Hepatic encephalopathy medical therapy: Difference between revisions
Jump to navigation
Jump to search
Aditya Ganti (talk | contribs) |
|||
| (19 intermediate revisions by 7 users not shown) | |||
| Line 1: | Line 1: | ||
__NOTOC__ | __NOTOC__ | ||
{{Hepatic encephalopathy}} | {{Hepatic encephalopathy}} | ||
{{CMG}} | {{CMG}};{{AE}}{{MMJ}} | ||
==Overview== | |||
Supportive therapy for hepatic encephalopathy includes reduce [[protein]] intake, [[endotracheal intubation]] and [[mechanical ventilation]] in high grade hepatic encephalopathy. Pharmacologic medical therapies for hepatic encephalopathy include [[lactulose]], [[Antibiotic|antibiotics]], [[rifaximin]], [[benzodiazepine]] receptor antagonists, L-[[ornithine]]-L-[[aspartate]] and correction of [[hypokalemia]]. | |||
==Medical Therapy== | ==Medical Therapy== | ||
Even minimal hepatic encephalopathy may benefit from treatment.<ref name="pmid17326150">{{cite journal |author=Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R |title=Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy |journal=Hepatology |volume=45 |issue=3 |pages=549-59 |year=2007 |pmid=17326150 |doi=10.1002/hep.21533}}</ref> | |||
* Reduce [[protein]] intake: | |||
Traditionally it has been presumed that excessive [[protein]] intake leads to increased generation of [[ammonia]], which, in the setting of severe [[liver]] impairment, will accumulate and worsen the hepatic encephalopathy. While very large [[protein]] loads (such as [[gastrointestinal hemorrhage]], because [[blood]] is rich in [[protein]]) are known to precipitate [[encephalopathy]], the need for patients with [[chronic liver disease]] patients to be [[protein]] restricted has been disproven.<ref>{{cite journal |author=Córdoba J, López-Hellín J, Planas M, et al |title=Normal protein diet for episodic hepatic encephalopathy: results of a randomized study |journal=J. Hepatol. |volume=41 |issue=1 |pages=38–43 |year=2004 |pmid=15246205 |doi=10.1016/j.jhep.2004.03.023}}</ref> Indeed, because [[chronic liver disease]] is a [[catabolic]] state, a [[protein]] restricted diet would lead to protein [[malnutrition]] and a negative [[nitrogen]] balance. | |||
* Correction of [[hypokalemia]]: | |||
Concomitant [[hypokalemia]] should be corrected as [[hypokalemia]] increases renal [[ammonia]] production and may promote conversion of [[ammonium]] into [[ammonia]] which can cross the [[blood-brain barrier]].<ref name="pmid5958605">{{cite journal |author=Artz SA, Paes IC, Faloon WW |title=Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy |journal=Gastroenterology |volume=51 |issue=6 |pages=1046-53 |year=1966 |pmid=5958605 |doi=}}</ref> | |||
* [[Lactulose]]: | |||
[[Lactulose]] is a compound that will cause osmotic [[diarrhea]], thus lessening the time available for intestinal [[bacteria]] to metabolize [[protein]] into [[ammonia]] within the [[bowel]]. Further, it acidifies the environment in the [[lumen]] of the [[bowel]]. This promotes the conversion of lumenal [[ammonia]] (NH<sub>3</sub>) to [[ammonium]] (NH<sub>4</sub><sup>+</sup>) which, by which virtue of its net charge, should be less readily absorbed into the [[bloodstream]] from the [[bowel]] [[lumen]]. Despite this theoretical and appealing mechanism, a [[meta-analysis]] of [[randomized controlled trials]] by the international [[Cochrane Collaboration]] found benefit, but suggests there is little evidence for its preferred use to treat hepatic [[encephalopathy]].<ref>{{cite journal |author=Als-Nielsen B, Gluud L, Gluud C |title=Nonabsorbable disaccharides for hepatic encephalopathy |journal=Cochrane Database Syst Rev |volume= |issue= |pages=CD003044 |year= |pmid=15106187}}</ref> Indeed, any drug ([[laxative]]) which speeds up transit through the [[bowel]] thereby lessening the time available for [[bacteria]] to metabolize [[protein]] into [[ammonia]], works just as well. | |||
:[[Lactulose]] can be given rectally for patients who cannot take oral medications.<ref name="pmid4682313">{{cite journal |author=Kersh ES, Rifkin H |title=Lactulose enemas |journal=Ann. Intern. Med. |volume=78 |issue=1 |pages=81-4 |year=1973 |pmid=4682313 |doi=}}</ref><ref name="pmid240347">{{cite journal |author=Ratnaike RN, Hicks EP, Hislop IG |title=The rectal administration of lactulose |journal=Australian and New Zealand journal of medicine |volume=5 |issue=2 |pages=137-40 |year=1975 |pmid=240347 |doi=}}</ref><ref name="pmid3301614">{{cite journal |author=Uribe M, Campollo O, Vargas F, et al |title=Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial |journal=Hepatology |volume=7 |issue=4 |pages=639-43 |year=1987 |pmid=3301614 |doi=}}</ref> One regimen is 300 mL (200 gm) of [[lactulose]] syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the [[Trendelenburg position]].<ref name="pmid11467622">{{cite journal |author=Blei AT, Córdoba J |title=Hepatic Encephalopathy |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=1968-76 |year=2001 |pmid=11467622 |doi=10.1111/j.1572-0241.2001.03964.x}}</ref> | |||
