Progress in neurosurgery, neuroradiology, and critical care medicine in the last 50 years (1) contributed to the drops of 9% per decade in traumatic brain injury (TBI) mortality among hospitalized patients between 1970 and 1990, and it has been stable since (2). However, TBI remains a major cause of mortality and morbidity: approximately 57,000 deaths related to TBI occur in the European Union every year (3). Moreover, the increasing proportion of survivors includes many with neurological disabilities and poor quality of life (4); it was estimated that 7.7 million patients live with TBI-related disabilities in Europe (5). For all these reasons, neuroprotective strategies could provide immense benefits.

Even if there is no broadly accepted definition, neuroprotection in TBI can be considered as the body of interventions aimed at improving the patient’s outcome, and preserving and restoring the integrity, function, and connectivity of the brain cells not irremediably damaged by the initial injury. While the primary injury at the moment of the impact (including hemorrhage, laceration, contusion, and primary axotomy) is not amenable to medical treatment, the complex cascade of molecular and cellular events (secondary injury) that follows the original damage can aggravate the initial harm. This cascade reduces the chances of functional recovery but could, at least theoretically, be counteracted (6, 7).

The first section of this paper discusses attempts to limit the progression of injury, focusing on preclinical research, and translational medicine. In the second section, we describe therapeutic interventions based on multimodal brain monitoring that could reduce the extent of additional insults to the injured brain.

Traumatic brain injury is the result of an external force applied to the head (8) which, depending on the energy and site of the impact, can result in a number of different lesions commonly referred to as primary injury. Contusions, lacerations, epidural hematomas, subdural hematomas, subarachnoid hemorrhage, and axonal injury may be seen in TBI patients, based on the different mechanisms of the injury (direct impact, acceleration and deceleration forces, penetrating object, explosion blast waves), singly or in combination.

Beyond the brain tissue disruption at the moment of the impact, a broad spectrum of secondary events is triggered by the initial biomechanical injury. This include acute, subacute, and chronic events that all contribute to cell death and/or degeneration and are referred to as secondary brain injury (9). Briefly, alteration in ionic permeability and release of excitatory neurotransmitters (especially glutamate) propagate damage through energy failure and free radicals overload. Spreading depolarization is thought to be linked to this excessive release of glutamate. Cellular permeability is altered and increases calcium influx; this causes mitochondrial dysfunction, priming further energy defects, and apoptosis. Neurons ultimately may die through necrotic and apoptotic processes; autophagy is believed to play a role as well. Damaged axons may further fall prey to secondary axotomy and demyelination. Trauma directly affects the blood–brain barrier, with increased permeability causing protein-rich edema, and activation of a pro-inflammatory state. Inflammation, also promoted by resident microglia, has a dual action, spreading damage and, at the same time, promoting neurorestorative processes. This complex series of events starts immediately (seconds or minutes) after trauma but may last for weeks or months, especially inflammation (4). The contributions of each of these pathways to the secondary brain injury vary depending on the specific TBI lesion; for example, inflammation-mediated brain injury seems predominant in contusion while calcium-mediated injury predominates in diffuse axonal injury (10).

Several TBI models reproduce specific types of lesion in homogeneous groups of animals. Based on the distinct force applied, they can be used to investigate the components of the primary and secondary injury in time and space. Each model has specific advantages and limitations (9). None of them can be considered ideal, but together they lead to an understanding of mechanisms contributing to cell death or dysfunction after TBI. Consequently, experimental models have allowed the identification of therapeutic targets and the study of a wide spectrum of neuroprotective molecules including drugs aiming at specific targets (such as calcium-antagonists, NMDA-antagonists, free radical scavengers, bradykinin antagonists) and also drugs targeting multiple/pleiotropic mechanisms (such as anti-inflammatory steroids, erythropoietin, progesterone) (11).

Despite promising results in preclinical settings, these pharmacological neuroprotective compounds have proved disappointing in human studies. In the last three decades, more than 20 neuroprotective agents have been tested in clinical trials (11) without proof of significant outcome improvement. A recent overview of more than 10 “robust” studies (multicenter, including more than 100 patients, with an appropriate design and a low risk of bias) enrolling more than 15,000 patients confirms their failure to demonstrate any positive result (12).

This translational failure may have numerous reasons, both in the clinical and in the preclinical settings.

