Acceso abierto

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

D Longrois
D Longrois
, 
F Petitjeans
F Petitjeans
, 
O Simonet
O Simonet
, 
M de Kock
M de Kock
, 
M Belliveau
M Belliveau
, 
C Pichot
C Pichot
, 
Th Lieutaud
Th Lieutaud
, 
M Ghignone
M Ghignone
 y 
L Quintin
L Quintin
   | 04 ene 2021
Romanian Journal of Anaesthesia and Intensive Care's Cover Image
Acerca de este artículo
Artículo anterior
Artículo siguiente
Cite
Article Category: Original Paper
Publicado en línea: 04 ene 2021
Páginas: 43 - 76
DOI: https://doi.org/10.2478/rjaic-2020-0018
Palabras clave
© 2020 Stelian L Quintin et al. published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

Impact of alpha-2 agonists on the noradrenergic dorsal bundle, adrenergic ventral bundle and cardiac parasympathetic motoneurons. Modified from Pichot, J Intens Care Med, 2012, 27 : 219–37.[15]a) Following depletion of the central and peripheral noradrenergic/adrenergic systems by reserpine, a bolus of a low-dose alpha-2 agonist generates hypertension (Kobinger 1967 quoted from (147)): hypertension is a consequence of an action on peripheral vascular alpha-1 receptors and extravascular alpha-2 receptors themselves (Figure 3), independent of the release of noradrenaline, that is, independent of the sympathetic nervous system. The observation of a peripheral effect of the alpha-2 agonist after depletion of sympathetic nerves (Kobinger, 1967) is replicated centrally: the anaesthetic-sparing effect of an alpha-2 agonist is observed after full destruction of catecholaminergic cell bodies (Figure 5 in (216)). Consequently, alpha-2 agonists cannot evoke sedation via pre-synaptic autoreceptors located on catecholaminergic cell bodies. The claim that alpha-2 agonists act through pre-synaptic alpha-2 autoreceptors located on noradrenergic locus coeruleus cell bodies[46,217] is misleading. A nuanced discussion appears in (50, 218).b) The alpha-2 agonists inhibit the adrenergic and glutamatergic neurons[219] located in the rostral ventrolateral medulla (pre-sympathetic neurons in the RVLM ‘vasomotor centre’), decreasing the set point of the vascular sympathetic baroreflex without diminishing the neurons’ reactivity to decreased systemic pressure (220). The pre-sympathetic adrenergic and glutamatergic neurons project from the lower brain stem to the spinal intermediolateral cell column, from which sympathetic pre-ganglionic neurons originate. Alpha-2 agonists inhibit RVLM neurons, reduce cardiac sympathetic activity (reduced noradrenaline release leading to slow ‘passive’ bradycardia in the presence of a slow intrasynaptic NA reuptake) and reduce vascular sympathetic activity (slow ‘passive’ vasodilation).c) Alpha-2 agonists stimulate alpha-2 receptors located on or near cardiac parasympathetic neurons (‘cardiac vagal motoneurons’) in the nucleus ambiguous external formation (dorsal and medial to the vasomotor centre). In a healthy, supine, resting volunteer, a microdose of vasopressor administered as a bolus (e.g., phenylephrine 10 to 30 mg) evokes minimal increase in systemic pressure next to the resting, baseline, pressure, stimulates the cardiac parasympathetic neurons and evokes fast ‘active’ bradycardia,[221] owing to active acetylcholine release and rapid intrasynaptic breakdown. This process increases the slope of the pressure-RR interval relationship[222] (slope of the cardiac baroreflex ‘reactivity’).This rapid bradycardia evokes stabilization of the blood pressure within one beat. [223] in the supine resting healthy volunteer.The circulatory properties of the alpha-2 agonists are explained by:a) increased active cardiac parasympathetic reactivity, andb) normalized cardiac and vascular sympathetic activity. In the CCU patient, this process occurs in the setting of high baseline sympathetic activity and suppressed baseline parasympathetic activity. In addition, full normalization of increased sympathetic activity is not necessarily achieved, according to the dose of the alpha-2 agonist and the amplitude of the sympathetic activation. In contrast, in the healthy, supine volunteer, the baseline low normal sympathetic activity is deactivated to residual activity, while the cardiac parasympathetic activity is activated.
