Empowering Respiratory Therapists to Restrict Nebulized 3% Saline and N-Acetylcysteine During Mechanical Ventilation

Abstract

Background:

We previously implemented a policy that enabled respiratory therapists to reject orders for nebulized 3% hypertonic saline and/or N-acetylcysteine (HTS/NAC) that did not conform to the American Association for Respiratory Care (AARC) Clinical Practice Guideline. Outcomes of adhering to this more conservative approach are not well studied. We sought to determine if an approach conforming to guidelines is noninferior to a previously practiced more liberal approach.

Methods:

We performed a retrospective analysis of 2,272 subjects receiving mechanical ventilation ≥48 h within 5 adult ICUs between June 2020 and August 2023. The primary outcome was ventilator-free days at day 28 (VFD28). Secondary outcomes included ventilator days, ICU days, hospital stay, re-intubation rates, and mortality. Analysis was stratified by before and after policy implementation (see intervention) and by receiving HTS/NAC or not (ϕHTS/NAC). The latter was examined before and after propensity matching. The Δ for noninferiority was −0.5 days for VFD28 and +0.5 days for other continuous variables. As outcomes were not normally distributed, we analyzed them using Mann–Whitney U statistics.

Results:

Two thousand two hundred seventy-two subjects were evaluated. The mean age was 58.70 + 16.13 years and 929 (40.9%) subjects were women. HTS/NAC administration was reduced after policy implementation (40.2% before policy and 8.9% after policy; a reduction of 77.9%). The post-policy group and ϕHTS/NAC before and after propensity matching groups were all noninferior to the comparators. Subjects had significantly more VFD28 in the post-policy group, median (IQR), post 21 (0–25), pre: 20 (0–24), P = .02; and in the ϕHTS/NAC group, before matching ϕHTS/NAC: 21 (0–25), HTS/NAC: 18 (0–23), P < .001 and after propensity matching ϕHTS/NAC: 21 (0–25), HTS/NAC; 18 (0–23), P < .001.

Conclusions:

Restricting practice to conform to the AARC Clinical Practice Guideline was noninferior to more liberal use. The use of HTS/NAC in mechanically ventilated subjects does not appear efficacious and is both costly and time-consuming.

Introduction

We previously published findings from a quality improvement project on de-implementation that resulted in a significant reduction in 3% hypertonic saline and/or N-acetylcysteine (HTS/NAC) nebulizer treatments.¹ A policy empowering respiratory therapists was implemented on October 1, 2021, to make hospital ICU practice consistent with the American Association for Respiratory Care (AARC) Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients.^1,2 The policy enabled respiratory therapists, after discussion with providers, to reject physician and advanced practice practitioner orders for HTS or NAC administration when not consistent with the AARC Clinical Practice Guideline.² This change of practice was associated with an approximately 84% reduction in HTS/NAC use. However, we lacked clinical outcome data, and thus while respiratory therapist effort and healthcare costs were reduced, we could not evaluate the unintended consequences.

HTS and NAC are the most common mucolytics and are used to enhance airway clearance. They are mechanistically different; HTS enhances mucociliary transport by osmotic dilution and airway neuron stimulation, whereas NAC reduces viscosity by dissolving disulfide bonds.^3,4 Clinicians use mucolytic agents in mechanically ventilated patients in hopes to impact ventilator-free days, duration of mechanical ventilation, ICU and hospital stay, as well as reintubations. However, there are relatively sparse outcome data and different findings with differing mucolytic agents.^5–8 We sought to determine if the change to a restrictive HTS/NAC utilization practice conforming to the AARC Clinical Practice Guideline was noninferior in comparison with liberal use.

QUICK LOOK

Current Knowledge

Guidelines for the use of nebulized hypertonic saline (HTS) and/or N-acetylcysteine (NAC) have been established since 2015. Only one study, a multi-centered randomized controlled trial (RCT) has evaluated nebulized NAC alone, and in this study, on-demand use was applied to over 40% of subjects. Another small RCT looking at nebulized HTS in ARDS found lower mortality (HTS 26.7% vs control 70.0%).