* | * [[Antibiotic|Antibiotics]]: | ||
[[Antibiotic|Antibiotics]] may be given to kill [[bacteria]] present in the [[bowel]] thereby decreasing [[Bacteria|bacterial]] conversion of [[protein]] to [[ammonia]] (and other [[toxic substances]]) there. Although effective, [[neomycin]], a non-absorbable [[aminoglycoside]] [[antibiotic]], is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased [[gut]] permeability, thus increasing the risk of [[renal failure]] and hearing loss (i.e. two of the potential side effects of [[neomycin]]). The former side-effect, in particular, is especially worrisome given the already increased likelihood of [[Renal insufficiency|renal failure]] in [[cirrhosis]] and [[portal hypertension]] (i.e. [[hepatorenal syndrome]]). [[Metronidazole]] has also been studied.<ref name="pmid7035298">{{cite journal |author=Morgan MH, Read AE, Speller DC |title=Treatment of hepatic encephalopathy with metronidazole |journal=Gut |volume=23 |issue=1 |pages=1-7 |year=1982 |pmid=7035298 |doi=}}</ref> | |||
* | * [[Rifaximin]]: | ||
[[Rifaximin]] , receieved orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to [[neomycin]], its tolerability profile is comparable to [[placebo]].<ref name="pmid10741936">{{cite journal |author=Williams R, James OF, Warnes TW, Morgan MY |title=Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study |journal=European journal of gastroenterology & hepatology |volume=12 |issue=2 |pages=203-8 |year=2000 |pmid=10741936 |doi=}}</ref> Multiple clinical trials have demonstrated that [[rifaximin]] at a dose of 400 mg taken orally 3 times a day was as effective as [[lactulose]] or lactilol at improving hepatic encephalopathy symptoms.<ref name="pmid8325041">{{cite journal |author=Bucci L, Palmieri GC |title=Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy |journal=Current medical research and opinion |volume=13 |issue=2 |pages=109-18 |year=1993 |pmid=8325041 |doi=}}</ref> Similarly, [[rifaximin]] was as effective as [[neomycin]] and [[Paromomycin sulfate|paromomycin]].<ref name="pmid1751811">{{cite journal |author=Pedretti G, Calzetti C, Missale G, Fiaccadori F |title=Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial |journal=The Italian journal of gastroenterology |volume=23 |issue=4 |pages=175-8 |year=1991 |pmid=1751811 |doi=}}</ref> [[Rifaximin]] was better tolerated than both the cathartics and the other nonabsorbable [[Antibiotic|antibiotics]]. A number of concerns remain regarding [[rifaximin]]'s role in the treatment of hepatic encephalopathy. It remains to be determined if [[rifaximin]] can improve severe encephalopathy symptoms as rapidly as [[lactulose]]. There are also concerns regarding the cost-effectiveness of the medication. | |||
:[[ | * [[Benzodiazepine]] receptor [[antagonists]]: | ||
A [[meta-analysis]] of [[randomized controlled trials]] by the international [[Cochrane Collaboration|cochrane collaboration]] found benefit from [[flumazenil]].<ref name="pmid15106178">{{cite journal |author=Als-Nielsen B, Gluud LL, Gluud C |title=Benzodiazepine receptor antagonists for hepatic encephalopathy |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD002798 |year=2004 |pmid=15106178 |doi=10.1002/14651858.CD002798.pub2}}</ref> The doses of [[flumazenil]] varied around a median of 2 milligrams over 10 minutes: [[flumazenil]] was given as a continuous infusion (12 trials), preceded by bolus [[injections]] in two trials. One trial used only [[bolus]] injections. Patients received [[flumazenil]] at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short. | |||
* | * L-[[ornithine]]-L-[[aspartate]]: | ||
