Clinical Practice: Should we radically alter our sedation of critical care patients, Especially given the COVID-19 pandemics?

Cardio-pulmonary interactions

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 continuous NIV for an extended period.[29, 30, 31, 32, 33]

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].

Alpha-2 agonists: anti-hypertensive vs. sedative agents? In the 1960s–1970s, the regulatory approval of alpha-2 agonists (clonidine, guanfacine, etc.) and imidazolines (rimelidine, etc.) as anti-hypertensive agents led to the equating of alpha-2 agonists with centrally acting anti-hypertensive agents, attenuating back towards baseline any possible excessive sympathetic activity targeted to the heart and vessels (‘cardiac and vasomotor sympathetic activity’ normalized to baseline activity). In the 1990–2000s, the regulatory approval of dexmedetomidine as a sedative for CCU sedation led to the equating of alpha-2 agonists with anaesthetic adjuncts[42] or sedative[43] agents. Both views are misleading: clonidine was synthetized as a nasal decongestant and then administered to a human ‘volunteer’, unexpectedly resulting in prolonged sleep, bradycardia and hypotension following nasal administration of the equivalent of 20 pills of clonidine.[44] Deducing sedative properties from circulatory properties[45] or vice-versa[46] is irrelevant: the doses of alpha-2 agonists necessary to achieve sedation are identical to the doses that evoke bradycardia or hypotension. In healthy volunteers, heart rate (HR) decreases (-10 to -20%) and normalization of blood pressure after the initial hypotensive phase are surrogate markers of sedation (40 < Bispectral Index (BIS) <60; more than 80% probability of loss of responsiveness).[47,48] The circulatory and cognitive/analgesic effects of alpha-2 agonists are anatomically and functionally[49] unrelated[50] part II, insert I). Indeed, the only common link is pharmacological, i.e., the alpha-2 adrenergic receptor itself. Since this alpha-2 adrenergic receptor is widely distributed[51,52] in the central (brain and spine) and autonomic (central and peripheral) nervous systems (Figure 1), multiple effects occur, including autonomic and cognitive effects. Indeed, a brief inventory (I, D) suggests that alpha-2 agonists present miraculous pharmacodynamics (‘wonder drugs’[53]). More simply, because these agents act via the sympathetic and parasympathetic systems and dorsal noradrenergic bundle (part II, insert I), they have numerous targets, via widely distributed central alpha-2 receptors[51,52] and numerous peripheral sites of action. The multiple effects explain their wide-ranging indications (hypertension, attention-deficit/hyperactivity, Tourette’s syndrome, rapid opioid detoxification, etc.), which are restricted here to CCU implications.[15,17,21,54]

Figure 1

Perspective: normalized sympathetic activity vs. sedation The autonomic nervous system is a coordinating system, acting during ‘fight or flight’ responses,[55] ‘freezing behaviour’, diving reflex, exercise, sleep and so on. The sympathetic system coordinates circulation and ventilation via alpha- and beta-receptors.[56] However, in the CCU, a patient cannot initiate either a fight or flight response because: a) sympathetic hyperactivity lasts for days or weeks, at variance with exercise (except ultralong trails in fit athletes[57]); and b) cardiac parasympathetic (‘cardiac vagal’) activity is suppressed, in contrast to observations in ultralong trails.[57] Then, after stabilization of the acute cardio-ventilatory distress observed upon admission to the CCU, the sympathetic nervous system is not adaptive any more but mal-adaptive[58,59]⁴: at variance with rest and recovery of the healthy volunteer, and beyond the period preceding and following admission, adaptation in the CCU is of minimal value. Worse, coordination is lost. In the CCU, after days or weeks, the end result is an overflow of noradrenaline and an exhausted individual. This outcome has also been observed in very different settings (‘voodoo death’,[65] sudden death observed in the setting of burn-out: karoshi).

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.

Pharmacology:

The effects of alpha-2 agonists are multiple:

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. Our view contrasts with the indications proposed by the US and European regulatory agencies. We contend that only personalized prescriptions can be administered after: a) a full work-up (history, physical examination, electrocardiogram, echocardiography, CT scan, etc., if appropriate); and b) consideration of the benefits and risks for each patient. Cautious niche prescriptions do not preclude prescriptions to most CCU patients, but we oppose generalized routine prescriptions (‘one size fits all’).

