Diabetic neuropathy: inhibitory G protein dysfunction involves PKC-dependent phosphorylation of G oα

We examined the hypothesis that decreased inhibitory G protein function in diabetic neuropathy is associated with increased protein kinase C (PKC)-dependent phosphorylation of the G oα subunit. Streptozotocin-induced diabetic rats were studied between 4 and 8 weeks after onset of diabetes and compared with aged-matched healthy animals as controls. Opioid-mediated inhibition of forskolin-stimulated cyclic AMP was significantly less in dorsal root ganglia (DRGs) from diabetic rats compared with controls. Activation of PKC in DRGs from control rats was associated with a significant decrease in opioid-mediated inhibition of forskolin-stimulated cyclic AMP that was similar to the decrease in inhibition observed in DRGs from diabetic rats. Both basal and PKC-mediated labeling of G oα with 32 P i was significantly less in DRGs from diabetic rats, supporting increased endogenous PKC-dependent phosphorylation of G oα . Probing of immunoprecipitated G oα with an anti-phospho-serine/threonine specific antibody revealed a significant increase in baseline phosphorylation in diabetic DRGs. Activation of PKC produced a significant increase in phosphorylation in control DRGs but no significant increase in G oα in diabetic DRGs. Phosphorylation of PKC-α was increased, PKC-β II was unchanged and PKC-δ decreased in diabetic DRGs. These results suggest that diminished inhibitory G protein function observed in DRGs neurons from diabetic rats involves an isoform-specific PKC-dependent pathway.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66385/1/j.1471-4159.2003.01912.x.pd

Severity of Pre-existing Cerebral Small Vessel Disease is Associated with Outcome after Traumatic Brain Injury

Background and purpose: It is now well accepted that traumatic white matter injury constitutes a critical determinant of post-traumatic functional impairment. However, the contribution of pre-existing white matter rarefaction on outcome following traumatic brain injury (TBI) is unknown. Hence, we sought to determine whether the burden of pre-existing cerebral small vessel disease related white matter rarefaction (leukoaraiosis) is independently associated with outcome after TBI. Methods: We retrospectively analyzed consecutive, prospectively enrolled patients of ≥50 years (n=136) that were admitted to a single neurological-trauma intensive care unit. Supratentorial white matter hypoattenuation on head CT was graded on a 5-point scale (range 0-4) reflecting increasing severity of leukoaraiosis. Outcome was ascertained according to the modified Rankin Scale (mRS) and Glasgow outcome scale (GOS) via telephone interview at 3 and 12 months, respectively. Results: After adjustment for other factors, leukoaraiosis-severity was significantly associated with a poor outcome at 3 and 12 months as defined as mRS 3-6 and GOS 1-3, respectively. The independent association between leukoaraiosis and a poor outcome remained when the analysis was restricted to patients that survived to 3 months, had moderate-to-severe TBI (enrolment Glasgow Coma Scale [GCS] ≤12; p=0.001), or had mild TBI (GCS 13-15; p=0.002), respectively. Conclusion: We provide first evidence that pre-existing cerebral small vessel disease independently predicts a poor functional outcome after closed head TBI. This association is independent of other established outcome predictors such as age, comorbid state as well as intensive care unit complications and interventions. This knowledge may help improve prognostic accuracy, clinical management, and resource utilization

BRAIN TOPiC Study: Assessing Variability in Traumatic Brain Injury (TBI) Outcome Prognostication – Do Self-Fulfilling Prophecies Exist in TBI, Too?

