Ethanol Inhalation in Treatment and Prevention of Coronavirus Disease (COVID-19)

*Ali Amoushahi*

#### **Abstract**

The goal of this study was to determine if nebulized ethanol (EtOH) is safe and effective in treating COVID-19. A randomized controlled trial was carried out on 99 symptomatic and RT-PCR-positive patients admitted to a hospital that were given Remdesivir and Dexamethasone. They were randomly given either a 35% EtOH spray (intervention group, IG) or distilled water spray (control group, CG). For a week, each group underwent three nebulizer puffs every 6 hours. Global Symptomatic Score (GSS) comparisons between the two groups at the initial visit and on days 3, 7, and 14. Secondary outcomes include the readmission rate and the Clinical Status Scale (CSS), a seven-point ordinal scale that ranges from death to full recovery. The intervention and control groups, respectively included 44 and 55 patients. The GSS and CSS considerably improved in the IG, despite the fact that there was no difference at admission (p = 0.016 and p = 0.001, respectively) (Zero vs. 10.9%; P = 0.02). The IG readmission rate was much reduced. Inhaled-nebulized EtOH responds well in quickly improving the clinical status and limiting the need for further therapy. Further investigation into the therapeutic and preventative properties of EtOH is advised due to its affordability, availability, and lack of/tolerable side effects.

**Keywords:** ethanol, inhalation, nebulizer, COVID-19, blood oxygen saturation

#### **1. Introduction**

Deaths from cytokine storms are frequently caused by COVID-19. Alcohol has been shown to have in vitro antiviral effects on coronavirus glycoprotein destruction [1] and the breakdown of the fat layer [2]. Ethyl alcohol (EtOH) has been shown to have antiviral effects on extracellular surfaces in the past [3]. Inflammatory factors such TLR, interleukin-6, and TL9, as well as TNF-mRNA protein and mitogenactivated protein kinase, have been proven in immunological investigations to have immunomodulatory effects on the innate immune system and to attenuate cytokine storm [4, 5]. Additionally, it promotes bronchoalveolar macrophages' chemotaxis [6]. Other effects of ethanol include the prevention of viral multiplication through RNA-dependent polymerase inhibition [7], bronchial dilatation by relaxing involuntary smooth muscles [8], patient sedation and relaxation [9], and analgesic effects on muscles [10]. Methanol poisoning [11], fat embolism [12], premature labor prevention [13], preeclampsia [14], and pulmonary edema [15] have all been treated with ethanol-specific treatments in the past. Castro-Balado et al. [16] have shown the histological safety of inhalation ethanol treatment on rats' lungs and respiratory systems. Ethanol was authorized by the Food and Drug Administration. Can ethanol inhalation treatment be beneficial in treating COVID-19? Given the effects of ethanol on virus wall breakdown, proliferation inhibition, and immunological hyperactivity inhibition, the use of inhaled ethanol as a COVID-19 treatment is still unknown. One month following the COVID-19 epidemic in Iran, this concept was initially put forth and published [17, 18]. Later, a paper explaining the justification for ethanol usage in this area was presented [19]. Recent research on the combined administration of dimethyl sulfoxide and ethanol in healthcare professionals, demonstrated positive effects on COVID-19 prevention [20]. We conducted a randomized clinical study to assess the impact of ethanol treatment on the clinical condition and prognosis of a predetermined group of patients in an effort to discover the solution. The Medical University of Isfahan Research and Ethics Committee accepted the study, which was then registered at https://irct.ir/trial/58201.

### **2. Materials and methods**

Study Design and Oversight (**Figure 1**). The Isabn-e-Maryam Hospital (Christian hospital) at the Medical University of Isfahan in Iran, where this study was carried out in September 2021, was the site of a randomized double-blind clinical trial with a control group and parallel design. The patients were matched one to one at random. The study was initially intended to be conducted on hospitalized patients, but because the country's policy had been changed to allow for the establishment of respiratory

**Figure 1.** *Flowchart of the study.*

clinics in hospitals and the prescription of Remdesivir and Dexamethasone to patients with moderate COVID-19, the study was instead carried out in this clinic. The referral of the patient to the respiratory clinic and this report were shared with the doctors of patients who were being treated in hospitals.

#### **2.1 Patients**

Patients who tested positive for SARS-CoV-2-RT-PCR are the foundation of the study population. They were admitted to the hospital's respiratory clinic because they had moderate COVID-19 (based on the national guideline for managing COVID-19, O2Sat 90–94% or lung involvement [21]). The following criteria were required for inclusion: informed consent, age of at least 12 years old, no pregnancy, no history of epilepsy, alcoholism, or asthma, no contraindications to ethanol usage, and no use of ethanolinteracting medications. Intolerance to inhaled ethanol and incomplete or partial therapy were the exclusion criteria. To investigate possible allergies to alcohol, a skin test with ethanol was performed. In this study, the patient's arm was linked to a gauze pad with an ethanol drop on it. Symptoms including skin redness, swelling, or itching were seen after around 7 minutes. These signs may be indicative of an alcohol allergy or intolerance.

#### **2.2 Intervention**

According to Iran's national clinical norms, both the control and intervention groups were enrolled in the standard medical treatment [21]. The national standard treatment included intramuscular Dexamethasone, 8 mg/day (5 days), and 200 mg of Remdesivir intravenously on day 1, followed by 100 mg of Remdesivir once daily for 4 days, infused over\s30–60 minutes. Patients received normal care as per routine and were then randomly allocated to either the control group (distilled water spray) or the intervention group (35% ethanol spray). The delivery of two 100 ml sets of spray was done in accordance with randomization. Each patient was told to spray the mask three times per day (every 6 to 8 hours) and inhale deeply. We stressed that, depending on the duration of symptoms, this procedure had to be repeated for 7 days. Patients were guided through the process by nurses until they were able to do it on their own. At each appointment for referrals and follow-up care, patient compliance was evaluated. Failure to follow the protocol (spray not used or used incorrectly) resulted in removal from the trial.

