​Clin Gastroenterol Hepatol. 2020 Mar 30;S1542-3565(20)30426-2

More literature

Daniels L et al. BJS:  https://doi.org/10.1002/bjs.10309

Int J Colorectal Dis. 2015 Sep;30(9):1229-34.

​The International Liaison Committee on Resuscitation has published the last guidelines for advanced cardiac life support (ACLS) on resuscitation ILCOR in 2015. Usually, these statements are updated every five years, but 'Circulation' has now published an AHA (American Heart Association) focused update due to an increased number of studies looking at ACLS-specific interventions.


These updates are focused on three specific areas:

1. Advanced airway management
2. Vasopressors
3. Extracorporeal cardiopulmonary resuscitation ECPR

​No News in regards to Vasopressors and ECPR

Vasopressors in Cardiac Arrest

• Epinephrine (aka Adrenaline) should be administered to patients with cardiac arrest (Class I; Level of Evidence B-R)
• It is reasonable to administer 1mg every 3 to 5 minutes (Class IIa; Level of Evidence C-LD)
• High-dose epinephrine is not recommended for routine use in cardiac arrest

The bottom line:​ Great, these recommendations are no real news and do not change current guidelines at all.


Extracorporeal Cardiopulmonary Resucitation ECPR

• There is insufficient evidence to recommend the routine use of ECPR for patients with cardiac arrest AND ECPR may be considered for selected patients as rescue therapy when conventional CPR efforts are failing in settings in which it can be expeditiously implemented and supported by skilled providers

The bottom line: ECPR is not for on the roads and remains an exception in general.



Advanced Airway Management

Taking recent evidence into account the updated guidelines 2019 conclude:
​

• Either BMV or an advanced airway strategy may be considered during CPR for adult cardiac arrest in any setting (Class 2b; Level of Evidence B-R).
• If an advanced airway is used, the SGA can be used for adults with OHCA in settings with low tracheal intubation success rate or minimal training opportunities for ETT placement (Class 2a; Level of Evidence B-R).
• If an advanced airway is used, either the SGA or ETT can be used for adults with OHCA in settings with high tracheal intubation success rates or optimal training opportunities for ETT placement (Class 2a; Level of Evidence B-R).
• If an advanced airway is used in the in-hospital setting by expert providers trained in these procedures, either the SGA or ETT can be used (Class 2a; Level of Evidence B-R).
• Frequent experience or frequent retraining is recommended for providers who perform ETI (Class 1; Level of Evidence B-NR).
• Emergency medical services systems that perform prehospital intubation should provide a program of ongoing quality improvement to minimize complications and to track overall SGA and ETT placement success rates (Class 1; Level of Evidence C-EO).​

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​

• Bag mask ventilation (BMV) can be quite tricky, especially when performed by untrained personnel. 
• BMV is NOT a secure airway; the risk of aspiration is significant!

On the other hand

• While providing a 'secure' airway, successful endotracheal intubation requires skilled hands and regular training
• ETI's are mostly outside the scope of practice among many doctors, nursing staff or paramedics
• Intubations under CPR conditions are never easy and might be even more challenging out-of-hospital
• Again, CPR is often interrupted to provide optimal conditions for endotracheal intubation

It, therefore, seems plausible to put the supraglottic airway first. Not only first as a choice of airway management, but also one of the first things to do:

• Placing a supraglottic airway (SGA) is simple and straight forward. Anyone can learn this procedure in a short time. We teach ICU doctors and nurses successfully on how to use non-inflatable supraglottic airways (e.g. the i-Gel device) for CPR.
• Placing an SGA is easier than simple bag-mask ventilation (BMV)!
• An SGA allows continuous compressions and ventilation simultaneously - no need for deleterious interruptions
• An SGA protects the airway from aspiration fairly well - some devices even allow the introduction of a small suction catheter into the stomach
• Moreover, if required, endotracheal intubation can still be performed by using a bougie through the SGA. This provides another option to perform ETI without interruptions of chest compressions.
• And last but not least, SGA's allow continuous measurement of end-tidal CO2 ​

​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.
​

• 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.)

