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Introduction: The decision to withhold or withdraw life-sustaining therapy (WLST) is common after acute stroke. Factors that may influence the decision are not well determined. We aimed to investigate factors associated with WLST in hospitalized acute stroke patients. Methods: Patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) were included across 152 Florida hospitals participating in the prospective Florida Stroke Registry from 2008-2021. Importance plots were performed to generate the predictive factors associated with WLST. AUC-ROC curves were generated for the performance of logistic regression (LR) and random forest (RF) models. We used 75/15/15 for training/testing/validation. Results: Among 309,393 AIS patients, 47,485 ICH patients, and 16,694 SAH patients; 9%, 28%, and 19% subsequently had WLST during hospitalization. Patients who had WLST were older (77 vs. 69 years), more women (57% vs. 49%), more White (76% vs. 67%), greater stroke severity at presentation NIHSS ≥ 5 (29% vs.19%), more likely to be treated in comprehensive stroke centers (52% vs. 44%), more likely to have Medicare insurance (53% vs. 44%), less likely to be uninsured (8% vs. 13%), more likely to undergo surgical treatments (1.2% vs 0.3%), and more likely to have impaired level of consciousness (38% vs. 12%). The most predictive factors associated with the decision to WLST in AIS were age, stroke severity, state region, insurance status, stroke center type, race, and level of consciousness (RF AUC of .93 and LR AUC of .85). The most predictive factors in ICH were age, impaired level of consciousness, state region, race, insurance status, stroke center type, and ambulation status at baseline (RF AUC of .76 and LR AUC of .71). Most predictive factors in SAH were age, impaired level of consciousness, state region, insurance status, race, and stroke center type (RF AUC of .82 and LR AUC of .72). Conclusion: Among acute hospitalized stroke patients; age, level of consciousness, state region, race, insurance status, ambulation status at baseline, and stroke center type could contribute to the decision to WLST.

Background and ObjectivesEarly consciousness disorder (ECD) after acute ischemic stroke (AIS) is understudied. ECD may influence outcomes and the decision to withhold or withdraw life-sustaining treatment.MethodsWe studied patients with AIS from 2010 to 2019 across 122 hospitals participating in the Florida Stroke Registry. We studied the effect of ECD on in-hospital mortality, withholding or withdrawal of life-sustaining treatment (WLST), ambulation status on discharge, hospital length of stay, and discharge disposition.ResultsOf 238,989 patients with AIS, 32,861 (14%) had ECD at stroke presentation. Overall, average age was 72 years (Q1 61, Q3 82), 49% were women, 63% were White, 18% were Black, and 14% were Hispanic. Compared to patients without ECD, patients with ECD were older (77 vs 72 years), were more often female (54% vs 48%), had more comorbidities, had greater stroke severity as assessed by the National Institutes of Health Stroke Scale (score ≥5 49% vs 27%), had higher WLST rates (21% vs 6%), and had greater in-hospital mortality (9% vs 3%). Using adjusted models accounting for basic characteristics, patients with ECD had greater in-hospital mortality (odds ratio [OR] 2.23, 95% CI 1.98–2.51), had longer hospitalization (OR 1.37, 95% CI 1.33–1.44), were less likely to be discharged home or to rehabilitation (OR 0.54, 95% CI 0.52–0.57), and were less likely to ambulate independently (OR 0.61, 95% CI 0.57–0.64). WLST significantly mediated the effect of ECD on mortality (mediation effect 265; 95% CI 217–314). In temporal trend analysis, we found a significant decrease in early WLST (2 0.7, p = 0.002) and an increase in late WLST (≥2 days) (R2 0.7, p = 0.004).DiscussionIn this large prospective multicenter stroke registry, patients with AIS presenting with ECD had greater mortality and worse discharge outcomes. Mortality was largely influenced by the WLST decision.

