BRAIN-PROTECT is an acronym for BRAin INjury: Prehospital Registry on Outcome, Treatment and Epidemiology of Cerebral Trauma. Ambulance personnel, Helicopter Mobile Medical Teams, Emergency Physicians and Trauma Centers work together with the aim to improve prehospital treatment and outcome of traumatic brain injury. The project has been initiated by the Department of Anesthesiology of the VU University Medical Center Amsterdam and is founded by the Dutch Brain Foundation.

Much research has been done and published around the world on treatment of traumatic brain injury (TBI). So why do we need more research on this topic? First, optimal treatment of TBI is a relevant problem for the individual patient as well as for the society, because TBI is a leading cause of death and permanent disability in the population under 45 years. Second, although much research has been done, little is known on how patients can be optimally treated. Current treatment guidelines are based on expert consensus rather than on scientific evidence, and even concepts which have widely been accepted as treatment standards, e.g. endotracheal intubation of patients with a GCS score ≤8, are currently challenged. Third, data collected elsewhere may not necessarily be applicable to the Netherlands, because population density and demographics, organization and training of emergency medical services, transport facilities, local protocols, response times as well as distance to trauma centers vary considerably between countries. For these reasons, the BRAIN-PROTECT group is implementing a prospective Dutch national registration system allowing extensive analyses of current prehospital treatment approaches and their effects on outcome, with the goal to identify prognostic factors and beneficial or hazardous treatments. While this database is the core BRAIN-PROTECT research instrument, we are involved in other research lines, such as the ALARM Research Group on neurotrauma and coagulopathy as well as in research on cerebral microcirculation and tissue oxygenation.

Why do we know so little on TBI treatment?

International guidelines for management of TBI have been published by the Brain Trauma Foundation, the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. Remarkably, scientific evidence was insufficient to recommend practice standards with a high degree of clinical certainty concerning any therapeutic intervention, treatment threshold or monitoring modality. Quality of evidence for prehospital treatment was even considered low and the strength of all recommendations was weak. Hence, optimal treatment is basically unknown and the current “evidence based” treatment guidelines are based on expert opinion rather than on evidence.

Several factors contribute to an uncertainty concerning optimal treatment. First, promising findings of retrospective data-analysis, e.g. a reported 21% absolute mortality benefit with prehospital intubation in severe TBI, have not been confirmed in prospective investigations and raise doubt on the usefulness of prehospital interventions. This, along with the known inherent limitations of retrospective data analysis, emphasizes the need for prospective data collection.

Second, TBI is a heterogeneous disease with multiple trauma mechanisms, variable intracranial pathology and diverse extra-cranial injuries, which by itself may limit the prognosis. It is therefore likely that any single intervention performed in such a heterogeneous condition will only have a small influence on overall outcome, and therefore data from a large number of patients are needed for sufficient statistical power. Indeed, previous studies have often been underpowered to detect potentially important benefits of specific therapeutic interventions.

A third factor for the inconsistency of data is that several therapies targeting at neuroprotection and amelioration of secondary injury have shown promising effects in animal experiments, however, these therapies failed to improve outcome in patients during clinical trials. While this may in part also be due to insufficient statistical power, timing of the study intervention may have played a critical role. In these trials, the study intervention was often delayed until several hours after the initial trauma. The brain’s tolerance to adverse secondary events such as hypoxia and ischemia is known to be very limited and therefore the window of opportunity for therapeutic interventions is likely short. Thus, it is possible that these trials failed to show favorable treatment effects of therapies that might be effective if applied more early, i.e. in the prehospital phase.

We are convinced that prehospital treatment has the potential to influence the further clinical course and outcome of the patient in several ways. Prehospital health care providers make several choices that influence prehospital on-scene time and can delay further neurosurgical treatment, including recovery and extrication techniques and decisions about patient transport modality and destination (ambulance vs. helicopter, regional hospital vs. trauma center). However, it is poorly known how these decisions influence outcome.

Evidently, medical treatment also plays an important role in prehospital management. Factors triggering secondary brain injury (see general section on TBI) are regularly observed at the accident scene. Herein, healthcare providers have the unique opportunity to prevent and correct such factors at the earliest possible stage. Since these factors are often associated either with respiratory failure (hypoxia, hyper- or hypocapnia, respiratory acidosis) or inadequate circulation (hypotension, inadequate cerebral perfusion, metabolic acidosis), optimal prehospital management of airway, breathing and circulation should likely improve outcome. However, it is unclear how to translate this apparently simple concept into optimal prehospital care. For example, respiratory depression can be observed in patients with severe TBI due to airway obstruction or aspiration, concomitant thoracic trauma or due to sedating drugs. In consequence, endotracheal intubation has traditionally been advocated for all patients with severe TBI to protect the airway and to ensure adequate oxygenation and ventilation. However this approach is currently questioned because evidence for its effectiveness is controversial. Guidelines only give the vague recommendation that “an airway should be established, by the most appropriate means available, in patients who have severe traumatic brain injury, the inability to maintain an adequate airway, or hypoxia not corrected by supplemental oxygen”. The question arises which the “most appropriate means” is and why the gold standard of airway management, tracheal intubation, cannot consistently be shown to improve but has even been suggested to deteriorate outcome. One possibility is that benefits of tracheal intubation are offset or reversed by side effects of intubation if not performed properly. If intubation is attempted without narcotic drugs, coughing and autonomic reflexes cause marked increases of ICP. On the other hand, inadequate use of narcotic drugs can induce hypotension. Prolonged intubation attempts cause hypoxia, hypercapnia and delay transportation to hospital, and intubation is more likely to be prolonged in the prehospital environment especially for inexperienced personnel because of neck immobilization, unusual positioning of the patient (e.g., sitting in a car) or difficulties to visualize vocal cords due to blood or dislocated teeth. Hence, the right tool in the right hands at the right time might likely improve outcome, while poor performance could deteriorate outcome. The question should therefore possibly not be “whether or not” to intubate patients, but rather “how” intubation should be performed in order to improve outcome. In the Netherlands, most patients with severe head injury are intubated by an MMT-emergency physician (anesthesiologist or surgeon, see section on prehospital treatment) with ample experience in drug-assisted endotracheal intubation, and it is possible that endotracheal intubation by experienced emergency physicians may improve outcome, and this question warrants further investigation.

