Oxygen-carrying Resuscitation Fluid Research Articles

US Navy Experience With Research on, and Development of, Hemoglobin-Based Oxygen Carriers

Abstract : Following 9/11 and the advent of the wars in Iraq and Afghanistan, the Naval Medical Research Center (NMRC, Silver Spring, MD} embarked on an effort to develop an improved resuscitation fluid for use in the prehospital phase of care when blood is not available for transfusion. The long-range goal of this program was to develop a multifunctional blood substitute that had oxygen-carrying, hemostatic, and anti-inflammatory capabilities. A shorter-term goal was to deliver an oxygen-carrying resuscitation fluid to both military and civilian trauma medical communities via clinical trial(s) leading to approval from the US Food and Drug Administration (FDA). Trauma is the leading cause of mortality among young adults and causes significant disability among survivors. Exsanguinating hemorrhage causing hemorrhagic shock (HS} has been reported to account for 28% of combat deaths overall and for the preponderance of civilian and potentially salvageable combat deaths (60% vs. 33% and 6% for tension pneumothorax and airway obstruction, respectively). In Operation Iraqi Freedom (Iraq war) and Operation Enduring Freedom (Afghanistan war}, 83% to 87% of potentially survivable fatalities were caused by hemorrhage occurring before hospital arrival in 55% of cases. In the event of traumatic cardiopulmonary arrest, mortality remains unacceptably high (84-98%). Traumatic anemia as a result of blood loss has been correlated directly with mortality.

An Open Letter to Institutional Review Boards Considering Northfield Laboratories’ PolyHeme® Trial

At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme®, an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme® and saline in the field and, still without consent, randomized between PolyHeme® and blood after arrival at an emergency department. The Federal regulations that govern the waiver of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood—the standard treatment for hemorrhagic shock—is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards.

An Open Letter to Institutional Review Boards Considering Northfield Laboratories' PolyHeme® Trial

At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme®, an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme® and saline in the field and, still without consent, randomized between PolyHeme® and blood after arrival at an emergency department. The Federal regulations that govern the waiver of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood—the standard treatment for hemorrhagic shock—is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards.

EFFECTS OF BOVINE POLYMERIZED HEMOGLOBIN ON COAGULATION IN CONTROLLED HEMORRHAGIC SHOCK IN SWINE

HBOC-201, a bovine polymerized hemoglobin, has been proposed as a novel oxygen-carrying resuscitative fluid for patients with hemorrhagic shock (HS). Herein, we evaluated the hemostatic effects of HBOC-201 in an animal model of HS. A 40% blood loss-controlled hemorrhage and soft tissue injury were performed in 24 invasively monitored Yucatan mini-pigs. Pigs were resuscitated with HBOC-201 (HBOC) or hydroxyethyl starch (HEX), or were not resuscitated (NON) based on cardiac parameters during a 4-h prehospital phase. Afterward, animals received simulated hospital care for 3 days with blood or saline transfusions. Hemostasis measurements included in vivo bleeding time (BT), thromboelastography (TEG), in vitro bleeding time (platelet function; PFA-CT), prothrombin time (PT), and partial thromboplastin time (PTT). Serum lactate was measured and lung sections were evaluated for microthrombi by electron microscopy. During the prehospital phase, BT remained unchanged in the HBOC group. TEG reaction time increased in HBOC pigs during the late prehospital phase and was greater than in NON or HEX pigs at 24 h (P = 0.03). TEG maximum amplitude was similar for the two fluid-resuscitated groups. PFA-CT increased in both resuscitated groups but less with HBOC (P = 0.02) in the prehospital phase; this effect was reversed by 24 h (P = 0.02). In the hospital phase, PT decreased (P < 0.02), whereas PTT increased above baseline (P < 0.01). Lactic acidosis in HBOC and HEX groups was similar. Aspartate aminotransferase was relatively elevated in the HBOC group at 24 h. Electron microscopy showed no evidence of platelet/fibrin clots or microthrombi in any of the animals. Twenty-four-hour group differences mainly reflected the fact that all HEX animals (8/8) received blood transfusions compared with only one HBOC animal (1/8). In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase. Mild delayed effects on platelet and clot formation during the hospital phase are transient and likely related to fewer blood transfusions. In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase but more thrombopathy in the hospital phase. The delayed effects on platelet and clot formation during the hospital phase are transient and may be related to the need for fewer blood transfusions.

