Should I avoid intravenous furosemide for management of ascites in my patient with cirrhosis?

Generally, yes! IV furosemide for treatment of ascites in patients with cirrhosis should be avoided for couple of reasons.

First, in contrast to patients with congestive heart failure in whom the absorption of oral furosemide may be impaired due to bowel wall edema, patients with cirrhosis and ascites appear to absorb oral furosemide efficiently, similarly to that of control patients.1   Another reason for avoiding IV furosemide in this setting is the possibility of a significant drop in the GFR with its attendant rise in BUN and serum creatinine, clinically resembling a picture of hepatorenal syndrome.2

Although the mechanism of the adverse effect of IV furosemide on the renal function of patients with cirrhosis is not totally clear, furosemide-induced vasoconstriction, not intrasvascular volume depletion due to sodium wasting, seems to play an important role.3

Nevertheless, certain situations may necessitate the use of IV furosemide in patients with cirrhosis and ascites, such as in single doses to help identify patients who will be responsive to diuretics, and in patients in need of prompt diuresis such as those with concurrent pulmonary edema. In a somewhat reassuring study, a single dose of 80 mg IV furosemide reliably identified cirrhotic patients with ascites responsive to diuretics, without a significant risk of deteriorating renal function.3

 

References

  1. Sawhney VK, Gregory PB, Swezey SE, et al. Furosemide disposition in cirrhotic patients. Gastroenterology 1981; 81: 1012-16. https://www.ncbi.nlm.nih.gov/pubmed/7286579
  2. Daskalopoulos G, Laffi G, Morgan T, et al. Immediate effects of furosemide on renal hemodynamics in chronic liver disease with ascites. Gastroenterology 1987;92:1859-1863. https://www.ncbi.nlm.nih.gov/pubmed/3569760
  3. Spahr, L., Villeneuve, J., Tran, H. K., & Pomier-Layrargues, G. Furosemide-induced natriuresis as a test to identify cirrhotic patients with refractory ascites. Hepatology 2001;33:28-31. https://www.ncbi.nlm.nih.gov/pubmed/11124817

 

Contributed by Sam Miller, MD, Mass General Hospital, Boston, MA.

 

Should I avoid intravenous furosemide for management of ascites in my patient with cirrhosis?

My patient with cirrhosis has a large right sided pleural effusion with only a small amount of ascites. Could this effusion still be related to his cirrhosis?

Yes! Although we often associate pleural effusions in patients with cirrhosis with the presence of large ascites, some patients present with hepatic hydrothorax even in the absence of significant ascites.1-3  

In fact, in a study involving 77 patients with hepatic hydrothorax, 49% had minimal or small and 9% had no detectable ascites!1  Interestingly, nearly three-quarters of patients in this study had right sided pleural effusion with 10% having bilateral and 17% having left sided effusion only. Hepatic hydrothorax without ascites as the first sign of liver cirrhosis has also been reported.2

Although the mechanism(s) behind hepatic hydrothorax is not fully clear, the passage of peritoneal fluid into the pleural cavity through defects in the tendinous portion of the diaphragm assisted by negative intrathoracic pressure during inspiration is commonly favored. 1-3  

Supportive evidence includes a number of studies involving intraperitoneal injection of air, dyes or technetium 99 m-sulfur colloid that have demonstrated the trans-diaphragmatic flow of ascites into the pleural cavity. 1-4  In the absence of ascites, a complete equilibrium between the amount of ascites produced and its flow into and reabsorption by the pleural cavity is assumed.1,2

Bonus Pearl: Did you know that although most patients with hepatic hydrothorax have a transudative pleural effusion according to Light’s criteria, 1 study showed that 18% of patients may meet the Light’s criteria for an exudative effusion? 5,6

References

  1. Badillo R, Rockey DC. Hepatic hydrothorax: Clinical features, management, and outcomes in 77 patients and review of the literature. Medicine 2014;93:135-142. https://www.ncbi.nlm.nih.gov/pubmed/24797168
  2. Kim JS, Kim CW, Nam HS, et al. Hepatic hydrothorax without ascites as the first sign of liver cirrhosis. Respirology Case Reports 2016;4:16-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722098/
  3. Rubinstein D, McInnes IE, Dudley FJ. Hepatic hydrothorax in the absence of clinical ascites: diagnosis and management. Gastroenterology 1985;88:188-91. https://www.ncbi.nlm.nih.gov/pubmed/3964765
  4. Holt KA, Oliviera E, Rohatgi PK. Hepatic hydrothorax demonstration by Tc-99 sulfur colloid ascites scan. Clin Nucl Med 1999;24:609. https://www.ncbi.nlm.nih.gov/pubmed/10439187 
  5. Light RW. New treatment for hepatic hydrothorax? Ann Am Thorac Soc 2016;13:773-74. https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201603-223ED
  6. Bielsa S, Porcel JM, Castellote J, et al. Solving the Light’s criteria misclassification rate of cardiac and hepatic transudates. Respirology 2012;17”721-726. https://www.ncbi.nlm.nih.gov/pubmed/22372660
My patient with cirrhosis has a large right sided pleural effusion with only a small amount of ascites. Could this effusion still be related to his cirrhosis?

How does excess licorice consumption cause hypertension and hypokalemia?

