Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH).

Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.

Protein composition of clots detected in pooled cryoprecipitate units.

BACKGROUND: On rare occasions, upon thawing of stored cryoprecipitate components, clots are observed on visual inspection. Although it has been assumed that the clot reflects fibrinogen to fibrin conversion, there are few published studies that document that this assumption is correct. Our studies were conducted to further identify the protein characteristics of the clotted material. STUDY DESIGN AND METHODS: Clotted material isolated from four thawed cryoprecipitate pools was examined by solubilization procedures and electrophoresis analysis. RESULTS: Solubilization of much of the clotted material in phosphate-buffered saline warmed to 37°C suggested the presence of soluble fibrin. Gel electrophoresis under reducing conditions showed that the most prevalent bands exhibited molecular weights corresponding to the α, ß, and γ subunits of fibrinogen with a much lighter band exhibiting the molecular weight of fibrinogen γ-γ dimer, consistent with the presence of partially crosslinked fibrin. The presence of the dimer indicated that the clotted material was caused by the action of thrombin, but also reflected the action of Factor XIIIa. No ongoing clot formation was observed. CONCLUSION: Our studies indicate that, on rare occasions, fibrinogen conversion to fibrin is responsible for observable clots in thawed cryoprecipitate pools. These clots are structurally heterogeneous, including both noncrosslinked (soluble) and crosslinked (insoluble) fibrin. This diversity in the fibrin structure may account for some of the diversity in the limited literature regarding their presence in cryoprecipitate pools.

New hemostatic dressing (FAST Dressing) reduces blood loss and improves survival in a grade V liver injury model in noncoagulopathic swine.

BACKGROUND: We performed this study to evaluate the hemostatic efficacy of the FAST Dressing in treating a grade V liver injury in noncoagulopathic swine. METHODS: Sixteen female splenectomized, noncoagulopathic swine underwent reproducible grade V liver injuries. The animals were blindly randomized to two treatment groups: (1) FAST Dressing (n = 8) or (2) IgG placebo dressing (n = 8). After 30 seconds of uncontrolled hemorrhage, dressings and manual compression were applied at 4-minute intervals. The number of dressings used, time to hemostasis, total blood loss, mean arterial pressure, blood chemistry, and total resuscitation fluid volume were monitored for 2 hours after injury. RESULTS: The mean total blood loss was 412.5 mL (SD 201.3) for the FAST Dressing group compared with 2296.6 mL (SD 1076.0) in the placebo group (p < 0.001). All animals in the FAST Dressing group achieved hemostasis and survived for the duration of the experiment (2 hours) after injury, whereas none of the animals in the placebo group attained hemostasis or survived to 2 hours after injury (p < 0.001). The mean time to hemostasis was 6.6 minutes (SD 2.5). A median of five dressings (mean absolute deviation 1.0, p = 0.007) was sufficient to control hemorrhage in the FAST Dressing group. CONCLUSION: The FAST Dressing reduced blood loss and improved survival compared with placebo in a noncoagulopathic, grade V liver injury swine model.

Clot-inducing minerals versus plasma protein dressing for topical treatment of external bleeding in the presence of coagulopathy.

BACKGROUND: Previous studies identified WoundStat (WS, smectite) and Combat Gauze (CG, kaolin-coated gauze) as the most effective available agents for controlling arterial bleeding with potential utility in casualty care. Tissue sealant properties of WS suggested its potential advantage over clot-promoting CG for treating coagulopathic bleeding. This study compared the efficacy of CG and WS with a fibrinogen-based (FAST) dressing to control bleeding in coagulopathic animals. METHODS: Coagulopathy was induced in pigs (n = 55, 35 kg) by ∼50% isovolemic hemodilution and hypothermia (core temperature, 33°C ± 0.5°C). A 6-mm arteriotomy was made in the femoral artery and free bleeding allowed for 30 seconds. A test agent (n = 13-15 per group) or control product (gauze, GZ, n = 12) was applied to the wounds and compressed with a Kerlix gauze for 2 minutes. Fluid resuscitation was given, titrated to a mean arterial pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Angiography using the computed tomography method was performed on survivors, and local tissues were collected for histology. RESULTS: No differences were seen in baseline measures. Coagulopathy, confirmed by a 31% increase in prothrombin time and a 28% reduction in clotting strength (maximum amplitude, thrombelastography assay), was similar in all groups before injury. The average pretreatment blood loss was 11.9 mL/kg ± 0.4 mL/kg with no difference among groups. Posttreatment blood loss, however, was significantly different (p = 0.015) ranging from 18.2 mL/kg ± 8.8 mL/kg (FAST) to 63.3 mL/kg ± 10.2 mL/kg (GZ controls). Stable hemostasis was achieved in 10 of 13 (FAST), 5 of 15 (CG), 2 of 15 (WS), and 1 of 12 (GZ) animals in each group, resulting in significantly different survival rates (8-77%; p = 0.001). The average survival times were 145 (FAST), 119 (CG), 75 (WS), and 74 (GZ) minutes for different groups (p < 0.002). The outcomes with the FAST dressing were significantly better than with WS or GZ in this coagulopathic bleeding model. Essentially, no difference was found between WS and GZ control. Computed tomography images showed limited blood flow only through the vessels treated with FAST dressings. Histologic observations of the vessels indicated minimal damage with FAST and CG and greater injury with WS with some residues present on the tissues. CONCLUSION: The tissue sealant property of WS is apparently mediated by clot formation in the wound; therefore, it was ineffective under coagulopathic conditions. CG was partially effective in maintaining blood pressure up to 1 hour after application. FAST dressing showed the highest efficacy because of the exogenous delivery of concentrated fibrinogen and thrombin to the wound, which bypasses coagulopathy and secures hemostasis.

