My elderly hospitalized patient with pneumonia has developed hypoglycemia within days of initiating piperacillin/tazobactam (Zosyn). Is there a connection between piperacillin/tazobactam and hypoglycemia?

Hypoglycemia is a rare (<1%) reported side effect of piperacillin/tazobactam (P/T) [1].  While the exact mechanism is unclear, hypoglycemia in this setting may be related to the adverse impact of P/T on renal function or possibly competitive inhibition of renal organic anion transporter 3 (OAT3).

The association of P/T with acute kidney injury (AKI) is well known. In a retrospective cohort analysis of 11,650 patients, P/T was associated with AKI in 7.8% of patients [2]. Of interest, compared to other antibiotics, P/T has also been shown to delay renal recovery in critically ill patients [3].  Decline in renal function may in turn reduce clearance of insulin and lead to hypoglycemia, particularly in patients who already have risk factors for hypoglycemia, such as malnutrition [4]. This is not surprising because renal clearance accounts for 25% of insulin clearance (rest is hepatic).  

Another plausible mechanism is the impact of P/T on glucose metabolism through competitive inhibition of OAT3 [5]. OAT3 is important in reabsorption of gluconeogenic precursors as well as excretion of uremic metabolites [6], which may further dysregulate hepatic gluconeogenesis and precipitate hypoglycemia. Fascinating!

Bonus pearl: Did you know that elderly patients may be at risk of reactive (post-prandial) hypoglycemia particularly in the setting of pre-diabetes or diabetes due to loss of coordination between glucose load and insulin secretion [7]? 

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Contributed by Michael Nance, MD, PhD, Department of Medicine, Mercy Hospital-St. Louis, St. Louis, Missouri

References:

  1. Wyeth Pharmaceutical Inc. Zosyn (piperacillin/tazobactam) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050684s88s89s90_050750s37s38s39lbl.pdf. Revised May 2017. Accessed January 16, 2021.
  2. Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis. J Hosp Med. 2017 Feb;12(2):77-82. doi: 10.12788/jhm.2684. PMID: 28182801; PMCID: PMC5573255. https://pubmed.ncbi.nlm.nih.gov/28182801/
  3. Jensen JS, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open 2012;2:doi: 10.1136/bmjopen-2011-000635  https://bmjopen.bmj.com/content/2/2/e000635
  4. Leibovitz E, Adler H, Giryes S, Ditch M, Burg NF, Boaz M. Malnutrition risk is associated with hypoglycemia among general population admitted to internal medicine units. Results from the MENU study. Eur J Clin Nutr. 2018 Jun;72(6):888-893. doi: 10.1038/s41430-018-0143-9. Epub 2018 Mar 27. PMID: 29588529. https://pubmed.ncbi.nlm.nih.gov/29588529/
  5. Wen S, Wang C, Duan Y, Huo X, Meng Q, Liu Z, Yang S, Zhu Y, Sun H, Ma X, Yang S, Liu K. OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam. Int J Pharm. 2018 Feb 15;537(1-2):172-182. doi: 10.1016/j.ijpharm.2017.12.037. Epub 2017 Dec 23. PMID: 29277663. https://pubmed.ncbi.nlm.nih.gov/29277663/
  6. Wu, W., Bush, K.T. & Nigam, S.K. Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivoHandling of Uremic Toxins and Solutes. Sci Rep 7, 4939 (2017). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504054/
  7. Tamura Y, Araki A, Chiba Y, Horiuchi T, Mori S, Hosoi T. Postprandial reactive hypoglycemia in an oldest-old patient effectively treated with low-dose acarbose. Endocr J. 2006 Dec;53(6):767-71. doi: 10.1507/endocrj.k05-140. Epub 2006 Sep 12. PMID: 16966825. https://pubmed.ncbi.nlm.nih.gov/16966825/ 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My elderly hospitalized patient with pneumonia has developed hypoglycemia within days of initiating piperacillin/tazobactam (Zosyn). Is there a connection between piperacillin/tazobactam and hypoglycemia?

Why doesn’t my patient with lactic acidosis have hyperkalemia?

Although hyperkalemia may be observed in a variety of conditions associated with metabolic acidosis, it is less likely to be seen in conditions associated with excess organic acids (eg, in lactic acidosis or diabetic ketoacidosis). A likely explanation for this finding revolves around the amazing organic anion transporter (OAT) and its attendant role in counteracting hyperkalemia by bringing potassium (K+) back into the cells.1-5 See details of impact of extracellular and intracellular pH on K+ homeostasis in Figure.1 

Recall that in metabolic acidosis the increased concentration of hydrogen ion (H+) outside the cell reduces sodium (Na+) influx into cells through the Na+-H+ exchange channel resulting in a drop in the intracellular Na+.  Since the Na+K+ATPase ion channel depends on the intracellular Na+ for bringing K+ into the cells, the end-result is higher K+ concentrations in the extracellular space, potentially resulting in hyperkalemia.  This is what is often seen in conditions of mineral (non-organic) acid excess (eg, in respiratory acidosis or poor renal function).

