Heparin Nebulization Research Articles

The Efficacy of Daily Administration of Nebulized Heparin on the Prevention of Endotracheal Tube Blockage in Patients With Pneumonia.

Nosocomial infections pose a significant public health concern, impacting over 100 million people worldwide annually. Within this research, we investigated heparin nebulization through the endotracheal tube and its effect on preventing blockage due to clots and mucus plugs compared to normal saline. A double-blind clinical experiment was done on a cohort of 40 pneumonia patients who were intubated and hospitalized in theintensive care unit (ICU) at Imam Khomeini Hospital in Ahvaz, Iran. The individuals were randomly assigned to two groups of 20 patients using a random allocation technique. The initial cohort was administered 5000 IU of heparin diluted in 4 ccs of 0.9% normal saline every eight hours via a nebulizer through a tracheal tube. In contrast, the second cohort was given 5 ccs of normal saline as a nebulizer through a tracheal tube. The study compared the incidence of tracheal tube obstruction caused by mucus plug or clot, the occurrence of patient hypoxia resulting in emergency tracheal tube replacement, and the frequency of emergency tracheal tube suction due to partial obstruction caused by mucus plug in both the heparin and saline groups. According to our data, the number of patients in the heparin group who could avoid the need for emergency tracheal tube replacement owing to blockage was more significant than in the ordinary saline group (P=0.013). Heparin was significantly correlated with the number of times emergency suction was required to remove a tracheal tube occlusion (P=0.01). Heparin had no significant effect on coagulation factors (international normalized ratio [INR], platelet[PLT], and partial thromboplastin time [PTT]), Acute Physiology and Chronic Health Evaluation (APACHE) score, pneumonia severity index (PSI), saturation of patients, or tracheal tube secretions. There was no statistically significant difference in total time spent in the intensive care unit (P=0.91). Further studies are suggested to determine the effect of heparin nebulization on preventing endotracheal tube obstruction due to clots and mucus plugs in intubated ICU patients.

Protective Effect of Nebulized Heparin in the Animal Models of Smoke Inhalation Injury: A Meta-analysis and Systematic Review of Experimental Studies.

The pathophysiological mechanism of abnormal coagulation can result from smoke inhalation injury (SII). Heparin nebulization is a common treatment for lung disorders. This study aimed to use meta-analysis in animal models to examine the effectiveness of atomized heparin on SII. For our online searches, we used the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese BioMedical Literature Database, and Wanfang Database up to January 2022. Data for SII were retrieved and compared to control animals. The studies' findings were determined by combining standardized mean difference (SMD) analysis with 95% confidence intervals (CIs). The findings showed that as compared to the control group, the heparin-treated group had a lower death rate (relative risk 0.42; 95% CI 0.22, 0.80; p < .05). The meta-analysis demonstrated favorable changes in lung physiology, including PaO2/FiO2 (SMD 1.04; 95% CI 0.65, 1.44; p < .001), lung wet-to-dry weight ratio (SMD -1.83; 95% CI -2.47, -1.18; p < .001), and pulmonary shunt Qs/Qt (SMD -0.69; 95% CI -1.29, -0.08; p < .05) after heparin nebulization for lung injury. The present data indicated that pulmonary artery mean pressure in the heparin therapy group was significantly lowered after 24 and 48 hours of therapy, suggesting that the cardiovascular system could recover following heparin treatment. As a result, heparin nebulization appeared to be more effective against SII and improved cardiopulmonary function compared to the control group. Graphical Abstract.

Role of nebulized heparin in mechanically ventilated critically ill patients

Background Mechanical ventilation is a technique for supporting or substituting respiration. Fibrin deposition in the pulmonary microcirculation and alveolar sacs (hyaline membrane generation) is a major inflammatory route of lung injury, as it hinders both alveolar perfusion and ventilation. Heparin lowers fibrin deposition in the lungs and improves clinical outcomes in mechanically ventilated patients, according to clinical and experimental studies. Heparin nebulization may be more efficient than systemic delivery.Aim The purpose of this study was to evaluate how nebulized heparin affected both morbidity and mortality rates in mechanically ventilated patients.Patients and methods A total of 50 patients who required mechanical ventilation for more than 48 h were assigned into two groups: group 1 (control group) received 0.9% nebulized saline and group 2 (treatment group) received nebulized heparin. All patients were subjected to complete history taking, complete physical examination, routine laboratory investigations, daily arterial blood gas analysis and chest imaging, and Sequential Organ Failure Assessment score every 48 h. The primary end point was to evaluate lung functions such as airway resistance, static compliance, hypoxic index, and ventilator-free days. The development of acute respiratory distress syndrome after enrollment, tracheostomy rate, vasopressor-free days, length of ICU stay, and mortality rate at days 7 and 28 were all secondary end points.Results On days 2, 3, 4, 5, and 7, the mean static compliance in the treatment group was considerably higher than in the control group, with a statistically significant difference at days 2 and 4. The mean hypoxic index in the nebulized heparin group was significantly higher than in the control group. The nebulized heparin group had significantly more days without using vasopressors than the control group.Conclusion In patients needing mechanical ventilation for more than 48 h, nebulized heparin significantly improved lung static compliance and hypoxic index and was associated with more vasopressor-free days.