#### **3. Clinical and laboratory monitoring**

The demographic and clinical information were separated into different sections on the data collecting sheet. A qualified nurse performed the data-collecting checklist based on clinical symptoms, clinical outcomes, and clinical examination after obtaining demographic data from the patient's records. Up to discharge, information on study variables, such as blood oxygen saturation measured by pulse oximetry, the requirement for supplementary care or hospital readmission, and clinical complaints in both groups, was gathered.

#### **3.1 Study outcomes**

Primary outcomes: The global symptomatic score (GSS), which is calculated by adding up the cumulative scores of clinical signs and symptoms like anorexia, fever, headache, body aches, sore throat, runny nose, chills, coughing, and loss of taste and smell, is regarded as a gauge of a patient's clinical condition. This index was created to provide a concise list of clinical symptoms. Using a pulse oximeter, oxygenation status was tracked and documented each day. The patient was not receiving any additional oxygen at the time of the measurement and was breathing room air with a fixed pulse oximeter. Changes in blood C-reactive protein (CRP) levels were used to characterize the presence of inflammation.

Secondary outcomes: On day 14 of the treatment period for the investigation, clinical conditions were evaluated using a modified 7-point ordinal scale [22].

There are seven indicators in this scale:


The necessity for critical care unit admission, adverse medication reactions, clinical symptoms, and death in the research samples were noted and tracked in both groups. The last follow-up was scheduled on the day fourteenth of the illness. Physical examinations, history-taking, phone calls, reviews of patient records, and documents from the hospital information system were all used during follow-up. After receiving informed consent, side effects were documented. The main endpoints have undergone some alterations. This was due to the study's implementation restrictions, which coincided with the disease's peak in Iran, and the fact that patients who required hospitalization were followed up on an outpatient basis in the respiratory clinic. We informed the sponsor and institutional review board in great detail of the protocol revisions. The length of stay was the key anticipated result. This index was replaced with a more detailed clinical status since all moderate patients were treated on a 5-day regimen during the surge.

#### **3.2 Sampling**

An easy random sample technique was used to do the sampling. Random assignment was performed using a computerized random number table. The order of the random distributions was decided by one nurse. Each participant who was qualified and gave their agreement to participate in the experiment was randomly assigned from a list that she kept confidential. One by one, a different nurse added 100 ml of diluted distilled water or ethanol-35% to the sprays (nebulizers) and labeled them

with the numbers from the list. Each spray was given to a participant, who was then instructed on how to use it by their family or companion. Blinding was carried out by analysts, nurses, and clinicians.

#### **4. Statistical analysis**

Using a 2-sided significance level of 0.05, we calculated that 88 patients (44 in each group) would offer higher than 90% power to detect an odds ratio of 3 for the ethanol group vs. the placebo group. The analysis was restricted to individuals who, in accordance with the research protocol and inclusion criteria, got full treatments and contributed to the outcomes, as per the "treatment-on" or "per-protocol" method. Means, standard deviations, and percentages (%) were used to report both quantitative and qualitative information. The chi-square test was used to evaluate qualitative characteristics between the two groups, and a mixed model was used to compare SpO2 readings and GSS on days 1, 3, 7, and 14. Repeated-measures analysis was used to calculate the average changes from baseline values. With the use of Mauchly's statistics and the Geisser-Greenhouse adjustment, the sphericity hypothesis was disproved. The cumulative odds ordinal logistic regression with proportional odds was used to compare clinical status between the two groups on day 14, and the two test was used to determine the proportion of patients in each group who required additional medical care after 14 days. These tests were carried out at 0, 3, and 14 days after the intervention. For the intervention group compared to the usual care group, an odds ratio larger than 1 showed changes in clinical status across all categories toward category 7. For clinical status, if a patient recovered, the ordinal score was recorded as 7 on the day of recovery and all subsequent days unless the patient was hospitalized for COVID-19-related reasons or others; all statistical analyses were performed using SPSS software version 22 (SPSS Inc., Chicago, IL, USA), and p < 0.05 was considered significant. The outcome markers were adjusted for the patient's gender.

#### **5. Results**

Patient Characteristics from September to November 2021, 150 patients from the COVID-19 Respiratory Outpatient Clinic of the Isabn-e-Maryam Hospital of the Isfahan University of Medical Sciences were assessed for participation in the research based on the positive outcome of the RT-CPR test. A total of 24 patients disagreed with the research, and 2 patients did not meet the inclusion requirements. Randomly, 124 more patients were divided into two groups (Intervention and Control). In the next days, 25 participants were removed from the trial due to intolerance to ethanol inhalation (6 patients); their intolerance was mostly caused by hiccups, eye irritation, coughing, shortness of breath, sneezing, and the unpleasant odor of alcohol. On the other hand, 19 patients (9 in the control group and 10 in the intervention group) were disqualified from the trial because of irregularities or failure to adhere to the suggested procedure. Finally, 99 patients entered the analysis: 44 patients in the IG and 55 patients in the CG (**Table 1**).

**Table 1** summarizes the baseline characteristics and demographics of the two groups of patients. The male-to-female patient ratio was 43/56 (42.4/56.6%). The patients were 46.4 years old on average. A total of 38 patients had multiple conditions. Diabetes mellitus was the most prevalent underlying condition in both groups, with 6


#### **Table 1.**

*Demographic characteristics in two research groups.*

(14.3%) in the intervention group and 4 (7%) in the control group. Seven individuals had high blood pressure and seven others had additional cardiovascular issues. The two groups' mean ages, weights, levels of education, and total number of risk variables did not significantly differ from one another.

#### **5.1 Clinical signs and symptoms at the time of admission**

The interval between the onset of symptoms and admission, lung involvement, and early clinical signs and symptoms at baseline did not substantially differ among the patients. The clinical signs and symptoms of the patient's fundamental characteristics are listed in **Table 2**.

