The use of deep sedation, that is, After clonidine 300 mg p.o., volunteers switch easily from light sleep to wakefulness (‘fairly alert’) and back.[11] In the CCU, under dexmedetomidine: a) an intubated child played a game of little horses with his nurse (P Delaire, RN, personal communication); and b) an intubated patient reported ischemic chest pain, allowing for treatment.[12]
The German guidelines[4] distinguish sedation strategies for pregnant and breastfeeding women; end-of-life patients; patients with severe burns, multiple trauma, or intracranial hypertension; post-cardiac surgery patients; and patients on extracorporeal membrane oxygenation (ECMO) or in the prone position. The present manuscript is restricted to clinical situations (part II: alcohol withdrawal, refractory delirium tremens (DT), hypotensive/hypovolemic patients, multiple trauma and cardiac surgery patients), in which we[15,17] have gained expertise since 1980 in the US, Quebec, Belgium and France. Admittedly, this manuscript delineates the clinical reasoning based on pathophysiological/pharmacological lineaments in the
This article includes the following formatting.
Part I: a rationale for the use of alpha-2 agonists in CCU sedation. Given the paucity of evidence-based data, speculations are separated from the remainder of the manuscript: the notation used by physiologists[19, 20, 21]
Part II: the use of alpha-2 agonists is delineated in specific settings (alcohol withdrawal, refractory delirium tremens (DT), hypotensive/hypovolemic patients, multiple trauma and cardiac surgery patients). Basic elements are provided in inserts I and II for understanding the autonomic nervous system physiology, the pharmacology of alpha-2 agonists, and the consequences with respect to adequate volume replacement before administering alpha-2 agonists. Abridged tables translate guidelines[22] into personalized clinical reasoning in these settings.
Several arguments suggest using alpha-2 agonists for CCU sedation: pharmacology (opioid-sparing effects, analgesia, sedation mimicking physiological stage 2 sleep), pathophysiology (modified autonomic nervous system, spontaneous ventilation, noninvasive ventilation [NIV]) and outcome-related.[23, 24, 25, 26, 27, 28]
An opioid-free analgo-sedation strategy combining non-opioid analgesics and alpha-2 agonists does not cause respiratory depression. This absence of respiratory depression combined with indifference to the environment (‘ataraxia’) has a major impact, allowing one to use In ARDS patients (PaO2/FiO2 [P/F]: face mask: 144; helmet: 118; Acute Physiology And Chronic Health Evaluation: APACHE=26), helmet NIV rather than mask NIV leads to a shorter duration of ventilation and lower mortality [34]. This finding might be related to a higher positive end-expiratory pressure (PEEP) level and lower pressure support [35], i.e., “inverted settings” [36]. Tolerance to NIV is substantially increased under sedation with alpha-2 agonists.[37] Accordingly, the duration of invasive ventilation[37] is reduced by delaying intubation or allowing for early extubation.[37]
The present hypothesis holds the following in the CCU:
a) Beta blockers[66,67] and/or alpha-2 agonists attenuate excessive sympathetic hyperactivity. This hyperactivity is normalized pharmacologically toward baseline activity. (sympathetic de-activation, suppressed overflow). b) Increased sympathetic activity could be a factor limiting survival when increasing APACHE score[27] or age[68] is considered.
The effects of alpha-2 agonists are multiple:
Minimized stage 2 sleep fragmentation,[69, 70, 71] increased or decreased rapid-eye-movement (REM) sleep as a function of dose,[69,72] indifference to the environment (‘ataraxia’, ‘rousability’[43] or ‘cooperative’ sedation[48]), minimized emergence delirium,[73,74] improved cognition[75] (Figure 2), analgesia,[76,77] indifference to pain or the absence of awareness of pain (‘analgognosia’),[10] reduced tremor.[78,79] A patient’s comfort and cooperation in the CCU depend on these properties.
No depression of the respiratory generator,[41,80] as opposed to observations with benzodiazepines, propofol and opioid analgesics, reduced hyperventilation Of interest in the setting of weaning under pressure support ventilation to lower ventilator-to-patient dys-synchrony.[81]
Improved expiratory mechanics in the setting of asthma (increased peak expiratory flow rate and forced expiratory volume) [85] Relevant in the setting of early ARDS (an intrinsic PEEP as high as 7 cm H20 is observed[86]) or severe bronchospasm/status asthmaticus.[87,33,32]
Decreased sensitivity to hypercapnia [88], as observed during slow-wave sleep, and improved tolerance to permissive hypercapnia [81, 89] Allowing one to set up a reduced tidal volume in the setting of acute respiratory distress syndrome (ARDS) in conjunction with fever control.[90]
Decreased VO2 under heightened [91, 92] and baseline [93] conditions and decreased baseline temperature [88] leading to lowered temperature in the CCU [94], thus improving fever control [90].
Reduced pulmonary hypertension [97, 98, 99] evoked by attenuated sympathetic hyperactivity [100].
Decreased sinus node activity (bradycardia), slowed atrio-ventricular conduction (increased P-R interval [101]), and a reduced incidence of ventricular arrhythmias following cardiac surgery [102].
In the setting of congestive heart failure: increased left ventricular (LV) diastolic [103] and systolic [104, 105, 106, 107] performance [104, 105, 106, 107]; experimentally: reduced arterial stiffness [108] and LV impedance [109].
Improved coronary circulation [110] in the setting of myocardial infarction [111] or coronary surgery [112].
Reduced cardiac filling pressure [104, 105] with effects depending on the state of the patient (improvement of cardiogenic pulmonary oedema [113] vs. aggravated hypotension when hypovolemia is present (part II, insert II).
Vasodilation of skin vessels with increased toe temperature [49]; reduced vasopressor requirements in the setting of sepsis [25] and septic shock [38, 40, 114]. Presumably, from a circulatory point of view, by normalizing sympathetic hyperactivity, alpha-2 agonists re-couple the ventricle, the arterial circulation and the microcirculation.
Increased diuresis in the setting of ascites,[115, 116, 117] cardiac failure[107] and critical care.[118]
Reduced intra-abdominal pressure;[121] improved gastrointestinal motility.[122]
Improved glucose control and reduced insulin requirements in type 2 diabetic patients undergoing surgery,[123] at variance with increased glycemia in healthy resting volunteers.
Decreased procalcitonin[39] and pro-inflammatory interleukin-6[124, 125, 126] and increased anti-inflammatory interleukin-10.[125,127]
In summary, alpha-2 agonists are associated with: a) sedation without cognitive impairment[75] (Figure 2);
increased parasympathetic activity and decreased sympathetic activity. This occurs in contrast to the reduced parasympathetic activity and increased sympathetic activity generated by surgical or medical illness; and
the absence of respiratory depression with possibly improved obstructive expiratory disease.[31, 32, 33,85] Despite such favourable pharmacodynamics, given the arterial hypotension, bradycardia or conduction block associated with the administration of alpha-2 agonists, alpha-2 agonists cannot be prescribed to all CCU patients.
