Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID‐19 Requiring invasive ventilation Meta‐Trial (CHARTER‐MT): Protocol and statistical analysis plan for an investigator‐initiated international meta‐trial of prospective randomised clinical studies

Haren, Frank van; Laffey, John G.; Artigas, Antonio; Page, Clive; Schultz, Marcus J.; Cosgrave, David; McNicholas, Bairbre; Smoot, Thomas; Nunes, Quentin; Yoon, Hwan‐Jin; Loon, Lex M. van; Ghosh, Angaj; Said, Simone; Panwar, Rakshit; Smith, Roger; Santamaria, John; Dixon, Barry

doi:10.1111/bcp.15253

Cited by 11 publications

(10 citation statements)

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“…LMWH administered by nebulization was found effective in protecting human nasal cells from infection with SARS-CoV-2, suggesting its possible prophylactic use [ 83 ]. Clinical trials of nebulized heparin in COVID-19 treatment are currently under way in several countries [ 11 , 12 , 13 , 84 ].…”

Section: Non-anticoagulant Action Of Heparin and Sepsismentioning

confidence: 99%

“…Investigations have also shown that binding of heparin to SARS-CoV-2 spike proteins may inhibit virus infectivity [ 9 , 10 ]. Indeed, clinical trials with nebulised heparin exploring the anti-inflammatory and anti-viral properties of heparin are ongoing [ 11 , 12 , 13 , 14 ]. Recent advances in heparin research indicated that heparin not only interacts with the coagulation cascades, but also with blood cells and numerous components of the complement system thereby influencing the innate immune responses to infection [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Hogwood

Gray

2023

Pharmaceuticals

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Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

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Section: Non-anticoagulant Action Of Heparin and Sepsismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Hogwood

Gray

2023

Pharmaceuticals

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“…This strategy has already been tested for heparin. 44 The starting material is derived from pentosan, a plant-derived polysaccharide xylan with a well-defined repeating structure 19 and, even following a chemical sulfation step, it remains highly homogeneous, making it easier to ensure both consistency and to avoid contamination; two problems that have dogged heparin production in recent years. 45,46 What is known about this topic?…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding

et al. 2022

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Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.

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“…Ideally, more time frame is required to follow the trend as these inflammatory markers take time to resolve our findings are in line with those from the published literature and clinical experience, which show that inhaled nebulized unfractionated heparin (UFH) is very safe for patients with a wide variety of respiratory diseases. 4 , 5 …”

mentioning

confidence: 99%

Nebulized Heparin to Reduce COVID-19-induced Acute Lung Injury: A Prospective Observational Study

Gupta¹,

Jain²,

Chandrakar³

et al. 2023

Indian Journal of Critical Care Medicine

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A bstract Background High mortality due to COVID-19 disease has been a serious concern, a few of the causes being disseminated intravascular coagulation (DIC) and venous thromboembolism. Considering this, some experts have used heparin. However, its role still needs to be validated. Materials and methods This study predicts the role of nebulized heparin in decreasing the severity of lung injury caused by COVID-19. Thirty patients admitted with COVID-19 acute respiratory distress syndrome (ARDS) in the intensive care unit (ICU) of All India Institute of Medical Sciences, Rishikesh, were included in this study, which was conducted over a period of 3 months. Patients were nebulized with 2 mL of heparin 5,000 units/mL IV formulation diluted with 3 mL of 0.9% sodium chloride, every 6 hours for a total duration of 7 days. Improvement in oxygenation (ratio of partial pressure of oxygen in blood and fraction of inspired oxygen delivered, pO 2 /FiO 2 ratio) was calculated as the primary outcome. Other parameters like effect on inflammatory markers (neutrophil-lymphocyte ratio, total leukocyte count, interleukin (IL-6), and D-dimer values), time to liberate from mechanical ventilation, and hospital stay were calculated as secondary outcomes. Results In our study population, the mean age was 54.5 years and the majority of patients were males (79.0%). All patients received prone ventilation and none of them required tracheostomy. However, 5 patients (16.6%) succumbed to illness. After nebulization with unfractionated heparin, no statistically significant difference was seen in the neutrophil-lymphocyte ratio (mean = 6.87, p = 0.318) and interleukin (IL-6) levels (mean = 62.85, p = 0.6) over 7 days. Similarly, the D-dimer level also had no statistically significant change (mean = 1853.73 p = 0.570). However, there was a statistically significant improvement in oxygenation (pO 2 /FiO 2 ratio) over 7 days (mean = 184.96, p = 0.00). Similarly, there was a significant improvement in PaO 2 (84.17 ± 33.82) and SO 2 (92.30 ± 3.49). Although, no significant changes were seen in the partial pressure of carbon dioxide on nebulized heparin administration. Conclusion Administration of nebulized heparin in COVID-19 pneumonia with mild ARDS may improve oxygenation and result in the improvement of inflammatory markers with variable sensitivity and specificity. How to cite this article Gupta B, Chandrakar S, Gupta N, Jain G. Nebulized Heparin to Reduce COVID-19-induced Acute Lung Injury: A Prospective Observational Study. Indian J Crit Care Med 2023;27(3): 222–224.

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Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID‐19 Requiring invasive ventilation Meta‐Trial (CHARTER‐MT): Protocol and statistical analysis plan for an investigator‐initiated international meta‐trial of prospective randomised clinical studies

Cited by 11 publications

References 51 publications

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding

Nebulized Heparin to Reduce COVID-19-induced Acute Lung Injury: A Prospective Observational Study

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