The life-sustaining capacity of human polymerized hemoglobin when red cells might be unavailable.

Human polymerized hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL) is a universally compatible, immediately available, disease-free, oxygen-carrying resuscitative fluid being developed as a red cell substitute for use in urgent blood loss. PolyHeme should be particularly useful when red cells may be temporarily unavailable. This article assesses survival at life-threatening RBC hemoglobin concentration ([Hb]) in massively bleeding patients who do not receive red cells. There were 171 patients who received rapid infusion of 1 to 20 units (1,000 g, 10 L) of PolyHeme in lieu of red cells as initial oxygen-carrying replacement in trauma and urgent surgery. The protocol simulated the unavailability of red cells, and the progressive fall in RBC [Hb] in bleeding patients was quantified. Thirty-day mortality was compared with a historical control group of 300 surgical patients who refused red cells on religious grounds. A total of 171 patients received rapid infusion of 1 to 2 units (n = 45), 3 to 4 units (n = 45), 5 to 9 units (n = 47), or 10 to 20 units (n = 34) of PolyHeme. Forty patients had a nadir RBC [Hb] < or = 3 g/dL (mean, 1.5 +/- 0.7 g/dL). But total [Hb] was adequately maintained (mean, 6.8 +/- 1.2 g/dL) because of plasma [Hb] added by PolyHeme. The 30-day mortality was 25.0% (10/40 patients) compared with 64.5% (20/31 patients) in historical control patients at these RBC [Hb] levels. PolyHeme increases survival at life-threatening RBC [Hb] by maintaining total [Hb] in the absence of red cell transfusion. PolyHeme should be useful in the early treatment of urgent blood loss and resolve the dilemma of unavailability of red cells.

The Best of the Best—1998

I n an attempt to highlight those articles published in 1998 that contributed most to the better understanding of the practice of clinical surgery, we solicited opinions from a range of surgeons familiar with the literature of their area of expertise. From their thoughtful suggestions, we have distilled this list of “The Best of the Best—1998.” Overall, the articles that have advanced our clinical expertise have been predominantly in the area of critical care. Our hope is that this list will be helpful to you in staying abreast of significant practice-related innovations. Gould SA, Moore EE, Hoyt DB, et al. The First Randomized Trial of Human Polymerized Hemoglobin as a Blood Substitute in Acute Trauma and Emergent Surgery. J Am Coll Surg. 1998;187:113-122. In a randomized trial of 44 trauma patients (ages 19-75 years, with a mean Injury Severity Score of 21), human polymerized hemoglobin, a universally compatible, disease-free, oxygen-carrying resuscitative fluid, was administered to 21 patients and red cell transfusion was used as the treatment for 23 patients. There were no serious or unexpected adverse events related to the polymerized hemoglobin (given in doses up to 6 U). Although 40% of the total circulating hemoglobin was in the plasma of the polymerized hemoglobin infusion group, the total hemoglobin was not different between the groups. Thus, polymerized hemoglobin appears to be safe in replacing acute blood loss and can be a useful blood substitute. After 30 years of investigation, stroma-free polymerized hemoglobin has found its way into the clinical armamentarium. Rozycki GS, Ballard RB, Feliciano DV, Schmidt JA, Pennington SD. Surgeon-Performed Ultrasound for the Assessment of Truncal Injuries. Ann Surg. 1998;228: 557-567. The focused assessment for the sonographic examination of the trauma patient (FAST) is a rapid test that sequentially surveys the pericardial region for hemopericardium and then the right and left upper abdominal quadrants and pelvis for hemoperitoneum in patients with potential truncal injuries. In this report, the examination was performed in 1540 patients (1227 with blunt injury, 313 with penetrating injury) with only 16 false-negative results and 4 false-positive results, for a sensitivity of 83.3% and a specificity of 99.7%. It was most sensitive and specific for the evaluation of patients with blunt abdominal trauma. This ultrasonographic technique should be the initial diagnostic modality for the evaluation of patients with precordial wounds and blunt truncal injuries because it is rapid and accurate, thus leading to immediate surgical intervention when positive in all patients with precordial wounds and in patients with blunt torso trauma who are hypotensive (blood pressure #90 mm Hg). Heald RJ, Moran BJ, Ryall RDH, Sexton R, MacFarlane JK. Rectal Cancer: The Basingstoke Experience of Total Mesorectal Excision, 1978-1997. Arch Surg. 1998; 133:894-899. From a district hospital and referral center in England comes a study of 519 surgical patients with proven adenocarcinoma of the rectum treated by anterior resection (n = 465, with 407 patients having total mesorectal excision under direct vision), abdominoperineal resection (n = 37), Hartmann procedure (n = 10), local excision (n = 4), and laparotomy only (n = 3). Ten percent of the patients received preoperative radiotherapy. Follow-up revealed a cancer-specific survival of all surgically treated patients of 68% at 5 years and 66% at 10 years. The local recurrence rate was 6% at 5 years and 8% at 10 years. In 405 “curative resections,” the local recurrence rate was 3% at 5 years and 4% at 10 years and disease-free survival was 80% at 5 years and 78% at 10 years. Thus, by the technique of mesorectal excision, 2 of 3 patients with rectal cancer can be cured by surgical therapy alone (all stages) and in those undergoing “curative resection,” 4 of 5 patients can experience longterm, disease-free survival. Although total mesorectal excision, as practiced, doubles the operating time, adds to the expense of operation, and is a challenge to surgical skill, it appears to be well worth the effort. Ivatury RR, Porter JM, Simon RJ, Islam S, John R, Stahl WM. Intra-abdominal Hypertension After LifeThreateningPenetratingAbdominalTrauma:Prophylaxis, Incidence, and Clinical Relevance to Gastric Mucosal pH and Abdominal Compartment Syndrome. J Trauma. 1998;44:1016-1023. Intra-abdominal hypertension is frequent after major abdominal trauma. To define the incidence, prophylaxis, and treatment of this phenomenon and its relevance to gut mucosal pH, multiorgan dysfunction syndrome, and the abdominal compartment syndrome, 70 patients with life-threatening penetrating abdominal trauma were monitored at a level I trauma center. Intra-abdominal pressure was estimated by measuring bladder pressure, and gut mucosal pH was evaluated by gastric tonometry every 4 to 6 hours. Intra-abdominal pressure greater than 25 cm of water was treated by bedside or operating room laparotomy. Two groups were compared: patients with loosely applied abdominal wall mesh closure and those