OBJECTIVE: In this study, we surveyed clinicians caring for patients with moderate-severe traumatic brain injury (msTBI) to assess (1) possible variability in outcome prognostication in TBI, varying by clinicians level of training and medical specialty, (2) possible biases and self-fulfilling prophecies, and (3) whether specific ICU medical complications may influence clinicians in their outcome prognostication. BACKGROUND: Patients with msTBI commonly die from withdrawal of support, likely as a consequence of an unfavorable outcome prognosis provided to the family by the treating physician. It is unknown whether prognostication may lead to self-fulfilling prophecies, and whether the presence of intensive care unit (ICU) complications may accentuate possible provider bias. DESIGN/METHODS: We conducted an anonymous electronic survey of clinicians, including faculty members (Neurology, Neurosurgery, Trauma, Anesthesia/Critical Care), neurology house staff, ICU affiliate practitioners and neuroICU nurses at a single Level I trauma center. The survey included three TBI case vignettes and their respective ICU courses. Questions were designed to assess the utilization of known TBI prognostic models, relative importance of ICU complications for outcome prognostication and aggressiveness of care recommended by the survey participant. RESULTS: The survey response rate was 72% (106 surveys returned). In all 3 cases, the majority of participants did not recommend withdrawal of care, but did predict unfavorable 6-month outcomes. 51% of participants consider medical ICU complications as very important in TBI prognostication. Age, ICU course and head CT findings are the prognostic variables considered most important to outcomes. CONCLUSIONS: We have discovered great variability in outcome predictions made by clinicians with different levels of experience in treating msTBI. Self-fulfilling prophecies may exist in msTBI outcomes. Outcome estimates should focus not only on admission variables, but also on ICU complications in order to guide clinicians in providing prognostication

Genetic determinants of cerebral edema in severe traumatic brain injury: A pilot study of the role of CACNA1 and AQP4 gene mutations

Cerebral edema is the one of the most significant predictors of poor outcome after traumatic brain injury. It is still unclear what the pathophysiological and cellular mechanisms and predictors of post-traumatic edema are. The exponential growth in genetic information has opened an avenue for investigation in traumatic brain injury and implicated specific genes in the pathophysiology of post-traumatic injury edema. Two examples are the Aquaporin-4 and CACNA1 genes, which respectively encode water and calcium channels. The Aquaporin-4 gene on chromosome 18q11.2-12.1 encodes the Aquaporin-4 protein (AQP4) water channel. AQP4 is one of the bidirectional high capacity water channels that is primarily expressed in astrocytic foot processes in the central nervous system at the blood-brain barrier and is thought to be critical for brain water homeostasis. Experimental studies showed that AQP4 deficient mice had significantly reduced cerebral edema and better survival in a water intoxication model. The CACNA1 gene on chromosome 19p13 encodes the a1A subunit of a neuronal calcium channel. Patients with Familial Hemiplegic Migraine and delayed fatal cerebral edema and seizuresfrom minor trauma have been found to have mutations in CACNA1, which are hypothesized to enhance development of cytotoxic edema. A missense mutation is reported to enhance risk of delayed fatal cerebral edema. Hypothesis: The CACNA1 gene missense mutation S218L and AQP4 polymorphisms will be over-represented in patients with post-traumatic cerebral edema. Our Specific Aim is to perform full exon sequence analysis of these two genes in 20 well-defined cases of excessive cerebral edema. Our long term goal is to systematically investigate genetic variants as determinants of risk of excessive cerebral edema. It is hoped that this will further elucidate secondary mechanisms of injury specifically in the formation of post-traumatic edema and lead to targeted therapies in the future

Can a detailed neurological exam improve prediction of extubation success in neurocritically ill patients?

Predictors of extubation success in neurocritically ill patients differ from those in the medical or surgical ICU without acute neurological injury. Presence of a cough and a higher Glasgow Coma Scale has previously been associated with extubation success. A recent study in neurocritically ill patients at Harvard Medical School has suggested that a detailed neurological exam may identify important additional signs of extubation success. This cohort, however, included predominantly stroke patients. We aimed to validate these findings in our mixed patient cohort including neurotrauma, stroke and status epilepticus. In this ongoing prospective observational cohort study, we have enrolled 61 neurocritically ill patients who have required intubation and followed them through their hospital course. Routine care included daily evaluation for extubation readiness, including spontaneous breathing trials, arterial blood gases and weaning according to an institutional weaning protocol. Prior to a planned extubation, patients underwent a simple neurological exam by the bedside nurse according to study protocol. After extubation, patients were followed for extubation failure, defined as re-intubation within 72 hours of extubation. Additional data on possible confounders is collected, including chest X-ray appearance, infectious complications, and other comorbid conditions. Mean age of the sample was 59 years and 64% were male, Mean GCS was 12. Extubation failure was seen in 6.5 %, diagnosis of pneumonia 72 hours prior to extubation 24%, after an average number of 3 intubation days. Enrollment will continue until July 2012. A planned analysis includes the identification of predictors of extubation success, focusing on aspects of the neurological examination while controlling for key confounders. We also plan to combine our cohort with the Harvard cohort to improve the power of our analysis. We hope to identify important predictors of extubation success in a broad neurocritical care cohort in order to build a more generalizable model that may improve the prediction of extubation success in neurocritically ill patients