Cough, body pains, chills, and headaches were the intervention group's main clinical complaints. The control group had a higher prevalence of anorexia, olfactory disturbance, and cough. There was no discernible change in symptoms. Overall Symptom Score The GSS was evaluated at the start of therapy, 3, 7, and 14 days afterward in two groups. The results are shown in **Figure 2**.

The GSS of the two groups was equal at the start of the research, according to statistical analysis, but in the IG group, clinical symptoms reduced more quickly than in the placebo group. The statistical significance of this difference was (p = 0.016).

#### **5.2 Blood oxygen saturation**

At the time of the trial, there was no noticeable change in the two groups' blood oxygen saturation levels (92.07 ± 4.6 in the control group vs. 91.56 ± 3.39 in the intervention group). As seen in **Figure 3**.


*Ethanol Inhalation in Treatment and Prevention of Coronavirus Disease (COVID-19) DOI: http://dx.doi.org/10.5772/intechopen.110724*

#### **Table 2.**

*Preliminary characteristics of signs and symptoms, risk factors, and laboratory values in baselines.*

#### **Figure 2.**

*Comparison of global symptomatic score (GSS) in the intervention and control groups at the beginning of admission, days 3, 7 and 14 after admission.*

#### **Figure 3.**

*Comparison of mean blood oxygen saturation (SPO2) in intervention and control groups at the beginning of admission, days 3, 7 and 14 after patient admission.*

#### **Figure 4.**

*Comparison of CRP (C-reactive protein) in the intervention and control groups at the beginning of admission and three days after patient admission.*

Both groups had an improvement in blood oxygenation, however, the ethanol group's slope of oxygenation was greater. The change is not statistically significant, though (p = 0.097) inflammatory factor (CRP) Multiple assessments and statistical comparisons between the two groups revealed a declining trend in CRP (**Figure 4**).

However, the rate of reduction was much faster and more intense in the IG (p = 0.05). Two sets of CSS based on the modified 7-point ordinal scale were compared. On day 14, the intervention group had 5.7 times the chance of having superior *Ethanol Inhalation in Treatment and Prevention of Coronavirus Disease (COVID-19) DOI: http://dx.doi.org/10.5772/intechopen.110724*


#### **Table 3.**

*Comparison of clinical status scale (CSS) of intervention and control groups on the 14th day of admission.*

CSS than the control group (95% CI, 2.47–13.19), which is a statistically significant difference (Wald 2 (1) =16.67, p = 0.001). **Table 3** provides details.

Six patients (10.9%) from the control group were readmitted after the therapy period had ended in order to obtain further care or hospitalization. None of the patients were readmitted to the ethanol group (p = 0.02).

#### **5.3 Adverse events and safety**

Six out of 50 patients in the ethanol group (12%) quit taking it due to adverse effects that started as soon as inhalation began, and we eliminated them from the research. Only one instance of each negative effect was noted, and it vanished after ethanol consumption was discontinued. Hiccups, eye discomfort, coughing, shortness of breath, sneezing, and a strong alcohol odor were a few of the undesirable side effects.

#### **6. Discussion**

The impact of adding nebulized Ethanol inhalation has been researched in this clinical study on patients having positive RT-PCR test results, mild clinical symptoms, and suitability for Remdesivir and Dexamethasone treatment, according to the Iran Ministry of Health protocol. The rationale for the use of EtOH in COVID-19 has been well discussed [19]. There is no question regarding the ability of ethanol in killing or making SARS-CoV-2 inactive, even at concentrations as low as 30% v/v and for only 30 seconds [23]. The virus's fat layer is broken down by the virucidal effects of EtOH, which then stop the virus from multiplying. EtOH has also been demonstrated to reduce the immune system's hyperactivity during COVID-19. It seems likely that ethanol is ineffective against intracellular viruses. It is crucial to continue ethanol inhalation for at least 3 days since viral multiplication happens within 48–72 hours, followed by cellular death and shedding. Additionally, ethanol is fundamentally effective against all SARS-CoV-2 variants and other "enveloped" viruses due to its non-specificity. The abnormal presence of Mycoplasma salivarium in the lower tract or the lack of Clostridia in the upper tract was linked to worse outcomes in ICU patients [24]. It is interesting to note that ethanol completely inactivates Mycoplasma

and SARS-CoV-2 (Eterpi et al.) [25]. Additionally, certain strains of Clostridia synthesize endogenous ethanol [26]. According to a hypothetical scenario, the lack of nasopharyngeal Clostridia would prevent the local generation of ethanol, which would prevent or drastically limit the inactivation of SARS-Cov-2 at this level, allowing the virus to propagate to the lower respiratory tract. A lot of concern has been expressed regarding the potential mucosal harm that breathed ethanol might cause. Castro-Balado et al. careful research [16] appears to have completely dispelled these concerns. It should be noted that spraying into the mask prolongs the action of the nebulized liquid and maintains its efficiency by reducing the dispersion and evaporation of the liquid. The different smells of the two solutions indicate a potential inherent bias. Patients could only recognize that one spray was different from another since they were unaware of the actual ingredient in the spray. To put it differently, the medication may have been in an odorless spray. Dexamethasone and Remdesivir are administered intramuscularly as part of the COVID-19 standard therapy [21]. According to a recent trial, introducing early antibiotic therapy for COVID-19 pneumonia had no positive effects on 30-day mortality [27]. Despite what was predicted [28, 29], the authors [27] did not discover any appreciable vaccination benefit in reducing illness severity and death among patients with COVID-19 pneumonia. The GSS fell more in the Intervention group than in the control group, according to our findings, and these data reached a statistically significant level (p = 0.016). Nebulized EtOH inhalation had positive effects on lowering CRP levels, which was a significant advantage (p = 0.05). This result supports EtOH's positive immune- modulation effects [3]. On the other hand, blood oxygenation increased more quickly and had a greater slope in the ethanol than it did in the control group. Regarding blood oxygenation, between the two groups, there was, however, no statistically significant difference (p = 0.097). In terms of CSS, the intervention responded better than the control since no patient had to be readmitted, as opposed to the control where 6 patients (10.8%) had to repeat the normal therapy or be hospitalized. These results provide credibility to EtOH's virucidal properties.