The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery

Background: Human polymerized hemoglobin (PolyHeme) is a universally compatible, disease-free, oxygen-carrying resuscitative fluid. This is the first prospective, randomized trial to compare directly the therapeutic benefit of PolyHeme with that of allogeneic red blood cells (RBCs) in the treatment of acute blood loss. Study Design: Forty-four trauma patients (33 male, 11 female) aged 19–75 years with an average Injury Severity Score (ISS) score of 21 ± 10 were randomized to receive red cells (n = 23) or up to 6 U (300 g) of PolyHeme (n = 21) as their initial blood replacement after trauma and during emergent operations. Results: There were no serious or unexpected adverse events related to PolyHeme. The PolyHeme infusion of 4.4 ± 2.0 units (mean ± SD) resulted in a plasma [Hb] of 3.9 ± 1.3 g/dL, which accounted for 40% of the total circulating [Hb]. There was no difference in total [Hb] between the groups before infusion (10.4 ± 2.3 g/dL control vs. 9.4 ± 1.9 g/dL experimental). At end-infusion the experimental RBC [Hb] fell to 5.8 ± 2.8 g/dL vs. 10.6 ± 1.8 g/dL (p < 0.05) in the control, although the total [Hb] was not different between the groups or from pre-infusion. The total number of allogeneic red cell transfusions for the control and experimental groups was 10.4 ± 4.2 units vs. 6.8 ± 3.9 units (p < 0.05) through day 1, and 11.3 ± 4.1 units vs. 7.8 ± 4.2 units (p = 0.06) through day 3. Conclusions: PolyHeme is safe in acute blood loss, maintains total [Hb] in lieu of red cells despite the marked fall in RBC [Hb], and reduces the use of allogeneic blood. PolyHeme appears to be a clinically useful blood substitute.

Effect of liposome-encapsulated hemoglobin on the development of endotoxin-induced shock in the rat.

