Jakob, S. M.

Ruokonen, E.

Takala, J.

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be interpreted in terms of the variations of its two determinants(HR and SV). In some cases, the absence of increase in CO in re-sponse to fluid infusion may not indicate the absence ofeffect. Monitoring SV may provide more reliable informationconcerning the effect of fluid infusion. It may be preferable touse a definition of fluid responsiveness based on SV variationin studies testing the ability of an indicator to predict fluidresponsiveness.Declaration of interestNone declared.P.-G. Guinot*B. UrbinaB. de BrocaE. BernardH. DupontE. LorneAmiens, France*E-mail: guinotpierregregoire@gmail.com1 Zhang Z, Lu B, Sheng X, Jin N. Accuracy of stroke volume variationin predicting fluid responsiveness: a systematic review and meta-analysis. J Anesth 2011; 25: 904–162 Guinot PG, de Broca B, Abou Arab O, et al. Ability of stroke volumevariation measured by oesophageal Doppler monitoring topredict fluid responsiveness during surgery. Br J Anaesth 2013;110: 28–333 Guyton AC. The relationship of cardiac output and arterial pressurecontrol. Circulation 1981; 64: 1079–88doi:10.1093/bja/aeu031Efficacy of dexmedetomidine comparedwith midazolam for sedation in adultintensive care patientsEditor—In a recently published article,1 Dr Adams and collea-gues review, among others, two of our studies addressing dex-medetomidine for sedation in critically ill patients.2 3 While weagree with their overall conclusion that ‘so far the evidence ofadvantages of dexmedetomidine in the ICU setting remainslimited’, we would like to address some of their criticism ofour studies.Dr Adams and colleagues mention that we did not findstatistically significant differences in sedation between midazo-lam and dexmedetomidine treatment groups. We believe thatthey have missed important aspects of our study design:3 ourmain interest was to assess the effect of the sedative drugs onlength of mechanical ventilation, with the prerequisite that dex-medetomidine is not inferior to midazolam (and propofol) inmaintaining the target sedation. We therefore used two hierar-chial co-primaryendpoints—first, assessing non-inferiority, andthen comparing the effect on duration of mechanical ventila-tion. Only if the non-inferiority was confirmed, could the effecton mechanical ventilation be assessed. Non-inferiority designshave not been used before in assessing any current sedativedrugs:ourdesignrequestingproofofnon-inferiority inmaintain-ing sedation before testing the hypothesis of shorter mechanic-al ventilation should be considered more rigorous comparedwith the conventional designs showing ‘no difference’. We alsotested the secondary outcome variables with the prerequisitethat dexmedetomidine sedation was non-inferior (or at leastas good) as sedation with the standard drug—something thathas not been shown for any prior sedative.Further, the authors state that ‘The main problem withassessing the effectiveness of sedation is that most measure-ments are made from subjective scales and that only oneTable 1 Comparison of a hemodynamic parameters between theresponders, non-responders, and discordant groups. Values areexpressed as mean (standard deviation) or mean (CI95%). CO,cardiac output; MAP, mean arterial pressure; HR, heart rate; SV,stroke volume; DrespSV, respiratory stroke volume variation.Data were compared using ANOVA with the post hoc Bonferonni test.aP,0.05 non-responder vs responder. bP,0.05 non-responder vsdiscordant. cP,0.05 responder vs discordant. *P,0.05 betweenbaseline and volume expansionNon-responders(n558)Responders toSVand CO(n564)Discordant(n516)HR (beats min21)Baseline 67 (18) 67 (17) 78 (18)b,cVolumeexpansion66 (17) 69 (17) 68 (12)*MAP (mm Hg)Baseline 75 (13) 76 (12) 74 (15)Volumeexpansion77 (15) 81 (14)* 77 (13)SV (ml)Baseline 84 (20) 69 (16)a 72 (19)bVolumeexpansion87 (22)* 91 (20)* 88 (22)*CO (ml min21)Baseline 5.5 (1.9) 4.5 (1.2)a 5.5 (1.5)cVolumeexpansion5.6 (1.9) 6.3 (2)* 6 (1.7)*DrespSV (%)Baseline 11 (5) 21 (9)a 26 (10)cVolumeexpansion10 (4) 11 (6)* 15 (11)*,b,cVariation ofHR withvolumeexpansion (%)21 (24; 2) 3 (0; 6) 211 (217; 26)b,cVariation of SVwith volumeexpansion (%)3 (1; 6) 34 (28; 40)a 20 (17; 24)b,cVariation ofCO withvolumeexpansion (%)2 (22; 5) 38 (32; 44)a 6 (0; 12)cCorrespondence BJA581study4 included BIS as an objective measurement’. We find thisstatement misleading. BIS has never been adequatelyvalidated for monitoring sedation in the ICU. We and othershave demonstrated the major problems associated withBIS-guided sedation at light to moderate sedation levels.5 6In contrast, standard sedation assessment with RASS hasbeen validated.7 While the proposal of Adams and colleaguesthat all assessments should have been performed by thesame blinded investigator is scientifically correct, this is ahighly unrealistic suggestion for a multi-centre study including1000 patients and 2-hourly sedation assessments.We believe that there are other inaccuracies of importantfeatures in their critique of our studies. The claim that we didnot report blinding of RASS assessors is incorrect: we describedthe double-blinded, double-dummy