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“I've never known any trouble than an hour's reading didn't assuage.”
The last few decades have infamously boasted numerous failed therapies for sepsis and septic shock. Because sepsis represents an explosive and chaotic cacophony of pro and anti-inflammatory mediators – treatments which are overly specific are unlikely to silence a dissonant septic crescendo. This may be akin to removing a single musician from a poorly orchestrated symphony; a more harmonious intervention may be to replace the conductor.
From the aforementioned reasoning, hydrocortisone, ascorbic acid and thiamine (HAT) may be beneficial in sepsis and septic shock as animal data and observational human data suggest that HAT therapy acts proximally upon the septic ensemble. Through the noise of the current discord encircling metabolic septic resuscitation, I had the opportunity to pose a handful of questions to the originator of HAT therapy – Dr. Paul Marik.
I attended your keynote address at the Canadian Critical Care Forum in Toronto this year. You started your talk with a story about how you came to initiate HAT therapy in early 2016 – can you explain to readers how you introduced this protocol into your practice?
Dr. Marik: This dates back to January of 2016. I was presented with a 53 year old previously healthy female who had acute cholecystitis and overwhelming septic shock with acute respiratory, cardiac, metabolic and kidney failure who appeared almost certain to be destined to die. In a situation like this one has to think out-side of the box and pull out all the stops. I was aware of the experimental data on the use of vitamin C for sepsis as well as Dr. Fowler’s preliminary data and decided I would try a combination of Vitamin C and corticosteroids, on the presumption that they would act synergistically to reverse the patient’s dire situation.
However, I did not expect her to survive and was dumb-founded the next day when I returned to work; she had been almost weaned off all vasopressors and her renal function had improved. She subsequently grew E.coli and Clostridia perfringens from her blood cultures. She was discharged from the ICU on day 4 with no residual organ dysfunction. I was completely amazed by the rapid reversal of what appeared to be a fatal disease. So I thought I had an obligation to try this again on our next patient with septic shock. This time we added intravenous thiamine to the mix … and the response was exactly the same as the first case. As all three agents are widely available and approved drugs which are devoid of side effects and extremely cheap - I felt I had an ethical obligation to continue to treat our patients with severe sepsis and septic shock with this cocktail. And indeed, the response was reproducible time over time over time. This led to us reporting our initial experience with this cocktail in a retrospective, before-after propensity adjusted study reported in Chest in June of 2017. We have to date treated over 850 patients with the same reproducible findings. In addition, hundreds of patients have been treated world-wide and this combination has become the standard of care in a number of hospital in the US and abroad.
Why is the dose and route of administration of ascorbic acid so important in sepsis/septic shock? Additionally, how should a clinician think about vitamin C provision in the setting of free heme moieties [e.g. hemolysis or rhabdomyolysis]?
Dr. Marik: Clinical studies have demonstrated that ALL patients with sepsis have low vitamin C levels; in many patients the levels are undetectable. The low levels are due to metabolic consumption as well as increased urinary losses. Due to saturable absorption kinetics and decreased absorption in critical illness it is not possible to restore normal levels with oral supplementation. Hence vitamin C must be given intravenously. In healthy volunteers, large doses of vitamin C can be given with no evidence of a pro-oxidant effect. However, in patients with sepsis and ischemia-reperfusion injuries free iron is present and in high doses vitamin C may have pro-oxidant effects (this is reviewed in my recent Nutrients paper – see the last question below). This concept has been confirmed in experimental models in which a relatively narrow therapeutic window exists. We have very preliminary data in our septic patients which confirms this concept. We therefore believe that a dose of 6g/day is close to the ideal dose, but further studies are clearly required. More importantly, it may be necessary to prolong the treatment course in some patients and possibly to convert the patients to oral vitamin C on discharge from the ICU.
If you were in a resource-limited setting and could only administer one or two components of HAT therapy, which component would you forfeit first? Second? Why?
Dr. Marik: I think that all three components act synergistically to reverse the pathological process in sepsis. I would therefore be reluctant to drop/eliminate any of the components; it’s like a recipe for a gourmet cake; it will flop without all the ingredients. I am hopeful that a pharmaceutical company can formulate all the components into an easy to administer vial; this would make the administration easier and more cost effective.
There are multiple on-going clinical trials looking at HAT therapy and/or its sub-components. Which 1-2 of these trials do you most look forward to learning the results and why?
Dr. Marik: The inclusion criteria and trial design differ amongst the studies (not all use all three components). Therefore, an analysis of all the trials will provide important insight into this therapy. The ACTS and ORANGEs trial should be completed by spring of 2019; these trials will therefore be important to provide early data on whether this protocol improves patient outcomes or not.
Do you think there is a duration of sepsis or septic shock after which HAT therapy may be less effective and why?
Dr. Marik: Yes. Definitely YES. The earlier the treatment is started the better. I think that after a “long delay,” patients evolve into a phase of irreversible multi-system organ failure and at this time treatment may be futile.
How do you respond to those critics who say your efforts to promote HAT therapy could make it harder for investigators to randomize patients to control arms of future trials?
Dr. Marik: Well, if the early multicenter RCT’s demonstrate that HAT therapy positively influences patient centered-outcomes, I believe that it would be unethical not to treat patients with this protocol and unethical to do further studies randomizing patients to placebo. However, many questions will still remain unanswered; i.e. optimal dosing, selection of patients most likely to benefit, the use of additional adjuvant therapies, etc. So this will not be the final word on the treatment of sepsis.
Could you recommend one or two good reviews on HAT therapy for our readers?
Dr. Marik: This is complex subject that requires in-depth reading. However, I would recommend two recent publications on this topic, namely:
Moskowitz A, Andersen LW, Huang D et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Crit Care 2018; 22:283.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org