A 35-year-old man was admitted through the Emergency Department with a three-day history of sore throat, drooling of saliva and fever. In the twenty-four hours leading up to his admission he had reported increasing difficulty breathing and hoarseness. His past medical history included obesity and non-insulin dependent diabetes mellitus.

On initial assessment he was found to be stridulous, drooling, tachypnoeic, tachycardic and febrile. Supplemental oxygen was applied and intravenous access obtained, with blood cultures being sent prior to administration of broad-spectrum antibiotics (Ceftriaxone, Benzylpenicillin and Metronidazole). Despite nebulised Adrenaline, intravenous fluid and intravenous dexamethasone, he continued to deteriorate and was transferred to the anaesthetic room for definitive airway management. Findings at intubation were consistent with acute epiglottitis. Swabs were taken and oral fibreoptic intubation was successfully performed.

Following admission to the ICU, he was mechanically ventilated and sedated with infusions of Propofol and Remifentanil. Antibiotic therapy was continued and he was commenced on regular dexamethasone to reduce epiglottic oedema. He required a low- dose noradrenaline infusion to maintain blood pressure, and was commenced on an insulin sliding scale. Two days after admission his airway was reassessed with direct laryngoscopy, and was found to be significantly less oedematous.

At this stage a sedation hold was performed, with the patient opening eyes spontaneously and seeming to obey commands. He was extubated to humidified facemask oxygen but shortly afterwards became agitated, combative and delirious (CAM-ICU positive). The patient was re-intubated within a two-hour period and Propofol and Remifentanil sedation was recommenced. Over the following two days, he remained inappropriate on daily sedation holds, and by this stage was receiving bolus doses of Haloperidol for episodes of acute agitation. CT imaging of his brain revealed no abnormality, and lumbar puncture was negative for central nervous system infection. Intravenous dexamethasone had been weaned, in view of the improvement in epiglotittis seen at laryngoscopy.

By day six of his admission he remained neurologically inappropriate on sedation hold, and was changed to an intravenous infusion of Dexmedetomidine at 0.7 mcg/kg/hr. Remifentanil was weaned off at this time, and Propofol infusion was reduced to baseline levels. This continued for a further twenty-four hours, by which time he was neurologically appropriate on sedation hold, obeying commands, and was extubated uneventfully.

On direct questioning, the patient did not recall his first extubation episode on Intensive Care. He did recall a combination of vivid visual and auditory hallucations, including the presence of insects in his bed, hearing persecutory voices and a feeling of helplessness and fear. He made a full recovery, and these symptoms had fully resolved by the time he was discharged from hospital.

What is the role of dexmedetomidine in the prevention and management of ICU delirium?

Nicholas Taylor

Delirium is a syndrome characterised by the acute onset of cerebral dysfunction with a change or fluctuation in baseline mental status, inattention, and either disorganised thinking or an altered level of consciousness [6].

A recent multi-centre study revealed a 32.3% prevalence of delirium amongst critically ill patients in North America, South American and Europe. Delirium is associated with poor outcome and increased disease severity, and independently associated with increased ICU and in-hospital mortality, and increased ICU and in-hospital length of stay [1]. The aetiology of delirium in the critical care setting is varied, but in the case described the risk factors include sepsis, mechanical ventilation, administration of steroids, critical illness and use of sedatives.

Dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist used within the ICU for its sedative and anxiolytic effects. Among patients requiring mechanical ventilation, Dexmedetomidine has been shown to be equal to propofol and midazolam in maintaining light to moderate sedation. Use of dexmedetomidine is associated with shorter duration of mechanical ventilation and improved patient interaction (measured using visual analogue scales) in comparison to propofol and midazolam. Length of ICU and hospital admission and mortality were similar, although Dexmedetomidine was associated with more hypotension and bradycardia [2].

The clinical benefits of dexmedetomidine versus propofol have been explored in a systematic review of adult ICU patients. Results from this meta-analysis suggested significantly reduced length of ICU stay and reduced incidence of delirium with dexmedetomidine where compared to propofol. There was no difference in duration of mechanical ventilation or ICU mortality between the two groups. Dexmedetomidine was associated with transient hypertension when administered with a loading dose or high infusion rate [5].