Subsequent reappraisals concerning the study design and conduction of clinical trials have been published (11, 13, 14). These analyses identified a number of possible critical factors that may have counteracted the neuroprotective potential of the compounds, for instance: –

the extent of side effects of the drugs and the occurrence of serious systemic complications

To overcome this long list of limitations inherent to randomized clinical trials an alternative approach, devoted to Comparative Effectiveness Research, is currently ongoing. An example is the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI¹), a large scale international project aiming at collection of demographic, clinical, imaging, genetic, and proteomic data from 5,400 TBI patients (15). The main objectives are to improve TBI characterization and classification and to identify the best clinical care, using comparative effectiveness research approach. CENTER-TBI and other similar projects running in Europe and North America, coordinated in the International Initiative for Traumatic Brain Injury Research (InTBIR²) are expected to provide high quality data, and rigorous statistical analysis, for improving care and outcome in TBI.

There is also the possibility that the preclinical findings were weaker than expected. First, there are limitations in the experimental models used, which exploit a single traumatic mechanism, such as direct impact or blast waves. However, no single mechanism can reproduce the wide pathophysiological and epidemiological heterogeneity of TBI—a very complex disorder. This means that a therapeutic effect detected in a homogeneous animal population exposed to a single type of injury may well not be generalizable to the human TBI population. Second, the quality of some experimental studies is variable (16, 17), and there is the risk of stressing positive results. It is recognized that blind assessment of the effect, animal randomization, and other indicators of quality are inversely related to the effect size in several published studies on brain injury (18). Third, the papers with negative results are less likely to be accepted for publication. This bias skews the literature and makes any thorough evaluation of treatment effects difficult or impossible (16–18).

In recent years, new approaches and research strategies have been proposed (19–21) to overcome these obstacles (see Panel). Operation Brain Trauma Therapy (21) moves in this direction. OBTT is a consortium of established preclinical TBI investigators supported by the US Army. It aims at identifying promising acute therapies for TBI, testing their efficacy across different animal models and laboratories through rigorous neurological examinations, motor and cognitive tests, brain and lesion volume measures, and biomarkers (22). OBTT recently reported that the neuroprotective effect of four (out of five) potential treatments, rigorously re-tested, was weaker than previously indicated in the literature (22). Those negative findings highlight the need for improving research standards in both preclinical and clinical research.

Repeated failures of pharmacological neuroprotective trials have blunted the enthusiasm for potential new wonder drugs. The number of industry-sponsored studies has markedly dropped, with eight new trials started in 1995–1999 but only one from 2005 to 2009 (13). Interestingly, failures occurred in the decades (1980–2010) during which the fundaments of neurocritical care were established and specialized care for severe brain injury emerged as a discipline.

The first textbook on “Neurological and Neurosurgical Intensive Care” was published by Alan Ropper and Sean Kennedy in 1983 (23). In 1995, the Society of Critical Care Medicine established a neuroscience section; in 2002, the NeuroCritical Care Society was founded. Growing interest in acute brain injury led to a pragmatic approach toward neuroprotection. While awaiting revolutionary pharmacological interventions, it became evident that additional, second insults after initial injury were frequent, and could be prevented and/or minimized in clinical practice. The hypothesis was that clear identification and correction of aggravating factors such as arterial hypotension could reduce the total burden imposed by TBI on the central nervous system and could consequently improve outcomes.

In this section, we describe some aspects of current ICU practice as part of a comprehensive strategy for minimizing insults to the injured brain and restoring brain homeostasis.

The paradox of neuroprotection in TBI is that, despite a long list of potential neuroprotective agents active under experimental conditions, no compound has demonstrated protection in clinical trials. Analysis of clinical and preclinical trials has identified several gaps and improvements are certainly needed. However, even the most rigorous scrutiny of evidence and the highest research standard, as proposed by OBTT, do not guarantee success: a similar initiative in ischemic stroke (73) led to a negative clinical trial (74).

While awaiting an effective molecule limiting secondary brain injury after trauma, good-quality neurointensive care can provide modest but effective neuroprotection. By monitoring systemic and neurological parameters, intracranial and extracranial threats can be identified. In this way, effective targeted therapies become possible, and the burden of additional insults to the brain might be lightened.

TZ, MC, and NS designed the review, assembled a preliminary draft, and incorporated further contributions from each author into subsequent versions. All the authors revised it critically for important intellectual content and approved the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.