What this paper contributes to our knowledge

Our study provides clinical outcome analysis that supports empowering respiratory therapists to assure strict adherence to the AARC Clinical Practice Guideline regarding nebulized HTS and NAC. Clinical outcomes of ventilator-free days, duration of mechanical ventilation, and ICU and hospital stay were noninferior, if not superior, after empowering respiratory therapists and lowering re-intubation rates. Given the reduced work load and cost while achieving as good if not better clinical outcomes, a practice that empowers respiratory therapists is preferred.

Methods

Our study was deemed exempt from review by the Medical College of Wisconsin Institutional Review Board. We included subjects admitted to any of five ICUs at Froedtert Hospital, an academic medical center in Milwaukee, WI. Subjects were included if they were intubated and mechanically ventilated for >48 h. De-identified data were collected before policy implementation from June 1, 2020, through June 30, 2021 (pre) and after policy implementation from October 1, 2021 through August 30, 2023 (post). We did not include data from July 1, 2021 through September 30, 2021 because of ongoing clinician education regarding the AARC Clinical Practice Guideline and the upcoming policy implementation effective October 1, 2021. In this retrospective review using discrete fields within the electronic medical record (Epic, Verona, Wisconsin), we collected demographic variables, chart documented and ICD-10 coded comorbidities associated with the Elixhauser comorbidities (Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project, 2024), Elixhauser mortality score, SARS-CoV-2 virus (COVID) status, use of extracorporeal membrane oxygenation (ECMO), whether HTS/NAC was provided, mechanical ventilation days, reintubations, initial ICU service, in-hospital mortality, ICU stay, and hospital stay. Primary diagnosis and expected mortality were collected from a clinical database (Vizient, Plano, Texas). Data integrity was assessed by an analyst prior to providing blinded data. Our primary outcome of interest was ventilator-free days at day 28 (VFD28). Secondary outcomes included ventilator days, ICU days, hospital stay, re-intubation rates, and in-hospital mortality.

We analyzed the data in three ways; 1) pre versus post policy implementation, 2) received HTS/NAC versus not received (ϕHTS/NAC), and 3) received HTS/NAC versus ϕHTS/NAC after propensity matching (SPSS v29.2.0 IBM, Armonk, New York). Propensity matching was utilized to better account for baseline differences. Using similar methods, we also performed secondary analyses for HTS and NAC separately. We included 124 subjects who received both HTS and NAC, although not concomitantly, during the hospitalization, in both HTS and NAC secondary analyses because HTS and NAC interventions are mechanistically different.^3,4 We also performed secondary analysis of HTS/NAC versus ϕHTS/NAC after excluding subjects with COVID.

We compared baseline characteristics using independent t test for continuous variables and Pearson’s chi-square for categorical variables. Non-normally distributed variables such as VFD28, ventilator days, ICU stay, and hospital stay were analyzed using the Mann–Whitney U test. We used the Hodges–Lehmann estimator to determine median of differences.⁹ We adjudicated noninferiority for VFD28 if the median of differences lower confidence limit (DMLCL) did not cross −0.5 days.¹⁰ For ventilator days, ICU stay, and hospital stay, noninferiority was established if median of differences upper confidence limit (DMUCL) did not cross +0.5 days. Significance was defined with an alpha ≤ 0.05. We chose to apply two-tailed analyses to examine for superiority after noninferiority, “closed testing.”¹¹ Re-intubation rates were measured throughout the hospitalization in two ways; 1) all re-intubations regardless of timing postextubation and 2) all re-intubations within 72 h of an extubation.

To account for differences in ϕHTS/NAC and HTS/NAC groups, we applied propensity matching to adjust for imbalances. Regardless of significance, we included Elixhauser comorbidities and expected mortality, COVID status, pre versus post period, age, gender, race, ethnicity, primary ICD-10 diagnostic category (first letter in ICD-10 code), and initial ICU service in this model. Propensity score was completed using logistic regression with nearest-neighbor matching without replacement. The caliper, which is the maximum difference in propensity scores, was set at 0.2.¹²

Results

There was a significant reduction in HTS and NAC use in the post period for each ICU service and for all ICUs combined. Subjects in the post group, compared with pre, were older, had more neurologic disorders, higher expected mortality, less alcohol use, liver disease, COVID, and lower ECMO use (Table 1). There were also differences in initial ICU service and ICD-10 diagnostic categories. The ϕHTS/NAC group, compared with the HTS/NAC group, had fewer subjects with pulmonary circulatory disorders, weight loss, and lower ECMO use. There were differences in initial ICU service as well. After propensity matching, baseline characteristics were similar in the HTS/NAC and ϕHTS/NAC cohorts. Propensity scores in the two groups show overlap (Fig. 1).

