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Reviews and Summaries

Surviving Sepsis Campaign COVID-19 Guidelines - Short Summary

22/3/2020

 
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The European Society of Intensive Care Medicine ESICM and the Society of Critical Care Medicine SCCM have been very efficient in providing us health care workers with a guideline manuscript giving recommendations on the treatment of COVID-19 patients in a critical care setting. It is imperative to keep in mind that research is moving forward very quickly in these times and changes to these recommendations are likely to occur.

A collection of many reliable OPEN ACCESS platforms on SARS-CoV-2 can be found on www.foam.education.

Infection Control

When performing aerosol-generating procedures on patients with COVID-19 in the ICU, fitted respirator masks (N95 respirators, FFP2) should be used (in combination with full Personal Protective Equipement PPE) 

Aerosol-generating procedures on ICU patients with COVID-19 should be performed in a negative pressure room

During usual care for non-ventilated and non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients surgical masks are adequate 

​For endotracheal intubation video-guided laryngoscopy should be used, if available 

​
In intubated and mechanically ventilated patients, endotracheal aspirates should be used for diagnostic testing

Supportive Care

In COVID-19 patients with shock, dynamic parameters like skin temperature, capillary refilling time, and/or serum lactate measurement should be used in order to assess fluid responsiveness

For the acute resuscitation of adults with COVID-19, a conservative over a liberal fluid strategy is recommended

For the acute resuscitation of adults cristalloids should be used - avoid colloids! 

Buffered/balanced crystalloids should be used over unbalanced crystalloids

Do NOT use hydroxyethyl starches!

Do NOT use gelatins!

Do NOT use dextrans!

Avoid the routine use of albumin for initial resuscitation!
​

In shock use norepinephrine/ noradrenaline as the first-line vasoactive agent 

The use of dopamine is NOT recommended

Add vasopressin, if target MAP cannot be reached


Titrate vasoactive agents to target a MAP of 60-65 mmHg, rather than higher MAP targets

For patients in shock and with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine, adding dobutamine should be used 

For persistent shock despite all these measures, low-dose corticosteroids should be tried


Ventilatory Support

Keep peripheral saturation SpO2 above 90% with supplemental oxygen

There is NO need for supplemental oxygen with SpO2 above 96%


In acute hypoxemic respiratory failure despite conventional oxygen therapy, high-flow nasal cannulas (HFNC or High-Flow) should be used next

High-Flow should be used over non-invasive ventilation (NIV)

If High-Flow is not available and there is no urgent need for endotracheal intubation, NIV with close monitoring can be tried

In the event of worsening respiratory status, early endotracheal intubation should be performed

In mechanically ventilated patients, low-tidal volume ventilation should be used:       4 to 8 ml/kg


In mechanically ventilated patients with ARDS targeting plateau pressures (Pplat) of < 30 cm H2O should be aimed for

In patients with moderate to severe ARDS, a high-PEEP strategy should be used (PEEP >10cmH2O). Patients have to be monitored for potential barotrauma
NOTE by Crit.Cloud:

The strategy for high PEEP levels in general is currently discussed controversially. Observations in our own unit showed, that high PEEP levels tend to impaire compliance and therefor the quality of ventilation.
Read also: ​"Less is More" in mechanical ventilatio, Gattinoni L. et al. Intensive Care Med (2020) 46:780-782

​Patients with ARDS should receive a conservative/restrictive fluid strategy

In moderate to severe ARDS, prone positioning for 12-16 hours is recommended

To facilitate lung protective ventilation in moderate to severe ARDS, intermittent boluses of neuromuscular blocking agents (NMBA) should be used first


In the event of persistent ventilator dyssynchrony, the need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures, a continuous NMBA infusion for up to 48 hours should be used next

Do NOT use inhaled nitric oxide in COVID-19 patients with ARDS routinely


​In severe ARDS and hypoxemia despite optimising ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilator as a rescue therapy can be considered; if no rapid improvement in oxygenation is observed, the treatment should be tapered off

​If hypoxemia persists despite optimising ventilation, recruitment manoeuvres should be applied

