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Editorial Commentary
Sedation in intensive care unit: Is Dexmedetomidine the best choice? Dexmedetomidine, since its approval in 1999, seems to gain a place in the intensive care unit (ICU) as a safer sedative agent, deftly replacing its predecessors like propofol, benzodiazepines etc. It combines the property of both sedation and analgesia, without compromising on respiration and co-operation. Only hitch seems to be the hemodynamic effect, which has also been proved statistically insignificant. Still, its clinical significance cannot be overlooked. A dive into the internet ocean would enlighten the readers about the umpteen number of research papers almost everything favoring the use of Dexmedetomidine. These research publications have analyzed both short and long term infusion of Dexmedetomidine, either as a main agent or compared with other sedatives. In the article published in this issue “Evaluation of Long-term Infusion of Dexmedetomidine in Critically ill Patients: A Retrospective Analysis”, the authors have compared the effects between long and short term infusion of Dexmedetomidine in the ICU, which of course is a newer perspective. The study design, though a retrospective one, and in-spite of certain limitations, still, stands out to throw some light on the safety profile of long term infusion of Dexmedetomidine once again. The results of their analysis show certain safety in terms of cardiovascular events when compared between shortterm and long-term infusions. Moreover, patients in the long-term infusion were similar to short-term infusion with respect to the duration of ventilation, length of ICU stay and mortality. The results of the study persuade us to accept the safety of Dexmedetomidine when infused for longer periods. Supportive evidence can be obtained through the extensive studies conducted by Shehabi et al., Riker et al., Guinter et al., Takayuki, Lirola et al., and several other authors.[1,2] Siobal et al., in 2006, had published a pilot study using Access this article online Website: www.ijciis.org DOI: 10.4103/2229-5151.94866
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dexmedetomidine to facilitate extubation in ICU patients. They concluded that Dexmedetomidine, appears to maintain adequate sedation without hemodynamic instability or respiratory-drive depression, and thus may facilitate extubation in agitated difficult-to-wean patients.[3] In the same year, Enomoto et al., used Dexmedetomidine for more than 2 months on a 9 month old infant with liver cirrhosis, who underwent liver transplantation. The respiratory conditions improved when Dexmedetomidine was added to midazolam and fentanyl. He was then successfully extubated 10 weeks later. They found no serious adverse effects or no disturbance of liver function when Dexmedetomidine was used as a prolonged infusion up to 1.4 mcg/kg/h.[4] Wolf et al., in 2001, had used Dexmedetomidine on 6 patients with severe renal impairment.Two-compartmental pharmacokinetic models were fit to the drug concentration versus time data. They also determined its hemodynamic, respiratory, and sedative effects and observed no difference between renal disease and control groups in either volume of distribution at steady state. However, Dexmedetomidine resulted in a more prolonged sedation in subjects with renal disease. A mild reduction in blood pressure occurred in most volunteers, which was clinically insignificant though.[5] From the earlier studies of Enomotoet al., and Wolf et al., it is clear that even in a compromised hepatic or renal status, prolonged infusions of Dexmedetomidine is unlikely to disturb the homeostasis. There seems to be no evidence of significant accumulation of any metabolic products that would limit the prolonged use of Dexmedetomidine. In the most recent study by Lirola et al., a metabolite called H3 was quantified, but seemed to have practically no relevant pharmacologic activity.[6] In a case report, Alan S Multz, employed Dexmedetomidine as a prolonged infusion for treating sedation induced withdrawal in a multiple substance abuser with ARDS, who was then successfully weaned.[7] In another case report, JamilDarrouj had used Dexmedetomidine in the treatment of alcohol withdrawal. Such anecdotes favor the use of Dexmedetomidine in adults for prolonged infusion in the ICU. Reiter et al., in 2007 did a retrospective medical chart review of 29 patients of up to 18 years of age, who had received Dexmedetomidine infusion for
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more than 24 h (range 32 – 378 h). They concluded that prolonged infusions were associated with a reduction in concomitant analgesia and sedation medications, with statistically significant reduction in the heart rate.[8] Guinter et al., in 2010, conducted a literature review to assess the clinical evidence regarding the efficacy and safety of Dexmedetomidine for longer than 24 h. A total of 11 studies were identified. Of these trials, 6 included adult patients and 5 included pediatric patients. Of the 6 adult trials, 3 comparative trials demonstrated a similar efficacy with benzodiazepines (i.e., midazolam and lorazepam) or propofol, with a reduction in the incidence of delirium and coma associated with Dexmedetomidine. In noncomparative trials, Dexmedetomidine was efficacious in achieving sedation goals with only mild adverse effects. In the 5 pediatric trials evaluated, though the efficacy to achieve a target sedation scale score could not be assessed, still the safety of Dexmedetomidine has been demonstrated throughout an extended duration of use.