- Email: [email protected]
A Common But Not so Typical Elevated Anion Gap
Accepted Manuscript A Common but not so Typical Elevated Anion Gap Barry Gorlitsky, MD, Edward Via Colloeg e of Osteopathic Medicine Assistant Clinical Professor, Shereef El-Ibiary, MD PII:
S0002-9343(16)30020-1
DOI:
10.1016/j.amjmed.2015.12.021
Reference:
AJM 13324
To appear in:
The American Journal of Medicine
Received Date: 23 December 2015 Accepted Date: 23 December 2015
Please cite this article as: Gorlitsky B, El-Ibiary S, A Common but not so Typical Elevated Anion Gap, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2015.12.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
A Common but not so Typical Elevated Anion Gap. Barry Gorlitsky MD Edward Via Colloeg e of Osteopathic Medicine Assistant Clinical Professor Shereef El-Ibiary MD
All authors had access to the data and a role in writing the manuscript No funding source or conflict of interests to declare for both authors
SC
Clinical Communication to the Editor
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This manuscript is original and not published or under consideration elsewhere
Key Words: Euglycemic DKA, Anion Gap, Acidosis, SGLT2 inhibitor, Diabetes, Canagliflozin
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Contact: Barry Gorlitsky MD email: [email protected], work address 203 Mills Avenue Greenville SC 29605 Work # 864-270-1844
ACCEPTED MANUSCRIPT
To the editor A 40 year old male patient with past medical history of schizophrenia, type 2 diabetes mellitus, mild mental retardation, and seizure disorder, presented from his care home with complaints of malaise,
RI PT
confusion, fevers and a draining lower extremity wound. He was found to have sepsis with blood cultures positive for MRSA and Streptococcus species. He received Vancomycin and
Piperacillin/Tazobactam, as well as normal saline hydration. On admission, and subsequent days, he
SC
was noted to have elevated anion gap metabolic acidosis. The initial laboratory values are shown in Table 1. Notably his bicarbonate was 12mmol/L and his anion gap was 21, corrected for albumin. A
M AN U
customary and thorough workup of the anion gap acidosis was undertaken and included normal serum creatinine, negative toxic alcohols, normal lactic acid, negative salicylates and acetaminophen. The blood sugar was 127 mg/dl. Over the next several days he received 150 mEq/L sodium bicarbonate in D5W without significant improvement in serum bicarbonate level and the anion gap remained above 20.
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On the 5th hospital day, the serum bicarbonate level had declined to 5.4 mmol/L , corrected anion gap was now 24 with a pH of 7.24 and PCO2 of 16 on arterial blood gas analysis. The patient remained altered.
EP
At this juncture, 100 mEq of bicarbonate was administered acutely with moderate improvement in serum bicarbonate and pH. Further testing and careful chart review began to elucidate the etiology. His
AC C
urine dip-stick revealed positive ketones and a sugar of >500 mg/dl despite having normoglycemia. Acetone was noted to be elevated on admission as part of the initial evaluation. Beta-hydroxybutyrate was then tested and also elevated at 90 mg /dl (0.2-2.8 reference range). It appeared the patient was in DKA, but curiously without an elevated blood sugar. On review of his home medications we discovered he had been prescribed the novel oral anti-diabetic agent Canagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT-2 inhibitor). The diagnosis of euglycemic DKA (euDKA) was established. The patient was started on tube feedings and began to receive insulin in small doses. Over several days, his anion
ACCEPTED MANUSCRIPT
gap closed. Interestingly, several weeks out from the initial insult, and off the Canagliflozin, he persisted in having glycosuria by dipstick with normoglycemia.
