Céline Guidoux

Brainstem responses can predict death and delirium in sedated patients in intensive care unit.

Objectives:In critically ill patients, the assessment of neurologic function can be difficult because of the use of sedative agents. It is not known whether neurologic signs observed under sedation can predict short-term outcomes. The objective of this study was to assess whether abnormal brainstem responses within the first 24 hrs of sedation are associated with mortality and altered mental status postsedation. Design:Observational prospective study including an initial single-center and a subsequent multicenter study to develop and then validate the prognostic models. Setting:Three mixed and two medical intensive care units. Patients:Mechanically ventilated intensive care unit patients sedated with midazolam (± sufentanyl). Interventions:Neurologic examination including the Glasgow Coma Scale, the Assessment to Intensive Care Environment score, cranial nerve examination, response to noxious stimuli, and the cough reflex was performed. Measurements and Main Results:Seventy-two patients were included in the initial group and 72 in a subsequent validation study. Neurologic responses were independent of sedative dose. Twenty-two patients in the development cohort and 21 (29%) in the validation group died within 28 days of inclusion. Adjusted for Simplified Acute Physiology Score II score, absent cough reflex was independently associated with 28-day mortality in the development (adjusted odds ratio [OR], 7.80; 95% confidence interval [CI], 2.00–30.4; p = .003) and validation groups (adjusted OR, 5.44; 95% CI, 1.35–22.0; p = .017). Absent oculocephalic response, adjusted for Simplified Acute Physiology Score II score, was independently associated with altered mental status after the withdrawal of sedation in the development (adjusted OR, 4.54; 95% CI, 1.34–15.4; p = .015) and validation groups (adjusted OR, 6.10; 95% CI, 1.18–25.5; p = .012). Conclusions:Assessment of brainstem responses is feasible in sedated critically ill patients and loss of selected responses is predictive of mortality and altered mental status.

Changes in CRH and ACTH synthesis during experimental and human septic shock.

Context The mechanisms of septic shock-associated adrenal insufficiency remain unclear. This study aimed at investigating the synthesis of corticotropin-releasing hormone (CRH) and vasopressin (AVP) by parvocellular neurons and the antehypophyseal expression of ACTH in human septic shock and in an experimental model of sepsis. Objective To test the hypothesis that ACTH secretion is decreased secondarily to alteration of CRH or AVP synthesis, we undertook a neuropathological study of the antehypophyseal system in patients who had died from septic shock and rats with experimental faecal peritonitis. Methods Brains obtained in 9 septic shock patients were compared to 10 nonseptic patients (controls). Parvocellular expression of AVP and CRH mRNA were evaluated by in situ hybridization. Antehypophyseal expression of ACTH, vasopressin V1b and CRH R1 receptors and parvocellular expression of iNOS in the PVN were evaluated by immunohistochemistry. The same experiments were carried out in a fecal peritonitis-induced model of sepsis. Data from septic rats with (n = 6) or without (n = 10) early death were compared to sham-operated (n = 8) animals. Results In patients and rats, septic shock was associated with a decreased expression of ACTH, unchanged expression of V1B receptor, CRHR1 and AVP mRNA, and increased expression of parvocellular iNOS compared to controls. Septic shock was also characterized by an increased expression of CRH mRNA in rats but not in patients, who notably had a greater duration of septic shock. Conclusion The present study suggests that in humans and in rats, septic shock is associated with decreased ACTH synthesis that is not compensated by its two natural secretagogues, AVP and CRH. One underlying mechanism might be increased expression of iNOS in hypothalamic parvocellular neurons.

Hyperglycaemia and apoptosis of microglial cells in human septic shock

IntroductionThe effect of hyperglycaemia on the brain cells of septic shock patients is unknown. The objective of this study was to evaluate the relationship between hyperglycaemia and apoptosis in the brains of septic shock patients.MethodsIn a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for neuronal ischaemia, neuronal and microglial apoptosis, neuronal Glucose Transporter (GLUT) 4, endothelial inducible Nitric Oxide Synthase (iNOS), microglial GLUT5 expression, microglial and astrocyte activation. Blood glucose (BG) was recorded five times a day from ICU admission to death. Hyperglycaemia was defined as a BG 200 mg/dL g/l and the area under the BG curve (AUBGC) > 2 g/l was assessed.ResultsMedian BG over ICU stay was 2.2 g/l. Neuronal apoptosis was correlated with endothelial iNOS expression (rho = 0.68, P = 0.04), while microglial apoptosis was associated with AUBGC > 2 g/l (rho = 0.70; P = 0.002). Neuronal and microglial apoptosis correlated with each other (rho = 0.69, P = 0.006), but neither correlated with the duration of septic shock, nor with GLUT4 and 5 expression. Neuronal apoptosis and ischaemia tended to correlate with duration of hypotension.ConclusionsIn patients with septic shock, neuronal apoptosis is rather associated with iNOS expression and microglial apoptosis with hyperglycaemia, possibly because GLUT5 is not downregulated. These data provide a mechanistic basis for understanding the neuroprotective effects of glycemic control.