​

The Journal of Intensive Care Medicine has recently published a review of websites providing educational content that is part of the Free Open Access Meducation (FOAMed) movement. The authors have searched the web for critical care medicine education websites and have identified 97 sites they consider relevant for critical care.

These websites were then reviewed and evaluated using the Critical Care Medical Education Website Quality Evaluation Tool (CCMEWQET). They were then split up into three tertiles according to their score.

Congratulations to the Top Ten websites that indeed provide excellent educational information freely accessible.

Oh, and by the way we might mention that our small site Crit.Cloud has been considered among 96 other as relavant in this field and has ended up in the middle tertile with its ranking. 🙃
​
A big thank you to the authors of this paper for their excellent work and for providing us with an updated list of websites worth taking a closer look! We are delighted to follow their wish by sharing the table of these websites.

​
Wolbrink TA et al. J Intensive Care Med. 2018 Jan;34(1):3-16

​

The Naming of Furosemide


Researchers soon noticed that the diuretic effect of furosemide lasted for about 6 hours... 'LAsts for SIX hours'... and therefore gave it the name: LASIX!
​

​

​
​What is Furosemide

​Furosemide is an organic anion from the group of loop diuretics (as are bumetanide and torasemide) and is sold under the brand name of Lasix©. Its indications are for the treatment of oedema due to heart or liver disease as well as kidney disease. It is also used for the treatment of mild or moderate hypertension. Furosemide has become one of the cornerstones in the treatment of heart failure.

How does it work?

Furosemide can be applied by oral intake as a tablet or as an intravenous injection. Once in the bloodstream, it is predominantly bound to proteins (>90%).

Loop diuretics do not undergo glomerular filtration. In fact, they pass the glomerulus and are actively secreted across proximal tubular cells by organic anion transporters and the multidrug resistance-associated protein 4 (area A). It is important to know that non-steroidal anti-inflammatory drugs (NSAID) and endogenous uremic anions compete with this loop diuretic secretion and can cause 'diuretic resistance'.

Once loop diuretics have reached the tubular system, they bind to sodium-potassium-chloride co-transporters (NKCC2) in the ascending limb of the loop of Henle and block the reabsorption of these ions directly (area B). Further down at the macula densa they inhibit the same co-transporter (area B) thereby stimulating renin secretion and inhibiting tubuloglomerular feedback. This results in preserved glomerular filtration despite increased salt delivery to the macula densa. All this finally results in the loss of sodium, chloride and potassium and therefore loss of water.

Other Effects

Furosemide also interacts with other sodium-potassium-chloride co-transporters (NKCC1) elsewhere in the body:
- Blocking NKCC1 in the ear probably explains the ototoxicity of loop diuretics
- Blocking NKCC1 in smooth muscle cells causes vasodilation
​- Blocking NKCC1 in the afferent arteriole and near the macula densa elevates renin secretion and the generation of angiotensin II

These complex interactions on haemodynamics explain that the net response in each patient might be different. On the one hand, loop diuretics dilate blood vessels directly and increase the level of vasodilatory prostaglandins. On the other hand, some of these effects counteract each other making it difficult to predict which effect will finally predominate.

Many studies have looked closer into the vasoactive properties of furosemide. Current evidence indicates that it has a systemic venodilator effect which actually reduced preload acutely. The same investigators found a reduction in the right atrial pressure and the pulmonary capillary wedge pressure, presumably reflecting the systemic venodilator effect of furosemide.​

While the acute venodilator effect may be beneficial to the failing heart, its action on arteries might be detrimental. Several studies have shown that in patients with chronic heart failure furosemide causes arterial vasoconstriction. Also, there is one study showing that pulmonary vascular resistance in healthy volunteers rose significantly. 

Francis GS et al. described how the administration of furosemide actually led to decreased LV function, increased LV filling pressures, increases in MAP, SVR, plasma renin activity, and plasma noradrenaline levels.​


Beneficial venodilator response predominates over arterial vasoconstriction in patients with (1) myocardial infarction and (2) salt depleted volunteers.

