Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb[trademark symbol]) as a vasopressor in critically ill patients

Reah, G.; Bodenham, Andrew; Mallick, A.; Daily, Elaine K.; Przybelski, Robert J.

doi:10.1097/00003246-199709000-00014

Cited by 110 publications

(42 citation statements)

References 30 publications

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“…A well-publicized clinical trial for traumatic hemorrhagic shock was terminated early because of a significantly increased mortality in the patient groups treated with a cross-linked HBOC (HCLHb TM ) relative to the control group (33). Recently reported studies in several small and large animals revealed the development of heart lesions after exchange transfusion with this Hb.…”

Section: Discussionmentioning

confidence: 99%

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

et al. 2007

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SummaryA review of the oxidative and nitrosative reactions of cell-free hemoglobin-based oxygen carriers (HBOCs) shows that these reactions are intimately linked and are subject to allosteric control. Cross-linking reactions used to produce HBOCs introduce conformational constraints and result in Hbs with reduced responses to heterotropic and homotropic allosteric effectors. The Nernst plots of heme oxidation of cross-linked HBOCs are shifted to higher potentials relative to unmodified Hb in the absence of allosteric effectors, in accord with their T-state stabilization and right-shifted Hill plots of O 2 binding. They exhibit enhanced rates of autoxidation and nitrite-induced oxidation, features that appear due to their having more solvent-accessible heme pockets. The stability of their NO-Hb derivatives varies as a result of allosteric effects on the extent of formation of pentacoordinate NO-heme geometry by a chains and subsequent oxidation of partner b chains. The physiological implications of these findings on the safety, efficacy and design of second generation HBOCs are discussed in the framework of a reaction scheme showing linkages between Hbmediated redox reactions. These redox reactions can drive formation of SNO-Hb and other reactive species and are of significance for the use of cell-free Hbs in vivo.

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Section: Discussionmentioning

confidence: 99%

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

et al. 2007

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“…It was also believed, based on the prior work with DCLHb, that the potential benefits to the patients enrolled in this study outweighed the potential risks, even with the use of a consent exception. [8][9][10][11] Although the study intended to include 850 patients, it was halted prematurely based on the recommendation of the independent DMC. This committee was charged with oversight of the consent process and patient safety.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] Diaspirin crosslinked hemoglobin (DCLHb), a purified and chemically modified human hemoglobin solution, was tested in several clinical trials, including this clinical trial, which sought to determine whether it could reduce mortality and morbidity when used as an adjunct to standard therapy in severely injured traumatic hemorrhagic shock patients. [8][9][10][11] To maximize the potential beneficial effects of this solution, this clinical trial required that patients be infused with the study solution within 30 minutes of meeting entry criteria in the participating trauma centers. 12 Given that trauma emergencies are unexpected and that prospective informed consent often is not feasible in such a short time period, this protocol used an exception to informed consent.…”

mentioning

confidence: 99%

The Informed Consent Process and the Use of the Exception to Informed Consent in the Clinical Trial of Diaspirin

Sloan

Koenigsberg

Houghton

et al. 1999

Academic Emergency Medicine

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Abstract. In the clinical trial of diaspirin crosslinked hemoglobin (DCLHb), optimal therapy required the immediate enrollment of patients with severe, uncompensated, traumatic hemorrhagic shock. When it was not feasible to obtain prospective consent, an exception to informed consent was used according to FDA regulation 21 CFR 50.24. Objectives: To examine the informed consent process and the use of the consent exception and consent to continue (CTC), and to describe the patients for whom this process was used. Methods: This was a multicenter, randomized, controlled, single-blinded efficacy trial of DCLHb as an adjunct to standard therapy in the treatment of severe, traumatic hemorrhagic shock. Patients with unstable vital signs or a critical base deficit were treated, with a primary study endpoint of 28-day mortality. Results: During the 11-month study period, 112 patients were randomized in 18 U.S. trauma centers, and data from 98 of the infused patients were analyzed. Prospective consent was obtained from two patients, three family members, and one legally authorized representative (LAR) (6%). Consent to continue was requested for 89 patients (89%), and full participation was granted for 87 of these patients (98%). Consent to continue was provided by 54 (98%) of the 55 patients approached. The mean number of days for family/LAR CTC was 1.1 Ϯ 3.8 days, and 50% of the time it was obtained on the day of study enrollment. Patient CTC was obtained in an average of 13 Ϯ 23 days, with a median of four days. Patients treated in this protocol were more likely to have sustained penetrating trauma than the overall trauma patient population treated in these trauma centers (44% vs 21%, p = 0.002). Conclusions: Informed consent in this study of an emergent therapy most often involved the use of the consent exception and consent to continue, the latter of which occurred in a timely manner. Nearly all of those who were approached for CTC approved full participation in the study, suggesting acceptance of the process outlined in the new regulations. Patients treated in a hemorrhagic shock clinical trial may differ from the general trauma patient population.

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“…Finally, in a trial of critically ill patients, DCLHb was reported to have a "marked vasopressor action, allowing norepinephrine requirements to be reduced," but at 7.5 hours after DCLHb administration there was increased pulmonary vascular resistance with decreased cardiac index and O 2 delivery. 45 Although the authors of the DCLHb trial cited several animal models that appeared to support their study hypothesis, none of these models replicated their study design -a lesson for future conduct of clinical trials with HBOCs. Of note, the mechanisms responsible for the vasoconstriction resulting from DCLHb administration were postulated before the trauma clinical trial was initiated.…”

Section: Clinical Evaluation Of Modified Tetrameric Hb In Trauma Carementioning

confidence: 99%

Emerging Role of Hemoglobin Solutions in Trauma Care

Moore

2005

Transfus Alt Transfus Med

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Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb[trademark symbol]) as a vasopressor in critically ill patients

Cited by 110 publications

References 30 publications

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

Allosteric effects on oxidative and nitrosative reactions of cell‐free hemoglobins

The Informed Consent Process and the Use of the Exception to Informed Consent in the Clinical Trial of Diaspirin

Emerging Role of Hemoglobin Solutions in Trauma Care

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