RI PT
SGLT-2 inhibitors impede the proximal tubule reabsorption of glucose, leading to glycosuria and modestly lowering blood glucose levels in an insulin independent fashion.1 The first of this class, Canagliflozin (Invokana) was FDA approved in 2013.2 Since approval, over 70 cases of possible
euglycemic DKA have been reported to the FDA Med Watch program. This finding prompted a safety
SC
alert on May 15, 2015 and a warning label was added on December 4, 2015.3 A 2015 review article identified 13 episodes of SGLT-2 inhibitor euDKA in both type 1 and type 2 diabetics.4 The prevailing
M AN U
pathophysiologic explanation is thought to be secondary to the drugs ability to cause noninsulindependent glucose lowering, hyperglucagonemia, and volume depletion.4 In closing, diabetes is a common ailment with multiple novel agents for treatment. As with any new medication, adverse effects are often discovered post-hoc and require hypervigilance by practicing
TE D
providers. It is therefore imperative when coming across a patient who is presenting similar to DKA, but without hyperglycemia (especially in the setting of normoglycemic glucosuria), we test urinary and serum ketones. Equally important, we must analyze the home medications astutely; perhaps your
AC C
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patient has been placed on an SGLT-2 inhibitor and is also suffering from euDKA.
References
1. Clar C., Gill J. A., Court R., Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5) doi: 10.1136/bmjopen-2012-001007.e001007 2. Liscinsky, M (2013, March, 29) FDA approves Invokana to treat type 2 Diabetes retrieved from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm
ACCEPTED MANUSCRIPT
3. (2015, December, 4) Drug Safety Notification: FDA revises labels of SGLT2 inhibitors for Diabetes to include warnings on too much acid in the blood and serious urinary tract infections retrieved from: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm
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4. Peters AL., Buschur EO., Buse JB., Cohan., et al. Eugylcemic Diabetic Ketoacidosis: A Potential Complication with Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015; 38 (9): 1687-93.
ACCEPTED MANUSCRIPT
Figure 1 Bicarbonate 12 mmol/L BUN 8 mg/dl Creatinine 0.7 mg/dl Corrected Anion Gap 21 mmol/L Calcium 8.5 mg/dl
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TE D
M AN U
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Sodium 135 mmol/L Chloride 104 mmol/L Potassium 4.2 mmol/L Albumin 3.3 mg/dl Glucose 127 mg/dl
mmol=Millimoles mg=Milligram L=Liter Dl=Deciliter
S0002-9343(16)30020-1
DOI:
10.1016/j.amjmed.2015.12.021
Reference:
AJM 13324
To appear in:
The American Journal of Medicine
Received Date: 23 December 2015 Accepted Date: 23 December 2015
Please cite this article as: Gorlitsky B, El-Ibiary S, A Common but not so Typical Elevated Anion Gap, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2015.12.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
A Common but not so Typical Elevated Anion Gap. Barry Gorlitsky MD Edward Via Colloeg e of Osteopathic Medicine Assistant Clinical Professor Shereef El-Ibiary MD
All authors had access to the data and a role in writing the manuscript No funding source or conflict of interests to declare for both authors
SC
Clinical Communication to the Editor
RI PT
This manuscript is original and not published or under consideration elsewhere
Key Words: Euglycemic DKA, Anion Gap, Acidosis, SGLT2 inhibitor, Diabetes, Canagliflozin
AC C
EP
TE D
M AN U
Contact: Barry Gorlitsky MD email: [email protected], work address 203 Mills Avenue Greenville SC 29605 Work # 864-270-1844
ACCEPTED MANUSCRIPT
To the editor A 40 year old male patient with past medical history of schizophrenia, type 2 diabetes mellitus, mild mental retardation, and seizure disorder, presented from his care home with complaints of malaise,
RI PT
confusion, fevers and a draining lower extremity wound. He was found to have sepsis with blood cultures positive for MRSA and Streptococcus species. He received Vancomycin and
Piperacillin/Tazobactam, as well as normal saline hydration. On admission, and subsequent days, he
SC
was noted to have elevated anion gap metabolic acidosis. The initial laboratory values are shown in Table 1. Notably his bicarbonate was 12mmol/L and his anion gap was 21, corrected for albumin. A
M AN U
customary and thorough workup of the anion gap acidosis was undertaken and included normal serum creatinine, negative toxic alcohols, normal lactic acid, negative salicylates and acetaminophen. The blood sugar was 127 mg/dl. Over the next several days he received 150 mEq/L sodium bicarbonate in D5W without significant improvement in serum bicarbonate level and the anion gap remained above 20.