Table 1.

Baseline variables

	All subjects		All subjects		Propensity matched
	Pre	Post	ϕ HTS/NAC	HTS/NAC	ϕ HTS/NAC	HTS/NAC
Subjects	873	1,399	1,796	476	476	476
HTS/NAC ordered %	40.2	8.9***
Age, years	57.7 ± 16.4	59.4 ± 16.0*	59 ± 16.2	58.4 ± 15.9	59.1 ± 14.5	58.4 ± 15.9
Race, ethnicity
Asian	15	27	35	7	9	7
Black, African American, Non-Hispanic	238	350	469	119	115	119
Hispanic	45	77	104	18	27	18
Native American, Hawaiian, Pacific Islander	6	9	12	3	5	3
Subject Refused, Unknown, Other Answer	19	44	51	12	11	12
White, Non-Hispanic	550	892	1125	317	309	317
Female, %	33.0	41.8	41.6	38.2	38.9	38.2
Elixhauser mortality score	0.04 ± 0.07	0.04 ± 0.07	0.04 ± 0.07	0.04 ± 0.07	0.04 ± 0.07	0.04 ± 0.07
Elixhauser chronic comorbidities
AIDS/HIV	6	5	7	4	4	4
Alcohol use disorder	62	60**	98	24	29	24
Anemia/blood loss	7	13	17	3	2	3
Metastatic cancer	21	45	58	8	14	8
Cardiac arrythmias	83	135	173	45	46	45
Chronic pulmonary disease	79	132	164	47	41	47
Coagulopathy	13	23	27	9	9	9
Congestive heart failure	95	174	214	55	43	55
Iron deficiency anemia	28	47	61	14	16	14
Depression	25	27	39	13	12	13
Diabetes: complicated	80	127	162	45	35	45
Diabetes: uncomplicated	79	104	140	43	36	43
Drug abuse	8	21	20	9	8	9
Fluid and electrolyte	71	121	154	38	41	38
Hypertension complicated	95	160	212	43	43	43
Hypertension uncomplicated	54	113	139	28	27	28
Hypothyroidism	19	39	46	12	11	12
Liver disease	104	100***	157	47	54	47
Lymphoma	15	28	32	11	11	11
Obesity	12	34	39	7	8	7
Other neurologic disorder	51	128**	134	45	36	45
Paralysis	19	35	37	17	11	17
Peptic ulcer disease	5	4	8	1	1	1
Peripheral vascular disorder	52	81	102	31	35	31
Psychoses	8	13	18	3	7	3
Pulmonary circulation disorder	38	54	65	27*	15	27
Renal failure	65	99	135	29	32	29
RA or CVD	20	32	41	11	9	11
Solid tumor no metastasis	85	123	163	45	40	45
Valvular disease	33	61	77	17	16	17
Weight loss	13	25	23	15**	8	15
ECMO	72	74**	99	47***	40	47
COVID	127	159*	231	55	56	55
Vizient expected mortality	0.28 ± 0.27	0.32 ± 0.28**	0.31 ± 0.27	0.28 ± 0.27	0.31 ± 0.27	0.28 ± 0.27
Initial ICU service	***		**
Cardiovascular ICU	120	180	222	78	75	78
Medical ICU	344	673	816	201	188	201
Neuroscience ICU	111	202	239	74	71	74
Surgical ICU	176	265	370	71	89	71
Transplant ICU	122	79	149	52	53	52
Individual ICD-10 categories	A–Z	A–Z***	A–Z	A–Z	A–Z	A–Z
ICU service ordering HTS/NAC	***
Cardiovascular ICU	170	10
Medical ICU	589	84
Neuroscience ICU	185	17
Surgical ICU	254	11
Transplant ICU	76	3

Data are shown as n or mean ± SD, unless otherwise noted.

*P < .05, **P < .01, ***P < .001.

HTS/NAC, 3% hypertonic saline/N-acetylcysteine; AIDS/HIV, aquired immunodeficiency syndrome/human immunodeficiency virus; CVD, cardiovascular disease; ECMO, extracorporeal membrane oxygenation; RA, rheumatoid arthritis.