Vasopressin Synthesis by the Magnocellular Neurons is Different in the Supraoptic Nucleus and in the Paraventricular Nucleus in Human and Experimental Septic Shock

Impaired arginine vasopressin (AVP) synthesis and release by the neurohypophyseal system, which includes the neurohypophysis and magnocellular neurons of the paraventricular and supraoptic nuclei, have been postulated in septic shock, but changes in this system have never been assessed in human septic shock, and only partially experimentally. We investigated AVP synthesis and release by the neurohypophyseal system in 9 patients who died from septic shock and 10 controls, and in 20 rats with fecal peritonitis‐induced sepsis and 8 sham‐operation controls. Ten rats died spontaneously from septic shock, and the others were sacrificed. In patients with septic shock, as in rats that died spontaneously following sepsis induction, AVP immunohistochemical expression was decreased in the neurohypophysis and supraoptic magnocellular neurons, whereas it was increased in the paraventricular magnocellular neurons. No significant change was observed in AVP messenger RiboNucleic Acid (mRNA) expression assessed by in situ hybridization in either paraventricular or supraoptic magnocellular cells. This study shows that both in human and experimental septic shock, AVP posttranscriptional synthesis and transport are differently modified in the magnocellular neurons of the supraoptic and paraventricular nuclei. This may account for the inappropriate AVP release in septic shock and suggests that distinct pathogenic mechanisms operate in these nuclei.

Clinical Significance of Isolated Atypical Transient Symptoms in a Cohort With Transient Ischemic Attack

Background and Purpose— Contrary to typical transient symptoms (TS), atypical TS, such as partial sensory deficit, dysarthria, vertigo/unsteadiness, unusual cortical visual deficit, and diplopia, are not usually classified as symptoms of transient ischemic attack when they occur in isolation, and their clinical relevance is frequently denied. Methods— Consecutive patients with recent TS admitted in our transient ischemic attack clinic (2003–2008) had systematic brain, arterial, and cardiac investigations. We compared the prevalence of recent infarction on brain imaging, major investigational findings (symptomatic intracranial or extracranial atherosclerotic stenosis ≥50%, cervical arterial dissection, and major source of cardiac embolism), and 1-year risk of major vascular events in patients with isolated typical or atypical TS and nonisolated TS, after exclusion of the main differential diagnoses. Results— Among 1850 patients with possible or definite ischemic diagnoses, 798 (43.1%) had isolated TS: 621 (33.6%) typical and 177 (9.6%) atypical. Acute infarction on brain imaging was similar in patients with isolated atypical and typical TS but less frequent than in patients with nonisolated TS, observed in 10.0%, 11.5%, and 15.3%, respectively (P<0.0001). Major investigational findings were found in 18.1%, 26.4%, and 26.3%, respectively (P=0.06). One-year risk of a major vascular events was not significantly different in the 3 groups. Conclusions— Transient ischemic attack diagnosis should be considered and investigated in patients with isolated atypical TS.

Posterior reversible encephalopathy syndrome in neuro-malaria.

We report a case of a 37-year-old patient with Plasmodium falciparum infestation who developed posterior reversible encephalopathy. In cerebral malaria, microscopic studies have shown endothelial dysfunction and disruption of the blood–brain barrier. Data from the literature show that one of the mechanisms of posterior reversible encephalopathy may be capillary leakage and acute disruption of the blood–brain barrier. Our case supports the theory of blood–brain barrier disruption being a key factor in the causation of cerebral malaria.