Outcomes

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]

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.

Recommended doses, titration to effect and changing requirements

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 mg. kg-1.h-1), which increase blood pressure, as discussed in the legend of Figure 3.

[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.

Sedation

Light sedation: Most groups use dexmedetomidine 0.7 μg.kg-1.h-1 to achieve calmness or light sedation (-2 < RASS < 0),[74] for example, adaptation to NIV,[29] or in a thoroughly stabilized patient. The use of dexmedetomidine is relevant immediately after stabilizing the acute cardio-ventilatory distress observed upon admission.

[In contrast, heavy sedation can be achieved by high-dose alpha-2 agonists (clonidine 2 μg.kg-1.h-1 or dexmedetomidine 1.5 μg.kg-1.h-1) as a single agent. High dose alpha-2 agonists will be combined with neuroleptics in the setting of refractory DT (-3 < RASS < -2 for 3–6 h; part II, I, E).[15,17] : alpha-2 agonists, by themselves, are also or combined to neuroleptics, are also applicable in the setting of acute cardio-ventilatory distress upon admission to the CCU[21,81,89,90,135, 136, 137] when neuromuscular blockers for a short period suppress the work of breathing, and in the presence of ventilator-to-patient dys-synchrony [3, 4, 5, 6, 7, 8, 9, 10, 11, 12 h: note 14].

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]

Circulation

[Hyperdynamic state (hypertension, tachycardia) without hypovolemia or shock: Dexmedetomidine 1.5 μg.kg-1.h-1 or clonidine 2 μg.kg-1.h-1 is used for as long as necessary. In rare instances of refractory hypertension and tachycardia in young patients in the CCU, high-dose alpha-2 agonists should be used first. Then beta-blockers should achieve 50 < HR < 60. Then angiotensin antagonists should be preferred to calcium antagonists or peripherally acting agents to lower BP, to avoid reflex tachycardia.

Shock state

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 (‘start slow and go slow’: part I, III, F). Presumably, much lower doses normalize tachycardia (part I, III, C).

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.]

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 combination

Polypharmacopeia (alpha-2 agonists, neuroleptics, benzodiazepines, melatonin/hydroxyzine, etc.) can cause deleterious interactions. Thus, polypharmacopeia is used for the shortest time possible.

Adaptation of dose of alpha-2 agonists over time

Changing requirements 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 different factors:

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 ‘activated when blood flow to contracting muscles is insufficient to allow both O2 delivery and metabolite washout’; optimized micro-circulation with an alpha-2 agonist could possibly lead to improved tissue acidosis and hypoxemia, presumably reducing tachycardia); and

inflammation, which generates tachycardia that is unblocked by a beta-blocker.[149]

Facilitation of nursing

Handling patients -4 < RASS < -3 vs. patients -2 < RASS < 0 requires a Copernican revolution in the CCU (part I, II). Accordingly, the use of rescue sedation[74] allows to keep a patient under light sedation throughout most of his stay (-2 < RASS < 0) and to implement deeper sedation for a few minutes to facilitate nursing procedures.

Rescue sedation upon or before initiation of alpha-2 agonist administration

When switching from conventional sedation to cooperative sedation, the possibility is either:

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 no rationale for running conventional sedation in addition to alpha-2 agonist administration, or the reverse, but a recipe for circulatory catastrophes. In addition, running conventional sedation in addition to cooperative sedation suppresses any possible benefit of cooperative sedation.[153] The use of a propofol bolus (mini-dose: 20 mg)[16] or propofol infusion, in addition to alpha-2 agonist administration during the night presumably reflect the practice of an experienced intensivist working with experienced critical care nurses.[16] In our hands, this practice increases the risk of unexpected severe arterial hypotension and bradycardia at night. Then, the alpha-2 agonist is blamed, leading to a switch back to conventional sedation, CMV, NMBs, and high-dose vasopressors.]

Night sedation

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.]

Monitoring

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.