First, under conventional sedation, when a nurse is in charge of the moment-to-moment adaptation of sedation, the incidence of ventilation-associated pneumonia and the duration of mechanical ventilation are significantly reduced.[128] However, CCU or hospital mortality is reduced non-significantly.[128] Whether a similar benefit occurs with alpha-2 agonists is unknown. Second, whether attenuated sympathetic hyperactivity allows for recovery from the initial insult, minimizes CCU-acquired disease and improves outcome requires stronger evidence than available.[23, 24, 25, 26, 27, 28,68]
Since the patient is not any further under general anaesthesia, the objectives for a motionless CCU patient are to minimize pain, anxiety and autonomic hyperactivity, early transition from controlled to spontaneous ventilation, and facilitate full patient cooperation. This
Iterative evaluations of sedation (Ramsay scale, Richmond Agitation and Sedation Scale [RASS]), pain (Behavioural Pain Scale [BPS],[129] Visual Analogue Scale) and delirium (CAM-ICU)[130]; and
Adaptation of nurses, physiotherapists and physicians to continuous cooperative sedation in an alert, spontaneously breathing patient, with active maintenance of day-night cycle, patient reassurance and orientation, and early physiotherapy.
The ‘recommended’ dose for clonidine is 0.2–2 μg.kg.h-1. [131] The recommended dose for dexmedetomidine is 0.4-1 μg.kg.h-1[16] to 1.5 μg.kg.h-1.[12] A ‘ceiling’ effect occurs with dexmedetomidine doses greater than 1.5 μg.kg.h-1.[12] Low-dose alpha-2 agonists include clonidine 0.1–0.4 μg.kg.h-1 and dexmedetomidine: 0.1–0.4 μg.kg.h-1. High-dose alpha-2 agonists (clonidine: 2 μg.kg.h-1, dexmedetomidine: 1.5 μg.kg.h-1) considered here should be differentiated from very high doses of alpha-2 agonists (e.g., clonidine 4
[A ‘sympathico-meter’ (Ghignone, personal communication) is elusive: plasma catecholamines, sympathetic microneurography or heart rate variability indices Parasympathetic indices (pNN50; Poincaré plot: SD1 vs. SD2; low-frequency/high-frequency ratio,etc.). In the present manuscript, normalization of sympathetic hyperactivity toward pre-disease baseline activity is emphasized. However, cardiac parasympathetic activity predicted performance in long-distance and ultra-long-distance runners[134,57] and is absent in brain-dead patients. At variance with the present emphasis on the sympathetic system, parasympathetic future research should consider recovery of cardiac parasympathetic activity in CCU patients, for example, following improved conditions and/or administration of alpha-2 agonists.
[In contrast,
In the setting of moderate/severe ARDS evoked by the SARS-CoV2, they can be safely used, with or without neuroleptics:
a) with intubation, fever control, optimisation of the acidosis/ cardiac output/microcirculation/acidosis, low pressure support-high PEEP and upright position,[138] b) with high oxygen flow in the setting of non-invasive ventilation, with impressive results (Longrois, unpublished data), following previous reports[29, 30, 31, 32, 33,89]
Systemic circulation (decreased aortic impedance, improved diastolic compliance, reduced sinus or supraventricular tachycardia): Doses as high as dexmedetomidine 1.5 μg.kg-1.h-1 or clonidine 2 μg.kg-1.h-1 can be used only if doses are incremented and volemia is adjusted (‘
Improved microcirculation and tissue acidosis: In the setting of septic shock, after normalization of cardiac output and systemic pH, the issue is restoring microcirculation. [139,140] One of the only tools available is normalizing sympathetic hyperactivity back to baseline. Presumably, lower doses of alpha-2 agonists are necessary to suppress peripheral shutdown and mottling, normalize capillary refill time and lower vasopressor requirements.[38, 39, 40,141]
Decreased inflammation[39,124,126,127]: Dose-range studies should delineate the dose range as a function of the amplitude of the inflammatory response.]
The dosage used as a rule of thumb in the setting of circulatory instability (e.g., dexmedetomidine 0.7 μg.kg-1.h-1[40] or clonidine 1 μg.kg-1.h-1[38]) is tentative. First, the dosage is a function of maintained[40] stroke volume. Second, the dosage must be documented in a dose-response manner with respect to the pathology and its severity and the considered target: sedation vs. systemic circulation vs. microcirculation vs. inflammation.
B) Clinical reasoning for the use of low- vs. high-dose alpha-2 agonists
GABA enhances tonic inhibition in the amygdala. Alcoholism can be related to lowered GABA clearance. GABA-B receptor agonists (baclofen, sodium oxybate) might lower GABA extracellular concentrations, presumably alleviating alcoholism.[142] In the setting of refractory DT, two issues require consideration:
Psychiatrists observed early that there is no fixed dose of neuroleptics to alleviate refractory DT. Indeed, the dose is the dose necessary to stop agitation and tremor completely, unless exhaustion and death would occur (Quintin, unpublished data); and
A Polypharmacopeia (alpha-2 agonists, neuroleptics, benzodiazepines, melatonin/hydroxyzine, etc.) can cause deleterious interactions. Thus, polypharmacopeia is used for the shortest time possible.
Clonidine up to 4 μg.kg.h-1 in some elderly patients to achieve calmness, which caused no side effects. Young, combative, patients suffering from poly-addiction (alcohol, cannabis, tobacco, cocaine) seem more responsive to alpha-2 agonists than elderly patients Elderly humans present with reduced cardiac parasympathetic activity. Alpha-2 agonists increase cardiac parasympathetic activity[145]: any relationship between reduced sedative effects of alpha-2 agonists and reduced central cholinergic or baseline cardiac parasympathetic activity is unknown. Conversely, a) Balinese massage the carotid sinus to induce sleep,[146] b) carotid sinus nerves stimulation tend to make the patient fall asleep (J Karemaker, personal communication).
Clonidine up to 4 μg.kg.h-1 combined to loxapine 400 mg*4 times per day in refractory DT patients presenting with a Gayet-Wernicke syndrome (Pichot-Quintin, unpublished data). Doses as high as clonidine 2700 μg (up to ≈ 38 μg.kg-1 administered over ≈ 30 min) normalize heightened VO2 in the setting of weaning from the ventilator and alcohol withdrawal (Figure 2 in [92]). Accordingly, clonidine p.o. up to 3600 μg was used in the setting of ambulatory hypertension.[147] In a medical CCU setting, dexmedetomidine up to 2.5 μg.kg.h-1 was used with minimal side-effects.[12]
Adaptation of dose of alpha-2 agonists over time
The dosage of alpha-2 agonists is not steady throughout the CCU stay for one patient. The dose requirement is very high during early refractory DT to abate agitation and tremors at once for a brief interval (≈ 3–6 h). Nevertheless, drug requirements subside over time.[143] [In the medical CCU setting, we observed a two-phase response CCU tachycardia is a function of pain; agitation vs. sedation; temperature[90]; cardiac baroreflex-mediated mechanisms, which are managed with adequate volemia and increased blood pressure using vasopressors, when necessary; metabo-reflex[148] mediated mechanisms (the metabolic reflex originating in skeletal muscle is ‘ inflammation, which generates tachycardia that is unblocked by a beta-blocker.[149] Thus,
In the ambulatory setting, a reduced sedative effect is observed after 2–4 weeks of administration of alpha-2 agonists. [147,150] In the CCU, this reduced sedative effect is observed after a few days (Quintin, unpublished data). The reasons are unclear. They might include improved cerebral perfusion, reduced septic confusion or tachyphylaxis in relation to the sedative effect, warranting a higher dose of alpha-2 agonist or supplementary drugs if required. Therefore, iterative, daily reassessments are necessary.