Impact of alpha-2 agonists on the noradrenergic dorsal bundle, adrenergic ventral bundle and cardiac parasympathetic motoneurons. Modified from Pichot, J Intens Care Med, 2012, 27 : 219–37.[15]a) Following depletion of the central and peripheral noradrenergic/adrenergic systems by reserpine, a bolus of a low-dose alpha-2 agonist generates hypertension (Kobinger 1967 quoted from (147)): hypertension is a consequence of an action on peripheral vascular alpha-1 receptors and extravascular alpha-2 receptors themselves (Figure 3), independent of the release of noradrenaline, that is, independent of the sympathetic nervous system. The observation of a peripheral effect of the alpha-2 agonist after depletion of sympathetic nerves (Kobinger, 1967) is replicated centrally: the anaesthetic-sparing effect of an alpha-2 agonist is observed after full destruction of catecholaminergic cell bodies (Figure 5 in (216)). Consequently, alpha-2 agonists cannot evoke sedation via pre-synaptic autoreceptors located on catecholaminergic cell bodies. The claim that alpha-2 agonists act through pre-synaptic alpha-2 autoreceptors located on noradrenergic locus coeruleus cell bodies[46,217] is misleading. A nuanced discussion appears in (50, 218).b) The alpha-2 agonists inhibit the adrenergic and glutamatergic neurons[219] located in the rostral ventrolateral medulla (pre-sympathetic neurons in the RVLM ‘vasomotor centre’), decreasing the set point of the vascular sympathetic baroreflex without diminishing the neurons’ reactivity to decreased systemic pressure (220). The pre-sympathetic adrenergic and glutamatergic neurons project from the lower brain stem to the spinal intermediolateral cell column, from which sympathetic pre-ganglionic neurons originate. Alpha-2 agonists inhibit RVLM neurons, reduce cardiac sympathetic activity (reduced noradrenaline release leading to slow ‘passive’ bradycardia in the presence of a slow intrasynaptic NA reuptake) and reduce vascular sympathetic activity (slow ‘passive’ vasodilation).c) Alpha-2 agonists stimulate alpha-2 receptors located on or near cardiac parasympathetic neurons (‘cardiac vagal motoneurons’) in the nucleus ambiguous external formation (dorsal and medial to the vasomotor centre). In a healthy, supine, resting volunteer, a microdose of vasopressor administered as a bolus (e.g., phenylephrine 10 to 30 mg) evokes minimal increase in systemic pressure next to the resting, baseline, pressure, stimulates the cardiac parasympathetic neurons and evokes fast ‘active’ bradycardia,[221] owing to active acetylcholine release and rapid intrasynaptic breakdown. This process increases the slope of the pressure-RR interval relationship[222] (slope of the cardiac baroreflex ‘reactivity’).This rapid bradycardia evokes stabilization of the blood pressure within one beat. [223] in the supine resting healthy volunteer.The circulatory properties of the alpha-2 agonists are explained by:a) increased active cardiac parasympathetic reactivity, andb) normalized cardiac and vascular sympathetic activity. In the CCU patient, this process occurs in the setting of high baseline sympathetic activity and suppressed baseline parasympathetic activity. In addition, full normalization of increased sympathetic activity is not necessarily achieved, according to the dose of the alpha-2 agonist and the amplitude of the sympathetic activation. In contrast, in the healthy, supine volunteer, the baseline low normal sympathetic activity is deactivated to residual activity, while the cardiac parasympathetic activity is activated.

