key: cord-0769660-gqnle7ar
authors: Schloss, Janet; Leach, Matthew; Brown, Danielle; Hannan, Nicole; Kendall-Reed, Penny; Steel, Amie
title: The effects of N-acetyl cysteine on acute viral respiratory infections in humans: A rapid review
date: 2020-08-03
journal: Adv Integr Med
DOI: 10.1016/j.aimed.2020.07.006
sha: 9514e50a84f80117dbbd865222051d7ee589009b
doc_id: 769660
cord_uid: gqnle7ar

nan

The risk of bias (RoB) of study findings was assessed using the revised Cochrane RoB tool for randomised trials (RoB 2) https://sites.google.com/site/riskofbiastool/welcome/rob-2-0tool/current-version-of-rob-2?authuser=0.

The search identified 640 citations. Seven duplicates were removed leaving 633 citations to be screened. After title and abstract reviews, 91 citations were left with 76 citations further excluded as they didn't meet the inclusion and exclusion criteria [wrong patient population = 48, wrong study design = 13, wrong intervention = 7, paediatric population = 6, wrong comparator = 1 and wrong outcome = 1]. The remaining 13 articles were included in this rapid review.

All but two studies were identified as randomised controlled trials (RCTs). The two non-RCTs comprised of a case report [1] and a controlled clinical trial [2] . Eight of the 13 (61.5%) included trials were placebo-controlled [3] [4] [5] [6] [7] [8] [9] [10] , and 6/13 (46.1%) were double-blinded [3, 5-7, 9, 10] .

Studies were conducted across five of six World Health Organisation (WHO) regions, with most undertaken in the European region (6/13 [46.2%] [4, 6, 7, [10] [11] [12] ), followed by the Eastern Mediterranean (3/13 [23.0%]; [2, 8, 9] ), Americas (2/13 [15.4%]; [3, 5] ), South East Asia (1/13 [7.7%];

[1]) and Western Pacific (1/13 [7.7%]; [13] ) regions. All studies were conducted in a hospital setting, and all but two [1, 13] were reportedly undertaken in an intensive care unit.

The 13 included studies comprised a total pool of 1,337 subjects, with study sample sizes ranging from 1 to 842 (median 42). All subjects had an acute respiratory condition, with diagnoses including ALI/ARDS (7/13 [53.9%]; [2-4, 6-8, 10] ) or pneumonia (2/13 [15.4%] ; [1, 13] ). Four studies (30.8%) did not define the respiratory disorder [5, 9, 11, 12] .

N-Acetyl Cysteine (NAC) was predominantly administered intravenously (10/13 [76.9%] ; 40-480 mg/kg/day or 400 mg TDS via intravenous infusion; [1-8, 10, 11] ), and to a lesser extent, as an oral tablet (2/13 [15.4%]; 600 mg BD; [9, 13] ) or via nebuliser (1/13 [7.7%]; 300 mg QID or on demand; [12] ). Control interventions included 5% dextrose in water (3/13 [23.1%] ; [3, 8, 11] ), saline (2/13 [15.4%]; [4, 7] ), water-soluble vitamin tablets (1/13 [7.7%]; [9] ), conventional treatment only (1/13 [7.7%] ; [13] ), and non-specified placebo (3/13 [23.1%] ; [5, 6, 10] ). The duration of treatment ranged from 3 to 28 days, with a median period of 3 days.

In the first Domain (randomisation process), two studies were rated as high risk of bias [1, 4] with all other studies rated as low. For Domain 2 (treatment assignment), one trial was identified as high risk of bias [6] , with seven trials rated as low [2-5, 9, 12] . Under Domain 3 (missing outcome data), two trials were considered to have high risk of bias [6, 7] , with eight trials rated as low [3-5, 8, 10, 12, 13] .