Venous relaxant effect has not been demonstrated in patients with chronic heart failure. In this setting detrimental arterial vasoconstriction seems to predominate.

Pardeep S et al. Br J Clin Pharmacol. 2000 Jul; 50(1): 9–13.

Francis GS et al. Ann Int Med 1985; 103(1): 1-6.


Pharmacological Properties

Administered furosemide orally has a limited and highly variable bioavailability. The diuretic effect starts within the first hour, and the duration of action is around 6 hours (4-8 hours). Injected furosemide intravenously is approximately twice as potent on a per-milligramme basis as oral doses. 

In acute decompensated heart failure sodium retention becomes more avid and higher peak levels might be required to become more effective. This can be achieved by giving furosemide intravenously.

Once a loop diuretic is administered, the excretion of sodium chloride is increased for several hours. This is then followed by a period of very low sodium excretion resulting in a so-called 'post-diuretic retention'.​


How to use Furosemide for Acute Decompensated Heart Failure (ADHF)

So far for the basics of furosemide, but what about its usage for acutely decompensated heart failure? Should furosemide be given as soon as possible or not?

The 2013 ACCF/AHA guidelines for the management of patients with heart failure give diuretics a class I recommendation. The evidence behind these recommendations though is level B or level C only! So these recommendations are not really helpful to answer this question.

The authors in UpToDate® mention diuretics directly after the use of oxygen. For patients with evidence of volume overload their recommendation is to give loop diuretics immediately (Grade 1B) as there is evidence that in this setting this may improve outcomes. They also suggest that patients with ADHF usually are volume overloaded, therefore indicating that most patients should receive diuretics ASAP.  
The only exception they mention where some delay in inducing diuresis might be required is in patients with severe hypotension or cardiogenic shock.

There is reasonable doubt that patients with ADHF are usually volume overloaded, as suggested by UpToDate®. Zile MR et al. demonstrated that while most patients with acute pulmonary oedema have increased filling pressures, most did not have significant increases from their dry weight on presentation! Fallick et al. actually argue that it isn't fluid gain but rather shift in fluids from other compartments, mainly shift from the splanchnic circulation, which usually is very compliant.

And as mentioned above, there is evidence that giving a straight shot of furosemide might actually influence haemodynamics negatively in different ways (decreased LV function, increased LV filling pressures, increases in MAP, SVR, plasma renin activity and plasma noradrenaline levels).

In conclusion there is no straight forward answer to this question, but I would put it down as follows:
​
​

​
​- Furosemide should not be routinely used for the immediate treatment of acute decompensated heart failure (ADHF)/ acute pulmonary oedema

- However, in patients with evidence of volume overload the administration of early furosemide (preferentially given as an intravenous bolus) seems beneficial and  improves outcome. But beware, most patients are not volume overloaded!

- In urgent situations the focus should be on early non-invasive ventilation and the administration of nitroglycerin!

​

This trial seems well performed with an acceptable sample size. The application of a single dose of ketamine before surgery neither prevented delirium nor induced it. With this sample size it seems safe to say that even if ketamine does prevent delirium, its effect would be rather small.

Furthermore, postoperative pain was not influenced by giving a single dose of ketamine and this is in contrast to previous findings and current guidelines. Importantly, most of the previous studies are smaller than this trial, making these findings remarkable.

But what really drew my attention was the fact that the appearance of hallucinations and night-mares was increased for at least 3 days after surgery.  

So if ketamine has no influence on postoperative delirium or pain but does induce hallucinations and nightmares, even 3 days after surgery, current guidelines might have to be revised.

The Bottom Line

- The application of a subanaesthetic dose of ketamine during surgery to tackle postoperative pain and delirium does not seem to be as effective as previously assumed

- The usage of ketamine in this setting even seems to have undesirable side-effects like hallucinations and nightmare - and this effect might even last for up to 3 days!

- This trial provides good reasons to look for other options to prevent postoperative delirium!

(Like dexmedetomidine? The answer to this question has just been answered: READ HERE!)

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.

​
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
​

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.
​

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).

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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...

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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
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