In the case of organic acidosis, however, the OAT also plays an important factor in K+ homeostasis (Figure)1.  As the name suggests, this transporter allows  organic acids such as lactic acid or ketones to enter the cell. As the H+ concentration increases intracellularly, there is more Na+-H+ exchange and more influx of Na+ into the cell.  More available Na+ intracellularly means more Na+ is pumped out by Na+K+ATPase, and more K+ is brought into the cell,1-5 mitigating the impact of metabolic acidosis on K+ efflux into the  extracellular space and potentially even causing hypokalemia! 

Concurrent hyperkalemia and lactic acidosis or diabetic ketoacidosis may of course still occur.  However, in such cases, hyperkalemia is often due to an epiphenomenon related to complicating factors.  In the case of lactic acidosis, this may be related to concurrent renal dysfunction,3 while in diabetic ketoacidosis it may be related to hyperosmolarity or insulin deficiency.1

So next time you see a patient who has hyperkalemia and lactic acidosis, ask yourself  “What else am I missing that can explain the hyperkalemia?“.

Bonus Pearl

Did you know that lactic acid in human blood was first discovered by the German physician–chemist, Johann Joseph Sherer, who sampled post-mortem blood from 2 women who died of puerperal fever in 1843? 6

Contributed by Nabi Chaudhri-Martinez MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Aronson PS, Giebisch G. Effects of pH on potassium: new explanations for old observations. J Am Soc Nephrol. 2011 Nov;22(11):1981-9. doi: 10.1681/ASN.2011040414. Epub 2011 Oct 6. PMID: 21980112; PMCID: PMC3231780. https://jasn.asnjournals.org/content/22/11/1981.long
  2. Orringer CE, Eustace JC, Wunsch CD, Gardner LB. Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. N Engl J Med. 1977 Oct 13;297(15):796-9. doi: 10.1056/NEJM197710132971502. PMID: 19702. https://www.nejm.org/doi/10.1056/NEJM197710132971502?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
  3. Fulop M. Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med. 1979 May 10;300(19):1087-9. doi: 10.1056/NEJM197905103001905. PMID: 34793. https://www.nejm.org/doi/10.1056/NEJM197905103001905?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed
  4. Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med. 1981 Sep;71(3):456-67. doi: 10.1016/0002-9343(81)90182-0. PMID: 7025622. https://www.amjmed.com/article/0002-9343(81)90182-0/pdf
  5. Nigam SK, Bush KT, Martovetsky G, et al. The organic anion transporter (OAT) family: A systems biology perspective. Physiol Rev 2015;95:83:123. The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective (physiology.org)
  6. Kompanje EJ, Jansen TC, van der Hoven B, Bakker J. The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer (1814-1869) in January 1843. Intensive Care Med. 2007;33(11):1967-1971. doi:10.1007/s00134-007-0788-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2040486/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why doesn’t my patient with lactic acidosis have hyperkalemia?

I am admitting a patient with diabetes mellitus (DM) due to chronic pancreatitis. Should I manage her diabetes any differently than my other patients with DM?

You may have to!  That’s because patients with DM due to pancreatic disease (also known as “pancreatogenic [Type 3C] diabetes”) tend to have more labile blood glucoses with particular predisposition to severe hypoglycemic episodes due to the impairment of glucagon production by pancreatic alpha-cells. 1-3

This observation dates back to a 1977 study where a high rate of hypoglycemic episodes was found among 59 patients with chronic pancreatitis (most with insulin-dependent DM), including 3 deaths and 2 suffering from severe brain damage following hypoglycemic coma. Interestingly, low basal glucagon levels were found in the latter patients, supporting impairment in glucagon synthesis. Of note, while hypoglycemia is a serious problem in these patients, they are not spared from complications of chronic hyperglycemia, including retinopathy and kidney disease.2

As for the blood glucose management in type 3C DM, since the principle endocrine defect is insulin deficiency, insulin therapy is preferred for most patients, particularly those who are acutely ill or are hospitalized. For otherwise more stable patients with mild hyperglycemia, metformin is an ideal agent as it enhances hepatic insulin sensitivity without the risk of hypoglycemia. As a bonus, metformin may also decrease the risk of pancreatic cancer in chronic pancreatitis, based on observational studies. 4

Also, don’t forget that concurrent pancreatic exocrine insufficiency is common in patients with type 3C DM and requires oral pancreatic enzyme requirement with meals.