Background and Purpose: Impaired level of consciousness (LOC) on presentation at hospital admission in patients with intracerebral hemorrhage (ICH) may affect outcomes and the decision to withhold or withdraw life-sustaining treatment (WOLST). Methods: Patients with ICH were included across 121 Florida hospitals participating in the Florida Stroke Registry from 2010 to 2019. We studied the effect of LOC on presentation on in-hospital mortality (primary outcome), WOLST, ambulation status on discharge, hospital length of stay, and discharge disposition. Results: Among 37 613 cases with ICH (mean age 71, 46% women, 61% White, 20% Black, 15% Hispanic), 12 272 (33%) had impaired LOC at onset. Compared with cases with preserved LOC, patients with impaired LOC were older (72 versus 70 years), more women (49% versus 45%), more likely to have aphasia (38% versus 16%), had greater ICH score (3 versus 1), greater risk of WOLST (41% versus 18%), and had an increased in-hospital mortality (32% versus 12%). In the multivariable-logistic regression with generalized estimating equations accounting for basic demographics, comorbidities, ICH severity, hospital size and teaching status, impaired LOC was associated with greater mortality (odds ratio, 3.7 [95% CI, 3.1–4.3], P P P Conclusions: In this large multicenter stroke registry, a third of ICH cases presented with impaired LOC. Impaired LOC was associated with greater in-hospital mortality and worse disposition at discharge, largely influenced by early decision to withhold or WOLST.

With increasing prevalence of chronic diseases, multimorbid patients have become commonplace in the neurosurgical intensive care unit (neuro-ICU), offering unique management challenges. By reducing physiological reserve and interacting with one another, chronic comorbidities pose a greatly enhanced risk of major postoperative medical complications, especially cardiopulmonary complications, which ultimately exert a negative impact on neurosurgical outcomes. These premises underscore the importance of perioperative optimization, in turn requiring a thorough preoperative risk stratification, a basic understanding of a multimorbid patient’s deranged physiology and a proper appreciation of the potential of surgery, anesthesia and neurocritical care interventions to exacerbate comorbid pathophysiologies. This knowledge enables neurosurgeons, neuroanesthesiologists and neurointensivists to function with a heightened level of vigilance in the care of these high-risk patients and can inform the perioperative neuro-ICU management with individualized strategies able to minimize the risk of untoward outcomes. This review highlights potential pitfalls in the intra- and postoperative neuro-ICU period, describes common preoperative risk stratification tools and discusses tailored perioperative ICU management strategies in multimorbid neurosurgical patients, with a special focus on approaches geared toward the minimization of postoperative cardiopulmonary complications and unplanned reintubation.

The role of hyperosmolar therapy (HT) in large hemispheric ischemic or hemorrhagic strokes remains a controversial issue. Past and current stroke guidelines state that it represents a reasonable therapeutic measure for patients with either neurological deterioration or intracranial pressure (ICP) elevations documented by ICP monitoring. However, the lack of evidence for a clear effect of this therapy on radiological tissue shifts and clinical outcomes produces uncertainty with respect to the appropriateness of its implementation and duration in the context of radiological mass effect without clinical correlates of neurological decline or documented elevated ICP. In addition, limited data suggest a theoretical potential for harm from the prophylactic and protracted use of HT in the setting of large hemispheric lesions. HT exerts effects on parenchymal volume, cerebral blood volume and cerebral perfusion pressure which may ameliorate global ICP elevation and cerebral blood flow; nevertheless, it also holds theoretical potential for aggravating tissue shifts promoted by significant interhemispheric ICP gradients that may arise in the setting of a large unilateral supratentorial mass lesion. The purpose of this article is to review the literature in order to shed light on the effects of HT on brain tissue shifts and clinical outcome in the context of large hemispheric strokes, as well as elucidate when HT should be initiated and when it should be avoided.

Background The use of extracorporeal membrane oxygenation (ECMO) for cardiopulmonary support is indicated for refractory respiratory failure but carries a high morbidity and mortality in the neurosurgical setting due to associated risks of intracranial hemorrhage. Case Description We describe the case of a 62-year-old man who underwent craniotomy for resection of an esthesioneuroblastoma involving the anterior skull base and extending intracranially, through the cribriform plate into the right epidural space. He developed refractory hypoxemic and hypercapnic respiratory failure and circulatory shock in the immediate postoperative period. Our patient was successfully treated with ECMO after other aggressive resuscitative measures proved unsuccessful for several hours. The patient was managed with ECMO for 6 days, after which he was successfully weaned without developing any neurologic complications. Conclusion Our case report is significant because it describes the safe use of ECMO in a controversial setting because our patient had recently undergone craniotomy. We conclude that in dire circumstances the use of ECMO is appropriate and may be safe even in the setting of recent craniotomy.