#### **7. Conclusions**

Overall, recovery from moderate COVID-19 is greatly improved by adding EtOH to the conventional therapy (Remdesivir+Dexamethasone). It is advised to do more research and invest more in order to assess ethanol's therapeutic and preventative effects in the early stages of COVID-19 given its accessibility, low cost, and lack of substantial adverse events. The patients in this experiment were far from our rigorous oversight and switched to other treatments, which was one of its shortcomings. The healthcare system is also concerned about unpleasant alcohol consumption and the potential for non-inhaled alcohol intake. This study is constrained by chance (due to the small sample size), confounding factors (due to the imbalance in gender distribution), and low power, among other things. The randomization sequence is broken by a per-protocol analysis, which also introduces bias into the study.

*Ethanol Inhalation in Treatment and Prevention of Coronavirus Disease (COVID-19) DOI: http://dx.doi.org/10.5772/intechopen.110724*

### **Author details**

Ali Amoushahi

Department of Anesthesiology and Intensive Care Unit, Isabn-e-Maryam Hospital, Isfahan University of Medical Sciences, Isfahan, Iran

\*Address all correspondence to: aliamoushah@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 7** Nebulized Ethanol: An Old Treatment for a New Disease

*Steven W. Stogner*

#### **Abstract**

Ethyl alcohol (ethanol) is known to inactivate SARS-CoV-2, and therefore, direct delivery to the upper and lower respiratory tracts hypothetically would inhibit the progression of COVID-19. After informed consent, nebulized EtOH was given to inpatients admitted with COVID-19, and outcomes were retrospectively compared to randomly selected controls. Benefits of nebulized EtOH included decreased average length of stay, improved inpatient survival, decreased intubation rate and need for transfer to intensive care, improvement in hypoxemia, and decreased need for transfer to another facility for ongoing post-acute care. Also, fewer patients required supplemental home oxygen after discharge to home. Interpretation: Nebulized EtOH is beneficial in the treatment of COVID-19. Further study is warranted.

**Keywords:** inhaled ethanol, COVID-19, SARS-CoV-2, hypoxemia, virucide

#### **1. Introduction**

The virus that causes COVID-19 Disease (designated SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2) has caused severe morbidity and mortality around the world. In addition to the human toll of disease, the pandemic triggered stark social as well as economic disruption around the world, affecting a global recession [1]. Supply shortages (including food), travel restrictions, business restrictions and closures, workplace hazard controls, quarantines, testing systems, and tracing contacts of the infected has been costly in not only financial terms as governments attempted to control the pandemic but also in societal customs and "norms" as well. Near-global lockdowns of educational institutions and other entities were partially or completely closed in many areas, as well as the postponement of needed surgeries placed major stress on communities across the globe, often resulting in a political uproar. In truth, the world has not experienced a similar pandemic and its results since the 1918 Flu Pandemic (February 1918 until April 1920 in four successive waves affecting 500 million people) [2, 3].

As of August 2022, COVID-19 has infected more than 600 million people and caused almost 6.5 million confirmed deaths worldwide—one of the deadliest in history [3]. First identified in Wuhan, China, in December 2019, the COVID-19 virus outbreak was identified by the World Health Organization (WHO) as a public health emergency of international concern on January 30, 2020, and the astronomical trajectory continued with it being declared a global pandemic only 2 weeks later [4]. In March of that year, hospitals and outpatient clinics alike found themselves overwhelmed with astonishing volumes of patients which stressed healthcare resources to the edge, to the point of having to contemplate the rationing of care [5], including intensive care beds and mechanical ventilators.

In addition to inadequate resources at the onset of the pandemic—other than standard treatment measures for respiratory failure, including ARDS—specific treatment for the COVID-19 virus did not exist. Healthcare workers found themselves having to care for critically ill and dying patients who were most often isolated from their loved ones. Saddled with the grim fact of no specific treatment, the apprehension of becoming infected themselves and transmission of the virus to their own loved ones at home, and the emotional (and *ethical*) nightmarish thoughts which occurred as the potential of rationing healthcare loomed, it is no shock the common *burn-out* of healthcare workers that ensued [6].

#### **2. COVID-19: the disease**

The degree of disease caused by COVID-19 ranges from undetectable to lethal, but most commonly includes fever, nonproductive cough, fatigue, and loss of taste and/ or smell in 40 percent of cases [7]. While severe illness such as organ failure occurs most frequently in elderly patients, it is also seen in younger patients with certain comorbidities such as chronic obstructive pulmonary disease, heart failure, malignancy, obesity, chronic steroid or immunosuppressive use, etc. [8]. Transmission occurs when people inhale droplets of airborne particles containing the virus, but also when viral-contaminated fluids reach the eyes, nose, mouth, and even contaminated objects (i.e. hands, etc.).

#### **3. Pathogenesis: a clue for an effective treatment**

The COVID-19 virus contains genetic material (RNA) packaged in a protein coat which is surrounded by an envelope composed of a lipid bilayer derived from the host cell membrane [9–11]. SARS-CoV-2 affects the upper and lower respiratory tracts, where its entry genes are highly expressed in epithelial cells of the nasal cavity and into the alveolar cells. Thus, the portal of entry of SARS-CoV-2 is the upper respiratory tract where the acute infection begins, then subsequently travels to the alveoli by viral aspiration. A *"cytokine storm"* can then ensue, likely due to an interleukin-6 amplifier resulting in a hyper-activation process that regulates the nuclear factor kappa B (NF-κB) [12–14]. Ultimately, this cascade of events can be fatal in 75% of cases due to the development of ARDS and other acute organ failures including thrombotic complications [15].