Fig. 1.

Distribution of propensity scores for ϕHTS/NAC and HTS/NAC in a butterfly graph.

Predefined thresholds were not crossed for post versus pre periods, indicating that the restrictive policy with empowered respiratory therapists is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −0.24, 0, and 0.19 days respectively (Table 2). Subjects in the post period had significantly more VFD28 (P = .02), fewer ventilator days (P < .001), and ICU days (P = .050). Re-intubation rates were lower in the post period group (28.8% vs 31.3%, P = .02). Mortality was not different in pre versus post periods (33.4% vs 32.8%, P = .75).

Table 2.

Outcomes

	Time period with respect to policy implementation			POST–PRE
Pre and Post policy	Pre	Post	P value	Median of differences, days	95% CI
Subjects, n	873	1,399
VFD28, median (IQR)	20 (0–24)	21 (0–25)	.01	0	00
Ventilator days, median (IQR)	5.71 (3.4–9.9)	4.75 (2.9–8.6)	<.001	−0.49	−0.76 to −0.24
ICU stay, days, median (IQR)	10.08 (5.9–17.1)	9.6 (5.8–15.5)	.050	−0.54	−1.04 to 0
Hospital stay, days, median (IQR)	18.05 (10.50–30.30)	16.96 (10.0–28.6)	.11	−0.85	−1.90 to 0.19
Re-intubations, %	31.3	28.8	.02
Re-intubations within 72 h, %	19.2	17.9	.80
Mortality, %	33.4	32.8	.75
				Before propensity matching
	Before propensity matching			ϕ HTS/NAC - HTS/NAC
HTS and/or NAC ordered	HTS/NAC	ϕ HTS/NAC	P value	Median of differences, days	95% CI
Subjects, n	476	1,796
VFD28, median (IQR)	18 (0–23)	21 (0–25)	<.001	1	0–2
Ventilator days, median (IQR)	7.69 (4.4–13.3)	4.6 (2.9–7.9)	<.001	−2.42	−2.92 to −1.94
ICU stay, days, median (IQR)	14.46 (8.9–24.7)	8.6 (5.29–14.2)	<.001	−5.21	−6.08 to −4.42
Hospital stay, days, median (IQR)	23.76 (15.4–41.4)	15.6 (9.2–26.4)	<.001	−8.03	−9.45 to −6.64
Re-intubations, %	46.0	25.4	<.001
Re-intubations within 72 h, %	30.5	15.2	<.001
Mortality, %	33.7	30.7	.21
				After propensity matching
	After propensity matching			ϕ HTS/NAC - HTS/NAC
HTS and/or NAC ordered	HTS/NAC	ϕ HTS/NAC	P value	Median of differences, days	95% CI
Subjects, n	476	476
VFD28, median (IQR)	18 (0–23)	21 (0–25)	<.001	1	0–1
Ventilator days, median (IQR)	7.69 (4.35–13.28)	4.66 (2.9–7.8)	<.001	−2.39	−3.04 to −1.80
ICU stay, days, median (IQR)	14.46 (8.93–24.66)	8.79 (5.58–15)	<.001	−4.96	−6.00 to −3.95
Hospital stay, days, median (IQR)	23.76 (15.42–41.36)	23.8 (15.42–41.4)	<.001	−7.74	−9.56 to −5.95
Re-intubations, %	46.0	24.2	<.001
Re-intubations within 72 h, %	30.5	13.3	<.001
Mortality, %	33.7	34.0	.27

VFD28, ventilator days. ICU stay, and hospital stay analyzed by Mann–Whitney U and Hodges–Lehmann tests.

Re-intubations analyzed by Pearson’s chi-square test; within 72 h refers to postextubation.

Before propensity matching, predefined thresholds were not crossed for ϕHTS/NAC versus HTS/NAC groups, indicating that ϕHTS/NAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.94, −4.42, and −6.64 days respectively. Subjects within the ϕHTS/NAC group had significantly more VFD28, fewer ventilator days, fewer ICU days, and shorter hospital stay (P < .001 for all). Re-intubation rates were lower in the ϕHTS/NAC group (25.4% vs 46.0%, P < .001) as were re-intubations within 72 h of extubation (15.2% vs 30.5%, P < .001). Mortality was not different in HTS/NAC and ϕHTS/NAC groups before propensity matching (33.7% vs 30.7%, P = .21).

