Re-analysis of the PolyHeme Phase III trial dataset: Lessons for future haemoglobin-based oxygen carrier trauma trials
INTRODUCTION To assist design of future HBOC clinical trials for pre-hospital and prolonged field care, the haemoglobin-based-oxygen carrier (HBOC) Phase III trauma trial database comparing PolyHeme to blood transfusion was re-analysed to identify causes of adverse early outcomes versus the 30-day mortality outcome of the original trial. We questioned if failure of PolyHeme (10 g/dl) to increase haemoglobin concentration and dilutional coagulopathy versus blood, caused higher Day 1 mortality in the PolyHeme arm of the trial. METHODS New analyses of the original trial database, including Fisher's exact test, examined impact of interval changes in total haemoglobin [THb], coagulation, fluid volumes administered and mortality on Day 1 in the Control (pre-hospital crystalloids, then blood after trauma centre admission) and PolyHeme arms of the trial. RESULTS Admission [THb] was significantly greater (p<0.05) in PolyHeme (12.3 [SD = 1.8] g/dl) versus Control (11.5 [SD= 2.9] g/dl) patients. This early [THb] advantage was reversed within 6 h. Early mortality was negatively correlated with [THb] and maximum 1.4 h after hospital admission (17/365 for Control vs. 5/349 for PolyHeme). The mortality trend began reversing, when Control arm received blood. Coagulopathy was more common in the PolyHeme arm. Mortality rate was 2-fold greater for patients with coagulopathy in the control arm (18% vs. 9%, p = 0.1008) and 4-fold greater in PolyHeme arm (33% vs. 8.5%, p < 0.001). In a subgroup analysis of patients with major haemorrhage (n = 55), mortality was significantly higher in PolyHeme patients [12/26 (46.2%) versus 4/29 (13.8%) in control cohort (p = 0.018)], related to mean 10 liters more IV fluid administration and more severe anaemia (6.2 g/dL vs. 9.2 g/dL) in the PolyHeme cohort. CONCLUSIONS PolyHeme (10 g/dL) diminished pre-hospital anaemia. The inability of PolyHeme to reverse acute anaemia in a subset of major haemorrhage patients was due to volume overload secondary to high PolyHeme doses, resulting in dilution of clotting factors and low circulating THb (versus transfused controls) during the first 12 h of the trial. Haemodilution was associated with prolonged administration of PolyHeme, while blood transfusion was available to Control patients following hospital admission. Coagulopathy exacerbated bleeding, anaemia, contributing to excess mortality in the PolyHeme arm. Future trials for prolonged field care should evaluate HBOC with higher haemoglobin concentration, lower volume administration and transition upon trauma centre admission to blood plus coagulation factors or whole blood.
Relative efficacies of HBOC-201 and polyheme to increase oxygen transport compared to blood and crystalloids. "2017 Military Supplement"
Shock (Augusta, Ga.). 2017
BACKGROUND Because total hemoglobin in circulation ([THb]) is an established predictor of clinical outcomes in anemic individuals, the relative efficacies of resuscitation fluids to increase [THb] can be used to design better hemoglobin-based oxygen carrier (HBOC) clinical trials. METHODS Expected efficacies of HBOC-201 (13 g Hb/dL) and packed RBCs (pRBCs, 24 g Hb/dL) to increase [THb] were calculated and interpreted in the context of SAEs in the HEM-0115 phase III clinical trial.The PolyHeme phase III clinical trial compared the HBOC, PolyHeme (10 g Hb/dL), to crystalloid control prehospital and packed RBCs in hospital. The comparative abilities of these resuscitation fluids to maintain [THb] were interpreted in the context of mortality. RESULTS In HEM-0115, infusion of HBOC-201 increased [THb] by 0.18 +/- 0.03 g/dL (N=121) compared to 0.87 +/- 0.07 g/dL (N = 115) following one unit of pRBCs. These observed increases in [THb] were similar to expected increases for these fluids. Use of HBOC-201 was associated with 0.34 SAEs per patient compared to 0.25 SAEs per patient in the pRBC arm (p = 0.016).Hemoglobin (Hb) Deficit was greater in HBOC-201-treated patients than in pRBC controls and emerged as a predictor of SAEs in a logistics model. Randomization to HBOC-201 had no power to predict SAEs.PolyHeme more effectively maintained [THb] than did crystalloid prior to arrival at hospital, associated with initially higher survival in the PolyHeme arm. Thereafter, PolyHeme subjects sustained lower [THb] and higher mortality than controls. CONCLUSION Greater anemia in subjects randomized to HBOC-201 was consistent with the relative efficacies of HBOC-201 and pRBCs to increase [THb] and may have contributed to more SAEs in the HBOC arm of HEM-0115 and greater long-term mortality in the PolyHeme trial.
Emergency resuscitation of patients enrolled in the US Diaspirin Cross-linked Hemoglobin (DCLHb) Clinical Efficacy Trial
Prehospital & Disaster Medicine. 2015;30((1):):54-61.
