutes. In a subsequent study, 14 patients underwent normobaric hyperoxia by increasing FiO2 from 35 +/- 5% to 60% and then 100% over a period of 6 hours. This was done to test the effect of normobaric hyperoxia on lact(md) and brain gluc(md), as measured by local microdialysis. Changes in PtiO2 in response to changes in FiO2 were analyzed by calculating the oxygen reactivity. Oxygen reactivity was then related to the 3-month outcome data. The levels of lact(md) and gluc(md) under hyperoxia were compared with the baseline levels, measured at 35% FiO2. Under normoxic conditions, there was a significant correlation between CBF and PtiO2 (R = 0.7; P < .001). In the sequential double CBF study, however, FiO2 was inversely correlated with CBF (P < .05). In the 14 patients undergoing the 6-hour 100% FiO2 challenge, the mean PtiO2 levels increased to 353 (87% compared with baseline), although the mean lact(md) levels decreased by 38 +/- 16% (P < .05). The PtiO2 response to 100% FiO2 (oxygen reactivity) was inversely correlated with outcome (P < .01). Monitoring PtiO2 after SHI provides valuable information about cerebral oxygenation and substrate delivery. Increasing arterial oxygen tension (PaO2) effectively increased PtiO2, and brain lact(md) was reduced by the same maneuver.     

Update in the treatment of traumatic brain injury

Opinion statement This review focuses on recent advances in the treatment of traumatic brain injury (TBI) during 2004 and 2005. Injured brain is a very heterogeneous structure, significantly evolving over time. Implementation of multimodal neuromonitoring will certainly provide more insights into pathophysiology of TBI. More studies are needed to determine how to best incorporate these new parameters into effective management protocols. Based on current literature, corticosteroids should not be indicated for the treatment of TBI. Avoidance or immediate treatment of secondary insults remains a mainstream of clinical care for patients with TBI. It seems that the therapy should focus on control of intracranial hypertension, and values of cerebral perfusion pressure around 60 mm Hg appear to correlate with favorable outcome in most patients. Hypertonic saline may become a preferred osmotherapeutic agent in severely head-injured patients, especially those with refractory intracranial hypertension. Benefit and indications for performing a decompressive craniectomy remain to be determined. Overall, individualized treatment respecting actual status of a patient’s intra- and extracranial homeostasis should be the key principle of our current therapeutic approach toward severely head-injured patients.     

La pupillométrie en anesthésie-réanimation

Pupil size reflects the balance between sympathetic and parasympathetic systems. Due to technological advances, accurate and repeated pupil size measurements are possible using infrared, video-recorded pupillometers. Two pupil size reflexes are assessed: the pupillary reflex dilation during noxious stimulation, and the pupil light reflex when the pupil is exposed to the light. The pupillary reflex dilation estimates the level of analgesia in response to a painful procedure or to a calibrated noxious stimulus, i.e., tetanic stimulus, in nonverbal patients. This might be of particular interest in optimizing the management of opioids in anaesthetized patients and in assessing pain levels in the intensive care unit. The pupil light reflex measurement is part of the routine monitoring for severely head-injured patients. The impact of pupillometry in this condition remains to be determined.     

Rôle délétère de l’hyperthermie en neuroréanimation

Fever is a secondary brain injury and may worsen neurological prognosis of neurological intensive care unit (NICU) patients. In response to an immunological threat, fever associates various physiological reactions, including hyperthermia. Its definition may vary but the most commonly used threshold is 37.5 °C. In animal studies, hyperthermia applied before, during or after cerebral ischemia may increase the volume of ischemic lesions. The mechanism of this effect may include increase in blood brain barrier permeability, increase in excitatory amino acid release and increase in free radical production. In NICU patients, fever is frequent, occurring in up to 20–30% of patients. Moreover, after haemorrhagic stroke, fever has been reported in 40–50% of patients. In half of the patients, fever may be related to an infectious cause but in more than 25% of patients, hyperthermia may be of central origin. After ischemic stroke, hyperthermia during the first 72 hours is associated with an increase in infarct size and increase in morbidity and mortality. This holds true also after subarachnoid haemorrhage. After traumatic brain injury, fever is not related to mortality but may increase morbidity. Whereas no causal link has been established between fever and unfavourable outcome, it seems reasonable to treat hyperthermia in patients suffering from brain injuries. In such patients, antipyretics have a moderate efficacy. In case of failure, they should be replaced by physical cooling techniques.     

Le syndrome post-arrêt cardiaque chez l’enfant

The occurrence of post-cardiac arrest syndrome may lead to death in some children who have recovered from a cardiac arrest. The post-cardiac arrest syndrome includes systemic ischaemia/reperfusion response, brain injury, myocardial dysfunction, and persistence of the precipitating pathology. The main cause of death is brain injury. Management includes strictly control of ventilation, oxygen therapy and haemodynamics associated with protection of the brain against any secondary injury: management of seizures, control of glycaemia and central temperature. Mild hypothermia should be considered in comatose children after cardiac arrest.     

Troubles de la coagulation lors du traumatisme cranio-encéphalique : physiopathologie et conséquences thérapeutiques

Early activation of coagulation is common after traumatic brain injury. Its origin is probably mainly intracerebral, due to tissue factor release from the injured brain. Abnormalities in blood coagulation tests are associated with poor neurological prognosis. Coagulation activation may induce disseminated intravascular coagulation and fibrinolysis. Disseminated intravascular coagulation is linked to brain ischemia caused by intravascular microthrombosis. This review will focus on pathophysiology of coagulation disorders after traumatic brain injury, and on their implications for therapeutic approaches.     

