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ORANGES RCT – More on “Metabolic” Resuscitation

August 11, 2020

Written by Clay Smith

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Hydrocortisone, ascorbate, and thiamine (HAT) may lead to more rapid resolution of shock. But don’t drink the ORANGE Kool-aid yet.

Why does this matter?
We have written about HAT before. CITRUS ALI did not meet primary outcomes but did have a possible signal of mortality benefit. VITAMINS was also a negative study. HYVCTTSSS did not show mortality benefit and was stopped early because of severe hypernatremia in the treatment arm, though SOFA score may have been better with HAT. What does ORANGES show?

Are these ORANGES still good?
This was a RCT comparing usual therapy and HAT that included 137 ICU patients with sepsis or septic shock. “HAT” consisted of hydrocortisone 50 mg q6h, ascorbic acid 1,500 mg q6h, and thiamine 200 mg every 12 hours x 4 days. Vasopressors were stopped 11 hours faster with HAT (27 vs 38 hours), indicating faster shock resolution, one of the primary outcomes. When we peel this back, the original primary outcome was mortality, which was changed to shock resolution and SOFA score after they had collected several months of data (interesting…). HAT remained significantly better for shock resolution even after statistical adjustment for steroid use in the placebo group, of which 41% received corticosteroids. The other primary outcome, change in SOFA score, was no different. There were no differences in secondary outcomes: short-term mortality, LOS, ventilator-free days, or procalcitonin clearance. There was no evidence of harm from HAT. They did not seem to see the hypernatremia that was part of HYVCTTSSS. But the word “sodium” did not appear anywhere in the full text, so I can’t say for certain. The fact that they changed the primary outcome leaves me a little sour. Given that there may be harm to HAT, and the benefit for patient-centered outcomes remains to be proven, I am not ready to drink the ORANGE Kool-aid yet. A number of trials are underway. I am going to wait and C. Three puns – a HAT trick? Sorry…I just can’t help myself.

Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest. 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049. Epub 2020 Mar 17.

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