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PubMed2005

Pharmaceutical aspects of hemoglobin-based oxygen carriers.

Oxygen delivery has evolved as a therapy of widespread interest in the clinical setting, especially in emergency medicine and anesthesiology. With the widespread recognition of blood-borne infections during the last two decades and the looming shortage of donor blood in future, efforts to formulate an artificial substitute for oxygen carrying capacity of RBCs have increased. Such blood substitutes, defined more correctly as oxygen therapeutics, are particularly valuable in circumstances such as war and trauma situations where properly matched blood may not be immediately available or is not accepted by the recipients for religious reasons. Several elegant formulations of hemoglobin, both free and encapsulated, have evolved recently and are collectively referred to as hemoglobin-based oxygen carriers (HBOCs). Few HBOCs have successfully entered into the clinical phase. This review discusses formulation requirements of HBOCs from a physiological viewpoint. Physico-pharmaceutical parameters, such as colloidal oncotic pressure, osmolality, viscosity, sterility, apyrogenicity and shelf-stability are traditionally a concern for large volume parenterals meant for resuscitation purposes. At the same time, properties such as oxygen affinity, hemoglobin content and in vivo efficacy of oxygen carriers are specific to HBOCs. Owing to the presence of a very active and functional protein (hemoglobin), requirements for adequate performance of HBOCs significantly differ from those of other large-volume parenterals, such as lactated Ringer's solution, and plasma expanders, such as dextran or albumin solutions.

Colloids↗
PubMed2006

Evaluation of historical factors influencing the occurrence and distribution of Mycobacterium bovis infection among wildlife in Michigan.

OBJECTIVES: To determine historical events leading to establishment of bovine tuberculosis in the white-tailed deer population in the northeastern corner of the lower peninsula (NELP) of Michigan and describe factors relevant to the present outbreak of bovine tuberculosis in Michigan. SAMPLE POPULATION: Cattle and white-tailed deer in Michigan from 1920 to 1990. PROCEDURES: A search of extant historical documents (eg, scientific journals, books, public reports, and correspondence and internal reports from governmental agencies) was conducted. Factors investigated included the number of cattle and prevalence of tuberculosis, deer population and density levels, and changes in regional environments affecting the population and management of cattle and wild deer. RESULTS: High deer numbers and severe winter feed shortages resulting from habitat destruction in the NELP in 1930 contributed to the transmission of tuberculosis from cattle to deer. Starvation increased the susceptibility of deer to infection and modified behavior such that exposure to infected cattle was increased. Relocation of deer resulted in spread of infection to other sites, including locations at which spatial clusters of tuberculosis presently exist. Ribotyping of Mycobacterium bovis from a human patient suggests that the strain of M. bovis presently infecting white-tailed deer in the region is the same strain that affected cattle farms at that time. CONCLUSIONS AND CLINICAL RELEVANCE: Feeding deer to maintain numbers above the normal carrying capacity of the NELP led to deer depending on consumption of livestock feed for survival during winter and increased contact with domestic cattle. This practice should be avoided.

Animals↗
PubMed2001

Correlation between leukocytosis and necropsy findings in dogs with immune-mediated hemolytic anemia: 34 cases (1994-1999).

OBJECTIVE: To determine whether severity of leukocytosis correlates with severity of postmortem lesions in dogs with immune-mediated hemolytic anemia (IMHA). DESIGN: Retrospective study. ANIMALS: 34 dogs with IMHA that had CBC performed within 48 hours prior to death and complete necropsy examinations. PROCEDURE: Dogs were independently assigned to 4 leukocytosis groups (within reference range; mild leukocytosis, moderate leukocytosis, marked leukocytosis) and 3 lesion severity groups (mild lesions, moderate lesions, severe lesions). RESULTS: Moderate to marked leukocytosis correlated with moderate to severe postmortem lesions. Ischemic necrosis within liver, kidney, heart, lung, and spleen attributable to thromboembolic disease or anemic hypoxia were the most common important lesions found at necropsy. None of the dogs with mild lesions had moderate or marked leukocytosis. Four of 14 severely affected dogs had WBC counts within reference range, but all 4 had neutrophilic left shifts. Three of these 4 dogs had toxic change in neutrophils. CONCLUSION AND CLINICAL RELEVANCE: Moderate to marked leukocytosis, neutrophilic left shift, and toxic change in neutrophils in dogs with IMHA should alert clinicians to the potential for moderate to severe tissue injury, which could complicate treatment and worsen prognosis. Lesions appear to be secondary to anemic hypoxia, thromboembolic disease, or both; therefore, treatment objectives should focus on improving blood oxygen-carrying capacity and monitoring for thromboembolic disease.

