Euglycemic DKA

What is it? 

DKA without the elevated glucose that usually triggers us to think about DKA in the first place. Patients often have blood glucose levels less than 250 mg/dl. 

Why do we care? 

Because untreated DKA can lead to cerebral edema, ARDS, renal failure, shock and death.

Why does it happen?

Euglycemic DKA can occur in any diabetic, but there is a rising incidence in those taking SGLT2 inhibtors (-gliflozins) (listed below). The pathophysiology behind this isn't totally clear yet though there are some theories. 

US approved: Dapagliflozin (Farxiga), Canagliflozin (Invokana), Empagliflozin (Jardiance)

It can also occur in those who have underlying disease that depletes the liver's ability to make glucose (putting those who are pregnant or have long bouts of nausea and vomiting under increased risk).

And of course, think of the usual triggers for DKA (ie infection, alcohol use, etc)

When to suspect it?

In any patient with a history of diabetes, including but not limited to those taking SGLT2 inhibitors, who come in for vomiting, generalized weakness, or SOB. Also consider euglycemic DKA in those who have a metabolic acidosis without other clear cause. Draw serum ketones or obtain urine ketones in these patients. 

Sounds a lot like alcoholic ketoacidosis--how to tell the difference?

History: history of heavy alcohol use vs a diabetic on an SGLT2 inhibitor.

Signs: those with alcoholic ketoacidosis tend to have a very low glucose. 

And maintain a high level of suspicion. 

How do we treat it differently than hyperglycemic DKA?

Overall, we treat it pretty similarly. A key difference is that you will need to start fluids with dextrose initially or much earlier than you would with hyperglycemic DKA. 

Sources

https://rebelem.com/euglycemic-dka-not-myth/

https://emcrit.org/ibcc/dka/#euglycemic_DKA

https://emergencymedicinecases.com/euglycemic-dka/

http://www.emdocs.net/diabetic-ketoacidosis-sneaky-triggers-clinical-pearls/

Indications for use of Tranexamic Acid (TXA)

Indications for use of Tranexamic Acid (TXA)

Trauma

Trial Name: CRASH 2 (Positive trial)

Trial Type: Multicenter, double-blind RCT

Sample size: 20,211

Dose/Route of TXA: Loading dose 1g over 10 min, then infusion of 1g over 8hr

Primary outcome: All-cause mortality within 4 weeks of injury

Secondary outcome: Vascular occlusive events (AMI, stroke, PE, and DVT), surgical intervention, receipt of blood transfusion, and units of blood products transfused

Results:  Reduced All-cause mortality p 0.0035, death due to hemorrhage p 0.0077, no significant vascular occlusion p 0.96

Risk of thrombotic events: No increase in risk

Take home point: The use of TXA in trauma patients with “significant bleeding” reduces all-cause mortality without an increase in thromboembolic events.  This effect seems to be greatest in the subset of patients with severe shock (SBP ≤70mmHg) and when given ≤3 hours from time of injury 

Shakur H et al. Effects of Tranexamic Acid on Death, Vascular Occlusive Events, and Blood Transfusion in Trauma Patients with Significant Haemorrhage. Lancet 2010. PMID: 20554319

Trial Name: MATTERs (Positive trial)

Trial Type: Single center, retrospective, observational study

Sample size: 896

Dose/ route of TXA: 1 g initially, 2nd dose per MD discretion

Primary outcome: 24hr mortality, 48hr mortality, and 30-day mortality

Secondary outcome: Transfusion requirements and rate of thromboembolic complications.

Results: Not significantly decreased 24 hr p >0.05, Significantly decreased 48hrs p 0.004 and 30 day mortality p 0.03

Risk of thrombotic events: Increased overall VTE p 0.001 but patients who had a VTE also had higher burden of injury

Take home point:  Patients with penetrating injuries, requiring blood transfusions within 1hr of presentation the use of TXA reduced overall mortality

Morrison JJ et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg 2012. PMID: 22006852

ICH

Trial Name: Meta-Analysis of TXA for Traumatic Brain Injury- negative trial

Trial Type: Meta-analysis and systematic review of RCTs or quasi-RCTs 

Sample size:  510

Outcome: Mortality, neurological function, hematoma expansion

Results: statistically significant reduction in ICH progression with TXA non-statistically significant improvement of clinical outcomes in ED patients with TBI.

Risk of thrombotic events: No adverse effects reported

Take home point: Did not lead to a statistically significant mortality benefit or improved neurological functional status. Further evidence is required to support its routine use in patients with TBI.

Zehtabchi S et al. Tranexamic Acid for Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Am J Emerg Med 2014. PMID: 25447601

Trial Name: Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2)- Negative

Trial Type: International, randomized, double-blind, placebo-controlled, parallel group

Sample size:  2325

Dose of TXA used: 1g IV TXA bolus followed by an 8hr infusion of 1g of TXA 

Outcome:  Functional Status at Day 90, Hematoma Expansion at Day 2, Mean Hematoma Volume Expansion from Baseline to 24hr, Death by Day 7, Death by Day 90

Results: No difference in neurological impairment (mean NIHSS score at day 7), 90-day functional outcomes, length of hospital stay, discharge disposition, venous thromboembolic events, or arterial occlusions

Risk of thrombotic events: None

Take home point: TXA was given >3hrs after stroke onset, patients had more severe strokes, and larger hematoma volumes (>60mLs) than prior studies. Possible benefit if given to a subset of patient within 3 hours with smaller strokes but cannot be recommended at this time in clinical practice for spontaneous ICH based on the results of these trials

