Continuing Education Activity

Ethanol is an alcohol by chemical composition used to manage and treat methanol/ethylene glycol toxicity. Ethanol has also been used efficiently in the clinical sector for disinfection and sterilization. The modern-day has seen ethanol being used as a novel therapy for neoplasms in lieu of surgical interventions. This activity revolves around the indications, mechanism of action, administration, adverse effects, and contraindications to the use of ethanol. This activity will also highlight the vigilance that the healthcare team should demonstrate in a clinical setting to enhance the therapeutic outcomes when using the drug.

Objectives:

• Identify the therapeutic uses of ethanol.
• Describe the mechanism of action of ethanol in its various clinical uses.
• Summarize how to manage ethanol toxicity.
• Explain the importance of collaboration and communication among the interprofessional team to ensure appropriate candidate selection for receiving a percutaneous ethanol ablation rather than surgery in cases of simple cyst or carcinomas to avoid comorbidity associated with surgery.

Indications

Ethanol derives from the fermentation of naturally occurring sugars. The International Union of Pure and Applied Chemistry (IUPAC) nomenclature for the chemical compound ethanol is a structural composition consisting of a pair of carbon atoms with an alkyl group coupled with an -OH functional group; the -OH group makes it chemically an alcohol. Unlike methanol, butanol, propanol, etc., humans can consume ethanol in its purest form without dying. 

Ethanol's Uses Include

1. Ethanol in place of fomepizole in methanol poisoning[1]  
2. Ethanol in place of fomepizole in ethylene glycol poisoning[2] 
3. As a hand sanitizer for the prevention of healthcare-associated infections (HCAI)[3] 
4. Ethanol lock therapy for reducing the incidence of bloodstream infections acquired through IV catheters[4]

Ethanol as an Embolic, Sclerosing and an Ablative Agent[5]  

1. As an ablative agent in hypertrophic obstructive cardiomyopathy by controlled septal infarction[6]
2. As an embolic agent for embolization of arteriovenous malformations[7] 
3. As a sclerosing agent to reduce pain in musculoskeletal hemangiomas, as an alternative to surgery or to reduce the morbidity associated with the tumor resection[8] 
4. As a sclerosant for lymphatic malformations occurring in the neck and the mediastinum under the guidance of CT[9] 
5. As a sclerosing agent in the treatment of symptomatic simple renal cysts[10] 
6. As an ablative agent against thyroid cystic nodules[11] 
7. As an ablative agent in endoscopic ultrasound (EUS) guided ablation of a single insulinoma[12]
8. As an ablative agent for hepatocellular carcinomas[13] 
9. Ethanol injected peripherally in abetting pain in trigeminal neuralgia[14]  
10. For neurolysis of brachial plexus pain associated with cancers[15]  
11. For neurolysis of splanchnic nerve to decrease cancer-associated upper abdominal pain[16] 

Mechanism of Action

As an Antidote

1. Methanol poisoning: Methanol per se is not as toxic as its metabolized counterpart, i.e., 'formic acid.' Methanol is acted upon by alcohol dehydrogenase to convert it into 'formaldehyde.' Aldehyde dehydrogenase (ADH), in turn, acts on formaldehyde to convert it into formic acid, and this metabolite brings about the deleterious effects of methanol poisoning such as vision loss and Parkinsonian movements. Ethanol metabolism is also by ADH; its affinity for ADH is significantly higher than methanol; hence ethanol administration results in competitive inhibition of methanol, slowing down formic acid formation. 
2. Ethylene glycol poisoning: Ethylene glycol, very much like methanol, gets metabolized by alcohol dehydrogenase (ADH) in the liver to form glycoaldehyde. Glycoaldehyde subsequently converts to glycolic acid and oxalic acid. Administration of ethanol results in competitive inhibition of ethylene glycol from binding to ADH as the former will saturate the enzyme. 

