Metabolic resuscitation for sepsis is currently quite controversial. Marik et al. published a before-after study in 2017 describing the combination of hydrocortisone, ascorbate, and thiamine for septic shock.1 That study incited a media storm of surprising intensity. Currently, several multi-center RCTs are underway to answer this question more definitively. In the interim, some additional before/after trials may emerge. These studies likely won’t answer the question, but they may provide us with some clues about whether metabolic resuscitation is on the right track.
Brief rationale for metabolic resuscitation in severe community-acquired pneumonia
Steroid: Mounting evidence supports the use of steroid for severe community-acquired pneumonia. This evidence was explored on this blog in 2015 here. Consensus guidelines by the SCCM and ESICM societies subsequently recommended steroid for severe community-acquired pneumonia in 2017.2 Thus, the use of steroid for severe community-acquired pneumonia is supported by several RCTs as well as society guidelines.3
Ascorbate & Thiamine: The rationale for using ascorbate and thiamine in sepsis was previously explored on the blog here. Ascorbate is often deficient among patients with pneumonia, with some evidence suggesting that it might be beneficial in this population.4
Kim et al 2018: Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study.
This is a single-center before-after trial describing the use of metabolic resuscitation for patients admitted to the ICU with severe pneumonia.5 In June 2017, their hospital started routinely using hydrocortisone, ascorbate, and thiamine for severe pneumonia. This allowed them to perform a retrospective before/after study comparing patients admitted in two consecutive years over a matching timeframe (June-January).
Exclusion criteria included the following:
- Patients who only required conventional oxygen therapy
- Delayed ICU admission (>48 hours after hospitalization)
- Delayed metabolic resuscitation (>48 hours after hospitalization)
The primary outcome was hospital mortality. Secondary outcomes included pressor-free days, vent-free days, and ICU length of stay.
Primary unadjusted analysis
Baseline characteristics of both patient groups are shown above. Patients in the treatment group were somewhat sicker (with a greater rate of renal replacement therapy and vasopressor use). Differences in renal replacement use were significant (p=0.004). Nonetheless, patients in the treatment group had a lower hospital mortality:
Thus, patients in the treatment group were sicker at baseline, but ultimately fared better. The unadjusted mortality difference isn’t statistically significant, but this inversion is notable.
Subgroup analysis
Subgroup analysis was performed to evaluated patients with APACHE II score >28 and PaO2/FiO2 ratio <120. These cutoff values are both the median values among all patients, so these subgroups evaluate the sicker half of patients in each cohort. In both cases, metabolic resuscitation seemed to improve mortality:
Propensity score analysis
Propensity matching is a statistical technique to account for differences in baseline variables (with the goal of eliminating confounding effects of these variables). This is accomplished roughly as follows:
- Differences in baseline variables between the treatment and control groups are analyzed. Baseline variables are combined to create a propensity score that describes the likelihood of the patient’s being assigned to the treatment group.
- Pairs of patients (one in the treatment and one in the control group) are identified whose propensity scores match. Combining numerous propensity-matched pairs generates two new groups (each of which is a subset of the original groups). These propensity-matched groups should ideally be better matched than the original groups.
Propensity-matching revealed two 36-patient groups. Compared to the original groups, these groups were better matched:
Within the propensity-matched groups, metabolic resuscitation did reduce mortality with a marginally significant p-value of 0.04:
Propensity matching can’t magically convert a retrospective study into a prospective, double-blind RCT. Rather, propensity matching is a bit like multivariable statistical analysis: it ought to get you closer to the truth but there’s no guarantee (especially if numerous interacting covariates are present). Propensity matching works best if no medical judgement is used to determine which patients receive treatment, which is actually the case here:
Ultimately this analysis isn’t definitive for several reasons: small sample size, marginal p-value, and use of propensity matching. No matter how good propensity matching is, it cannot correct for non-random sources of bias (e.g. improvements in critical care between 2016 and 2017).
Adverse events
No increase in acute kidney injury or superinfection was detected. However, this study wasn’t powered to detect rare adverse events.
Limitations
They are numerous:
- Small size
- Single-center
- Non-randomized, non-blinded
- Baseline imbalance in patient groups (which is partially addressed by propensity-matching analysis)
- 65% of patients in the control group received steroid. This suggests that most treatment differences will reflect the addition of ascorbate & thiamine treatment. However, some benefit due to steroid alone cannot be excluded.