Nebulized heparin for inhalation injury in burn patients: a systematic review and meta-analysis.

BackgroundSmoke inhalation injury increases overall burn mortality. Locally applied heparin attenuates lung injury in burn animal models of smoke inhalation. It is uncertain whether local treatment of heparin is benefit for burn patients with inhalation trauma. We systematically reviewed published clinical trial data to evaluate the effectiveness of nebulized heparin in treating burn patients with inhalation injury.MethodsA systematic search was undertaken in PubMed, the Cochrane Library, Embase, Web of Science, the Chinese Journals Full-text Database, the China Biomedical Literature Database and the Wanfang Database to obtain clinical controlled trails evaluating nebulized heparin in the treatment of burn patients with inhalation injury. Patient and clinical characteristics, interventions and physiological and clinical outcomes were recorded. Cochrane Risk of Bias Evaluation Tool and the Newcastle–Ottawa Scale were used to evaluate data quality. Potential publication bias was assessed by Egger’s test. A sensitivity analysis was conducted to assess the stability of the results. The meta-analysis was conducted in R 3.5.1 software.ResultsNine trials were eligible for the systematic review and meta-analysis. Nebulized heparin can reduce lung injury and improve lung function in burn patients with inhalation injury without abnormal coagulation or bleeding, but the findings are still controversial. Mortality in the heparin-treated group was lower than that of the traditional treatment group (relative risk (RR) 0.75). The duration of mechanical ventilation (DOMV) was shorter in the heparin-treated group compared to the traditional treatment group (standardized mean difference (SMD) −0.78). Length of hospital stay was significantly shorter than that in the traditional treatment group (SMD −0.42), but incidence rates of pneumonia and unplanned reintubation were not significantly different in the study groups (RRs 0.97 and 0.88, respectively). No statistically significant publication biases were detected for the above clinical endpoints (p > 0.05).ConclusionsBased on conventional aerosol therapy, heparin nebulization can further reduce lung injury, improve lung function, shorten DOMV and length of hospital stay, and reduce mortality, although it does not reduce the incidence of pneumonia and/or the unplanned reintubation rate.

Streptokinase Versus Unfractionated Heparin Nebulization in Patients With Severe Acute Respiratory Distress Syndrome (ARDS): A Randomized Controlled Trial With Observational Controls

To examine and compare nebulizing heparin versus streptokinase for reversing alveolar collapse nonresponsive to recruitment. A clinical trial at a tertiary intensive care unit (ICU). Sixty patients with severe acute respiratory distress syndrome (ARDS) (PaO2/FIO2 <100) nonresponsive to recruitment maneuver (RM), prone position, and neuromuscular block (NMB) were randomized into intervention arms or the standard-of-care arm. The ICU at Beni-Suef University Hospital. Sixty patients with severe ARDS (PaO2/FIO2 <100) nonresponsive to RM, PP, and NMB. Nebulized heparin (10,000 IU/4 h), nebulized streptokinase (250,000 IU/4 h), and conservative management. The primary outcome was the change in PaO2/FIO2; the secondary outcomes included the change in compliance, plateau pressure, coagulation, and ICU mortality. The PaO2/FIO2 was significantly higher in the streptokinase group from day 1 to day 8 compared to the heparin and standard-of-care groups. Streptokinase produced PaO2/FIO2>100 at day 1, >200 at day 5, and >300 at day 7. The heparin group achieved a PaO2/FIO2 >100 at day 5 but remained <200 until day 8. The standard-of-care group did not achieve a PaO2/FIO2>100 after 8 days. Streptokinase significantly reduced plateau pressure and improved compliance at day 8. Only streptokinase decreased PaCO2 (p < 0.0001). Moreover, ICU mortality was significantly lower in streptokinase patients compared to other groups. Additionally, no heparin-induced thrombocytopenia was observed in all groups. Inhaled streptokinase serves as rescue therapy in patients with severe ARDS with improving oxygenation and lung mechanics more quickly than heparin or conventional management.