If recruitment manoeuvres are used, DO NOT use staircase (incremental PEEP) recruitment manoeuvres 

If all these measures fail, the patient should be considered for venovenous ECMO

COVID-19 Therapy

In mechanically ventilated patients WITHOUT ARDS, systemic corticosteroids should NOT be used routinely

In contrast, mechanically ventilated patients WITH ARDS, the use of systemic corticosteroids is recommended

Mechanically ventilated patients with respiratory failure should be treated with 
empiric antimicrobials/antibacterial agents

Critically ill patients with fever should be treated with paracetamol (acetominophen) for temperature control

In critically ill patients standard intravenous immunoglobulins (IVIG) should NOT be used routinely

Also, the routine use of convalescent plasma is NOT recommended

The routine use of lopinavir/ritonavir (Kaletra
®) is NOT recommended

Currently, there is insufficient evidence to issue a recommendation on the use of other antiviral agents in critically ill adults with COVID-19

Currently, there is insufficient evidence to issue a recommendation on the use of recombinant interferons (rIFNs); chloroquine or hydroxychloroquine; tocilizumab (humanised immunoglobulin)


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Direct Download of the pdf file:

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

Vitamin C in Sepsis - Fails!

20/1/2020

 
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​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.

​

The VITAMINS Trial - First Failure 

Since 2017 a tiny bunch of studies were published, many of them with significant limitations like a small number of patients, often not randomized-controlled and with conflicting results.

Nabil Habib T, Ahmed I (2017) Early Adjuvant Intravenous Vitamin C Treatment in Septic Shock may Resolve the Vasopressor Dependence. Int J Microbiol Adv Immunol. 05(1), 77-81.

Shin et al. J Clin Med. 2019 Jan; 8(1): 102.

Fowler et al. JAMA. 2019 Oct 1;322(13):1261-1270.


Fujii et al. have just now published the first more substantial and rigorous trial taking a closer look at the influence on vitamin c in sepsis.


They performed an

international, multicenter, randomized-controlled open label trial

In which they enrolled 211 patients with septic shock admitted to an ICU.

They compared

Treatment with Vitamin C 1.5g 6-hourly IV, hydrocortisone 50mg 6-hourly IV and thiamin 200mg 12-hourly IV

to

Hydrocortisone 50mg 6-hourly IV only.

They found

No difference in time alive and time free of vasopressors (primary endpoint) and

No difference 28 days or 90 days mortality (secondary endpoint)
This first study on a larger scale, unfortunately, disappoints. More trials are on the way and might give a clearer picture of this topic to come to a final decision eventually. 

For the moment it is appropriate to state:
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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​

7 Reasons for the Use Vasopressors through Peripheral Catheters

16/12/2019

 
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​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?
​

​

What about the peripheral access (PVC) - Any dangers there?


​Study #1

In 2015 Cardenas-Garcia et al. have published a 

​open-label, single-centre trial 

in which they treated

a total of 734 patients with the vasopressors noradrenaline (506), dobutamine (101 and phenylephrine 176 via peripheral access only.

The average duration of infusion was 49 hours.

They found


extravasation in only 2% of all patients without any further tissue injury following treatment with local phentolamine injection and nitroglycerin paste.
These findings indicate that:
​
  • Correctly applied vasopressors via a peripheral line are safe, even if given over several hours
  • Complications like extravasation are generally rare and are unlikely to cause any further harm​

J Hosp Med. 2015 Sep;10(9):581-5. doi: 10.1002/jhm.2394. Epub 2015 May 26.


​Study #2

In 2015 Loubani et al. performed a systematic review of extravasation and local tissue injury from the administration of vasopressors through peripheral intravenous catheters and central venous catheters. They looked at
​
  • Local tissue injury close to the infusion site
  • Extravasation of a vasopressor into surrounding tissue or a body cavity
  • Major disability of the patient

An excellent summary of this study can be found on REBELEM, who correctly states that this review was only for complications from administration of vasopressor, and not a review of the frequency of complications (i.e. instances where no complications occurred).

