Case of the Week: Weakness, Fatigue and Diarrhea
Author: Christian Gerhart, MD
Reviewed by: Sam Stringer, MD, Michael Mullins, MD
You are working in the trauma and critical care pod. You get a page for a triage patient to 4R. The patient is a 72 yo female.
Here is the triage note:
"Pt presents from PMD office with concern for weakness, fatigue and diarrhea x 1 week. Had a dental implants approx 1 week ago and immediately developed these symptoms afterward. Denies fever/chills/body aches. Also reporting inability to void since procedure. PMD office did straight cath with no volume in bladder, so office placed a foley catheter. Pt arrives very easily fatigued, answering questions appropriately but very drowsy. Needed to have BM immediately upon arrival to ED (diarrhea). Up with cane and x1 assist, appears very deconditioned while ambulating."
Her vital signs are as follows:
BP: 121/68
HR: 110
RR: 18
O2 Sat: 100% on RA
T: 36.7 C
Point of care glucose: 82
History was obtained from the patient and her daughter at bedside. The patient is drowsy but able to say that her abdomen hurts and that she has not been able to urinate for a few days. She has had a few loose stools. She had dental surgery about a week ago and reports decreased PO intake. She has not had any fevers, dental pain or swelling. She does not have any chest pain or shortness of breath. Her daughter confirms this history. She was found to have a past medical history of CAD, HTN, non-insulin dependent DM, CKD, previous renal stones and ureteral stents (now removed) and a previous sleeve gastrectomy.
On exam the patient is ill appearing, awake, alert but mildly confused. She is protecting her airway and is able to speak in full sentences without respiratory distress. She does not have any focal neurological deficits. Her abdomen has mild diffuse tenderness. Her oropharynx is clear, she is edentulous. She does not have any trismus, stridor or evidence of mandibular swelling or tenderness over the site of her reported dental surgery. She has a foley in place with <5 cc of cloudy urine in the tubing.
How would you work this patient up?
The results of the patient's workup are shown below:
The results of the patient's workup are shown below:
A non-contrast CT abdomen/pelvis was obtained which is shown below:
IMPRESSION:
Nonspecific stranding adjacent to bilateral kidneys without
hydronephrosis.
Stable dilation of the extrahepatic bile duct. Correlate with biliary
enzymes if there is clinical concern for obstruction.
The foley catheter was in the bladder and the bladder was empty. The foley catheter was flushed without any urine output.
How would you summarize her laboratory findings?
This patient’s labs were indicative of acute renal failure with an anion gap metabolic acidosis. The differential diagnosis for renal failure includes pre, intrinsic and post renal injury. Urinary obstruction is crucial to rule out which this patient did not have based on no urine output with catheter placement and CT scan. It was thought that her acute kidney injury was most likely secondary to hypovolemia and possible sepsis given her leukocytosis and elevated lactate.
What would your next move be to address her renal failure?
A repeat point of care glucose was obtained which was now 53. The patient was given 500 mL of D10 with improvement of her glucose to the 200s. She was started on cefepime and linezolid for presumed sepsis. Linezolid was chosen over vancomycin given her acute renal failure. An amp of bicarbonate was given followed by a 500 mL bolus of isotonic bicarbonate when the solution arrived from pharmacy. The patient was then started on an isotonic bicarbonate infusion at 150 mL/hr. Nephrology was consulted who recommended repeat labs and close monitoring for consideration of emergent dialysis.
The BICAR-ICU trial (1) provides fairly compelling evidence for the use of bicarbonate to temporize patients with acute renal failure and acidosis. This was a well-done RCT in which ICU patients with metabolic acidosis and an elevated SOFA score were randomized to receive IV bicarbonate. Those with acute renal failure had a mortality benefit and decreased need for dialysis. The number needed to treat for avoidance of dialysis was 6. This is quite a difference considering IV bicarbonate is generally a safe therapy. Remember that bicarbonate can be used to treat non-anion gap metabolic acidosis but is not the treatment for other causes of acidosis such as ketoacidosis or lactic acidosis. The treatment for acidosis in these cases is to address the underlying cause. However, for patients with uremic acidosis from renal failure, bicarbonate can be very effective.
The patient was admitted to the ICU. The patient's repeat labs on arrival to the ICU worsened and a trialysis line was placed. The patient's blood pressure dropped later that evening and she was initiated on vasopressors. Continuous renal replacement therapy (CRRT) was initiated given her severe acidosis which was refractory to aggressive medical management.
What is the most likely cause for her elevated lactate?
The patient's elevated lactate was initially thought to be secondary to sepsis or hypovolemia. Her repeat lactate in the ED was 14. On arrival to the ICU a repeat lactate was drawn which was 20. At this point further history was obtained which revealed that the patient was on Metformin as an outpatient despite this not being listed in her chart. The patient was evaluated by the toxicology team. Given her severe anion gap metabolic acidosis and extremely high lactate, it was agreed that her clinical picture was most consistent with Metformin-Associated Lactic Acidosis (MALA). Dialysis was continued as the primary treatment. Her lactate and pH improved dramatically with renal replacement therapy.
We are fortunate to have Dr. Michael Mullins provide expert commentary on the case (italicized portion). As you probably already know, Dr. Mullins is a world-renowned toxicologist and an enthusiastic educator. Thank you Dr. Mullins!
Metformin is on the short list of causes of extremely high [lactate] (i.e. well above 10 mmol/L). While excluding other causes, you should double check the medication history and whether the Pt hasT2DM.
Most cases involve chronic metformin use and seldom occur by acute overdose. Whether any dose-response relationship exists is unclear.
