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?

How is prealbumin related to albumin?

Aside from being synthesized in the liver and serving as a transport protein in the blood, prealbumin (PA) doesn’t really have much in common with albumin. More specifically, PA is not derived from albumin and, in fact, the two proteins are structurally distinct from each other!

So where does PA get its name? PA is the original name for transthyretin (TTR), a transport protein that primarily carries thyroxine (T4) and a protein bound to retinol (vitamin A). The name arose because TTR migrated faster than albumin on gel electrophoresis of human serum.1

Because of its much shorter serum half-life compared to that of albumin ( ~2 days vs ~20 days),2 PA is more sensitive to recent changes in protein synthesis and more accurately reflects recent dietary intake (not necessarily overall nutritional status) than albumin. 3

But, just like albumin, PA may represent a negative acute phase reactant, as its synthesis drops during inflammatory states in favor of acute phase reactants such as C-reactive protein. 4 So be cautious about interpreting low PA levels in patients with active infection, inflammation or trauma.

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Reference

  1. Socolow EL, Woeber KA, Purdy RH, et al. Preparation of I-131-labeled human serum prealbumin and its metabolism in normal and sick patients. J. Clin Invest 1965; 44: 1600-1609. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292644/
  2. Oppenheimer JH, Surks MI, Bernstein G, and Smith JC. Metabolism of Iodine-131-labeled Thyroxine-Binding Prealbumin in Man. Science 1965; 149: 748-750. https://www.ncbi.nlm.nih.gov/pubmed/14330531
  3. Ingenbleek Y, Young VR. Significance of prealbumin in protein metabolism. Clin Chem Lab Med 2002; 40: 1281-1291. https://www.ncbi.nlm.nih.gov/pubmed/12553432
  4. Shenkin A. Serum prealbumin: is it a marker of nutritional status or of risk of malnutrition? Clin Chem 2006;52:2177 – 2179. http://clinchem.aaccjnls.org/content/52/12/2177

Contributed by Colin Fadzen, Medical Student, Harvard Medical School, Boston, MA.

 

 

How is prealbumin related to albumin?

My elderly patient with acute heart failure with preserved ejection fraction (HFpEF) has a low serum albumin. Can hypoalbuminemia be associated with HFpEF?

Absolutely! As early as 1959, Guyton and Lindsey demonstrated the importance of serum colloid osmotic pressure in the pathogenesis of pulmonary edema1.

Specifically, they found that in dogs with normal plasma protein concentrations fluid began to transudate into the lungs when the left atrial pressure rose above an average of 24 mm Hg vs only 11 mm Hg when plasma protein concentration was reduced by about 50%.

Fast forward to 2003, Arques et al studied serum albumin and pulmonary artery wedge pressures in 4 groups of patients: acute HFpEF, heart failure with reduced ejection fraction (HFrEF), acute dyspnea from pulmonary origin and normal controls2.   Patients with HFpEF were significantly more likely to have hypoalbuminemia , compared to those with HFrEF, pulmonary disease or normal controls.  The main cause of hypoalbuminemia in the HFpEF was malnutrition in 77% and/or sepsis in 41% of patients.   Hypoalbuminemia was inversely related to age and plasma C-reactive protein.

Perhaps, we should pay more attention the nutritional status of our patients with HFpEF!

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References

  1. Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 1959;7: 649-657.
  2. Arquès S, Ambrosi P, Gélisse R et al. Hypoalbuminemia in elderly patients with acute diastolic heart failure. J Am Coll Card 2003;42:712-16. http://www.onlinejacc.org/content/42/4/71                                                                                                    
My elderly patient with acute heart failure with preserved ejection fraction (HFpEF) has a low serum albumin. Can hypoalbuminemia be associated with HFpEF?