Bronchospasm and circulatory instability [1) Bronchospasm[31, 32, 33,87]:

When, severe, prolonged bronchospasm or status asthmaticus are considered, despite optimal management, a low-dose alpha-2 agonist (inhaled[85] or intravenous clonidine 4–9 μg.kg-1 over 2–4 h[31] or dexmedetomidine 0.2–0.7 mg.kg-1.h-1[32,33] suppresses expiratory obstruction (wheezing, forced expiration, ventilatory discomfort) and agitation within ≈ 60–120 min. However, when presented with aversive psychological stimuli, relatives and so on, some patients require a high-dose alpha-2 agonist (clonidine 2 μg.kg.h-1, dexmedetomidine 1.5 μg.kg.h-1) titrated to effect (quietness and the absence of wheezing even when an aversive stimulus is presented), as in refractory DT. Failure to achieve quietness and suppressed wheezing warrants intubation, sedation and conventional mechanical ventilation before ventilatory fatigue.

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 lower the dose of vasopressor required in the setting of sepsis[25,160,161] or septic shock,[38, 39, 40] in a dose dependant manner,[162] within ≈ 3 h of administration (Pichot, unpublished data).[38,39]

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.

De novo administration in a circulatory-stable patient

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, without hypovolemia, an alpha-2 agonist is administered at a fixed dose (e.g., dexmedetomidine 1.5 μg.kg-1.h-1 or clonidine 2 μg.kg-1.h-1) to achieve quick sedation. Rescue sedation is administered to RASS ≤ 0, if needed (part I, III, D).]

De novo administration of alpha-2 agonist in the setting of hypovolemia

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,

De novo administration of an alpha-2 agonist in the presence of vasopressor

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 before each incremental increase in an alpha-2 agonist (part I, III, F); andb) arterial dilation.

Switch from conventional to cooperative sedation

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 at once (part I, III, D), and an alpha-2 agonist infusion is initiated. A high dose (dexmedetomidine: 1.5 μg.kg-1.h-1; clonidine: 2 μg.kg-1.h-1; part I, III) will be selected as a function of the desired effect, for example, quick implementation of sedation in refractory

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) after documentation of hypnosis (40 < BIS < 60) and analgesia (BPS), under high-dose alpha-2 agonist supplemented first with neuroleptics).]

Switch to spontaneous breathing

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. Alpha-2 agonist administration following light TIVA: Most intensivists use alpha-2 agonists as second-line sedatives, that is, during recovery after switching from conventional sedation. Deep sedation (i.e., general anaesthesia) is required to manage severe acute respiratory distress syndrome (ARDS), traumatic brain injury, septic shock[177] and status epilepticus: this unproven[178] belief has been challenged.[179,180] [When severe diffuse ARDS is managed under general anaesthesia, paralysis,[181] and prone positioning,[182] the patient is positioned with the head up[183] (“upright” position) and then switched to an alpha-2 agonist. Conventional sedation is withdrawn immediately up to steady cooperative sedation used alone (part I, III, D). Then, spontaneous breathing is resumed.]

[Alpha-2 agonist administration immediately following endotracheal intubation: In the setting of early severe diffuse ARDS, we do not use midazolam+sufentanil or propofol+remifentanil.[21,89,90] To reduce the duration of mechanical ventilation and intubation,[37,184] we administer an alpha-2 agonist immediately after intubation to achieve an -2 < RASS < 0. A neuroleptic is added to a RASS < -2, if needed. Ultra-short-term paralysis (3–12 h, 40 < BIS < 60) is used only to allow for normalizing all of the factors evoking a high respiratory drive in an itemized manner.[21]

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]

Tapering of alpha-2 agonists

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.]

Discharge to the ward

[If progressive tapering of an alpha-2 agonist is not guaranteed in the ward, then the patient should stay in the intermediate care unit. Premature discharge to the ward can lead to later readmission to the CCU. Accordingly, when DT is improving, the patient should remain in the intermediate care unit to assess positively the total disappearance of tremors and hallucinations for ≥ 24 h.]

