Critical care
the past two decades when we have tested everyday interventions, a lot of them have shown no benefit, and some actually caused quite marked harm.” Over time, he says, clinicians “have been doing less and less, as it has been shown to be difficult to improve the outcomes of these patients by doing more”.
Could vitamin C help the body combat infection?
Adhikari and his colleague François Lamontagne undertook an international randomised controlled trial to determine the effectiveness of vitamin C in treating sepsis and septic shock. There were good reasons to believe that vitamin C could be an effective intervention. In patients with sepsis, levels of vitamin C in the blood are very low, says Adhikari. Because vitamin C “has a number of roles in metabolic pathways in the body” including antioxidant properties that improve the function of neutrophils in fighting infection, it seemed reasonable to hypothesise that raising levels of vitamin C could improve the body’s ability to combat sepsis. It is also an essential ingredient in enabling the body to make its own vasopressors, he adds. An animal study had shown promising results, as had a small placebo-controlled study in humans, where the patients given a high dose of vitamin C improved organ function faster over the first three or four days. There had also been a retrospective before-after study, which compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a seven-month period with a control group treated in the same ICU during the preceding seven months. There were 47 patients in each group, and the mortality rate for the treatment group was 8.5%, compared with 40.4% in the control group.
In the trial led by Adhikari and Lamontagne, 872 patients with sepsis receiving vasopressor therapy in the ICU were divided into two groups, one receiving an infusion of vitamin C, at a dose of 50mg per kilogram every six hours for four days, the other receiving a placebo over the same time period. Rather than improve patients’ chances of survival, says Adhikari, the high dose of vitamin C “increased the risk of a bad outcome”. In this case, a bad outcome was defined as either death at 28 days or being alive at 28 days, but with persistent organ dysfunction, with the patient either still dependent on the ventilator, or still receiving blood pressure medications or dialysis. This primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group. It was, says Adhikari, an “alarming” result, and the data didn’t provide insights into the reasons
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behind it. Although the team had collected biomarkers from some patients, they found “no real difference” in biomarkers between the vitamin C and control groups.
Less is more
The result is the latest disappointment in a series of disappointing trial results for sepsis treatments. While antibiotics remain essential to managing sepsis, there have, says Adhikari, been about 100 trials of other treatments designed to improve the body’s response to infection, and none has worked.
“Over the past two decades when we have tested everyday interventions, a lot of them have shown no benefit, and some actually caused quite marked harm.” Anders Perner
Perner believes the problem with some of the interventions tried is that physicians have misunderstood the body’s response. In evolutionary terms, humans have developed adaptive mechanisms for fighting infection, he says: “In the past two decades we have probably misunderstood some of these adaptive mechanisms and thought that they were therapeutic targets that we would try to normalise, but they were actually beneficial adaptive responses, and when you then try to normalise adaptations, you may harm the patient by doing so.” As a result, Perner argues that we have now reached a “new normal, where less is more”. While personalised medicine is increasingly used in conditions such as cancer, all patients with sepsis have received the same care. He believes that the most promising areas of research now lie in subdividing patients with septic shock into smaller clusters of patients that “may benefit from more precision-based medicine”, which would take into account different types of infection and different types of host response.
The result of Adhikari and Lamontagne's vitamin C trial showed "no real difference" in biomarkers.
100 Neill Adhikari 49
There have been this many treatment trials designed to improve the body's response to infection and none has worked.
Numstocker/
Shutterstock.com
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