L-[[ornithine]]-L-[[aspartate]] stimulates the [[urea cycle]], and has shown encouraging results in [[randomized controlled trials]].<ref>{{cite journal |author=Poo J, Góngora J, Sánchez-Avila F, Aguilar-Castillo S, García-Ramos G, Fernández-Zertuche M, Rodríguez-Fragoso L, Uribe M |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Ann Hepatol |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582}}</ref><ref name="pmid17151582">{{cite journal |author=Poo JL, Góngora J, Sánchez-Avila F, et al |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Annals of hepatology : official journal of the Mexican Association of Hepatology |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582 |doi=}}</ref><ref name="pmid9625322">{{cite journal |author=Stauch S, Kircheis G, Adler G, et al |title=Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study |journal=J. Hepatol. |volume=28 |issue=5 |pages=856-64 |year=1998 |pmid=9625322 |doi=}}</ref> | |||
====Contraindicated medications==== | |||
{{MedCondContrAbs|MedCond = Hepatic coma|Bumetanide|Metolazone}} | |||
==Recommendations for the Treatment of Hepatic Encephalopathy (DO NOT EDIT)== | |||
{{cquote| | |||
# In early stages of encephalopathy, [[lactulose]] may be used either orally or rectally to effect a bowel purge, but should not be administered to the point of [[diarrhea]], and may interfere with the surgical field by increasing bowel distention during [[liver transplantation]]. | |||
# Patients who progress to high-grade hepatic encephalopathy (grade III or IV) should undergo [[endotracheal intubation]]. | |||
# [[Seizure activity]] should be treated with [[phenytoin]] and [[benzodiazepines]] with short half-lives. Prophylactic phenytoin is not recommended. | |||
# [[Intracranial pressure]] (ICP) monitoring is recommended in ALF patients with high-grade hepatic encephalopathy, in centers with expertise in ICP monitoring, in patients awaiting and undergoing liver transplantation. | |||
# In the absence of ICP monitoring, frequent (hourly) neurological evaluation is recommended to identify early evidence of intracranial hypertension. | |||
# In the event of intracranial hypertension, a mannitol bolus (0.5-1.0 gm/kg body weight) is recommended as first-line therapy; however, the prophylactic administration of [[mannitol]] is not recommended. | |||
# In ALF patients at highest risk for [[cerebral edema]] (serum [[ammonia]] >150 µM, grade 3/4 hepatic encephalopathy, [[acute renal failure]], requiring [[vasopressors]] to maintain [[mean arterial pressure]] [MAP]), the prophylactic induction of [[hypernatremia]] with hypertonic saline to a [[sodium]] level of 145-155 mEq/L is recommended. | |||
# Short-acting [[barbiturates]] and the induction of [[hypothermia]] to a core body temperature of 34-35ºC may be considered for [[intracranial hypertension]] refractory to osmotic agents as a bridge to liver transplantation. | |||
# [[Corticosteroids]] should not be used to control elevated ICP in patients with ALF. | |||
}} | |||
==References== | ==References== | ||
{{Reflist|2}} | |||
[[Category:Disease]] | [[Category:Disease]] | ||
[[Category:Gastroenterology]] | [[Category:Gastroenterology]] | ||
[[Category:Hepatology]] | |||
[[Category:Neurology]] | |||
[[Category:Emergency medicine]] | |||
[[Category:Needs overview]] | [[Category:Needs overview]] | ||
{{WH}} | |||
{{WS}} | |||
Latest revision as of 05:32, 6 July 2020
|
Hepatic encephalopathy Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Hepatic encephalopathy medical therapy On the Web |
|
American Roentgen Ray Society Images of Hepatic encephalopathy medical therapy |
|
Risk calculators and risk factors for Hepatic encephalopathy medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Supportive therapy for hepatic encephalopathy includes reduce protein intake, endotracheal intubation and mechanical ventilation in high grade hepatic encephalopathy. Pharmacologic medical therapies for hepatic encephalopathy include lactulose, antibiotics, rifaximin, benzodiazepine receptor antagonists, L-ornithine-L-aspartate and correction of hypokalemia.
Medical Therapy
Even minimal hepatic encephalopathy may benefit from treatment.[1]
- Reduce protein intake:
Traditionally it has been presumed that excessive protein intake leads to increased generation of ammonia, which, in the setting of severe liver impairment, will accumulate and worsen the hepatic encephalopathy. While very large protein loads (such as gastrointestinal hemorrhage, because blood is rich in protein) are known to precipitate encephalopathy, the need for patients with chronic liver disease patients to be protein restricted has been disproven.[2] Indeed, because chronic liver disease is a catabolic state, a protein restricted diet would lead to protein malnutrition and a negative nitrogen balance.
