Skip to main content
NCBI home page
Health Science Reports logoLink to Health Science Reports
. 2026 Oct 5;9(10):e73334. doi: 10.1002/hsr2.73334

Inhaled Heparin to Shorten Antibiotic Duration in Ventilator‐Associated Pneumonia: A Randomized Double‐Blind Controlled Trial

Anoush Dehnadi Moghadam 1,✉, Mostafa Saeedinia 1, Fatemeh Dehnadi Moghadam 2
PMCID: PMC13635806  PMID: 42835754

ABSTRACT

Background and Aims

Prolonged antibiotic therapy in ventilator‐associated pneumonia (VAP) contributes to antimicrobial resistance. Inhaled heparin has pleiotropic anti‐inflammatory and mucolytic properties. This trial evaluated whether adjunctive nebulized heparin reduces antibiotic duration in VAP using a procalcitonin (PCT)‐guided discontinuation algorithm.

Methods

In this single‐center, double‐blind, randomized controlled trial, 82 mechanically ventilated adults with VAP (CPIS ≥ 6) were assigned to standard care plus nebulized heparin (10,000 IU every 6 h) or placebo (sterile distilled water). Both groups followed a PCT‐guided antibiotic discontinuation algorithm (≤ 0.2 µg/L or ≥ 90% reduction from peak, plus clinical stability). Primary outcome: antibiotic duration (days). Secondary outcomes: duration of mechanical ventilation, ICU/hospital length of stay (LOS), serial CPIS, CRP, PCT, SOFA, APACHE II, adverse events, and 28‐day mortality rate.

Results

Antibiotic duration was significantly shorter with heparin (mean difference −3.2 days; 95% CI: −4.8 to −1.6; p < 0.001). Baseline characteristics were similar except for higher mean APACHE II in the control group (18.8 vs. 15.2). After adjusting for baseline APACHE II imbalance, the treatment effect remained significant (adjusted mean difference −2.9 days; 95% CI: −4.5 to −1.3; p = 0.001). Heparin also reduced duration of mechanical ventilation (mean difference −1.47 days; p = 0.01), ICU LOS (− 3.5 days; p = 0.02), and hospital LOS (− 4.1 days; p = 0.01). CPIS and CRP improved more rapidly in the heparin group (group×time interaction p < 0.05). No major bleeding or heparin‐related adverse events occurred.

Conclusion

Adjunctive nebulized heparin (40,000 IU/day) significantly shortens antibiotic duration and improves clinical recovery in VAP without increasing adverse events. However, given the single‐center design and modest sample size, our results require confirmation in future multicenter trials with optimum heparin doses and comprehensive biomarker panels to better elucidate the mechanisms of action and establish the definitive role of inhaled heparin in antimicrobial stewardship.

Keywords: antibiotic stewardship, critical care, inhaled heparin, procalcitonin‐guided therapy, ventilator‐associated pneumonia

1. Introduction

Ventilator‐associated pneumonia (VAP) is a common and serious nosocomial infection that develops more than 48 h after endotracheal intubation and mechanical ventilation [1, 2]. Crude mortality rates for VAP range from 30% to 70%, but attributable mortality is estimated at approximately 13% [3]. VAP remains a major contributor to intensive care unit (ICU) morbidity, mortality, and healthcare costs [4, 5]. It accounts for nearly half of all antibiotic use in the ICU [6], thereby driving the emergence of multidrug‐resistant (MDR) organisms [7].

The pathogenesis of VAP involves both bacterial invasion and a dysregulated host inflammatory response in the lungs [8]. Activation of coagulation pathways and intra‐alveolar fibrin deposition impair gas exchange and create a scaffold for bacterial proliferation [9, 10]. According to the 2016 ATS/IDSA guidelines, the optimal duration of antibiotic therapy for VAP is 7 days in immunocompetent patients [11]. The European Respiratory Society guidelines similarly recommend a 7–8‐day course, although this is a weak recommendation based on moderate‐quality of evidence [12]. While antibiotics are the cornerstone of therapy, their prolonged use fuels resistance. Thus, adjunctive strategies that target the underlying inflammatory and coagulopathic mechanisms, rather than bacteria alone, are urgently needed.

