Sustained improvement in left ventricular function after bone marrow derived cell therapy in patients with acute ST elevation myocardial infarction. A 5-year follow-up from the Stem Cell Transplantation in Ischaemic Myocardium Study.

BACKGROUND: Intracoronary injection of autologous bone marrow-derived mononucleated cells (BM-MNC) may improve LV function shortly after acute ST elevation myocardial infarction (STEMI), but little is known about the long-term durability of the treatment effect. METHODS: In a single-centre trial a total of 60 patients with acute anterior STEMI, successful reperfusion therapy and a left ventricular ejection fraction (LVEF) of <50% were screened for the study. 23 patients were actively treated with intracoronary infusion of BM-MNC within a median of 3 days. The open-label control group consisted of 19 patients who did not consent to undergo BM-MNC treatment but agreed to undergo regular clinical and echocardiographic follow-up for up to 5 years after AMI. RESULTS: Whereas at 4 months there was no significant difference between the increase in LVEF in the BM-MNC group and the control group (+7.0%, 95%CI 3.6; 10.4) vs. +3.9%, 95%CI -2.1; 10), the absolute increase at 5 years remained stable in the BM-MNC but not in the control group (+7.95%, 95%CI 3.5; 12.4 vs. -0.5%, 95%CI -5.4; 4.4; p for interaction between groups = 0.035). DISCUSSION: In this single-centre, open-labelled study, intracoronary administration of BM-MNC is feasible and safe in the short term. It is also associated with sustained improvement of left ventricular function in patients with acute myocardial infarction, encouraging phase III studies to examine the potential BM-MNC effect on clinical outcome.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study.

PURPOSE: An optimal target for glucose control in ICU patients remains unclear. This prospective randomized controlled trial compared the effects on ICU mortality of intensive insulin therapy (IIT) with an intermediate glucose control. METHODS: Adult patients admitted to the 21 participating medico-surgical ICUs were randomized to group 1 (target BG 7.8-10.0 mmol/L) or to group 2 (target BG 4.4-6.1 mmol/L). RESULTS: While the required sample size was 1,750 per group, the trial was stopped early due to a high rate of unintended protocol violations. From 1,101 admissions, the outcomes of 542 patients assigned to group 1 and 536 of group 2 were analysed. The groups were well balanced. BG levels averaged in group 1 8.0 mmol/L (IQR 7.1-9.0) (median of all values) and 7.7 mmol/L (IQR 6.7-8.8) (median of morning BG) versus 6.5 mmol/L (IQR 6.0-7.2) and 6.1 mmol/L (IQR 5.5-6.8) for group 2 (p < 0.0001 for both comparisons). The percentage of patients treated with insulin averaged 66.2 and 96.3%, respectively. Proportion of time spent in target BG was similar, averaging 39.5% and 45.1% (median (IQR) 34.3 (18.5-50.0) and 39.3 (26.2-53.6)%) in the groups 1 and 2, respectively. The rate of hypoglycaemia was higher in the group 2 (8.7%) than in group 1 (2.7%, p < 0.0001). ICU mortality was similar in the two groups (15.3 vs. 17.2%). CONCLUSIONS: In this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy (target 4.4-6.1 mmol/L), associated with an increased incidence of hypoglycaemia, as compared to a 7.8-10.0 mmol/L target. (ClinicalTrials.gov # NCT00107601, EUDRA-CT Number: 200400391440).

Gene therapy.

