Bernhard Baumgartner

Swelling, sealing, and hemostatic ability of a novel biomaterial: A polyethylene glycol-coated collagen pad

Trends in the development of hemostatic agents are towards self-adhering pads. This study investigates a novel biomaterial made of a polyethylene glycol-coated collagen pad (PCC). The swelling and adherence of PCC were investigated in vitro, and the hemostatic and sealing ability was investigated in vivo. In vitro, the maximum swell of PCC submerged in human plasma for 24 h is 65%. The greatest swell was in thickness, averaging 24% to a mean thickness of 2.5 ± 0.19 mm (mean±SD) (N = 20). PCC withstood clinically relevant pressures when applied to a collagen casing washed with bile, lymph, urine, saline, and cerebrospinal fluid mixed at 33% and 67% with blood. In vivo, PCC provided complete hemostasis when applied to severe, arterial bleeds of actively ventilated pulmonary parenchyma at 3, 5, 8, and 10 min after application in a heparinized porcine pulmonary segmentectomy model. The mean rate of bleeding was 17.7 ± 8.6 ml/min. The lungs were ventilated at 15 ± 4 breaths per min and an airway pressure of 19 ± 2 cm H2O. PCC had no incidence of hematoma and an 11% incidence of intraoperative air leak (N = 36). These data are promising for future clinical application of a new versatile, self-adhering hemostatic sealing pad consisting of a polyethylene glycol-coated collagen.

Optimization, refinement and reduction of murine in vivo experiments to assess therapeutic approaches for haemophilia A:

The tail cut bleeding model (CUT) is routinely used in factor VIII-deficient mice to assess pharmacodynamic effects of therapeutic strategies for haemophilia A. Results from this model are highly variable, many modifications to the model are reported and at times the animals’ wellbeing may be compromised by recording survival as an endpoint. We therefore investigated if the ferric chloride carotid occlusion model (COM) used for thrombosis research can be applied to enhance data quality and animal welfare in haemophilia A research. Relative dose effects and relative dose variations were calculated for the CUT and COM. The requisite sample sizes were estimated and the importance of survival rates to assess rebleeds during recovery was evaluated by correlating initial blood loss to mortality. Relative dose effects increased with higher doses in both models. The COM was more sensitive at lower doses than the CUT, had up to 82% less variation across doses and clearly showed superior accuracy. Only 5% of the sample size required for the CUT would be needed to establish non-inferiority between a specific therapeutic dose in haemophilia A mice and healthy wild-type animals. A strong statistically significant correlation was found between initial blood loss and mortality within 24 h. Our findings clearly suggest that the COM is a valid tool for assessing haemophilia A treatment in vivo. The highly reproducible data means that significantly fewer animals are required and a more humane endpoint can be used by directly assessing clot stability instead of survival rate.

Treatment of Severe Aortic Bleeding Using Hemopatch in Swine on Dual Antiplatelet Therapy

ABSTRACT Purpose: The perioperative management of patients on antithrombotic therapy is currently an unresolved problem as these therapies pose a considerable risk for perioperative hemorrhagic complications. The presented studies investigated the efficacy of a new collagen technology to achieve hemostasis. A polyethylene glycol-coated collagen pad (PCC) was compared to a marketed fibrinogen-thrombin coated collagen pad (FTC) for the treatment of an aortotomy incision in heparinized swine on dual antiplatelet therapy. Materials and Methods: Twenty-eight 3-mm aortotomy incisions were created in nine heparinized pigs without antiplatelet therapy and treated with PCC. Sixty-eight aortotomy incisions were created in ten heparinized pigs that received clopidogrel (10–11 mg/kg) and acetylsalicylic acid (8–11 mg/kg) orally for 5 days, and treated with either PCC or FTC (N = 34/group). Dual antiplatelet therapy resulted in significantly reduced platelet function. Aortotomy incisions resulted in life-threatening bleeding of 35–292 ml/min. Results: In animals without antiplatelet treatment, PCC provided 96% immediate hemostatic success. In animals with antiplatelet treatment, FTC provided 18% immediate hemostatic success increasing to 74% after 10 min. Strikingly, PCC provided 94% immediate success increasing to 100% after 10 min. Controlling for differences in pretreatment bleeding rates, statistical model-estimated time to hemostasis was 12 times shorter in PCC-treated lesions (p < .02). Conclusion: The combination of a procoagulant collagen pad with a synthetic sealing component provides excellent hemostatic properties under a worst-case scenario. PCC rapidly and firmly adheres to tissue, thereby controlling severe arterial bleeding, even when platelet function is significantly reduced. Treatment with PCC provided superior time to hemostasis compared to FTC.

Safety and Efficacy of a Novel, Self-Adhering Dural Substitute in a Canine Supratentorial Durotomy Model

Abstract BACKGROUND Cerebrospinal fluid (CSF) leaks increase postoperative risk for complication, likelihood of reoperation, and costs. OBJECTIVE To investigate a novel, self-adhering polyethylene glycol-coated collagen pad (PCC) as a dural substitute relative to Duragen XS (DGX; Integra LifeSciences Corporation, Plainsboro, New Jersey) and as a dural sealant relative to Tachosil (Takeda Austria GmbH, Linz, Austria), a fibrinogen and thrombin-coated collagen pad (FTC). METHODS A canine supratentorial durotomy surgical model was used to investigate the safety and efficacy of PCC. For safety, 4 animals were bilaterally treated with DGX or PCC and recovered for 1, 8, or 16 wk; total 24 animals. Each animal underwent physical and neurological examinations weekly and 16-wk animals underwent a magnetic resonance imaging (MRI) examination at each time point. For efficacy, 9 animals were unilaterally treated with FTC or PCC and underwent a burst pressure test intraoperatively or 14 d postoperatively; total 36 animals. RESULTS In the safety study, no abnormal clinical signs or changes were noted on physical and neurological examinations, or in clinical pathology, CSF analysis or histopathology of DGX or PCC-treated animals. No consistent signs of cerebral compression, CSF leak, hemorrhage, or hydrocephalus were noted on MRI. In the efficacy study, no significant difference was found between FTC and PCC at each time point or overall (13.9 vs 12.3 mm Hg, n = 18 per group, P = .46). CONCLUSION PCC is safe for use as a dural substitute and effective as a dural sealant. The novel, self-adhering combination of a polyethylene glycol-based sealant and a collagen pad may offer unique benefits to the advancement of duraplasty.

