Alpha-2 agonists for sedation

 

A 66 year old woman was admitted to the ICU with acute type II respiratory failure secondary to a community acquired pneumonia (CURB-65 score 4) complicating severe COPD (FEV1 40% predicted). Collateral history revealed many concerning features; the patient had a poor exercise tolerance (mMRC dyspnoea scale score 3, exercise tolerance <100m), was alcohol dependent (drinking 120 units per week) and previously had been admitted to hospital with an exacerbation of COPD requiring NIV, and treatment for acute alcohol withdrawal.

 

Mechanical ventilation was commenced using a lung-protective strategy with permissive hypercapnia. Sedation was achieved using remifentanil and propofol, targeting a Richmond Agitation Scale Score (RASS) of -2 to 0. A noradrenaline infusion was commenced to maintain a mean arterial pressure of ≥65mmHg. A neutral cumulative fluid balance was targeted. Broad-spectrum antimicrobial therapy was continued as per local antimicrobial guidelines. Intravenous B vitamins were administered and enteral feeding was established via a nasogastric tube.

In view of the patient’s comparatively poor pre-morbid function and high risk of delirium, early extubation to NIV was identified as the preferred strategy. By day 3 the patient had improved such that this became a realistic goal. In order to prevent acute alcohol withdrawal, yet use benzodiazepines sparingly to avoid associated respiratory depression, remifentanil-propofol sedation was substituted for a clonidine infusion, which was continued following extubation. Low doses of chlordiazepoxide were used as rescue therapy in accordance with Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) scoring.

The patient progressed well, was weaned from both NIV and clonidine and was discharged from HDU to a respiratory ward on day 8. She survived to hospital discharge.

 

What role do Alpha-2 Agonists have for sedation in critical care?

Christopher Westall

Pain, agitation and delirium are commonly experienced by patients in the ICU; their presence is associated with worse outcomes in terms of mortality, duration of mechanical ventilation and long-term psychological sequelae. These phenomena are inextricably linked and one cannot be successfully managed without attention to the others. Pain, depth of sedation and delirium should be frequently assessed in all patients. While there is no evidence that any single sedative regime is wholly superior to the others, strategies that focus on an “analgesia first” approach coupled with the aim of using the lowest dose of sedative necessary are associated with shorter durations of mechanical ventilation and a lower incidence of delirium. Accordingly, agents that are short acting and rapidly titratable are preferred.1,2

Current clinical practice guidelines recommend propofol or dexmedetomidine as the preferred sedatives in critically ill patients.2 Dexmedetomidine was first licenced for use by the United States Food and Drug Administration (FDA) in 1999, but did not enter common usage until 2009. Clonidine, like dexmedetomidine, is a selective α2-agonist that can be used [off licence] for sedation in the ICU and for the treatment of drug and opioid withdrawal. Although the use of clonidine for these indications was described in 1990, there are no clinical trials examining clonidine as a sedative agent.3

Clonidine and dexmedetomidine are selective α2-agonists, though dexmedetomidine has greater α2:α1 selectivity than clonidine (1620:1 vs. 220:1). Their sedative action is mediated through α2-adrenoceptors located in the locus coeruleus (posterior pons). The locus coeruleus has neuronal projections to the cortex, hippocampus, cerebellum, thalamus and spinal cord; noradrenaline is the predominant neurotransmitter. The collective description of this system is the locus coeruleus-noradrenergic system (LC-NA). It is implicated in the management of arousal and the sleep-wake cycle, cognitive control (including attention and memory) and behavioural response to psychological stress. Tonic neuronal transmission (sustained, highly regular discharge patterns) peak during wakefulness and are abolished during REM sleep. Stimulation of α2-adrenoceptors exerts an inhibitory effect on this system.3,4

The inhibitory effect of α2-agonists on the LC-NA system results in a qualitatively different sedation compared to propofol and benzodiazepines, producing a state of co-operative, easily rousable sedation where respiratory drive is unaffected. Consequently clonidine and dexmedetomidine can be used for sedation in non-intubated patients. The onset of sedation with dexmedetomidine occurs within 15 minutes and reaches peak at 1 hour. Dexmedetomidine compares favourably with clonidine with respect to elimination; it has an elimination half-life of 1.9- 2.5 hours (increased in hepatic dysfunction, where accumulation may occur), compared with 8.5 hours for clonidine.1-3 Importantly, dexmedetomidine at current licenced doses appears unable to reliably achieve deeper levels of sedation. A pilot study comparing dexmedetomidine and midazolam sedation found that a target RASS of -4 was achieved in only 42% of patients receiving dexmedetomidine (compared with 62% in the midazolam group, p<0.006), as such dexmedetomidine should not be used when neuromuscular blockade is required.

