Didier Ledoux

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.

Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level‐dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico‐thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico‐cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio‐respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age‐matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task‐positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long‐distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population. Hum Brain Mapp, 2009.

VOLUNTARY BRAIN PROCESSING IN DISORDERS OF CONSCIOUSNESS

Background: Disentangling the vegetative state from the minimally conscious state is often difficult when relying only on behavioral observation. In this study, we explored a new active evoked-related potentials paradigm as an alternative method for the detection of voluntary brain activity. Methods: The participants were 22 right-handed patients (10 traumatic) diagnosed as being in a vegetative state (VS) (n = 8) or in a minimally conscious state (MCS) (n = 14). They were presented sequences of names containing the patient’s own name or other names, in both passive and active conditions. In the active condition, the patients were instructed to count her or his own name or to count another target name. Results: Like controls, MCS patients presented a larger P3 to the patient’s own name, in the passive and in the active conditions. Moreover, the P3 to target stimuli was higher in the active than in the passive condition, suggesting voluntary compliance to task instructions like controls. These responses were even observed in patients with low behavioral responses (e.g., visual fixation and pursuit). In contrast, no P3 differences between passive and active conditions were observed for VS patients. Conclusions: The present results suggest that active evoked-related potentials paradigms may permit detection of voluntary brain function in patients with severe brain damage who present with a disorder of consciousness, even when the patient may present with very limited to questionably any signs of awareness.

Connectivity Changes Underlying Spectral EEG Changes during Propofol-Induced Loss of Consciousness

The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

A survey on self-assessed well-being in a cohort of chronic locked-in syndrome patients: happy majority, miserable minority

Objectives Locked-in syndrome (LIS) consists of anarthria and quadriplegia while consciousness is preserved. Classically, vertical eye movements or blinking allow coded communication. Given appropriate medical care, patients can survive for decades. We studied the self-reported quality of life in chronic LIS patients. Design 168 LIS members of the French Association for LIS were invited to answer a questionnaire on medical history, current status and end-of-life issues. They self-assessed their global subjective well-being with the Anamnestic Comparative Self-Assessment (ACSA) scale, whose +5 and −5 anchors were their memories of the best period in their life before LIS and their worst period ever, respectively. Results 91 patients (54%) responded and 26 were excluded because of missing data on quality of life. 47 patients professed happiness (median ACSA +3) and 18 unhappiness (median ACSA −4). Variables associated with unhappiness included anxiety and dissatisfaction with mobility in the community, recreational activities and recovery of speech production. A longer time in LIS was correlated with happiness. 58% declared they did not wish to be resuscitated in case of cardiac arrest and 7% expressed a wish for euthanasia. Conclusions Our data stress the need for extra palliative efforts directed at mobility and recreational activities in LIS and the importance of anxiolytic therapy. Recently affected LIS patients who wish to die should be assured that there is a high chance they will regain a happy meaningful life. End-of-life decisions, including euthanasia, should not be avoided, but a moratorium to allow a steady state to be reached should be proposed.

The nociception coma scale: A new tool to assess nociception in disorders of consciousness.

&NA; Assessing behavioral responses to nociception is difficult in severely brain‐injured patients recovering from coma. We here propose a new scale developed for assessing nociception in vegetative (VS) and minimally conscious (MCS) coma survivors, the Nociception Coma Scale (NCS), and explore its concurrent validity, inter‐rater agreement and sensitivity. Concurrent validity was assessed by analyzing behavioral responses of 48 post‐comatose patients to a noxious stimulation (pressure applied to the fingernail) (28 VS and 20 MCS; age range 20–82 years; 17 of traumatic etiology). Patients’ were assessed using the NCS and four other scales employed in non‐communicative patients: the ‘Neonatal Infant Pain Scale’ (NIPS) and the ‘Faces, Legs, Activity, Cry, Consolability’ (FLACC) used in newborns; and the ‘Pain Assessment In Advanced Dementia Scale’ (PAINAD) and the ‘Checklist of Non‐verbal Pain Indicators’ (CNPI) used in dementia. For the establishment of inter‐rater agreement, fifteen patients were concurrently assessed by two examiners. Concurrent validity, assessed by Spearman rank order correlations between the NCS and the four other validated scales, was good. Cohens kappa analyses revealed a good to excellent inter‐rater agreement for the NCS total and subscore measures, indicating that the scale yields reproducible findings across examiners. Finally, a significant difference between NCS total scores was observed as a function of diagnosis (i.e., VS or MCS). The NCS constitutes a sensitive clinical tool for assessing nociception in severely brain‐injured patients. This scale constitutes the first step to a better management of patients recovering from coma.

tDCS in patients with disorders of consciousness Sham-controlled randomized double-blind study