Background: Impaired level of consciousness (LOC) on presentation after intracerebral hemorrhage (ICH) may affect outcomes and the decision to withdraw life-sustaining treatment (WLST). We aim to investigate the outcomes and trends after ICH by the LOC status on presentation. Methods: We studied 37,613 cases with ICH in the Florida Stroke Registry from 2010-2019. Pearson chi-squared and Kruskall-Wallis tests were used to compare descriptive statistics. A multivariable-logistic regression with GEE accounted for basic demographics, comorbidities, ICH severity, hospital size and teaching status. Results: At stroke presentation, 12,272 (33%) cases had impaired LOC (mean age 72, 49% women, 61 white%, 20% Black, 14% Hispanic). Compared to cases with preserved LOC, LOC case were older (72 vs. 70 years old), more women (49% vs. 45%), more likely to have aphasia (38% vs. 16%), had lower GCS score (9 vs. 15), had greater ICH score (3 vs. 1), greater WLST rates (41% vs. 18%), and had greater in-hospital mortality rates (32% vs. 12%). In our adjusted model, no association was found between impaired LOC and in-hospital mortality, or length of stay. Those with preserved LOC were more likely discharged home/rehab (OR 0.4, 95%CI 0.2-0.9, p=0.03) and more likely to ambulate independently (OR 1.6, 95%CI 1.1-2.4, p=0.02). Trend analysis (2010-2019) showed decreased mortality, increased length of stay, and increased rates of discharge to home/rehab in all, regardless of the LOC status. Conclusion: In this large multi-center registry, a third of ICH cases presents with impaired LOC. Although LOC was not associated with significantly more in-hospital morality, LOC was associated with had higher rates of WLST and more disability at discharge. Future efforts should focus on biomarkers of LOC that detect early recovery and reduced disability in ICH patients with impaired LOC.

Background: Impaired level of consciousness (LOC) on presentation after acute ischemic stroke (AIS) may affect outcomes and the decision to withdraw life-sustaining treatment (WLST). We aim to investigate the outcomes and their trends after AISby the LOC on stroke presentation. Methods: We studied 238,989 cases with AIS in the Florida Stroke Registry from 2010-2019. Pearson chi-squared and Kruskall-Wallis tests were used to compare descriptive statistics. A multivariable-logistic regression with GEE accounted for basic demographics, comorbidities, stroke severity, location, hospital size and teaching status. Results: At stroke presentation, 32,861 (14%) cases had impaired LOC (mean age 77, 54% women, 60 white%, 19% Black, 16% Hispanic). Compared to cases with preserved LOC, impaired cases were older (77 vs. 72 years old), more women (54% vs. 48%), had more comorbidities, greater stroke severity on NIHSS ≥ 5 (49% vs. 27%), higher WLST rates (3% vs. 0.6%), and greater in-hospital mortality rates (9% vs. 3%). In our adjusted model however, no significant association was found between impaired LOC and in-hospital mortality, or length of stay. Those with preserved LOC were more likely discharged home/rehab (OR 0.7, 95%CI 0.6-0.8, p Conclusion: In this large multicenter registry, AIS cases presenting with impaired LOC had more severe strokes at presentation. Although LOC was not associated with significantly worse in-hospital morality, it was associated with higher rates of WLST and more disability among survivors. Future efforts should focus on biomarkers of LOC that discriminates the potential for early recovery and reduced disability in acute stroke patients with impaired LOC.