As a Hand Sanitizer and Preventing Sepsis

1. Many credible surveys report the global burden of healthcare-associated infections (HCAI). Alcohols have an inherent antimicrobial property, which works by denaturing and coagulating proteins, disrupting their cell wall, and killing them. Ethanol is highly efficient against viruses and can be used in adjunct with other alcohols to obtain a powerful synergistic effect against microorganisms. 
2. Ethanol lock therapy (ELT) follows the ideals mentioned earlier of killing bacterias and disrupting their biofilms. This concept is mainly useful for patients receiving total parenteral nutrition. An ethanol lock created in the lumen of the IV catheter both kills and inhibits the growth of bacterias, thus significantly reducing catheter-related bloodstream infections (CRBSI). 

 As an Ablative/Sclerosing/Embolic Agent

1. Ethanol works by damaging the endothelial lining and dehydrating the cells, resulting in fibrotic changes. Consequently, tumor/hyperplastic growth suffers an ischemia and size reduction.[17]

Administration

For methanol and ethylene glycol poisoning, ethanol administration can be either through an IV line, a nasogastric tube, or orally. Still, an IV ethanol infusion is always preferable to other routes. A plasma concentration of methanol exceeding 20 mg/dL is a reference for starting ethanol therapy.

Commercially available, 10% ethanol solution dosing is as follows:

• 7.6 mL/kg IV x 1 if the patient's ethanol level is zero, decrease if ethanol is present in the bloodstream
• Maintenance infusion is 0.83 mL/kg/hour for non-drinker, 1.96 mL/kg/hour for chronic alcohol consumers

This regimen can occur in an intensive care setting with the plasma concentrations of alcohol requiring hourly monitoring until reaching a desired plasma ethanol concentration of 100 mg/dL, following which the plasma sampling frequency is reducible to 2 to 4 hours. One must keep in mind that the FDA approved IV fomepizole for methanol/ethylene glycol poisoning, and it is a specific inhibitor of ADH. It has a far superior affinity for ADH than ethanol. Even though fomepizole is a superior antidote compared to ethanol, the availability and the limited knowledge of fomepizole have resulted in the continuance of ethanol infusions as a treatment in these cases.[18][19] 

Alcohol-based hand sanitizers (ABHS) are time-proven weapons for preventing nosocomial infections. However, the efficacy of the same against neutralizing microorganisms rests on the effectiveness of its use. Several studies dedicated to establishing complete disinfection on the surface of the hands have concluded that an amount of 2.4 to 3 mL is the recommendation with an application time of a minimum of 25 to 30 seconds to establish maximum disinfection.[3] 

Ethanol lock therapy (ELT) uses 70% ethanol over a minimum of 4 hours; reaching a maximum of 6 hours in conjunction with the regular antibiotic therapy has significantly brought down the rate of catheter-related bloodstream infection (CRBSI). This therapy is especially beneficial as there have been no reports of bacteria exhibiting resistance to ethanol. 

As a chemical ablative/sclerosing agent, ethanol has been put to rigorous use in treating varying neoplasms, cysts, vascular malformations, and even chemical neurolysis. Ethanol is injected into the parenchyma/lesion of the specific organ. It can utilize the guidance of endoscopic ultrasound, or in some cases, the injection can be under CT guidance.  

Adverse Effects

When ethanol converts to acetaldehyde, NAD+ reduces to NADH. NAD+ serves as an electron carrier and donates 2 electrons in this reaction. This reaction increases the NADH/NAD+ ratio in the hepatocytes. This increase in ratio causes:

Ketoacidosis: Via inhibition of the citric acid (TCA) cycle, increasing acetyl-CoA levels. This increased acetyl-CoA is shunted into the ketogenesis pathway resulting in ketoacidosis. 

Fasting hypoglycemia: The increased ratio inhibits the conversion of malate to oxaloacetate (OAA). This inhibition changes the reaction equilibrium by converting OAA back to malate, impairing gluconeogenesis because the meager amount of OAA is left to convert to phosphoenolpyruvate (PEP) for gluconeogenesis.