Amyloid Angiopathy in Brain Hemorrhage: A Postmortem Neuropathological-Magnetic Resonance Imaging Study

Background: Risk factors for intracerebral hemorrhage (ICH) include hypertension and cerebral amyloid angiopathy (CAA). The objective of this study was to determine the autopsy prevalence of CAA and the potential overlap with other risk factors among patients who died from ICH and also the correlation of CAA with cerebral microbleeds. Methods: We analyzed 81 consecutive autopsy brains from patients with ICH. Staining for CAA detection was performed. We used an age- and sex-matched control group of routine brain autopsies of nonneurological patients to determine the frequencies of CAA and hypertension. Postmortem 3D T2-weighted gradient-echo magnetic resonance imaging (MRI) with a 1.5-T magnet was performed in 11 brains with ICH (5 with CAA and 6 without) and histological correlation was performed when microbleeds were detected. Results: Hypertension and CAA were found in 69.1 and 24.7% of cases respectively. Among patients with CAA, 65.0% also had hypertension. The prevalence of CAA was similar among non-hypertensive cases and controls (33.3 and 23.1%; p = 0.54), whereas a significant difference was found between hypertensive cases vs. controls (28.9% vs. 0; p = 0.01). MRI documented 48 microbleeds and all 5 brains with CAA had ≥1 microbleed, compared to 3/6 brains without CAA. Among 48 microbleeds on MRI, 45 corresponded histologically to microbleeds surrounding microvessels (23 <200 µm in diameter, 19 between 200 µm and 2 mm, 3 were hemosiderin granules). Conclusions: Both hypertension and CAA frequently coexist in patients with ICH. MRI-detected microbleeds, proven by histological analysis, were twice as common in patients with CAA as in those with hypertensive ICH.

0171: Identification of complicated carotid plaques by adding functional fluorodeoxyglucose-positron emission tomographic imaging to morphological characteristics on computed tomographic angiography

Aim We developed a simple semi-quantitative score for the analysis of carotid plaques with FDG-PET-CTA imaging and tested whether adding functional imaging criteria extracted from FDG-PET imaging to morphological plaque characteristics identified with CTA might improve the detection of complicated plaques. Material and Methods Twenty-eight patients scheduled for carotid endarterectomy were imaged with PET after injection of FDG followed by CTA of the supra-aortic trunks. Morphological aspects of plaques identified with CTA and metabolic activity quantified with FDG-PET (Tissue to Background ratio, TBR) were measured in the carotid segment with the highest degree of luminal stenosis and graded using semi-quantitative CT and PET scores. Combined score was calculated for each carotid artery by summing CT and PET scores. After carotid endarterectomy, vascular surgeons classified carotid plaques macroscopically as complicated or non-complicated. Results Twenty-eight carotid arteries were operated in 26 patients (24 symptomatic patients). Sixteen plaques were classified macroscopically as complicated. CTA detected hypodense regions and ulcerations in 81% and 25%, of complicated plaques, and in 33% and 0% of non-complicated plaques, respectively. Hypodense areas on CTA identified complicated plaques with a sensitivity of 87% and a specificity of 67%. Mean TBR with FDG-PET was measured at 2.2±0.4 in complicated plaques and 1.9±0.3 in non-complicated plaques (p Conclusions Adding FDG-PET imaging criteria to morphological characteristics of plaques on CTA improved the sensitivity of the detection of complicated carotid plaques.

Sepsis-Associated Delirium

Sepsis is, in 27% to 55% of cases, complicated by a deterioration of mental status, which is consistent with delirium as consciousness, awareness, cognition, and behavior are preferentially affected. Electroencephalogram and somatosensory-evoked potentials are often abnormal, plasma levels of S-100b protein or neuron-specific enolase increased, and magnetic resonance imaging may show leukoencephalopathy. Pathophysiological mechanisms include cerebrovascular alteration, blood-brain barrier breakdown, inflammatory and metabolic factors, notably tumor necrosis factor-α, inducible NO synthase, and abnormal blood glucose levels. These processes may induce brain damage, stress oxidative-related cellular dysfunction, or apoptosis. In septic patients, mortality is increased with severity of delirium, degree of electrophysiological abnormalities, and neuron-specific enolase or S-100b plasma levels. The daily evaluation of patients with sepsis should systematically include appropriate delirium scores and, if delirium is present, laboratory investigations may help assess the potential damage to the brain. There is no specific treatment for sepsis associated delirium. Patient management is mainly based on controlling infection, organ system failure, and metabolic homeostasis, while avoiding neurotoxic drugs. Future therapies may target neuroinflammation, blood-brain barrier dysfunction, brain cell oxidative stress, or apoptosis.