Figure 2

Putative mechanism for cooperative sedation and minimization of CCU delirium following alpha-2 agonists. Top and upper middle: In paralyzed rats emerging from halothane anaesthesia, during recording of locus coeruleus neurons following administration of clonidine, the slow baseline (‘tonic’) electrical activity observable between volleys of action potentials (‘phasic’ activity, middle inset a) is suppressed while leaving intact the phasic activity (middle inset b). Reversal of the effect of clonidine is achieved by the alpha-2 antagonist idazoxan (middle inset c).Lower middle left: a) A glutamate antagonist, kynurenic acid (KYN), micro-injected next to the locus coeruleus neuron, suppresses the remaining phasic electrical activity observed in middle inset b. Therefore, at least two components, alpha-2 mediated vs. glutamate mediated, are involved in the cooperative sedation evoked by the alpha-2 agonist. Modified from Saunier, Anesthesiology, 1993, 79, 1072–82.[224]Lower middle right: Putative functioning of the dorsal noradrenergic system following administration of an alpha-2 agonist. In a monkey presenting with hyperactivity, lack of attention, and poor discrimination between signal and detection tasks, a micro-injection of clonidine within the locus coeruleus reduces errors. This effect occurs possibly by lowering the tonic activity and increasing the phasic activity. Thus, alpha-2 agonists reinforce the filtering of the locus coeruleus toward a 0-1 functioning, that is, activation vs. inhibition. The neuron shifts towards a 0-1 functioning. An increase in gain (dotted lines) increases the activity of an LC neuron, which receives an excitatory stimulus (increased cognitive activity). The same increase in gain lowers the activity of the same neuron when it receives an inhibitory stimulus (indifference to environment: ataraxia). This schema accounts for the cooperative sedation observed in the CCU when a patient is left undisturbed and fully rousable upon stimulation. Modified from Servan-Schreiber, Science, 1990, 249: 892–5.[225] Aston-Jones, J Comp Neurol, 2005, 493: 99–110[226] and Pichot, Ann Fr Anesth Rean, 2012, 31: 876–96.[17]Bottom left: Following administration of dexmedetomidine, the cognitive function (adapted cognitive examination: ACE) increases more in patients with a worse initial condition, that is, lower baseline ACE, compared to propofol sedation (not shown). Bottom right: Changes in cognitive examination during propofol (ordinate) vs. dexmedetomidine (abscissae) from relative baseline in each of the 30 patients completing the study (black dot: brain injury; open dot: no brain injury). Note the few cognitive deteriorations following dexmedetomidine and few cognitive improvements following propofol sedation. Dexmedetomidine improves cognition more than propofol (p < 0.001). Modified from Mirski, Intens Care Med, 2010, 36, 1505–13.[75] Working memory is improved when an alpha-2 agonist, guanfacine is administered following mild traumatic brain injury.[227]
Putative mechanism for cooperative sedation and minimization of CCU delirium following alpha-2 agonists. Top and upper middle: In paralyzed rats emerging from halothane anaesthesia, during recording of locus coeruleus neurons following administration of clonidine, the slow baseline (‘tonic’) electrical activity observable between volleys of action potentials (‘phasic’ activity, middle inset a) is suppressed while leaving intact the phasic activity (middle inset b). Reversal of the effect of clonidine is achieved by the alpha-2 antagonist idazoxan (middle inset c).Lower middle left: a) A glutamate antagonist, kynurenic acid (KYN), micro-injected next to the locus coeruleus neuron, suppresses the remaining phasic electrical activity observed in middle inset b. Therefore, at least two components, alpha-2 mediated vs. glutamate mediated, are involved in the cooperative sedation evoked by the alpha-2 agonist. Modified from Saunier, Anesthesiology, 1993, 79, 1072–82.[224]Lower middle right: Putative functioning of the dorsal noradrenergic system following administration of an alpha-2 agonist. In a monkey presenting with hyperactivity, lack of attention, and poor discrimination between signal and detection tasks, a micro-injection of clonidine within the locus coeruleus reduces errors. This effect occurs possibly by lowering the tonic activity and increasing the phasic activity. Thus, alpha-2 agonists reinforce the filtering of the locus coeruleus toward a 0-1 functioning, that is, activation vs. inhibition. The neuron shifts towards a 0-1 functioning. An increase in gain (dotted lines) increases the activity of an LC neuron, which receives an excitatory stimulus (increased cognitive activity). The same increase in gain lowers the activity of the same neuron when it receives an inhibitory stimulus (indifference to environment: ataraxia). This schema accounts for the cooperative sedation observed in the CCU when a patient is left undisturbed and fully rousable upon stimulation. Modified from Servan-Schreiber, Science, 1990, 249: 892–5.[225] Aston-Jones, J Comp Neurol, 2005, 493: 99–110[226] and Pichot, Ann Fr Anesth Rean, 2012, 31: 876–96.[17]Bottom left: Following administration of dexmedetomidine, the cognitive function (adapted cognitive examination: ACE) increases more in patients with a worse initial condition, that is, lower baseline ACE, compared to propofol sedation (not shown). Bottom right: Changes in cognitive examination during propofol (ordinate) vs. dexmedetomidine (abscissae) from relative baseline in each of the 30 patients completing the study (black dot: brain injury; open dot: no brain injury). Note the few cognitive deteriorations following dexmedetomidine and few cognitive improvements following propofol sedation. Dexmedetomidine improves cognition more than propofol (p < 0.001). Modified from Mirski, Intens Care Med, 2010, 36, 1505–13.[75] Working memory is improved when an alpha-2 agonist, guanfacine is administered following mild traumatic brain injury.[227]