Her recent diarrhea coupled with poor PO intake likely caused metformin concentrations to climb but also accounted for some of her acidosis (starvation ketosis)
Metformin concentrations: Therapeutic range is about 1 - 2 mcg/mL. Cases of MALA usually have plasma [Metformin] > 5 mcg/mL. Unfortunately, this test is not available in real-time but is a send-out with TAT of about a week. You have to decide only on the lactate, pH, and history of metformin exposure.
Hemodialysis removes metformin (MW of 129 Da) and corrects acidosis. NaHCO3 may be helpful while buying time to get HD started.
If a patient takes metformin (or unknown oral meds for T2DM) and is sick for any reason, check the lactate.
Metformin-Associated Lactic Acidosis
Metformin toxicity exists on a continuum from Metformin-Unrelated Lactic Acidosis (MULA) to MALA to Metformin-Induced Lactic Acidosis (MILA). On one end of the spectrum, MULA is seen when a patient has an elevated lactate, and is on Metformin but the Metformin is thought to not be contributing to the patient’s illness. MALA, which can be challenging to distinguish between from MULA, is when a patient develops an acute illness and Metformin amplifies the degree of lactic acidosis. On the other end of the spectrum is MILA. This is when elevated Metformin levels are the primary cause for a patient’s acute illness, and is generally seen in the setting of acute overdose or subacute accumulation from renal impairment. This case, where the patient developed renal failure from sepsis and hypovolemia, fits best in the MALA category. Metformin likely amplified the degree of lactic acidosis but was less likely to be the primary driver of her illness.
The following chart from the Internet Book of Critical Care is an excellent visual aid to understand this spectrum of disease.
Fortunately, this patient was already being dialyzed for her renal failure. However, in cases of Metformin toxicity, making the diagnosis early may expedite initiation of dialysis. The EXTRIP guidelines can aid in the decision for when to pursue dialysis in these patients.
This case reinforces the point that we must be sure to address all abnormal lab values. This can be especially challenging in complex, critically ill patients such as this one. Though Occam's razor has many applications in medicine, this is a case where Hickum's dictum (patients can have as many diseases as they darn well please) may be more applicable. In addition, this case emphasizes the importance of avoiding anchoring. When new information, such as a worsening lactate despite resuscitation, is available, it is important to consider if there is another disease process at play or if the initial diagnosis should be questioned.
This case brings up an important differential diagnosis for us to consider: the very high lactate, or what I like to call the legit lactic acidosis. A very high lactate (above 8ish) should give us pause that something other than simply shock may be occurring. An excellent article from 2020 in the Annals of Emergency Medicine provides a helpful framework for thinking though this. Lactic acidosis is generally divided into two main categories:
Type A: Lactate elevation is caused by poor tissue oxygenation. This is the form of lactate elevation we are most familiar with and is most commonly caused by shock triggered by disease processes such as limb or gut ischemia, seizures, or infection.
Type B: Lactate elevation can be caused by a variety of factors but there is normal tissue oxygenation. This is generally divided into subcategories which include the following:
i) Systemic underlying disease process
-Examples: liver disease, malignancy, thiamine deficiency, alcoholic ketoacidosis
ii) Drugs or toxins
-Examples: Metformin toxicity, acetaminophen toxicity, beta-2 agonists, toxic alcohols, cyanide, carbon monoxide
iii) Inborn errors of metabolism
-Examples: pyruvate dehydrogenase deficiency, mitochondrial disorders
This patient probably had a mixed picture with at least a portion of her lactate being from sepsis and hypovolemia, and a large portion being secondary to Metformin. Our patients arrive undifferentiated and in cases like this, we can create a convincing picture of sepsis causing acute renal failure leading to an elevated lactate and acidosis. So, when should we consider that there might be something else going on? It is a hard question to answer, but this fascinating study in the pharmacy literature provides some insight. The authors examined ICU patients admitted with possible MALA or septic shock with a lactate over 4 mmol/L. Patients with MALA had a significantly higher lactate compared to those who only had sepsis (14.7 vs 5.9 mmol/l, p < 0.01). In this data set, the combination of a creatinine >2.9, lactate >8.4 and confirmed Metformin use had an 85% sensitivity and 99% specificity. Though this is not a perfect algorithm, if the lactate is persistently in the 8-10 range, we should probably at least consider that there may be a Type B lactic acidosis present and gather further history regarding toxic ingestions and medication history.
Take Home Points:
- Consider Metformin toxicity in patients with a very high lactate (usually over 8), especially if renal failure is present
- Hemodialysis is an effective treatment for severe Metformin toxicity, discuss with nephrology and toxicology early for severe cases
- An elevated lactate has many potential causes, consider toxins, ischemia and thiamine deficiency in addition to sepsis
References:
1. Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial [published correction appears in Lancet. 2018 Dec 8;392(10163):2440]. Lancet. 2018;392(10141):31-40. doi:10.1016/S0140-6736(18)31080-8
2. Wardi G, Brice J, Correia M, Liu D, Self M, Tainter C. Demystifying Lactate in the Emergency Department [published correction appears in Ann Emerg Med. 2020 Apr;75(4):557]. Ann Emerg Med. 2020;75(2):287-298. doi:10.1016/j.annemergmed.2019.06.027
3. van Berlo-van de Laar IRF, Gedik A, van 't Riet E, de Meijer A, Taxis K, Jansman FGA. Identifying patients with metformin associated lactic acidosis in the emergency department. Int J Clin Pharm. 2020;42(5):1286-1292. doi:10.1007/s11096-020-01069-2
4. Farkas J. Metformin toxicity. EMCrit Project. February 12, 2023. Accessed July 30, 2023. https://emcrit.org/ibcc/metformin/.
5. EXTRIP Recommendations. EXTRIP workgroup. Accessed July 30, 2023. https://www.extrip-workgroup.org/recommendations.