Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-27T09:18:15.499Z Has data issue: false hasContentIssue false
  • English
  • Français

A Safety Assessment of Diaspirin Cross-Linked Hemoglobin (DCLHb) in the Treatment of Hemorrhagic, Hypovolemic Shock

Published online by Cambridge University Press:  28 June 2012

Robert J. Przybelski ,
Elaine K. Daily ,
Jean Micheels ,
Edward Sloan ,
Pierre Mols ,
Luc Corne ,
Max D. Koenigsberg ,
William H. Bickell ,
Dan R. Thompson  and
Jay D. Harviel
...Show all authors
Robert J. Przybelski
Affiliation:
Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin USA; former Medical Vice President, Hemoglobin Therapeutics, Baxter Healthcare, Round Lake, Illinois, USA
Elaine K. Daily*
Affiliation:
Cardiovascular Research and Education Consulting, Madison, Wisconsin, USA
Jean Micheels
Affiliation:
Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier Universitaire, Liége, Belgium
Edward Sloan
Affiliation:
Trauma Emergency Services, Cook County Hospital, Chicago, Illinois, USA
Pierre Mols
Affiliation:
Service des Urgences, Hopital Saint Pierre, Brussels, Belgium
Luc Corne
Affiliation:
Academisch Zeikenhuis Vrije, Universiteit Brussels, Brussels, Belgium
Max D. Koenigsberg
Affiliation:
Department of Emergency Medicine, Illinois Masonic Medical Center, Chicago, Illinois, USA
William H. Bickell
Affiliation:
Emergency Department, Saint Francis Hospital, Tulsa, Oklahoma, USA
Dan R. Thompson
Affiliation:
Intensive Care Unit and Trauma Life Support Center, The Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
Jay D. Harviel
Affiliation:
MedSTAR Trauma Unit, Washington Hospital Center, Washington, DC, USA
Stephen M. Cohn
Affiliation:
Formerly, Trauma Service, Yale University School of Medicine, New Haven, Connecticut, USA
*
FCCM 5887 Woods Edge Road Madison, Wisconsin 53711 USA
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

To determine the safety and possible efficacy of diaspirin cross-linked hemoglobin (DCLHb) in the treatment of patients in Class II–IV hemorrhagic, hypovolemic shock.

Design:

Multicenter, randomized, normal saline-controlled, dose-escalation study.

Setting:

Eleven hospitals in the U.S. and Belgium.

Subjects:

One hundred and thirty-nine (139) hospitalized patients with Class II–IV hemorrhagic, hypovolemic shock within the previous 4 hours who still were requiring therapy for shock.

Interventions:

Beginning with the lowest dose, patients were randomized to receive 50,100, or 200 mL of either 10% DCLHb or normal saline infused intravenously over 15 minutes. Following infusion of either treatment, further fluid resuscitation could be given, as necessary, to maintain perfusion. Vital signs, laboratory assessments, blood and fluid administration, complications, and adverse events were recorded at various times from the end of infusion through 72 hours after infusion.

Results:

A total of 29 (13 DCLHb- and 16 saline-treated) patients died during the study period. Adverse events were experienced by 61% of patients in the DCLHb group and 53% of patients in the saline group; serious adverse events occurred in 28% of DCLHb-treated patients and 30% of saline-treated patients. The incidence of prospectively defined, clinical complications, including renal insufficiency and renal failure, was similar between the treatment groups except for the occurrence of dysrhythmias/conduction disorders, which occurred significantly more frequently in the saline-treated patients than the DCLHb-treated patients (p = 0.041). At the highest dose level (200 mL), statistically significant between-group differences were observed with greater increases in serum amylase, LDH, the isoenzymes LD1,2,4 and 5, and CK-MB in the DCLHb group compared to the control group; none were of clinical significance. The volume of blood administered did not differ between the groups. Overall 24- and 72-hour survival rates were similar between treatment groups, although the hospital discharge rate was slightly higher in the DCLHb-treated patients (80%) compared with the saline-treated patients (74%).

Conclusion:

Administration of 50 to 200 mL of DCLHb to patients in hemorrhagic, hypovolemic shock was not associated with evidence of end organ toxuity or significant adverse events. Further studies involving larger doses and, perhaps, earlier administration of DCLHb are warranted.