Fascinating Pearl: Did you know that in patients with type 3C DM, hyperglycemia is mediated not only by decreased production of insulin, but also by decreased synthesis of pancreatic polypeptide, a peptide that mediates hepatic insulin sensitivity and glucose production? 5

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References

  1. Linde, J, Nilsson LH, Barany FR. Diabetes and hypoglycemia in chronic pancreatitis. Scand J Gastroenterol. 2012;12, 369–373. https://www.ncbi.nlm.nih.gov/pubmed/867001
  2. Andersen D. The practical importance of recognizing pancreatogenic or type 3c diabetes. Diabetes Metab Res Rev. 2012;28:326-328. https://onlinelibrary.wiley.com/doi/abs/10.1002/dmrr.2285
  3. Cui YF, Andersen DK. Pancreatogenic diabetes: Special considerations for management. Pancreatology. 2011;11(3):279-294. doi:10.1159/000329188. https://jhu.pure.elsevier.com/en/publications/pancreatogenic-diabetes-special-considerations-for-management-4
  4. Evans J, Donnelly L, Emsley-Smith A. Metformin and reduced risk of cancer in diabetic patients. Br Med J. 2005;330:1304-1305. https://www.researchgate.net/publication/7888859_Metformin_and_reduced_risk_of_cancer_in_diabetic_patients
  5. Rabiee A. Gafiatsatos P, Salas-Carnillo R. Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patents on insulin pump therapy. Diabetes Sci Technol 2011;5:1521-28.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262724/

Contributed by Hugo Torres, MD, MPH, Hospital Medicine Unit, Mass General Hospital, Boston, Massachusetts

I am admitting a patient with diabetes mellitus (DM) due to chronic pancreatitis. Should I manage her diabetes any differently than my other patients with DM?

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

Although we may expect patients with DKA to present with hypotension due to hypovolemia, many patients with DKA may actually be hypertensive. This finding is particularly intriguing because hyperinsulinemia, not insulinopenia as found in DKA, has been associated with hypertension. 1,2

Though not proven, potential explanations for hypertension in DKA include elevated serum levels of catecholamines, pro-inflammatory cytokines, renin, angiotension II and aldosterone.3-5 Hyperosmolality may also lead to the release of antidiuretic hormone (ADH) which increases blood pressure via V2 receptors.  Another possibility is that the high insulin levels associated with the treatment of DKA suppress the catecholamine-stimulated production of vasodilative eicosanoids (eg, prostaglandins) by adipose tissue. 1 It’s possible that in any given patient, 1 or more of these mechanisms may be enough to override the potential hypotensive effect of insulin deficiency in DKA.

We should note that reports of frequent hypertension in DKA have primarily involved pediatric patients. A 2011 study found that 82% of pediatric patients with DKA had hypertension during the first 6 hours of admission with no patient having hypotension.3  

On the other extreme, refractory hypotension without obvious cause (eg, sepsis, acute adrenal insufficiency, cardiogenic causes) has also been reported in DKA.5Because insulin inhibits the production of vasodilative prostaglandins (eg, PGI2 and PGE2), severe insulin deficiency in DKA can also contribute to hypotension along with volume depletion. 

Potential genetic polymorphism in the synthesis and metabolism of prostaglandins may at least partially explain the varied blood pressure response and whether a patient with DKA presents with hypertension or hypotension. 5  

The author would like to acknowledge the valuable contribution of Lloyd Axelrod MD, Massachusetts General Hospital, to this post.

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References

  1. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991;40:1223-1227. https://diabetes.diabetesjournals.org/content/40/10/1223&nbsp;
  2. Chatzipantelli K, Head C, Megerman J, et al. The relationship between plasma insulin level, prostaglandin productin by adipose tissue and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis. Metabolism 1996;45:691-98. https://www.sciencedirect.com/science/article/abs/pii/S002604959690133X&nbsp;
  3. Deeter KH, Roberts JS, Bradford H, et al. Hypertension despite dehydration during severe pediatric diabetic ketoacidosis. Pediatr Diabetes 2011;12:295-301. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-5448.2010.00695.x&nbsp;
  4. Ferris JB, O’Hare JA, Kelleher CM, et al. Diabetic control and the renin-angiotensin system, catecholamines and blood pressure. Hypertension 1985 7(Suppl II):II-58-II-63. https://www.ahajournals.org/doi/abs/10.1161/01.HYP.7.6_Pt_2.II58  
  5. Singh D, Cantu M, Marx MHM, et al. Diabetic ketoacidosis and fluid refractory hypotension. Clin Pediatrics 2016;55:182-84. https://journals.sagepub.com/doi/abs/10.1177/0009922815584549?journalCode=cpja&nbsp;

 

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?