Anemia, Hemolytic, Autoimmune↗
PubMed2002

Heinz-body hemolytic anemia associated with ingestion of methylene blue in a river otter.

Heinz-body hemolytic anemia and nephrosis associated with hemoglobinuria were diagnosed in a North American river otter. Fluids were administered, and the signs of renal failure improved immediately. Severe anemia developed, and the otter received a semisynthetic hemoglobin product to maintain the oxygen-carrying capacity of the blood until a blood transfusion could be given. Immediate clinical improvement was observed following hemoglobin administration, and adverse effects were not seen. Six days after admission, the otter began to produce its own RBC and recovered without complications. The Heinz-body anemia was determined to be caused by methylene blue that was in the water of minnows consumed by the otter the night before it became ill. Methylene blue is a common ingredient in products used to extend the life of bait fish. Bait fish kept in water treated with methylene blue should not be used as food for fish-eating animals.

Anemia, Hemolytic↗
PubMed2005

Neonatal isoerythrolysis in horse foals and a mule foal: 18 cases (1988-2003).

OBJECTIVE: To assess data regarding clinical features, clinicopathologic and blood gas variables, and outcome from horse and mule foals with confirmed neonatal isoerythrolysis (NI). DESIGN: Retrospective case series. ANIMALS: 17 horse and 1 mule foals. PROCEDURE: Medical records of foals (< 14 days old) with NI were reviewed. Information collected included signalment; clinical examination findings; results of hematologic, serum and plasma biochemical, and venous blood gas analyses and urinalysis; treatments; and outcome. RESULTS: Data from 17 horse foals and 1 mule foal with NI (mean age, 71 hours) were evaluated. Many foals had high serum indirect and direct bilirubin concentrations and sorbitol dehydrogenase activity. Whole blood immunoglobulin concentrations were < 400 mg/dL in 4 of 15 foals. Fresh whole blood transfusions were administered to 10 of 18 foals. Among the blood factors implicated in 11 foals, one (Dg) had not previously been associated with NI. Of 10 foals that received blood transfusions, 7 had significant improvements in Hct and hemoglobin concentration and 2 had significant improvements in central venous oxygen tension. Fifteen foals survived to discharge. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggest that blood factor Dg may be associated with NI in foals. Liver disease may be concurrent with NI in foals, and NI can develop in foals with inadequate passive transfer of colostral antibodies. Whole blood transfusions were successful at increasing oxygen-carrying capacity and improving peripheral tissue oxygenation in NI-affected foals. With appropriate treatment, the prognosis for foals with NI is good.

Anemia, Hemolytic, Autoimmune↗
PubMed1994

Evaluation of Brassicas in grazing systems for sheep: I. Quality of forage and animal performance.

Four years of grazing trials were conducted with Brassica forages to evaluate their chemical composition and effect on ADG of fattening lambs and breeding ewes in late fall. Brassicas tested included kales (Brassica oleracea L. var. acephala DC), turnips (B. rapa L.), and a chinese cabbage hybrid (B. rapa L. x B. pekinensis [Lour.] Rupr.). Daily gains of lambs varied widely among years (19 to 330 g/d); ADG on Brassicas were, however, generally higher than on stockpiled Kentucky 31 tall fescue (Festuca arundinacea Schreb.) or orchardgrass (Dactylis glomerata L.)-red clover (Trifolium pratense L.) pastures grazed at the same time. In 1 yr, dietary supplementation of lambs grazing a hybrid turnip (Forage Star) with iodine and copper oxide needles improved (P < .05) ADG; however, there was no effect on gains in two later years. In 2 yr, lambs showed higher ADG on Tyfon chinese cabbage hybrid (241 and 330 g/d) than on Forage Star turnip (197 and 275 g/d) or stockpiled grass-clover (135 and 233 g/d), but yield of Tyfon was lower. Indications that supplementary hay improved ADG of lambs and ewes were not confirmed in the final year, in which hay increased (P < .05) ADG of lambs in the first 3 wk of grazing Brassicas but decreased gains later. Thyroid weights were increased (P < .01) consistently in all trials on Brassicas, but enlargement was modest and not related to ADG. Brassica forages provided high yields (5.6 to 10.5 t/ha) of DM in the late fall to early winter period, with high carrying capacity for sheep but large variability in ADG.

Animal Feed↗
PubMed2001

A comparison of native tallgrass prairie and plains bluestem forage systems for cow-calf production in the southern great plains.

