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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Cocaine overdose

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Cocaine Overdose


Pathophysiology - Sympathomimetic toxidrome associated with following signs and symptoms:  

 

CNS: Cerebral ischemia/infarct, intraparenchymal or subarachnoid hemorrhage, cerebral artery vasospasm, cerebral vasculitis, cerebral atrophy, and cerebral vascular thrombosis.

 

Cardiac: Myocardial ischemia/infarct, cardiac arrhythmias, dilated cardiomyopathy, infective endocarditis (IVDA), aortic rupture/dissection, acceleration of coronary atherosclerosis.

Pulmonary: Nasal septal perforation, oropharyngeal ulceration, inhalational injuries (smoking crack cocaine), pneumomediastinum, pneumothorax, pulmonary infarct, hypersensitivity pneumonitis.

GI: Gastroduodenal ulceration/perforation, intestinal infarct/perforation, colitis.

Renal: ARF secondary to rhabdomyolysis, renal infarct.



OB: Placental abruption, low birth weight, microcephaly.


Psych: Paranoia, delirium, suicidal ideation


Initial approach and management:

Start with ABCs:

Airway and breathing — O2 as needed. 

If RSI intubation is needed  avoid succinylcholine - plasma cholinesterase (PChE) metabolizes both succinylcholine and cocaine, and coadministration of succinylcholine can prolong the effects of cocaine and the paralysis from succinylcholine 

In the setting of rhabdomyolysis and hyperthermia, succinylcholine may worsen hyperkalemia and cause life-threatening arrhythmias

Use rocuronium as paralytic and  benzodiazepines, etomidate, or propofol for induction

 

Cardiovascular complications result in 

Central cardiovascular stimulation responds well to benzodiazepines

Refractory or symptomatic cocaine-induced hypertension can use phentolamine (bolus of 5 to 10 mg intravenously (IV) every 5 to 15 min PRN) 

Alternatives nitroglycerin or nitroprusside

Avoid beta-blockers (unopposed α-adrenergic activity) 

Avoid calcium channel blockers (may potentiate seizures and death)

 

Massive cocaine toxicity may result in hypotension due to sodium-channel blockade, cardiac dysrhythmias, or cardiac ischemia

treat with 2 to 3 L of rapidly infused isotonic saline

if no improvement use direct-acting vasopressors such as norepinephrine or phenylephrine 

Obtain EKG to evaluate QRS for widening, if present use hypertonic sodium bicarbonate at a dose of 1 to 2 mEq/kg 

 

Psychomotor agitation can be treated with benzodiazepines like diazepam be given in an initial dose of 10 mg IV, then 5 to 10 mg IV every 3 to 5 minutes 

 

Hyperthermia -  cool rapidly, optimally in 30 minutes or less, to a goal core body temperature of <102°F. 

 

Gastrointestinal decontamination should be considered especially in cases of body packing but remember that the popular methods of cocaine use are nonenteral 

Activated charcoal reduces the lethality of oral cocaine - adminitter at 1 g per kg body weight (up to 50 g) Q4h. 

Cocaine abuse + abdominal pain => concern for aortic pathology or intestinal ischemia/infarct or colitis

 

Specific syndromes:

 

Chest pain — it causes vasoconstriction and enhances thrombus formation, increasing the risk of myocardial ischemia even in a very young patients. 

EKG changes and positive trops consider ASA +/- nitroglycerin, phentolamine (( IV bolus of 1 to 2.5 mg every 5 to 15 minutes PRN) to reverse cocaine-induced vasospasm, cardiology consult for cath

 

Crack lung — Crack lung is a syndrome of hemorrhagic alveolitis from inhalational cocaine use 

Ensure oxygenation, ventilation, and symptomatic care

Early intubation

 

Disposition:

Severe complications of cocaine abuse - admission

If acute findings from cocaine toxicity resolve - obs 6 to 8 hours and d/c if pt back to baseline. 

 

Pts with cocaine-associated chest pain (CACP) are observed for 8 to 12 hours while two sets of cardiac biomarkers and repeat electrocardiograms (ECGs) are obtained. 

 

Pts with psychomotor agitation, hyperthermia, or other neurological complications consider admission unless pt is back to baseline and symptom free after  6 to 8 hours of observation.

Pearls:

The differential diagnosis of cocaine toxicity should include: methamphetamine abuse, ecstasy abuse, cathinone abuse, and LSD abuse

Smoking and IV injection offer rapid cocaine absorption (< 30 sec), as opposed to snorting (2.5 min) and ingestion (PO 2-5 mins).


Cocaine-induced MIs have been reported as late as 15 hours following substance abuse


References: Uptodate, EMDocs

What kind of mood elevator are you on?

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Lithium toxicity

 

Background:

Uses: Lithium often prescribed for Bipolar disorder

Has a narrow therapeutic index: therapeutic dose close to a toxic dose

Mechanism of action is still incompletely understood. Lithium increases serotonin release and receptor sensitivity as well as inhibiting release of dopamine and norepinephrine. 

Elimination: Lithium is excreted exclusively by the kidneys. Any insult to kidneys can lead to impaired elimination 

 

Causes:

For acute overdose mainly intentional overdose

For chronic Li+ toxicity with present body stores any changes changes in absorption or elimination lead to lithium levels above the narrow therapeutic window like:

  • volume depletion

  • salt restriction

  • advanced age with resultant decrease in GFR, 

  • thiazide diuretics, NSAIDs, ACE inhibitors

  • heart failure

 

 

Workup at the ED:

  • Basic labs: CBC, BMP

  • Lithium level

  • Urinalysis

  • thyroid function panel 

  • Co-ingestants: acetaminophen, salicylates if intentional overdose is suspected 

 

Acute Lithium Toxicity presentation:

  • GI symptoms such as nausea, vomiting, and diarrhea, at times with significant volume loss. 

  • Dry mouth 

  • Lack of coordination

  • systemic and neurologic findings manifest late in acute lithium toxicity because  it takes time for lithium to distribute into tissues and the CNS

 

Chronic Lithium Toxicity presentation:

  • Potent neurotoxin,altered mental status, seizures, tremor, hyper-reflexia, clonus, fasciculations, and extra-pyramidal symptoms which can persist for month regardless of serum concentration 

  • serotonin syndrome, as well as neuroleptic malignant syndrome. 

  • nephrogenic diabetes insipidus (creates resistance to vasopressin)

  • abnormal ECG findings, including QT prolongation, T-wave inversions across the precordial leads, sinoatrial dysfunction, bradycardia, complete heart block, or unmasking of a Brugada pattern. 

  • Hypothyroidism 

  • hyperthyroidism and thyrotoxicosis

  • hyperparathyroidism and hypercalcemia

 

Treatment and Disposicion:

  • Supportive care and fluids at the ED

  • Consult Poison control center 

  • Renal service, for hemodialysis in severe intoxications

  • Psychiatric service, for patients with intentional overdose

  • Pt will most likely require admission for monitoring of electrolytes and renal function, hydration, medication adjustment

 

References:

https://www.acep.org/how-we-serve/sections/toxicology/news/august-2016/acute-and-chronic-lithium-toxicity/

Uptodate