Keywords

bloodcross-linked hemoglobindiaspirinefficacyhemoglobin solutionshemophagiehypobolemic shockoxygen deliverypressorresuscitation solutionssafetytrauma
Type
Original Research
Information
Prehospital and Disaster Medicine , Volume 14 , Issue 4 , December 1999 , pp. 47 - 60
Copyright
Copyright © World Association for Disaster and Emergency Medicine 1999

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Dove, DB, Stahl, WM, DelGuercio, LRM: Five year review of deaths following urban trauma. J Trauma 1980;20(9):760–766.CrossRefGoogle ScholarPubMed
2. Falk, JL, O'Brien, JF, Kerr, R: Fluid resuscitation in traumatic hemorrhagic shock. Crit Care Clinks 1992;8(2):323–340.CrossRefGoogle ScholarPubMed
3. Bickell, WH, Wall, MJ Jr, Pepe, PE et al. : Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105–1109.CrossRefGoogle ScholarPubMed
4. Dodd, RY: The risk of transfusion-transmitted infection. N Engl J Med 1992;327:419–421.CrossRefGoogle ScholarPubMed
5. Klein, HG: Allogeneic transfusion risks in the surgical patient. Am J Surg 1995;170(6A):21S–26S.CrossRefGoogle ScholarPubMed
6. Amberson, WR, Jennings, JJ, Rhode, CM: Clinical experience with hemoglobin saline solutions. J Appl Physiol 1949;1(7):469–489.CrossRefGoogle ScholarPubMed
7. Savitsky, JP, Doczi, J, Black, J, Arnold, JD: A clinical safety trial of stromafree hemoglobin. Clin Pharmacol Ther 1978;23:73–80.CrossRefGoogle Scholar
8. Feola, MJ, Simoni, J, Canizaro, PC, Traqn, R, Raschbaum, G, Behal, FJ: Toxicity of polymerized hemoglobin solutions. Surg Gynecol Obstet 1988;166:211–222.Google ScholarPubMed
9. Przybelski, RJ, Malcolm, DS, Burris, DG, Winslow, RM: Cross-linked hemoglobin solution as a resuscitative fluid after hemorrhage in the rat. J Lab Clin Med 1991;117(2):143–151.Google ScholarPubMed
10. Malcolm, D, Kissinger, D: Diaspirin cross-linked hemoglobin solution as a resuscitative fluid following severe hemorrhage in the rat. Biomat Art Cells Immobil Biotech 1992;20:495–497.Google ScholarPubMed
11. Dunlap, E, Farrell, L, Marchand, G, Gillies, B, Estep, T, Burhop, K: New blood product: Diaspirin cross-linked hemoglobin as a blood substitute. Efficacy in a pig model of hemorrhagic shock. Transfusion 1992;32S–9S.Google Scholar
12. Malcolm, D, Andrus, J: Exchange-transfusion with diaspirin cross-linked hemoglobin in rats. Circ Shock 1992;37(1):19. Abstract.Google Scholar
13. Cohn, SM, Farrell, TJ: Diaspirin cross-linked hemoglobin resuscitation of hemorrhage: Comparison of a blood substitute with hypertonic saline and isotonic saline. J Trauma: Injury Infection Crit Care 1995;39(2): 210–217.CrossRefGoogle ScholarPubMed
14. Schultz, SC, Hamilton, IN, Malcolm, DS: Use of base deficit to compare resuscitation with lactated Ringer's solution, haemaccel, whole blood, and diaspirin cross-linked hemoglobin following hemorrhage in rats. J Trauma 1993;35(4):619–626.CrossRefGoogle ScholarPubMed
15. Powell, CC, Schultz, SC, Burris, DG, Drucker, WR, Malcolm, DS: Resuscitation with diaspirin cross-linked hemoglobin (DCLHb) restores subcutaneous oxygen tension as well as blood in rats. Surg Forum 1993;44:40–42.Google Scholar
16. Frankel, HL, Nguyen, HB, Shea-Donohue, T, Alton, L, Ratigan, J, Malcolm, DS: Diaspirin cross-linked hemoglobin (DCLHb) is efficacious in gut resuscitation as measured by a GI tract optode. J Trauma 1996;40(2):231–241.CrossRefGoogle ScholarPubMed
17. Schultz, SC, Powell, CC, Burris, DG, Nguyen, H, Jaffin, J, Malcolm, DS: The efficacy of diaspirin crosslinked hemoglobin solution resuscitation in a model of uncontrolled hemorrhage. J Trauma 1994;3(73):408–412.CrossRefGoogle Scholar
18. McKenzie, JE, Scandling, DM, Rohrer, MJ, Jacot, JL: Diaspirin crosslinked hemoglobin (DCLHb): Improvement in regional blood flow following administration in hypovolemic shock in the swine. Vtb Int'l Symposium on Blood Substitutes 1993 Program and Abstracts.Google Scholar
19. Gulati, A, Sen, AP, Singh, R: Diaspirin crosslinked hemoglobin, a hemoglobin-based blood substitute, improves the survival and regional blood circulation in severely hemorrhaged rats. Artif Cells Blood Subs Immobil Biotech 1996;24(4):344. Abstract.Google Scholar