Objective: We assessed the effects of left dorsolateral prefrontal cortex transcranial direct current stimulation (DLPF-tDCS) on Coma Recovery Scale–Revised (CRS-R) scores in severely brain-damaged patients with disorders of consciousness. Methods: In a double-blind sham-controlled crossover design, anodal and sham tDCS were delivered in randomized order over the left DLPF cortex for 20 minutes in patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in a minimally conscious state (MCS) assessed at least 1 week after acute traumatic or nontraumatic insult. Clinical assessments were performed using the CRS-R directly before and after anodal and sham tDCS stimulation. Follow-up outcome data were acquired 12 months after inclusion using the Glasgow Outcome Scale–Extended. Results: Patients in MCS (n = 30; interval 43 ± 63 mo; 19 traumatic, 11 nontraumatic) showed a significant treatment effect (p = 0.003) as measured by CRS-R total scores. In patients with VS/UWS (n = 25; interval 24 ± 48 mo; 6 traumatic, 19 nontraumatic), no treatment effect was observed (p = 0.952). Thirteen (43%) patients in MCS and 2 (8%) patients in VS/UWS further showed postanodal tDCS-related signs of consciousness, which were observed neither during the pre-tDCS evaluation nor during the pre- or post-sham evaluation (i.e., tDCS responders). Outcome did not differ between tDCS responders and nonresponders. Conclusion: tDCS over left DLPF cortex may transiently improve signs of consciousness in MCS following severe brain damage as measured by changes in CRS-R total scores. Classification of evidence: This study provides Class II evidence that short-duration tDCS of the left DLPF cortex transiently improves consciousness as measured by CRS-R assessment in patients with MCS.

Diagnostic and prognostic use of bispectral index in coma, vegetative state and related disorders

Primary objective: This study investigates (1) the utility of the bispectral index (BIS) to distinguish levels of consciousness in severely brain damaged patients and, particularly, disentangle vegetative state (VS) from minimally conscious state (MCS), as compared to other EEG parameters; (2) the prognostic value of BIS with regards to recovery after 1 year. Research design: Multi-centric prospective study. Method and procedures: Unsedated patients recovering from coma were followed until death or transferal. Automated electrophysiological and standardized behavioural assessments were carried out twice a week. EEG recordings were categorized according to level of consciousness (coma, VS, MCS and Exit MCS). Outcome was assessed at 1 year post-insult. Main outcomes and results: One hundred and fifty-six EEG epochs obtained in 43 patients were included in the analyses. BIS showed a higher correlation with behavioural scales as compared to other EEG parameters. Moreover, BIS values differentiated levels of consciousness and distinguished VS from MCS while other EEG parameters did not. Finally, higher BIS values were found in patients who recovered at 1 year post-insult as compared to patients who did not recover. Conclusion: EEG-BIS recording is an interesting additional method to help in the diagnosis as well as in the prognosis of severely brain injured patients recovering from coma.

Relieving suffering or intentionally hastening death: where do you draw the line?

Objective:End-of-life practices vary worldwide. The objective was to demonstrate that there is no clear-cut distinction between treatments administered to relieve pain and suffering and those intended to shorten the dying process. Design:Secondary analysis of a prospective, observational study. Setting:Thirty-seven intensive care units in 17 European countries. Patients:Consecutive patients dying or with any limitation of therapy. Interventions:Evaluation of the type of end-of-life category; dates and times of intensive care unit admission, death, or discharge; and decisions to limit therapy, medication, and doses used for active shortening of the dying process and the intent of the doctors prescribing the medication. Measurements and Main Results:Limitation of life-sustaining therapy occurred in 3,086 (72.6%) of 4,248 patients, and 94 (2.2%) underwent active shortening of the dying process. Medication for active shortening of the dying process included administration of opiates (morphine to 71 patients) or benzodiazepines (diazepam to 54 patients) alone or in combination. The median dosage for morphine was 25.0 mg/hr and for diazepam 20.8 mg/hr. Doses of opiates and benzodiazepines were no higher than mean doses used with withdrawal in previous studies in 20 of 66 patients and were within the ranges of doses used in all but one patient. Doctors considered that medications for active shortening of the dying process definitely led to the patients death in 72 patients (77%), probably led to the patients death in 11 (12%), and were unlikely to have led to death in 11 (12%) patients. Conclusions:There is a gray area in end-of-life care between treatments administered to relieve pain and suffering and those intended to shorten the dying process.

Comparison between blood serum and salivary cortisol concentrations in horses using an adrenocorticotropic hormone challenge.

REASONS FOR PERFORMING STUDY In horses, serum cortisol concentration is considered to provide an indirect measurement of stress. However, it includes both free and bound fractions. The sampling method is also invasive and often stressful. This is not the case for salivary cortisol, which is collected using a more welfare-friendly method and represents a part of the free cortisol fraction, which is the biologically active form. OBJECTIVES To compare salivary and serum cortisol assays in horses, in a wide range of concentrations, using an adrenocorticotropic hormone (ACTH) stimulation test, in order to validate salivary cortisol for stress assessment in horse. METHODS In 5 horses, blood samples were drawn using an i.v. catheter. Saliva samples were taken using swabs. Cortisol was assayed by radioimmunoassay. All data were treated with a regression method, which pools and analyses data from multiple subjects for linear analysis. RESULTS Mean ± s.d. cortisol concentrations measured at rest were 188.81 ± 51.46 nmol/l in serum and 1.19 ± 0.54 nmol/l in saliva. They started increasing immediately after ACTH injection and peaks were reached after 96 ± 16.7 min in serum (356.98 ± 55.29 nmol/l) and after 124 ± 8.9 min in saliva (21.79 ± 7.74 nmol/l, P<0.05). Discharge percentages were also different (225% in serum and 2150% in saliva, P<0.05). Correlation between serum and salivary cortisol concentrations showed an adjusted r(2) = 0.80 (P<0.001). The strong link between serum and salivary cortisol concentrations was also estimated by a regression analysis. CONCLUSIONS The reliability of both RIAs and regression found between serum and salivary cortisol concentrations permits the validation of saliva-sampling as a noninvasive technique for cortisol level assessment in horses.