UNLABELLED Introduction Optimal emergent management of traumatic hemorrhagic shock patients requires a better understanding of treatment provided in the prehospital/Emergency Medical Services (EMS) and emergency department (ED) settings. Hypothesis/Problem Described in this research are the initial clinical status, airway management, fluid and blood infusions, and time course of severely-injured hemorrhagic shock patients in the EMS and ED settings from the diaspirin cross-linked hemoglobin (DCLHb) clinical trial. METHODS Data were analyzed from 17 US trauma centers gathered during a randomized, controlled, single-blinded efficacy trial of a hemoglobin solution (DCLHb) as add-on therapy versus standard therapy. RESULTS Among the 98 randomized patients, the mean EMS Glasgow Coma Scale (GCS) was 10.6 (SD = 5.0), the mean EMS revised trauma score (RTS) was 6.3 (SD = 1.9), and the mean injury severity score (ISS) was 31 (SD = 17). Upon arrival to the ED, the GCS was 20% lower (7.8 (SD = 5.3) vs 9.7 (SD = 6.3)) and the RTS was 12% lower (5.3 (SD = 2.0) vs 6.0 (SD = 2.1)) than EMS values in blunt trauma patients (P < .001). By ED disposition, 80% of patients (78/98) were intubated. Rapid sequence intubation (RSI) was utilized in 77% (60/78), most often utilizing succinylcholine (65%) and midazolam (50%). The mean crystalloid volume infused was 4.2 L (SD = 3.4 L), 80% of which was infused within the ED. Emergency department blood transfusion occurred in 62% of patients, with an average transfused volume of 1.2 L (SD = 2.0 L). Blunt trauma patients received 2.1 times more total fluids (7.4 L vs 3.5 L, < .001) and 2.4 times more blood (2.4 L vs 1.0 L, P < .001). The mean time of patients taken from injury site to operating room (OR) was 113 minutes (SD = 87 minutes). Twenty-one (30%) of the 70 patients taken to the OR from the ED were sent within 60 minutes of the estimated injury time. Penetrating trauma patients were taken to the OR 52% sooner than blunt trauma patients (72 minutes vs 149 minutes, P < .001). CONCLUSION Both GCS and RTS decreased prior to ED arrival in blunt trauma patients. Intubation was performed using RSI, and crystalloid infusion of three times the estimated blood loss volume (L) and blood transfusion of the estimated blood loss volume (L) were provided in the EMS and ED settings. Surgical intervention for these trauma patients most often occurred more than one hour from the time of injury. Penetrating trauma patients received surgical intervention more rapidly than those with a blunt trauma mechanism. Sloan EP , Koenigsberg M , Weir WB , Clark JM , O'Connor R , Olinger M , Cydulka R . Emergency resuscitation of patients enrolled in the US diaspirin cross-linked hemoglobin (DCLHb) clinical efficacy trial. Prehosp Disaster Med. 2015;30(1):1-8 .
The USA Multicenter Prehosptial Hemoglobin-based Oxygen Carrier Resuscitation Trial: scientific rationale, study design, and results
Critical Care Clinics. 2009;25((2):):325-56.
Human polymerized hemoglobin (PolyHeme) is a universally compatible oxygen carrier developed for use when red blood cells are unavailable and oxygen-carrying replacement is needed to treat life-threatening anemia. This multicenter phase III trial assessed survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Patients resuscitated with PolyHeme had outcomes comparable to those receiving the standard of care including rapid access to stored red blood cells. Although there were more adverse events in the PolyHeme group compared with control patients receiving blood, the observed safety profile is acceptable for the intended population. The benefit-to-risk ratio of PolyHeme is favorable when blood is needed but is not available or an option.
Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial
Journal of the American College of Surgeons. 2009;208((1):):1-13.
BACKGROUND Human polymerized hemoglobin (PolyHeme, Northfield Laboratories) is a universally compatible oxygen carrier developed to treat life-threatening anemia. This multicenter phase III trial was the first US study to assess survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. STUDY DESIGN Injured patients with a systolic blood pressure≤90 mmHg were randomized to receive field resuscitation with PolyHeme or crystalloid. Study patients continued to receive up to 6 U of PolyHeme during the first 12 hours postinjury before receiving blood. Control patients received blood on arrival in the trauma center. This trial was conducted as a dual superiority/noninferiority primary end point. RESULTS Seven hundred fourteen patients were enrolled at 29 urban Level I trauma centers (79% men; mean age 37. 1 years). Injury mechanism was blunt trauma in 48%, and median transport time was 26 minutes. There was no significant difference between day 30 mortality in the as-randomized (13. 4% PolyHeme versus 9. 6% control) or per-protocol (11. 1% PolyHeme versus 9. 3% control) cohorts. Allogeneic blood use was lower in the PolyHeme group (68% versus 50% in the first 12 hours). The incidence of multiple organ failure was similar (7. 4% PolyHeme versus 5. 5% control). Adverse events (93% versus 88%; p=0. 04) and serious adverse events (40% versus 35%; p=0. 12), as anticipated, were frequent in the PolyHeme and control groups, respectively. Although myocardial infarction was reported by the investigators more frequently in the PolyHeme group (3% PolyHeme versus 1% control), a blinded committee of experts reviewed records of all enrolled patients and found no discernable difference between groups. CONCLUSIONS Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.