design, where sedativesand dummys were prepared, connected, and removed by inde-pendent personnel, so that those making the RASS assess-ments were indeed blinded to the treatment (Methodssection, paragraph ‘randomization and masking’). Adamsand colleagues also comment that patients who received ordid not receive rescue sedation were not independently ana-lysed. In both PRODEX and MIDEX trials,3 almost 50% of thepatients needed rescue sedation at some time point (Table 2of the original manuscript). In the study by Ruokonen and col-leagues,2 the percentage was close to 80% in each group (Elec-tronic supplement, paragraph ‘rescue medication’). The resultof analysing the primary outcome separately in only thosepatients who could be sedated by the study drug alone wouldbe of little clinical significance. We do not agree that omittingsuch an analysis ‘leads to difficulties in accurately interpretingthe conclusions’.Finally, Adams and colleagues claim that there are numer-ical inconsistencies with respect to total number of excludedpatients, and of patients with treatment withdrawal. We aresurprised by this claim, especially since we have explainedthis to the authors in response to their direct correspondencewith us: the total numbers are smaller than the sum of allreasons since several reasons could simultaneously apply, asclearly mentioned in the legend to Figure 1 of the originalmanuscript.3 The ‘inconsistency’ in the number of patientswith serious adverse events in the article by Ruokonen and col-leagues2 relates to mix-up of ‘numbers of SAE’ and ‘patientswith SAE’: the correct numbers of SAE and patients with SAEare found in the electronic supplement of the manuscript byRuokonen and colleagues.Declaration of interestS.J. and J.T.: the Department of Intensive Care Medicine has, orhas had in the past, research contracts with Abbott NutritionInternational, B. Braun Medical AG, CSEM SA, Edwards Life-sciences Services GmbH, Kenta Biotech Ltd, Maquet CriticalCare AB, and Omnicare Clinical Research AG; and research& development/consulting contracts with Orion Pharma,Edwards Lifesciences SA, Maquet Critical Care AB, and Nestle´.The money is/was paid into a departmental fund; no authorreceives/received any personal financial gain. The departmenthas received unrestricted educational grants from the followingorganizations for organizing a quarterly postgraduate educa-tionalsymposium,theBernerForumforIntensiveCare:FreseniusKabi; gsk; MSD; Lilly; Baxter; Astellas; AstraZeneca; B. Braun; CSLBehring; Maquet; Novartis; Covidien; Mycomed; RobaPharma.E.R.: Kuopio University received a grant from Orion Pharma tocarry out sedation studies, and for consulting and travel.S. M. Jakob1*E. Ruokonen2J. Takala11Bern, Switzerland2Kuopio, Finland*E-mail: stephan.jakob@insel.ch1 Adams R, Brown GT, Davidson M, et al. Efficacy of dexmedetomidinecompared with midazolam for sedation in adult intensive carepatients: a systematic review. Br J Anaesth 2013; 111: 703–102 Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versuspropofol/midazolam for long-term sedation during mechanical ven-tilation. Intensive Care Med 2009; 35: 282–903 Jakob SM, Ruokonen E, Grounds RM,et al.Dexmedetomidine vs. mid-azolam or propofol for sedation during prolonged mechanical venti-lation: two randomized controlled trials. J AmMed Assoc 2012; 307:1151–604 Senoglu N, Oksuz H, Dogan Z, Yildiz H, Demirkiran H, Ekerbicer H.Sedation during noninvasive mechanical ventilation with dexmede-tomidine or midazolam: a randomized, double-blind, prospectivestudy. Cur Ther Res Clin Exp 2010; 71: 141–535 Haenggi M, Ypparila-Wolters H, Buerki S,et al.Auditory event-relatedpotentials, bispectral index, and entropy for the discrimination of dif-ferent levels of sedation in intensive care unit patients.Anesth Analg2009; 109: 807–166 Haenggi M, Ypparila-Wolters H, Hauser K, et al. Intra- and inter-individual variation of BIS-index and Entropy during controlledsedation with midazolam/ remifentanil and dexmedetomidine/remifentanil in healthy volunteers: an interventional study. CritCare 2009; 13: R207 Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unitpatients. Am J Respir Crit Care Med 2002; 166: 1338–44doi:10.1093/bja/aeu032Reply from the authorEditor—Thank you for the opportunity to respond to the letterof Jakob and colleagues which was written regarding a recentreview published in theBritish Journal of Anaesthesia.1 I shouldsay at the outset that we accept that Jakob and colleagueshave performed the best designed trials in this area and apolo-gize if the article gave the impression that this was not the case.On the subject of non-inferiority trials, I am afraid we aregoing to have to agree to disagree. I acknowledge that thereis a problem facing clinical research in that trials are increa-singly being required to show benefits on clinically meaningfulendpoints rather than surrogate endpoints (e.g. biochemical).This has resulted in investigators using an ‘equivalence’ orBJA Correspondence582

Efficacy of dexmedetomidine compared with midazolam for sedation in adult intensive care patients

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