When addressing the acute cardio-ventilatory distress observed upon arrival to the CCU, stabilization of the acute cardio-ventilatory distress is a priority (‘salvage therapy’, ‘resuscitation’). [The sedation requirement is minimal during cardio-ventilatory stabilization. The patient is often unconscious during the acute period (low cerebral perfusion in the setting of hypovolemia; confusion secondary to sepsis). In contrast, as a patient improves, the alpha-2 agonist requirement increases (Quintin, unpublished data). The patient’s comfort is prioritized after the completion of salvage therapy. Titration is performed to the required effect (cognition vs. circulation vs. ventilation vs. inflammation), with the requirement changing over time accordingly.]
Interactions with other CCU sedatives
[Since alpha-2 agonists evoke analgesia[76] and analgognosia,[10] pain in a conscious, alert patient without respiratory depression is treated with nonopioid analgesics as first-line agents (opioid-free analgo-sedation) as in the setting of opioid-free anaesthesia. ‘Rescue’ opiates[151] are prescribed only as a second-line option (part II, tables 1 and 2).]
If neuroleptics are necessary to supplement alpha-2 agonists,
Delirium Tremens (DT)
Positive diagnosis | History of chronic alcohol intoxication and alcohol withdrawal, inability to sustain attention, disorganized thinking, 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 (PLR) if arterial line in place: normalize volemia before administration of alpha-2 agonists |
Ventilation: ‚focal’ pneumonia? | |
Kidney, liver, pancreas, metabolism | |
Consider BIS or equivalent when benzodiazepine or propofol infusion are used. | |
Supportive treatment | Ventilation: O2 supplementation |
Hydration: consider hyperthermia and agitation to evoke adequate diuresis (> 1 mL.kg.d-1, i.e., > 1700 mL/70 kg/24 h) | |
Vitamins (B1, B6), nicotine patch(s), 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 | |
Sedation | Goal: quiet patient (-1 < RASS < 0): no brisk movements, hallucinations and fine tremor controlled > 24 h |
1) Discontinue benzodiazepine, opioid analgesics and so on immediately upon admission. According to our clinical experience, use benzodiazepines or opioid analgesics only as ‚rescue’ sedation or ‚rescue’ analgesia. | |
2) Continue neuroleptics to avoid bout of abrupt agitation upon benzodiazepine/opiates cessation then suppress neuroleptics to make treatment as simple as possible. Would breakthrough occurs, consider haloperidol 5-10 mg i.v. as a “stat” prescription. | |
NB: monitor QT when administering any neuroleptics | |
Only when alpha-2 agonists are NOT sufficient to evoke -1 < RASS < 0, supplementation with second-line drugs, consider: | |
Use preferably haloperidol when hallucinations are the primary symptom, phenothiazines or oxazepines when agitation is the primary symptom. | |
a) Loxapine: start using 100 mg orally or through nasogastric tube every 6 h then de-escalate as early as possible down to, for example, 25 mg*4: the goal is -1 < RASS < 0. | |
b) Haloperidol 5 mg every 6 h (20 mg/day) or preferably continuous infusion: 50 mg/48 ml/ 0.5–1 ml.h-1 (i.e., start with circa 12–24 mg/day) adjusted to -1 < RASS < 0 | |
NB: maximal recommended dose for haloperidol : ≈ 30 mg.day-1 (Carrasco, 2016). | |
3) Alpha-2 agonists: contra-indication: sick sinus, A-V block II-III, hypovolemia | |
Non-intubated patient with some cooperation : clonidine p.o. 6–8 μg.kg-1 (3–4 pills/vials in Europe; beware of various dosages: 1 pill/vial=150 μg in Europe; 1 pill = 100 or 200 or 300 μg in the US) every 4 to 6 h to be administered orally up to 2–3 μg.kg.h-1 for 48–96 h (no tremor > 24 h). | |
Suppression of agitation following administration of oral clonidine occurs usually within 30–120 min. This should not imply discharging the patient within 24 h from intermediate care unit: the patient should remain in the intermediate care unit and administered with alpha-2 agonists for 48–96 h (absence of tremor > 24 h) to avoid a second bout of DT after being discharged from the intermediate care unit back to the ward. | |
Intubated-mechanically ventilated patient: dexmedetomidine 1.5 μg.kg.h-1 or clonidine 2 μg.kg.h-1 (beware of dosages: Europe: 1 vial =1 mL = 150 μg.mL-1; US epidural clonidine: 100 or 500 μg.mL-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 (Shehabi 2010). | |
Surprisingly, some elderly patients require higher doses of alpha-2 agonists to achieve quietness; by contrast, most young patients, including those on cannabis, heroin, cocaine and so on appear quite sensitive to alpha-2 agonist induced sedation. | |
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 will evoke sleep (RASS <- 2), early during the night (administration: 9 pm). Propofol infusion is risky (severe hypotension and/or bradycardia, hypoventilation) when alpha-2 agonists are administered. | |
NB: beware of acute urinary retention following hydroxyzine in patients without Folley catheter. | |
Refractory delirium tremens | See table 2. |
Rescue sedation | NB: if sedation is not sufficient with the alpha-2 agonist, do no t EVER administer a bolus of alpha-2 agonist: use ‚rescue’ sedation to be repeated if necessary and increase the administration of i.v. continuous dexmedetomidine up to ‚ceiling’ effect (1.5 μg.kg-1.h-1). consider haloperidol bolus if breakthro ugh occurs. |
To avoid making a complex situation more complex, conventional sedation is to be discontinued abruptly. In intubated mechanically ventilated patients, as i.v. dexmedetomidine or clonidine-induced sedation after ≈ 60 to 180 min respectively, ‚rescue’ sedation (midazolam bolus 3–5 mg titrated to effect) is to be administered repeatedly as required until the alpha-2 agonist evokes quietness to -1 < RASS < 0, combined with a neuroleptics, if needed. | |
Before nursing, in intubated mechanically ventilated patients, if needed, consider midazolam bolus 3–5 mg titrated to effect. | |
Simple but repeated information of 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 > 24 h), neuroleptics are tapered. Then alpha-2 agonists are tapered progressively over several days to avoid the rare occurrence of alpha-2 agonist withdrawal. |
Extubation | Alpha-2 agonists do not suppress airway reflexes: a) assess ventilation and overall clinical status (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. |
Following extubation, if needed, continued non-invasive ventilation under continued alpha-2 agonists as indicated by ventilatory status. | |
Discharge from CCU | Refrain from discharging the patient early to the ward (hallucinations or tremor should be suppressed for > 24 h): unfortunately, alpha-2 agonists are usually withdrawn on the ward with re-introduction of benzodiazepines leading often for re-admission to CCU and re-intubation. |
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. |
Handling patients -4 < RASS < -3 vs. patients -2 < RASS < 0 requires a
When switching from conventional sedation to cooperative sedation, the possibility is either:
a slow, even, transition, for example, when an elderly patient has received high-dose midazolam and sufentanil for days or weeks An infusion of midazolam 5 mg.h-1 totals circa 120 mg over 24 h, usually for several days. This dosage is a massive overdose for an elderly, frail patient, leading to delayed emergence.