Once a patient is intubated, he or she usually requires ventilation. Optimal ventilation, however, is also matter of debate and inadequate ventilation may offset benefits of intubation. First, high intrathoracic airway pressures compromise venous return leading to arterial hypotension and venous congestion in the brain. Second, hypo- and hyperventilation lead to hyper- and hypocapnia, both of which may be potentially detrimental. A growing body of evidence suggests that hyperventilation deteriorates outcome and prophylactic hyperventilation is therefore no longer recommended. Guidelines now recommend to maintain end-tidal pCO2 values between 35 and 40 mmHg (i.e. low-normocapnic), however optimal pCO2 thresholds are unknown and some animal studies suggest that ventilation at a high-normocapnic level or moderate hypercapnic level might be beneficial. Similarly, optimal inspiratory oxygen concentration for TBI patients is not known. It is recommended to maintain oxygen saturation above an arbitrary threshold of 90% because it is generally accepted that hypoxia is harmful, however hyperoxia promotes free oxygen radical formation and could theoretically be equally harmful.

Hemodynamic management in TBI patients is also highly controversial. In areas with disturbed autoregulation, cerebral blood flow (CBF) directly depends on cerebral perfusion pressure (CPP) and hence on arterial blood pressure. Guidelines recommend to avoid systolic blood pressures below 90 mmHg because hypotension has been shown to deteriorate outcome [4]. However, optimal blood pressure is unknown and it is also unclear how hypotensive patients should be treated. Here again it is possible that potential benefits of hemodynamic management are offset by side effects. There are a variety of ways to treat hypotension, including administration of crystalloid or colloid fluids, hypertonic saline but also a variety of catecholamines and non-catecholamine vasopressors. However, different fluids have different compositions, different volumes of distribution and different effects on the coagulation system. Excessive fluid infusion promotes brain edema, critically dilutes the hematocrit and causes relevant coagulopathy. Prehospital guidelines simply recommend that hypotonic patients should be treated with “isotonic fluids” and state that hypertonic resuscitation is a treatment option for severe TBI. However, type and amount of fluids as well as the role of vasopressors remains unclear. Interestingly, an alternative approach termed the “Lund concept” is widely used in Sweden, which differs in essential aspects from international guidelines. Instead of targeting at a CPP above a certain threshold, this approach emphasizes the need to reduce vascular resistance and focuses on antihypertensive therapy and on sedation to avoid stress induced sympathetic discharge. Supporters of the Lund concept argue that increased vascular resistance elevates CPP hence promoting transcapillary leakage and brain edema in areas with disrupted blood-brain-barrier. The resulting increase in ICP counteracts desired increases in CBF, while the brain will only come closer to the state of herniation. These concurring concepts and the vague guideline recommendations demonstrate that very little is known about optimal hemodynamic management in TBI patients despite a large number of studies. Beside respiratory and circulatory support, other therapies are regularly used in the prehospital phase, such as administration of antibiotics or administration of mannitol to reduce ICP. The impact of such measures on outcome is also unclear and warrants further investigation.

In summary, patients with severe TBI have usually undergone a number of treatments and interventions before they arrive in a trauma-center. Most TBI outcome research focuses on in-hospital interventions including emergency department admission, neurosurgical interventions and critical care therapy. However, decisions made in the first minutes after TBI may significantly influence patient outcome. Until now, little is known between the relationship of prehospital treatment and outcome, and hence we still know little on how to treat our patients optimally.

The aim of the BRAIN-PROTECT research project is to establish a comprehensive national prospective prehospital Dutch TBI database, allowing extensive analyses of current prehospital treatment approaches and their effects on outcome, with the goal to identify prognostic factors and beneficial or hazardous treatments. At the moment, we are still developing and testing the database, and due to the prospective character of the study and the large number of patients needed for sufficient statistical power, first results will not be available in a short period of time. Nevertheless, we hope that you will remain interested in our project! Please check the site regularly for updates and don‘t hesitate to contact us if you require additional information.

Aegroti salus suprema lex

(a practitioner should act in the best interest of the patient)