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying resuscitation fluid. Because LEH is cleared from the circulation primarily by the reticuloendothelial system, its effect on the development of sepsis remains a major concern. Thus, the present study aimed to evaluate whether LEH modifies consequences of endotoxemia in the conscious normovolemic rat. LEH infusion at 10% of estimated blood volume (n = 10) did not affect mortality (30%, p < .05) and serum tumor necrosis factor-alpha levels (6204 +/- 414, p < .05) induced by 3.6 mg/kg Escherichia coli endotoxin administered (intravenous bolus) 22 h later. In contrast, when a shorter LEH-endotoxin time interval (<12 h, n = 10) or a higher dose of endotoxin (14.4 mg/kg, n = 20) was tested, LEH enhanced endotoxin-induced mortality (90% and 100%, respectively, p < .05) and broadened serum tumor necrosis factor-alpha response without modifying its peak levels. LEH (n = 20) did not exacerbate the endotoxin-induced tachycardia, leukopenia, and thrombocytopenia. Therefore, in this model, the effect of LEH on endotoxin-induced responses was dependent on the time interval between LEH and endotoxin administration as well as the endotoxin dose. The clinical relevance of these results should be further investigated.

Effect of liposome-encapsulated hemoglobin on triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein cholesterol measurements.

The present study investigated the effect of liposome-encapsulated hemoglobin (LEH), an experimental oxygen-carrying resuscitation fluid, on triglyceride, total cholesterol, and low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol measurements. In vivo, the intravenous infusion of LEH (5.6 mL/kg, n = 6) elevated serum triglycerides (+92% vs. baseline, P < .05), total cholesterol (+25% vs. baseline, P < .01), LDL cholesterol (+72% vs. baseline, P < .01) and had no effect on serum HDL cholesterol. In addition, LEH did not alter the elevation in serum triglycerides (+302% vs. baseline, P < .01) and LDL cholesterol (+86% vs. baseline, P < .01) induced by lipopolysaccharide (3.6 mg/kg, i.v., n = 6. Ex vivo, measurements of triglycerides and total cholesterol as well as LDL and HDL cholesterol in whole blood from naive rats were not changed by the addition of LEH (0-50%, n = 6). In vitro, the addition of a fixed concentration of LEH (50%, n = 6) to varying concentrations of cholesterol solution (0-50%), or vice versa, had no effect on cholesterol determination. It is therefore concluded that LEH only minimally affects serum levels of triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol and does not interfere with their measurement.

Physiological responses, organ distribution, and circulation kinetics in anesthetized rats after hypovolemic exchange transfusion with technetium-99m-labeled liposome-encapsulated hemoglobin.

Physiological responses and circulation properties of liposome-encapsulated hemoglobin (LEH) labeled with technetium-99m (99mTc) were measured in rats after a 10% (170 mg/kg hemoglobin; 430 mg/kg phospholipid) or a 50% (450 mg/kg hemoglobin, 2.3 g/kg phospholipid) hypovolemic exchange transfusion (n = 5 per exchange group). Mean arterial pressure returned to baseline values (105 +/- 8 mmHg) by 90 min post-infusion for both groups. By 20 h, mean arterial pressure remained at baseline values for the 10% group, but dropped to 30 +/- 14 mmHg for the 50% group. For both groups, bradycardia was seen after the exchange period, but heart rate recovered by 30 min for the 10% group and by 90 min for the 50% group. The 99mTc-LEH remained in circulation longer for the 50% group (18.2 h half-life) than for the 10% group (2.4 h half-life). Removal of 99mTc-LEH from the bloodstream was via the liver and spleen. At 20 h, 99mTc-LEH accumulation in these organs was greater for the 10% group (liver, 36.2 +/- 1.7%; spleen, 37.5 +/- 2.5%) than for the 50% group (liver, 17.0 +/- 1.4%; spleen, 17.1 +/- 1.4%). The data show that there is less clearance of 99mTc-LEH from the bloodstream by the reticuloendothelial system after a 50% hypovolemic exchange transfusion, thus supporting the possible use of LEH as an oxygen-carrying resuscitative fluid in situations of severe blood loss.

A NEW SALUTARY RESUSCITATIVE FLUID

Low-volume resuscitation with hypertonic (7.5%) saline (HTS) is an evolving therapeutic modality for patients with hemorrhagic shock. This solution has been shown to exert protective hemodynamic effects in models of controlled hemorrhagic shock and in several clinical trials. However, HTS has no oxygen-carrying capacity and therefore does not improve oxygen delivery directly. One of the leading strategies in developing an oxygen-carrying resuscitative fluid is the encapsulation of hemoglobin within phospholipid vesicles (LEH). This preparation has the advantage of being blood type and antigen free, easily adaptable to scale-up production, and remarkably stable with a long shelf life. We therefore tested the hypothesis that lyophilized LEH reconstituted with HTS will improve tissue oxygenation and survival in rats exposed to a lethal controlled hemorrhagic shock. Shock was induced by withdrawal of 70% of blood volume and therapy (n = 10-16) with HTS (5 mL/kg), LEH (5 mL/kg), lactated Ringer's solution (vol:vol = 1:3), LEH-HTS (5 mL/kg), or oxygen (100%) was initiated 15 minutes later. The LEH-HTS improved skeletal muscle oxygen tension directly measured using a thin-film chamber oxygen sensor (PO2 87 +/- 13 mm Hg vs. 40-50 mm Hg in other groups, p < 0.05). This was associated with improved blood pressure, reduced acidosis, and increased survival at 24 hours (75% vs. 6%-25% in other groups, p < 0.05). In conclusion, the study demonstrates a remarkably salutary effect of LEH reconstituted with HTS as a blood substitute in the treatment of hemorrhagic shock.

Liposome encapsulated hemoglobin: long-term storage stability and in vivo characterization.

Liposome Encapsulated Hemoglobin (LEH) has been the focus of research and development at the Naval Research Laboratory in an effort to find a viable oxygen-carrying resuscitative fluid. Previous reports from our laboratory have shown that LEH binds and releases oxygen in a manner similar to red blood cells, and that it can sustain life when red cell hematocrits are decreased to critical levels. We have also reported on LEH with regards to preparative methods, scale-up feasibility, toxicity, hemodynamics, hemoglobin P50 modification by coencapsulation of organic phosphates, liposomal surface modification, and storage strategies. In this report, the issue of LEH efficacy following long-term storage in the dry state will be addressed. We have shown that hemoglobin, liposomes, and LEH may be successfully lyophilized and rehydrated to viable states. The modification of the LEH formulation by addition of the carbohydrate trehalose results in the successful lyophilization and storage of LEH. In vitro characterization of LEH stored in the dry state for up to six months includes measurement of oxygen-carrying capacity, liposome size retention, methemoglobin production, and the intraliposomal hemoglobin concentration. The in vivo studies report on physiological parameters such as circulation persistence, blood chemistry, and pathological examination in mice.

Effect of fluosol DA 20% on antibody response to type 3 pneumococcal polysaccharide in rats

Exchange transfusion with the oxygen-carrying resuscitation fluid, Fluosol DA 20% (FDA), interferes with the efficacy of penicillin therapy of pneumococcal infection in rats. Because this effect could not be attributed to an interaction between FDA and penicillin, the effect of FDA on the ability of rats to mount an antibody response to type 3 pneumococcal polysaccharide was tested. FDA (25 ml) was administered by isovolumetric exchange transfusion. Rats were immunized intravenously with 0.2 μg of type 3 pneumococcal polysaccharide 3 days before, 1 day before, 1 day after, or 3 days after transfusion with FDA. IgM and IgG antibody responses were determined by ELISA 0, 3, 7, 10, 14, 21, and 28 days after immunization. When rats were immunized 3 days before or 1 day before transfusion with FDA, antibody levels were increased above control levels and remained relatively high through Day 28. When the animals were immunized 1 day after transfusion, antibody levels were approximately the same as in the control group. When the rats were immunized 3 days after transfusion, antibody levels were suppressed. These data suggest that FDA does not inhibit the humoral immune response when administered after or within 1 day before immunization, but does inhibit the response when immunization is given 3 days after transfusion.

Preparation and evaluation of hemoglobin-polyethylene glycol conjugate (pyridoxalated polyethylene glycol hemoglobin) as an oxygen-carrying resuscitation fluid.

