Table 2.

Refractory delirium tremens

Positive diagnosis	History of chronic alcohol intoxication and alcohol withdrawal, hallucinations, agitation, fine tremor.
Differential diagnosis	Confusion due to sepsis (beware of occurrence of sepsis or septic shock immediately after resolution of DT or simultaneous to DT), metabolic abnormalities, physical/neurological examination.
Overall assessment	Circulation: iterative response to passive leg raising if arterial line in place: normalize volemia before and during administration of alpha-2 agonists.
	Ventilation: ‚focal’ pneumonia?
	Kidney (consider dexmedetomidine if acute kidney injury), liver (consider clonidine if liver insufficiency), pancreas, metabolism.
	Consider BIS or equivalent if benzodiazepines or propofol infusion are to be used.
Supportive treatment	Ventilation: high 02 flow (Optiflow®) or continuous non invasive ventilation (NIV: consider helmet) as soon as quietness is achieved. The tolerance to continuous, 24/24, NIV is excellent under alpha-2 agonist. Alternate High O2 flow and NIV to minimize skin alterations.
	Hydration: consider hyperthermia and agitation to evoke adequate diuresis (> 1 mL.kg.d, i.e., > 1700 mL/70 kg/24 h)
	Vitamins (B1, B6), nicotine patch(es), eu-glycemia, trace elements, phosphorus, magnesium, calcium supplementation, anti-infectious therapy if appropriate.
	Prophylaxis of thrombosis and gastro-intestinal hemorrhage.
	Daily monitoring of K+, Mg++, phosphorus, calcium.
	Should seizures occur, treat accordingly : benzodiazepine (clonazepam 2 mg bolus, Rivotril® as stat treatment) followed immediately by levetiracetam (Keppra®) and phenytoin (Dilantin®) to avoid over sedation with benzodiazepine.
Sedation	Goal: quiet patient (day: -1 < RASS < 0; night: -2 < RASS < 0): no brisk movements, hallucinations and fine tremor controlled for > 24 h.
	1) Discontinue benzodiazepine, hypnotics, opioid and non-opioid analgesics and so on, immediately upon admission.
	2) Continue administering neuroleptics to avoid bout of abrupt agitation upon benzodiazepine/opiates cessation of administration.
	Only when alpha-2 agonists are not sufficient to evoke -1 < RASS < 0, supplementation with second-line drugs, consider:
	a) Core symptom : agitation: loxapine 100 mg*4-6/day through n/g tube adjusted as early as possible to, for example, 25mg*4 to achieve -1 < RASS < 0.
	NB : monitor QT when administering loxapine.
	or cyamemazine (Tercian®) 25 mg*3 up to 50*3
	or levomepromazine (Nozinan®) 50–200 mg/day continuous i.v.
	or chlorpromazine (Largactil®) 50–200 mg/day continuous i.v.
	b) Core symptom : hallucination: haloperidol 5mg every 6 h (20 mg/day) or preferably continuous infusion: 50 mg/48 ml/ 4 mL.h-1 (i.e., start with circa 100 mg/day) adjusted to 25 mg/day to -1 < RASS < 0.
	NB: maximal recommended dose for haloperidol : ≈ 30 mg.day-1 (Carrasco, 2016). De-escalate as early as possible.
	c) Tiapride 100–1200 mg/day : 1200 mg/48 ml 2 mL.h-1 adjusted to -1 < RASS < 0.
	3) Start administering alpha-2 agonists:
	Contra-indication: sick sinus, A-V block II-III, hypovolemia.
	Refractory DT is very rarely managed without tracheal intubation. The usual presentation in the CCU is a patient who has been intubated to allow for conventional sedation (light total intravenous anesthesia, analgo-sedation). In non-intubated patient with some cooperation: clonidine 3–4 pills/vials (1 pill/vial = 150 μg in Europe) every 4–6 h to be administered orally up to 2–3 μg.kg.h-1 for 48–96 h.
	Suppression of agitation following administration of oral clonidine occur usually within 60–120 min. This should not imply discharging the patient within 24 h from critical care unit (CCU): the patient should remain in the CCU and administered with alpha-2 agonists for 48–96 h (absence of tremor) to avoid a second bout of DT after being discharged from the intermediate care unit to the ward.