Heparin is a widely used anticoagulant with pleiotropic effects beyond coagulation. When delivered via inhalation, heparin achieves high local concentrations in the alveoli. In addition to anticoagulation, it exerts anti‐inflammatory activity, inhibits neutrophil elastase, suppresses pro‐inflammatory cytokines, and neutralizes mediators such as HMGB1 [13, 14]. It also has mucolytic properties, improving mucus clearance and disrupting biofilms [15, 16]. Preclinical studies have shown that nebulized heparin reduces lung injury and enhances bacterial clearance [17]. Early clinical studies reported improvements in lung compliance and ventilator outcomes, although results have been inconsistent [18, 19]. More recently, a large individual patient data meta‐analysis of six randomized trials found that inhaled heparin significantly reduced intubation risk and mortality [20]. Additionally, a multicenter phase 3 trial reported no benefit on ventilator‐free days in acute respiratory distress syndrome but noted improved oxygenation and reduced pulmonary coagulopathy [21].

A major strategy to reduce antibiotic exposure in critically ill patients is biomarker‐guided therapy. Procalcitonin (PCT) has emerged as a reliable biomarker to differentiate bacterial from non‐bacterial inflammation and to support early antibiotic discontinuation [22, 23]. PCT‐based protocols have been shown to reduce antibiotic use safely in respiratory infections, including VAP [24].

Given the rising global challenge of antimicrobial resistance and the unmet need for adjunctive therapies, inhaled heparin represents a promising candidate. By modulating pulmonary coagulation and inflammation, it may accelerate clinical resolution of VAP and enable earlier cessation of antibiotics. This study therefore aimed to investigate the effect of adjunctive nebulized heparin on the duration of antibiotic therapy in VAP patients, using a PCT‐guided discontinuation strategy.

2. Methods

2.1. Study Design and Participants

This trial followed the CONSORT 2010 guidelines. The CONSORT checklist and flow diagram are provided as Supplementary Materials (Figure S1 and Table S1).

This single‐center, randomized, double‐blind, placebo‐controlled clinical trial was conducted in the intensive care units (ICUs) of Razi and Poursina Hospitals between June and August 2019. The study protocol was approved by the Ethics Committee of Guilan University of Medical Sciences and registered with the Iranian Registry of Clinical Trials (IRCT20140310016917N8). Written informed consent was obtained from the legal guardians of all participants prior to enrollment.

Eligible patients were adults (≥ 18 years) who had been mechanically ventilated for more than 48 h and developed suspected ventilator‐associated pneumonia (VAP), determined by clinical and bacteriologic cultures. The clinical pulmonary infection score (CPIS) ≥ 6 with a good correlation (r = 0.84, p < 0.0001) between clinical score and quantitative bacteriology was used to diagnose VAP [11].

Exclusion criteria included: active bleeding or coagulopathy, known heparin allergy or heparin‐induced thrombocytopenia, therapeutic anticoagulation, recent intracranial hemorrhage, immunosuppression, and morbid obesity (BMI > 40 kg/m2). Immunosuppression (e.g., chemotherapy, neutropenia, chronic steroids consumption > 20 mg/day prednisone equivalent) was excluded because it may alter inflammatory and coagulation responses, confounding the assessment of heparin's effects. Morbid obesity (BMI > 40 kg/m2) was excluded due to altered drug distribution and increased risk of atelectasis, which could affect CPIS interpretation.

2.2. Randomization and Blinding

Eligible patients were randomly assigned (1:1) to either the intervention group (standard care + nebulized heparin sodium, 10,000 IU in 10 mL sterile distilled water every 6 h) or the control group (standard care + nebulized placebo, 10 mL sterile distilled water every 6 h). Sterile distilled water was used as the diluent and placebo to avoid potential pharmacologic effects of saline (e.g., bronchoconstriction or alteration of heparin binding). While hypotonic solutions can theoretically provoke cough, we observed no difference in cough frequency between groups (see Results). This choice follows prior studies of nebulized heparin in critically ill patients [14]. Unfractionated heparin sodium (Darou Pakhsh Pharma, Tehran, Iran) was used. Each dose (10,000 IU, equivalent to 2 mL of the 5000 IU/mL solution) was diluted in 10 mL sterile distilled water immediately before nebulization. Nebulization was performed using a jet nebulizer (Boya Medical, China) placed in the inspiratory limb of the ventilator circuit. Each session lasted approximately 15–20 min. Randomization was computer‐generated, and allocation concealment was maintained using sequentially numbered, sealed opaque envelopes. Patients, investigators, and care providers were blinded to treatment assignments throughout the study.