After propensity matching, predefined thresholds were not crossed for ϕHTS/NAC versus HTS/NAC groups, indicating that ϕHTS/NAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.80, −3.95, and −5.95 days, respectively. In the propensity matched cohort, the ϕHTS/NAC group had significantly more VFD28, fewer ventilator days, fewer ICU days, and shorter hospital stay (P < .001 for all). Re-intubation rates were lower in the ϕHTS/NAC group (24.2% vs 46.0%, P < .001) as were re-intubations within 72 h of extubation (13.3% vs 30.5%, P < .001). Mortality was not different in HTS/NAC and ϕHTS/NAC groups after propensity matching (33.7% vs 34.0%, P = .27).

To examine impact of HTS, we included those who only received HTS and the 124 subjects who received both HTS and NAC during the hospitalization. In the pre versus post policy analysis, the post group was older, had less HTS ordered, greater expected mortality, more neurological disorders, less alcohol use disorder, liver disease, and ECMO use (Supplementary Table S1). There were differences in initial ICU service and ICD-10 diagnostic categories. Before propensity matching, the ϕHTS group had more women, complicated hypertension, a higher expected mortality, less paralysis, weight loss, and ECMO use. There were differences in initial ICU service. After propensity matching, the ϕHTS group had more alcohol use disorder, renal failure, COVID, and less weight loss. There were differences in initial ICU service and ICD-10 diagnostic categories.

Predefined thresholds were not crossed for post versus pre periods, indicating that the restrictive policy with empowered respiratory therapists is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −0.23, −0.04, and −0.11 days, respectively (Supplementary Table S2). Significant differences were seen in re-intubations, pre –31.1% versus post 28.2%, P = .01. No difference was seen in mortality. Before propensity matching, predefined thresholds were not crossed for ϕHTS versus HTS groups, indicating that ϕHTS is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −2.01, −4.96, and −7.54 days, respectively. After propensity matching, predefined thresholds were not crossed for ϕHTS versus HTS groups, indicating that ϕHTS is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.95, −5.00, and −7.52 days, respectively. Significant differences in VFD28, ventilator days, ICU stay, hospital stay, and re-intubations (all and within 72 h of extubation) were noted for ϕHTS before and after propensity matching (P < .001 for all). Mortality was significantly lower in the HTS group before propensity matching (27.9% vs 33.7%, P = .034) but not after (27.9% vs 33.1%, P = .14).

To examine the impact of NAC, we included those who only received NAC and the 124 subjects who received both HTS and NAC during the hospitalization. In the pre versus post policy analysis, the post group was older, had less NAC ordered, greater expected mortality, more neurological disorders, less alcohol use disorder, liver disease, COVID, and ECMO use (e Supplementary Table S3). There were differences in initial ICU service and ICD-10 diagnostic categories. Before propensity matching, the ϕNAC group had less paralysis, weight loss, and ECMO use. Initial ICU service and ICD-10 diagnostic codes differed between NAC and ϕNAC groups. After propensity matching, the ϕNAC group had more alcohol use disorder and liver disease and less neurologic disorders and paralysis. Initial ICU service and ICD-10 diagnostic codes differed between ϕNAC and NAC groups.

Predefined thresholds were not crossed for VFD28 and ventilator days for post versus pre periods, indicating that the restrictive policy with empowered respiratory therapists is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days was 0.10. The DMUCL for ICU and hospital stay were 0.62 and 1.39 days, respectively (Supplementary Table S4). No differences in re-intubations or mortality were seen between pre and post groups. Before propensity matching, predefined thresholds were not crossed for ϕNAC versus NAC groups, indicating that ϕNAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.99, −4.42, and −6.26 days, respectively. After propensity matching, predefined thresholds were not crossed for ϕNAC versus NAC groups, indicating that ϕNAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.74, −3.95, and −0.31 days, respectively. Significant differences in VFD28, ventilator days, ICU stay, hospital stay, and re-intubations (all and within 72 h of extubation) were noted for ϕNAC before and after propensity matching (P < .001 for all except P = .01 for hospital stay). Mortality was not different in NAC and ϕNAC groups before or after propensity matching.

