Metformin Associated Lactic Acidosis 

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Metformin Associated Lactic Acidosis 

"The dose makes the poison"

Metformin a common medication used to treat DM II can cause metformin-associated lactic acidosis and Metformin toxicity with a mortality rate between 45-48%. Neither arterial lactate levels nor plasma metformin concentrations predicted mortality.

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  • · The main effect of metformin is inhibition of the mitochondrial transport chain complex-I, which essentially poisons the mitochondria.

  • · If the mitochondrial transport chain stops working: NADH builds up, Krebs cycle eventually gets backed up, Pyruvate gets converted into lactate which builds up.


 

Best described a spectrum depending on cause of lactic acidosis








Metformin-induced lactic acidosis (MILA)


  • · High levels of metformin are the primary cause of illness.


Acute metformin overdose


    • · Acute poisoning may lead to MILA in the absence of renal dysfunction.

    • · Precise amount of metformin required to do this is unclear, but seems to be high (e.g. >20 grams).

    • · Patients with acute ingestion look fine initially, but deteriorate subsequently (“toxin bomb”).

Subacute accumulation of metformin due to renal failure



    • · Metformin is renally cleared

    • · Progressive renal failure (with GFR << 30 ml/min) eventually leads to metformin accumulation and toxicity.

    • · These patients may present with marked lactic acidosis, yet have fairly preserved hemodynamics and look OK.




Metformin-associated lactic acidosis (MALA)

Patient on metformin develops an acute life-threatening illness (e.g. septic shock, cardiogenic shock). Metformin amplifies the degree of lactic acidosis, but it's not the sole cause of the illness. Risk factors include renal insufficiency, higher doses of metformin, and alcoholism.

 

Metformin-unrelated lactic acidosis (MULA)


  • · Metformin levels are low; metformin is an innocent bystander.

  • · Clinically it will be impossible to differentiate this from MALA. Differentiation of MULA from MALA requires measurement of metformin levels, which isn't available at most hospitals.




Signs & symptoms


  • · Vitals: The following abnormalities may be seen: Hypothermia, Hypotension progressing to vasopressor-refractory shock can occur.

  • · GI symptoms often predominate: Nausea, vomiting, diarrhea, epigastric pain.

  • · Delirium, decreased consciousness


 

Management


  • · Fingerstick glucose (hypoglycemia may occur)

  • · VBG with lactate

  • · Complete set of chemistries (including Ca/Mg/Phos), Coags

  • · Beta-hydroxybutyrate level (frequently elevated)

  • · Liver function tests

  • · Blood cultures, urinalysis, chest X-ray, procalcitonin.

  • · Administer Broad-spectrum empiric antibiotics

  • · Additional toxicologic evaluation (e.g. acetaminophen, salicylate levels, toxic alcohols, carboxyhemoglobin).

  • · Obtaining a serum metformin concentration is unhelpful in most cases because few hospitals perform the test and thus timely results are rarely available, and because the serum concentration often does not correlate with the severity of the poisoning or patient outcome

  • · Obtain early consultation with a medical toxicologist and a nephrologist


 

Metformin-induced lactic acidosis vs. DKA


  • · Compared to isolated DKA, patients with metformin-induced lactic acidosis have greater degree of hyperlactatemia, with less extensive ketoacidosis.

  • · Difficult to sort this out in some situations- treat both conditions (the treatment for DKA may actually improve MILA/MALA).

  • · Activated charcoal may be considered for patients who present very shortly following acute ingestion, without contraindications (e.g. normal mental status without risk of aspiration)

  • · Evaluate for alternative causes of illness, especially septic shock.

  • · Insulin therapy may be beneficial for metformin poisoning (aside from any question of DKA) by reducing generation of lactate and ketosis thereby improving acidosis



 

Bicarbonate?


  • · Undesirable for a few reasons: Might increase cellular permeability to metformin, Bicarbonate has never been shown to be a useful therapy for lactic acidosis, Raising the pH with bicarbonate may actually stimulate glycolysis and thereby increase lactate generation

  • · Normal saline is an acidotic fluid that will exacerbate the acidosis.

  • · Lactated Ringers and Plasmalyte not good choice, as these patients cannot metabolize lactate or acetate respectively


 

Other options?


  • · D5W with 1/2 normal saline, plus one ampule (50 mEq) of bicarbonate added per liter.

  • · Simultaneous infusions of normal saline and isotonic bicarbonate

  • · High-flow nasal cannula may be used to improve ventilatory efficiency and reduce the work of breathing



 

Indications for dialysis


  • · Main indications

    • · Lactate >15-20 mM

    • · pH <7.0-7.1

    • · Failure to improve despite standard supportive measures

  • · Comorbid conditions which may lower the threshold for dialysis

  • · If the patient is hemodynamically unstable, CVVH or CVVHD should be considered. The clearance of drug by CVVH was less than that generally reported to occur with conventional hemodialysis and should only be considered in patients who are too hemodynamically unstable to tolerate hemodialysis.