This review shows nicely though that
​
  • Most complications concerned peripheral IV-lines distal to the antecubital or popliteal fossae, and
  • Almost all occurred in infusions running for more than 4 hours

J Crit Care. 2015 Jun;30(3):653.e9-17. doi: 10.1016/j.jcrc.2015.01.014. Epub 2015 Jan 22


​Study #3

In 2017 Lewis at al. performed a retrospective chart review of 202 patients who received vasopressors through a PVL. The primary vasopressors used were norepinephrine and phenylephrine. The most common PVL sites used were the forearm and antecubital fossa. The incidence of extravasation was 4%. All of the events were managed conservatively; none required an antidote or surgical management. Although with many limitations to this review, there is further evidence indicating:

  • Extravasation seems to be a rather rare complication and again did not result in any further harm for the patient

J Intensive Care Med. 2017 Jan 1:885066616686035.


​Study #4

In 2018 Medlej et al. tried to determine the incidence of complications of running vasopressors through PIVs in patients with circulatory shock in a prospective, observational trial. Again, REBELEM has nicely summarized this rather small trial. It is another small indicator that:
​
  • In patients with shock, the use of peripheral vasopressors (noradrenaline and dopamine) in a large bore PVC at a proximal site for less than 4 hours is safe!

​J Emerg Med. 2018 Jan;54(1):47-53.


​Well, how do PVC's compare to CVC's then?


​Study #5

In 2018 Ricard JD et al. performed a

Multicenter, controlled, parallel-group, open-label randomized trial

in which

Patients were randomized to receive central venous catheters (135 patients) or peripheral venous catheters (128 patients) as initial venous access.

The primary endpoint was the rate of major catheter-related complications within 28 days.

They found significantly more PVC-related complications per patient when only treated with peripheral lines compared to patients that received at least one CVC.


And they concluded: "central venous catheters should preferably be inserted: a strategy associated with less major complications"
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REALLY? Hold on! - let's have a close look at those 'major complications, the PRIMARY endpoint of this study!

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Although going through this article several times, it remains difficult to understand how PVC insertion difficulties are comparable major complications.
First of all, difficult venous access is one of the indications for the insertion of a CVC, not its complication. Patients were randomly allocated in a one-to-one ratio to receive a CVC or a PVC. So how can difficult peripheral access be a complication when going for central access directly?
​
Also, there is considerable doubt whether the occurrence of a pneumothorax can be used to compare complications of these two procedures!


However, when eliminating difficult peripheral access as an indication, there is not much left to say PVCs are associated with more complications than CVCs. Moreover, most clinicians will agree that catheter infections in PVCs are less problematic than when occurring in CVCs.

Given these considerations, it seems safe to say:


  • In critically ill patients peripheral access can be tricky indeed
  • PVCs might be associated with more frequent local erythema and extravasation of fluids
  • Good to know: peripheral access is not associated with more pneumothoraces ; )

Crit Care Med. 2013 Sep;41(9):2108-15 


​2019 - More Evidence Keeps Rolling In!
​

Study #6

Tian et al. have performed a 

Systematic review 

in order to assess

 the frequency of complications associated with the delivery of vasopressors via PVCs.

They included

Studies of continuous infusions of vasopressor medications (noradrenaline, adrenaline, metaraminol, phenylephrine, dopamine and vasopressin) delivered via a PiVCs that included at least 20 patients. This resulted in seven observational studies (only) with a total of 1384 patients.

They found that

Extravasation occurred in 3.4% (95% CI 2.5-4.7%) of patients. There were no reported episodes of tissue necrosis or limb ischaemia. All extravasation events were successfully managed conservatively or with vasodilatory medications.


 
  • Extravasation seems to be an issue with PVCs, but there is no further information on the size or location of the peripheral line.
  • Again, no serious side effects were reported, indicating that peripherally administered vasopressors are safe over all when given for a limited duration.

Emerg Med Australas. 2019 Nov 7.


