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!
​

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.
​

What's the Problem?

Most radiologic exams, especially computed tomography (CT) scans, use iodinated contrast media in order to improve image quality and therefore 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 dangerous ☠


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 were 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 AMAZING trial published in February 2017 provides fairly good evidence that prophylactic hydration with normal saline does not lower the incidence of CIN.

EC Nijssen et al. The Lancet, Feb. 2017


The Bottom Line:

- Until proven otherwise IV contrast media should be considered potentially nephrotoxic. This is supported by preclinical and cardiac studies. If this is relevant in clinical practice (escpecially for CT scans) is not proven so far... but also difficult to disapprove!

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

​- While prophylactic hydration of the patient has no benefit in regards of CIN, keeping patients well hydrated in general is certainly strongly recommended.

- Quick and proper treatment of the patients underlying condition is most probably more important than worrying about CIN and therefore withholding an indicated enhanced CT-scan!

When filling out the form for a CT scan in you hospital you will not only have to provide clinical information about the patient but almost certainly also the latest creatinine levels. This information is required as many clinicians are worried that IV contrast media might cause iatrogenic acute kidney injury and therefore increased rates of dialysis, renal failure, and death. Despite several reports of contrast-induced nephropathies in the past, the causal relationship between IV contrast media and the development of acute kidney injury has been challenged recently (Read our previous summary​ HERE).

​
The major problem is that performing a randomized controlled trial to elucidate the true incidence of contrast-induced nephropathy is considered unethical because of the presumption that contrast media administration is a direct cause of acute kidney injury.

While the discussion goes on Hinson et al. have come up with another nice piece of evidence that in emergency situations there is no reason to withhold the application of IV contrast for CT scans when required.

​In this single-center retrospective cohort study researchers have included a total of 17'934 patient visits to their emergency department over a period of 5 years. They analysed three patient groups that where demographically similar: contrast-enhanced CT, unenhanced CT and no CT scan performed. Patients were included when their initial serum creatinine level was between 35 umol/L and 352 umol/L. Of all CT scans, 57.2 percent were contrast-enhanced. The probability of developing acute kidney injury was 6.8 percent for patients undergoing contrast-enhanced CT, 8.9 percent for patients receiving unenhanced CT and 8.1 percent for patients not receiving CT at all. This proofs to be the largest controlled study of its kind in the emergency department and shows that:

In current clinical context, contrast media administration for CT scans is NOT associated with an increased incidence of acute kidney injury. And even though a large randomised controlled trial is still missing it seems safe...

​
To Conclude:
​
There is no reason to withhold the use of IV contrast media in cases where contrast-enhanced CT is indicated to avoid delayed or missed diagnosis of critical disease.


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

Crit Cloud Review from 18/01/2015

For the resuscitation out-of-hospital one of the mainstays besides compression and defibrillation ist the application of adrenalin and amiodarone. According to the new ACLS guidelines 2015 these are the only drugs remaining in the treatment for shockable rhythms.

​While adrenaline is given for maximum vasoconstriction in order to promote coronary perfusion pressure CPP, amiodarone and sometimes lidocaine are used to promote successful defibrillation of shock-refractory ventricular fibrillation VF or pulseless ventricular tachycardia VT. While the usage of these drugs is undoubtedly very effective in patients with existing circulation the effectiveness during resuscitation remains a matter of debate.

The Effect of Adrenaline

As a matter of fact it has never been proven that adrenalin actually improves long-term outcome. In 2014 Steve Lin and colleagues published a systemativ review on the efficacy of adrenaline in adult out-of-hospital cardiac arrest (OHCA). They were able to show that according to current evidence standard dose adrenaline (1mg) improved rates of survival to hospital admission and return of spontaneous circulation (ROSC) but had no benefit in means of survival to discharge or neurologic outcomes.

What about Amiodarone and Lidocaine?

Kudenchuck et al. now made the effort to look into the efficacy of amiodarone and lidocaine in the setting of OHCA. Used according to the ACLS guidelines 2016 amidarone is given after the third shock applied when treating a shockable rhythm. Two rather small controlled trials have shown so far that using amidarone actually does increase the likelihood of ROSC and the chance to arrive at a hospital alive. It's impact on survival to hospital discharge and neurologic outcome though remains uncertain.

