Should I continue nadolol in my patient with cirrhosis and refractory ascites?

Under certain circumstances, you may need to! Although nonselective beta blockers (NSBBs), such as nadolol and propranolol, have been the cornerstone of medical treatment of portal hypertension in preventing variceal bleeding in patients with cirrhosis for decades, recent reports of their association with worsening survival, increased risk of hepatorenal syndrome and acute kidney injury in patients with refractory ascites or spontaneous bacterial peritonitis [SBP]) 1,2 have added controversy to their routine use in end-stage cirrhosis.

This is because patients with end-stage cirrhosis may be highly dependent on their cardiac output (particularly the heart rate) in maintaining an adequate arterial blood pressure 3-5 and the negative inotropic and chronotropic effects of NSBBs blunt this compensatory mechanism. The result is a drop in the cardiac output that may be particularly significant in the presence of conditions already associated with hypotension, such as sepsis, spontaneous bacterial peritonitis (SBP), or hemorrhage, further increasing the risk of renal hypoperfusion and hepatorenal syndrome.3

Although 2 meta-analysis studies failed to find an association between NSBBs and increased mortality among patients with cirrhosis and ascites, 6,7 serious concerns over the adverse effects of these drugs in at least a subset of patients has not waned.  Some have recommended reducing NSBB dose or discontinuing treatment in patients with refractory ascites or SBP and any of the following parameters: 4

  • Systolic blood pressure <90 mmHg
  • Serum creatinine >1.5 mg/dL
  • Hyponatremia <130 mmol/L

Similar recommendations were made by a 2015 consensus conference on individualizing the care of patients with portal hypertension.

In the absence of randomized-controlled studies, it seems prudent to proceed with more caution when using NSBBs in patients with end-stage cirrhosis and watch closely for any signs of hypotension or renal function deterioration.

References

  1. Serste T, Njimi H, Degre D, et al. The use of beta-lackers is associated with the occurrence of acute kidney injury in severe hepatitis. Liver In 2015;35:1974-82. https://www.ncbi.nlm.nih.gov/pubmed/25611961
  2. Mandorfer M, Bota S, Schwabl P, et al. Nonselective beta blockers increase risk of hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterol 2014;146:1680-90. https://www.sciencedirect.com/science/article/pii/S0016508514003060?via%3Dihub
  3. Garcia-Tsao G. The use of nonselective beta blockers for treatment of portal hypertension. Gastroenterol Hepatol 2017;13: 617-19. http://www.gastroenterologyandhepatology.net/archives/october-2017/the-use-of-nonselective-beta-blockers-for-treatment-of-portal-hypertension/
  4. Reiberger T, Mandorfer M. Beta adrenergic blockade and decompensated cirrhosis. J Hepatol 2017;66: 849-59. https://www.ncbi.nlm.nih.gov/pubmed/27864004
  5. Giannelli V, Lattanzi, Thalheimer U, et al. Beta-blockers in liver cirrhosis. Ann Gastroenterol 2014;27:20-26. https://www.ncbi.nlm.nih.gov/pubmed/24714633
  6. Facciorusso A, Roy S, Livadas S, et al. Nonselective beta-blockers do not affect survival in cirrhotic patients with ascites. Digest Dis Sci 2018;63:1737-46. https://link.springer.com/article/10.1007%2Fs10620-018-5092-6
  7. Njei B, McCarty TR, Garcia-Tsao G. Beta-blockers in patients with cirrhosis and ascites: type of betablocker matters. Gut 206;65:1393-4. https://gut.bmj.com/content/gutjnl/65/8/1393.full.pdf
  8. De Franchis R. Expanding consensus in portal hypertension. Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.  J Hepatol 2015;63:743-52.  https://www.ncbi.nlm.nih.gov/pubmed/26047908  

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Should I continue nadolol in my patient with cirrhosis and refractory ascites?

My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. 1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.3

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? 7

 

References

  1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
  2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
  3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
  4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
  5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
  6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
  7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Can I rule out primary adrenal insufficiency by obtaining a single morning serum cortisol level in my hospitalized patient with unexplained hyponatremia?

Primary adrenal insufficiency (PAI) can be confidently ruled out when the morning (eg, 6 AM) serum cortisol level is greater than 17 ug/dl. Lower cut-off values are associated with lower probability of excluding PAI: > 10 ug/dl, 62%-67% and ≥5 ug/dl, 36%. 1,2 Conversely, PAI is highly likely when the morning serum cortisol level is less than 3 ug/dl. 3

Since many patients may have serum cortisol levels between 3 ug/dl and 17 ug/dl (ie, in the “indeterminate” range), confirmatory testing commonly performed through cosyntropin stimulation test (CST) is often necessary.

Although the standard CST involves measuring serum cortisol levels at baseline, 30 min, and 60 min with peak cortisol level <18 ug/dl indicative of PAI, several studies have reported that a single post-CST cortisol level obtained at 60 min may also be diagnostic. 3

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References

  1. Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 83;2350-54. https://www.ncbi.nlm.nih.gov/pubmed/9661607
  2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101:364-89. https://academic.oup.com/jcem/article/101/2/364/2810222
  3. Odom DC, Gronowski AM, Odom E, et al. A single, post-ACTH cortisol measurement to screen for adrenal insufficiency in the hospitalized patient. J Hosp Med 2018;13: E1-E5. https://www.ncbi.nlm.nih.gov/pubmed/29444197
Can I rule out primary adrenal insufficiency by obtaining a single morning serum cortisol level in my hospitalized patient with unexplained hyponatremia?

What is the significance of hyponatremia in my patient with acute decompensated congestive heart failure (ADCHF)?

Hyponatremia, defined as a serum sodium <135 meq/L, is observed in ~20% of patients hospitalized with ADCHF, and is often dilutional, not “depletional” (ie, not associated with hypovolemia) in this condition1.

In ADCHF, hyponatremia is primarily caused by the production of arginine vasopressin (AVP) (also known as anti-diuretic hormone, or ADH) as a result of decreased perfusion pressures in the aortic arch and renal afferent arterioles, and increased thirst due to the activation of the renin-angiotensin system.  Hyponatremia correlates with the severity of ADCHF and adverse clinical outcomes2.   

 A common approach to dilutional hyponatremia in ADCHF is fluid restriction. Other potential therapies include angiotension converting enzyme inhibitors (by increasing cardiac output and decreasing thirst), loop diuretics (by reducing water reabsorption in the renal distal tubule), and AVP antagonists (eg, tolvapatan, satavaptan)1,3.  Otherwise, in the absence of symptoms, no specific therapy is generally indicated for serum sodium levels ≥ 120mEq/L.

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References 

  1. Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WHW, Mullens W. Hyponatremia in acute decompensated heart failure: Depletion versus dilution. J Am Coll Cardiol 2015;65:480-92. https://www.sciencedirect.com/science/article/pii/S073510971407394X?via%3Dihub
  2. Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J. 1994;128:564.  https://www.sciencedirect.com/science/article/pii/0002870394906335
  3. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C, SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099. https://www.ncbi.nlm.nih.gov/pubmed/17105757

 

Contributed by Ricardo Ortiz, Medical Student, Harvard Medical School

What is the significance of hyponatremia in my patient with acute decompensated congestive heart failure (ADCHF)?