​Study #7

Pancaro et al. published

a retrospective cohort study

in which  identified


14'385 surgical patients who received peripheral norepinephrine infusions perioperatively with a concentration of 20 µg/mL (a rather low concentration)

They found

Extravasation of norepinephrine in only 5 patients and there where zero related complications requiring surgical or medical intervention. The median time of norepinephrine infusion among these patients was 20 minutes.
This is a fairly good indicator that:

  • Giving vasopressors through PVC for a limited duration is safe
  • Extravasation might actually be harmless when applied in rather lower contentrations

Anesthesia & Analgesia. SEPTEMBER 27, 2019

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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.)
​

Vitamin C - To the Rescue?

26/3/2017

 
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:
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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

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

29/2/2016

 
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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.
​
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
​
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 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 
  AND
- a serum lactate level of more than 2mmol/L... after adequate fluid resuscitation 
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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 - From Bad to Good? An Explanation Trial

14/2/2016

 
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The discussion on the so-called lactic acidosis and its causes have become increasingly attractive over the last couple of years as several biochemical explanations are challenged. A significant confusion persists on the various relationships between lactate, lactic acid and metabolic acidosis. 

Most clinicians continue to refer to the traditional understanding of impaired tissue oxygenation causing increased lactate production, impaired lactate clearance and therefore resultant metabolic acidosis. Just recently we had a discussion on our ward round on this topic when a team member presented the most recent article of UpToDate online on the causes of lactic acidosis. The authors state that 'Lactic acidosis is the most common cause of metabolic acidosis in hospitalised patients' and that 'Lactic acidosis occurs when lactate production exceeds lactate clearance. The increase in lactate production is usually caused by impaired tissue oxygenation...'... finally suggesting that lactate is no good!

These statements support the classical understanding that:
- Hyperlactatemia is caused by tissue hypoxemia, and
- This in turn then leads to a metabolic acidosis called lactic acidosis


This biochemical understanding has persisted for decades, but there are some good reasons to vigorously challenge this traditional aspect on the 'bad' lactate. Lactate turns out to be by far more complex in its characteristics and functions, so I decided to try and make a short but comprehensive overview of this molecule.

What is lactate?

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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.

Picture


​Where does it come from?

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Typically most people think of muscles first as an origin of lactate. As a matter of fact lactate originates from many other organs, including our red blood cells. Red blood cells always produce lactate as they lack the mitochondria required to regenerate NAD+ needed for glycolysis.  In general, you can say that tissues with lots of LDH are the primary producers of lactate. Around 20mmol/kg/day of lactate are produced under normal circumstances.

Lactate is not only produced in skeletal muscle.

Muscle: 25%
Skin: 25%
Brain: 20%
RBC: 20%
Intestine: 10%

What happens with it?

Lactate is not just for nothing. After its production by anaerobic glycolysis lactate is reutilised, for instance in the liver and the cortex of the kidneys. As an example: under the influence of cortisol it is used for gluconeogenesis in hepatocytes and restores glucose and glycogen. Also, it is a part of oxidative phosphorylation in the liver, kidney, muscles, the heart and the brain. Like this lactate helps conserve glucose levels in our blood.
​
​Lactate actually serves as a fuel for oxidation and glucose regeneration and therefore is a source for energy itself.
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From The Lancet Endocrinology 2013


​
​How does hyperlactatemia develop?

In general, you can assume that there is a balance between lactate production and its consumption or usage. The classical understanding that tissue hypoxia leads to overproduction and underutilisation by impaired mitochondrial oxidation is correct.

The critical point though is that lactate is also produced via aerobic glycolysis as a response to stress. This happens in septic patients, asthmatic exacerbations, trauma and other critical conditions. In these situations, the trigger for lactate production is adrenergic stimulation and NOT tissue hypoxia. There are also several other reasons for hyperlactatemia other than tissue hypoxia:


Sepsis:      Adrenergic drive
Asthma:    Adrenergic drive
Trauma:    Adrenergic drive
Cardiogenic and haemorrhagic shock: Adrenergic drive
Pheochromocytoma: Adrenergic drive
Inflammation: Cytokine drive
Alkalosis, antiretroviral medication and others


Also, there is good evidence showing that organs like the lungs are an important producer of lactate during stress. And of course in all these conditions hypoxic and non-hypoxic hyperlactatemia might also co-exist.