- The use of steroid for community-acquired pneumonia is supported by several RCTs and currently recommended by SCCM/ESICM guidelines.2 However, metabolic resuscitation with hydrocortisone, ascorbate, and thiamine remains quite controversial.
- Kim 2018 performed a before/after study evaluating metabolic resuscitation for patients admitted to an ICU with severe pneumonia.5 Various analyses suggest a mortality benefit, particularly among the sickest patients. However, this study is far from definitive due to numerous limitations.
- A multi-center RCT is needed to address this question. In the interim, outcomes from this hospital suggest that metabolic resuscitation is currently a reasonable treatment option for severe community-acquired pneumonia admitted to the ICU.
Opening image courtesy of Dr Chris O'Donnell.
Josh Farkas
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Not a crit care doc but from my outside perspective I don’t understand the reluctance in the FOAM community to embrace this metabolic resuscitation cocktail- at least until better evidence comes out. I understand it is cool to be a skeptic. But considering all of the other stuff we have done in the past and continue to do that has very weak evidence this therapy has the trifecta of being cheap, low side effect profile and potentially very high upside. If it ends up being a fluke we can scrap it and move on.
We’re all basically dancing on a fence here – trying to avoid premature adoption of stuff that doesn’t work, but simultaneously trying to promote early adoption of stuff that does. It’s not easy. Inevitably we will all be wrong from time to time.
Gerald: I agree with you. The reluctance of the FOAM community as well as the Critical Care Medicine community to even consider this a viable treatment option is quite stunning and horrifying. This is highlighted by the latest publication from the Sepsis Research community; see Surviving Sepsis Campaign: Research Priorities for Sepsis and Septic Shock;; Craig M. Coopersmith, MD, FCCM (Co-chair); Daniel De Backer, MD, PhD (Co-chair) recently published in Critical Care Medicine; this potentially life-saving intervention is not even mentioned in this document. We (at our medical center) have now treated over 700 patients and over 1000 patients (I get e-mails daily from families and clinicians around the world) have been treated with this therapeutic intervention with great success. One anecdote is one anecdote, however, 1700 anecdotes is a large, real-world case series. Furthermore with the dosing strategy that we suggest we are unaware of a single reported complication or side effect. If one combines the 2 observational studies (testing the combination) as well as the “3 1/2” RCT’s testing the use of vitamin C “alone” in sepsis produces an impressive mortality reduction; OR 0.30 (95% CI 0.16-0.56, p=0.0001) . The NNT to save live one life is 4.2.… Read more »
I agree Dr. Marik- even if the benefit is 10x more modest- 1:40 – I shudder to think of the number of potential lives lost awaiting the more robust RCT data. All because skeptics have been burnt in the past and yet continue to provide much more expensive therapies with NNTs of infinity.
I understand the reluctance. The critical care community has been duped before (Xigris, etc) and the Surviving Sepsis Campaign has been slow to adopt change. Multiple physicians at my institution remain very skeptical; however, most patients with sepsis/severe PNA already receive steroids. The addition of thiamine/VitC seems very reasonable given cost/side effect profile/etc. I currently prescribe to the metabolic resuscitation of sepsis and eagerly await more robust data.
Thanks for the nice concise review. I’m interested about the strength of benefit of steroids in CAP. Many of the studies in prior posts had soft endpoints. Recent systematic review in clinical infectious diseases found no benefit to steroids for 30-day mortality (which probably shouldn’t be a surprise as hard to show mortality benefit with such a simple intervention). AS we’ve discussed before, I’m hopeful that metabolic therapy will work but I’m not sure the strength of rec for the steroids is that strong. Interested to hear more from you on this.
Thanks!
Study: Corticosteroids In Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review And Individual Patient Data Meta-Analysis Briel, M., et al, Clin Infect Dis 66(3):346, January 18, 2018
CAP is tricky because it spans a spectrum of severity from outpatients to ICU. The benefit of steroid depends on severity. Also many potential benefits are hazy (shown in only a small number of studies or appear only in meta-analysis). A reasonable summary might be as follows:
[1] For patients getting admitted to the wards with moderate-severe pneumonia, steroid probably reduces the length of stay by about a day.