2.3. Standard Care and Data Collection

All patients received empirical antibiotic therapy according to the 2016 ATS/IDSA guidelines [11], adjusted based on local antibiograms and the results of semi‐quantitative endotracheal cultures obtained by mini‐bronchoalveolar lavage (mini‐BAL). Therapy was de‐escalated or modified once pathogen identification and susceptibilities were available.

Clinical and laboratory data including temperature, white blood cell (WBC) count, PaO2/FiO2 ratio, and chest radiographic findings were recorded daily for up to 14 days. Serum procalcitonin (PCT), C‐reactive protein (CRP), and clinical scores (CPIS, SOFA, and APACHE II) were measured at baseline and then every 48 h.

2.4. Antibiotic Discontinuation Policy

Both groups were managed with an identical PCT‐guided antibiotic discontinuation protocol. Serum PCT was measured every 48 h in all patients, and the results were used to guide antibiotic discontinuation decisions in both groups.

Antibiotics were discontinued when the PCT level decreased to ≤ 0.2 µg/L or showed a ≥ 90% reduction from its peak value, provided that clinical stability was achieved (temperature ≤ 38.3°C, WBC count < 10,000/µL or ≥ 25% decrease from peak value, improvement or no progression on chest X‐ray, absence of purulent secretions, and PaO2/FiO2 ratio > 250). This approach was adapted from the PRORATA trial [22] and similar ICU‐based protocols [23, 24]. The complete algorithm is shown in Supplementary Figure S2.

The intervention group received nebulized heparin (10,000 IU every 6 h), while the control group received nebulized placebo (sterile distilled water). All other aspects of care, including the PCT‐guided discontinuation protocol, were identical between groups.

2.5. Outcomes

The primary outcome was the duration (in days) of antibiotic therapy from initiation to final discontinuation. Secondary outcomes included duration of mechanical ventilation, ICU and hospital length of stay, and serial changes in CPIS, SOFA, APACHE II, CRP, and PCT over the 14‐day observation period.

2.6. Statistical Analysis

Continuous variables were first tested for normality using the Shapiro–Wilk test. Normally distributed data are presented as mean ± SD; non‐normally distributed data as median (IQR). Between‐group comparisons used independent‐samples t‐test (or Mann–Whitney U test). Categorical variables are reported as n (%) and compared using chi‐square or Fisher's exact test. For the primary outcome (antibiotic duration), we report the mean difference with 95% confidence interval (CI) and Cohen's *d* effect size. Secondary outcomes (duration of mechanical ventilation, ICU/hospital LOS) are similarly reported with mean differences and 95% CIs.

Given the significant baseline difference in APACHE II scores between groups (mean 15.2 [heparin] vs. 18.8 [placebo], p = 0.02), we performed a post‐hoc sensitivity analysis adjusting for baseline APACHE II using analysis of covariance (ANCOVA) to evaluate the robustness of the primary treatment effect. Results are reported as adjusted mean difference with 95% CI and p‐value. Additionally, we stratified the primary outcome analysis by APACHE II quartile to assess consistency of treatment effects across severity strata.

Longitudinal data (CPIS, CRP, PCT, SOFA, APACHE II) were analyzed using repeated‐measures ANOVA with Greenhouse–Geisser correction for sphericity. We report the main effect of time, the group × time interaction, and partial η2 effect sizes. All hypothesis tests were two‐sided with a prespecified alpha level of 0.05. p‐values are reported as: p < 0.001; for 0.001–0.01 to three decimal places; for 0.01–0.99 to two decimal places; p > 0.99 as such.

Analyses were performed using IBM SPSS Statistics version 26 (IBM Corp., Armonk, NY, USA).

The primary outcome (antibiotic duration) and all secondary outcomes listed in the outcome's subsection was prespecified. No subgroup analysis was performed apart from the post‐hoc APACHE II sensitivity analysis. Secondary outcomes were considered exploratory, and thus no adjustment for multiple comparisons was made.

3. Result

3.1. Participant Flow and Baseline Characteristics

A total of 98 mechanically ventilated patients were screened for eligibility. Of these, 16 were excluded: 10 did not meet CPIS ≥ 6 criteria (including 4 with negative mini‐BAL cultures), 4 had exclusion criteria (2 with coagulopathy, 1 with immunosuppression, 1 with BMI > 40 kg/m2), and 2 declined consent. The remaining 82 patients were randomized equally to the heparin group (n = 41) or placebo group (n = 41). All 82 completed the 14‐day observation period, and no patients were lost to follow‐up (Supplementary Figure S1).