Hepatic steatosis: The increased NADH/NAD+ ratio increases the synthesis of fatty acid and glycerol-3-phosphate, thereby increasing the levels of TAGs resulting in fatty liver. 

Ingested ethanol mainly metabolizes in the liver; hence hepatic damage is profoundly seen in chronic alcoholism. This damage includes steatosis, cirrhosis, and hepatic carcinoma. Other organs/organ systems involved are:

1. Gastrointestinal System: gastritis, malabsorption, carcinomas 
2. Cardiovascular System: hypertension, cardiomyopathies, arrhythmias 
3. Pancreas: through acinar damage progressing to pancreatitis
4. Renal System: glomerulonephritis and AKI 
5. Reproductive System: infertility, premature birth, SGI babies, and fetal alcohol syndrome
6. Breast carcinoma 
7. Neuro/psychiatric consequences: stroke, major depression, meningitis, alcoholic cerebellar degeneration[20]

Contraindications

In Cases of Methanol/Ethylene Glycol Toxicity 

The loading and the maintenance dose should be carefully monitored in an intensive care setting to prevent the patient from any toxic manifestation of the antidote ethanol itself. Furthermore, ethanol must not be administered concurrently with fomepizole as the latter will inhibit the metabolism of ethanol in the same way as it inhibits the metabolism of methanol/ethylene glycol. This inhibition will result in an exaggerated rise in ethanol level in the body as its half-life is now prolonged and will inadvertently result in the manifestation of ethanol's intoxicating nature. Contraindications to ethanol also include pregnancy and breastfeeding.

For ABHS

Though there is no clear-cut contraindication in any particular medical setup, it has been well established that ABHS doesn't kill the spores of several microorganisms, including the likes of Clostridium difficile. It is also not effective against certain protozoan oocysts, for example, cryptosporidium. ABHS has also been inefficient against a certain non-enveloped virus-like norovirus.[3]

As an Ablative Agent

Percutaneous ethanol injection is contraindicated when:

1. Prothrombin time (PT) is less than 40% of the normal.
2. In thrombocytopenia (count < 40,000/ mm^3)[21] 

Monitoring

Ethanol follows zero-order kinetics. Alcohol absorption occurs mostly in the proximal part of the small intestine, but a little fraction is also absorbed by the mucosal layer of the mouth, esophagus, and stomach. Alcohol metabolism mostly occurs in the liver, with a rate of oxidation per unit time yielding a linear curve. Physiological conditions like starvation lower the rate of metabolism of ethanol, whereas insulin enhances it. Alcohol metabolism occurs via an oxidative and non-oxidative pathway. Various enzymes play a role in the oxidative pathway. They are alcohol dehydrogenase (ADH) (present in the cytosol), aldehyde dehydrogenase (ALDH) (present in mitochondria), cytochrome P450 (CYP2E1) (present in microsomes), and catalase (present in peroxisomes). The non-oxidative pathway includes the enzymes fatty acid ethyl ester synthase (FAEES) and phospholipase D (PLD). Both of these pathways are interrelated since drugs inhibiting the enzymes in the oxidative pathway drive the metabolism through the non-oxidative pathway.[22]  

In the oxidative pathway, ethanol is first converted to acetaldehyde by alcohol dehydrogenase (ADH), present in the cytosol. NAD+ serves as an electron carrier for this reaction and gets reduced to NADH. This process significantly reduces hepatic cytosol, paving the way for hepatocyte damage by reactive oxygen species (ROS) and other byproducts of alcohol metabolism. The drug fomepizole competitively inhibits ADH, thereby preventing the formation of toxic metabolites. 