Figure 3

Effect of increasing clonidine plasma concentrations on systemic blood pressure. The lowest blood pressure is observed when the plasma clonidine concentration is 0.65±0.07 ng.mL-1. The effective pressor concentration is observed when the concentration is: 1.28±0.16 ng. mL-1. Modified from Frisk-Holmberg.[211] Therapeutic plasma concentrations for dexmedetomidine are 0.4-1.2 ng.mL-1.[228]Usual doses of clonidine 300 μg p.o. as administered in the cardiology setting achieve within 1–3 h (48) a large decrease in systemic pressure (clonidine concentration = 0.9–1.4 ng.mL-1). In contrast, very high-dose alpha-2 agonists (clonidine p.o. ≈ 5400–6000 μg/day: plasma concentration = 14–26 ng.mL-1; dexmedetomidine i.v. = 4 μg.kg-1.h-1 for 12 h) evoke hypertension.[210,212] Accordingly, in healthy volunteers, high-dose dexmedetomidine (plasma concentration ≈ 5 ng.mL-1) evokes high BP, lowered ejection fraction and cardiac output.[228]The use of alpha-2 agonists as a bolus or as a loading dose is unwise, especially in unstable CCU patients. Three different effects are to be considered.a) A bolus of an alpha-1 agonist (vasopressor : noradrenaline, phenylephrine, etc.) leads to a brisk, short lasting pressure increase[222] via alpha-1 peripheral vascular receptors; the pressure increase stimulates the cardiac parasympathetic system within < 1-2 s[229,230] and generates swift, active bradycardia. This bradycardia is usually not observed in the critical care setting since the cardiac parasympathetic system is wiped out, owing to illness and/or age.b) A bolus dose of alpha-2 agonist (dexmedetomidine, clonidine) generates, first, an increase in pressure via activation of peripheral vascular alpha-1 receptors and, second, bradycardia evoked via activation of the cardiac parasympathetic baroreflex (fast active bradycardia), as with any vasopressor. The bradycardia evoked by a pressure increase evoked by a bolus of alpha-2 agonists is exaggerated when parasympathomimetic drugs,[196] opioids[197] or other anti-arrhythmics are present: diltiazem, verapamil, beta blockers and so on.c) After waning of the pressure increase evoked by a bolus of alpha-2 agonist, a centrally-mediated hypotension occurs once a steady state alpha-2 agonist concentration is achieved (low-dose clonidine concentration). A steady state alpha-2 agonist concentration acts via alpha-2 receptors located in the brain stem and spinal cord, generating a slowly occurring, passive, vascular vasodilation and a slowly occurring, passive, bradycardia.
Effect of increasing clonidine plasma concentrations on systemic blood pressure. The lowest blood pressure is observed when the plasma clonidine concentration is 0.65±0.07 ng.mL-1. The effective pressor concentration is observed when the concentration is: 1.28±0.16 ng. mL-1. Modified from Frisk-Holmberg.[211] Therapeutic plasma concentrations for dexmedetomidine are 0.4-1.2 ng.mL-1.[228]Usual doses of clonidine 300 μg p.o. as administered in the cardiology setting achieve within 1–3 h (48) a large decrease in systemic pressure (clonidine concentration = 0.9–1.4 ng.mL-1). In contrast, very high-dose alpha-2 agonists (clonidine p.o. ≈ 5400–6000 μg/day: plasma concentration = 14–26 ng.mL-1; dexmedetomidine i.v. = 4 μg.kg-1.h-1 for 12 h) evoke hypertension.[210,212] Accordingly, in healthy volunteers, high-dose dexmedetomidine (plasma concentration ≈ 5 ng.mL-1) evokes high BP, lowered ejection fraction and cardiac output.[228]The use of alpha-2 agonists as a bolus or as a loading dose is unwise, especially in unstable CCU patients. Three different effects are to be considered.a) A bolus of an alpha-1 agonist (vasopressor : noradrenaline, phenylephrine, etc.) leads to a brisk, short lasting pressure increase[222] via alpha-1 peripheral vascular receptors; the pressure increase stimulates the cardiac parasympathetic system within < 1-2 s[229,230] and generates swift, active bradycardia. This bradycardia is usually not observed in the critical care setting since the cardiac parasympathetic system is wiped out, owing to illness and/or age.b) A bolus dose of alpha-2 agonist (dexmedetomidine, clonidine) generates, first, an increase in pressure via activation of peripheral vascular alpha-1 receptors and, second, bradycardia evoked via activation of the cardiac parasympathetic baroreflex (fast active bradycardia), as with any vasopressor. The bradycardia evoked by a pressure increase evoked by a bolus of alpha-2 agonists is exaggerated when parasympathomimetic drugs,[196] opioids[197] or other anti-arrhythmics are present: diltiazem, verapamil, beta blockers and so on.c) After waning of the pressure increase evoked by a bolus of alpha-2 agonist, a centrally-mediated hypotension occurs once a steady state alpha-2 agonist concentration is achieved (low-dose clonidine concentration). A steady state alpha-2 agonist concentration acts via alpha-2 receptors located in the brain stem and spinal cord, generating a slowly occurring, passive, vascular vasodilation and a slowly occurring, passive, bradycardia.