Baseline demographic and clinical characteristics were generally well balanced between the two groups, except for a higher mean APACHE II score in the placebo group (Table 1).

Table 1.

Baseline demographic and clinical characteristics.

Variable Heparin (n = 41) Placebo (n = 41) p‐value
Age, years, mean ± SD 58.4 ± 14.2 60.1 ± 13.7 0.58
Male, n (%) 26 (63.4) 24 (58.5) 0.65
BMI, kg/m2, mean ± SD 27.3 ± 5.1 28.0 ± 4.9 0.52
Admission category, n (%) 0.71
– Medical 22 (53.7) 24 (58.5)
– Surgical 12 (29.3) 9 (22.0)
– Trauma 7 (17.1) 8 (19.5)
APACHE II at enrollment, mean ± SD 15.2 ± 6.8 18.8 ± 1.5 0.02
SOFA at enrollment, mean ± SD 7.1 ± 1.4 6.9 ± 2.2 0.63
CPIS at enrollment, mean ± SD 7.2 ± 1.6 6.4 ± 2.0 0.08
PCT at enrollment, µg/L, median (IQR) 2.3 (0.9–9.6) 2.0 (0.8–5.8) 0.41
CRP at enrollment, mg/L, mean ± SD 49.6 ± 28.7 47.7 ± 29.8 0.77
Open in a new tab

3.2. Primary Outcome

The mean duration of antibiotic therapy was significantly shorter in the heparin group (8.1 days, SD = 2.7) compared with the placebo group (11.3 days, SD = 3.1). The mean difference was −3.2 days (95% confidence interval [CI]: −4.8 to −1.6; Cohen's *d* = −1.09; p < 0.001).

Given the significant baseline difference in APACHE II scores between groups (mean 15.2 [heparin] vs. 18.8 [placebo], p = 0.02), we performed a post‐hoc sensitivity analysis adjusting for baseline APACHE II using analysis of covariance (ANCOVA). After adjusting for baseline APACHE II, the intervention effect on antibiotic duration remained significant (adjusted mean difference −2.9 days; 95% CI: −4.5 to −1.3; p = 0.001), confirming the robustness of our primary finding. Additionally, we stratified the analysis by APACHE II quartile and found consistent effects across severity strata (interaction p = 0.41).

3.3. Secondary Outcomes

duration of mechanical ventilation, length of stay, and mortality. Patients receiving heparin had a significantly shorter duration of mechanical ventilation (mean difference −1.47 days; 95% CI: +0.7 to +5.1; p = 0.01), shorter ICU length of stay (mean difference −3.5 days; 95% CI: −6.2 to −0.8; p = 0.02), and shorter hospital length of stay (mean difference −4.1 days; 95% CI: −7.0 to −1.2; p = 0.01). The 28‐day mortality rate was 9.8% (4/41) in the heparin group versus 12.2% (5/41) in the placebo group (p = 0.72).

3.4. Longitudinal Clinical and Laboratory Indices

Serial measurements of CPIS, CRP, PCT, APACHE II, and SOFA were recorded daily for 14 days. Detailed daily values are presented in supplementary Tables S2–S6. Both groups showed progressive improvement, but the heparin group demonstrated a more rapid decline in CPIS and CRP. Repeated‐measures ANOVA revealed a significant main effect of time (p < 0.001 for both CPIS and CRP) and a significant group × time interaction for CPIS (p = 0.02, partial η2 = 0.11) and CRP (p = 0.02, partial η2 = 0.10), indicating faster resolution in the heparin group. For PCT, the main effect of time was significant (p < 0.001) but the group × time interaction was not (p = 0.34). APACHE II and SOFA scores improved over time without significant between‐group differences (interaction p> 0.05 for both). Figures 1, 2, 3, 4, 5 illustrate the trends for CRP, PCT, CPIS, APACHE II, and SOFA, respectively.

Figure 1.