Acetaldehyde is further oxidized by acetaldehyde dehydrogenase to acetone. Acetone finally oxidizes to CO2 in the heart muscle, skeletal muscles, and brain. Interestingly, a drug called disulfiram competitively inhibits acetaldehyde dehydrogenase, thereby delaying the clearance of acetaldehyde, causing dire symptoms like nausea, vomiting, chest and abdominal pain, dizziness, and worsening hangover. This mechanism of the drug has an application in treating alcohol use disorders. Several drugs exhibit the same property as disulfiram. They are metronidazole, sulfamethoxazole and trimethoprim, chloramphenicol, quinacrine, first-generation sulfonylureas, griseofulvin, and some cephalosporins like cefotetan and cefoperazone. 

The non-oxidative pathway involves the formation of fatty acid ethyl esters (FAEE) and phosphatidyl ethanol in the end. FAEE causes tissue damage wherein phosphatidyl ethanol forms at the expense of depleting phospholipase D (PLD), which participates in cell signaling.[22] 

Toxicity

Alcohol intoxication results in CNS depression by enhancing the effect of GABA, an inhibitory neurotransmitter, on its receptors. It also inhibits the actions of 'glutamate' on the NMDA receptors, resulting in an incautious and dull state of mind. Intoxication by ethanol also gives rise to slurred speech, stupor, and gait abnormalities and may even result in a coma. Clinicians should correct thiamine deficiency, which can accompany chronic alcohol misuse, by supplementing B1. Electrolyte imbalance should be appropriately corrected through infusions. Extensive sympathetic counseling is essential for alcohol abuse. Some drugs focused on promoting alcohol cessation include 'naltrexone' (via antagonism of mu-opioid receptors), disulfiram (via creating negative conditioning through pathways mentioned above), topiramate, and gabapentin.

Alcohol withdrawal is another common morbidity that arises as a sequela to alcohol use disorder (AUD). It results from the abrupt cessation of alcohol consumption after binge drinking or long-term dependence. The signs and symptoms usually arise within 6 to 24 hours of stopping alcohol consumption. It may range from milder symptoms like anxiety, headache, palpitations to severe symptoms like withdrawal seizures and delirium tremens. The treatment should focus on providing supportive therapy for all the complaints. Any associated comorbidities should have a 'banana bag' therapy of essential vitamins. The severe symptoms require the use of benzodiazepines.[23]

Enhancing Healthcare Team Outcomes

Ethanol has existed almost from the start of civilization as a drink for merriment. Only in the recent century, through extensive research, have we been able to use ethanol in treating diseases. As a constituent of hand sanitizers in a medical setting, ethanol has become indispensable in impeding hospital-acquired infections practitioners to the patient and vice versa via the transfer of microorganisms. The care provider's duty, including the clinician, mid-level providers, nurses, pharmacists, and anyone involved in the overall case management, is to ensure that they sanitize their hands, wear gloves before approaching and handling the patient, catheters tubes, cannulas, etc. The same principle is necessary for choosing ethanol lock therapy in an ICU setting to prevent sepsis associated with infected catheters.

As an ablative, ethanol is under ongoing research for different neoplastic conditions where surgery is not feasible. The surgeon must identify such patients by their age, financial status, and comorbid conditions to prefer an ethanol ablation over a classic surgery to prevent mortality. As an antidote to methanol or ethylene glycol poisoning, ethanol has been used for decades. Even though fomepizole has emerged to be a better drug due to reasons including, but not limited to, better neutralization of the offending agent, predictable pharmacokinetics, and decreased mortality, ethanol is still preferred by many owing to its low cost and greater physician familiarity.  

Alcohol use disorder remains a global challenge considering the mortality that correlates with misusing. More than 135 million people in the USA, age 12 and older, actively use alcohol.[24] The clinician must identify such patients and counsel them, and if need be, they should be hospitalized and receive appropriate treatment. 

An interprofessional healthcare team is an optimal approach to the proper therapeutic use of ethanol. This team includes clinicians (including NPs and PAs), nursing staff, and pharmacists, working collaboratively to achieve optimal patient outcomes with minimal adverse events. [Level 5]