- Correction of hypokalemia:
Concomitant hypokalemia should be corrected as hypokalemia increases renal ammonia production and may promote conversion of ammonium into ammonia which can cross the blood-brain barrier.[3]
Lactulose is a compound that will cause osmotic diarrhea, thus lessening the time available for intestinal bacteria to metabolize protein into ammonia within the bowel. Further, it acidifies the environment in the lumen of the bowel. This promotes the conversion of lumenal ammonia (NH3) to ammonium (NH4+) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a meta-analysis of randomized controlled trials by the international Cochrane Collaboration found benefit, but suggests there is little evidence for its preferred use to treat hepatic encephalopathy.[4] Indeed, any drug (laxative) which speeds up transit through the bowel thereby lessening the time available for bacteria to metabolize protein into ammonia, works just as well.
- Lactulose can be given rectally for patients who cannot take oral medications.[5][6][7] One regimen is 300 mL (200 gm) of lactulose syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.[8]
Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, neomycin, a non-absorbable aminoglycoside antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of renal failure and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in cirrhosis and portal hypertension (i.e. hepatorenal syndrome). Metronidazole has also been studied.[9]
Rifaximin , receieved orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo.[10] Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.[11] Similarly, rifaximin was as effective as neomycin and paromomycin.[12] Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication.
- Benzodiazepine receptor antagonists:
A meta-analysis of randomized controlled trials by the international cochrane collaboration found benefit from flumazenil.[13] The doses of flumazenil varied around a median of 2 milligrams over 10 minutes: flumazenil was given as a continuous infusion (12 trials), preceded by bolus injections in two trials. One trial used only bolus injections. Patients received flumazenil at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short.
L-ornithine-L-aspartate stimulates the urea cycle, and has shown encouraging results in randomized controlled trials.[14][15][16]
Contraindicated medications
Hepatic coma is considered an absolute contraindication to the use of the following medications:
Recommendations for the Treatment of Hepatic Encephalopathy (DO NOT EDIT)
| “ |
|
” |
References
- ↑ Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007). "Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy". Hepatology. 45 (3): 549–59. doi:10.1002/hep.21533. PMID 17326150.
- ↑ Córdoba J, López-Hellín J, Planas M; et al. (2004). "Normal protein diet for episodic hepatic encephalopathy: results of a randomized study". J. Hepatol. 41 (1): 38–43. doi:10.1016/j.jhep.2004.03.023. PMID 15246205.
- ↑ Artz SA, Paes IC, Faloon WW (1966). "Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy". Gastroenterology. 51 (6): 1046–53. PMID 5958605.
- ↑ Als-Nielsen B, Gluud L, Gluud C. "Nonabsorbable disaccharides for hepatic encephalopathy". Cochrane Database Syst Rev: CD003044. PMID 15106187.
- ↑ Kersh ES, Rifkin H (1973). "Lactulose enemas". Ann. Intern. Med. 78 (1): 81–4. PMID 4682313.
- ↑ Ratnaike RN, Hicks EP, Hislop IG (1975). "The rectal administration of lactulose". Australian and New Zealand journal of medicine. 5 (2): 137–40. PMID 240347.
- ↑ Uribe M, Campollo O, Vargas F; et al. (1987). "Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial". Hepatology. 7 (4): 639–43. PMID 3301614.
- ↑ Blei AT, Córdoba J (2001). "Hepatic Encephalopathy". Am. J. Gastroenterol. 96 (7): 1968–76. doi:10.1111/j.1572-0241.2001.03964.x. PMID 11467622.
- ↑ Morgan MH, Read AE, Speller DC (1982). "Treatment of hepatic encephalopathy with metronidazole". Gut. 23 (1): 1–7. PMID 7035298.
- ↑ Williams R, James OF, Warnes TW, Morgan MY (2000). "Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study". European journal of gastroenterology & hepatology. 12 (2): 203–8. PMID 10741936.
- ↑ Bucci L, Palmieri GC (1993). "Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy". Current medical research and opinion. 13 (2): 109–18. PMID 8325041.
- ↑ Pedretti G, Calzetti C, Missale G, Fiaccadori F (1991). "Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial". The Italian journal of gastroenterology. 23 (4): 175–8. PMID 1751811.
- ↑ Als-Nielsen B, Gluud LL, Gluud C (2004). "Benzodiazepine receptor antagonists for hepatic encephalopathy". Cochrane database of systematic reviews (Online) (2): CD002798. doi:10.1002/14651858.CD002798.pub2. PMID 15106178.
- ↑ Poo J, Góngora J, Sánchez-Avila F, Aguilar-Castillo S, García-Ramos G, Fernández-Zertuche M, Rodríguez-Fragoso L, Uribe M (2006). "Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study". Ann Hepatol. 5 (4): 281–8. PMID 17151582.
- ↑ Poo JL, Góngora J, Sánchez-Avila F; et al. (2006). "Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study". Annals of hepatology : official journal of the Mexican Association of Hepatology. 5 (4): 281–8. PMID 17151582.
- ↑ Stauch S, Kircheis G, Adler G; et al. (1998). "Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study". J. Hepatol. 28 (5): 856–64. PMID 9625322.