TE D
On the 5th hospital day, the serum bicarbonate level had declined to 5.4 mmol/L , corrected anion gap was now 24 with a pH of 7.24 and PCO2 of 16 on arterial blood gas analysis. The patient remained altered.
EP
At this juncture, 100 mEq of bicarbonate was administered acutely with moderate improvement in serum bicarbonate and pH. Further testing and careful chart review began to elucidate the etiology. His
AC C
urine dip-stick revealed positive ketones and a sugar of >500 mg/dl despite having normoglycemia. Acetone was noted to be elevated on admission as part of the initial evaluation. Beta-hydroxybutyrate was then tested and also elevated at 90 mg /dl (0.2-2.8 reference range). It appeared the patient was in DKA, but curiously without an elevated blood sugar. On review of his home medications we discovered he had been prescribed the novel oral anti-diabetic agent Canagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT-2 inhibitor). The diagnosis of euglycemic DKA (euDKA) was established. The patient was started on tube feedings and began to receive insulin in small doses. Over several days, his anion
ACCEPTED MANUSCRIPT
gap closed. Interestingly, several weeks out from the initial insult, and off the Canagliflozin, he persisted in having glycosuria by dipstick with normoglycemia.
RI PT
SGLT-2 inhibitors impede the proximal tubule reabsorption of glucose, leading to glycosuria and modestly lowering blood glucose levels in an insulin independent fashion.1 The first of this class, Canagliflozin (Invokana) was FDA approved in 2013.2 Since approval, over 70 cases of possible
euglycemic DKA have been reported to the FDA Med Watch program. This finding prompted a safety
SC
alert on May 15, 2015 and a warning label was added on December 4, 2015.3 A 2015 review article identified 13 episodes of SGLT-2 inhibitor euDKA in both type 1 and type 2 diabetics.4 The prevailing
M AN U
pathophysiologic explanation is thought to be secondary to the drugs ability to cause noninsulindependent glucose lowering, hyperglucagonemia, and volume depletion.4 In closing, diabetes is a common ailment with multiple novel agents for treatment. As with any new medication, adverse effects are often discovered post-hoc and require hypervigilance by practicing
TE D
providers. It is therefore imperative when coming across a patient who is presenting similar to DKA, but without hyperglycemia (especially in the setting of normoglycemic glucosuria), we test urinary and serum ketones. Equally important, we must analyze the home medications astutely; perhaps your
AC C
EP
patient has been placed on an SGLT-2 inhibitor and is also suffering from euDKA.
References
1. Clar C., Gill J. A., Court R., Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5) doi: 10.1136/bmjopen-2012-001007.e001007 2. Liscinsky, M (2013, March, 29) FDA approves Invokana to treat type 2 Diabetes retrieved from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm
ACCEPTED MANUSCRIPT
3. (2015, December, 4) Drug Safety Notification: FDA revises labels of SGLT2 inhibitors for Diabetes to include warnings on too much acid in the blood and serious urinary tract infections retrieved from: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm
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EP
TE D
M AN U
SC
RI PT
4. Peters AL., Buschur EO., Buse JB., Cohan., et al. Eugylcemic Diabetic Ketoacidosis: A Potential Complication with Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015; 38 (9): 1687-93.
ACCEPTED MANUSCRIPT
Figure 1 Bicarbonate 12 mmol/L BUN 8 mg/dl Creatinine 0.7 mg/dl Corrected Anion Gap 21 mmol/L Calcium 8.5 mg/dl
AC C
EP
TE D
M AN U
SC
RI PT
Sodium 135 mmol/L Chloride 104 mmol/L Potassium 4.2 mmol/L Albumin 3.3 mg/dl Glucose 127 mg/dl
mmol=Millimoles mg=Milligram L=Liter Dl=Deciliter