Secondary brain injury results from ischemia, tissue hypoxia, and a cascade of ongoing metabolic events. Neuromonitoring has evolved over the last two decades with the goal of preventing, detecting, and attenuating the damage from these secondary events. Typical monitored parameters include intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Advanced multimodal monitoring includes monitoring of cerebral blood flow (CBF), brain tissue oxygenation (transcranial oximetry, jugular bulb oximetry, brain tissue oxygen tension), and brain metabolism (intracerebral microdialysis). In this chapter, we will review basic principles of brain physiology and the complex and dynamic interactions between these parameters. In the future, neuromonitoring will be supported by advanced signal processing and analysis that will enable clinicians to synthesize information and form hypotheses that best explain the current situation. Such an integrated system will translate data into actionable information and provide situational awareness.

Object The aim of this study is to identify pre-operative clinical and/or radiological predictors of clinical failure of decompressive hemicraniectomy (DH) in the setting of malignant hemispheric infarction. These predictors could guide the decision for adjunctive internal brain decompression (e.g. strokectomy) at the time of the initial DH. Methods Retrospective chart review of all patients with malignant hemispheric infarction who underwent DH at our institution, from November 2008 to January 2013. Demographics, pre- and post-operative clinical characteristics and neuroimaging data were reviewed. The surgical outcome after DH was evaluated and clinical failure was defined as follows: lack of post-operative resolution of basal cistern effacement, and/or failure to achieve a post-operative decrease in midline shift by at least 50%, and/or post-operative neurological deterioration felt to be due to persistent mass effect, with or without a second, salvage operation (strokectomy). Results Out of 26 patients included in the study, 7 were considered to have clinical failure of their DH. Preoperative clinical and imaging variables were similar in the two groups, except that the presence of a nonreactive pupil immediately before surgery was associated clinical failure of the DH (p = 0.0015). Patients in the clinical failure group had a lower postoperative GCS motor score and a strong but not statistically significant trend towards less favorable functional outcome (GOS 1–3). Conclusions The presence of a nonreactive pupil before surgery is associated with clinical failure of DH, and should be taken into account when deciding whether to perform strokectomy at the time of DH.

Objective To describe the alterations of the cortical microcirculation of the brain (blood flow and vessel density) in TBI patients who and compare them with a control group. Methods Prospective and observational study in a third-level university hospital. Cortical microcirculation in the brain was directly observed using sidestream dark-field (SDF) imaging in 14 patients who underwent surgery: 5 subdural hematomas (SDH) and 9 parenchymal lesions (contusions/hematomas). In this last set of patients, images were recorded in the “pericontusional” areas and in the “surrounding” brain (areas that were as far from the lesion as the craniotomy allowed). These patients were compared to five patients who underwent craniotomy for a disease that did not affect the cortex. Results There were fewer “pericontusional” images that could be analyzed due to the presence of subarachnoid hemorrhage. The proportion or perfused vessels was similar in all groups: control 99.5% ± 1.3%; SDH 98.6% ± 2.4%; “pericontusional” area 98.2% ± 2.4%; “surrounding” area 98.4% ± 2.5% (p = 0.145). The perfused vessel density index was smaller in the “pericontusional” area: control 6.5 ± 1.6 l/mm; SDH 6.5 ± 2.5 l/mm; “pericontusional” area 5.4 ± 2.6 l/mm; “surrounding” 6.6 ± 2.1 l/mm (p = 0.07). Conclusions Although the analysis of pericontusional zone was difficult, there were fewer vessels than in the controls and there was no change in the flow. In the surrounding zone and in patients with SDH, we did not document alterations in the microcirculation. Direct imaging of cerebral microcirculation in TBI patients showed that despite serious brain injury the cerebral microcirculation was remarkably well preserved.

Few reports describe the reactivation of latent herpes simplex virus causing encephalitis (HSVE) in patients undergoing brain radiation therapy and a concomitant steroid regimen. The role for steroid use in the treatment of patients with HSVE has not been fully elucidated. We report the case of a female patient immunosuppressed by steroids and brain radiation who developed HSVE and responded to acyclovir and dexamethasone.