emergence and agitation, as observed in combative patients as soon as conventional sedation is withdrawn. Such a patient will be likely poorly sedated and agitated as long as steady cooperative sedation has not yet been achieved. Thus, rescue sedation[74] allows one to transition from conventional sedation to dexmedetomidine: midazolam 0.01–0.05 mg.kg-1 (1–3.5 mg/70 kg) is administered at 10 to 15-min intervals to achieve -2 ≤ RASS ≤ -1.[74] [In our group, midazolam boluses of 3–5 mg are repeated every 3–5 min up to -2 ≤ RASS ≤ -1 until steady cooperative sedation is achieved (≈ 60 and 180 min for dexmedetomidine 1.5 μg.kg.h-1 or clonidine 2 μg.kg-1.h-1, respectively). Under extreme circumstances (e.g., DT with refractory agitation), neuroleptics are administered
Progressively withdrawing conventional sedation while gradually introducing an alpha-2 agonist[16] leads to severe bradycardia/hypotension (summation of sympatholysis), in our hands. This occurs often at night if the night shift personnel has not been taught about using rescue sedation rather than propofol boluses or infusions. There is
The depth of sedation in septic patients may be varied during the day-night cycle (day time: -1 < RASS < 0; night time: -2 < RASS < 0).[27] In the CCU setting, increased sedation at night (-2 < RASS < -1; medium-dose dexmedetomidine: 0.4–0.7 μg.kg.h-1 or low-dose dexmedetomidine: 0.1 μg.kg.h-1) reduces the fragmentation of sleep and increases sleep stage 2 (N2) without affecting REM sleep.[71,154] In healthy volunteers, low-dose clonidine (25 μg) increases the REM sleep duration.[69] By contrast, medium-dose clonidine (150 μg) lowers the REM sleep duration and increases the slow-wave sleep duration.[69] [In our experience, once steady cooperative sedation has been achieved with an alpha-2 agonist alone or in combination with neuroleptics, our prescription regimen maintains the alpha-2 agonist at a steady dose. To deepen night sedation, if necessary, administration of melatonin provides good clinical results (administration ~ 8–9 pm considering its delayed effect; 2 mg orally or through an n/g tube). However, the results are equivocal.[155,156] Alternatively, hydroxyzine 100–150 mg administered i.v. over 10 min or orally through an n/g tube achieves early awakening the next day without delayed somnolence. A combination of these drugs at lower doses may also be used.]
To avoid oversedation, electroencephalographic monitoring (BIS or equivalent) is advocated when deep sedation is required (NMB use, status epilepticus, etc.).[5] To our knowledge, BIS monitoring under cooperative sedation has been rarely reported. A sedation scale ‘to effect’ verified iteratively should be preferred to a tentative 60 < BIS < 95 throughout a patient’s stay[157] as the issue is not the displayed BIS value but the actual sedative effect.
When, severe, prolonged bronchospasm or status asthmaticus are considered,
Addressing the indication and dose of alpha-2 agonists in the setting of elderly patients, co-morbidities, shock and peripheral shut-down (mottling) is complex. Our practice is threefold:
Iterative individualized volume loading, based on iterative passive leg raising (PLR; Figure 6) and echocardiography. [158]
Restoration of systemic pressure with vasopressors when diastolic pressure is low.[159] In this respect, alpha-2 agonists
Restoration of the microcirculation[139] in the setting of peripheral shut-down, increased lactate, etc. Patients with a low temperature in the setting of sepsis present higher mortality[163,164]: they are either unable to generate ‘core’ heat or to transfer ‘core’ heat to the periphery. Peripheral shutdown could be a cause or consequence of this inability.
F) Speed of administration
Before administering an alpha-2 agonist, physical examination, benefits/risks, bradycardia, sick sinus syndrome, A-V block, and hypovolemia should be assessed. [In the setting of alcohol withdrawal/agitation,
CCU patients are often hypovolemic. Hypovolemia becomes apparent emerges when sedation (conventional or cooperative) is administered (part II, insert II) and controlled mandatory ventilation is initiated with positive end-expiratory pressure (PEEP). Therefore,
Pre-emptive volume loading is wise when CMV is anticipated.[169]
Volemia should be assessed and corrected appropriately[158] before initiating the administration of an alpha-2 agonist (e.g., iterative PLR[170] [Figure 6]; transthoracic echocardiography [TTE]: ventilation-induced changes in the inferior vena cava[171]; transoesophageal echocardiography [TEE]: collapsibility of the superior vena cava[172]). Capillary refill, diuresis, the CO2 gap, the lactate concentration, and the arterio-venous difference should be monitored before any further increase in the speed of administration of the alpha-2 agonist up to the required effect (sedation vs. circulation vs. ventilation vs. inflammation).
‘ A ‘ Given the high bioavailability of oral clonidine, slow loading is also possible through an n/g tube, for example, clonidine 150 μg crushed and administered through the nasogastric tube. Then, 2 h later, after PLR and ETT re-assessments, clonidine 300 μg can be administered through the n/g tube iteratively until the desired effect is achieved, followed by i.v. administration of the required dose. This route of administration appears suitable in mechanically ventilated patients as a bridge (12–24 h) to i.v. administration; then, gastric accumulation occurs with possible bradycardia (Quintin, unpublished data).
Vasopressors squeeze the venous capacitance.[175] In contrast, alpha-2 agonists inhibit the vasomotor sympathetic activity targeted to the veins. Therefore, iterative assessments of venous return and replenishment of the venous capacitance will avoid: a) lowering venous return any further
When conventional sedation is used prior to an alpha-2 agonist, the benefits/risks should be assessed, as above. [Withdrawal of conventional sedation is performed
DT. In contrast, a low-dose alpha-2 agonist will be selected (dexmedetomidine or clonidine: 0.125 or 0.25 μg.kg-1.h-1 for 3 h, followed by an increasing dose when shock or circulatory instability is present (part I, III, A).] Rescue sedation[74] is administered repeatedly if agitation occurs before achieving steady cooperative sedation (part I, III).
[When high-dose dexmedetomidine or clonidine does not achieve quietness (-2 < RASS < -0) within 3 and 6 h, respectively, neuroleptics should be added according to the primary symptom (hallucination: haloperidol vs. agitation: loxapine; Pichot, personal communication; part II, I, E). Benzodiazepines should not be used except for rescue sedation, anxiolysis and emergency treatment of seizures. Midazolam infusion set minimally (e.g., 0.5 mg.h-1) may be considered only if anterograde amnesia is a concern, for example, with a patient in the prone position under short-term neuromuscular blockade requiring deep sedation (RASS < -2)
The switch to spontaneous breathing should occur as soon as cardio-ventilatory distress has improved,[21,90,176] regardless of selecting conventional vs. cooperative sedation.