Review of the book "The new healers", by William R. Clarck, Oxford University Press, Oxford, UK

Eligibility for statin therapy in primary prevention: discrepancies using different guidelines in a population-based study in Switzerland

Introduction: Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10-year CHD risk. We compared the 10-year CHD risk assessments and eligibility percentages for statin therapy using three scoring algorithms currently used in Switzerland. Methods: We studied 5683 women and men, aged 35-75, without overt cardiovascular disease (CVD), in a population-based study in Lausanne, Switzerland. We compared the 10-year CHD risk using three scoring schemes, i.e., the Framingham risk score (FRS) from the U.S. National Cholesterol Education Program's Adult Treatment Panel III (ATP III), the PROCAM scoring scheme from the International Atherosclerosis Society (IAS), and the European risk SCORE for low-risk countries, without and with extrapolation to 60 years as recommended by the European Society of Cardiology guidelines (ESC). With FRS and PROCAM, high-risk was defined as a 10-year risk of fatal or non-fatal CHD >20% and a 10-year risk of fatal CVD >= 5% with SCORE. We compared the proportions of high-risk participants and eligibility for statin use according to these three schemes. For each guideline, we estimated the impact of increased statin use from current partial compliance to full compliance on potential CHD deaths averted over 10 years, using a success proportion of 27% for statins. Results: Participants classified at high-risk (both genders) were 5.8% according to FRS and 3.0% to the PROCAM, whereas the European risk SCORE classified 12.5% at high-risk (15.4% with extrapolation to 60 years). For the primary prevention of CHD, 18.5% of participants were eligible for statin therapy using ATP III, 16.6% using IAS, and 10.3% using ESC (13.0% with extrapolation) because ESC guidelines recommend statin therapy only in high-risk subjects. In comparison with IAS, agreement to identify eligible adults for statins was good with ATP III, but moderate with ESC (Figure). Using a population perspective, a full compliance with ATP III guidelines would reduce up to 17.9% of the 24'310 CHD deaths expected over 10 years in Switzerland, 17.3% with IAS and 10.8% with ESC (11.5% with extrapolation). Conclusion: Full compliance with guidelines for statin therapy would result in substantial health benefits, but proportions of high-risk adults and eligible adults for statin use varied substantially depending on the scoring systems and corresponding guidelines used for estimating CHD risk in Switzerland.

Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice.

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE(-/-) mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(-/-) mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis.

Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n=13) or limited-stage disease (n=7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

Improved blood pressure control by monitoring compliance with antihypertensive therapy.

Compliance with antihypertensive therapy was monitored for three months using an electronic medication dispenser in 35 patients remaining hypertensive despite the once-daily administration of a blood pressure lowering drug (either as monotherapy or as fixed-dose combination therapy). During the monitoring of compliance, the treatment was unchanged but blood pressure decreased significantly (p < 0.001) from 167.9/100.4 +/- 16.3/7.2 mmHg (mean +/- SD) to 152.5/90.9 +/- 20.9/11.5 mmHg. The percentage of days with one opening per day was 80.8 +/- 20.5. Thus, discussing with the patient about compliance with the prescribed drug regimen and monitoring compliance for a few months allows better control of blood pressure. This most likely reflects increased compliance with antihypertensive drug therapy.

Optimum in vitro expansion of human antigen-specific CD8 T cells for adoptive transfer therapy.

Increasing evidence suggests that adoptive transfer of antigen-specific CD8(+) T cells could represent an effective strategy in the fight against chronic viral infections and malignancies such as melanoma. None the less, a major limitation in the implementation of such therapy resides in the difficulties associated with achieving rapid and efficient expansion of functional T cells in culture necessary to obtain the large numbers required for intravenous infusion. Recently, the critical role of the cytokines interleukin (IL)-2, IL-7 and IL-15 in driving T cell proliferation has been emphasized, thus suggesting their use in the optimization of expansion protocols. We have used major histocompatibility complex (MHC) class I/peptide multimers to monitor the expansion of antigen-specific CD8 T lymphocytes from whole blood, exploring the effect of antigenic peptide dose, IL-2, IL-7 and IL-15 concentrations on the magnitude and functional characteristics of the antigen-specific CD8(+) T cells generated. We show here that significant expansions of antigen-specific T cells, up to 50% of the CD8(+) T cell population, can be obtained after a single round of antigen/cytokine (IL-2 or IL-15) stimulation, and that these cells display good cytolytic and interferon (IFN)-gamma secretion capabilities. Our results provide an important basis for the rapid in vitro expansion of autologous T cells from the circulating lymphocyte pool using a simple procedure, which is necessary for the development of adoptive transfer therapies.

Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy.

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. AIMS: To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. METHODS: T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-gamma-ELISpot responses to HCV core peptides, that predominantly stimulate CD4(+) T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals. RESULTS: The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log(10) IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (-0.3 log10 IU/ml, p=0.02). CONCLUSIONS: Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

Perinatal nitric oxide therapy prevents adverse effects of perinatal hypoxia on the adult pulmonary circulation.

Adverse events in utero are associated with the occurrence of chronic diseases in adulthood. We previously demonstrated in mice that perinatal hypoxia resulted in altered pulmonary circulation in adulthood, with a decreased endothelium-dependent relaxation of pulmonary arteries, associated with long-term alterations in the nitric oxide (NO)/cyclic GMP pathway. The present study investigated whether inhaled NO (iNO) administered simultaneously to perinatal hypoxia could have potential beneficial effects on the adult pulmonary circulation. Indeed, iNO is the therapy of choice in humans presenting neonatal pulmonary hypertension. Long-term effects of neonatal iNO therapy on adult pulmonary circulation have not yet been investigated. Pregnant mice were placed in hypoxia (13% O2) with simultaneous administration of iNO 5 days before delivery until 5 days after birth. Pups were then raised in normoxia until adulthood. Perinatal iNO administration completely restored acetylcholine-induced relaxation, as well as endothelial nitric oxide synthase protein content, in isolated pulmonary arteries of adult mice born in hypoxia. Right ventricular hypertrophy observed in old mice born in hypoxia compared to controls was also prevented by perinatal iNO treatment. Therefore, simultaneous administration of iNO during perinatal hypoxic exposure seems able to prevent adverse effects of perinatal hypoxia on the adult pulmonary circulation.