In critically ill patients often other reasons than tissue hypoxia are responsible for hyperlactatemia (e.g. adrenergic drive).
​

Is lactate harmful?

In contrast to the classical understanding of lactate and lactic acidosis more and more evidence comes up indicating that lactate during stress actually serves as a fuel for energy production. Various tissues, e.g. the myocardium increase their lactate uptake during stress significantly. Also, our brain consumes more lactate during stress which is used for oxidation. Research has shown that lactate infusions improve cardiac output in pigs and even in patients with heart failure. 

Experimental work on isolated muscles suggests that circulating catecholamines and development of acidic conditions during exhaustive exercise may improve muscles' tolerance to elevated K+ levels. This implies that during high-intensity activity with high extracellular K+
 and adrenaline, lactate serves as a performance-enhancing chemical, rather than being the cause of muscle fatigue.

Lactate is not harmful to our organism. On the contrary, recent compelling evidence suggests that lactate might be beneficial, rather than detrimental, during high-intensity activity and to force development in working heart and skeletal muscle.
​

Why do critically ill patients with hyperlactatemia die more often then?

In critical care hyperlactatemia indeed is a marker of illness severity and a strong indicator of mortality. This is especially true for patients with sepsis. However, as described above, hyperlactatemia often doesn't indicate hypoperfusion or tissue hypoxia. Hyperlactatemia rather reflects the severity of illness by representing the degree of our body's activation to stress. A fall in lactate concentration following treatment of critically ill patients is due to an attenuation of the stress response rather than to correction of oxygen debt.

​Hyperlactatemia reflects a severe disease and the patients' response to stress. Patients die due to their illness, not because of high lactate.
​

What about Ringer's lactate?

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Ringer's lactate (RL) is not harmful in patients with hyperlactatemia.

As a matter of fact RL turns out to be superior compared to normal saline in hyperlactatemia, acidotic patients and patients with hyperkalemia.
​

The bottom line

- Lactate is an indicator of stress, a marker of illness severity and a strong predictor of mortality, but not harmful as a molecule itself.

- Lactate is helpful
 as an essential source of energy and an important fuel for oxidation and glucose generation.

- During conditions like septic shock, there is no proof that lactate is produced only due to tissue hypoxia. In fact, well-ventilated lungs provide a large amount of lactate during sepsis. Lactate in sepsis and other critical conditions is mostly not due to hypoxemia or hypoperfusion.

- Ringer's lactate contains sodium lactate, but not lactic acid. Lactate itself, as mentioned above, is beneficial in severe disease. Therefore RL remains the fluid of choice during severe disease like for instance septic shock.

- Ringer's lactate is superior to normal saline in patients with metabolic acidosis, hyperlactatemia and also hyperkalemia.
​

Got interested in some better understanding? START READING HERE:

Emmettt et al. UpToDate online, August 2015, Causes of lactic acidosis

Garcia-Alvarez et al. Critical Care 2014, 18:503


Marik PE, Bellomo R. OA Critical Care 2013 Mar 01;1(1):3

Garcia-Alvarez et al. Lancet Diabetes Endocrinol. 2014 Apr;2(4):339-47.

Andersen JB et al. Journal of Experimental Biology  
2007  210: vii doi: 10.1242/jeb.001107​

Bakker J et al. Intensive Care Med (2016) 42:472–474



Also, have a listen to Bellomo's review on lactate:
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Click in image to listen to podcast

Lancet vs Cochrane: ICU's Should Keep Neuraminidase Inhibitors in Stock

6/5/2015

 
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Almost exactly one year ago the Cochrane Library published an intervention review on the prevention and treatment of influenza with neuraminidase inhibitors in adults and children. The reason for this review was the fact that many countries stockpile these drugs and the WHO classified them as an essential medicine.
Jefferson et al. used the data of 46 trials with oseltamivir or zanamivir for this review. They basically conclude that:

- Both drugs shorten the duration of symptoms of influenza-like symptoms by less than a day
- Oseltamivir did not affect the number of hospitalizations
- Prophylaxis trials showed a reduced risk of symptomatic influenza in individuals and households, but no definite conclusion can be made
- Oseltamivir use was associated though with nausea, vomiting, headaches, renal and psychiatric events

...and finally write: 'The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence'. This review certainly undermined the importance of oseltamivir for many of us.