Frequency and Impact of Intensive Care Unit Complications on Moderate-Severe Traumatic Brain Injury – Early Results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study

Background: Known predictors of adverse outcomes in patients with moderate-severe TBI (msTBI) explain only a relatively small proportion of patient-related outcomes. The frequency and impact of intensive care unit complications (ICU-COMPL) on msTBI-associated outcomes is poorly understood. Methods: In 213 consecutive msTBI patients admitted to a Level-I-Trauma-Center neuro-trauma-ICU, twenty-eight ICU-COMPL (21 medical and 7 neurological) were prospectively collected and adjudicated by group consensus, using pre-defined criteria. We determined frequencies, and explored associations of ICU-COMPL and functional neurological outcomes measured by Glasgow Outcome Scale (GOS) at hospital discharge using multivariable logistic regression. Results: The average age of the study sample was 53 years, and the median presenting Glasgow Coma Scale and Injury Severity Scores were 5 and 27, respectively. Hyperglycemia (79%), fever (62%), systemic inflammatory response syndrome (60%), and hypotension requiring vasopressors (42%) were the four most common medical ICU-COMPL. Herniation (39%), intracranial rebleed (39%), and brain edema requiring osmotherapy (37%) were the three most common neurological ICU-COMPL. After adjusting for admission variables, duration of ventilation, and ICU length-of-stay, patients with brain edema (OR 5.8; 95% CI 2,16.7) had a significantly increased odds for dying during hospitalization whereas patients with hospital-acquired urinary tract infection (UTI) had a decreased odds (OR 0.05; 95% CI 0.005,0.6). Sensitivity-analysis revealed that UTI occurred later, suggesting a non-causal association with survival. Brain herniation (OR 15.7; 95% CI 2.6,95.4) was associated with an unfavorable functional status (GOS 1-3). Conclusion: ICU-COMPL are very common after msTBI, have a considerable impact on short-term outcomes, and should be considered in the prognostication of these high-risk patients. Survival associations of time-dependent complications warrant cautious interpretation

Impact of medical and neurological ICU complications on moderate-severe traumatic brain injury (TBI)

Certain admission characteristics are known predictors of adverse outcomes in patients with moderate-severe TBI, but explain only 1/3 of outcome variability. Intensive care unit (ICU) complications occur frequently in this population, but their impact on patient outcomes remains poorly defined. In a prospective observational cohort study of 170 consecutive moderate-severe TBI patients admitted to Level I trauma center (UMASS) over the period 11/2009–2/2012, we examined the association of ICU complications and 3-month outcome (Glasgow Outcome Scale [GOS]). The mean age was 51 years, 72% were men, and the median GCS and injury severity scores were 4 and 29, respectively. Using multiple logistic regression analysis, hypotension requiring vasopressors (HRV) was the strongest predictor of poor outcome (GOS 1-3 [OR 2.8; 95% CI 1-7.5]) among medical complications. After combining medical with neurological ICU complications, brain herniation (OR 5.8; 95% CI 1.1-30.2) and intracranial rebleeding (OR 2.9; 95% CI 1-8.4) were the strongest predictors of poor outcome, while HRV approached significance (OR 2.4; 95% CI 0.9-6.4). We identified important potentially modifiable predictors of adverse outcomes after moderate-severe TBI. Confirmation of our findings in a larger cohort is warranted

Incidence rates of ICU complications in moderate-severe traumatic brain injury (TBI)