Experimental approaches in the targeting of photodynamic therapeutics

RÉSUMÉ : Chez l'homme, le manque de sélectivité des agents thérapeutiques représente souvent une limitation pour le traitement des maladies. Le ciblage de ces agents pour un tissu défini pourrait augmenter leur sélectivité et ainsi diminuer les effets secondaires en comparaison d'agents qui s'accumuleraient dans tout le corps. Cela pourrait aussi améliorer l'efficacité des traitements en permettant d'avoir une concentration localisée plus importante. Le ciblage d'agents thérapeutiques est un champ de recherche très actif. Les stratégies sont généralement basées sur les différences entre cellules normales et malades. Ces différences peuvent porter soit sur l'expression des molécules à leurs surfaces comme des récepteurs ou des transporteurs, soit sur les activités enzymatiques exprimées. Le traitement thérapeutique choisi ici est la thérapie photodynamique et est déjà utilisé pour le traitement de certains cancers. Cette thérapie repose sur l'utilisation de molécules qui réagissent à la lumière, les photosensibilisants. Elles absorbent l'énergie lumineuse et réagissent avec l'oxygène pour former des radicaux toxiques pour les cellules. Les photosensibilisants utilisés ici sont de deux natures : (i) soit ils sont tétrapyroliques (comme les porphyrines et chlorines), c'est à dire qu'ils sont directement activables par la lumière ; (ii) soit ce sont des prodrogues de photosensibilisants comme l'acide 5aminolévulinique (ALA) qui est transformé dans la cellule en protoporphyrine IX photosensibilisante. Dans le but d'augmenter la sélectivité des photosensibilisants, nous avons utilisé deux stratégies différentes : (i) le photosensibilisant est modifié par le greffage d'un agent de ciblage ; (ii) le photosensibilisant est incorporé dans des structures moléculaires de quelques centaines de nanomètres. Les sucres et l'acide folique sont des agents de ciblage largement établis et ont été utilisés ici car leurs récepteurs sont surexprimés à la surface de nombreuses cellules malades. Ainsi, des dérivés sucres ou acide folique de l'ALA ont été synthétisés et évalués in vitro sur de nombreuses lignées cellulaires cancéreuses. La stratégie utilisant l'acide folique est apparue incompatible avec l'utilisation de l'ALA puisque aucune photosensibilité n'a été induite par le composé. La stratégie utilisant les sucres a, par ailleurs, provoquée de bonnes photosensibilités mais pas d'augmentation de sélectivité. En parallèle, la combinaison entre les propriétés anticancéreuses des complexes métalliques au ruthénium avec les propriétés photosensibilisantes des porphyrines, a été évaluée. En effet, les thérapies combinées ont émergé il y a une dizaine d'années et représentent aujourd'hui de bonnes alternatives aux monothérapies classiques. Des ruthenium(I1)-arènes complexés avec la tetrapyridylporphyrine ont ainsi présenté de bonnes cytotoxicités et de bonnes phototoxicités pour des cellules de mélanomes. Des porphyrines ont aussi été compléxées avec des noyaux de diruthénium et ce type de dérivé a présenté de bonnes phototoxicités et une bonne sélectivité pour les cellules cancéreuses de l'appareil reproducteur féminin. L'incorporation de photosensibilisants tétrapyroliques a finalement été effectuée en utilisant des nanoparticules (NP) biocompatibles composées de chitosan et de hyaluronate. L'effet de ces NP a été évalué pour le traitement de la polyarthrite rhumatoïde (PR). Les NP ont d'abord été testées in vitro avec des macrophages de souris et les résultats ont mis en évidence de bonnes sélectivités et photosensibilités pour ces cellules. In vivo chez un modèle marin de la PR, l'utilisation de ces NP a révélé un plus grand temps de résidence des NP dans le genou de la souris en comparaison du temps obtenu avec le photosensibilisant seul. Le traitement par PDT a aussi démontré une bonne efficacité par ailleurs égale à celle obtenue avec les corticoïdes utilisés en clinique. Pour finir, les NP ont aussi démontré une bonne efficacité sur les myelomonocytes phagocytaires humains et sur les cellules contenues dans le liquide synovial de patients présentant une PR. Tous ces résultats suggèrent que les deux stratégies de ciblage peuvent être efficaces pour les agents thérapeutiques. Afm d'obtenir de bons résultats, il est toutefois nécessaire de réaliser une analyse minutieuse de la cible et du mode d'action de l'agent thérapeutique. Concernant les perspectives, la combinaison des deux stratégies c'est à dire incorporer des agents thérapeutiques dans des nanostructures porteuses d'agents de ciblage, représente probablement une solution très prometteuse. SUMMARY : In humans, the lack of selectivity of drugs and their high effective concentrations often represent limitations for the treatment of diseases. Targeting the therapeutical agents to a defined tissue could enhance their selectivity and then diminish their side effects when compared to drugs that accumulate in the entire body and could also improve treatment efûciency by allowing a localized high concentration of the agents. Targeting therapeutics to defined cells in human pathologies is a main challenge and a very active field of research. Strategies are generally based on the different behaviors and patterns of expression of diseased cells compared to normal cells such as receptors, proteases or trans-membrane carriers. The therapeutic treatment chosen here is the photodynamic therapy and is already used in the treatment of many cancers. This therapy relies on the administration of a photosensitizer (PS) which will under light, react with oxygen and induce formation of reactive oxygen species which are toxic for cells. The PSs used here are either tetrapyrolic (i. e. porphyries and chlorins) or prodrugs of PS (5-aminolevulinic acid precursor of the endogenous protoporphyrin Imo. In order to improve PS internalization and selectivity, we have used two different strategies: the modification of the PSs with diseased cell-targeting agents as well as their encapsulation into nanostructures. Sugars and folic acid are well established as targeting entities for diseased cells and were used here since their transporters are overexpressed on the surface of many cancer cells. Therefore sugar- and folic acid-derivatives of 5-aminolevulinic acid (ALA) were synthesized and evaluated in vitro in several cancer cell lines. The folic acid strategy appeared to be incompatible with ALA since no photosensitivity was induced while the strategy with sugars induced good photosensitivites but no increase of selectivity. Alternatively, the feasibility of combining the antineoplastic properties of ruthenium complexes with the porphyrin's photosensitizing properties, was evaluated since combined therapies have emerged as good alternatives to classical treatments. Tetrapyridylporphyrins complexed to ruthenium (I17 arenes presented good cytotoxicities and good phototoxicities toward melanoma cells. Porphyries were also complexed to diruthenium cores and this type of compound presented good phototoxicities and good selectivity for female reproductive cancer cells. The encapsulation of tetrapyrolic PSs was finally investigated using biocompatible nanogels composed of chitosan and hyaluronate. The behavior of these nanoparticles was evaluated for the treatment of rheumatoid arthritis (RA). They were first tested in vitro in mouse macrophages and results revealed good selectivities and phototoxicities toward these cells. In vivo in mice model of RA, the use of such nanoparticles instead of free PS showed longer time of residence in mice knees. Photodynamic protocols also demonstrated good efficiency of the treatment comparable to the corticoid injection used in the clinic. Finally our system was also efficient in human cells using phagocytic myelomonocytes or using cells of synovial fluids taken from patients with RA. Altogether, these results revealed that both strategies of modification or encapsulation of drugs can be successful in the targeting of diseased cells. However, a careful analysis of the target and of the mode of action of the drug, are needed in order to obtain good results. Looking ahead to the future, the combination of the two strategies (i.e. drugs loaded into nanostructures bearing the targeting agents) would represent probably the best solution.