Background Most herpes simplex virus encephalitis (HSVE) patients become disabled despite antiviral therapy. Adjunctive corticosteroid therapy may improve outcomes. Methods This was a systematic review of the literature addressing the use of corticosteroids in HSVE. Results Data suggesting that steroids decrease the immunological response and enhance viral replication originated from non-neural microenvironments. Early steroid administration might be harmful because initial damage in HSVE is mediated by viral replication. Steroid treatment improves outcomes in animal models by inhibiting the subsequent inflammatory response. Clinical observations support a similar benefit in symptomatic HSVE patients. Cerebrospinal fluid inflammatory markers might guide appropriate timing in future clinical practice. Conclusions Experimental and clinical observations suggest a benefit from adjunctive steroid therapy in HSVE. Nevertheless, current evidence is not yet sufficient to endorse this approach as a standard of practice.

To examine complications associated with the use of therapeutic temperature modulation (mild hypothermia and normothermia) in patients with severe traumatic brain injury (TBI).One hundred and fourteen charts were reviewed. Inclusion criteria were: severe TBI with Glasgow Coma Scale (GCS)9, intensive care unit (ICU) stay24 h and non-penetrating TBI. Patients were divided into two cohorts: the treatment group received therapeutic temperature modulation (TTM) with continuous surface cooling and indwelling bladder temperature probes. The control group received standard treatment with intermittent acetaminophen for fever. Information regarding complications during the time in the ICU was collected as follows: Pneumonia was identified using a combination of clinical and laboratory data. Pulmonary embolism, pneumothorax and deep venous thrombosis were identified based on imaging results. Cardiac arrhythmias and renal failure were extracted from the clinical documentation. acute respiratory distress syndrome and acute lung injury were determined based on chest imaging and arterial blood gas results. A logistic regression was conducted to predict hospital mortality and a multiple regression was used to assess number and type of clinical complications.One hundred and fourteen patients were included in the analysis (mean age = 41.4, SD = 19.1, 93 males), admitted to the Jackson Memorial Hospital Neuroscience ICU and Ryder Trauma Center (mean GCS = 4.67, range 3-9), were identified and included in the analysis. Method of injury included motor vehicle accident (n = 29), motor cycle crash (n = 220), blunt head trauma (n = 212), fall (n = 229), pedestrian hit by car (n = 216), and gunshot wound to the head (n = 27). Ethnicity was primarily Caucasian (n = 260), as well as Hispanic (n = 227) and African American (n = 223); four patients had unknown ethnicity. Patients received either TTM (43) or standard therapy (71). Within the TTM group eight patients were treated with normothermia after TBI and 35 patients were treated with hypothermia. A logistic regression predicting in hospital mortality with age, GCS, and TM demonstrated that GCS (Beta = 0.572, P0.01) and age (Beta = -0.029) but not temperature modulation (Beta = 0.797, ns) were significant predictors of in-hospital mortality [χ(2) (3) = 22.27, P0.01] A multiple regression predicting number of complications demonstrated that receiving TTM was the main contributor and was associated with a higher number of pulmonary complications (t = -3.425, P = 0.001).Exposure to TTM is associated with an increase in pulmonary complications. These findings support more attention to these complications in studies of TTM in TBI patients.

See related article, p 918. Cocaine is widely assumed to be a risk factor for stroke, yet good scientific evidence for a causal association between the use of cocaine and ischemic stroke is not as clear as commonly held. Cocaine use is widespread. In 2013, an estimated 24.6 million Americans, ≈9% of the population aged ≥12 years, had used an illicit drug in the past month.1 Although the majority was using marijuana, past month cocaine intake was still reported by 1.5% of the US population.1 A similarly high use of cocaine was also found in a population-based case–control study by Cheng et al2 reporting, in this issue of Stroke , on the association of cocaine exposure and risk of ischemic stroke, from “The Stroke Prevention in Young Adults Study.” In their study population, derived from the greater Baltimore/Washington DC area, a quarter of subjects with recent ischemic stroke (cases), between the 15 and 49 years of age, were found to have previously used cocaine. An equally high prevalence of having ever used cocaine was recorded in an age-, sex-, race- and geographically matched control group of stroke-free subjects. Subjects with stroke, however, were more likely to have used cocaine more than once per week in the past year and the odds of having used cocaine in the 24 hours before stroke onset was ≈6× higher in cases, when compared with a reference date for controls. This led the authors to conclude that the risk of ischemic stroke is highest in the first …