Briefly: fever control,[90] suppressed agitation,[21,89,135,136, 185,137] normalized systemic pH,[136] upright position,[183] a low ‘CO2 gap’,[186] normalized lactate, normalized superior vena cava O2 saturation, minimal permissive hypercapnia[187] [as during physiological stage 2 sleep, a lowered sensitivity to CO2 is observed following alpha-2 agonist administration[88]], a normalized metaboreflex (note 11),[148] normalized tissue pH and improved capillary refill, reduced inflammation, reduced lung water.[188]
Clonidine[189] or dexmedetomidine withdrawal syndrome is rare. [To avoid alpha-2 agonist withdrawal syndrome, when a high-dose alpha-2 agonist has been administered for an extended period, a short-acting alpha-2 agonist is transitioned to a longer-acting alpha-2 agonist: intravenous dexmedetomidine (t1/2β ≈ 180 min) is transitioned to oral clonidine, which is then discontinued over several days (clonidine: t1/2β ≈ 8-–24 h[48,190]; clonidine 0.2–0.5 mg every 6 h and then every 9 h, and so on, over 1–7 days; median: 2.4 days[191]). Similarly, i.v. clonidine is transitioned to oral clonidine or oral guanfacine (extended release Intuniv®, Estulic®, t1/2β ≈ 10–30 h). Where available (e.g., the US), transdermal clonidine (Catapres-TTS® 7.0 or 10.5 cm2) can be considered as soon as capillary refill is normalized.]
[If
G) Side effects
The side effects of alpha-2 agonists[192] are a function of the: a) adequacy of venous return (part II, insert II); and b) adaptation of the cardiac and vasomotor limbs of the baroreflex (legend of Figure 1):
Clonidine upregulates beta receptors in healthy supine volunteers.[193] Clonidine is used in the setting of severe idiopathic orthostatic hypotension because it increases blood pressure[194] by upregulating alpha-1 receptors.[141] When p.o. clonidine is administered to normotensive or hypertensive patients without idiopathic orthostatic hypotension, systemic hypotension (SBP < 100 mm Hg) is seldom observed. When systemic arterial hypotension occurs, the patient seems unaffected (adequate capillary refill, preserved urine output). Nevertheless, since mild hypotension is not tolerated in the ward, the patient should stay in the intermediate care unit.
[Adequate volemia and atrio-ventricular conduction should be achieved before infusion of alpha-2 agonists (part I, III, F). When a continuous i.v. infusion of alpha-2 agonists is used, hypotension+bradycardia is observed in 5–33% of patients. [12,195] Management of side effects includes:
Avoiding boluses or a loading infusion (a sticker stating ‘DO NOT BOLUS’ is placed on the i.v. line infusing the alpha-2 agonist[16]);
Increasing venous return (stockings/military anti-shock trousers, Trendelenburg position, volume loading) before the administration of alpha-2 agonist;
Avoiding drugs that increase parasympathetic activity, leading to severe bradycardia and hypotension, for example, opioids[196,197];
Avoiding drugs that suppress cardiac or vasomotor sympathetic activity, for example, beta-blockers and propofol; and
Administration of micro-doses of norepinephrine (infusion: 0.01–0.05 μg.kg-1.min-1)[195] when urine output or peripheral or cerebral perfusion is a concern.
Ventilatory depression does not occur with alpha-2 agonists[41] except in the setting of accidental or intended overdose. The absence of ventilatory depression makes alpha-2 agonists the first-line drug in the setting of non-invasive ventilation[29,30,198] (high flow oxygen, helmet or mask ventilation): could this be extended to proning in awake patients, for example, with respect to the covid-19 pandemics?[199] In the CCU, at the doses described above[12,131] (part I, III), respiratory depression is not observed.[41,47,80,88,200] When high-dose benzodiazepines are administered Midazolam i.v. (2 mg) after oral administration of clonidine (300 μg) leads to transient respiratory depression, rarely (Quintin, unpublished data). In fact, low-dose benzodiazepines administered alone evoke transient respiratory arrest, rarely.[201]
Upper airway obstruction is observed in patients presenting with sleep apnoea[72] and healthy volunteers,[202] presumably during slow-wave sleep (‘snoring’). Whether such obstructions are clinically relevant during NIV requires study.
Hyperthermia following administration of dexmedetomidine has been reported (n = 9[203]), although alpha-2 agonists act on the hypothalamic activation threshold (‘set point’), generating mild hypothermia (35–35.5°C).[88,94,204,205] [This report contradicts our clinical experience with alpha-2 agonists in facilitating fever control in the setting of septic shock or ARDS.[90]] Nevertheless, hyperthermia should be borne in mind as a possible adverse drug reaction.
When alpha-2 agonists are used as premedication or within the setting of opioid-free anaesthesia[122] (Quintin, unpublished data), bowel movement is observed before surgery. Clonidine reduces diarrhoea in the setting of rapid opioid detoxification under general anaesthesia.[206] Accordingly, Ogilvie syndrome has been observed immediately following the introduction of alpha-2 agonists[207] in the setting of heavy sedation.[208] Could the pro- or antikinetic overall effect be related to baseline parasympathetic vs. sympathetic dominance?
Medetomidine (racemic of levo- and dexmedetomidine) exhibits an alpha-2/alpha-1 selectivity ratio of 1620; conversely, clonidine has a selectivity of 220.[209] Selectivity for alpha-2 receptors is only
Clonidine is available as a p.o., i.v., or transdermal drug only in some countries. Conversely, dexmedetomidine is an i.v. drug, usable as a spray in children.
Clonidine is inexpensive and widely available. Dexmedetomidine is more expensive than clonidine; however, the reduced duration of ventilation and length of CCU stay compared to those with conventional sedation[37,83] generate savings.
Clonidine is bioavailable with oral (90%)[44] and rectal (95%) administration.[213] Dexmedetomidine is less available when administered orally (15%).[214] Both drugs are well absorbed intranasally.
Clonidine is metabolized to inactive metabolites through the liver (50%) and excreted unchanged via the kidneys (50%). [214] Therefore, clonidine is relatively contraindicated in the setting of acute kidney injury. [Nevertheless, since renal replacement therapy (RRT) is available in the CCU, this contraindication is relative. If RRT is used, then the dose of clonidine is usually titrated upwards to achieve the desired effect (Quintin, unpublished data).]
Dexmedetomidine is excreted via the liver; therefore, acute liver insufficiency is a contraindication. Alternatively, the dose should be lowered.
[In stable patients, sedation is achieved earlier with dexmedetomidine (30–120 min) than with clonidine (120–240 min). Thus,
The elimination half-life of dexmedetomidine is ≈ 180 min vs. ≈ 8–24 h for clonidine.[190] A shorter half-life is an advantage if abrupt discontinuation of the alpha-2 agonist is needed and a disadvantage during tapering (part I, III, F).
Currently, no evidence-based data support any expert-based recommendations or an international consensus regarding the use of alpha-2 agonists in the CCU. Furthermore, no extensive randomized, controlled trials have addressed the use of alpha-2 agonists
b) move toward unstable patients (‘
CCU delirium, alcohol withdrawal, established delirium tremens and delirium tremens refractory to haloperidol[200] are considered sequentially.
Delirium is characterized by: a) the acute onset of cerebral dysfunction with a change or fluctuation in baseline mental status, b) a reduced ability to focus, shift or sustain attention, a disturbed level of consciousness, or reduced clarity of awareness of the environment, and c) cognitive (disorganized thinking, memory deficits, disorientation, or language disturbance) or perceptual disturbance (hallucinations or delusions).[2] Delirium may be ‘hypo-active’ (66% of CCU patients; inattention, disordered thinking, or a decreased level of consciousness without agitation),[5] for which prognosis is poor.[234] Conversely, delirium may be hyperactive (2% of CCU patients[5]). Delirium is associated with increased mortality, prolonged CCU and hospital stays, and cognitive impairment.[2] CCU mortality increases from 0–15% when delirium does not occur[143] to 34% when delirium occurs[152]: a 10% increase in the relative risk of death for each day of delirium exists (quoted from (234)). Therefore, early diagnosis[130] and treatment of delirium are required. However, evidence linking treated delirium and improved outcomes is missing.[234]
Before diagnosing nonspecific delirium, other causes should be considered after neurological examination and neuro-imaging: sepsis, pain, hypoxia, hypoglycaemia and hypotension, followed by withdrawal from alcohol, opioids or illegal drugs.