#### **4. Nebulized ethanol: potential benefits and risks**

*Potential benefits:* Direct delivery of a drug with viricidal activity against SARS-CoV-2 (or other susceptible respiratory viruses, i.e., influenza) to the epithelial cells of the upper and lower respiratory tracts in an effort to destroy the virus before severe disease can ensue seem advantageous—and is logical. Ethanol/ethyl alcohol/

EtOH suits this purpose. Ethanol is volatile and has long been used as an antiseptic/ disinfectant, and constitutes the basis for many hand rubs and disinfectants used in healthcare settings [16, 17] as well as by the general public. Ethanol and other alcohols are known to inactivate many enveloped viruses like SARS-CoV-2 by dissolving the virus' lipid membrane causing its destruction [18–20]. Notably, alcohol-based hand rub solutions have been shown to inactivate SARS-CoV-2 in as little as 30 s [21]. In addition to coronavirus, the effective viricidal activity of ethanol against many other common viruses (i.e., influenza, adenovirus, etc.) as well as Zika and Ebola has been demonstrated [22].

Ethanol is presently used worldwide as a generally nontoxic antiseptic and disinfectant and has been effectively and safely used in medicine for methanol poisoning [23], and as late as the 1950s as an inhalational treatment of pulmonary edema [24, 25] and alcohol withdrawal [26, 27].

Published reports suggest promise for the use of inhaled ethanol in the treatment of ARDS [28]. Ethanol is a well-known efficient surfactant (wetting agent), as it is an amphiphilic chemical compound possessing both hydrophilic and lipophilic properties. Surfactant proteins are critical components of alveolar function, and laboratory studies on animal lungs indicate ethanol has the potential to restore surfactant activity in experimentally-induced non-compliant lungs (produced with nebulized saline) [29]. Notably, analysis of SARS-CoV-2-infected lung tissues has revealed that surfactant proteins are indeed severely downregulated in infected lungs, causing respiratory distress [30].

Ethanol has mediator effects on inflammation [31] and thus could potentially have a beneficial effect on the prevention of cytokine storms [13]. In addition, there may be a possible benefit with ethanol in the prevention of thrombus formation shown by autopsy findings to frequently occur in COVID-19 [15, 32, 33]. Ordinarily, cutting of the fibrin mesh by plasmin enzyme leads to the production of circulating fragments that are cleared by other proteases or by the kidney and liver. Tissue plasminogen activator (t-PA) and urokinase then convert plasminogen to the active plasmin, allowing normal fibrinolysis to occur. Ethanol has been shown to "upregulate" the urokinase receptor in human endothelial cells and thus may be helpful in the elimination of thrombi [34].

*Potential risks:* Ethanol is flammable and combustible, and if ignited, can cause severe injury or even death. Appropriate cautionary measures are absolutely mandatory with its usage.

The risks and negative health effects on the immune, cardiovascular, pulmonary, gastrointestinal-hepatic, and neurologic systems of chronic oral consumption of ethanol are well-known [35]. Even acute oral consumption of large amounts is known to have the potential for serious health consequences, including even fatal toxicity. Vaporized ethanol used recreationally (*AWOL* = "alcohol without liquid") appears to some extent becoming more prevalent, and serious concerns have appropriately been raised about its acute and unknown long-term health consequences, especially in young adults. However, a review of the literature fails to show any significant acutely negative effects of the short-term intake of small amounts of ethanol on the immune system or other organ systems [36–40].

Inhaled ethanol can irritate the eyes, as well as the nose, throat, and plausibly the lungs [41, 42]. In one small study, a decrease in ventilator flow rates on partial expiratory flow volumes [43] was found up to ninety minutes after inhalation, but no significant change in FEV1 (forced expiratory volume) occurred compared to placebo (inhaled saline solution). Interestingly, pretreatment with disodium cromoglycate considerably diminished the acute reductions of flow rates caused by ethanol inhalation, suggesting that ethanol in some persons may act, at least partly, through the release of mediators with bronchoconstrictive action.

As with any nebulized treatment, nebulized ethanol poses a risk for aerosolization of respiratory viruses like SARS-CoV-2 and transmission of the disease. Appropriate infection control precautions must be strictly followed when such conditions exist.

In the swarm of patients requiring inpatient care for acute hypoxemic respiratory failure due to SARS-CoV-2 in March 2020, those patients who deteriorated necessitating intubation for adult respiratory distress syndrome (ARDS) were having mortality exceeding 75% [3]. While governments were scrambling to issue emergency-use authorization for experimental treatments as well as civil protections for healthcare providers trying to best care for these patients, patients continued to literally smother ultimately requiring intubation and mechanical ventilation. The situation was not only grim, but it seemed hopeless. The urgency to find an effective treatment for this novel virus had never before been witnessed in the lives of most medical professionals. While some treatments were showing promise (i.e., remdesivir, dexamethasone, etc.), there remained an existential need for an effective readily available treatment. Given its proven viricidal efficacy, history of harmless use in the treatment of other medical conditions, as well as a lack of evidence for acute detrimental health effects when used in mild, non-chronic, non-excessive intake, the reasoning that nebulized ethanol may prove beneficial in the treatment of COVID-19 is rational.

#### **5. Nebulized ethanol for treatment of COVID-19: results of a clinical study**

In March 2020, at Forrest General Hospital (a non-profit community hospital in Hattiesburg, Mississippi) due to the emergent onslaught of this lethal and "untreatable" disease, and out of necessity and companionate care, a novel treatment regimen of nebulized ethanol was developed to offer patients with COVID-19 who required inpatient treatment for acute hypoxemia as a sole or supplemental treatment option, at the discretion of their attending physicians. While Shintake [44] had proposed the potential use of inhaled ethanol to eradicate the virus in the respiratory tract, extensive research of the medical literature otherwise revealed no reports of inhaled ethanol for treatment of COVID-19 infection1 (or any other viral respiratory infection for that matter).