Role of nebulized heparin inhalation on mechanically ventilated critically ill patients

Mechanical ventilation is one of the most important tools in the treatment of respiratory failure in critically ill patients, but it may cause lung injury and inflammatory response in the whole body. The aim of our study was to justify the effect of nebulized heparin on morbidity, oxygenation parameters, lung mechanics, and mortality in mechanically ventilated critically ill patients who are assumed to require mechanical ventilation for more than 48 h for different indications. This study was conducted on 50 ICU patients who were in need of mechanical ventilation for more than 48 h. They were grouped randomly into two groups. One of the two groups was given nebulized heparin sodium until weaning or for a maximum of 14 days. Patients with coagulopathy or scheduled for any invasive intervention that may lead to bleeding were excluded. In addition, patients who were weaned or who died before day 4of admission were also excluded. Both groups were followed up for a maximum of 28 days. The study medication was reduced or withheld if any significant bleeding occurred. The endpoint results were primary oxygenation parameters [mainly arterial oxygen partial pressure (PaO2)/inspired oxygen fraction (FIO2)] and ventilator-free days. All other data were recorded and analyzed to find out the adverse positive effect of heparin nebulization. Data analysis revealed that the following data showed no statistically significant difference within groups over time or between the two groups: PaCO2, pH, PaO2, HCO3, SO2, PaO2/FIO2, FIO2×mean airway pressure/PaO2, peak inspiratory pressure, mean airway pressure, tumor necrosis factor α , systolic blood pressure, diastolic blood pressure, hemoglobin, hematocrit value, white blood cells count, platelet count, prothrombin concentration, international normalized ratio, presence of bloody sputum, ICU-free days at day 28, ventilator-free days at day 28, acute renal failure-free days at day 28, vasopressor-free days at day 28, and mortality and sputum culture results at day 4. However, the following data showed a statistically significant difference in the heparin-treated group: plateau pressure showed a statistically significant decrease between days 1 and 4 in the heparin-treated group (P=0.003) and a statistically significant difference when we compared the percentage change between the two groups (P=0.015). Compliance rate showed a statistically significant increase between days 1 and 4 in the heparin-treated group (P=0.019) but when we compared the percentage change between the two groups the difference was not statistically significant (P=0.256). Activated partial thromboplastin time showed a statistically significant increase between days 1 and 4 in the heparin-treated group (P=0.001), but when we compared the percentage change between the two groups the difference was not statistically significant (P=0.153). No cases of heparin-induced thrombocytopenia was noted in the heparin-treated group, nor was there major bleeding or need for blood transfusion related to the tested medication in this group. We recommend nebulized heparin as a safe drug that has a favorable effect in patients receiving mechanical ventilation especially with reduced compliance as in cases of acute respiratory distress syndrome.

Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis.

Pulmonary coagulopathy is a characteristic feature of lung injury including ventilator-induced lung injury. The aim of this individual patient data meta-analysis is to assess the effects of nebulized anticoagulants on outcome of ventilated intensive care unit (ICU) patients. A systematic search of PubMed (1966–2014), Scopus, EMBASE, and Web of Science was conducted to identify relevant publications. Studies evaluating nebulization of anticoagulants in ventilated patients were screened for inclusion, and corresponding authors of included studies were contacted to provide individual patient data. The primary endpoint was the number of ventilator-free days and alive at day 28. Secondary endpoints included hospital mortality, ICU- and hospital-free days at day 28, and lung injury scores at day seven. We constructed a propensity score-matched cohort for comparisons between patients treated with nebulized anticoagulants and controls. Data from five studies (one randomized controlled trial, one open label study, and three studies using historical controls) were included in the meta-analysis, compassing 286 patients. In all studies unfractionated heparin was used as anticoagulant. The number of ventilator-free days and alive at day 28 was higher in patients treated with nebulized heparin compared to patients in the control group (14 [IQR 0–23] vs. 6 [IQR 0–22]), though the difference did not reach statistical significance (P = 0.459). The number of ICU-free days and alive at day 28 was significantly higher, and the lung injury scores at day seven were significantly lower in patients treated with nebulized heparin. In the propensity score-matched analysis, there were no differences in any of the endpoints. This individual patient data meta-analysis provides no convincing evidence for benefit of heparin nebulization in intubated and ventilated ICU patients. The small patient numbers and methodological shortcomings of included studies underline the need for high-quality well-powered randomized controlled trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-016-0138-4) contains supplementary material, which is available to authorized users.

Nebulized heparin for patients under mechanical ventilation: a conventional data meta-analysis

Mechanical ventilation has the potential to induce pulmonary coagulopathy. Local treatment by nebulization of heparin could be beneficial in ventilated patients. The aim of this data metaanalysis is to determine the association between nebulization of heparin and outcome of mechanically ventilated critically ill patients.