Are initial radiographic and clinical scales associated with subsequent intracranial pressure and brain oxygen levels after severe traumatic brain injury?

BACKGROUND: Prediction of clinical course and outcome after severe traumatic brain injury (TBI) is important. OBJECTIVE: To examine whether clinical scales (Glasgow Coma Scale [GCS], Injury Severity Score [ISS], and Acute Physiology and Chronic Health Evaluation II [APACHE II]) or radiographic scales based on admission computed tomography (Marshall and Rotterdam) were associated with intensive care unit (ICU) physiology (intracranial pressure [ICP], brain tissue oxygen tension [PbtO2]), and clinical outcome after severe TBI. METHODS: One hundred one patients (median age, 41.0 years; interquartile range [26-55]) with severe TBI who had ICP and PbtO2 monitoring were identified. The relationship between admission GCS, ISS, APACHE II, Marshall and Rotterdam scores and ICP, PbtO2, and outcome was examined by using mixed-effects models and logistic regression. RESULTS: Median (25%-75% interquartile range) admission GCS and APACHE II without GCS scores were 3.0 (3-7) and 11.0 (8-13), respectively. Marshall and Rotterdam scores were 3.0 (3-5) and 4.0 (4-5). Mean ICP and PbtO2 during the patients' ICU course were 15.5 ± 10.7 mm Hg and 29.9 ± 10.8 mm Hg, respectively. Three-month mortality was 37.6%. Admission GCS was not associated with mortality. APACHE II (P = .003), APACHE-non-GCS (P = .004), Marshall (P < .001), and Rotterdam scores (P < .001) were associated with mortality. No relationship between GCS, ISS, Marshall, or Rotterdam scores and subsequent ICP or PbtO2 was observed. The APACHE II score was inversely associated with median PbtO2 (P = .03) and minimum PbtO2 (P = .008) and had a stronger correlation with amount of time of reduced PbtO2. CONCLUSION: Following severe TBI, factors associated with outcome may not always predict a patient's ICU course and, in particular, intracranial physiology.