Spontaneous portosystemic shunting: an under recognized cause of hepatic encephalopathy

This question recently came up on wards regarding a patient with early cirrhosis, otherwise compensated, who would abruptly, without identifiable precipitants, develop hepatic encephalopathy.

The issue was nicely addressed in a review published in Therapeutic Advances in Gastroenterology: 

Spontaneous portosystemic shunts in liver cirrhosis: new approaches to an old problem

According to the review, this condition is common in patients with cirrhosis and correlates strongly with the development of hepatic encephalopathy.  IR embolization of spontaneous shunts may be an effective treatment, depending on the anatomy, particularly in those patients whose underlying liver disease is relatively mild and whose episodes of encephalopathy are abrupt and without identifiable precipitants.

An algorithm for patient selection is presented. In the algorithm, if patients respond well to standard treatment no further investigation is necessary. Otherwise, consideration for IR embolization is recommended in those with a MELD of 11 or less.  Imaging in search of shunts should take place in such patients. Should shunts be found, if anatomically feasible, IR embolization should be considered. Patients with portal hypertension related complications would be excluded. In patients with a MELD of 12 to14 decision making should be individualized. In patients with MELD of 15 or above transplantation is the preferred treatment.

What is the method for giving naloxone in very small doses to avoid acute opiate withdrawal?

Naloxone is often considered in hospitalized patients with altered mental status or respiratory depression who are on opiates. Many hospital order sets call for doses of 0.1 to 0.4 mg for these purposes. However, such doses may precipitate acute opiate withdrawal (in narcotic tolerant patients) or acute exacerbation of pain. What might be an alternative means of dosing that would be safer in such patients? 

This concern was addressed in the following review:

Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review  Expert Opinion on Drug Safety   Volume 14, 2015 - Issue 7

From the abstract of that review:

Introduction: Opioid overdose fatality has increased threefold since 1999. As a result, prescription drug overdose surpassed motor vehicle collision as the leading cause of unintentional injury-related death in the USA. Naloxone, an opioid antagonist that has been available for decades, can safely reverse opioid overdose if used promptly and correctly. However, clinicians often overestimate the dose of naloxone needed to achieve the desired clinical outcome, precipitating acute opioid withdrawal syndrome (OWS).

Areas covered: This article provides a comprehensive review of naloxone’s pharmacologic properties and its clinical application to promote the safe use of naloxone in acute management of opioid intoxication and to mitigate the risk of precipitated OWS. Available clinical data on opioid-receptor kinetics that influence the reversal of opioid agonism by naloxone are discussed. Additionally, the legal and social barriers to take home naloxone programs are addressed.

Expert opinion: Naloxone is an intrinsically safe drug, and may be administered in large doses with minimal clinical effect in non-opioid-dependent patients. However, when administered to opioid-dependent patients, naloxone can result in acute opioid withdrawal. Therefore, it is prudent to use low-dose naloxone (0.04 mg) with appropriate titration to reverse ventilatory depression in this population.

As is pointed out in the review, caveats include the need to provide ventilatory support in some cases and special considerations regarding the reversal of buprenorphine. These include limited effectiveness of naloxone, slower onset of action and larger dose requirements.

Why does Ticagrelor (Brilinta) cause dyspnea?

This issue was addressed in the following three linked articles:

The effects of P2Y12 adenosine receptors' inhibitors on central and peripheral chemoreflexes

Potential Role of Endogenous Adenosine in Ticagrelor-Induced Dyspnea.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease: An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

Key points from these articles are:

Ticagrelor causes dyspnea in 15 to 20 percent of patients.  It is usually mild

and usually resolves with continuedtreatment, although is occasionally intolerable to where discontinuation is necessary.

The mechanism is poorly understood

It alters adenosine kinetics but that's not the only effect and likely not the main reason it causes dyspnea. More on that below. 

How does Ticagrelor alter adenosine kinetics?

Ticagrelor inhibits cellular uptake of adenosine, prolonging its half life in the circulation. 

Excess adenosine can cause stimulation of vagal C fibers in the lungs but that does not seem to be an adequate explanation for the dyspnea.

Ticagrelor has another mechanism that is a more likely cause.

It increases chemoreceptor sensitivity, increasing the hypoxic and hypercapnic drives thus heightening the sense of dyspnea.

It is safe and not considered contraindicated in patients with COPD. 

Despite theoretical concerns about increased adenosine levels and the potential for bronchospasm, Ticagrelor does not alter pulmonary function in patients with mild asthma or mild to moderate COPD. 

Rationale and published recommendations for the use of thiamine in hospitalized patients

 

Several times recently on wards we have discussed thiamine administration in

hospitalized patients. My literature search on this topic  found two very helpful 

reviews linked below:

Wernicke Encephalopathy—Clinical Pearls

Mayo Clinic Proceedings  Volume 94, Issue 6p1065-1072June 2019

Myths and misconceptions of Wernicke's encephalopathy: what every emergency physician should know

Ann Emerg Med  Volume 50, Issue 6p715-721December 2007

Here are the key points from these articles: 

Although treatment and prevention of WE are overlapping categories, 

thiamine is most effectively used as prevention. 

In other words, if you wait to give thiamine until you “ suspect”  WE you have

 probably waited until it's too late. Approximately 80% of patients recognized as

WE already have dementia.

The recommended route for thiamine is IV not PO. 

Although dose recommendations are not supported by high-level data, published 

recommendations range from 200 mg q12 hours to 500 mg Q8 hours, IV. 

WE can result from any state of malnutrition, not just alcoholism. 

Risk factors other than alcoholism include:

Cancer

Post operative patients especially those who have had gastric bypass

Hyperemesis gravidarum 

Eating Disorders 

Hospitalized patients given dextrose. 

The existence of WE is common although recognition is rare. 

80% of the time WE is first recognized at autopsy.

Wernicke encephalopathy is a clinical diagnosis. 

Lab testing may be reasonable but is seldom helpful. Neuroimaging (although 

routinely done in cases of altered mental status and sometimes showing 

confirmatory findings) has low sensitivity. 

The triad of ocular manifestations, ataxia and altered mental status is seen

in only 10% of patients. 

Thiamine deficiency is associated with clinical syndromes other than WE

 including unexplained hypotension, unexplained lactic acidosis,

 neuropathy, heart failure and unexplained hypothermia.