The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial

Luca Cioccari, Nora Luethi, Michael Bailey, Yahya Shehabi, Belinda Howe, Anna S Messmer, Helena K Proimos, Leah Peck, Helen Young, Glenn M Eastwood, Tobias M Merz, Jukka Takala, Stephan M Jakob, Rinaldo Bellomo, ANZICS Clinical Trials Group and the SPICE III Investigators, Yahya Shehabi, Yaseen Arabi, Frances Bass, Rinaldo Bellomo, Simon Erickson, Belinda Howe, Suhaini Kadiman, Colin McArthur, Lynnette Murray, Michael Reade, Ian Seppelt, Jukka Takala, Steve A Webb, Matthew P Wise, Yahya Shehabi, Belinda Howe, Rinaldo Bellomo, Yaseen M Arabi, Michael J Bailey, Frances Bass, Suhaini Kadiman, Colin McArthur, Lynnette Murray, Michael Reade, Ian Seppelt, Jukka Takala, Steve A Webb, Matthew P Wise, Michael J Bailey, Belinda D Howe, Lynette Murray, Vanessa Singh, Luca Cioccari, Nora Luethi, Michael Bailey, Yahya Shehabi, Belinda Howe, Anna S Messmer, Helena K Proimos, Leah Peck, Helen Young, Glenn M Eastwood, Tobias M Merz, Jukka Takala, Stephan M Jakob, Rinaldo Bellomo, ANZICS Clinical Trials Group and the SPICE III Investigators, Yahya Shehabi, Yaseen Arabi, Frances Bass, Rinaldo Bellomo, Simon Erickson, Belinda Howe, Suhaini Kadiman, Colin McArthur, Lynnette Murray, Michael Reade, Ian Seppelt, Jukka Takala, Steve A Webb, Matthew P Wise, Yahya Shehabi, Belinda Howe, Rinaldo Bellomo, Yaseen M Arabi, Michael J Bailey, Frances Bass, Suhaini Kadiman, Colin McArthur, Lynnette Murray, Michael Reade, Ian Seppelt, Jukka Takala, Steve A Webb, Matthew P Wise, Michael J Bailey, Belinda D Howe, Lynette Murray, Vanessa Singh

Abstract

Background: Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting.

Methods: In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4).

Results: Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group (p = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio.

Conclusions: In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP.

Trial registration: The SPICE III trial was registered at ClinicalTrials.gov ( NCT01728558 ).

Keywords: Dexmedetomidine; Hemodynamics; Noradrenaline; Sedation; Sepsis; Septic shock.

Conflict of interest statement

Dr. Shehabi reports receiving travel support and lecture fees, paid to Monash Health, and lecture fees from Pfizer (Malaysia) and Orion Pharma and fees for expert testimony from Stephens Lawyers and Consultants, Melbourne; Dr. Bellomo, receiving fees for expert testimony from Pfizer; and Dr. Takala, receiving consulting fees from Nestec. The Department of Intensive Care Medicine (Inselspital), Bern University Hospital has, or has had in the past, research contracts with Abionic SA, AVA AG, CSEM SA, Cube Dx GmbH, Cyto Sorbents Europe GmbH, Edwards Lifesciences LLC, GE Healthcare, ImaCor Inc., MedImmune LLC, Orion Corporation, Phagenesis Ltd. and research and development/consulting contracts with Edwards Lifesciences LLC, Nestec SA, Wyss Zurich. The money was paid into a departmental fund; the investigators received no personal financial gain.

Figures

Fig. 1
Fig. 1
Noradrenaline equivalent dose in the first 48 h after randomization. Data are presented as geometric means and 95% confidence intervals, overall group difference p = 0.054
Fig. 2
Fig. 2
Mean arterial pressure in the first 48 h after randomization. Data are presented as mean with standard error, overall group difference p = 0.06
Fig. 3
Fig. 3
Adjusted ratio of noradrenaline equivalents divided by MAP (NEq/MAP ratio) in the first 48 h after randomization. Adjusted for admission diagnosis, hospital site, baseline NEq/MAP ratio, continuous renal replacement therapy, age, administration of hydrocortisone and presence of liver cirrhosis. NEq/MAP: Noradrenaline equivalents to mean arterial pressure ratio (a higher ratio indicates higher vasopressor need to maintain a certain MAP). Data are presented as geometric means and 95% confidence intervals, overall group difference p = 0.02
Fig. 4
Fig. 4
Cumulative incidence curves for time to vasopressor weaning (with deaths treated as a competing risk) and comparison using Grey’s test. Shaded areas represent 95% confidence intervals
Fig. 5
Fig. 5
Cumulative incidence curves for the duration of invasive ventilation from randomization (with deaths treated as a competing risk) and comparison using Grey’s test. Shaded areas represent 95% confidence intervals
Fig. 6
Fig. 6
Kaplan-Meier curve for the probability of survival, with the number of subjects at risk

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