As a sole or additional option, a protocolized order set for the administration of nebulized ethanol was made available to hospital physicians in the electronic medical record beginning in April 2020. Education of all involved healthcare personnel was conducted prior to making the order set available. Administration of all nebulized treatments was performed by respiratory therapists, who in addition to nurses, monitored the patients. Access to and dispensing of the ethanol was meticulously controlled by the hospital pharmacy, which also confirmed that all of the following criteria were met prior to dispensing:


<sup>1</sup> The results of this study have not been published elsewhere.


#### **5.1 Dose and administration**

Ninety-five percent pure grain ethanol was used for a three-day regimen (3 total doses). Each daily dose was weight-based (actual body weight): female patients = 0.31 g/kg, and males = 0.33 g/kg. An equal volume of sterile water was mixed with the ethanol for a final concentration of 47.5%, and given continuously via face mask over approximately 60–75 min using a standard large-volume nebulizer driven by wall oxygen or air (determined by the patient's pre-treatment supplemental oxygen requirement) at a flow rate of 10 l/min. An anti-viral filter was connected to the exhalation port of the face mask. Respiratory therapists closely observed the patients and monitored SpO2 (oxygen saturation via pulse oximetry) during treatments, and nurses recorded pre-treatment blood pressure, pulse and respiratory rates, and temperature, as well as every 15 min during and for one-hour post-treatment. No other persons were allowed in the room during or post-nebulization except per hospital policy, which included strict adherence to isolation precautions and protection measures such as personal protection equipment.

#### **5.2 Data collection, statistical analysis, and outcomes**

Demographic, clinical, and outcomes data were collected by retrospective review of the medical records of three hundred-six patients admitted for COVID-19 with respiratory disease from April through December 2020. Patients who completed the three-day regimen (Ethanol Group) were compared to randomly selected patients (Control Group) who had been admitted to the general medical floor during the same time-period but had received only "standard" therapy for COVID-19 (i.e., no ethanol treatment). Statistical analysis was performed using the T-Test and Fisher's Exact Test, with a statistical significance of p-value < 0.05.

#### **5.3 Demographics**

Ninety-one patients received one or more doses of nebulized ethanol, while two hundred twenty-five randomly selected "control" patients were identified. Of the ninety-one patients who received any ethanol treatment, eighty-one (89%) completed the three-day regimen. (*Note: The total number of patients who were offered but refused treatment with alcohol is not known.*)

#### **5.4 Severity of hypoxemia**

The severity of hypoxemia was assessed in all patients before receiving any COVID-19 treatment, at 96 h after the first treatment, and again at the time of discharge from the hospital, using the SFR (SpO2/FiO2 ratio; "normal" ≥ 4.57) [45–47].

#### **5.5 Outcome metrics**

The following data and clinical outcomes of the two groups were collected and compared:


#### **5.6 Results**

Eighty-one patients completed the three-day regimen (Ethanol Group), and were compared to the Control Group (225). Ten patients (11%) who initially gave informed consent to try inhaled ethanol treatment did not complete the three-dose regimen and were not included in the final data analysis. One was in the respiratory extremis prior to starting the first treatment and received an unknown quantity before requiring emergent intubation and immediate transfer to the ICU, and received no further ethanol treatments. This patient subsequently expired after a prolonged hospital stay on mechanical ventilation. The other nine (9.9%) did not complete the first treatment dose or refused the second dose due to a universally reported side effect of immediate mild coughing and / or burning sensation in the naso-oropharynx. Two of these nine patients (22.2%) later required transfer to ICU and intubation for disease progression, and both subsequently expired. Seven of the nine patients (77.8%) improved after prolonged hospital stays and were subsequently discharged from the hospital with home health or to a skilled nursing facility.

As shown in **Table 1**, average age of both groups was similar: 63.6 years (median 64; range 41–96) in the Ethanol Group, compared to 65.5 years (median 62; range 28–99) in the Control Group (p = 0.50). Gender distribution was also comparable between the two groups: 42% (34) females and 58% (47) males, 51.6% (116) females and 48.4% (109) males in the Control Group (p = 0.15). Average BMI (body mass index = kg/m2 ) was similar: 35.3 (median 34), compared to 33.4 (median 34) in the Control Group (p = 0.06).

Likewise, the presence of one or more significant co-morbidities was similar in both groups, including diabetes mellitus, chronic obstructive pulmonary disease, drug-induced immunosuppression (i.e., chemotherapy for cancer), obesity, hypertension, end-stage renal disease, and autoimmune disease (i.e., rheumatoid arthritis): 92.5% (75) in the Ethanol Group, and 87.1% (196) in the Control Group, (p = 0.22). The average pre-treatment SFR was statistically *worse* (p < 0.001) in the Ethanol Group (2.86) compared to the Control Group (3.83).

#### *Nebulized Ethanol: An Old Treatment for a New Disease DOI: http://dx.doi.org/10.5772/intechopen.111695*


*\*Statistical significance: p < 0.05.*

*\*\*BMI = body mass index, kg/m2 .*

*\*\*\*Comorbidities include diabetes mellitus, chronic obstructive pulmonary disease, drug-induced. immunosuppression (i.e. chemotherapy for cancer), obesity, hypertension, end-stage renal disease, and autoimmune disease (i.e. rheumatoid arthritis).*

*\*\*\*\*SFR = SpO2/FiO2 Ratio (Example: "normal" SFR: SpO2 0.98/0.21 = 4.67).*

#### **Table 1.**

*Demographic data.*

**Table 2** shows the use of "standard" (non-ethanol) treatments in both groups were similar, with all patients having received one or more of the following drugs: remdesivir, tocilizumab, azithromycin, intravenous steroids (dexamethasone or methylprednisolone), and convalescent plasma. The most frequent in both groups were remdesivir and intravenous steroids, but no statistical difference was found between both groups for anyone "standard" treatment (p = 0.07–0.86).

