Intraoperative Ketamine: A Big Hooray for Special K?

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Postoperative pain and delirium is a common concern and currently approached by different interventions. There is  some evidence suggesting that ketamine given intra-operatively might have an influence on postoperative pain and delirium. Some anaesthetists commonly give a single dose of ketamine intra-operatively for exactly this reason.

Thumbs up for Ket

Ketamine has kept its fascination in various settings, from retrieval medicine onto the the care of critically ill patients in the ICU.  Ketamine reduces postoperative markers of inflammation, is a rapid-acting antidepressant drug with an effect lasting for several days and might have neuroprotective properties. 

Ketamine also has become increasingly popular as an adjunct to other sedatives in the ICU. There is evidence showing that ketamine used in the ICU has the potential to reduce cumulative opioid consumption after surgery (Asad E. et al. J Intensive Care Med December 8 2015 ).


Even better: It does not cause any kidney injuries, preserves laryngeal protective reflexes, lower airway resistance and much more...

And: Ketamine is cheap and has been used safely for over 50 years by anaesthetists!

The Dark Side of Ket

But there's the other side of ketamine making all of this a little more complicated. After all, Ketamine is a psychoactive drug and has well known hallucinogenic properties. Developed in the 1960s as a dissociative anaesthetic agent it started to appear on the street in the early 1970s and made its way to the 1980s as Special K, Acid and Super C (Dotson JW et al. J of Drug Abuse, Vol 25, Issue 4, 1995).

From a medical point of view there are some worries that these psychotomimetic effects, which are of concern in the critically ill patient, might predispose to delirium (Erstad BL, J Crit Care, Oct 2016, Vol 35, p 145-149​).

The PODCAST Trial

On the background of all this facts this trial revealed some interesting findings. Avidan et al. performed a

multicentre, international randomised trial

in which they randomly assigned

672 patients undergoing major cardiac and non-cardiac surgery under general anaethesia

into three groups to either receive a bolus of

placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision.

 Participants, clinicians, and investigators were blinded to group assignment. They found

NO difference in in the incidence of postoperative delirium among these groups

but

significantly more postoperative hallucinations and nightmares with increasing ketamine doses compared to placebo
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!)

Intraoperative Ketamine: A Big Hooray for Special K?

Picture
Postoperative pain and delirium is a common concern and currently approached by different interventions. There is  some evidence suggesting that ketamine given intra-operatively might have an influence on postoperative pain and delirium. Some anaesthetists commonly give a single dose of ketamine intra-operatively for exactly this reason.

Thumbs up for Ket

Ketamine has kept its fascination in various settings, from retrieval medicine onto the the care of critically ill patients in the ICU.  Ketamine reduces postoperative markers of inflammation, is a rapid-acting antidepressant drug with an effect lasting for several days and might have neuroprotective properties. 

Ketamine also has become increasingly popular as an adjunct to other sedatives in the ICU. There is evidence showing that ketamine used in the ICU has the potential to reduce cumulative opioid consumption after surgery (Asad E. et al. J Intensive Care Med December 8 2015 ).


Even better: It does not cause any kidney injuries, preserves laryngeal protective reflexes, lower airway resistance and much more...

And: Ketamine is cheap and has been used safely for over 50 years by anaesthetists!

The Dark Side of Ket

But there's the other side of ketamine making all of this a little more complicated. After all, Ketamine is a psychoactive drug and has well known hallucinogenic properties. Developed in the 1960s as a dissociative anaesthetic agent it started to appear on the street in the early 1970s and made its way to the 1980s as Special K, Acid and Super C (Dotson JW et al. J of Drug Abuse, Vol 25, Issue 4, 1995).

From a medical point of view there are some worries that these psychotomimetic effects, which are of concern in the critically ill patient, might predispose to delirium (Erstad BL, J Crit Care, Oct 2016, Vol 35, p 145-149​).

The PODCAST Trial

On the background of all this facts this trial revealed some interesting findings. Avidan et al. performed a

multicentre, international randomised trial

in which they randomly assigned

672 patients undergoing major cardiac and non-cardiac surgery under general anaethesia

into three groups to either receive a bolus of

placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision.

 Participants, clinicians, and investigators were blinded to group assignment. They found

NO difference in in the incidence of postoperative delirium among these groups

but

significantly more postoperative hallucinations and nightmares with increasing ketamine doses compared to placebo
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!)

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 stemlynsblog.org HERE

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

Why Vitamin C in Sepsis?

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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.


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