Hemoglobin-based oxygen carriers in trauma care: scientific rationale for the US multicenter prehosptial trial
World Journal of Surgery. 2006;30((7):):1247-57.
BACKGROUND The greatest need for blood substitutes worldwide is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes derived from hemoglobin. The hemoglobin-based oxygen carriers (HBOCs) tested currently in advanced clinical trials are polymerized hemoglobin solutions. METHODS In the USA, the standard approach to restoring oxygen delivery for hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. Allogeneic RBCs, however, may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II in hospital clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with an HBOC--in lieu of stored RBCs--attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC-provoked polymorphonuclear neutrophil (PMN) priming, endothelial activation, and systemic release of interleukins (IL) 6, 8, and 10. In a 2-event rodent study of shock-induced PMN-mediated acute respiratory distress syndrome (ARDS), the simulated prehospital administration of an HBOC markedly attenuated lung injury. RESULTS Based on this background and work by others, we have initiated a US multicenter prehospital trial in which severely injured patients with major blood loss [systolic blood pressure (SBP) CONCLUSIONS To date, >500 injured patients have been enrolled in this multicenter trial, and the final interim analyses support the original target of 720.
Insights from studies of blood substitutes in trauma
Most authorities believe that the greatest need for blood substitutes is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes, derived from hemoglobin. The hemoglobin-based oxygen carriers (HBOCs) tested currently in FDA Phase III clinical trials are polymerized hemoglobin solutions. The standard approach to restoring oxygen delivery in hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. However, allogenic RBCs may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with a HBOC-in lieu of stored RBCs-attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC provoked neutrophil priming, endothelial activation, and systemic release of interleukins 6,8, and 10. Based on this background and work by others, we have initiated a multicenter prehospital trial in which severely injured patients with major blood loss (systemic blood pressure <90 mmHg) are randomized to initial field resuscitation with crystalloid versus HBOC. During the hospital phase, the control group is further resuscitated with stored RBCs, whereas the study group receives HBOC (up to 6 units) in the first 12 h. The primary study endpoint is 30-day mortality, and secondary endpoints include reduction in allogenic RBCs, hemoglobin levels <5 g/dL, uncrossmatched RBCs, and MOF. The potential efficacy of HBOCs extends beyond the temporary replacement for stored RBCs. Hemoglobin solutions might ultimately prove superior in delivering oxygen to ischemie or injured tissue. The current generation of HBOCs can be lifesaving for acute blood loss today, but the next generation might be biochemically tailored for specific clinical indications. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
Resuscitation with a blood substitute abrogates pathologic postinjury neutrophil cytotoxic function
Journal of Trauma-Injury Infection & Critical Care. 2001;50((3):):449-55; discussion 456.
BACKGROUND Resuscitation with oxygen-carrying fluids is critically important in the patient with hemorrhagic shock caused by trauma. However, it is clear that a number of biologic mediators present in stored blood (packed red blood cells [PRBCs]) have the potential to exacerbate early postinjury hyperinflammation and multiple organ failure through priming of circulating neutrophils (PMNs). PolyHeme (Northfield Laboratories, Evanston, IL), a hemoglobin-based substitute that is free of priming agents, provides an alternative. We hypothesized that PMN priming would be attenuated in patients resuscitated with PolyHeme in lieu of stored blood. METHODS Injured patients requiring urgent transfusion were given either PolyHeme (up to 20 units) or PRBCs. Early postinjury PMN priming was measured via beta-2 integrin expression, superoxide production, and elastase release. RESULTS Treatment groups were comparable with respect to extent of injury and early physiologic compromise. PMNs from patients resuscitated with PRBCs showed priming in the early postinjury period by all three measures. No such priming was evident in patients resuscitated with PolyHeme. CONCLUSION The use of a blood substitute in the early postinjury period avoids PMN priming and may thereby provide an avenue to decrease the incidence or severity of postinjury multiple organ failure.
A safety assessment of diaspirin cross-linked hemoglobin (DCLHb) in the treatment of hemorrhagic, hypovolemic shock
Prehospital & Disaster Medicine. 1999;14((4):):47-60.
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 toxicity or significant adverse events. Further studies involving larger doses and, perhaps, earlier administration of DCLHb are warranted.
The informed consent process and the use of the exception to informed consent in the clinical trial of diaspirin cross-linked hemoglobin (DCLHb) in severe traumatic hemorrhagic shock. DCLHb Traumatic Hemorrhagic Shock study group
Academic Emergency Medicine. 1999;6((12):):1203-9.
UNLABELLED In the clinical trial of diaspirin cross-linked 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 +/-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 +/- 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.