**Table 3** shows pre-treatment SFR, and average post-treatment SFRs for both groups. In the ethanol group, the average SFR at 96 h (2.89) compared to pre-treatment (2.86) was unremarkable. Notable, the average SFR at 96 h in the Control Group had *decreased* from 3.83 to 3.69, but not statistically significant from the Ethanol Group (p = 0.21). Although not quite statistically significant (p = 0.06), the Ethanol Group had considerable improvement (21.7%) from the average pre-treatment SFR


*\*All patients in both groups received vitamins C, D3, and zinc.*

*\*\*Statistical significance: p < 0.05; no statistical difference was found between the two groups.*

*\*\*\*Dexamethasone or methylprednisolone.*

*\*\*\*\*Removed from hospital "COVID-19 Formulary" in July 2020.*

#### **Table 2.**

*"Standard" COVID-19 medications received.*

#### *Ethanol and Glycerol Chemistry – Production, Modelling, Applications, and Technological Aspects*


#### **Table 3.**

*Pre- and post-treatment SPO2/FIO2 ratios.*

(2.86) to discharge (3.48), compared to the Control Group which had a minor increase (1.3%) from the average pre-treatment SFR (3.83) to discharge (3.88).

Comparison of clinical outcomes is shown in **Table 4**. Progression (e.g., worsening) of COVID-19 disease requiring transfer to the intensive care unit (ICU) occurred less in the Ethanol Group compared to the Control Group: 8.6% (7), and 14.7% (33), respectively (p = 0.18), equating to a 41% less chance of requiring transfer to ICU for disease progression in the Ethanol Group. Intubation was necessary for all seven patients in the Ethanol Group who required transfer to ICU, compared to 82% (27) in


*\*One patient developed hospital-acquired pneumonia and progressive shock due to S. marcescens on day 5. hospitalization; another required intubation for sudden cardiac arrest the day after 3rd EtOH treatment.\*\*Facility = long-term acute care, nursing home, other skilled nursing, or rehabilitation. Abbreviations: ALOS = average length of inpatient stay; DC = discharge from hospital.*

**Table 4.** *Clinical outcomes.* the Control Group but was not statistically significant (p = 0.57). Notably, one of the seven patients in the Ethanol Group who required transfer to ICU had developed progressive respiratory failure and sepsis due to hospital-acquired pneumonia (*Serratia marcescens*) on day five of admission (two days post-third ethanol treatment), requiring intubation and vasopressor support for shock, and subsequently expired in ICU. Another patient expired having required transfer to ICU after emergent intubation for sudden cardiac arrest the day following the third EtOH treatment, although having been stable pre-arrest with no worsening hypoxemia or hemodynamic instability.

ALOS was less in the Ethanol Group (6.88 days, median 5.5, range 4–27) versus the Control Group, (9.98, median 8, range 6–33) and was statistically significant (p = 0.03).

Inpatient mortality was also statistically less in the Ethanol Group (6) compared to the Control Group (40): 7.4% and 17.8%, respectively (p = 0.03), translating to a significantly improved survival in the Ethanol Group of 92.6% (75) compared to 82.2% (185) in the Control Group (p = 0.03). The mortality rates of patients who required transfer to ICU because of disease progression were not statistically different between the two groups (p = 0.41), although a larger percentage of patients in the Ethanol Group (71%; n = 5) died compared to the Control Group (48.5%; n = 16). *Note: Post-discharge mortality rate is not known at this time.*

Interestingly, and statistically significant, 81.4% (66) in the Ethanol Group were able to be discharged to their homes compared to 40.9% (92) in the Control Group (p < 0.001), and only five (6.2%) in the Ethanol Group required discharge/transfer and admission to another healthcare facility for ongoing care (i.e. long-term acute care, nursing home, skilled nursing, or rehabilitation) compared to 38.2% (86) in the Control Group (p < 0.001). Four survivors (4.9%) in the Ethanol Group were discharged to hospice care, comparable to 7 (3.1%) in the Control Group (p = 0.49). The need for home health services post-discharge was similar: 34.6% (28) in the Ethanol Group, and 28.9% (65) in the Control Group (p = 0.40). Considerably fewer patients required supplemental home oxygen in the Ethanol Group (45.7%; n = 37) versus the Control Group (64.4%; n = 82), though not statistically significant (p = 0.15).

#### **5.7 Discussion**

The results of this study suggest a number of positive benefits of inhaled ethanol in the treatment of COVID-19 in non-ICU patients with acute hypoxemia. Statistically significant benefits included decreased ALOS, improved survival, and increased chance of discharge to home as opposed to requiring post-hospital treatment in longterm acute care, extended care facility (i.e., nursing home), or other skilled nursing facility (i.e. rehabilitation center, etc.). Other benefits included the decreased need for transfer to ICU due to disease progression, decreased need for intubation and decreased need for home oxygen. If such outcomes are confirmed in larger studies, the benefits to patients and healthcare systems worldwide would be incredible.

The science is sound as noted by other researchers [48, 49] regarding the potential use of inhaled ethanol as a treatment for COVID-19. Ethanol is rapidly absorbed in the respiratory tract and then transported via the circulatory system to other tissues. Nebulization into the nares (and mouth) has the benefit of direct deposition and contact with the virus in the upper and lower respiratory tissues, from which it can then circulate to other tissues where the virus has been shown to be present in autopsy findings [12], allowing ethanol to circumvent the "first pass" metabolism by alcohol dehydrogenase in the liver. The hypothesis is logical: direct deposition of ethanol

on respiratory tissues may inactivate the virus in the respiratory epithelium thereby inhibiting viral replication and thus decreasing the viral load—and the risk of the inflammatory response (i.e., cytokine storm) which is responsible for organ failure (i.e., ARDS, acute kidney injury, etc.). The clinical results in this study support the hypothesis.