[9] In all of the studies evaluated, Dexmedetomidine was associated with bradycardia. However, there were no reports of withdrawal effects, including rebound tachycardia and hypertension, upon discontinuation of Dexmedetomidine infusion. Takayuki Kunisawa, in his review of prolonged infusion of dexmedetomidine at varying doses (0.1–2.5 μg/kg/h) and durations up to 30 days, discussed the literature examining prolonged use of Dexmedetomidine, adding more supportive evidence to the efficacy and safety of Dexmedetomidine when it is used for more than 24 h.[10] He concluded that the major advantage of Dexmedetomidine is a reduction in the incidence of deliriumand coma during long-term sedation in the intensive care unit setting. Secondary analysis showed a reduction in the incidence of infection, due to shorter stay, as well as lower ICU cost when prolonged infusions were used. Joseph D Tobias, analyzed various trials conducted on long term administration of dexmedetomidine in pediatric population. Issues such as tachyphylaxis, withdrawal and rebound after abrupt cessation of prolonged infusion have been addressed. Even neurological events have been reported.[11] Fortunately, no such issues seem to arise in adults. Riker et al., reported that rebound hypertension and tachycardia did not occur following abrupt discontinuation of dexmedetomidine infusion. Studies conducted by Ruokonen et al., Venn et al., and Shehabi et al., support these observations with more evidence. Lirola et al., in 2011, did a detailed research regarding the pharmacokinetics of prolonged infusion of high dose of Dexmedetomidine in critically ill patients.This study was designed to characterize the pharmacokinetics of long Dexmedetomidine infusions and specifically to assess the dose linearity of high doses. [6] Dexmedetomidine was continued as long as required to a maximum of 4
14 days. They also quantified for the first time in humans the concentrations of the previously poorly characterized H-3 metabolite of Dexmedetomidine. The result of their study suggests that Dexmedetomidine obeys linear pharmacokinetics up to the dose of 2.5 mcg/kg/h. They couldn’t establish any new safety findings despite the high dosing regimen and prolonged infusions. A total of 24 trials involving 2,419 critically ill patients from over 11 countries were identified and subjected to meta-analysis by Jen et al., (2010). This meta-analysis showed that significant heterogeneity existed between studies on Dexmedetomidine. They concluded that Dexmedetomidine reduced the length of ICU stay. The risk of bradycardia was, however, higher when both a loading dose and high maintenance doses of dexmedetomidine were used.[12] From the discussions above, it is obvious that Dexmedetomidine has promoted better, smooth and even earlier weaning practice.Its potential to reduce the length of ICU stay has paved way to exploit its promising benefits such as reduced cost as well as lower infection rates than traditional sedative agents. Evidence continues to accumulate through several prospective studies targeted towards prolonged infusion of Dexmedetomidine. It is clear that the benefits have outweighed the little risks involved when treating critically ill patients in the ICU. The approval for long term administration of Dexmedetomidine is on the rise since 2008 (Columbia) till now (Japan being the 6th country). With its unique pharmacodynamics, Dexmedetomidine may become THE CHOICE of sedation in ICU and would find an undeniable place in the intensive care archives. Such a day is not so far. Vijay G. Anand
Senior Assistant Professor of Anesthesiology, Department of Anesthesiology and Critical care, Tirunelveli Medical College, Tirunelveli - 627011 (Under Govt. of Tamilnadu), India Address for correspondence: Dr. Vijay G. Anand, Plot no. 3, Udhaya nagar 2, NGO ‘B’ colony, Tirunelveli – 627007, Tamilnadu, India. E-mail:
[email protected]
REFERENCES 1.
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Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M.Dexmedetomidine infusion for more than 24 hours in critically ill patients: Sedative and cardiovascular effects. Intensive Care Med 2004;30:2188-96. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidinevs midazolam for sedation of critically ill patients: A randomized trial.JAMA 2009;301:489-99. Siobal MS, Kallet RH, Kivett VA, Tang JF. Use of dexmedetomidine to facilitate extubation in surgical intensive-care-unit patients who failed previous weaning attempts following prolonged mechanical ventilation: A pilot study. Respir Care 2006;51:492-6.
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Enomoto Y, Kudo T, Saito T, Hori T, Kaneko M, Matsui A, et al. Prolonged use of dexmedetomidine in an infant with respiratory failure following living donor liver transplantation. PaediatrAnaesth 2006;16:1285-8. De Wolf AM, Fragen RJ, Avram MJ, Fitzgerald PC, Rahimi-Danesh F. The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment. AnesthAnalg 2001;93:1205-9. Lirola T, Aantaa R, Laitio R, Kentala E, Lahtinen M, Wighton A, et al. Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients. Crit Care 2011;15:R257. Multz AS. Prolonged dexmedetomidine infusion as an adjunct in treating sedation-induced withdrawal. AnesthAnalg 2003;96:1054-5. Reiter PD, Pietras M, Dobyns EL. Prolonged dexmedetomidine infusions in critically ill infants and children. Indian Pediatr 2009;46:767-73. Guinter JR, Kristeller JL. Prolonged infusions of dexmedetomidine in
critically ill patients. Am J Health Syst Pharm 2010;67:1246-53. 10. Kunisawa T.Dexmedetomidine hydrochloride as a long-term sedative. TherClin Risk Manag 2011;7:291-9. 11. Tobias JD. Dexmedetomidine: Are there going to be issues with prolonged administration? J PediatrPharmacolTher 2010;15:4-9. 12. Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: A meta-analysis.Intensive Care Med 2010;36:926-39. Cite this article as: Anand VG. Sedation in intensive care unit: Is Dexmedetomidine the best choice?. Int J Crit Illn Inj Sci 2012;2:3-5 Source of Support: Nil, Conflict of Interest: None declared.
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