The Cochrane review though did not look at outcomes like mortality, but the Lancet Respiratory Medicine did! Stella G at al. have now published a large systematic review which included 29'234 patients from 78 studies during the period from 2009 to 2014. Their findings come rather surprisingly:

-
Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk
- Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk
- The reduction in mortality risk was observed when treatment was started up to 5 days of symptoms onset



There still seem to be some good reasons to use oseltamivir in critically ill patients with suspected or proven influenza... up to 5 days of symptoms onset!


Jefferson T et al. The Cochrane Collaboration,
Published Online: 10 APR 2014

The Cochrane Collaboration News Release 10 April 2014

Muthuri, Stella G et al. The Lancet Respiratory Medicine , Volume 2 , Issue 5 , 395 - 404



As ProMISe'd... the Trial is Complete!

25/3/2015

 
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As every child already knows by now the study by Rivers et al. in 2002 has raised the awareness about sepsis and led to the establishment of the surviving sepsis campaign. As we have posted on BIJC before, many elements of the early goal directed therapy (EGDT) have been discussed controversially since. In order to answer some of the questions of sepsis treatment three big trials have been started, involving different parts of this world. These efforts have led to a unique situation as we now have three high quality trials looking at the classical EGDT versus 'usual care'.

ARISE and ProCESS had been published before (read here) and both of them showed no difference between EGDT and 'usual care'.

ProMISe included 1251 patients with severe sepsis or septic shock that were admitted to a total 56 hospitals in the UK. Again classical EGDT with measurement of continuous central venous oxygenation was compared to so called 'usual treatment'. It's remarkable to notice that in the 'usual treatment' group about half of the patient didn't get a central line and central venous oxygenation wasn't even measured in the ones who got one. And here's the result:
There was no difference in 90-day mortality and no differences in secondary outcomes. In contrast EGDT actually increased costs.

It has become difficult to ignore these three trials!


Our conclusion: The classical EGDT therapy has ended here and now... but EGDT will keep its central role in the treatment of septic patients!

Early:
- Identify septic patient quickly, start screening for patients if indicated
- Administer antibiotics within the first our of recognition of sepsis
- Start IV-fluid therapy immediately
- Take (blood) cultures as quick as possible, but do not delay antibiotic treatment

Goal Directed:
- Aim for a reasonable mean arterial pressure (e.g. 65mmHg)
- Aim for a sufficient urinary output (0.5ml/h)
-
Central venous pressure (CVP) certainly and most probably central venous oxygenation (ScvO2) are not parameters to measure fluid responsiveness
- Lactate remains an issue of debate

Therapy:
- Simple: Whatever the physician feels is best!



ProMISe Trial, Mouncey et al. N Engl J Med. 2015 Mar 17.

BIJC Review on ARISE and ProCESS



Picture displayed taken from the Ice Cream Trilogy by Wright, Pegg and Frost

Eleftheria terrae... Will this Organism Change Our Clinical Work?

10/1/2015

 
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Just recently in 2014 the WHO has requested to develop a draft global action plan to combat emergent antimicrobial resistance (AMR). AMR is present in all parts of the world, new resistance mechanisms emerge and spread globally. And most importantly: Patients with infections by drug-resistant bacteria are generally at risk of worse clinical outcome and death.

On the background of this the recent publication in Nature by Ling et al. is remarkable as it might offer the key to a new antimicrobial weapon in the near future. Teixobactin is the name of a macrocylic peptide representing a new class of antibiotics. It appears to be potent bactericidal agent against a broad panel of bacterial pathogens, especially gram-positive bacteria including MRSA, enterococci and VRE as well as M. tuberculosis, C. difficile and Anthrax. Teixobactin inhibits cell wall synthesis and most remarkably showed no development of resistance so far.