Obviously, while ethanol is known to inactivate SARS-CoV-2 on skin surfaces, the amount needed to inactivate SARS-CoV-2 in the respiratory tract (and other human tissues) is not known. The dose in this regimen was weight-based (0.31 g/kg for females, and 0.33 g/kg for males), estimated to produce a blood alcohol concentration of less than 0.08 mg %. Five ounces or 148 ml of wine is 12% EtOH by volume and contains about 14 g of EtOH, or 0.095 g/ml, whereas 95% EtOH contains 0.75 g/ml. Thus, in this regimen, for example, a 70 kg male would receive a nebulized dose of EtOH of about 23 cc of EtOH or about 17 g of EtOH—3 g more than that in one glass of wine [50]. (Of note, serum EtOH levels were not detectable 1-h post nebulization treatments.) While the dosing of EtOH in this study showed benefits, the optimal dosing and method of administration need further study. Plausibly, different dosing, frequency, and duration of therapy may prove even more beneficial, and it may prove more beneficial if initiated earlier, or within a specified time period of the initial onset of COVID-19 symptoms. (*Note: In this study, the duration of symptoms before seeking treatment is not available.*)

This regimen proved safe and was well tolerated in the great majority (89%) of patients who were known to have been offered the treatment. No severe adverse or untoward events were reported or discovered on review of the medical records. No patient reported a feeling of intoxication, and none became noticeably intoxicated during observance by medical personnel. All patients had onset of a temporary minor cough and/or burning sensation in the nasopharynx and throat, which lasted about 2 min, but these were the reasons given by those who initially gave consent to try the nebulized EtOH but refused subsequent treatments. No patient who received any or all of the three-day regimen was found to have physical evidence of naso-oropharyngeal mucosal inflammation. Likely, dilution of the nebulized weight-based dose with sterile water by one-half is beneficial in reducing the mild cough and/or burning sensation.

#### **6. Where we currently stand**

The ability of COVID-19 to cause widespread morbidity, mortality, and profound stress on healthcare systems worldwide has been harrowing. Not only increased costs of healthcare due to COVID-19 on the world economy, but this pandemic has had major negative effects on the entire well-being of society—previously unseen for many decades. No other disease has affected the current generation of medical professionals (or the world) like COVID-19. While other diseases exist for which there is no effective treatment, the mere volume of cases of COVID-19 has made its indelible mark.

From its beginning, the entire world felt the urgent need to find an effective treatment for this novel virus, and the discovery and development of new treatments for SARS-CoV-2 have been remarkable. Published data suggest definite benefits with a variety of medications including antivirals, monoclonal antibodies [51, 52], and high-titer convalescent plasma [51]. Based on COVID-19 pathogenesis, therapies that attack the virus itself are more likely to work *early* in the course of infection, whereas

treatments that restrain the immune response (*cytokine storm*) may have more influence later in the disease [13, 14, 53]. Unfortunately, these medications are costly, and the prescriber of such treatments as the antiviral nirmatrelvir-ritonavir must also consider the potential for significant adverse reactions and interactions with a wide variety of other common medications that are highly dependent on *CYP3A* for clearance and for which elevated concentrations are associated with serious and or life-threatening reactions [54].

Obviously, as new COVID-19 variants arise, current therapy guidelines will need to be amended. For example, bebtelovimab has activity against Omicron *BA.2*, but there is a paucity of good clinical data showing an associated reduction in COVID-19 mortality [55, 56]. Monoclonal antibody therapies like sotrovimab, casirivimabimdevimab, and bamlanivimab-etesevimab have shown a reduction in death and the need for hospitalization in outpatients who have a non-severe disease but at risk for progression [57, 58]. However, these formulations are not appropriate for use in areas where COVID-19 infection is most probably due to SARS-CoV-2 variants that are not susceptible (i.e., Omicron, subvariants, etc.) [59].

Beyond question, prevention of this devastating disease is of utmost importance, and vaccines are very promising. Several COVID-19 vaccines are available globally, but unfortunately, there are areas and populations of people who do not have access to vaccinations [60, 61]. In addition, as with current therapeutic treatments (e.g., anti-virals, monoclonal antibodies, etc.), the existing and future effectiveness of vaccines is a genuine concern given the recurrent mutations already witnessed in the SARS-CoV-2 genome. However, while vaccinations are a mainstay of prevention, *there will always remain a need for efficacious treatment for those who become acutely infected.*

#### **6.1 Final comments**

The results of this novel study should not be ignored. Not to downplay the importance of new treatments and vaccines which have been developed since the start of the COVID-19 Pandemic, unfortunately for the foreseeable future as new variants arise, the proclivity of SARS-CoV-2 to mutate and cause widespread infection and wreckage to the health of individuals and society alike remains a global health concern. The world needs an effective, safe, widely-available, and inexpensive treatment for COVID-19—and inhaled ethanol may well be that needed treatment. Extensive studies are needed to confirm and better define the use of inhaled ethanol in combatting this disease—and other susceptible respiratory viruses (i.e. influenza, etc.). If confirmed, inhaled ethanol has the potential to prevent morbidity, and save lives, healthcare resources, and economies the world over. Extensive research is needed to confirm the findings herein, but the results must not be unheeded.<sup>2</sup>

<sup>2</sup> Addendum: Since this writing, data that suggests the benefits of inhaled ethanol in the treatment of COVID-19 has been published, and supports the findings in this study [62].

#### **Author details**

Steven W. Stogner Hattiesburg Clinic Pulmonary Medicine, Hattiesburg, MS, USA

\*Address all correspondence to: sstogner@forrestgeneral.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Nebulized Ethanol: An Old Treatment for a New Disease DOI: http://dx.doi.org/10.5772/intechopen.111695*

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*Nebulized Ethanol: An Old Treatment for a New Disease DOI: http://dx.doi.org/10.5772/intechopen.111695*

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#### **Chapter 8**