20. Zingarelli, B, Squadrito, F, Altavilla, D, Calapai, G, Campo, GM, Calo, M, Saitta, A, Caputi, AP: Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock. J Cardiovasc Pharmacol 1992;19:982–986.CrossRefGoogle ScholarPubMed
21. Yao, Y-M, Bahrami, S, Leichtfried, G, Redl, H, Schlag, G: Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats. Am J Physiol 1996;270:H1616–1623.Google ScholarPubMed
22. Sharma, AC, Gulati, A: Role of nitric oxide in cardiovascular effects of diaspirin cross-linked (DCLHb) and stroma reduced hemoglobin (SRHb). FASEBJ 1994;8(5):A625. Abstract.Google Scholar
23. Xu, L, Sun, L, Rollwagen, FM, Li, Y, Pacheco, N, Pikoulis, E, Leppniemi, A, Soltero, R, Burris, D, Malcolm, D, Nielsen, TB: Cellular response to surgical trauma, hemorrhage, and resuscitation with diaspirin crosslinked hemoglobin in rats. J Trauma 1997;42(1):32–1.CrossRefGoogle ScholarPubMed
24. Birnbaum, ML, Lipman, J, Garrioch, M, Daily, E, Przybelski, R: Diaspirin cross-linked hemoglobin (DCLHb) vs. blood in acutely anemic patients. Intensive Care Med 1997;23 (Supplement 1):S85. Abstract.Google Scholar
25. Malcolm, DS, Hamilton, IN, Schultz, SC, Cole, F, Burhop, K: Characterization of the hemodynamic response to intravenous diaspirin crosslinked hemoglobin solution in rats. Art Cells Blood Subs and Immob Biotech 1994;22(1):91–107.CrossRefGoogle ScholarPubMed
26. Sharma, AC, Gulati, A: Effect of diaspirin cross-linked hemoglobin and norepinephrine on systemic hemodynamics and regional circulation in rats. J Lab Clin Med 1994;123(2):299–308.Google ScholarPubMed
27. Gulati, A, Singh, G, Rebello, S, Sharma, AC: Effect of diaspirin crosslinked and stroma-reduced hemoglobin on mean arterial pressure and endothelin-1 concentration in rats. Life Sciences 1995;56(17):1433–1442.CrossRefGoogle ScholarPubMed
28. Gulati, A, Rebello, S: Diaspirin crosslinked hemoglobin (DCLHbTM): Involvement of adrenergic mechanisms in the pressor effect. Artif Cells Blood Subs and Immob Biotech 1994;22(3):603–612.CrossRefGoogle Scholar
29. Przybelski, RJ, Daily, EK, Kisicki, JC, Goldberg, CM, Bounds, MJ, Colburn, WA: Phase I study of the safety and pharmacologic effects of diaspirin cross-linked hemoglobin solution. Crit Care Med 1996;24(12):1993–2000.CrossRefGoogle ScholarPubMed
30. Swan, SK, Halstenson, CE, Collins, AJ, Colburn, WA, Blue, J, Przybelski, RJ: Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients. Amer J Kid Dis 1995;26(6):918–923.CrossRefGoogle ScholarPubMed
31. Garrioch, M, Larbuisson, R, Brichant, JF, Lamy, M, Daily, E, Pryzbelski, R: The hemodynamic effects of diaspirin cross-linked hemoglobin (DCLHb) in the operative setting. Crit Care Med 1996;24(1):A39. AbstractGoogle Scholar
32. Rhea, G, Bodenham, AR, Mallick, A, Przybelski, R, Daily, EK: Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb) as a vasopressor in critically ill patients. Crit Care Med 1997;25(9):1480–1488.CrossRefGoogle Scholar
33. Azari, M, Rohn, K, Picken, J: Diaspirin cross-linked hemoglobin (DCLHbTM): Characterization of the process and the product manufactured under GMP requirements for clinical studies. Art Cells Blood Subs and Immob Biotech 1994;22(3):701–708.CrossRefGoogle Scholar
34. Estep, TM, Bechtel, MK, Miller, TJ, Bagdasarian, A: Virus inactivation in hemoglobin solutions by heat. Biomat Art Cells Art Org 1988;16:129–134.Google ScholarPubMed
35. Ryan, S, Sandler, A, Trenhaile, S, Ephgrave, K, Garner, S: Pancreatic enzyme elevations after blunt trauma. Surgery 1994;116:622–627.Google ScholarPubMed
36. Boulanger, BR, Milzman, DP, Rosaati, C, Rodriguez, A: The clinical significance of acute hyperamylasemia after blunt trauma. Can J Surg 1993;36:63–69.Google ScholarPubMed
37. Bouwman, DL, Weaver, DW, Walt, AJ: Serum amylase and its isoenzymes: A clarification of their implications in trauma. J Trauma; 1984:573–578.CrossRefGoogle Scholar
38. Takahashi, M, Maemura, K, Sawada, Y, Yoshioka, T, Sugimoto, T: Hyperamylasemia in critically injured patients. J Trauma 1980;20:951–955.CrossRefGoogle ScholarPubMed
39. Jurkovich, GJ and Carrico, CJ: Pancreatic trauma. Surg Clin North Am 1990;70:575–593.CrossRefGoogle ScholarPubMed