Hemostatic Comparison of a Polysaccharide Powder and a Gelatin Powder

ABSTRACT Purpose/Aim: Powdered hemostats have been widely adopted for their ease-of-use; however, their efficacy has been limited resulting in applications restricted to low-level bleeds. This study investigates the use of bovine-derived gelatin particles (BGP) as a standalone hemostatic powder and compare BGP to commercially available microporous polysaccharide hemospheres (MPH). Materials and Methods: The powders were investigated for their hemostatic efficacy in a heparinized pre-clinical bleeding model limited to grade 1 and 2 bleeds on a validated intraoperative bleeding scale, which represents the accepted, clinical use of hemostatic powders. Results: At 10 minutes, the hemostatic success of lesions treated with BGP were 78% while MPH were 22%. The odds ratio for hemostatic success of BGP relative to MPH was 15.18 (95% CI: 7.37, 31.27). The 95% lower limit of the odds ratio was greater than 1. This indicates that BGP are superior to MPH (p < 0.001). The median time to hemostasis for BGP was 1.6 minutes and MPH was 14.5 minutes. The ratio for time to hemostasis of MPH relative to BGP was 9.23 (95% CI: 6.99, 12.19). This indicates that BGP achieve significantly faster time to hemostasis (p < 0.001). Conclusions: Characterization of tissue explant ultrastructure, particle size, and swelling revealed differences in the materials. BGP, in addition to absorbing fluid and concentrating clotting factors and platelets, integrate into the clot and stabilize the fibrin matrix. BGP have advantages over MPH in terms of speed and efficacy. BGP are a favorable biomaterial for further research that greatly improve the limited efficacy of powdered hemostats.

Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis

ABSTRACT New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease‐related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure‐related disease‐modifying activity in experimentally induced rat GN. BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration in vitro. After intravenous administration in rats, BaxB01 demonstrated favorable pharmacokinetics, with a half‐life of up to nine days. Disease modification was dose‐related (≥ 10 mg/kg) as demonstrated by significantly reduced proteinuria and diminished histopathological glomerular crescent formation. Importantly, a single dose was sufficient to establish an exposure‐related, anti‐inflammatory milieu via amelioration of glomerular cellular inflammation. Pharmacodynamic modeling corroborated these findings, consistently predicting plasma exposures that were effective in attenuating both anti‐inflammatory activity and reducing loss of kidney function. This pharmacologic benefit on glomerular function and structure was sustained during established disease, while correlation analyses confirmed a link between the antibodys anti‐inflammatory activity and reduced crescent formation in individual rats. Finally, safety assessment in rats showed that the experimental therapeutic was well tolerated without signs of systemic toxicity or negative impact on kidney function. These data define therapeutically relevant exposures correlated with mechanism‐based activity in GN, while toxicological evaluation suggests a large therapeutic index and provides evidence for achieving safe and effective exposure to a MIF isoform‐directed therapeutic in nephritis‐associated disease.

An Enantiomerically Pure Formulation of Esmolol Attenuates Hypotension and Preserves Heart Rate Control in Dogs

Background:Esmolol is marketed as a racemate (RS-esmolol) with hypotension being the most frequently reported adverse event. Previously, it has been shown that the S-enantiomer (S-esmolol) possesses all of the heart rate (HR) control. The authors studied whether S-esmolol alone mitigates hypotension at similar degrees of HR control compared with RS-esmolol. Methods:The effects of RS- and S-esmolol on blood pressure (BP) were compared at multiple infusion rates producing similar HR control in dogs (N = 21). Differences in BP were further interrogated by monitoring global cardiovascular function and included the R-enantiomer (R-esmolol) (N = 3). Results:S-esmolol at half the rate (&mgr;g kg−1 min−1) of RS-esmolol provided the same degree of HR control over all infusion rates. RS-esmolol lowered BP by 3, 6, 11, 20, and 38 mmHg at 90, 300, 600, 1,000, and 2,000 &mgr;g kg−1 min−1, compared with 2, 4, 5, 10, and 16 mmHg at 45, 150, 300, 500, and 1,000 &mgr;g kg−1 min−1 for S-esmolol. Decreased BP with RS-esmolol was attributed to decreases in left ventricular developed pressure (LVDP) (−34 mmHg), LVdP/dt+max (−702 mmHg/s), and cardiac output (−1 l/min). R-esmolol also decreased BP (−10 mmHg), LVDP (−10 mmHg), LVdP/dt+max (−241 mmHg/s), and cardiac output (to −0.2 l/min). S-esmolol reversed these trends toward pre-esmolol values by increasing BP (+13 mmHg), LVDP (+12 mmHg), LVdP/dt+max (+76 mmHg/s), and cardiac output (+0.4 l/min). Conclusions:R-enantiomer provided no HR control, but contributed to the hypotension with RS-esmolol, which appears to be due to negative inotropy. Thus, an S-enantiomer formulation of esmolol may provide similar HR control with less hypotension.