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

BackgroundData from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.MethodWe performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.ResultsThe efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.ConclusionLocal anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

The complex role of fibrin in acute lung injury

in the last decade there have been many advances in our understanding of the pathogenesis of acute lung injury (ALI), but there have been frustratingly few successful therapeutic interventions. In fact, the only treatment proven to reduce mortality is low tidal volume lung-protective mechanical

Heparin Nebulization with Recombinant Human Antithrombin Supplementation Improves Pulmonary Gas Exchange in Sepsis Following Smoke Inhalation in Sheep

Heparin Nebulization with Recombinant Human Antithrombin Supplementation Improves Pulmonary Gas Exchange in Sepsis Following Smoke Inhalation in Sheep

Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.

Bleomycin is a well known fibrogenic agent, provoking an initial adult respiratory distress syndrome-like injury with subsequent strong fibroproliferative response. Severe abnormalities of the alveolar surfactant system, which may be linked to the appearance of alveolar fibrin deposition, have been implicated in the pathogenetic sequence of events. Using a model of standardized aerosol delivery of 1.8 U bleomycin/kg body weight in rabbits, we investigated the influence of repetitive nebulization of heparin or urokinase-type plasminogen activator (u-PA) on the development of lung fibrosis. In an "early" (Days 2-12 postbleomycin) or "late" (Days 14-24 post-bleomycin) treatment protocol, approximately 3,500 U heparin or approximately 6,500 U u-PA was delivered to the bronchoalveolar space. Within four weeks, the bleomycin challenge provoked severe pulmonary fibrosis with reduction of lung compliance, marked increase in soluble collagen (bronchoalveolar lavage fluid) and hydroxyproline content (lung tissue), a typical reticular fibrosis pattern on high-resolution computed tomography, and typical histologic findings. Therapeutic intervention resulted in a far-reaching normalization of compliance, suppression of soluble collagen and hydroxyproline accumulation, and virtual abrogation of the computed tomography scan and histologic features of lung fibrosis, with most prominent effects seen in the early heparin and late u-PA administration. No bleeding complications occurred. These findings strongly support the concept that alveolar fibrin generation is an important event in the development of postbleomycin lung fibrosis. "Compartmentalized" anticoagulation and/or fibrinolysis via inhalational deposition of interventional agents in the alveolar compartment may thus offer a new therapeutic strategy for prevention of fibrosis.

Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep.

Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40 degrees C) were inflated into the airway. Afterwards, live Pseudomonas aeruginosa (5 x 10(11) CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2 and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.

Effect of Heparin Nebulization in Burn and Smoke Inhalation Injury In Sheep.

Katahira, J.; Murakami, K.; Mlcak, R.; Cox, R.; Hawkins, H.; Herndon, D. N.; Traber, L.; Traber, D. Author Information

Heparin nebulization attenuates acute lung injury with sepsis after smoke inhalation in sheep

Fibrin formation in the airway is a common occurrence with acute lung injury. Mucous plugging in the airway prevents alveoli expansion and may increase shunt blood flow. The aim of this study was to investigate the effect of heparin nebulization in acute lung injury (ALI) with sepsis or burn after smoke inhalation in sheep.

Effect of Pretreatment with Heparin on Pulmonary and Cutaneous Response

Although anticoagulant properties of glycosaminoglycan heparin are primary in medicine, a variety of other biological functions related to heparin have been suggested. Since heparin is a selective inhibitor of inositol triphosphate (IP3) receptors that are involved in release of calcium in mast cells and many other cells, it is possible that heparin may act as a natural anti-inflammatory molecule and modify these reactions. Therefore, the purpose of the present study was to determine the role of heparin in allergic inflammatory responses: the pulmonary reaction and the cutaneous response, in a double-blind, placebo-controlled, crossover randomized trial. To evaluate the effect of heparin on methacholine-induced bronchoconstriction, nebulized heparin (20,000 units) was administered to 12 asthmatics and nonspecific challenge was performed immediately thereafter. Measurements of Raw and SGaw were obtained before and 1 hr after nebulization of heparin. In 12 other allergic subjects, heparin (25 U/kg) was given intravenously 10 min before skin prick test. We demonstrated that pretreatment with heparin reduced skin test reactivity from 24.06 ± 1.2 mm to 18.26 ± 2.27 mm and increased the methacholine PC20 value from 1.69 ± 0.48 mg/ml to 8.14 ± 3.11 mg/ml (p < 0.05), but did not prevent an increase in Raw and/or a decrease in SGaw. Heparin modified the methacholine-induced bronchoconstrictor response, but this did not reflect a protective effect in airway resistance and specific conductance. These data suggest that anti-inflammatory effects of heparin are time-dependent and/or that heparin may have a transient inhibitory role in allergic reactions.