Figure 1

Open in a new tab

C‐reactive protein (CRP) trajectory over 14 days. Data are mean ± SD. Heparin group (n = 41) shown as blue circles, placebo group (n = 41) as red squares. Repeated‐measures ANOVA showed a significant main effect of time (p < 0.001, partial η2 = 0.62) and a significant group × time interaction (p = 0.02, partial η2 = 0.10), indicating faster CRP decline in the heparin group. The shaded area indicates the period when most patients completed antibiotic treatment (days 6–10).

Figure 2.

Figure 2

Open in a new tab

Procalcitonin (PCT) trajectory over 14 days. Data are mean ± SD. Heparin group (blue circles), placebo group (red squares). Repeated‐measures ANOVA showed a significant main effect of time (p < 0.001) but no significant group × time interaction (p = 0.34). The median time to reach PCT ≤ 0.2 µg/L was 6 days (heparin) versus 9 days (placebo), p = 0.01 (see Results).

Figure 3.

Figure 3

Open in a new tab

Clinical Pulmonary Infection Score (CPIS) trajectory over 14 days. Data are mean ± SD. Heparin group (blue circles), placebo group (red squares). Repeated‐measures ANOVA showed a significant main effect of time (p < 0.001) and a significant group × time interaction (p = 0.02, partial η2 = 0.11), indicating faster clinical improvement with heparin.

Figure 4.

Figure 4

Open in a new tab

APACHE II score trajectory over 14 days. Data are mean ± SD. Heparin group (blue circles), placebo group (red squares). Repeated‐measures ANOVA showed a significant main effect of time (p < 0.001) but no significant group × time interaction (p = 0.18), indicating similar improvement in both groups.

Figure 5.

Figure 5

Open in a new tab

Sequential Organ Failure Assessment (SOFA) score trajectory over 14 days. Data are mean ± SD. Heparin group (blue circles), placebo group (red squares). Repeated‐measures ANOVA showed a significant main effect of time (p < 0.001) but no significant group × time interaction (p = 0.42), indicating no added benefit of heparin on systemic organ dysfunction.

3.5. Procalcitonin Stop Threshold

The median time to reach the PCT discontinuation threshold (≤ 0.2 µg/L) was 6 days (IQR 5–8) in the heparin group versus 9 days (IQR 7–11) in the placebo group (p = 0.01). The PCT algorithm is shown in Supplementary Figure S2.

3.6. Adverse Events and Tolerability

No major bleeding events (intracranial, gastrointestinal, or requiring transfusion) occurred in either group. Minor bleeding (oozing from puncture sites or mucous membranes) was reported in 2 of 41 patients (4.9%) in the heparin group and 1 of 41 (2.4%) in the placebo group (p = 0.56). No patient developed heparin‐induced thrombocytopenia, anaphylaxis, or clinically significant bronchospasm. Cough during nebulization was reported in 3 patients (7.3%) in the heparin group and 2 patients (4.9%) in the placebo group (p = 0.65), with no significant difference between groups.

4. Discussion

In this randomized controlled trial, adjunctive nebulized heparin significantly shortened the duration of antibiotic therapy in patients with ventilator‐associated pneumonia (VAP) when treatment was guided by a procalcitonin‐based algorithm applied to the intervention group. This benefit was accompanied by reductions in the duration of mechanical ventilation, ICU stay, and hospital stay, as well as greater improvements in CPIS and CRP. By contrast, no significant effects were observed on SOFA or APACHE II scores, indicating that the primary impact of heparin was localized to pulmonary infection and inflammation rather than systemic organ dysfunction.

When we applied the time‐to‐event analysis (median time to threshold, Mann‐Whitney U test), the heparin group reached the threshold significantly earlier: 6 days (IQR 5–8) versus 9 days (IQR 7–11) in the placebo group (p = 0.01). Therefore, the heparin group achieved the biomarker‐driven antibiotic stop criterion faster, consistent with the shorter duration of antibiotic therapy.

To date, evidence for inhaled heparin in VAP has been limited and inconsistent. The IPHIVAP trial reported no benefit from prophylactic low‐dose inhaled heparin (5,000 IU every 6 h), suggesting that the absence of effect may have been due to inadequate dosing. Our findings align more closely with studies that used higher doses. For example, Shute et al. [13] demonstrated clinical improvement in COPD patients using 32,000 IU/day, and Mohammad et al. [18] observed improved respiratory mechanics with 150,000 IU/day. These results, together with our findings (40,000 IU/day), support a dose‐dependent effect, in which higher local concentrations of heparin are required to achieve clinically meaningful outcomes. Meta‐analyses have also shown heterogeneous results. Glas et al. [19] found no effect on ventilator‐free days but did report a higher ICU‐free days and improved lung injury scores, which parallels our observed improvements in CPIS. More recently, a large individual patient data meta‐analysis found that inhaled heparin significantly reduced intubation risk and mortality, and a multicenter phase 3 trial) reported improved oxygenation and reduced pulmonary coagulopathy in ARDS, although no benefit on ventilator‐free days was observed [20].

