Metformin Associated Lactic Acidosis

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.

• · 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

EKG in Tox

EKG#1

80 year old demented female, unresponsive, BP 55/20, blood glucose 24

1. What’s the rhythm?

2. What’s the differential for bradycardia?

3. Think tox – now narrow your differential. What do the vitals suggest?

4. How do you want to treat this patient?

EKG#2

21 year old male, suicidal, intentional overdose

1. Rate, rhythm, axis, intervals – you can glean a lot of information from these pieces alone

2. What’s the suspected overdose?

3. Treatment?

EKG#3

41 year old female, sent from methadone clinic for nausea. Given Zofran at the clinic. Was acting belligerent at triage and required Haldol. Records show she is currently on azithromycin outpt for recent pneumonia.

You get this EKG right before she goes into cardiac arrest.

1. What the hell happened?

2. How you gonna treat?

EKG#4

92 year old demented man, wife found him unresponsive near an open medicine cabinet

1. This is a classic dysrhythmia secondary to which toxicity?

2. What is a classic, more subtle finding you can see when the patient in normal sinus rhythm?

ANSWERS

EKGotW #4 – Tox Edition

Brown and University of Cincinnati have amazing reference websites for this topic!

Here are some reference tables from their sites with links that you should totes check out!

http://brownemblog.com/blog-1/2018/6/20/the-poor-mans-tox-screen

http://www.tamingthesru.com/blog/diagnostics/ekg-toxicology, Table by Dr. James Li

EKG#1

Beta Blocker Overdose

1.     What’s the rhythm?

a. Junctional bradycardia.

These are QRS complexes without P waves – no P waves means the ventricles are either being triggered from the AV node or more distally (in the actual ventricles).

The complexes are narrow, which means the AV node is likely triggering the impulses, conducting electricity down the bundle of his through the normal conduction pathway.

If the complexes were wide, these might be ventricular escape rhythms – not only do the SA and AV node have their own automaticity, but the actual myocytes themselves may trigger impulses as well.

1.     What’s the differential for bradycardia?

a.     H.I.D.E.

                                               i.     Hypothyroid/Hypothermia

                                             ii.     Ischemia/Increased ICP

                                           iii.     Drugs

                                            iv.     Electrolytes (K, Ca, Mag)

2.     Think tox – now narrow your differential. What do the vitals suggest?

a.     Several toxidromes may cause severe bradycardia. Commonly we talk about calcium channel blockers and beta blockers. (Don’t forget digoxin from David Elkin’s M&M a few weeks ago!)

Classically, hypoglycemia + bradycardia = beta blocker overdose.

Beware of bronchospasm as a clue as well.

3.     How do you want to treat this patient?

a. Glucagon – increases intracellular cAMP and calcium

                      i.   Give with Zofran!

b. Calcium – increase inotropy

c. Epi Drip – for cardiogenic shock

d. High Dose Insulin – 1u/kg/hr, 30-60 min to take effect

e. Lipid Emulsion Therapy – uncertain mechanism

f. Atropine / Pacing can be considered – atropine often ineffective. (Remember, atropine counteracts excessive vagal stimulation, but this is not the etiology of bradycardia in BB OD patients!)
My fave article on this:
https://emcrit.org/pulmcrit/epinephrine-atropine-bradycardia/

EKG#2

TCA Overdose

1.     Rate, rhythm, axis, intervals

a.      Rate = QRS x 6 = 21 x 6 = 126

b.     Rhythm – You can see P waves hiding in I, V5/V6, and maybe small irregularities in the T waves of V3/V4 that hint at presence of P waves. This is sinus.

c.      Axis - Downward deflection in I, upward in aVF = RIGHT AXIS

d.     Intervals

                                               i.     PR < 200msec

                                              ii.     QRS > 120msec

                                            iii.     QTc = QT/Ö(RàR’) = 0.312 / Ö0.48 = 450msec

^^^(I used V2 for this)

Sinus tachycardia with RIGHT AXIS deviation and WIDE QRS complex

2.     What’s the suspected overdose?

a. Hallmarks of TCA Overdose EKG

                 i.  Widened QRS

                ii.  Big-ass R wave in aVR

              iii.  New right axis

iv. Deep slurred S waves, I & aVL

3.     Treatment?

a. Sodium Bicarb pushes

                      i.   Until the QRS narrows

b. Lidocaine for refractory arrythmia

Read about TCA -- http://www.emdocs.net/ecg-pointers-tca-overdose/

Video about TCA -- https://emin5.com/2015/12/22/tca-toxicity/

EKG#3

Long QT

1.     What the hell happened?

a. Haldol, azithromycin, methadone are all QT prolonging agents, which predispose to Torsades de Pointes, or Polymorphic Ventricular Tachycardia

b.     Using V5…
QTc = QT / (Square root of R->R’) = 0.74 / (SqRt(1.08) = 711msec

2.     How you gonna treat?

a. Defibrillate if in arrest

b. 2g Mag Sulfate slow IV push

c. Isoproterenol +/- pacer if super brady

This case: http://hqmeded-ecg.blogspot.com/2014/06/acquired-long-qt-do-not-trust.html

Torsades overview: https://wikem.org/wiki/Torsades_de_pointes

EKG#4

Digoxin Toxicity

1.     Classic Findings

a. This is Bidirectional V-Tach, classic for digoxin toxicity

b. Like David Elkin talked about a few weeks ago in M&M, lots of different arrhythmias possible with digoxin

c. Beware of atrial arrythmias and dangerous bradycardias

d. Classic EKG finding of scooped, down-sloping, Salvador Dali moustache ST segment

Remember the theoretical phenomenon of stone heart – dig tox may give you hyperK. When you treat with calcium, the theory is that it may cause tetany of the myocardium and precipitate cardiac arrest. Digifab (antidote) will treat hyperK, so consider your options.

Dig Toxicity EKG - https://litfl.com/digoxin-toxicity-ecg-library/

Treatment - https://www.wikem.org/wiki/Digoxin_toxicity

References

https://litfl.com/tricyclic-overdose-sodium-channel-blocker-toxicity/

http://brownemblog.com/blog-1/2018/6/20/the-poor-mans-tox-screen

http://www.tamingthesru.com/blog/diagnostics/ekg-toxicology

http://hqmeded-ecg.blogspot.com/2014/06/acquired-long-qt-do-not-trust.html

ECMO

Extracorporeal Membrane Oxygenation

What:

Prolonged cardiopulmonary support is called extracorporeal membrane oxygenation (ECMO), extracorporeal life support, or extracorporeal lung assist.

Criteria for the initiation of ECMO include acute severe cardiac or pulmonary failure that is potentially reversible and unresponsive to conventional management. Examples of clinical situations that may prompt the initiation of ECMO include the following:

Who:

·       Hypoxemic respiratory failure with a ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of <100 mmHg despite optimization of the ventilator settings, including the tidal volume, positive end-expiratory pressure (PEEP), and inspiratory to expiratory (I:E) ratio. The Berlin consensus document on acute respiratory distress syndrome (ARDS) suggests ECMO in severe respiratory failure (PaO2/FiO2 <70)

·       Hypercapnic respiratory failure with an arterial pH less than 7.20

·       Ventilatory support as a bridge to lung transplantation.

·       Cardiac/circulatory failure/Refractory cardiogenic shock

·       Massive pulmonary embolism.

·       Cardiac arrest

How:

During ECMO, blood is drained from the native vascular system, circulated outside the body by a mechanical pump, and reinfused into the circulation. While outside the body, the blood passes through an oxygenator and heat exchanger. In the oxygenator, hemoglobin becomes fully saturated with oxygen, while carbon dioxide (CO2) is removed. Oxygenation is determined by flow rate, where elimination of CO2 can be controlled by adjusting the rate of countercurrent gas flow through the oxygenator

There are two types of ECMO – venoarterial (VA) and venovenous (VV).

Both provide respiratory support, but only VA ECMO provides hemodynamic support

VV or Veno-Venous - blood is extracted from the vena cava or right atrium and returned to the right atrium. VV ECMO provides respiratory support, but the patient is dependent upon his or her own hemodynamics.

·       Venous drainage from large central veins -> oxygenator -> venous system near RA

·       Support for severe respiratory failure (no cardiac dysfunction)

·       Pathology: pneumonia, ARDS, acute GVHD, pulmonary contusion, smoke inhalation, status asthmaticus, airway obstruction, aspiration, drowning

·       Specific contraindications: unsupportable cardiac failure, severe pulmonary hypertension, cardiac arrest, immunosuppression (severe)

·       For VV ECMO, venous cannulae are usually placed in the right or left common femoral vein (for drainage) and right internal jugular vein (for infusion). Alternatively, a double lumen cannula is available 

VA or Veno-Arterial: peripheral or central- During VA ECMO, blood is extracted from the right atrium and returned to the arterial system, bypassing the heart and lungs. VA ECMO provides both respiratory and hemodynamic support

·       For VA ECMO, a venous cannula is placed in the inferior vena cava or right atrium (for drainage) and an arterial cannula is placed into the right femoral artery (for infusion). Femoral access is preferred for VA ECMO because insertion is relatively easy. The main drawback of femoral access is ischemia of the ipsilateral lower extremity

• support for cardiac failure (+/- respiratory failure)

• pathology: graft failure post heart or heart lung transplant, non-ischemic cardiogenic shock, drug OD, sepsis, PE, cardiac or major vessel trauma, massive pulmonary hemorrhage, pulmonary trauma, acute anaphylaxis

• specific contraindications: aortic dissection and severe AR

GENERAL CONTRAINDICATIONS

Absolute

• progressive non-recoverable cardiac disease (not transplant candidate)

• progressive and non-recoverable respiratory disease (irrespective of transplant status)

• chronic severe pulmonary hypertension

• advanced malignancy

• >120kg

• unwitnessed cardiac arrest

Relative

• age > 75

• multi-trauma with multiple bleeding sites

• CPR > 60 minutes

• multiple organ failure

• CNS injury
  
  
  
  

Procedure: Once it has been decided that ECMO will be initiated, the patient is anticoagulated (usually with intravenous heparin) and then the cannula are inserted. ECMO support is initiated once the cannula are connected to the appropriate limbs of the ECMO circuit. Cannulas are usually placed percutaneously by Seldinger technique. The largest cannulas that can be placed in the vessels are used.  

Things to consider for the Emergency Physician

• Emergency Physicians have an important role in identifying patients that might benefit from ECMO

• Be cognizant of central line placement choice

• Transfer out to center with ECMO capabilities earlier

• Make sure patient is not bleeding (recent surgeries, recent hemorrhagic CVA)

• When calling for ECMO, try to figure out what type of ECMO would benefit the patient

• Perform Bedside POCUS to determine cardiac function

• Consider certain therapies with caution if you anticipate ECMO initiation- Lipid Emulsion therapy likely a contraindication as it affects the ECMO circuit

• Be familiar with the common contraindications to ECMO- Age, BMI etc

References:

LITFL

UptoDate