Comparative study of the efficacy of the common topical hemostatic agents with fibrin sealant in a rabbit aortic anastomosis model.

OBJECTIVE: The purpose of this study was to compare the hemostatic efficacy of the common surgical hemostatic agents with fibrin sealant (FS) and to assess their functional strength to secure hemostasis in lieu of placing additional sutures. METHODS: End-to-end anastomosis of transected abdominal aorta was performed in moderately anticoagulated rabbits using 4 or 6 interrupted sutures. The suture line was covered either with gauze alone ("untreated") or with gauze plus Gelfoam, Avitene, Surgicel, FloSeal, or FS, following which blood flow was restored. Blood loss was absorbed by gauze and measured. The surviving rabbits were recovered and the repaired vessel was examined histologically 4 weeks after operation. The investigators were blinded to the treatment groups. Aortic anastomoses using 8 or 12 sutures (untreated) were also performed. RESULTS: Untreated 4-suture anastomosis of aorta resulted in a profuse hemorrhage with an average 108.0 +/- 19.2 (mean +/- SD) ml blood loss and 100% mortality (n = 4). FS application sealed the anastomoses, prevented blood loss (P < 0.01 vs untreated) and exsanguination of the rabbits (n = 4). Other hemostatic agents reduced the bleeding to varying degrees compared to the untreated animals (Gelfoam 66.4 +/- 17.6, Avitene 80.6 +/- 34, Surgicel 66.7 +/- 16.7, FloSeal 44.2 +/- 8.5 ml blood loss, n = 4/group), but the changes were not statistically significant. One to three rabbits in each group survived the operation. Six-suture aortic anastomoses, untreated, resulted in 67.7 +/- 21.8 ml blood loss and 100% survival (n = 6). Application of FS produced immediate and sustained hemostasis in all the animals (P < 0.01 vs untreated). Other hemostatic agents also reduced the bleeding (Gelfoam 42.5 +/- 10, Avitene 50.9 +/- 12.4, Surgicel 32.1 +/- 14, FloSeal 33.9 +/- 5.4 ml blood loss, n = 6/group), but the changes were not statistically significant. The 8- and 12-suture aorta repairs resulted in a moderate blood loss (43.9 +/- 19 and 21.3 +/- 14.9 ml, respectively), followed by a stable hemostasis that precluded the need to use any hemostatic agent. The aortic cross-clamping time of the 12-suture and time to hemostasis for both the 8- and the 12-suture techniques were significantly longer than those of the 4-suture plus FS application (P < 0.01, P < 0.01 and P < 0.05, respectively). CONCLUSION: In a moderate coagulopathy, FS was proven to be the most efficacious hemostatic agent, producing immediate and sustained hemostasis at the arterial anastomotic site. This high efficacy is in part attributed to the strong tissue adhesive property of this agent. FS application may potentially ease the anastomosis and shorten the duration of timely critical vascular procedures.

Comparative study of the hemostatic efficacy of a new human fibrin sealant: is an antifibrinolytic agent necessary?

BACKGROUND: Sustained hemostasis by fibrin sealant (FS) is critically important when it is used in trauma surgery. To purportedly delay fibrin degradation and prevent premature hemostatic failure, some FS products added an antifibrinolytic agent (e.g., bovine aprotinin). The purpose of this study was to compare the overall hemostatic efficacy of a new inhibitor-free FS obtained from the American Red Cross (ARC-FS) to a clinically available aprotinin-containing FS preparation (Tisseel). The need for addition of an antifibrinolytic agent was assessed under normal and high-fibrinolytic conditions. METHODS: The abdominal aortas of anesthetized rabbits were transected and anastomosed, end-to end, using only four interrupted sutures. The suture line was covered with approximately 2 mL of either type of FS and blood flow was restored. Blood loss was absorbed by gauze and measured. All rabbits were recovered and underwent histologic examination 4 weeks after operation. The efficacy of FS was also tested under a high-fibrinolytic state by treating the rabbits with human recombinant tissue plasminogen activator (0.15 mg/kg, 3-hour infusion). The investigators were blinded to the treatment groups. RESULTS: The majority (11 of 12) of deaths occurred because of bleeding at the suture line within 7 days of surgery. Sustained hemostasis by FS (>1 week) was required for normal tissue healing and long-term survival of animals. Application of ARC-FS to the suture line produced immediate hemostasis in 43% of animals (three of seven), with mean blood loss of 4.8 +/- 1.8 mL, and 86% long-term survival. Tisseel application produced immediate hemostasis in 13% of animals (one of eight), with mean blood loss of 26.9 +/- 7.0 mL (p < 0.05 vs. ARC-FS) and survival rate of 37% (three of eight). Under high-fibrinolytic conditions, ARC-FS produced immediate and complete hemostasis in seven of eight animals (88%), whereas the Tisseel demonstrated complete hemostasis in one of seven (p < 0.01). The ARC-FS rabbits had a blood loss of 1.9 +/- 1.9 mL and survival rate of 75% (six of eight), whereas the Tisseel animals had a mean blood loss of 30 +/- 6.0 mL and survival rate of 43% (three of seven) (p < 0.01). No detrimental effect on healing was noted with either product. CONCLUSION: ARC-FS provides effective and secure hemostasis against high-pressure arterial bleeding under both normal and high-fibrinolytic conditions. Addition of an antifibrinolytic agent such as aprotinin is not required to sustain the hemostatic function of this fibrin sealant.