Our findings align with studies using higher heparin doses (e.g., 40,000 IU/day). However, the delivered lung dose depends not only on the nominal dose but also on the nebulizer type. Jet nebulizers typically achieve only 10%–20% lung deposition, whereas vibrating mesh devices can reach 40%–60%. We used a jet nebulizer (see Methods), which may differ from prior studies. Thus, both dose and delivery method influence efficacy, and future studies should report both.

Reducing unnecessary antibiotic exposure is central to antimicrobial stewardship. Our findings suggest that inhaled heparin can complement biomarker‐guided strategies by accelerating clinical resolution, thereby shortening of antibiotic courses. This not only reduces the risk of multidrug‐resistant infections and Clostridioides difficile but may also lower healthcare costs through shorter ICU and hospital stays.

No major bleeding events (intracranial, gastrointestinal, or requiring transfusion) occurred in either group. Minor bleeding (oozing from puncture sites or mucous membranes) was reported in 2/41 (4.9%) heparin group versus 1/41 (2.4%) placebo (p = 0.56). No patient developed heparin‐induced thrombocytopenia or anaphylaxis. These data indicate that the 40,000 IU/day regimen is safe in this critically ill population.

4.1. Limitations of This Study

First, it was conducted at a single center with a relatively small sample size, which may limit external validity. Second, the lack of significant changes in SOFA and APACHE II scores may reflect either insufficient statistical power or the fact that heparin acts primarily on pulmonary rather than systemic processes. Third, although the dose used was effective, the optimal regimen including total daily dose, frequency, and duration remains to be determined. Fourth, we used CPIS ≥ 6 as an enrollment criterion, but CPIS has a sensitivity of 73.8% (95% CI 50.6–88.5) and specificity of 66.4% (95% CI 43.9–83.3) to diagnose VAP [25]. This may have led to inclusion of some patients without true VAP, although randomized allocation mitigates bias. Future studies should include quantitative cultures. Fifth, baseline APACHE II scores were higher in the placebo group (18.8 vs. 15.2, p = 0.02), indicating greater illness severity in the control group despite randomization. This imbalance, while not ideal, may biases the results against the intervention, as higher severity would be expected to be associated with longer antibiotic duration and worse outcomes. The fact that we still observed a significant benefit in the heparin group strengthens confidence in the treatment effect. Nevertheless, to address this concern, we performed a sensitivity analysis adjusting for baseline APACHE II (see Results), which confirmed the robustness of the primary finding (adjusted mean difference −2.9 days; 95% CI: −4.5 to −1.3; p = 0.001).

5. Conclusion

In this randomized controlled clinical trial, adjunctive nebulized heparin (40,000 IU/day) significantly shortened the duration of antibiotic therapy in patients with ventilator‐associated pneumonia (VAP). Both groups were managed with the same PCT‐guided discontinuation algorithm; the only interventional difference was the use of nebulized heparin in the intervention group versus placebo in the control group. The use of inhaled heparin was associated with faster clinical and inflammatory recovery as reflected by marked improvements in CPIS and CRP along with a shorter duration of mechanical ventilation and shorter ICU and hospital stays.

Importantly, no major bleeding events or significant adverse effects were observed, indicating that this regimen is both effective and safe when used at moderate doses in critically ill patients.

These findings highlight inhaled heparin as a promising adjunctive strategy to support antimicrobial stewardship in critical care by reducing unnecessary antibiotic exposure and its associated risks. However, given the single‐center design and modest sample size, our results should be interpreted with caution.

Further large‐scale multicenter studies with optimum heparin doses and comprehensive biomarker panels to better elucidate the mechanisms of action and establish the definitive role of inhaled heparin in antimicrobial stewardship are warranted to confirm efficacy, establish optimal dosing protocols, and comprehensively evaluate the long‐term safety profile of inhaled heparin in diverse ICU populations.