[2] For septic/intubated pneumonia patients, steroid probably accelerates weaning off mechanical ventilation (ADRENAL, APPROACHSS trials).
[3] The sicker and more systemically inflamed the patient is, the more they may may benefit from steroid (e.g. pointless for the outpatient, most beneficial in septic/intubated patient).
There are other benefits which are probable but not well proven (e.g. avoidance of intubation). I don’t think there’s any good mortality evidence, but that would be difficult to obtain. Steroids don’t seem to work well for viral pneumonia (e.g. influenza) and should probably be avoided in severe immunocompromise.
Anand: Steroids alone have a limited role in the treatment of CAP (see; The role of glucocorticoids as adjunctive treatment for sepsis in the modern era. Lancet Resp Med 2018). However steroids act synergystically with Vitamin C and thiamine in patients with sepsis to alter the patho-physiological process and improve patient outcome. Each component is essential for the metabolic resuscitation protocol to act optimally.
Even the “comprehensive” review posted of steroids in CAP this article reference overall shows poor if any reliable data to use steroids. More recent studies since that review have further showed a modest if any existing benefit to steroids. There has been zero RELIABLE evidence giving IV vitamins is helpful for anything besides nutritional deficiencies or things like wernickes. Huge fan of this site but I feel you all have cherry picked data from a weak pool of studies to support an unproven regimen. If you wanna use the regimen be my guest but at least admit it’s based on your gut and no true quality evidence. Yes it seems to have a low ADR profile but so do many therapies that are unproven. We all want to give the best care but call a spade a spade please. Not trying to throw shade on this website as I faithfully read all its articles but I think a healthy dose of skepticism would’ve done this article well. Perhaps this regimen will one day be actually proven to work and that would be a game changer and amazing but I have seen so many promising therapies come and go that I… Read more »
Agree the data is far from conclusive and lots of smart people are not using this tx.
With regards to the cherry-picking issue: prior to the initial post on metabolic resus I looked up all studies regarding IV vitamin C in sepsis or related topics. They were essentially all positive studies (with regards to some outcomes at least – not all showed improvement in the primary endpoint). Weak, yes. Small, yes. Debatable, for sure. But there seemed to be a consistent signal of some benefit. That’s why I wrote the post. Are you aware of studies which showed harm that I’ve left out? If so it certainly wasn’t my intention.
Sorry that was more a reference of steroids in CAP. Which I should’ve specified. My issue with IV vitamins is simply a lack of reliable and meaningful data. And the small/weak data supporting it I simply don’t think passes an astute clinicians standards to make it clinically useful. Again not to say it shouldn’t be done and I have colleagues who advocate for this regimen but as a foam community teaching providers who haven’t maybe seen as many “promising” therapies fade away as us, I just wanted to point out to some of the younger readers that the clinical bottom line is there’s really no reliable evidence to show this therapy works. Again if the therapy is proven to work I will whole heartedly endorse it. In the meantime if you wanna give it by all means do so but recognize there is no good Data to support you either way (in my very humble opinion). I do recognize that you acknowledged this in the original article though the undertone seemed to be an overall endorsement of the therapy. Thanks for the thoughtful reply and keep up the good work. I always enjoy pretty much every article on this site.… Read more »
Dr. Mariks point above that “HAT” therapy has an estimated NNT of 4.2 to save a life should suggest to the skeptic that this therapy is potent enough that its effects can be “palpated”/”sensed” by even a junior clinician at the bedside, as opposed to, for instance, ASA in AMI (i.e 4,2 is a potency/impact 2nd only to the power of defibrillating VT/VF patients which has a NNT of 2.5). I would like to argue you dont need large trials to assess the efficacy of such a potent therapy. The safety and cost of these medicines are unparalleled and with an estimated potency this large, I would simply encourage skeptics to try it, without fear of harm to the patient (decades of unparalleled safety associated with this therapy). They will be pleasantly surprised with consistent appearance of 1) rapid, temporally associated decreases in vasopressors, of magnitudes that will be truly surprising, (if you have treated septic shock patients for a living for any appreciable amount of time) leading to vasopressor durations of consistently less than one day, even in 2-3 pressor shock states and 2) surprising preservation of urine output/renal function. Truly clinically startling to even the minimally experienced clinician.… Read more »
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