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Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) by ESICM and SCCM

​The headlines in the news 2017 were remarkable indeed: "Doctor believes he has found the cure for sepsis..." or "Doctor says improvised 'cure' for sepsis has had remarkable results".

Dr. Paul Marik described his observation in an interview in 2017, where he mentions several cases of sepsis that have almost miraculously responded to the application of vitamin c (watch here: Interview on WAVY TV). He even continues, that since then they see "the same thing over and over again". This implicated that these results were reproducible. He finally stated that the current data at that stage were "impressive" and that there was enough basic science to show that it works.

Vitamin C has many interesting properties that theoretically could be on benefit in sepsis. (read here: Crit☁ post on Vitamin C). Its application was already proposed for the treatment of other diseases like the common cold of Influenza. Despite some moderate positive influence observed, these results could not be reproduced in trials.

While the news picked up on this story as a miracle drug, Paul Marik et al. published their results of a before-and-after single-centre, retrospective cohort study in Chest 2017. In this paper, they compared 47 patients with sepsis that received the metabolic cocktail (Vitamin C 1.5g 6-hourly, hydrocortisone 50mg 6-hourly and thiamine 200mg 12-hourly) to 47 patients which did not - notably in a non-double-blinded, non-randomized fashion. Their results showed overall hospital mortality of 8.5% with the 'cocktail' and 40.4% without its application.​

This publication was reason enough to launch a small war of faith about sense and nonsense of this cocktail for sepsis.
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• At this stage there is NO evidence to support the routine use of Vitamin C in sepsis

 

• Sepsis is a complex syndrome and not a disease, it is unlikely a single substance will bring simple 'cure' to all patients

 

• Why on earth does it seem that the use of steroids are basic mainstay of sepsis treatment?

​Just as a reminder: Guidelines recommend against the routine use of glucocorticoids in patients with sepsis. However, corticosteroid therapy is appropriate in patients with septic shock that is refractory to adequate fluid resuscitation and vasopressor administration.


Fujii et al. JAMA. Published online January 17, 2020. doi:10.1001/jama.2019.22176​

​Teaching in medical school and opinions in literature are in agreement: The application of vasopressors requires central venous access. The reason for this are concerns that vasopressors given over a peripheral venous catheter (PCV) may cause phlebitis or even worse necrosis or ischemia through extravasation. 

​While irritation of a peripheral vein is often observed with the administration of drugs like potassium or amiodarone, this usually is not the case with the application of, e.g. norepinephrine. Besides, it is essential to keep in mind that the insertion of a central venous catheter (CVC) is technically demanding and takes a certain amount of time when performed correctly. The procedure is also associated with potentially dangerous complications that might be hazardous to the patient.

Therefore a fundamental question arises:

Do all patients that require vasopressors need a central venous catheter?
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Giving the current evidence available, it seems appropriate to conclude:

• The need for vasopressors itself is not a mandatory indication for central venous access

 

• Vasopressors can be safely given through a peripheral venous catheter
  • This is especially true when used for a limited time (e.g. less than 4 hours) and when applied in rather lower concentrations.

 

• ​In the critically ill central venous access will inevitably still be required (advantage of multiple lumens, difficult peripheral access, other drugs that do entitle the use of a  CVC etc.)

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These results are quite amazing on the first look, but there's more behind these numbers. Paul Marik has first of all published an observational study: unblinded, uncontrolled, retrospective and low in patient numbers.

There are several limitations that go hand in hand with studies as such and unblinded before-and-after studies have a lot. A major challenge in conducting observational studies is to draw inferences that are acceptably free from influences by overt biases, as well as to assess the influence of potential hidden biases. One of the biggest drawbacks in this current study is the timely/ seasonal difference when patients have been selected.
If you are interested to have a closer look on this you should read Dan's blog entry on stemlynsblog.org HERE. 

Studies like this one are an important part of science, but observational studies are observational... not proof!
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There is a scientific rationale behind all of this. As mentioned by Paul in his paper vitamin C levels do fall low in sepsis and the most efficient way to administer it is intravenously. The same is true for thiamin which also goes low in up to one third of all septic patients.

There are two rather small randomised control trials suggesting that vitamin C is safe in septic patients and might actually be of some degree of benefit for the patient.

Vitamin C

- Neutralizes free radicals and has therefore antioxydative properties 

- Is an important conenzyme for the procollagen-proline dioxygenase, which itself is necessary for the biosynthesis of stable collagen in our body. Vitamin C deficiency leeds to unstable collagen and therefore scurvy

- Is an important cofactor in the synthesis of steroids like cortisol and catecholamines like dopamine and noradrenalin as well 

- and it has many more functions that go beyond the scope of this blog entry!

However, the importance of vitamin C in the treatment and prevention of diseases like e.g. the common cold or influenza remains highly contrversial. The observation of some moderate positive influence on the course of disease in some studies could not be reproduced in other trials. 

Under normal circumstances vitamin C deficiency is practically non-existent in Europe, but becomes a fact during sepsis. If this is clinically relevant in septic patients seems plausible but remains to be elucidated.