Retrospective studies suggest that non-neurologic organ failure may contribute to 2/3 of all deaths after TBI, but the actual incidence rates of specific intensive care unit (ICU) complications in moderate-severe TBI are not known. In a prospective observational cohort study of consecutive TBI patients from a single Level I trauma center (UMASS) over the period 11/2009 – 2/2012, we identified the ten most common medical complications after ICU admission according to strict pre-specified criteria in 170 moderate-severe TBI patients. The mean age of the study sample was 51 years, 72% were men, and the median GCS and injury severity scores were 4 and 29, respectively. Incidence rates of the ten most common medical complications in the ICU were: hyperglycemia (75%), fever (62%), systemic inflammatory response syndrome (38%), cardiac complications (36%), hypotension requiring vasopressors (35%), pneumonia (any type [34%]); sepsis (33%), anemia requiring transfusion (31%), other pulmonary complications (ARDS, pulmonary edema [26%]), and hyponatremia (sodium ≤134mEq/L; [23%]). Medical complications in moderate-severe TBI are very common, and their association with important patient outcomes should be further investigated. Specific medical complications may pose attractive modifiable treatment targets to improve the outcome of moderate-severe TBI patients

Serum sodium values and their association with adverse outcomes in moderate-severe traumatic brain injury (TBI)

Hypernatremia in neurocritically ill patients has been associated with worse neurological outcomes. There may, however, be a treatment effect from osmotherapy combating herniation and hyponatremia, which in turn may exacerbate brain edema, resulting in iatrogenic sodium repletion. In moderate-severe TBI, serum sodium (sNa) disturbances are common, but their impact on patient outcomes is unknown. In a prospective observational cohort study of 144 consecutive moderate-severe TBI patients admitted to a Level I trauma center (UMASS) over the period 11/2009–11/2011, we examined the association of mean, nadir, and peak sNa and hospital discharge neurological outcome (Glasgow Outcome Scale [GOS]). The mean age of this cohort was 51 years, 70% were men, and the median GCS and injury severity scores were 5 and 32, respectively. Using ordinal regression analysis, controlling for admission variables, length of ICU stay, severity of injury, presence of brain edema on head CT, administered hypertonic saline and mannitol, higher mean (p\u3c0.001), higher peak (p=0.01), and higher nadir (p\u3c0.001) sNa values were significantly associated with worse outcome. Our findings suggest that higher sNa values are associated with worse neurological outcome, independent of treatment effect by osmotherapy

Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage – a Randomized Placebo-Controlled Trial to assess Safety, Tolerability and Feasibility

Introduction: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) in humans. We evaluated safety/tolerability and feasibility of intravenous dantrolene (IV-D) after aSAH. Methods: In this single-center, randomized, double blind, placebo-controlled trial, 31 patients with acute aSAH were randomized to IV-D 1.25 mg IV every 6 hours x 7 days (n=16) or placebo (n=15). Primary endpoint was incidence of hyponatremia (sNa ≤ 134 mmol/L) and liver toxicity (% patients with ALT, AST and AlkPhos \u3e5x upper limit of normal). Secondary safety endpoints included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored by clinical, transcranial Doppler (TCD) or angiographic cVSP occurrence, delayed cerebral ischemia (DCI) and 3-month modified-Rankin-Scale, Glasgow Outcome Scale and Barthel Index. Statistical analysis was performed using non-parametric tests, generalized estimating equations and mixed models. Results: Between IV-D vs. placebo, no differences were observed in the primary outcome (hyponatremia: 44% vs. 67% [p=0.29]; liver toxicity 6% vs. 0% [p=1.0]). Numerically more AEs and SAEs were seen in the IV-D group, but did not reach statistical significance (16 vs. 5 AEs, of which 5 vs. 2 were severe; RR 2.2; 95% CI 0.7-6.7; p=0.16). Three IV-D vs. two placebo patients reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain edema requiring osmotherapy. No differences in angiographic, TCD, clinical cVSP, DCI, or 3-month functional outcomes were seen. Quantitative angiogram analysis revealed a trend towards increased vessel diameters in the IV-D group after the 7-day infusion-period (p=0.05). Conclusions: In this small trial, IV-Dantrolene after aSAH was feasible, tolerable and safe, but was underpowered to show efficacy or outcome differences