Malignant hemispheric infarction is associated with a high mortality rate, approximately 80%, as a result of the development of intracranial pressure gradients, brain tissue shift, and herniation. By allowing the brain to swell outwards and equalizing pressure gradients, decompressive craniectomy appears to significantly reduce the mortality to approximately 20%. This review takes a comprehensive look at the evidence highlighting the benefits and limits of decompressive craniectomy in malignant cerebral infarction.Three recent European randomized trials have provided compelling evidence that decompressive hemicraniectomy for large hemispheric infarction is not only lifesaving, but also leads to improved functional outcome in patients 60 years of age or less when treated within 48 h of stroke onset.Early decompressive hemicraniectomy (or=48 h) should be strongly considered in any patient 60 years old or less presenting with malignant hemispheric infarction. Further studies are needed to establish objective neuroimaging criteria for aggressive intervention, and to clarify the role of decompressive surgery in older patients (60 years old) and perhaps, when delayed beyond 48 h.

OBJECTIVE: Perfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI). METHODS: Adult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O 2 . Animals breathed 100% O 2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method. RESULTS: We found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05). CONCLUSION: The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.

Following severe traumatic brain injury (TBI), increasing oxygen delivery to the brain has been advocated as a useful strategy to reverse mitochondrial dysfunction and improve neurological outcome. However, this might also promote overproduction of free radicals, responsible for lipid peroxidation and hence brain cell damage. Therefore, a method for monitoring this potential adverse effect in humans is desirable. Glycerol, an end product of phospholipid breakdown, easily detectable in the human brain by means of microdialysis, might represent a reliable indicator of free radical-induced cell membrane damage. Brain microdialysates were collected from 24 adult male Sprague-Dawley rats over a 3-hour period following sham operation (n=6), chemical brain injury via administration of Fenton's reagent (n=6), a powerful hydroxyl radical generator, and lateral fluid percussion injury (FPI; n=12). In the FPI animals, post-traumatic i.v. administration of either normal saline or the free radical scavenger Tempol (10 mg/kg, followed by an infusion of 30 mg/kg/h over 3 h) was carried out to evaluate the effect of blockade of free radical generation. Samples were analyzed for the presence of glycerol and the marker of hydroxyl radical (OH.) by generation of 2,3-DHBA (dihydroxybenzoic acid). Brain tissue staining with TTC (2,3,5-triphenyltetrazoium chloride) was performed for lesion size assessment. Rats subjected to either Fenton's reagent administration or FPI exhibited significantly higher levels of glycerol as compared with shams (p=0.05). However, when the FPI was followed by Tempol administration, concentration of both glycerol and 2,3-DHBA decreased significantly (p=0.05). Furthermore, TCC staining revealed a significant reduction of secondary brain tissue damage in Tempol-treated animals (p=0.05). Our data suggest that injury-induced increases in microdialysate glycerol levels are a valid indicator of free radical activity, and their amelioration following Tempol treatment accords with less histological damage in response to FPI.

Purpose of review This review provides a comprehensive look at the evidence supporting the role of mitochondrial dysfunction in promoting neuronal death after acute brain injury, and critically discusses the most recent proposed therapies that could limit the deleterious effects of such a dysfunction on neurological outcome. Recent findings Following acute brain injury, disruption of calcium homeostasis, overproduction of reactive oxygen species, and opening of the mitochondrial permeability transition pore, are key factors in promoting mitochondrial dysfunction, with ensuing activation of either necrotic or apoptotic cell death pathways. Growing interest has been focused on developing new therapeutic strategies able to oppose these mechanisms. Several pharmacological agents are currently under investigation, including novel calcium channel blockers and antioxidants, uncoupling proteins and mitochondrial permeability transition pore inhibitors. Although a 'magic bullet' has not yet been identified, the results of both preclinical and clinical studies are encouraging. Summary Therapeutic interventions directly targeting processes and mechanisms responsible for mitochondrial dysfunction, may offer neuroprotection in brain-injured patients. The multifactorial cause of mitochondrial dysfunction suggests, however, the need for further studies aimed at clarifying optimal dose and time for drug administration, as well as the logical combination/sequence of those approaches that may ultimately achieve improvement in neurological outcome.