Sprigg N et al. Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial. Lancet 2018. PMID: 29778325

Post Partum Hemorrhage

Trial Name: WOMAN trial – Negative trial

Trial Type: Randomized, double-blind, placebo-controlled trial,

Sample size:  20,060 ≥16 years of age with post-partum hemorrhage after vaginal delivery or caesarean section 

Dose of TXA used: 1 g IV vs matching placebo, If bleeding continued after 30 minutes or stopped and restarted within 24hrs, a second dose of 1g of TXA or placebo was given

Outcome: Initial outcome of all-cause mortality and/or hysterectomy within 42 days of giving birth

Final Primary Outcome: Death from PPH

Results: No difference in all cause mortality or hysterctomy

Risk of thrombotic events:

Take home point: It is difficult to draw definitive conclusions from this trial as the NNT was still large (i.e. ≈250) and the study had a fragility index of 0. Data showed a consistent association of delayed administration of TXA with no benefit

WOMAN Trial Collaborators. Effect of Early Tranexamic Acid Administration on Mortality, Hysterectomy, and Other Morbidities in Women with Post-Partum Haemorrhage (WOMAN): An International, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet 2017. PMID: 28456509

UGIB

Trial Name: Cochrane review

Trial Type: Systematic review and meta-analysis of 8 RCTs

Sample size:  1700

Dose of TXA used: Total daily dose of TXA ranged from 4 – 8g and ranged from 2 – 7 days with both PO and IV adminsteration

Outcome: Primary: all-cause mortality and adverse events

Secondary: Rebleeding and surgery

Results: All-Cause Mortality p 0.007, rebleeding P = 0.07

Risk of thrombotic events: No difference in thromboembolic events (only evaluated in 4 trials)

Take home point: May benefit in higher risk patients but better RCTs required to confirm or refute evidence. HALT IT trial underway currently with N of 12000

Bennett C et al. Tranexamic Acid for Upper Gastrointestinal Bleeding (Review). Cochrane Database Syst Rev 2014. PMID: 25414987

Epistaxis

Trial Name: Zahed et al 2017 – Positive study

Trial Type: Randomized, parallel group clinical trial

Sample size:  124 on antiplatelets

Dose of TXA used: topical TXA (500mg in 5mL) or anterior nasal packing.

Outcome: Primary outcome resolution at 10 minutes. Secondary outcomes were re-bleeding rate at 24hours and one week, ED length of stay, and patient satisfaction

Results: epistaxis treatment with topical application of TXA resulted in faster bleeding cessation (NNT 2) , less re-bleeding at 1-week, shorter ED LOS, and higher patient satisfaction as compared with anterior nasal packing.

Risk of thrombotic events: not evaluated

Take home point: Do it!

Zahed R et al. Topical Tranexamic Acid Compared With Anterior Nasal Packing or Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial. Acad Emerg Med 2017. PMID: 29125679

Post-Tonsillectomy Bleeding

Trial Name: Meta-Analysis 2012

Trial Type: Systematic review and meta-analysis

Sample size:  7 studies with 2,444 patients

Dose of TXA used: 250mg for children <25kg, 500mg for children >25kg

Outcome: mean volume of blood loss

Results: TXA led to a significant reduction of tonsillectomy blood loss volume but had no impact on the rate of patients with post-tonsillectomy hemorrhage.

Risk of thrombotic events: Not evaluated

Take home point:  In patients with minor post-tonsillectomy bleeding consider using nebulized TXA to reduce or stop bleeding.  

Chan CC et al. Systematic Review and Meta-Analysis of the Use of Tranexamic Acid in Tonsillectomy. Eur Arch Otorhinolaryngol 2013. PMID: 22996082

Heavy Menstrual Bleeding

Trial Name: Cochrane Review

Trial Type: Systematic review and metanalysis

Sample size:  1312 in 13 RCTs

Dose of TXA used: majority of studies used regular dose TXA (ranging from 3 g/day to 4 g/day), Four other studies used low‐dose TXA (ranging from 2 g/day to 2.4 g/day) 

Outcome: Volume of blood loss, Quality of life

Results:  Appears effective for treating HMB compared to placebo, NSAIDs, Oral luteal progestogens, ethamsylate or herbal remedies but less effective than levonorgestrel intrauterine system

Risk of thrombotic events: Not studied in most RCTs

Take Home point: Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.

Bryant-Smith AC, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD000249. DOI: 10.1002/14651858.CD000249.pub2

Hemoptysis

Trial Name: Inhaled TXA RCT 2018

Trial Type: Prospective, double-blind, placebo-controlled randomized controlled trial 

Sample size:  47

Dose of TXA used: nebulized TXA (500mg/5mL

Primary outcome: rate of complete resolution of hemoptysis during first 5 days from admission, difference in daily volume of expectorated blood

Secondary outcome: rate of interventional bronchoscopy, rate of angiographic embolization, rate of surgery, mean hospital LOS

Results: Resolution of hemoptysis within 5 days of admission, NNT = 2, P<0.0005. Statistically shorter LOS, less invasive procedures

Risk of thrombotic events: not studied

Take home point: Although this was a small study, the advantages of inhaled TXA vs placebo in patients with non-massive hemoptysis included faster resolution of hemoptysis, shorter hospital LOS, fewer invasive procedures, and although not statistically significant, a trend toward improved 30d mortality.

Wand O et al. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial. Chest 2018. PMID: 30321510

References:

See above

RebelEM

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