A small randomised, open-label trial has compared dexmedetomidine infusion with haloperidol infusion in addition to pre-exisiting sedation in mechanically ventilated patients with agitated delirium. Use of dexmedetomidine was associated with shorter time to extubation, decreased length of stay, and reduced propofol infusion time [3].

A recent meta-analysis of 14 trials (encompassing over 3000 patients) has studied the effect of dexmedetomidine on delirium in the ICU setting. Overall analysis showed lower incidence of delirium, agitation and confusion in the dexmedetomidine (19%) versus control group (23%) (RR = 0.68, p= 0.03). These findings were demonstrated in patients receiving both mechanical and non-invasive ventilation [4].

Recent guidelines of the Society of Critical Care Medicine recommend using non- benzodiazepine agents, such as propofol or dexmedetomidine, over benzodiazepines as a first-line sedative agent, and Dexmedetomidine in patients at risk for delirium that is unrelated to alcohol and benzodiazepine use [6].

Lessons Learnt

It is clear that delirium is a complex and multifactorial syndrome. The evidence supporting dexmedetomidine in preventing or reducing delirium has mainly come from small studies or meta-analyses. This in itself reflects the complexity of the overall clinical picture and the presence of many other confounding variables other than type of sedation. Comparisons with benzodiazepine-related sedation strategies are less useful in ICU practice in the UK, where this is rarely a first-line sedation regimen.

Sedation with dexmedetomidine has been consistently associated with a reduced duration of mechanical ventilation and fewer episodes of deep sedation, which confers a potential benefit in reducing the risk of delirium. The greater ability of patients to communicate (especially to communicate pain) when sedated with dexmedetomidine is a significant advantage, and may help to alleviate the feelings of anxiety and pain associated with post- traumatic stress disorder.

The comparison with dexmedetomidine and haloperidol as rescue therapy is relevant, although this merits further investigation with a larger, double-blinded study. At present, prescribing costs hinder the widespread adoption of on-patent dexmedetomidine in the management of delirium. Implementation of the Society of Critical Care Medicine recommendation that dexmedetomidine should be used in patients at risk of delirium is unlikely to take place before cost-effectiveness can be demonstrated in the general adult ICU population.

Beyond the potential benefits outlined above, dexmedetomidine remains an important sedative option that holds some significant advantages over other agents. In my practice, the combination of sedation and axiolysis in the context of minimal respiratory depression makes it an ideal agent for the agitated patient requiring non-invasive ventilation.

References

1. Salluh JI, Soares M, Teles JM, Ceraso D, Raimondi N, Nava VS, Blasquez P, Ugarte S, Ibanez-Guzman C, Centeno JV, Laca M, Grecco G, Jimenez E, Árias-Rivera S, Duenas C, Rocha MG; Delirium Epidemiology in Critical Care Study Group. Delirium epidemiology in critical care (DECCA): an international study. Crit Care. 2010;14(6):R210.

2. Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60.

3. Reade MC, O’Sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo R. Crit Care. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial. Crit. Care 2009;13(3):R75.

4. Pasin L, Landoni G, Nardelli P, Belletti A, Di Prima AL, Taddeo D, Isella F, Zangrillo A. Dexmedetomidine Reduces the Risk of Delirium, Agitation and Confusion in Critically Ill

Patients: A Meta-analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2014 Jul 14.

5. Xia ZQ1, Chen SQ, Yao X, Xie CB, Wen SH, Liu KX. Clinical benefits of dexmedetomidine versus propofol in adult intensive care unit patients: a meta-analysis of randomized clinical trials. J Surg Res. 2013 Dec;185(2):833-43.

6. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, Coursin DB, Herr DL, Tung A, Robinson BR, Fontaine DK, Ramsay MA, Riker RR, Sessler CN, Pun B, Skrobik Y, Jaeschke R; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41(1):263-306.