Teixobactin is produced by E. terrae, a microorganism discovered in  the soil of a grassy field in Maine. As mentioned in the article, these 'uncultured' bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. 


An interesting article, especially if you want to see what's going on outside the hospital!


Ling LL et al. Nature 2015; doi:10.1038/nature14098

Restricitve Transfusion Threshold is OK in Sepsis - The TRISS Trial

29/10/2014

 
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Several studies in the past have looked into the topic of red blood cell (RBC) transfusions in the ICU and each one of them supports a rather restrictive approach in the ICU. Still though various guidelines around the world vary due to the lack of evidence (see below).

This october the New England Journal of Medicine (unnoticeably  and slowly transforming into a critical care journal ;) published a large multi-centered, partially blinded  trial that randomised septic patients in intensive care units to receive RBC at a threshold of 70g/L or 90g/L. The primary outcome was mortality after 90 days. A total of 998 patients finally underwent randomisation and as a result there was no significant difference in mortality after 90 days. Also there were no statistically significant differences in all secondary endpoints like use of life supporting measures, ischemic events, and severe adverse reactions.


This trial adds up to a list of studies showing that a liberal transfusion strategy is not beneficial for patients in critical care. This seems to be especially true for patients with sepsis. And not to forget: a considerable amount of packed RBC can be saved this way.

A higher transfusion threshold of 90g/L in patients with sepsis is non-superior to a lower threshold of 70g/L.


Get an insight into this topic yourself, here's the 'must read's about transfusions:

The TRICC trial 

The CRIT study

Sherwood M et al. JAMA. 2014 Feb 26;Vol 311, No.8

The FOCUS trial

A short educational overview can be found here: http://lifeinthefastlane.com/education/ccc/blood-transfusion-in-icu/

Clinical Practice Guidelines from the AABB 2012: Ann Inten Med. 2012;157:49-58

Clinical Practice Guidelines 2009: Red blood cell transfusion in adult trauma and critical care, Crit Care Med 2009


No Way Around Prone Positioning in ARDS

23/4/2014

 
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It has been almost for 40 years that the positive effect of prone positioning in ARDS patients was recognised. But even up to 2012 no benefit on mortality could be found in several studies and also the duration of prone positioning was not found to make any difference.

In June 2013 Guerin et al. published the PROSEVA trial which indeed showed some amazing results. It is the 5th biggest trial of it's kind and finally was able to actually now show a dramatic reduction in mortality: the 28 day mortality was 32.8% in the supine group (229 patients), compared to only 16% in the prone group (237 patients). This benefit in outcome persisted also after 90 days... a miracle? 
Most probably these results reflect the very strict adherence to the guidelines of ARDSnet in regards of paralysation and use of very low tidal volumes. One thing that has to be mentioned is the high number of patients with ARDS which have excluded from the trial for several reasons.
So should we now follow this study and prone more aggressively?

One answer might be the just recently published meta-analysis by Lee at al. in Critical Care Medicine. This paper looked at a total of 11 randomised controlled trials and therefore takes all recent publications into account. The authors come to the conclusion that prone positioning indeed does reduce mortality significantly and were marked in the subgroup where the duration of prone positioning was more than 10 hours. This is the first time somebody actually comments on the length of prone positioning in terms of benefit for the patient.
As always though there are also adverse effects of this therapy as prone positioning was significantly associated with pressure sores and maybe most importantly major airway problems.


Overall, the concept of prone positioning in severe ARDS seems to be well established and should be implemented in the clinical procedures of every intensive care unit. This is particularly true for regions where quick access to extra corporal CO2 removal or oxygenation devices is difficult.

Guerin C et al. N Engl J Med. 2013 Jun 6;368(23):2159-68.

Lee JM et al. Crit Care Med. 2014 May;42(5):1252-62.

Ferguson et al. Intensive Care Med. 2012 Oct;38(10):1573-82. 


A very nice and quick overview on treatment options for ARDS was presented by Ferguson et al. in Intensive Care Medicine 2012:

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Albumin and Sepsis: The ALBIOS Trial and its Appendix

22/3/2014

 
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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


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