After excluding subjects with COVID, those in the post period were older, had a higher expected mortality and more neurologic disorders and less alcohol use disorder and liver disease (Supplementary Table S5). There were differences in initial ICU service and ICD-10 diagnostic categories. Before propensity matching, the ϕHTS/NAC group had less weight loss. Initial ICU service differed between HTS/NAC and ϕHTS/NAC groups. After propensity matching, ϕHTS/NAC group had more alcohol use disorder and less neurologic disorders and weight loss. Initial ICU service and ICD-10 diagnostic categories differed between HTS/NAC and ϕHTS/NAC groups.

Predefined thresholds, in subjects without COVID, were not crossed for post versus pre periods, indicating that the restrictive policy with empowered respiratory therapists is noninferior; DMLCL for VFD28 was 0 days and the DMUCLs for ventilator days, ICU stay, and hospital stay were −0.18, 0.21, and 0.42 days, respectively (Supplementary Table S6). Significant difference was noted for ventilator days for the post group. Before propensity matching, predefined thresholds were not crossed for ϕHTS/NAC versus HTS/NAC groups, indicating that ϕHTS/NAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCLs for ventilator days, ICU stay, and hospital stay were −1.85, −4.08, and −5.97 days, respectively. After propensity matching, predefined thresholds were not crossed for ϕHTS/NAC versus HTS/NAC groups, indicating that ϕHTS/NAC is noninferior; DMLCL for VFD28 was 0 days and the DMUCL for ventilator days, ICU stay, and hospital stay were −1.70, −3.63, and −5.34 days, respectively. Significant differences in VFD28, ventilator days, ICU stay, and hospital stay (all re-intubations and re-intubations within 72 h of extubation) were noted for ϕHTS/NAC before and after propensity matching (P < .001 for all). The post group had significantly less ventilator days (P < .001). Mortality was not different in pre and post periods or HTS/NAC and ϕHTS/NAC groups before or after propensity matching.

Discussion

The results of our study demonstrate that restricting use of HTS and NAC by empowering respiratory therapists to strictly adhere to the AARC Clinical Practice Guidelines results in similar if not better clinical outcomes, while reducing cost and respiratory therapist work load. Our findings suggest superiority, but we choose to term this restrictive practice as the “preferred approach,” as a nonrandomized study has some limitations that we outline below. It is worth noting that should HTS/NAC be beneficial, then having only 8.9% receive in the post and 40.2% in pre groups would argue against finding noninferiority or superiority.

Clinician use of nebulized mucolytics is variable and limited data exist regarding outcomes in intubated subjects. Most data on NAC are via intravenous administration. In a randomized controlled trial (RCT), Van Meenen et al found that on-demand use of NAC nebulization was noninferior in comparison with routine use but not superior.⁹ In this study, use of NAC fell from 99% of subjects to 41%; still a substantial number of patients receiving NAC.⁹ Masoompour et al studied 40 mechanically ventilated subjects in an RCT of nebulized NAC versus nebulized normal saline and did not find differences in airway pressures or mortality.⁵ Sharafkhah et al, in an RCT of 60 subjects, found oral NAC reduced ventilator-associated pneumonia, ICU and hospital stay, but not duration of mechanical ventilation.⁸ Zaytoun et al examined nebulized HTS compared with no intervention in an RCT of 60 subjects with ARDS.⁷ They found a reduced mortality in the HTS group versus control (26.7% vs 70%) and reduced mechanical ventilation days and ICU stay.⁷

Our study is broader than that of van Meenen et al, as we included HTS as well as NAC and our comparator group was the use of these agents when meeting the AARC Clinical Practice Guideline.^2,9 As compared with van Meenen et al, our study had much lower use of HTS/NAC in both arms and greater reduction between arms (HTS/NAC vs ϕHTS/NAC).⁹ Unlike Zaytoun, who studied HTS in ARDS, we did not find a difference in the mortality after propensity matching, nor in the duration of mechanical ventilation.⁷ Of note, the control group in the Zaytoun study had a high mortality rate (70%).⁷ Our study was not limited to ARDS and was restrictive on whom HTS, or NAC, could be given to. An RCT of on-demand HTS/NAC versus indicated by AARC Clinical Practice Guideline would be stronger than our retrospective study and enhance the work of van Meenen et al by determining the efficacy, or lack thereof, of HTS/NAC in mechanically ventilated subjects lacking an indication as established in the AARC Clinical Practice Guideline.^2,9 An additional arm could include oral NAC, as Sharafkhah did find reduced ventilator-associated pneumonia, ICU and hospital stay, but not duration of mechanical ventilation.⁸ Subset analysis of HTS from an RCT would also allow for better assessment of mortality differences. Findings could substantially impact the extent of which HTS/NAC is used, cost, and respiratory therapist work load.