Current recommendations suggest avoiding benzodiazepines with long terminal half-lives.[4] Benzodiazepines are currently used only as
Alcohol dependence is present in 15–20% of all hospitalized patients.[143] During hospitalization, 8–31% of these alcohol-dependent patients develop alcohol withdrawal symptoms (AWS) with neurologic and autonomic dysfunctions. Approximately 15 and 5% of these AWS patients will develop tonic-clonic seizures or hyperactive DT (agitation, delirium, seizures, hypertension, tachycardia, arrhythmia, hyperpyrexia, diaphoresis), respectively.[2]
Conventional prevention of DT includes identification and monitoring of patients at risk, early mobilization, cognitive stimulation, physiotherapy, noise reduction, a preserved day-night cycle, vision and hearing, continued orientation and information, ample hydration,[234] and vitamins (B1: thiamine; B6: pyridoxine). [Pre-emptively treating a patient pharmacologically before overt DT may lead to overtreatment of patients who will not develop DT. As long as a patient is continuously scrutinized in the intermediate care unit, monitoring the Confusion Assessment Method for the ICU (CAM-ICU) score, hallucinations, agitation and tremors is the deterrent to the development of DT.]
Patients in the ward or the CCU/intermediate care unit are often agitated, under physical restraint and receiving intermittent doses of benzodiazepines i.v. or p.o. (Table 1). [However, they retain some coherence for a few seconds or dozens of seconds, allowing administration of clonidine 450–600 μg See insert for the various dosages for pills/vials in Europe vs. the USA. The i.v. route (2 μg.kg-1.h-1 for 24 h) is used if the oral route cannot be used. To our knowledge, the use of oral/nasal/rectal dexmedetomidine in such a setting has not been described.
When a DT patient is admitted from the ward to the CCU following oversedation with benzodiazepines, the patient presents a combination of oversedation and/or agitation, a degree of hypoventilation, sepsis (usually pulmonary) and minimal acute kidney injury. Supportive treatment is provided (table 1) and benzodiazepine administration is stopped immediately. Alpha-2 agonists should be administered immediately after physical examination and assessment
of contra-indications: dexmedetomidine 0.7[200] to 1.5 μg.kg-1.h-1 or clonidine i.v. 1-2 μg.kg-1.h-1 adjusted to –2 < RASS < 0. The low dose (0.7 μg.kg-1.h-1) is used[200] after an unsuccessful haloperidol trial (maximum daily dose of haloperidol: 30 mg (200)). [In our hands, high-dose alpha-2 agonists represent one strategy to control agitation as quickly as possible in the context of pre-existing benzodiazepine or haloperidol treatment (part I, III, F). The alpha-2 agonist is tapered as above (part I, III, F).]
[Following benzodiazepine overdose and failure to control DT, the objective is to
A patient admitted to the CCU presenting with established DT often exhibits multiple trauma and/or organ failure (MOF): pneumonia or ‘focal’ ARDS, oliguria or acute kidney injury, agitation occurring during weaning from conventional sedation and so on. The risk of sepsis or septic shock in a patient with an initial diagnosis of DT persists during or immediately after complete recovery of delirium, with possible delayed diagnostic.
[In the setting of established DT: a) conventional sedation is stopped immediately before initiation of a dexmedetomidine/ clonidine infusion, b) only i.v. alpha-2 agonists should be used, that is, dexmedetomidine 1.5 μg.kg-1.h-1 adjusted to heavy sedation (–3 < RASS < -2), for the shortest possible interval and lightened as soon as possible. As agitation may persist for 30–180 min before achieving steady sedation with dexmedetomidine, iterative bolus rescue sedation (midazolam)[74] may be administered (part I, III,D).] Conversely, would breakthrough occurs, haloperidol bolus 5-10 mg is considered.
Alpha-2 agonists were used early in the setting of refractory DT.[236, 237, 238] [In this setting, there is no upper limit for the dose of an alpha-2 agonist. The issue is achieving quietness without brisk movements, hallucinations or tremors for ≥ 24
h. If alpha-2 agonists used alone cannot achieve quietness (dexmedetomidine 1.5 μg.kg-1.h-1 or clonidine 2 μg.kg-1.h-1), then neuroleptics should be added (Table 2)]. High-dose alpha-2 agonists and neuroleptic agents should be adjusted downward as soon as suppression of tremor and agitation 3>24 h are observed. [Neuroleptics are selected according to primary symptom (Pichot, unpublished data):
hallucinations: haloperidol Olanzapine vs. haloperidol treatments show no diference. However, an open-label study shows the superiority of dexmedetomidine vs. haloperidol (quoted from (234)). Quietapine, an atypical neuroleptic with a minimal efect on the QT interval, at 50– 200 mg orally or via n/g tube every 12 h appears to be more efective than ‘as needed’ haloperidol to address critical care delirium.[239]
agitation: loxapine 100 mg through an n/g tube every 6 h to achieve deep sedation (3 < RASS < -2) for 3–6 h and control agitation, followed by adjustment to -2 < RASS < 0 as early as possible (part I, III). A period (≈ 3–6 h) of deep sedation (-3 < RAAS < -2) is usually inescapable, followed by lightened sedation (-2 < RASS < 0). Loxapine 100 mg every 6 h is modified to loxapine every 12 h with the addition of, for example, dexmedetomidine 1.5 μg.kg-1.h-1. Then, the loxapine dosage is reduced as early as possible (part I, III, D).
In our hands, a combination of high-dose alpha-2 agonists and high-dose neuroleptics abates refractory DT. Baclofen 50–150 mg[144] or low-dose midazolam (e.g., 1 mg.h-1) are never necessary to achieve quietness. As these drugs are GABA agonists and as GABA is involved in alcoholism, this possibility presents nevertheless relevance.]
Withdrawal from illegal drugs
Administration of alpha-2 agonists in the setting of heroin withdrawal[240] lead to the use of alpha-2 agonists in the setting of anaesthesia,[45,241,242] alcohol[236] or tobacco withdrawal. [243] Alpha-2 agonists are widely used in rapid detoxification management. Accordingly, early rapid detoxification in methadone addicts has been observed: clonidine (17 μg.kg-1. day-1, i.e., ≈ 1.2 mg.day-1), without general anaesthesia, achieved a high success rate and near-total suppression of withdrawal symptoms.[244]
For tobacco withdrawal, as most DT patients present mixed alcohol and tobacco intoxication, alpha-2 agonists are administered to achieve the desired sedative efect in addition to transdermal nicotine.
Medical patients require higher doses of alpha-2 agonists. [12] By contrast, postoperative[12] or trauma patients require higher doses of analgesics.[12] These data require replication and emphasize iterative objective evaluations of pain in intubated vs. nonintubated patients.
