Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial

Moore, Ernest E.; Moore, Frederick A.; Fabian, Timothy C.; Bernard, Andrew C.; Fulda, Gerard J.; Hoyt, David B.; Duane, Therèse M.; Weireter, Leonard J.; Gómez, Gerardo; Cipolle, Mark; Rodman, George H.; Malangoni, Mark A.; Hides, George A.; Omert, Laurel; Gould, Steven A.

doi:10.1016/j.jamcollsurg.2008.09.023

Cited by 219 publications

(183 citation statements)

References 56 publications

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“…This urgent rush has resulted in a number of failures. Two of the more successful ones are Polyhemoglobin (Jahr et al 2008, Moore et al 2009) and pegylated hemoglobin (Winslow 2006, Liu andXiu 2008).…”

Section: Introductionmentioning

confidence: 99%

“…(Chang 1971, Chang 2007 The commercial products are prepared using hemoglobin containing no RBC enzymes like superoxide dismutase, catalase and carbonic anhydrase. (Jahr et al 2008, Moore et al 2009) PolyHb has advantages of more than 1 year storage at room temperature, free from infective agents, no blood group antigens and unlimited supply. It has been tested extensively in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Bian

Gao

Chang

2013

Artificial Cells, Nanomedicine, and Biotechnology

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Even though erythrocytes transport both oxygen and carbon dioxide, research on blood substitutes has concentrated on the transport of oxygen and its vasoactivity and oxidative effects. Recent study in a hemorrhagic shock animal model shows that the degree of tissue PCO 2 elevation is directly related to mortality rates. We therefore prepared a novel nanobiotechnological carrier for both O 2 and CO 2 with enhanced antioxidant properties. This is based on the use of glutaraldehyde to crosslink stroma free hemoglobin (SFHb), superoxide dismutase (SOD), catalase (CAT) and carbonic anhydrase(CA)to form a soluble PolySFHb-SOD-CAT-CA. It was compared to blood and different resuscitation fluids on the ability to lower elevated tissue PCO 2 in a 2/3 blood volume loss rat hemorrhagic shock model. Sixty minutes of sustained hemorrhagic shock at 30 mm Hg resulted in the increase of tissue PCO 2 to 95 mm ± 3 mmHg from the control level of 55 mm Hg. Reinfusion of whole blood (Hb 15 g/dL with its RBC enzymes) lowered the tissue PCO2 to 72 ± 4.5 mmHg 60 minutes after reinfusion. PolySFHb-SOD-CAT-CA (SFHb 10 g/dL plus additional enzymes) was more effective than whole blood in lowering PCO 2 lowering this to 66.2 ±3.5 mmHg. Ringer's Lactated solution or polyhemoglobin lowered the elevated PCO2 only slightly to 87 ± 4.5 mmHg and 84.8 ± 1.5 mmHg, respectively. Moreover, ST-elevation for whole blood (Hb 15 g/dL) and PolySFHb-SOD-CAT-CA (Hb 10 g/dL) was respectively 12.8% ± 4% and 13.0% ± 2% of the control 60 minutes after reinfusion. Both are significantly better than those in the Ringer's lactated group and the PolyHb group. In conclusion, this novel approach for blood substitute design has resulted in a novel nanobiotechnological carrier for both O 2 and CO 2 with enhanced antioxidant properties.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Bian

Gao

Chang

2013

Artificial Cells, Nanomedicine, and Biotechnology

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“…Red blood cell substitutes have many advantages over human donor blood: they are sterilized, free of infectious agents, universally bio-compatible, have a longer shelf life, and can be made available in large quantities [3,6,9]. There are different approaches for the preparation of hemoglobin-based blood substitutes: one of these is polyhemoglobin.…”

Section: Introductionmentioning

confidence: 99%

“…Bifunctional agents can crosslink hemoglobin into polyhemoglobin (polyHb) [1,2]. This has been developed by many groups [3][4][5][6]9,10]. PolyHb have been studied in Phase III clinical trials in the USA, and are approved for routine clinical use in South Africa [6,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…This has been developed by many groups [3][4][5][6]9,10]. PolyHb have been studied in Phase III clinical trials in the USA, and are approved for routine clinical use in South Africa [6,9,10]. In the preparation of polyHb, it is first necessary to isolate hemoglobin and purify it from contaminants such as red blood cell membrane, remnants of platelets, or other components.…”

Section: Introductionmentioning

confidence: 99%

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Use of the Labscale Tangential Flow Diafiltrator to Remove Tetrameric Hemoglobin from Polyhemoglobin, Purify Hemolysate, and Concentrate Polyhemoglobin

Stefanescu

Chang

2009

Artificial Cells, Blood Substitutes, and Biotechnology

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The Labscale tangential flow diafiltration system in conjunction with polyethersulfone Biomax filters (both purchased from Millipore Inc.) were used in the following studies: (1) A crucial step in the preparation of polyhemoglobin (polyHb) is the removal of tetrameric hemoglobin (Hb), which can cause adverse side-effects. The efficiency for this depends on the integrity of the 100 kDa filters. Those with lower integrity were not effective whereas those with a higher integrity of 0.075 ml/min were more effective. A filter with an integrity of 0.075 ml/min can reduce the initial 11.2% tetrameric Hb concentration to 1.3% using a flow rate of 0.2 ml/min. Higher flow rate of 2.2 ml/min was not as effective. (2) Filtration with a 100 kDa filter was quick and efficient in separating stroma-free hemoglobin solutions from cellular debris from hemolysate. (3) Both 5 kDa and 100 kDa filters are efficient in concentrating hemoglobin solutions.

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Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Holcomb¹,

Tilley

Baraniuk

et al. 2015

JAMA

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2,006

1,561

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IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232

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Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial

Cited by 219 publications

References 56 publications

Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Use of the Labscale Tangential Flow Diafiltrator to Remove Tetrameric Hemoglobin from Polyhemoglobin, Purify Hemolysate, and Concentrate Polyhemoglobin

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

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Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial

Cited by 219 publications

References 56 publications

Lowering of elevated tissue PCO2in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Lowering of elevated tissue PCO2in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Use of the Labscale Tangential Flow Diafiltrator to Remove Tetrameric Hemoglobin from Polyhemoglobin, Purify Hemolysate, and Concentrate Polyhemoglobin

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Contact Info

Product

Resources

About

Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties

Lowering of elevated tissue PCO₂in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties