Mind the Gap

Metformin toxicity is a life-threatening and challenging diagnosis. Brit Long discusses how to make this diagnosis and what we need to think about for management.  In our next segment, Matt, Anne, and Brett discuss ways to help guide a new APP through onboarding, orientation, and their first year of clinical practice.

 

Metformin Toxicity

Drew Kalnow, DO, and Brit Long, MD

 

Pearls:

• Metformin toxicity exists on a spectrum—MILA (true overdose), MALA (metformin plus another critical illness), and MULA (lactic acidosis unrelated to metformin).
• Differentiating them relies on history, clinical context, and labs.
• Suspect metformin toxicity in any sick patient on metformin with a high anion gap metabolic acidosis, double-digit lactate, and single-digit bicarbonate—especially if the glucose is normal or low.
• Early involvement of toxicology and nephrology is key; severe cases (lactate >20, pH <7.0, shock, renal failure) may require hemodialysis.

 

Background:

• Metformin is one of the most prescribed medications for type 2 diabetes and is generally safe.
• Most adverse effects are mild and GI-related.
• The feared complication is metformin-associated lactic acidosis (MALA).
• Mortality for severe cases (particularly MALA) can range from 25–50%.
• Metformin inhibits hepatic gluconeogenesis, decreases intestinal glucose absorption, and increases insulin sensitivity.
• Metformin oral bioavailability is 40-60% and is absorbed within 6 hours of ingestion. 
• Half-life =  2-9 hours, and 90% of the drug is renally excreted unchanged.
• Therapeutic concentration of metformin is 0.5-3 mg/L.
• Lethal plasma concentration is >50 mg/L; toxic dose is > 5g in adults and >100 mg/kg in pediatric patients.
• Metformin also acts as an electron transport chain inhibitor, limiting ATP production and promoting lactate accumulation.

 

The Spectrum: MILA, MALA, and MULA

• MILA – Metformin-Induced Lactic Acidosis
• True metformin toxicity from high serum levels, typically:
• Massive acute ingestion (>20 grams), or
• Chronic use with severe renal failure impairs clearance.
• Serum metformin level: typically >5 mg/L (often much higher).
• Therapeutic range: ~0.5–3 mg/L.
• Metformin is the primary driver of lactic acidosis.
• MALA – Metformin-Associated Lactic Acidosis
• Most dangerous form (highest mortality).
• Patient is taking metformin appropriately, but develops another critical illness:
• Sepsis
• Cardiogenic shock
• Stroke
• Acute renal injury
• Metformin contributes to worsening lactic acidosis, but is not the sole cause.
• Metformin levels may be elevated (>5 mg/L) but lower than MILA.
• Patients with significant renal disease have a prolonged half-life of metformin and are at greater risk of metformin toxicity.
• MULA – Metformin-Unrelated Lactic Acidosis
• Most common ED scenario.
• Elevated lactate with therapeutic or low metformin levels.
• Lactic acidosis due entirely to another disease process.

 

When to Suspect Metformin Toxicity

• History is a major driving factor. 
• Presentation: 
• GI symptoms predominate (nausea, vomiting, diarrhea, pain).
• Hypothermia.
• Hypotension (may be refractory to vasopressors).
• Bradycardia.
• Altered mental status.
• These patients typically appear critically ill.
• Risk factors for MALA: alcohol use, chronic hypoxia, sepsis, advanced age, dehydration, renal dysfunction, and shock.
• Any sick patient on metformin with:
• High anion gap metabolic acidosis.
• Markedly elevated lactate.
• No clear explanation
•  Patients with renal disease.
• Intentional overdose.

 

Laboratory Evaluation

• Cast a wide net:
• Glucose
• VBG/ABG
• BMP
• LFTs
• Coags
• Lactate
• Beta-hydroxybutyrate
• Serum osmolality (if toxic alcohol suspected)
• Acetaminophen, salicylate, and alcohol levels (if overdose/co-ingestion is possible).
• Classic Lab Pattern
• Double-digit lactate
• Single-digit bicarbonate
• Severe high anion gap metabolic acidosis
• pH <7.0 in severe cases
• Helpful Differentiation from DKA
• Metformin toxicity:
• Higher lactate.
• Lower beta-hydroxybutyrate.
• Glucose is often normal or low.
• DKA
• Elevated beta-hydroxybutyrate
• Marked hyperglycemia

 

Differential for Severe Lactic Acidosis

• Toxicologic Causes
• Acetaminophen (massive overdose)
• Barbiturates
• Linezolid
• Lorazepam
• Propofol
• Tricyclic antidepressants
• Valproic Acid
• Salicylates
• Beta-agonists
• Cyanide
• Carbon monoxide
• Toxic alcohols (ethylene glycol)
• NRTIs
• Medical Causes
• Cardiac arrest/ischemia
• Severe sepsis/septic shock
• DKA/euglycemic DKA
• Alcoholic ketoacidosis
• Liver failure
• Seizures
• Starvation ketoacidosis
• Thiamine deficiency
• Inborn errors of metabolism (pediatrics)
• Laboratory Error
• Laboratory error or interference (ethylene glycol intoxication). 
• The most common with using point-of-care lactate versus serum lactate testing.
• POC testing may not be able to differentiate the metabolites of ethylene glycol, glycolate, and glyoxalate (structurally similar to lactate). 
• Serum testing of lactate does not have this issue. 
• May result in “lactate gap,” which can assist in diagnosis. 
• Always confirm elevated POC lactate with serum lactate.
• A discrepancy suggests a “lactate gap” and possible toxic alcohol ingestion.

 

Management

• Early Consultation with Toxicology, Nephrology, and Critical Care
• Treat Concurrent Illness
• Do not anchor prematurely on metformin.
• Give broad-spectrum antibiotics if sepsis is possible.
• Continue evaluating for alternative causes.
• Glucose Monitoring
• Hypoglycemia is common.
• Frequent glucose checks.
• Administer IV dextrose as needed.
• IV Fluids:
• Goal: volume resuscitation.
• Fluid considerations:
• NS – risk of hyperchloremic metabolic acidosis.
• LR – contains lactate (may not be well metabolized).
• Plasma-Lyte – contains acetate (requires Krebs cycle metabolism).
• Practical approach:
• Balanced fluids are reasonable initially.
• More complex strategies (e.g., D5W + ½ NS + bicarbonate) may be used with pharmacist/nephrology input.
• Bicarbonate:
• Consider when:
• pH <7.0
• Severe metabolic acidosis
• Bridge to dialysis
• Hemodialysis: 
• Despite a high volume of distribution, metformin is moderately dialyzable.
• Strong indications:
• Lactate >20
• pH <7.0
• Failure to improve with fluids and vasopressors
• Lower threshold if:
• Shock
• Renal failure
• Liver failure
• Decreased level of consciousness
• Advanced/Rescue Therapies (Consult Toxicology)
• Reserved for refractory cases:
• Glucose–Insulin–Potassium Therapy
• Reduces lactate and ketoacid generation.
• Requires close glucose monitoring (hypoglycemia risk).
• May resemble a treatment approach for euglycemic DKA.
• Methylene Blue
• Acts as a mitochondrial electron acceptor.
• Also vasoconstrictive.
• Dose: 2 mg/kg IV over 30 minutes, then infusion.
• Airway Consideration:
• Intubation is not routinely required.
• If intubated, maintain high minute ventilation to compensate for metabolic acidosis.
• Consider a high-flow nasal cannula first to reduce the work of breathing.

 

Common Pitfalls

• Anchoring on metformin without ruling out other causes.
• Delaying toxicology/nephrology consultation.
• Failing to repeat labs frequently.
• Missing hypoglycemia.
• Not confirming POC lactate with serum testing.

 

Takeaways

• Metformin toxicity spans MILA, MALA, and MULA.
• Suspect it in critically ill diabetics with unexplained severe lactic acidosis.
• Double-digit lactate + single-digit bicarbonate in a patient on metformin should raise concern.
• Management requires aggressive resuscitation, treatment of concurrent illness, glucose monitoring, and early consideration of dialysis.

 

Please share your experience with these types of patient interactions.  Click the discussion tab on the right to join the conversation!

 

References:

1. Rivera D, Onisko N, Cao JD, Koyfman A, Long B. High-risk and low-prevalence diseases: Metformin toxicities. Am J Emerg Med. 2023;72:107-112.  PMID: 37517113

 

Onboarding in the ED

Brett Murray, MD, Anne Steckowych, CRNP, and Matthew Hall, CRNP

 

Pearls:

•  The credentialing and onboarding period is an opportunity for preparation, not downtime. 
• Structured use of FOAMed resources, mentorship, and clinical exposure can help new graduate APPs build foundational ED knowledge before seeing patients independently.
• A standardized orientation with graduated clinical responsibility improves confidence and safety. 
• Progressive patient loads, regular feedback, and mentorship from attendings and experienced APPs help new clinicians transition effectively into ED practice.
• The first year is critical for developing clinical gestalt. 
• Repetition, thoughtful differential diagnosis building, procedure training, and ongoing education help new APPs identify red flags and safely manage both common and high-acuity presentations.

 

Background:

• The onboarding process for healthcare providers usually involves two phases.
• Credentialing
• Orientation
• Often, this time is taken for granted or overlooked as time waiting to get started clinically seeing patients.
• However, if used properly, these phases of becoming a new provider can be harnessed to further your knowledge and sharpen your skill set.

 

Credentialing:

• The credentialing process occurs after finishing school, passing boards, and accepting a job. 
• This can be a frustrating phase for new graduates as it often takes up to 90 days of filing paperwork, paying fees, and getting background checks that are required by your state or institution.
• Often, new Nurse Practitioners end up going back to the bedside as a nurse to get paid while they wait for credentialing. 
• PAs often don’t have that same option, so this timeframe can be tough financially.
• However, this period doesn’t need to feel like “wasted time”. There are many things you can do to better prep yourself for your career while you await that all-important credentialing letter, or things you can encourage your new hires to do to sharpen their skills.
• FOAMed resources for emergency medicine are abundant and can help reinforce foundational ED knowledge or even broaden horizons a little.
• Be careful not to overwhelm new learners with excessive material. There is a lot to learn, and you can’t stuff it all into your brain at one time.
• If you are doing the hiring, avoid requiring purchasing courses or learning materials, as CME often does not cover expenses before an official start date.
• Some facilities allow new hires to work as scribes in the ED to keep them close to the ED workflow and provide some income and benefits while awaiting credentialing.
• To help smooth the process, it may be beneficial to assign a more experienced or knowledgeable staff member to be a credentialing resource for the new hire.
• Someone who understands the process, who the contact points are, and what documentation is required.
• Organization will be key.
• New hires should keep copies of documents and submissions to be sure everything gets submitted on time.
• Like charting, it could come down to a situation of “if you don’t document it, it didn’t happen.”
• Follow up with your contact points to be sure the process is moving along.
• Credentialing Pitfalls:
• Be sure your letters of recommendation for privileges come from someone supportive.
• Don’t ask someone you have a shaky relationship with to write you a letter or be a reference. Choose your references wisely.
• Don’t work clinically without the proper credentialing.
• Know your local regulations and don’t provide any patient care if it’s not allowed by law, even if your group asks you to.
• i.e., don’t round on patients or write notes under someone else's login to “learn the system”.

 

ED Orientation:

• Orientation can come in lots of forms, from a very organized approach broken into phases to a somewhat more chaotic “learn to swim by jumping in” approach.
• Ideally, however, orientation is broken down into a few blocks or phases that have clear expectations of patient care responsibilities and time frame objectives assigned to each phase.
• 90 days, broken into three blocks, seems to be a reasonable starting point.
• Block 1: Early Orientation
• Manage 1–2 active patients at a time.
• Focus on workflow, documentation, and initial clinical reasoning.
• Block 2: Intermediate Phase
• Increase to 3–4 active patients.
• Emphasis in this block is on efficiency, diagnostic reasoning, and patient management.
• Block 3: Late Orientation
• Increase to 6+ active patients.
• This block is prepping for a full clinical workload.
• To be maximally successful in orienting new grads, an onboarding program should include dedicated staff or mentors to monitor and provide feedback.
• These could be APP educators, ED attendings, and fellow APPs.
• Two possible approaches to this are being on shift with the same person repeatedly or moving between preceptors on each shift.
• There is a benefit to being on shift or being instructed by the same person, as it gives a longitudinal view of progress.
• However, there is also value in seeing how multiple people practice, so the value of longitudinal evaluation and exposure to other ways of doing things needs to be balanced.
• Feedback needs to be given often, early, honestly, and directly.
• Address deficiencies during the shift if possible.
• It's very hard to remember details and learn from a patient encounter that occurred last week.
• Feedback should be non-punitive and encourage self-assessment.
• It should provide a way to identify areas of weakness to work on, not create defensiveness.
•  The first year of practice is the most important growth period for new APPs.
• Clinical development relies heavily on repetition, seeing common ED presentations, recognizing atypical presentations, and learning to identify clinical red flags.
• A practical framework for differential diagnosis is to start with “worst first”.
• Rash → Stevens-Johnson Syndrome
• Chest pain → Aortic dissection
• Shortness of breath → Pulmonary embolism
• Pregnancy with abdominal pain → Ectopic pregnancy
  ○Subpoint #3
• This approach helps clinicians recognize high-risk diagnoses, identify pertinent positives and negatives, and build a defensible differential diagnosis.
• Attending physicians should prioritize teaching clinical reasoning
• Explain why decisions are made, don’t just tell new APPs what to do.
• Encourage APPs to justify their diagnostic and treatment plans.

Procedural Skills:

• Regular procedure labs help maintain proficiency in less-frequently used skills, and simulation labs help integrate decision-making with procedural proficiency.
• Examples of procedural training:
• Advanced suturing techniques
• Point-of-care ultrasound (POCUS)
• Intraosseous (IO) drill insertion
• High-Acuity Low-Occurrence (HALO) scenarios
• Simulation topics may include:
• Pediatric cardiac arrest
• Rare emergency scenarios
• Difficult family or end-of-life conversations
• Guest educators may include palliative care specialists for difficult communication training.

 

Please share your experience with these types of patient interactions.  Click the discussion tab on the right to join the conversation!

 

References:

1. Chekijian SA, Elia TR, Monti JE, Temin ES. Integration of Advanced Practice Providers in Academic Emergency Departments: Best Practices and Considerations. AEM Educ Train. 2018;2(Suppl Suppl 1):S48-S55. Published 2018 Nov 27. PMID: 30607379
2. Girshausen R, Graf S, Holz T, et al. Einarbeitung in der Notfallmedizin : Methoden, Herausforderungen und Chancen [Onboarding in emergency medicine : Methods, challenges and opportunities]. Med Klin Intensivmed Notfmed. 2025;120(6):473-480. PMID: 40293484