Multiple-trauma patients (Table 3) experience problems beyond the scope of this manuscript, as: a) definitive surgery and haemostasis; b) inflammation, infection and so on; and c) alcohol, cannabis, heroin and so on withdrawal (part II, I), regardless of comorbidities.
Pain should be iteratively evaluated by combining behavioural[129] and circulatory parameters. A complete shift of emphasis has emerged: opioid analgesics are currently used only as rescue analgesics,[151] which may evoke exaggerated bradycardia in the presence of dexmedetomidine.[197]
The analgesics with the fewest side-effects should be selected considering the importance of spontaneous breathing. [Accordingly, opioid-free analgo-sedation should be used: a) intact respiratory genesis evoked by alpha-2 agonists[41,80,88] and b) analgesia[76] and analgognosia[10] evoked by alpha-2 agonists. This lowers the analgesic requirements. Nonopioid analgesics (or opioid analgesics with minimal respiratory effects, such as tramadol) should be considered, that is, ketamine, nefopam, aminotryptilline, pregabalin/gabapentin, carbamazepine and nonsteroidal anti-inflammatory agents (Table 3). Relative contra-indications exist according to age (nefopam), acute kidney injury (tramadol), anti-inflammatory agents, seizures, etc.]
The standardization of cardiac surgery with/without cardiopulmonary bypass (CPB) led to the establishment of fast-track cardiac anaesthesia and early discharge from the CCU. Patients’ conditions are complex because of extensive comorbidities beyond the scope of this manuscript: age, left ventricular systolic or diastolic impairment, chronic obstructive lung disease, chronic kidney insufficiency, diabetes, and obesity and so on (Table 4).
Multiple trauma
Overall assessment | Iterative use of Richmond Agitation Sedation scale and Behavioural Pain Scale. |
Circulation: iterative peripheral mottling, capillary refill, diuresis, passive leg raising. | |
Iterative echocardiography: normalize volemia before administration of alpha-2 agonists. | |
Ventilation: assess ‚wet’ lung/ARDS following multiple transfusion. | |
NB: ‚wet’ lung or peripheral edema does not contra-indicate the use of alpha-2 agonists; alpha-2 agonists evoke anti-ADH effect, diuresis and improved kidney function. | |
Kidney, liver, metabolic function. | |
Infection, inflammation. | |
Supportive treatment | Ventilation: as appropriate, O2 supplementation or High Oxygen flow (Optiflow®) or non-invasive ventilation or invasive ventilation as soon as sedation is achieved. |
Hydration to adequate diuresis (e.g. > 1 mL.kg.d, i.e., > 1700 mL/70 kg/24 h) vs. renal replacement therapy, if appropriate. | |
After full haemostasis, prophylaxis of thrombosis. | |
Prophylaxis of gastro-intestinal haemorrhage. | |
Supportive treatment specific to considered trauma. | |
Consider BIS or equivalent if benzodiazepine or propofol infusion are to be used. | |
Sedation | 1) Goal : quietness (intubated patient: -3 < RASS < 0; non-intubated patient: -2 < RASS < 0), analgesia (BPS < 3–5), spontaneous ventilation (e.g., pressure support with minimized work of breathing: pH, PaCO2) as soon as possible. |
1) Discontinue propofol, benzodiazepine, opioid analgesics. | |
2) Dexmedetomidine 0.75 μg.kg-1.h-1 up to 1.5 μg.kg-1.h-1 adjusted to -3 < RASS < 0. | |
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). | |
Insert a sticker ‚DO NOT BOLUS’ on the i.v. line (Shehabi 2010). | |
3) If insufficient, loxapine 100 mg through n/g adjusted to, for example, 25 mg*4 or haloperidol 1 mg.h-1 lowered to 0.25-0.5 mg.h-1 adjusted to -1 < RASS < 0. | |
4) Non-opioid analgesia: | |
Ketamine 50–100 mg.day-1, tramadol 400 mg.day-1, nefopam 100 mg.day-1/48 ml : 2 mL.h-1. These dosages may be reduced to 1 mL.h-1 then 0.5 ml.h-1 after 1-3 days of administration. The clinical impression is that after full impregnation with an alpha-2 agonist for 1-3 days, the patient needs little analgesia per se, presumably due to the analgognosia evoked by the alpha-2 agonist (see text). | |
NB: In elderly patients administer nefopam 20mg/day for 1–2 days then increase nefopam if necessary up to 100 mg if no cognitive side-effects occur. Beware of possible acute urine retention if Folley catheterization is not performed. | |
NB: Tramadol is a weak opioid analgesics acting on μ receptors, contra-indicated if acute kidney insufficiency is present | |
To avoid completely opioid analgesics or for an early stop of the administration of tramadol-nefopam especially when elderly patients are considered, consider: | |
amitryptyline (Laroxyl®) 25 mg i.v.*4 or lidocaine 0.5 mg/kg/h (loading dose: 1 mg. kg-1.h-1) or ketamine (0.25 mg kg-1.h-1) infusion. | |
or pregabaline (Lyrica®) 150–600 mg/day : start with 25 mg*2 through n/g (day 0), then 50*2 (day 2) then 75*2 (day 4). When pancreatitis or CCU neuromyopathy is considered: 150*2 and up to total daily dose: 600 mg. | |
or gabapentine (Neurontin® 100–900 mg/day) or carbamazepine (Tegretol® 200–400 mg/day). | |
5) ‚Rescue opioids’: if needed, opioid analgesics to be re-introduced sparingly; allow for early spontaneous ventilation, absence of effect on intestinal motility, hyper-algesia. | |
Rescue sedation | To avoid making a complex situation more complex , 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. |
Immediately prior to nursing, ‚rescue’ sedation (midazolam 1–2 mg (titrated to effect) may be administered to maintain -3 < RASS < 0. |
Postoperative management following cardiac surgery
Positive diagnosis | Functional history, preoperative catheterization/coronary angiography or echocardiography, intra-operative echocardiography findings, surgical procedure, cross-clamp and cardiopulmonary bypass time, administration of cardioplegia (volume, interval), vasopressors, inotropes, antiarrhythmics, blood losses and products. |
Overall assessment | Circulation: iterative assessment of bleeding, mottling, capillary refill, diuresis, ECG, troponin, echocardiography and blood gases (arterial and central venous); iterative assessment of A-V block, volemia, compliance, contractility. |
Ventilation: chest X-ray or lung echography. | |
Kidney/metabolic function. | |
Consider BIS or equivalent if benzodiazepine or propofol infusion is to be used, especially if low cardiac output occurs. | |
Supportive treatment | Address ventilation/chest X ray, volume, inotropic and vasopressor/dilator status. |
Peripheral external rewarming. | |
Suppress shivering (bolus of i.v. meperidine 100 mg or clonidine 37.5 μg i.v.). | |
Sedation | 1) Goal: extubation as soon as possible in a quiet unpainful patient: -1 < RASS < 0 after addressing normothermia, bleeding, circulation, ventilation. |
2) Discontinue anaesthesia. | |
3) Dexmedetomidine 0.75 μg.kg.h-1 adjusted to -1 < RASS < 0 (contra-indications: A-V block II-III unless pacing in place, hypovolemia). | |
Hypotension : check inotropism and volemia, then low dose noradrenaline 0.001.005 μg.kg.min-1, if critical stenosis exists. | |
NB : Alpha-2 agonists have repeatedly been shown to increase sensitivity to noradrenaline and dobutamine in the setting of cardiac surgery. | |
4) Extubation as early as possible, ideally within OR, following end of rewarming and absence of bleeding. | |