The active ingredient of licorice, glycyrrhizic acid or glycyrrhizin, is first converted to glycyrrhetinic acid (GRA) in the bowel which is then absorbed. Once in the circulation, GRA inhibits activation of 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD2), an enzyme in renal tissue that converts active cortisol to inactive cortisone. Without the full action of this enzyme, proper sodium and potassium homeostasis would be difficult because cortisol is just as effective in stimulating mineralocorticoid receptors as aldosterone but with 100-1000 times higher concentration than that of aldosterone! 1-3

Other ways that GRA may cause hypertension and hypokalemia include inhibition of 5 β-reductase in the liver, an enzyme that metabolizes aldosterone and direct stimulation of mineralocorticoid receptors, though overall these mechanisms may not be as important as the effect of GRA on cortisol metabolism in renal tissue.1,2

Besides causing fluid retention, licorice ingestion has also been found to increase systemic vascular resistance possibly by increasing vascular tone and remodeling of the vascular wall, potentiating the vasoconstrictor actions of angiotensin II and catecholamines in smooth muscle, and suppressing vasodilatory systems, including endothelial nitric oxide synthase and prostacyclin synthesis.

It’s no wonder that the FDA issued a statement in 2017: “If you’re 40 or older, eating 2 ounces of black licorice a day for a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.” 5

Bonus Pearl: Did you know that as early as 1951, extract of licorice was reported for treatment of Addison’s disease, a combination of licorice and soy sauce has been reported to be “life-saving” in a patient with Addison’s disease (2007), and GRA food supplementation may lower serum potassium in chronic hemodialysis patients (2009)? 6,7

 

References

  1. Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice and hypertension. J Clin Hypertens (Greenwich) 2008; 10:153-57. https://www.ncbi.nlm.nih.gov/pubmed/18256580
  2. Omar HR, Komarova I, El-Ghonemi M, et al. Licorice abuse: time to send a warning message. The Adv Endocrinol Metab 2012;3:125-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/
  3. Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: as systematic review and meta-analysis. Journal of Human Hypertension 2017;31:699-707. https://www.ncbi.nlm.nih.gov/pubmed/28660884
  4. Black licorice: trik or treat? https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm 277152.htm
  5. Hautaniemi EJ, Tahvanainen AM, Koskela JK, et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep 2017;7:10947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591274/
  6. Groen J, Pelser H, Willebrands AF, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-75. https://www.ncbi.nlm.nih.gov/pubmed/14806786
  7. Cooper H, Bhattacharya B, Verma V, et al. Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann Clin Biochem 2007;44:397-99. https://www.ncbi.nlm.nih.gov/pubmed/17594790
  8. Farese S, Kruse Anja, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney International 2009;76:877-84. https://www.ncbi.nlm.nih.gov/pubmed/19641483
How does excess licorice consumption cause hypertension and hypokalemia?

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?

Most likely!

We should routinely assess for poor sleep as a potential impediment to adequate pain control in our patients. Substantial research supports a bidirectional relationship between pain and sleep.  That is, not only can pain disrupt sleep but sleep quality can also adversely affect pain.1   In fact, even a short-term disturbance in a stable sleep pattern may lower the pain threshold 2 and the ability to tolerate previously controlled pain.3

These observations are thought to result from activated stress responses from poor sleep hygiene which in turn produce cellular oxidative stress and inflammation of tissues and the nervous system. 4 This process can result in a vicious cycle between increasing pain and persistent insomnia.4,5  Breaking this cycle can reduce pain and improve function, among other desired outcomes.

Ongoing insomnia may also be a sign of a variety of other conditions that should be treated, such as mood disorder and sleep apnea. For example, besides standard non-pharmaceutical measures to improve sleep hygiene, continuous positive air pressure (CPAP) can reduce pain and opioid use in the setting of sleep apnea .2,6

Remember also that controlling pain with opioids in hopes of improving sleep may be counterproductive as opioids can contribute to sleep apnea.7,8  Melatonin may be a better sleep aid in this setting. 9

References

  1. Wei Y, Blanken TF, Van Someren EJW. Insomnia really hurts: effect of a bad night’s sleep on pain increases with insomnia severity. Front Psychiatry 2018;9:377. doi: 10.3389/fpsyt.2018.00377. https://www.ncbi.nlm.nih.gov/pubmed/30210367
  2. Charokopos A, Card ME, Gunderson C, Steffens C, Bastian LA. The association of obstructive sleep apnea and pain outcomes in adults: a systematic review. Pain Med 2018;19(suppl_1):S69-S75. doi: 10.1093/pm/pny140. https://www.ncbi.nlm.nih.gov/pubmed/30203008
  3. Sivertsen B, Lallukka T, Petrie KJ, et al. Sleep and pain sensitivity in adults. Pain. 2015;156:1433-9. https://www.ncbi.nlm.nih.gov/pubmed/25915149
  4. Iacovides S, George K, Kamerman P, Baker FC. Sleep fragmentation hypersensitizes healthy young women to deep and superficial experimental pain. J Pain. 2017;18:844-854. doi: https://doi.org/10.1016/j.jpain.2017.02.436. https://www.ncbi.nlm.nih.gov/pubmed/28300651
  5. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008;137:202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  6. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008 Jul;137(1):202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  7. Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry 2018 20;87:234-244. https://www.ncbi.nlm.nih.gov/pubmed/28734941
  8. Jungquist CR, Flannery M, Perlis ML, Grace JT. Relationship of chronic pain and opioid use with respiratory disturbance during sleep. Pain Manag Nurs 2012;13:70-9. doi: 10.1016/j.pmn.2010.04.003. https://www.ncbi.nlm.nih.gov/pubmed/22652280
  9. Landis CA. Is melatonin the next “new” therapy to improve sleep and reduce pain? Sleep 2014; 37: 1405–1406. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153056/

Contributed by Paul Arnstein, PhD, RN, FAAN, Mass General Hospital, Boston, MA.

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?