The predominant adverse effects of selective α2-agonists are bradycardia and hypotension. These responses are mediated via α2-reseptors in the medulla and motor complex and are independent of sedative effect. Rebound tachycardia and hypertension are common with abrupt withdrawal. Clonidine and dexmedetomidine are contraindicated in the presence of pre-existing bradycardia and high-grade atrioventricular block, uncontrolled hypotension and in acute neurological injury.1-8

The efficacy of dexmedetomidine sedation has been evaluated in three recent prospective, double-blind, randomised control trials (SEDCOM, MIDEX and PRODEX).6,7 All three trials were non-inferiority studies of dexmedetomidine versus either propofol (PRODEX) or midazolam (SEDCOM and MIDEX) sedation, defined by time in target sedation range (RASS -3 to 0). Each examined duration of mechanical ventilation and time to extubation as secondary endpoints using a superiority design. Collectively, dexmedetomidine was non-inferior to midazolam and propofol to maintain a target RASS of -3 to 0, percentage time in range was quoted as 56- 77% for all agents. A reduction in duration of mechanical ventilation was seen in both trials comparing dexmedetomidine and midazolam (reporting similar reductions), but was not seen when dexmedetomidine was compared with propofol.6,7 A Cochrane Library meta-analysis found that dexmedetomidine reduced the mean duration of mechanical ventilation by 22% (95% CI 10-33%) and ICU length of stay by 14% (95% CI 1-24%), though characterised the evidence as low to very low due to “high risk of bias, serious inconsistency and imprecision, and strongly suspected publication bias”.3

A commonly cited concern is that Orion Pharmaceuticals (the patent holder for dexmedetomidine) financially-sponsored and designed the statistical analysis plan for the MIDEX and PRODEX trials; these heavily influenced the Cochrane analysis, contributing 1000 patients to the 1624 patient dataset. In both trials there was a significantly higher drop out in the dexmedetomidine arm compared with the control arms, this was not reflected in the [per-protocol] non-inferiority analysis of time in target RASS range. The trials were also criticised for “fragile blinding”; the accusation is that the haemodynamic profile of dexmedetomidine allowed investigators to identify the study drug and that for PRODEX, the physical presentation of propofol made blinding almost impossible. More generally, Orion Pharmaceuticals has been accused of publication bias.

Some data exists that suggests that compared with benzodiazepines, dexmedetomidine sedation is associated with “less” delirium, as detected by the CAM-ICU tool. The data is drawn from two randomised trials (SEDCOM and MENDS). The SEDCOM investigators identified delirium in 54% of patients in the dexmedetomidine group compared with 76.6% in the midazolam group (p<0.001), while the MENDS investigators, comparing dexmedetomidine with lorazepam, reported median days alive without delirium or coma of 7 vs. 3 days respectively (p<0.01).6,8 This has not been confirmed in meta-analysis and may reflect the [known] deliriogenic effects of benzodiazepines rather than a protective effect from dexmedetomidine.

The widespread use of [on-patent] dexmedetomidine may be hindered by cost, certainly it compares unfavourable to [generic] clonidine. Typical infusion doses for clonidine are 0.5- 2mcg/kg/hr-1 (oral dosing 50- 600mcg TDS) and 0.2- 1.4mcg/kg/hr-1 for dexmedetomidine. Based on standard acquisition costs and an “average” 70kg patient, 24 hours of dexmedetomidine sedation costs £31- 188, compared to clonidine at £12- 46 and propofol at £10- 100.

The use of α2-agonists in the management of acute alcohol or opioid withdrawal is theoretically attractive and has been described in case series, though no prospective, randomised data exists. Chronic alcohol abuse is known to inhibit the activity of excitatory NMDA receptors and noradrenergic systems within the brain while causing decreased endogenous [inhibitory] GABA release and GABA-receptor downregulation. The characteristic hyperexcitability and autonomic hyperactivity of delirium tremens occurs when sudden cessation of alcohol intake leads to the sudden release of inhibition on excitatory pathways, which the depleted GABA signalling system cannot contain. Published case series typically report favourable safety profiles and reduced benzodiazepine administration.9,10


Lessons learnt

I consider short acting opioids with the addition of propofol sedation as the current reference standard for an analgesia-first approach to sedation in the ICU. Selective α2-agonists may be considered an alternative in haemodynamically stable patients approaching extubation in the context of alcohol withdrawal or previous prolonged opioid infusions. I can see no benefit to their use where the duration of mechanical ventilation is anticipated to be short, and their role in sedation post-extubation for control of agitated or mixed delirium compared with atypical antipsychotic medication is unclear. Dexmedetomidine posses favourable pharmacodynamics compared with clonidine and at least has some supporting scientific evidence, though this is offset by both cost and general unfamiliarity of use.


References

1. Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med,  2014:444-54

2. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation and delirium in adult patients in the intensive care unit. Crit Care Med, 2013; 41:263-306

3. Chen K, Lu Z, Xin YC, et al. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients (Review). Cochrane Database of Systematic Reviews 2015, Issue 1. Art No.: CD010269. DOI: 10.1002/14651858.CD010269.pub2

4. Benarroch EE. The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology, 2009; 73:1699-1704

5. Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus propofol/ midazolam for long term sedation during mechanical ventilation. Intensive Care Med, 2009; 35:282-290.

6. Riker RR, Shehabi Y, Bokesch PM, et al. The SEDCOM Study Group.  Dexmedetomidine vs midazolam for sedation of critically ill patients. A randomized trial. JAMA, 2009: 489-99

7. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation. Two randomized controlled trials (MIDEX & PRODEX). JAMA, 2012; 307:1151-1160

8. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients. The MENDS randomized control trial. JAMA, 2007; 298:2644-2653

9. Rayner SG, Weinert CR, Peng H, et al. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care, 2012; 2:12

10. Dailey RW, Leatherman JW, Sprenkle MD. Dexmedetomidine in the management of alcohol withdrawal and alcohol withdrawal delirium. Am J Respir Crit Care Med, 2011; 183:A3164

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