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):

Circulation

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:

Interactions between antiarrhythmics and alpha-2 agonists: All antiarrhythmics can be used with alpha-2 agonists. However, as a rule of thumb, lowered dosages and a reduced speed of administration should be considered with continuous P-R monitoring. For example, amiodarone (Cordarone®) administration is decreased over 2–3 days: a high dose (900 mg/ day) without co-administration of alpha-2 agonists is reduced to a low dose (300 mg day-1) with co-administration of an alpha-2 agonist or preferably to complete cessation, as a function of HR or arrhythmias. Amiodarone boluses will be reduced, especially if hypovolemia or BP instability is present (from 300 mg over 20 min without co-administration of an alpha-2 agonist to 150 mg over 40 min when an alpha-2 agonist has been administered before amiodarone). Verapamil (Isoptine®) can be administered using a 1.25 mg bolus repeated every 2–5 min as required. When severe hypovolemia and bradycardia occur, the Trendelenburg position and immediate administration of CaCl₂ 1 g and ephedrine 15 mg are applied, followed by brisk volume expansion.]

Ventilation

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 before admission to the CCU, oversedation, respiratory depression,

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.

Temperature

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.

Ogilvie syndrome

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?

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 nursing staff considers dexmedetomidine easier to use (Simonet, de Kock, personal communication). Nevertheless, rescue sedation[74] (part I, III, D) is necessary to compensate for the non-instantaneous sedative effect evoked by both alpha-2 agonists. The drawback of the slower effect of clonidine is relative. Since a patient will stay in the CCU for an extended period, a difference of ≈ 2–3 h to achieve a peak sedative effect will not affect the length of stay or costs (steady cooperative sedation with dexmedetomidine: 2–4 h; with clonidine: 3–6 h; Pichot, unpublished data). Furthermore, unstable patients require a ‘start low and go slow’ approach, regardless of whether dexmedetomidine or clonidine is used (part I, III, F).]

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).

CCU delirium

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 short-term medications for co-induction of general anaesthesia, rescue sedation,[74] anxiety, seizures and amnesia. Among ventilated patients (assist control, proportional assist ventilation, pressure control), a reduced incidence of delirium is observed when low-dose dexmedetomidine is administered to prevent delirium as a night-time sedative (RASS=-1, 9 pm–6 am).[235] When opioid doses were unchanged and sedative doses were halved,[235] 80% of patients in the dexmedetomidine group did not present with delirium vs. 54% in the control group. Dexmedetomidine patients are less tired, presumably due to reduced sleep fragmentation.[71]

[Extubation and agitation after extubation: As protective airway reflexes are unaffected following administration of high-dose alpha-2 agonists in the ambulatory cardiology setting,[147] reducing the dose of the alpha-2 agonist before extubation is not necessary. The point is not the dose of the alpha-2 agonist, but the alertness of the patient (-2 < RASS < 0) without inappropriate agitation after extubation. Lastly, when an alpha-2 agonist has not been administered prior to extubation, and if the patient becomes agitated after extubation, then an alpha-2 agonist is administered and titrated to achieve calmness after extubation. This eases the management when continuous non-invasive ventilation (NIV) is undertaken for several days before intubation or after early extubation.]

Prevention of alcohol withdrawal

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.]

‘De novo’ alcohol withdrawal

Established delirium tremens

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.

Refractory delirium tremens

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):

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.

Multiple trauma

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.]

Cardiac surgery

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).

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).

‘autonomic’ loop: the ascending pain pathways branch in the lower brain stem on the vasomotor centre,[248] which in turn projects to the spinal intermediolateral cell column; this explains the lowered cardiac parasympathetic activity (cardiac parasympathetic withdrawal) and increased sympathetic activity occurring during a nociceptive stimulus (somato-sympathetic reflex[249,250]) (Figure 1).

‘pain’ loop[231]: the ascending pain pathways branch in the upper brain stem on the descending noradrenergic and serotoninergic pathways. These descending noradrenergic and serotoninergic pathways in turn suppress ascending pain messages within the spinal lamina I-II (‘gate control’ theory; Figure 4). Therefore, alpha-2 agonists coordinate pain suppression and autonomic effects (e.g., sympathetic de-activation or parasympathetic activation) simultaneously via different loops.

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).

how to assess and address hypovolemia when noradrenaline is used and sympatholytics superimposed?

This is simple, nevertheless meticulous.

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).

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), with additional volume to maintain stroke volume in 7 out of 38 patients.[40]

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.