Human hemoglobin was pyridoxalated and subsequently coupled with the activated ester of polyethylene glycol (PEG) to provide an oxygen-carrying resuscitation fluid. The PEG conjugate of pyridoxalated hemoglobin (pyridoxalated PEG hemoglobin) has a longer half-life in the circulation (12.8 h) than does hemoglobin (2.2 h) when the solutions are exchange-transfused by approximately 60%. The P50 of pyridoxalated PEG hemoglobin, which is the partial pressure of oxygen at which one-half of the absorbed oxygen is released, was 21.3 +/- 1.4 mm Hg (mean +/- SD, n = 5) (37 degrees C, pH = 7.4), which is close to that of human whole blood (25.9 +/- 0.6 mm Hg). The colloidal osmotic pressure and the viscosity were 36.5 +/- 2.4 mm Hg (n = 5) and 2.6 +/- 0.4 cp (n = 5), respectively. The results indicate that the pyridoxalated PEG hemoglobin solution has favorable properties for use as an oxygen-carrying resuscitation fluid.

Effect of exchange transfusion with an oxygen-carrying resuscitation fluid on the efficacy of penicillin therapy of pneumococcal infection in rats.

The effects of exchange transfusion with Fluosol DA (FDA) or stroma-free hemoglobin on the outcome of pneumococcal infection in rats were determined. Rats were sham transfused or exchange transfused with 25 ml of FDA or stroma-free hemoglobin. They were then challenged intraperitoneally with Streptococcus pneumoniae type 3 and treated with penicillin for 120 h. Only 2 of 15 (13.3%) FDA-transfused rats were alive at 312 h compared with 11 of 15 (73.3%) concurrently studied sham-transfused control rats (P = 0.0016). Of 10 stroma-free hemoglobin-transfused rats and 10 concurrently studied sham-transfused control rats (P = 0.98), 8 from each group (80%) were alive at 312 h. Penicillin therapy only suppressed pneumococcal infection in FDA-transfused rats, and relapse occurred after therapy was stopped. This effect could not be attributed to interference with the bactericidal activity of penicillin against pneumococci, to an alteration in the pneumococcal burden before penicillin therapy or to an alteration of the leukocyte and polymorphonuclear leukocyte response by FDA. In contrast, pneumococcal infection in stroma-free hemoglobin-transfused rats was cured with penicillin therapy. These data showed that FDA altered the ability of rats to respond to pneumococcal infection.

Modified Hemoglobin Solution as a Resuscitation Fluid

Hemoglobin solution, as a potential oxygen-carrying resuscitation fluid in blood volume replacement therapy, has two limitations: higher oxygen affinity (P50 approximately 12-16 mm Hg) and shorter vascular retention time (plasma half-disappearance time approximately 2-4 h) of free hemoglobin as compared to hemoglobin in the red cells. To overcome these two limitations, several investigators have used a variety of reactions and procedures for the modification of the hemoglobin molecule. This article presents a review of the modifications of the hemoglobin, including reactions with different agents for the intra- or intermolecular cross-linking of hemoglobin, reactions with pyridoxal phosphate with or without subsequent polymerization, and manipulations for the encapsulation of hemoglobin to obtain artificial cells. The P50 and the vascular retention time of the products obtained are indicated whenever they have been reported in the literature. The oxygen transport characteristics of a resuscitation fluid, in general, and of modified hemoglobin solution, in particular, have been correlated to the oxygen dissociation curve and to the hemoglobin concentration.

Resuscitation with pyridoxalated stroma free hemoglobin: tolerance to sepsis.

The contribution of the reticuloendothelial system (RES) in pyridoxalated stroma-free hemoglobin (SFH-P) clearance may be insignificant. The magnitude of this is not at present clear. Any compromise of RES function would militate against its potential benefit as an oxygen-carrying resuscitation fluid. The relationship between lethal hemorrhagic shock resuscitation with SFH-P and subsequent host depression was examined in a rat model. Host tolerance to a standard intra-abdominal polymicrobial septic challenge was assessed 5 days after hemorrhagic shock. Shock resuscitation with pyridoxalated stroma-free hemoglobin was equal to or better than all other resuscitation groups evaluated. Tolerance to a standard septic challenge 5 days after resuscitation was no different between resuscitation groups. There appears to be no compromise to host defense in general in tolerating intra-abdominal sepsis 5 days following shock resuscitation with pyridoxalated stroma-free hemoglobin.