	Intubated-mechanically ventilated patient: dexmedetomidine 1.5 μg.kg.h-1 or clonidine 2 μg.kg.h-1 for 48–96 h adjusted to -2 < RASS < 0; no loading dose: use rescue midazolam (3–5 mg to be repeated) during the interval necessary for alpha-2 agonists to induce ‚cooperative’ sedation (30–60 min for dexmedetomidine; 3–6 h for i.v. clonidine).
	Insert a sticker ‚DO NOT BOLUS’ on the i.v. line for alpha-2 agonist (Shehbi 2010).
	Some elderly patients require higher dose of alpha-2 agonists (clonidine up to 4 μg.kg.h-1) to achieve quietness; by contrast, most young patients on cannabis, heroin, cocaine and so on (alone or in addition to alcohol) appear quite sensitive to alpha-2 agonist evoked sedation.
	The treatment of refractory DT rests on the association of several drugs (alpha-2 agonists+neuroleptics: alpha-2+haloperidol+tiapride or alpha-2+loxapine+tiapride) to evoke quietness through different mechanisms with minimal circulatory or ventilatory side-effects. As the patient improves, de-escalate drugs as early as possible : suppression of neuroleptics, then of alpha-2 agonists.
	In rare instances, SBP may be low: a) check for etiology (volemia, sepsis, etc.); b) use low dose noradrenaline rather than tapering alpha-2 agonists; c) a second best practice is to lower the dose or suppress alpha-2 agonist administration and carry on with neuroleptics, scaled up to absence of agitation, hallucination, tremor. Basically, there is no maximal dose for neuroleptics: the patient should be quiet without tremor without resorting to general anesthesia or high dose benzodiazepine (ventilatory side-effects).
	In case of Gayet-Wernicke or refractory DT, very high doses of alpha-2 agonists and neuroleptics are needed to achieve quietness and absence of tremor (e.g., clonidine 4 μg.kg.h-1+loxapine 400 mg*4±tiapride). The issue is to clinically overcome agitation, hallucinations and tremor, irrespective of the dose administered, then de-escalate as early as possible (no tremor > 24 h).
Night sedation	Preservation of day-night cycle:
	Hydroxyzine 2 mg.kg-1 (≈ 150 mg/70 kg i.v. or p.o.) or melatonin 1–2 mg (or their combination with lower doses) will evoke sleep, early during the night (administration: 8–9 pm). Propofol or midazolam infusion appear unwise especially in the setting of hypotension or hypoventilation.
	NB: acute urinary retention is a possibility following administration of hydroxyzine in patients without Folley catheter.
Rescue sedation	NB: if sedation is not sufficient with the alpha-2 agonist, do not EVER administer a bolus of alpha-2 agonist: use ‚rescue’ sedation to be repeated if necessary and increase the administration of i.v. continuous dexmedetomodine up to ‚ceiling’ effect (1.5 μg.kg-1.h-1).
	To avoid making more complex a complex situation, conventional sedation is to be discontinued abruptly. In intubated mechanically ventilated patients, as i.v. dexmedetomidine or clonidine evoke sedation after ≈ 60 to 180 min respectively, ‚rescue’ sedation (midazolam bolus 3–5 mg) is to be administered repeatedly as required until the alpha-2 agonist evokes quietness to -1 < RASS < 0, combined with a neuroleptics, if needed. Would breakthrough occurs, consider haloperidol 5-10 mg bolus.
	Before nursing, in intubated mechanically ventilated patients, consider midazolam bolus 3 mg (repeatedly if needed, i.e., titrated to effect) if needed.
	Simple information repeatedly given to the patient regarding his disease and his care is important to minimize emergence delirium.
Tapering sedation	Following control of DT (no hallucinations nor tremor for > 24h), neuroleptics are tapered. Then alpha-2 agonists are tapered progressively over several days to avoid the (rare) occurrence of alpha-2 agonist withdrawal.
Extubation	a) Assess overall clinical status (ventilation, circulation, infection, inflammation, etc.); b) taper neuroleptics first; c) reduce administration of alpha-2 agonists to -1 < RASS < 0, then extubation of the trachea, under alpha-2 agonists: alpha-2 agonists do not suppress airway reflexes.
	Following extubation, continued NIV and/or Optiflow® under continued alpha-2 agonists as indicated by ventilatory status.
Discharge from CCU	Refrain from discharging the patient early to ward (no hallucinations nor tremor for > 24 h): alpha-2 agonists are usually withdrawn on the ward with re-introduction of benzodiazepines leading often to re-admission to CCU and re-intubation.