The Evolving Approach to Brain Dysfunction in Critically Ill Patients

Critically ill patients present unique management challenges; however, some clinical problems in the intensive care unit (ICU) setting are remarkably consistent and ubiquitous. For instance, virtually every intensivist is likely toencounter the recurrent problemexamined in theDexmedetomidine to Lessen ICUAgitation (DahLIA) trial reported byReade and colleagues1 in this issue of JAMA, but is equally likely not to have a data-driven answer to address it. This common scenario in the ICU involves caring for a patientwhose critical illness has resolved, butwhohas deliriumwith severe agitation that necessitates some form of continued restraint (physical, chemical, or both) for the safety of the patient and staff and prolongs mechanical ventilation. Cliniciansareoftenuncertainabout thebestcourseof treatment because decreasing the level of a patient’s sedation can beassociatedwithmorbidity, suchasunintentional removalof medicaldevices,2but increasingthe levelofsedationmayswing thepatient’s cognitivependulumintohypoactivedelirium,and risks failed spontaneous breathing and prolongedmechanical ventilation.3,4 Limited evidence is available to guide the clinician facedwith this clinical challenge,which iswhytheDahLIA trial1 is an important contribution to the literature. TheDahLIA trial1wasconducted in 15 ICUs inAustralia and New Zealand during a year and a half enrollment period. Patientswhose critical illness had otherwise resolved, but for whomdiscontinuingmechanical ventilationwashamperedby hyperactive or agitated delirium, were randomized in this double-blind placebo-controlled trial to receive up to 7 days of intravenousdexmedetomidine (n = 41) or placebo (n = 33), targeted tokeep themcalmandawake.All other aspects of patient management, including concurrent sedation, were left to the discretion of the medical team. Regardlessofhowthedatawereanalyzed,patients treated withdexmedetomidinehad increasedventilator-freehours at 7days (median, 144.8hoursvs 127.5hours in those treatedwith placebo; ie, thepatientswho receiveddexmedetomidinewere successfully liberated from the ventilator about threefourthsof 1day sooner), experienceda similar reduction induration of delirium, and had faster resolution of their delirium symptoms (median, 23.3 hours vs 40.0 hours with placebo). Thegroupsweregenerallywellbalancedother thantimereceivingmechanicalventilationprior torandomization,andthey had a reasonably high severity of illness, considering that the AcutePhysiologyandChronicHealthEvaluation II scoreswere calculatedabout2days intotheir ICUstayat thetimeofrandomization(andafter resolutionofmanyelementsofcritical illness). Thedifference in timereceivingmechanicalventilationprior to randomization could be accounted for by the distribution of medical ICUpatients (higher indexmedetomidinegroup)vssurgical ICUpatients (higher inplacebogroup)becausesurgicalpatients tendtoreceiveventilatorsupport for lesscomplicatedreasons and generally can achieve successful extubation sooner. Themost important limitationof thestudy is its samplesize (n = 74); the investigatorsstoppedthestudyshortof itsplanned sample size of 96 due to slow enrollment and spent funding. Basedonthedatapresented, thetrial likelywouldhavemettypical stopping rules prior to completion. In addition, a study of this nature is difficult to conduct, especiallywith thedegreeof robust methods used by these investigators. The DahLIA trial provides important information regarding the treatmentof agitateddeliriuminpatients receivingmechanicalventilation.First, this investigationoffershelpfulclinical data to guide clinicians caring for these common and clinically challenging ICU patients. The group randomized to the α2-agonist dexmedetomidine (which is 8 times more α2-specific than clonidine and is now available as a generic in many countries) not only experienced reduced agitated delirium,more ventilator-free days, and use of fewer other psychoactive medications, but also rarely experienced the bradycardia sometimes seen when dexmedetomidine is used earlier in the course of mechanical ventilation.5-7 Second, the DahLIA study must be viewed with a wideangle lens looking back 15 years to appreciate its place among this genre of articles that have changed the view of the patient and the scenery of the ICU. In 2001,when theConfusion Assessment Method-ICU (CAM-ICU)8 and the Intensive Care DeliriumScreeningChecklist (ICDSC)9 validation studieswere published, only about 10 articles per year appeared on ICU delirium.At that time, the conceptof “ICUpsychosis”was still widelyused, incorrectly suggesting that confusionamong ICU patients may have been an innocent bystander accompanying critical illness. Subsequent reports have added to the understandingofdeliriumamongcritically ill patients, and to the armamentariumof tools10 andprognostic information11 available to clinicians, such that today, an estimated 300 articles on ICU delirium are published each year. Third, the DahLIA study provides further data supporting theutilizationofdexmedetomidineasaclinicallyusefulandadvantageous medication for many ICU patients with complications.5-7Duringthe late1990s, ICUsworldwidehadadopted the perilous culture of very deep and prolonged sedationandparalysis.Pharmaceuticalcompaniesthereforesawthis Related article page 1460 Opinion