Vitamin C – To the Rescue?

Sometimes there's this moment you read about medical research in the news... sometimes you read lots of rubbish on medical issues in the news... but sometimes you stop and read, and you don't know what to think. This happened to quite some of us a couple of days ago when reading the headlines in the British Independent:

Well, it's not very often you read the term sepsis in the news but the word 'cure' causes estonishment or rather misbelief.  Further reading certainly catches your attention: 'A doctor in the US state of Virginia claims to have found his own cure for sepsis' and 'Since then, he has used it to treat 150 sepsis patients.  Just one has died of the condition, claims Dr Marik'. And it's not an article from some remote pseude magazine... no, it has been published in 'Chest'! And all this is not due to some novel molecule... it's all about Vitamin C!

Thanks to #FOAMed quite some smart brains have looked into this topic already... 

So here's the most important facts you need to know - in short:

What's the Story?

Paul Marik et al. have published  a 

single-centre retrospective cohort study 

in which they have treated

47 consecutive septic patients over a periode of 7 months with intravenous vitamin C (1.5g 6-hourly), hydrocortisone (50mg 6-hourly) and thiamine (200mg 12-hourly)

and then compared these patients to

47 septic patients treated in their unit during the preceding 7 months

They performed

Propensity score matching

and found 

An overall hospital mortality of 40.4% in the control group compared to 8.5% in the intervention group

This means

An absolute risk reduction of 31.9% and also according to the authors none of the patients in the intervention arm died of sepsis!

What Does This Mean?

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 HERE

Studies like this one are an important part of science,
but observational studies are observational... not proof!

Why Vitamin C in Sepsis?

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.

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

More Ifs and Buts

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.

The Current Bottom Line

​- The study published by Marik et al. is purely observational and provides no proof at all.

- Just because vitamine C might be safe in Sepsis does not mean this has to be given. At this stage no recommendation can be made for the use of vitamin C in sepsis.

- Studies like these are an part of research itself - However, the use of the term 'cure' seem problematic and inappropriate in this context.

Marik et. al, J Chest 2017

Contrast-Induced Nephropathy: Preventing Complications That Don’t Exist?


What's the Problem?

Most radiologic exams, especially computed tomography (CT) scans, use iodinated contrast media in order to improve image quality and therefore improve diagnostic accuracy. The decision on whether to use IV contrast media is also made on the background of pre-existing renal function as the use of these agents has been linked to increased risk of adverse events like: acute kidney injury, initiation of dialysis, renal failure, stroke, myocardial infarction, and death.
-> So called 'contrast-induced nephropathy' or short CIN!

The REAL PROBLEM is that randomising patients to receive or not receive a contrast-enhanced imaging study when indicated is simply not feasible.

- It has been presumed that these agents are a direct cause of acute kidney injury - and therefore dangerou

But, Hold On: Is There Really a Problem?

The causal relationship between the application of IV contrast media and the development of acute kidney injury has recently been questioned - Seriously questioned!

- It is interesting to notice that most of our current understanding of contrast-induced nephropathy derives from arterial angiography studies.

- Also, many studies looking into this problem we performed without any control populations. These investigators obviously assumed that CIN undoubtably exists but did not compare their cohort to patients not receiving contrast media!

Mitchell AM et al. nn Emerg Med. 2015 Sep;66(3):267-274 or Mitchell AM et al. lin J Am Soc Nephrol. 2010 Jan;5(1):4-9. doi: 10 and more!

- As a matter of fact, serum creatinine level fluctuations (meeting the criteria for contrast induced nephropathy) occur in patients in patients undergoing unenhanced CT at similar rates to those published after contrast-enhanced CT. Newhouse JH et al. (see reference below) for instance looked at a total of over 32'000 patients and noticed that creatinine level increases in patients who are not receiving contrast material as often as it does in published series of patients who are receiving contrast material.

AJR Am J Roentgenol. 2008 Aug;191(2):376-82

Newhouse already suspected that CIN may have been overestimated so far! Also other studies found no increased of acute kidney injury after after contrast media administration in any patient group, regardless of baseline renal function.

Crit Cloud review from March 2014

Crit Cloud review from January 2015

Maybe There is No Major Problem

Two recently published paper further challenge the paradigm of contrast-induced nephropathy.

Hinson J et al. published a single-center retrospective cohort study in 2016 in which a total of 17'934 patient visits to their emergency department over a period of 5 years. were included. They analysed three patient groups that where demographically similar: contrast-enhanced CT, unenhanced CT and no CT scan performed. In this largest controlled study of it's kind no difference was found in the incidence of acute kidney injury.

Hinson J et al. Annals of Emergency Medicine, 2017; DOI: 10.1016/j.annemergmed.2016.11.021

And just now Wilhelm-Leen et al. have published their analysis of almost 6'000'000 hospitalised patients in the united states and their risk of radio-contrast associated nephropathy. Their results strongly suggest, that the incremental risk of AKI that can be attributed to contrast-media is modest at worst, and almost certainly overestimated!

Wilhelm-Leen Emilee, J Am Soc Nephrol 28: 653-659,2017

A most recent editorial by Lopez-Ruiz at al. puts this new knowledge into a new perspective.

J Am Soc Nephrol. 2017 Feb;28(2):397-399

- If contrast induced nephropathy does exist, it's relevance in clinical practice seems to have been overestimated so far!

Is There a Way to Prevents Contrast-Induced Nephropathy?

The application of sodium bicarbonate, N-acetylcysteine, statins, ascorbic acid and pre-hydration with IV fluids have been recommended for the prevention of CIN in patients with compromised renal function. Among all of these measures hydration with intravenous saline is considered the cornerstone in the prevention of CIN.

And luckily enough just now The Lancet provides us with a first answer to this specific question. 

The Bottom Line:

- Radiocontrast-media seem to have some nephrotoxic properties. This is supported by preclinical and cardiac studies. If this is relevant in clinical practice is not proven... but also difficult to disapprove!

- The risk of contrast-induced nephropathy itself though has certainly been oversetimated so far

​- Hypdration certainly is one cornerstone in this whole topic. While 

The BAT and the SOFA! The 3rd Consensus Definitions for Sepsis are out

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.

Sepsis (related organ dysfunction) is now defined by a SOFA score of 2 points or more

The Quick Approach to Sepsis - The BAT

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:

The New Approach to Septic Shock -Vasopressors and Lactate

Septic shock is now defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of death than sepsis alone. Keeping a long story short:

Septic Shock is now:

- The need for vasopressors to maintain a mean arterial pressure of at least 65mmHg 
- a serum lactate level of more than 2mmol/L... after adequate fluid resuscitation 

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.