Neuronal injury and neuroprotection

Cerebral ischaemia is responsible for many deaths and causes an enormous amount of disability. Neurons are particularly susceptible to ischaemic injury because of their high metabolic rate and associated oxygen and energy requirements, and because brain repair mechanisms in humans appear to be absent or very limited. Primary neuronal injury may result from focal or global ischaemia, or traumatic brain injury. After injury, chains of physiological and pathophysiological events occur (e.g. inflammation) that cause secondary brain injury. This article describes these processes, and the efforts that have been made to intervene to improve outcome after cerebral ischaemia. Although the benefit of optimizing oxygenation and controlling intracranial pressure are beyond doubt, many potentially neuroprotective compounds that have been studied have been unsuccessful, despite promising results in experimental animal models. The authors discuss the reasons why this may be, and the growing realization that not all the processes previously thought to cause secondary injury are deleterious after all, and that a subtle interplay between them may offer some degree of neuroprotection or even brain repair.     

Hypothermie thérapeutique en traumatologie crânienne grave

Therapeutic hypothermia (TH) is considered a standard of care in the post-resuscitation phase of cardiac arrest. In experimental models of traumatic brain injury (TBI), TH was found to have neuroprotective properties. However, TH failed to demonstrate beneficial effects on neurological outcome in patients with TBI. The absence of benefits of TH uniformly applied in TBI patients should not question the use of TH as a second-tier therapy to treat elevated intracranial pressure. The management of all the practical aspects of TH is a key factor to avoid side effects and to optimize the potential benefit of TH in the treatment of intracranial hypertension. Induction of TH can be achieved with external surface cooling or with intra-vascular devices. The therapeutic target should be set at a 35 °C using brain temperature as reference, and should be maintained at least during 48 hours and ideally over the entire period of elevated intracranial pressure. The control of the rewarming phase is crucial to avoid temperature overshooting and should not exceed 1 °C/day. Besides its use in the management of intracranial hypertension, therapeutic cooling is also essential to treat hyperthermia in brain-injured patients. In this review, we will discuss the benefit-risk balance and practical aspects of therapeutic temperature management in TBI patients.     

Œdème cérébral : nouvelles pistes thérapeutiques

Cerebral oedema (CO) after brain injury can occur from different ways. The vasogenic and cytotoxic oedema are usually described but osmotic and hydrostatic CO, respectively secondary to plasmatic hypotonia or increase in blood pressure, can also be encountered. Addition of these several mechanisms can worsen injuries. Consequences are major, leading quickly to death secondary to intracerebral hypertension and later to neuropsychic sequelae. So therapeutic care to control this phenomenon is essential and osmotherapy is actually the only way. A better understanding of physiopathological disorders, particularly energetic ways (lactate), aquaporine function, inflammation lead to new therapeutic hopes. The promising experimental results need now to be confirmed by clinical data.     

Active cooling in traumatic brain‐injured patients: a questionable therapy?

Hypothermia is shown to be beneficial for the outcome after a transient global brain ischaemia through its neuroprotective effect. Whether this is also the case after focal ischaemia, such as following a severe traumatic brain injury (TBI), has been investigated in numerous studies, some of which have shown a tendency towards an improved outcome, whereas others have not been able to demonstrate any beneficial effect. A Cochrane report concluded that the majority of the trials that have already been published have been of low quality, with unclear allocation concealment. If only high-quality trials are considered, TBI patients treated with active cooling were more likely to die, a conclusion supported by a recent high-quality Canadian trial on children. Still, there is a belief that a modified protocol with a shorter time from the accident to the start of active cooling, longer cooling and rewarming time and better control of blood pressure and intracranial pressure would be beneficial for TBI patients. This belief has led to the instigation of new trials in adults and in children, including these types of protocol adjustments. The present review provides a short summary of our present knowledge of the use of active cooling in TBI patients, and presents some tentative explanations as to why active cooling has not been shown to be effective for outcome after TBI. We focus particularly on the compromised circulation of the penumbra zone, which may be further reduced by the stress caused by the difference in thermostat and body temperature and by the hypothermia-induced more frequent use of vasoconstrictors, and by the increased risk of contusional bleedings under hypothermia. We suggest that high fever should be reduced pharmacologically.     

Continuous monitoring of jugular bulb oxygen saturation in comatose patients — Therapeutic implications

Summary Comatose patients run a high risk of developing cerebral ischaemia which may considerably influence final outcome. It would therefore be extremely useful if one could monitor cerebral blood flow in these patients. Since there is a close correlation between the arteriovenous difference of oxygen and cerebral blood flow, it was a logical step to place a fiberoptic catheter in the jugular bulb for continuous measurement of cerebrovenous oxygen saturation.We have monitored cerebral oxygenation in 54 patients, comatose because of severe head injury, intracerebral haemorrhage or subarachnoid haemorrhage.Normal jugular venous oxygen saturation (SJVO₂) ranges between 60 and 90%. A decline to below 50% is considered indicative of cerebral ischaemia. Spontaneous episodes of desaturation (SJVO₂<50% for at least 15 min) were frequent during the acute phase of these insults. Many of these desaturation episodes could be attributed to hyperventilation, even though considered moderate. Likewise, insufficient cerebral perfusion pressure and severe vasospasm were found to be important causes of desaturation episodes. In many instances, tailoring of ventilation or induced hypervolaemia and hypertension were capable of reversing these low flow states.The new method of continuous cerebrovenous oximetry is expected to contribute to a better outcome by enabling timely detection and treatment of insufficient cerebral perfusion.