Figure 4

Hierarchical organization of neural homeostasis involving the sympathetic nervous system at lower brain stem and spinal levels only: Small-diameter afferent fibres that report the physiological conditions of all of the tissues of the body terminate in lamina I of the spinal dorsal horns. The ascending projections of lamina I neurons provide the bases for somato-autonomic reflex arcs at the spinal and medullary levels (e.g., ‘somato-sympathetic reflex’ evoking hypertension and tachycardia following a nociceptive stimulus). By contrast, at the spinal levels, lamina I projects strongly to the sympathetic regions in the intermediolateral cell columns of the thoracolumbar cord, where the sympathetic preganglionic neurons originate (ANS: autonomic nervous system; direct spinal somato-sympathetic reflex). In the medulla, lamina I neurons project to the A1 and A2 catecholaminergic cell groups (RVLM: rostral ventrolateral medulla, i.e., vasomotor centre; VMM: ventromedial medulla). Modified from Craig, Nature Neuroscience, 2002, 3, 655–66.[231]
Hierarchical organization of neural homeostasis involving the sympathetic nervous system at lower brain stem and spinal levels only: Small-diameter afferent fibres that report the physiological conditions of all of the tissues of the body terminate in lamina I of the spinal dorsal horns. The ascending projections of lamina I neurons provide the bases for somato-autonomic reflex arcs at the spinal and medullary levels (e.g., ‘somato-sympathetic reflex’ evoking hypertension and tachycardia following a nociceptive stimulus). By contrast, at the spinal levels, lamina I projects strongly to the sympathetic regions in the intermediolateral cell columns of the thoracolumbar cord, where the sympathetic preganglionic neurons originate (ANS: autonomic nervous system; direct spinal somato-sympathetic reflex). In the medulla, lamina I neurons project to the A1 and A2 catecholaminergic cell groups (RVLM: rostral ventrolateral medulla, i.e., vasomotor centre; VMM: ventromedial medulla). Modified from Craig, Nature Neuroscience, 2002, 3, 655–66.[231]

Figure 5

Passive leg raising (PLR) while pivoting the entire bed causes no hip flexion (no sympathetic activation) and evokes a larger transfer of blood from the unstressed venous blood volume to the heart. Changes in cardiac output evoked by PLR predict the response of cardiac output to volume expansion in the setting of circulatory failure. The specificity of PLR is acceptable when changes in pulse pressure are assessed; however, the sensitivity is poor.[233] Modified from Monnet, Intens Care Med, 2008, 34: 659–63.[170]
Passive leg raising (PLR) while pivoting the entire bed causes no hip flexion (no sympathetic activation) and evokes a larger transfer of blood from the unstressed venous blood volume to the heart. Changes in cardiac output evoked by PLR predict the response of cardiac output to volume expansion in the setting of circulatory failure. The specificity of PLR is acceptable when changes in pulse pressure are assessed; however, the sensitivity is poor.[233] Modified from Monnet, Intens Care Med, 2008, 34: 659–63.[170]