5) Discontinue alpha-2 agonist as soon as possible (usually next morning): absence of tachycardia or hypertension, spontaneous ventilation. | |
6) Analgesia : | |
Intraoperatively and before emergence: paracetamol 1g, nefopam 20, ketoprofen 50 mg depending upon high dose opioid anaesthesia vs. opioid free anaesthesia. | |
Consider non-opioid analgesics: ketamine 50 mg.day-1, tramadol 400 mg.day-1, nefopam 100 mg.day-1 for 48 h. | |
To completely avoid opioid analgesics or to achieve early stop of the administration of tramadol-nefopam in elderly patients, consider amitriptyline (Laroxyl® 25 mg*4), gabapentine (Neurotin® 100-900 mg.day-1), pregabaline (Lyrica® 150-600 mg.day-1), carbamazepine (Tegretol 200-400 mg.day-1). | |
7) If not sufficient, use morphine (‚rescue opiates’) sparingly following administration of non-opioid analgesics. | |
NB: If sedation is not sufficient with the alpha-2 agonist, do not EVER administer a bolus of alpha-2 agonist : use ‚rescue’ sedation (midazolam 3–5 mg) 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). | |
Rescue sedation | Upon CCU admission, as dexmedetomidine requires ≈60 min to evoke sedation, if needed, midazolam bolus 3–5 mg or propofol 10-20 mg, repeated as required, to achieve -1 < RASS < 0: the patient should stay quiet to allow for transfer, nursing and assessment. Consider extubation as soon as temperature, circulatory and ventilatory stability is achieved. |
NB: Use of propofol bolus as opposed to midazolam bolus in the presence of alpha-2 agonist exposes to a higher risk of hypotension and bradycardia |
[Cooperative sedation with an alpha-2 agonist will allow discontinuation of opioid analgesia intraoperatively or upon reaching the CCU with appropriate use of rescue sedation. In addition, opioid-free anaesthesia is now used in the cardiac anaesthesia setting.[245] Reduced cognitive and respiratory effects due to minimal anaesthesia or opioid-free anaesthesia will ease intraoperative and postoperative circulatory instability. Cooperative sedation with opioid-free postoperative analgesia (Table 4) will achieve circulatory stability with adequate analgesia, analgognosia and sympathetic deactivation evoked by alpha-2 agonists. The alpha-2 agonist is preferably administered as a premedication.[45,184] Conversely, the alpha-2 agonist can be administered either intraoperatively before or upon admission to the CCU.[184,246]
Alpha-2 agonists are to be used as first-line sedatives, based on individual assessment and dosage, not on a ‘one size fits all’ approach. By easing cognitive, ventilatory and circulatory management, a wise use of cooperative sedation will ease the overall CCU stay.
Alpha-2 agonists act on alpha-2 adrenergic receptors located on or near the central noradrenergic and peripheral sympathetic neurons: a) ‘presynaptic’ The matter is complex. Suppression of central noradrenergic/ adrenergic cell bodies (i.e., of autoreceptors) do not suppress the cognitive[216] or antihypertensive[50] effects of alpha-2 agonists. Therefore, the effects of alpha-2 agonists are consecutive to actions on non-adrenergic neurons. They presumably act on multiple cell types in the brain stem,[219] that is, on auto- and heteroreceptors on noradrenergic and non-adrenergic neurons respectively.
In the CNS, alpha-2 agonists act:
a) on the ventral noradrenergic bundle, which projects from the rostral ventrolateral medulla (glutamatergic and adrenergic C1 neurons within the ‘vasomotor centre’: pre-sympathetic neurons) to the spinal intermediolateral cell column, where sympathetic pre-ganglionic neurons originate from (Figure 1). The alpha-2 agonist evokes sympatho-inhibition in the healthy resting supine volunteer. In the CCU patient, sympathetic deactivation occurs which normalizes the sympathetic activity back toward baseline.
on the dorsal noradrenergic bundle, which projects from major noradrenergic nuclei (locus coeruleus-A6, etc.) to rostral sites (cortex, hippocampus, etc.) (Figure 1). This explains the sedative and antipsychotic effects of alpha-2 agonists to counteract the ‘CCU triade’: pain, altered cognition/delirium, agitation[234] (Figure 2).
on or near cardiac parasympathetic neurons (cholinergic ‘cardiac vagal motoneurons’: CVM located next the vasomotor centre: nucleus ambiguous ventro-lateral[247]), which projects on the sinus node). The alpha-2 agonist generates cardiac parasympathomimetic effects[145] (cardiac parasympathetic activation: bradycardia; Figure 3).
Central noradrenergic and adrenergic systems are included within three hierarchized systems (Figures 1 and 4) coordinating the behavioural and autonomic adjustments to the external environment:
the rostral projections originating from the locus coeruleus to the dorsal noradrenergic bundle and cognitive brain helpexplain the anti-delirium properties,[225,226,251] possibly a direct effect of alpha-2 agonists (Figure 2).
Two different issues are to be considered:
how to assess and address hypovolemia when noradrenaline is used and sympatholytics superimposed?
This is simple, nevertheless
Within 30–90 s after PLR, systemic blood pressure, vena cava, Ventilatory-evoked changes of the diameter of the vena cava: End-expiratory inferior vena cava diameter IVCEE < 8 mm predicts fluid responsiveness with a 95% specificity. Conversely, IVCEE > 28 mm predicts absence of fluid responsiveness with 95% specificity.[171]
what is the physiological and pharmacological rationale behind such management? The matter is complex, involving capacitance vs. resistance vessels, alpha-1 vs. alpha-2 receptors, pre-load dependence, sympathetic block vs. normalization and the considered disease (cardiogenic vs. septic shock).
Pharmacology: In the setting of septic shock, systemic administration of noradrenaline squeezes the venous capacitance and increases venous return.[175] Contractile response of vascular smooth muscle to NA may be initiated on the arterial side by alpha-1 receptors and on the venous side by alpha-2 receptors.[253] Accordingly,
When preload-dependent, the patient moves from the flat part of the Frank-Starling curve to the steep part, implying reduced central venous pressure and lowered cardiac output.
Propofol 1 mg.kg-1.h-1 generates pre-load dependence: 14 patients out of 22 preload-independent patients became pre-load dependent, after propofol infusion.[255]
Dexmedetomidine 0.7 μg.kg-1.h-1 does not generate as much pre-load dependence: only 5 patients out of 20 preload-independent patients became preload dependent.[255] Accordingly, no side effects were observed when dexmedetomidine 0.7 μg.kg-1.h-1 was administered in patients presenting with septic shock (NA requirements ≈ 0.69 μg.kg-1.min-1, i.e., ≈ 3 mg.h-1/70 kg),
When volume loading is not administered before general anaesthesia and intubation,[169] the venous capacitance is not replenished
detrimental side-effects in the setting of hypovolemia (trauma, sepsis): superimposed on hypovolemia, sympathetic deactivation reduces the venous return and evokes pump failure. Lowered return and lowered impedance may increase dynamic outflow obstruction.
beneficial side-effects in the setting of cardiogenic pulmonary oedema: lowered filling pressure, improved diastolic and systolic performance.