Circadian Rhythmicity During Coma Awakening

Acute brain injury is a major cause of admission to intensive care units, as well as of mortality and morbidity, worldwide and for all age groups. With most patients surviving these injuries thanks to recent medical advances, society is facing not only the growing burden of disability, but above all the ethical issues involved in withdrawal of life-sustaining therapies (WSLT). To resolve this dilemma, effective treatment would be necessary, but this is hampered by our limited knowledge of the pathophysiological mechanisms of the natural history of coma, from onset to recovery. A more systematic description of coma awakening using a multimodal battery in intensive care unit patients would enable us to refine the awakening and re-emergence of consciousness and define appropriate biomarkers for selecting candidates in interventional studies.

The investigators hypothesize that the current postulate of successive stages (i.e. from one clinical class to the next) of coma recovery is incomplete, as it does not take into account the rhythmic nature of wakefulness. The investigators propose that the best correlate of the natural history of coma recovery is a gradual shift from the loss of physiological cycles to a circadian rhythmicity of arousal indices (behavioural and neurophysiological) and a wide amplitude of metric fluctuations in assessing content richness.


Eligibility Criteria:
Inclusion Criteria:

Group 1

* Admission to the Neurological Intensive Care Unit
* Initial disorder of consciousness (GCS \< 8) or initial brain lesion (on CT or MRI) requiring intubation and sedation during management (for upper airway protection or due to coma)
* Duration of sedation by general anesthesia (Propofol, Midazolam) \> 24 h or any use of barbiturate coma or surgery to treat intracranial hypertension
* Intubated patient under mechanical ventilation with ongoing sedation in sufficient dose (Propofol \> 1 mg/Kg/h and/or Midazolam \< 0.05 mg/Kg/h and/or any dose of Nesdonal)
* Weaning from sedation possible within 7 days of inclusion in the absence of new complications
* Severity of clinical or morphological impairment leading to risk of persistent disturbance of consciousness on discontinuation of sedations
* Sedation discontinuation can be scheduled within 1 month of initial management of the disorder of consciousness or brain injury
* Effective treatment of the cause of admission without risk of short-term recurrence
* Patient aged 17 or over
* Urinary catheter in place at the time of inclusion and to remain in place until Visit N°1
* Presence of relatives able to sign consent or of the minor's legal representative

Group 2

* Admission to the Neurological Intensive Care Unit or the Neurological Continuing Care Unit
* Absence of severe disorder of consciousness but possibility of minimal alteration of the initial Glasgow score (GCS between 9 and 15) with no time limit, with a stratification of three consecutive patient populations distinguished by the initial neurological alteration:

  * GCS = 15
  * GCS \< 15 by predominance of an initial defect in responses to simple or complex commands obtained by motor or verbal means, without abnormality of arousal (E score = 4 but M score \< 6 and/or V score \< 5)
  * GCS \< 15 with predominant initial somnolence, with or without abnormal motor or verbal responses to simple or complex commands (E score = 2 or 3 but M score = 6 and/or V score = 5).
* Existence of functional communication or functional use of objects at inclusion
* Mechanism of injury for which the aetiology is no longer active or at risk of recurrence
* Patient aged 17 or over
* Urinary catheter in place at the time of inclusion and to remain in place until Visit N°1
* In the case of impaired judgement despite functional communication or in the case of aphasia with functional use of objects: presence of relatives able to sign consent or of the legal representative of the minor or of the legal representative of the protected adult.

Group 3

* Admission to the Adult Post-Resuscitation Rehabilitation Department
* Disturbance of consciousness defined by an absence of communication or an absence of functional use of objects (for patients with aphasia), i.e. the two signs that could indicate emergence from the pauci-relational state, which includes patients presenting :

  * persistent coma
  * a vegetative state (or unresponsive wakefulness syndrome)
  * a pauci-relational state (MCS- or MCS+ if responding to simple commands).
* Persistent within the following timeframe

  * More than 3 months after the initial management of the disorder of consciousness or brain injury
  * More than 1 month after a post-anoxic coma.
* Mechanism of injury for which the aetiology is no longer active or at risk of recurrence
* Patient aged 17 or over
* Presence of relatives likely to sign the consent or of the legal representative of a minor or of the legal representative of a protected adult

Exclusion Criteria:

Group 1

* Subjects with a contraindication to MRI scans
* Admission for status epilepticus
* Existence of status epilepticus during the stay and persisting for \> 24h or presenting an electrical remission for less than 48h prior to inclusion
* Post-anoxic coma with bilateral abolition of N20 PES cortical responses
* Coma related to a potentially recurrent cause of coma (tumours, infectious diseases with risk of relapse and inflammatory diseases)
* Moribund patient (life expectancy \< 24h) or in WLST (no assessment possible of the dynamics of ongoing awakening)
* Haemodynamic or respiratory instability incompatible with a prolonged attempt to stop sedation (except in the case of scheduled surgery outside the visit dates)
* Patients under guardianship, curatorship or safeguard of justice
* Patients not affiliated to the French health insurance system
* Pregnant women or women of childbearing age without proof of the absence of a current pregnancy

Group 2

* Subjects with a contraindication to MRI scans
* Epileptic seizures on admission or during the stay

  * Single seizure: if no rapid return to consciousness (GCS \< 8 for \> 12 hours)
  * \> 2 distinct epileptic seizures regardless of the duration of loss of consciousness
  * Status epilepticus
* Post-anoxic coma with bilateral abolition of N20 cortical PES responses.
* Coma linked to a potentially recurrent cause of coma (tumour, infection with risk of relapse and inflammation).
* A moribund patient (life expectancy \< 24 hours) or a patient undergoing WLST with a high risk of death before the end of the study (inclusion possible if no therapeutic escalation is decided in a stabilised patient).
* Haemodynamic or respiratory instability incompatible with prolonged evaluation of the absence of sedation (risk of general anaesthesia for further failure, except in the case of scheduled surgery outside the visit dates).
* Patients under guardianship, curatorship or safeguard of justice
* Patients not affiliated to the French health insurance system
* Pregnant women or women of childbearing age without proof of the absence of a current pregnancy

Group 3

* Subjects with a contraindication to MRI scans
* Epileptic seizures during the week preceding inclusion:

  * Single seizure: if no rapid return to usual state of consciousness for \> 12 hours
  * \> 2 separate comitial seizures regardless of duration of loss of consciousness
  * Epileptic malaise
* Post-anoxic coma with bilateral abolition of N20 cortical responses to SEP
* Coma related to a potentially recurrent cause of coma (tumour, infection with risk of relapse and inflammation)
* Moribund patients (life expectancy \< 24 hours) or patients undergoing WSLT with a high risk of death before the end of the study (inclusion possible if no therapeutic escalation is decided in a stabilised patient).
* Haemodynamic or respiratory instability incompatible with prolonged evaluation of the absence of sedation (risk of general anaesthesia for further failure, except in the case of scheduled surgery outside the visit dates).
* Patients under guardianship, curatorship or safeguard of justice prior to the event that provoked their state of chronic disturbance of consciousness. Patients under guardianship because of their chronic disorder of consciousness are eligible for the study.
* Patients not affiliated to the French health insurance system
* Pregnant women or women of childbearing age without proof of the absence of a current pregnancy