As noted in our previous publication, the success of restricting use of nebulized HTS/NAC was dependent upon empowering respiratory therapists.¹ After communicating with the physician or advanced practice practitioner, the respiratory therapist cancelled orders for clinical diagnoses not outlined as indications in the AARC Clinical Practice Guideline. This empowerment was critical to success, as we had respiratory therapists as champions who already bought into the guideline, thereby eliminating clinician biases from individual cases in ordering HTS/NAC. The communication between respiratory therapists and clinicians also was important as it helped address the endowment effect, clinicians losing full control over ordering HTS/NAC.¹³

Our study has important limitations. It is a retrospective analysis of an intervention at a single center and not a multi-center RCT. An RCT would provide much greater strength in concluding both noninferiority and/or superiority of ϕHTS/NAC. Van Meenen et al conducted an RCT of on-demand versus routine use of nebulized NAC alone and found no differences in VFD28 between the two arms and but noted more tachyarrhythmias and agitation in the routine use arm.⁹ They used one-sided analysis with a confidence interval [CI] at 90th percentile and the VFD28 Δ was set at −0.5, which was 10% of the projected ventilator days. Their population excluded patients ventilated <24 h, and our study excluded patients ventilated <48 h, however we adopted their Δ as it was reasonable and likely to be accepted by clinicians. We also chose a two-sided analysis with confidence intervals at 5th and 95th percentile. Van Meenen et al showed reduced ICU and hospital stay with the on-demand group and no difference in mortality.⁹ We also have similar findings, including mortality.

Despite efforts to account for baseline imbalances, we cannot exclude selection bias as a reason for our findings. We do not have any data on the degree of mucus production nor the consistency of mucus, which would have been useful for propensity matching. It is likely that mucus production and consistency impacts most ordering providers’ decision to use HTS/NAC, although one subservice did have HTS/NAC orders in the admission order set. Other factors influencing outcomes could be temporal differences in care, such as evolution in care for subjects with COVID, however we did include time frame and COVID status in propensity matching. We also analyzed the data excluding subjects with COVID and found results consistent with our primary analysis. We are missing other factors, such as precise primary diagnosis, endotracheal tube size, appropriateness of therapies, use of HTS/NAC during bronchoscopy (we restricted only nebulization usage), and more. Given these limitations, we chose to limit our interpretation to ϕHTS/NAC being noninferior to HTS/NAC. When analyzing HTS and NAC separately, we found results consistent with our primary analysis. However, imbalances between comparator groups existed and all were not resolved after propensity matching.

Conclusions

The previously published findings indicate that implementing a policy empowering respiratory therapists to promote adherence to AARC Clinical Practice Guidelines reduced low-value therapies, costs, and staffing needs, leading to a significant decrease in the use of HTS and NAC nebulizer treatments.¹ Our retrospective study demonstrates noninferiority when empowering respiratory therapists to accept or reject HTS and NAC orders based on these guidelines. However, an RCT would be needed to assess the efficacy, or lack thereof, of HTS and NAC when used outside the AARC guidelines.

Author Disclosure Statement

Jonathon D. Truwit: DSMB Chair for NIH study - GRAIL-3. Kellianne Fleming: Aerogen, Galway Ireland; Fisher & Paykel Healthcare, Auckland, New Zealand; Airlife, Grand Rapids, MI (Medical Advisory Board Member); Monaghan Medical, Plattsburgh, NY. Rahul S. Nanchal: REPAVID (NCT05254990), Dompé farmaceutici, Italy; RESPIRATIO (NCT05496868), Dompé farmaceutici, Italy; VitaSIRO soloTM (NCT06689423), Credo Diagnostics Biomedical, Taiwan; JUST BREATHE (NCT06703073), PPD, BARDA; VIRUS (NCT04323787), Society of Critical Care Medicine; TiMal: Time and Motion albumin, Takeda.

Funding Information

No funding was received for this article.

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