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Shailja Chambial, Shailendra Dwivedi, Kamla Kant Shukla, Placheril J. John, and Praveen Sharma. Vitamin C in Disease Prevention and Cure: An Overview. Indian Journal of Clinical Biochemistry. Oktober 2013; 28(4): S. 314–328

H. Hemilä, E. Chalker: Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2013

R. M. Douglas, E. B. Chalker, B. Treacy: Vitamin C for preventing and treating the common cold. In: Cochrane Database of Systematic Reviews. 2000; 2:CD000980.

Another great read into the details: Josh Farkas from pulmcrit
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Sepsis is not a disease, its a clinical syndrome that has physiologic, biologic and biochemical abnormalities caused by a dysregulated inflammatory response to infection. The fact that different definitions have evolved since the early 1990s shows that we still struggle to definde sepsis as a single entity. This is one reason why a single therapy might not always be the best for each diesease causing sepsis.
 
Paul Marik’s publication is interesting and deserves respect. It’s an observational study but provides no evidence by far. Vitamin C might be an interesting novel approach to sepsis but the term ‘cure’ used in the media is inappropriate and misleading.
 
The term ‘cure for sepsis’ also implicates that vitamin C is a cure for all infections causing sepsis and is therefore problematic.
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Sepsis certainly keeps us going... either when treating patients on ICU or when it comes to the discussion on what actually sepsis is and how to define it. So far the SIRS (Systemic Inflammatory Response Syndrome) criteria have provided some degree of handle to cope with this syndrome but of course we weren't all quite happy with this. In fact every person with any sort of infectious disease will respond with 2 or more SIRS criteria... but doesn't necessarily have to be septic. As a matter of fact a SIRS is nothing else but a physiologic response to any sort of inflammation.


The New Approach to Sepsis - The SOFA

The new international consensus definitions for sepsis and septic shock try to focus on the fact that sepsis itself defines a life-threatening organ dysfunction caused by a dysregulated host response to infection. By saying this the aim is to provide a definition that allows early detection of septic patients and allow prompt and appropriate response. As even a modest degree of organ dysfunction is associated with an increased in-hospital mortality the SOFA score (Sequential or 'Sepsis-related' Organ Failure Assessment) was found to be the best scoring system for this purpose. It's well known, simple to use and has a well-validated relationship to mortality risk.
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Sepsis (related organ dysfunction) is now defined by a SOFA score increase of 2 points or more

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The Quick Approach to Sepsis - The BAT
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In the out-of-hospital setting, on the general wards or in the emergency department the task force recommends an altered bed side clinical score called the quickSOFA - or alternatively 'the BAT' score:

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The Bottom Line:

The way it looks like we are left with Sepsis and Septic Shock

Severe Sepsis has vanished and the question remains, whether these new definitions will actually benefit the ones that need it most... our septic patients!


​Singer M et al. JAMA. 2016;315(8):801-810.

Seymour CW et al. JAMA. 2016;315(8):762-774.

Shankar-Hari M et al.  JAMA. 2016;315(8):775-787.

Lactate is a small organic molecule with the chemical formula CH3CH(OH)CO2H and structurally looks like on the image to the left. It is produced in the cytoplasm of human cells mainly by anaerobic glycolysis by the conversion of pyruvate to lactate by LDH. This chemical reaction results typically in a blood lactate to pyruvate ratio of about 10:1. And while lactate is produced, NAD+ also is incurred, and this actually can accept protons itself, so does not result in acidosis itself.

Lactate arises from the production of energy by consuming glycogen and glucose.

As published in the New England Journal the ALBIOS trial has already received a lot of attention and was also one of the hot topics at the ISICEM in Brussels last week. So what’s the story. 

First there is the original article published in the recent NEJM. Gattinoni et al. have looked into the potential advantages in giving 20% albumin and cristalloid solutions to hypoalbuminic patients with severe sepsis compared to cristalloid solutions only. In the albumin group they aimed for a serum albumin concentration of 30g/L (a number hardly ever seen in any ICU patient) until discharge from the ICU or 28 days after randomization. 1818 patients were included and to make things short: The trial found no difference in 28-day mortality (primary outcome), 90-day mortality (secondary outcome), or any other relevant clinical endpoint (number of patients with organ dysfunction, degree of dysfunction, length of stay in ICU and the hospital).

So far for the original article. But now there is also this wonder-some supplementary appendix where the group has performed an unplanned subgroup analysis in septic shock patients only where a significant difference in the 90-day mortality was found - in favor for albumin. 

Indeed there is a lower number of deaths in the albumin group, but not in the p value when adjusted for clinically relevant variables. It might also be interesting to note that the 90-day mortality was a secondary endpoint and no subgroup analysis was performed of 28-day mortality among patients with septic shock.

My personal view on this topic is that the original article and the supplemental appendix provide no good reason to favor albumin in the treatment of septic patients in general. The evidence provided to support the application of hypertonic albumin in septic shock patient is also not very convincing. 

In regards of the SAFE study from 2004 the use of albumin will remain controversial and it will be interesting to see further trials upcoming in this field. It is also worthwhile remembering that albumin remains reasonably expensive and as Prof. Takala, Bern Switzerland, mentioned in Brussels last week: the money saved on avoiding unnecessary albumin infusions might be better invested in other ICU resourced proven to improve patient outcome. Comments?

Gattinoni L et al. N Engl J Med March 18, 2014

Gattinoni L et al. N Engl J Med March 18 2014: Supplemental Appendix

SAFE study. N Engl J Med 2004; 350:2247-2256