Author Contributions

Anoush Dehnadi Moghadam: writing – original draft, data curation, resources, methodology, conceptualization, writing – review and editing, project administration, supervision, validation. Mostafa Saeedinia: software, visualization, formal analysis, resources, investigation, data curation. Fatemeh Dehnadi Moghadam: investigation, supervision, project administration, validation, data curation, visualization, resources.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author, Anoush Dehnadi Moghadam, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and if relevant, registered) have been explained.

Supporting information

Supporting File

HSR2-9-e73334-s001.docx (697.7KB, docx)

Acknowledgments

The authors would like to thank the nursing and medical staff of the intensive care units at Razi and Poursina Hospitals for their dedicated patient care and support during the study. We are also grateful to the patients and their families for their participation. Also, the authors would like to thank the editorial team and reviewers for their valuable comments and suggestions, which have significantly improved the quality of this manuscript.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The corresponding author had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

References

  • 1. Vincent J.‐L., Abraham E., Kochanek P., Moore F. A., and Fink M. P., Textbook of Critical Care E‐Book (Elsevier Health Sciences, 2017). [Google Scholar]
  • 2. Mizgerd J. P., “Pathogenesis of Severe Pneumonia: Advances and Knowledge Gaps,” Current Opinion in Pulmonary Medicine 23, no. 3 (2017): 193–197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Melsen W. G., Rovers M. M., Groenwold R. H., et al., “Attributable Mortality of Ventilator‐Associated Pneumonia: A Meta‐Analysis of Individual Patient Data,” Lancet Infectious Diseases 13, no. 8 (2013): 665–671. [DOI] [PubMed] [Google Scholar]
  • 4. Sharma L., Wu J., Patel V., et al., “Partially‐Desulfated Heparin Improves Survival in Pseudomonas Pneumonia by Enhancing Bacterial Clearance and Ameliorating Lung Injury,” Journal of Immunotoxicology 11, no. 3 (2014): 260–267. [DOI] [PubMed] [Google Scholar]
  • 5. Schultz M. J., Haitsma J. J., Zhang H., and Slutsky A. S., “Pulmonary Coagulopathy as a New Target in Therapeutic Studies of Acute Lung Injury or Pneumonia—a Review,” Critical Care Medicine 34, no. 3 (2006): 871–877. [PubMed] [Google Scholar]
  • 6. Bergmans D., “Indications for Antibiotic Use in ICU Patients: A One‐Year Prospective Surveillance,” Journal of Antimicrobial Chemotherapy 39, no. 4 (1997): 527–535. [DOI] [PubMed] [Google Scholar]
  • 7. Juschten J., Tuinman P. R., Juffermans N. P., Dixon B., Levi M., and Schultz M. J., “Nebulized Anticoagulants in Lung Injury in Critically ill Patients—an Updated Systematic Review of Preclinical and Clinical Studies,” Annals of Translational Medicine 5, no. 22 (2017): 444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Yuan S., Hollinger M., Lachowicz‐Scroggins M. E., et al., “Oxidation Increases Mucin Polymer Cross‐Links to Stiffen Airway Mucus Gels,” Science Translational Medicine 7 (2015): 276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Dr.babitha M., Ashlin T. J., Vineeth J., Varghese P. A., and K V., “Inhaled Unbruised Heparin a New Way to Improve Lung Function: A Review,” World Journal of Pharmaceutical Research 8, no. 7 (2019): 523–529. [Google Scholar]
  • 10. Luckraz H., Manga N., Senanayake E. L., et al., “Cost of Treating Ventilator‐Associated Pneumonia Post Cardiac Surgery in the National Health Service: Results From a Propensity‐Matched Cohort Study,” Journal of the Intensive Care Society 19, no. 2 (2018): 94–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Pugin J., Auckenthaler R., Mili N., Janssens J. P., Lew P. D., and Suter P. M., “Diagnosis of Ventilator‐Associated Pneumonia by Bacteriologic Analysis of Bronchoscopic and Nonbronchoscopic ‘Blind’ Bronchoalveolar Lavage Fluid,” American Review of Respiratory Disease 143, no. 5 Pt 1 (1991): 1121–1129, 10.1164/ajrccm/143.5_Pt_1.1121. [DOI] [PubMed] [Google Scholar]