For Domain 4 (measure of outcomes), all trials were rated as low risk of bias, except Lai et al. [1] , which was assessed as having some concerns. In Domain 5 (selective reporting), one trial [11] was identified as high risk of bias, with the remaining trials rated as having some concerns or low risk of bias. Overall, five studies were judged as having high risk of bias [1, 4, 6, 7, 11] , six rated as having some concerns [2, 5, [8] [9] [10] 13] and two judged as low risk of bias [3, 12] . These judgements should be taken into consideration when interpreting the findings of this review.

The 13 included studies reported on nine broad outcomes: markers of inflammation and oxidation, changes in CT or x-ray images, patient length of stay, mortality rate, pulmonary complications, ventilation-related issues, recovery rate, clinical improvement and adverse events.

Four RCTs [3, 7, 11, 13] reported changes in markers of inflammation or oxidation. These studies reported significant improvements in GSH, tumour necrosis factor -α (TNF-α), malondialdehyde, total thioles, lipoperoxidation, total antioxidant power and polymorphonuclear cell activity following NAC administration when compared to controls. These findings were consistent with those reported in the two non-RCTs [1, 2]). No differences between groups were reported for superoxide dismutase and elastase.

Changes in CT or x-ray images were measured in two RCTs [6, 13] . Both studies found no differences in this outcome between NAC and control.

Three RCTs [5, 9, 12] assessed patient length of stay. Although one RCT [9] reported a significant reduction in ICU and hospital length of stay in the NAC group versus control, two studies [5, 12] found no differences between groups in patient length of stay.

Mortality rate was measured in six RCTs [3-5, 8, 10, 12] . Four studies [3, 5, 10, 12] reported no differences in mortality rates between NAC and control. The remaining studies reported conflicting results, with one RCT [8] revealing a reduction in the rate of mortality following NAC administration (relative to control), and the other RCT [4] reporting an increase in mortality rate with NAC administration.

Three RCTs [9, 10, 12] examined the efficacy of NAC in preventing pulmonary complications. When compared to control, NAC administration was associated with a significant reduction in ventilatorassociated pneumonia and time to ventilator-associated pneumonia in 1 RCT [9] . However, in two RCTs [10, 12] , no difference was found between groups in the prevalence of pulmonary complications.

Ventilation-related issues were reported as an outcome in four RCTs [4, 5, 8, 10] . NAC administration was associated with improvements in systemic oxygenation in two [8, 10] of 3 RCTs, and a reduction in the need for / duration of ventilation in two [5, 10] of three RCTs.

J o u r n a l P r e -p r o o f Four RCTs [3, 6, 9, 11] and one case report [1] examined recovery rate following NAC administration.

All but one study [6] reported a significant improvement in the rate of recovery from an acute respiratory condition with NAC administration when compared with control.

Clinical improvement was assessed in one controlled clinical trial [2] . The authors indicated that NAC administration was associated with an improvement in Acute Physiology and Chronic Health Evaluation (APACHE II) score -a measure of clinical improvement and a predictor of mortality risk.

Adverse event monitoring was reported in three RCTs [6, 9, 13] . Two studies [9, 13] reported no adverse events with NAC administration, and 1 [6] reported a rash during the administration of a loading dose of NAC.

From the evidence identified in this review, it is recommended that NAC could be used for people who have contracted Covid-19. At early stages of the disease, health practitioners could recommend oral NAC [600 mg BD] to assist in reducing respiratory mucus and inflammation, increasing systemic GSH levels and possibly averting hospital admission. As only three trials assessed the oral administration of NAC, and there were some concerns with the risk of bias of these studies, these suggestions need to be considered with caution until conclusive evidence becomes available. If health professionals have access and ability to administer NAC via nebuliser or IV, the review findings suggest that doses of NAC ranging from 40-480 mg/kg/day for at least 3 days may be suitable for patients who are deteriorating. Again, as two of the ten studies on IV administration of NAC were rated as high risk of bias, patients who are administered NAC intravenously need to be monitored closely.

Health practitioners are advised that these recommendations should complement, and not replace, standard medical care, and if required, the patient is recommended to obtain emergency care where needed. 

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