 

Methylene Blue


  • Methylene blue is capable of accepting electrons from NADH could function as a bridge to re-establish the flow of electrons through the mitochondria and can theoretically re-starts the stalled Krebs cycle and re-establishes normal metabolism

  • Vasoconstriction: Methylene blue can also function as a vasoconstrictor (by scavenging nitric oxide). It's possible that its efficacy in some cases of refractory shock with metformin toxicity is due purely to its efficacy as a vasoconstrictor.



 

References:

UptoDate

EMCrit

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Add Adenosine to the Flush

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You have a patient in SVT, failed vagal maneuvers. Time to treat with adenosine. 

You all know this cute little three-way stop cock. Seems simple enough. That is until you need to use it... the stop and go seems somehow far more confusing than it really is.

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And the one time you MUST know how to use it is to rapidly administer adenosine. You need access in the antecubital or proximal upper extremity.

Why the rush? Adenosine is rapidly metabolized by erythrocytes and vascular endothelial cells - so with its 10 second half-life, we have to administer and flush it quickly so it can reach the heart. 

Surely, there has to be an easier way! Well, folks. There is!

Make sure you have your ECG rhythm strip running, zoll pads on the patient, and explain the patient that this might "feel funny"  (as their heart stops for just a wee bit). 

  • Grab a 20-mL (or 30-mL) syringe.

  • Desired dose of Adenosine (6 mg or 12 mg)

  • Draw up the adenosine AND the normal saline in the same 20-mL syringe.

  • Administer via fast IV push

That's it! 

Adenosine is safe and maintains its effectiveness mixed with normal saline. One study even used OI access for conversion of SVT in an infant. 

Only have central access (hemodialysis port, central line)??? Per 2010 ACLS guidelines drop the dosing: 

  • 1st dose: 3 mg (instead of 6)

  • 2nd/3rd doses: 6 mg (instead of 12)

This lower dosing minimized risks of prolonged bradycardia. ALSO - use this lower dosing if the patient is taking dipyridamole or carbamazepine as these two medications potentiate the effects of adenosine.


REFERENCES:

J Korean Soc Emerg Med. 2003 Aug;14(3):224-227 

https://www.resus.com.au/2015/03/26/a-new-way-to-give-adenosine-in-svt/

https://www.aliem.com/2012/12/trick-of-trade-combine-adenosine-and/
Weberding NT, et al. Adenosine Administration With Stopcock Technique Delivers Lower-Than-Intended Drug Doses. Ann Emerg Med 2018;71(2):220-4.

https://acls-algorithms.com/acls-drugs/acls-and-adenosine/comment-page-2/

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Intranasal Analgesia and Anxiolysis

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Today we will be discussing IN anxiolysis and analgesia, especially useful in our pediatric population.  An appendix with a BAN administration outline is also attached. Indications

Perfect for kids coming in with acute trauma (laceration, need for x-rays, etc) or patients undergoing procedures such as I&D of an abscess.

May be used prior to obtaining x-rays for pain control in children not necessarily needing a line for reduction (or even in those needing a line as this may be a faster way to reduce pain, and may help provider in obtaining IV line).

 

Routine Medications – Analgesia/Anxiolysis Dose

  • Analgesia: Fentanyl (1-1.5mcg/kg), Ketamine (0.5mg/kg)

  • Anxiolysis: Midazolam (0.2mg/kg)

 

Other IN Medications: Midazolam, Precedex (dexmedotomidine), flumazenil, naloxone

 

Pearls of Administration

Have patients blow their nose first if possible.

Try to limit dose to 0.3mL per nostril (certainly no more than 1 mL per nostril), using concentrated solutions. 

Divide larger volumes over two nostrils.

May deliver in aliquots 10-15 minutes apart if larger.

Remember, it’s a good idea to put patients on a pulse ox prior to administration.

Account for “dead space” of atomizer (~1mL).  

APPENDIX

BAN Dosing

Remember, there is also the BAN (breath actuated nebulizer) for medication administration which is a an alternative to intranasal medications when tolerated.  Only use BAN in Breath Actuated Mode in ED.

Here is the dosing for BAN:

  • Fentanyl:

    • Adults: 4mcg/kg dose titrated q 10 min up to three doses

    • Pediatrics: 2-4 mcg/kg titrated q 10 min up to three doses

  • Morphine:

    • Adults: 10-20 mg titrate q 10-15 min up to three doses

    • Pediatrics: 0.2 mg/kg q15 min up to three doses

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