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In Response: In our article [1], we warned against the risk of mathematical coupling of data when oxygen uptake (VO2) and oxygen delivery (DO2) are calculated from the same values of hemoglobin, arterial oxygen saturation (SaO2), and especially cardiac index. There is generally a good agreement between direct and indirect determinations of VO2[2], but both methods have their limitations. In this study [1] as in others [3,4], we preferred to assess the relationship between cardiac index and oxygen extraction, because this relationship is not subject to mathematical coupling of data [5]. We strongly disagree with Dr. Myles and Dr. McRae when they state that a strong relationship between VO2 and DO2 implies VO2/DO2 dependency. On the contrary, we wrote that the close relationship between VO2 and DO2 should not be interpreted as VO2/DO2 dependency. The demonstration of VO2/DO2 dependency should be based on repeated assessments of VO2 during an acute change in DO2[6]. We claimed that the progressive increased in VO2 reflected the progressive increase in oxygen demand after cardiac surgery, and that changes in cardiac index were adaptive. When the cardiac index response was insufficient, mixed venous oxygen saturation decreased, reflecting an increase in oxygen extraction. Jean-Louis Vincent, MD, PhD Christina Routsi, MD Department of Intensive Care, Cliniques Universitaires de Bruxelles, Hospital Erasme, Brussels, Belgium
SCOPUS: no.j
Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.
SCOPUS: cp.j
Introduction: The non-selective vasopressin agonist, arginine vasopressin (AVP) is widely used as second line vasopressor in septic shock patients as add-on to norepinephrine (NE). However, animal septic shock studies have shown selective V1a receptor agonists to be superior to AVP in alleviating organ dysfunction. Selepressin (FE 202158) is the first selective V1a agonist to be evaluated in septic shock patients. Hypothesis: Selepressin reduces NE requirements and duration of organ dysfunction in human septic shock. Methods: In a randomized double-blind, placebo controlled trial, septic shock patients in need of vasopressor support (?0.1 µg/kg/min NE for?2h) received selepressin (1.25 ng/kg/min (n=10) or 2.5 ng/kg/min (n=19) or placebo (n=21) until shock resolution or for up to 7 days. If target mean arterial pressure (MAP) of 65 mmHg could not be achieved, open-label NE was added. The co-primary endpoints were ability to maintain target MAP without NE, NE infusion rate and cumulative dose of NE. Secondary endpoints included organ dysfunction and fluid balance. Results: Selepressin dose-dependently reduced the 7-day cumulative dose of open-label NE (placebo: 772 µg/kg, 1.25 ng/kg/min selepressin: 617 µg/kg and 2.5 ng/kg/min selepressin: 249 µg/kg, p=0.007). NE was weaned more rapidly in the selepressin group: 2.5 ng/kg/min selepressin increased the proportion of patients maintaining target MAP without open-label NE compared to placebo (69% vs. 20%, p=0.005) and reduced mean NE infusion rate (0.04 vs. 0.18, p=0.0001) in the first 24h following initiation of study drug. Interestingly, the 2.5 ng/kg/min selepressin group had faster recovery than placebo as shown by a higher proportion of patients out of shock at 48h (57.9 vs. 28.6%, p=0.1) and higher proportion of days alive and free of ventilation within the first 7 days (53.8 vs. 23.1%, p=0.01) in spite of similar baseline NE requirements and SOFA score. Moreover, 7-day cumulative fluid balance was lower in the 2.5 ng/kg/min selepressin group than in placebo (9.0 vs. 6.5 L, p=0.1). Conclusions: Selepressin dose-dependently reduced NE requirements, as well as the need for mechanical ventilation, and appeared to shorten time to shock resolution in septic shock patients.