Figure 6

Frequency-response curve deduced for resistance (dashed) and capacitance (continuous) in cat skin-muscle. Effects of lumbar vasoconstrictor fibre stimulation calculated in a percentage of the maximum response for the 2 vascular sections. The curve for the capacitance vessels (veins) is to the left: this curve implies more pronounced effects in this section in the low frequency range, compared with those in the resistance vessels (arteries). One third of the regional blood volume is expelled at a low frequency stimulation rate, thus increasing venous return. A fully developed response occurs within 30–40 s for both resistance and capacitance vessels.Immediate relaxation occurs after cessation of sympathetic stimulation. In contrast, there is delayed relaxation at high rates of sympathetic stimulation; this delayed relaxation could be of relevance after prolonged administration of high-dose noradrenaline, for example, in septic shock: prolonged vasomotor sympathetic hyperactivity is associated temporally with poor microcirculation. In turn, prolonged impaired microcirculation is associated with increased mortality.[139] Would normalization of vasomotor sympathetic activity back toward baseline levels be observed before shock, and would improve microcirculation improve outcomes? Modified from Mellander, Acta Physiol Scand, Suppl, 1960, 50: 1–86[61] and Prys-Roberts, Regulation of Circulation, In The circulation in anaesthesia: applied physiology and pharmacology, Blackwell, Oxford, 1980, pp 179–207.[232]
Frequency-response curve deduced for resistance (dashed) and capacitance (continuous) in cat skin-muscle. Effects of lumbar vasoconstrictor fibre stimulation calculated in a percentage of the maximum response for the 2 vascular sections. The curve for the capacitance vessels (veins) is to the left: this curve implies more pronounced effects in this section in the low frequency range, compared with those in the resistance vessels (arteries). One third of the regional blood volume is expelled at a low frequency stimulation rate, thus increasing venous return. A fully developed response occurs within 30–40 s for both resistance and capacitance vessels.Immediate relaxation occurs after cessation of sympathetic stimulation. In contrast, there is delayed relaxation at high rates of sympathetic stimulation; this delayed relaxation could be of relevance after prolonged administration of high-dose noradrenaline, for example, in septic shock: prolonged vasomotor sympathetic hyperactivity is associated temporally with poor microcirculation. In turn, prolonged impaired microcirculation is associated with increased mortality.[139] Would normalization of vasomotor sympathetic activity back toward baseline levels be observed before shock, and would improve microcirculation improve outcomes? Modified from Mellander, Acta Physiol Scand, Suppl, 1960, 50: 1–86[61] and Prys-Roberts, Regulation of Circulation, In The circulation in anaesthesia: applied physiology and pharmacology, Blackwell, Oxford, 1980, pp 179–207.[232]

Refractory delirium tremens

Positive diagnosisHistory of chronic alcohol intoxication and alcohol withdrawal, hallucinations, agitation, fine tremor.
Differential diagnosisConfusion 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 assessmentCirculation: 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 treatmentVentilation: 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.
SedationGoal: 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 sedationPreservation 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 sedationNB: 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 sedationFollowing 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.
Extubationa) 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 CCURefrain 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.

Multiple trauma

Overall assessmentIterative 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 treatmentVentilation: 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.
Sedation1) 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 sedationTo 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 diagnosisFunctional 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 assessmentCirculation: 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 treatmentAddress 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.).
Sedation1) 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 sedationUpon 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

Delirium Tremens (DT)

Positive diagnosisHistory of chronic alcohol intoxication and alcohol withdrawal, inability to sustain attention, disorganized thinking, hallucinations, agitation, fine tremor.
Differential diagnosisConfusion 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 assessmentCirculation: 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 treatmentVentilation: 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
SedationGoal: 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 sedationPreservation 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 tremensSee table 2.
Rescue sedationNB: 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 sedationFollowing 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.
ExtubationAlpha-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 CCURefrain 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.
eISSN:
2502-0307
Idioma:
Inglés
Calendario de la edición:
2 veces al año
Temas de la revista:
Medicine, Clinical Medicine, other, Surgery, Anaesthesiology, Emergency Medicine and Intensive-Care Medicine
RSS Feed de revista