In this randomized, double-blind trial, the investigators compared parenteral amiodarone, lidocaine and saline placebo in adult, non-traumatic, OHCA. They ended up with 3026 patients meeting inclusion criteria and which were randomly assigned to receive amiodarone, lidocaine or saline placebo for treatment. They finally found that neither amiodarone nor lidocaine improved rate of survival to discharge or neurologic outcome significantly. There were also no differences in these outcomes between amiodarone and lidocaine. Across these trial groups also in-hospital care like frequency of coronary catheterisation, therapeutic hypothermia and withdrawal of life-sustaining  treatments did not really differ, making a bias due to treatments after admission unlikely.

- This study was not able to show any benefit of amiodarone or lidocaine in the the setting of OHCA  in terms of survival to hospital discharge and neurologic outcome

- Amiodarone seems to improve the likelihood of ROSC and survival to hospital admission (similar to adrenaline)

- As there are no other options, I believe amiodarone should remain part of the standard treatment for shockable rhythms in OHCA

- Lidocaine can be safely removed from CPR sets as there is no benefit of over amiodarone

​
Read here:

N Engl J Med 2016;374:1711-22

Resuscitation, June 2014, Vol 85, Issue 6, p 732-740

New ACLS Guidelines 2015, The Changes

As posted on BIJC before, Asad et al. had performed a systematic review on the usage of ketamine as a continuous infusion (>24h) in intensive care patients. The same authors have now published a narrative review providing a more depth discussion about the pharmacological and pharmacokinetic properties of ketamine. Also they present recommendations for dosing and monitoring in an ICU setting.

Current evidence shows that Ketamine... 

- Has no adverse effects on the gastrointestinal tract (bleeding) and does not cause acute kidney injury (compared to nonsteroidal anti-inflammatory drungs, NSAID's) 

- Does not negatively influence bowel motility (in contrast to opioids)

- Preserves laryngeal protective reflexes

- Lowers airway resistance

- Increases lung compliance

- Is less likely to cause respiratory depression

- Is sympathomimetic, facilitates adrenergic transmission and inhibits synaptic catecholamine reuptake, therefore increasing heart rate and blood pressure

Ketamine...

- Might increase pulmonary airway pressure and therefore aggravate pulmonary hypertension

​- Might cause well known psychotomimetic effects which are of concern in the critically ill patient as this might predispose to delirium

- Interacts with benzodiazepines via the P450 pathway which could result in drug accumulation and prolonged recovery
​

- Ketamine need not to be avoided in patients at risk for seizures, particularly when used for analgosedation for short periods in the ICU setting

- Current evidence shows no increased intracranial pressure or associated adverse neurologic outcomes associated with ketamine administration in critically ill patients
​

Fluids are one of the cornerstones in the treatment of patients with shock. But with any drug applied, also fluids can harm if given inappropriately! While inadequate fluid resuscitation might result in tissue hypoperfusion and worsening of end-organ function, to much fluid might lead to problems like pulmonary oedema and finally increased mortality. Many measures are used in clinical practice, but most of them lack specificity and are not very representative as a sole marker. One of the better methods to evaluate fluid requirements is the use of dynamic measures that estimate the change in cardiac output (CO) in response to a fluid bolus.

In this regard the use of point-of-care ultrasound (POCUS) has become increasingly attractive in order to use basic critical care ultrasound to asses the need of fluids in a specific clinical setting. Lee at al. have now looked at the sonographic assessment of the inferior vena cava and lung ultrasound in order to quite fluid therapy in intensive care. By taking into account current evidence they have produced an algorithm using these measures to help guiding fluid therapy.

As with any measurement in critically ill patients the pathophysiologic cause of shock must be taken into account. The algorithm presented here seems to work best in patients in hypovolemic shock. To fully understand the following algorithm and its limitations we recommend to read the open access article (see link below).

In conclusion:
The algorithm provided is a helpful tool to help assess the need of fluids in a simple and quick manner.


Lee C et al. J of Crit Care 31 (2016) 96-100          OPEN ACCESS

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 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:

​

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.