  • 12. Torres A., Niederman M. S., Chastre J., et al., “International ERS/ESICM/ESCMID/ALAT Guidelines for the Management of Hospital‐Acquired Pneumonia and Ventilator‐Associated Pneumonia,” European Respiratory Journal 50, no. 3 (2017): 1700582. [DOI] [PubMed] [Google Scholar]
  • 13. Shute J. K., Puxeddu E., and Calzetta L., “Therapeutic Use of Heparin and Derivatives Beyond Anticoagulation in Patients with Bronchial Asthma or COPD,” Current Opinion in Pharmacology 40 (2018): 39–45. [DOI] [PubMed] [Google Scholar]
  • 14. Dixon B., Schultz M. J., Hofstra J. J., Campbell D. J., and Santamaria J. D., “Nebulized Heparin Reduces Levels of Pulmonary Coagulation Activation in Acute Lung Injury,” Critical Care 14, no. 5 (2010): 445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Edwards S. J., Wordsworth S., and Clarke M. J., “Treating Pneumonia in Critical Care in the United Kingdom Following Failure of Initial Antibiotic: A Cost‐Utility Analysis Comparing Meropenem with Piperacillin/Tazobactam,” European Journal of Health Economics 13, no. 2 (2012): 181–192. [DOI] [PubMed] [Google Scholar]
  • 16. Chastre J., Wolff M., Fagon J.‐Y., et al., “Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator‐Associated Pneumonia in Adults: A Randomized Trial,” Journal of the American Medical Association (Chicago, IL) 290, no. 19 (2003): 2588–2598. [DOI] [PubMed] [Google Scholar]
  • 17. Kalanuria A. A., Zai W., and Mirski M., “Ventilator‐Associated Pneumonia in the ICU,” Critical Care 18, no. 2 (2014): 208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Mohammad R. S., El‐Maraghi S. K., El‐Sorougi W. M., Sabri S. M., and Mohammad M. F., “Role of Nebulized Heparin Inhalation on Mechanically Ventilated Critically ill Patients,” Egyptian Journal of Bronchology 10, no. 2 (2016): 179–188. [Google Scholar]
  • 19. Glas G. J., Serpa Neto A., Horn J., et al., “Nebulized Heparin for Patients under Mechanical Ventilation: An Individual Patient Data Meta‐Analysis,” Annals of Intensive Care 6, no. 1 (2016): 33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Glas G. J., Horn J., van der Poll T., and Schultz M. J., “Inhaled Anticoagulants for Mechanically Ventilated Patients: An Individual Patient Data Meta‐Analysis of Randomized Trials,” eClinicalMedicine 12 (2025): 100856. [Google Scholar]
  • 21. Dixon B., Smith R. J., Campbell D. J., et al., “Nebulised Heparin for Patients with or at Risk of Acute Respiratory Distress Syndrome: A Multicentre, Randomised, Double‐Blind, Placebo‐Controlled Phase 3 Trial,” Lancet Respiratory Medicine 9, no. 4 (2021): 360–372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Bouadma L., Luyt C.‐E., Tubach F., et al., “Use of Procalcitonin to Reduce Patients' Exposure to Antibiotics in Intensive Care Units (Prorata Trial): A Multicentre Randomised Controlled Trial,” Lancet 375, no. 9713 (2010): 463–474. [DOI] [PubMed] [Google Scholar]
  • 23. Schuetz P., Wirz Y., Sager R., et al., “Effect of Procalcitonin‐Guided Antibiotic Treatment on Mortality in Acute Respiratory Infections: A Patient Level Meta‐Analysis,” Lancet Infectious Diseases 18, no. 1 (2018): 95–107. [DOI] [PubMed] [Google Scholar]
  • 24. Heyland D. K., Johnson A. P., Reynolds S. C., and Muscedere J., “Procalcitonin for Reduced Antibiotic Exposure in the Critical Care Setting: A Systematic Review and an Economic Evaluation,” Critical Care Medicine 39, no. 9 (2011): 1792–1799. [DOI] [PubMed] [Google Scholar]
  • 25. Fernando S. M., Tran A., Cheng W., et al., “Diagnosis of Ventilator‐Associated Pneumonia in Critically ill Adult Patients—A Systematic Review and Meta‐Analysis,” Intensive Care Medicine 46 (2020): 1170–1179, 10.1007/s00134-020-06036-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting File

HSR2-9-e73334-s001.docx (697.7KB, docx)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The corresponding author had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

Articles from Health Science Reports are provided here courtesy of Wiley

RESOURCES