The objective of this study was to compare an introduced warm-season perennial grass (plains bluestem, Bothriochloa ischaemum) to native tallgrass prairie for cow-calf production. Three systems were used, two based on tallgrass prairie with two different forms of protein supplementation and one based on plains bluestem as the primary forage. The systems were as follows: 1) native tallgrass prairie with pelleted oilseed meal as the winter protein supplement (native-control); 2) native tallgrass prairie with limited access to wheat pasture as the winter protein supplement (native-wheat); and 3) plains bluestem with limited access to wheat pasture as the protein supplement (bluestem-wheat). Oilseed meal protein supplements were fed twice weekly. Cows grazing wheat pasture were allowed 6 h of grazing twice weekly. Ninety-nine cows per year were used over the 3-yr study. Cows were sired by either Charolais, Gelbvieh, Angus, or Hereford bulls out of commercial Angus-Hereford dams. Calves were sired by Simmental bulls. Calving and weaning rate increased over time but did not differ among systems or breed types. System did not influence the size or body condition score of cows or the performance of calves, but changes in the weight and condition scores of cows were greater on either native system than on the bluestem-wheat system. Cows from Charolais and Gelbvieh bulls were taller (P < 0.05), and heavier (P < 0.05), and weaned heavier (P < 0.05) calves than cows from Angus or Hereford bulls. The weight of cows on the bluestem-wheat system tended to decrease over time, whereas cows grazing on the native systems tended to gain weight over time. The native-control system was the most profitable system based on cow production. If excess hay produced from the bluestem-wheat system was sold as a cash crop, then this system was the most profitable. In general, we conclude that limit-grazing wheat pasture is a viable alternative to oilseed meal as protein supplement for wintering dry cows. Although the bluestem system had 2.5 times the carrying capacity of the native prairie systems, increased productivity was offset by increased production costs. All systems were equal on a cow basis for providing nutrients for the cow-calf production system.

Animal Feed↗
PubMed2005

Effects of stocking and nitrogen fertilization rates on steers grazing dallisgrass-dominated pasture.

To compare the performance of steer calves managed under different stocking rates (SR; 3.7, 6.2, 8.6, and 11.1 steers/ha for 140 d; chi(I1)) and N fertilization rates (112, 224, and 336 kg of N/ha; chi(I2)) in May 1996, 1997, and 1998, 72 steer calves (BW = 231 +/- 2.5 kg) were assigned randomly to one of 12 0.81-ha dallisgrass (51%)/common bermudagrass (32%) pastures. One-third of the fertilizer was applied in the form of ammonium nitrate in May, June, and August to achieve the prescribed totals. Treatments were separated using a polynomial regression equation: gammai = beta0 + beta1chi(I1) + beta2chi(I2) + beta(11)chi2(I1) + beta(12)chi2(I2) + beta(12)chi(i1)chi(i2) + epsilonI, with years as replicates. Within the range of the data, ADG and BW gain per steer were greatest at a stocking rate of 3.7 steers/ha and 336 kg/ha of N. Body weight gain per hectare peaked at 701 kg when cattle were stocked at 8.9 steers/ha and the pasture was fertilized with 336 kg/ha of N. The least cost of production was at a stocking rate of 3.7 steers/ha, with 112 kg/ha of fertilizer N applied, and the greatest cost of production was at a stocking rate of 11.1 steers/ha with 336 kg/ha of fertilizer N applied. Fertilization at 336 kg/ha of N produced the most profitable stocking rate at 7.3 steers/ha and returned 355.64 dollars. The optimal stocking rate for net return was 79, 81, and 82% of that for maximum BW gain per hectare for 112, 224, and 336 kg/ha of N, respectively. Under the assumptions made in the financial analysis, these data show that the economically optimal carrying capacity of similar pastures can be increased with N fertilizer up to at least 336 kg/ha annually.

Analysis of Variance↗
PubMed2006

Incorporation of thymol into corncob granules for reduction of odor and pathogens in feedlot cattle waste.

Confined animal feeding operations can be a source of odor emissions, global warming gases, water pollution, and food contamination. Laboratory studies have indicated that plant oils with antimicrobial activity can be used to control pathogens and odor emissions from cattle and swine wastes. However, these oils are aromatic and may volatilize when applied topically. Our objectives were to evaluate the volatility of thymol from a feedlot surface and the effectiveness of topically applying thyme oil (2.5% thymol), incorporated into corncob granules and added once per week, to control odor emissions and total coliforms in feedlot manure. In the first study, thymol either volatilized or was degraded within 28 d after topical application. In a second study, thyme oil (2.5% thymol) was incorporated into corncobs and applied to pen surfaces weekly. Manure samples from 6 locations in each pen were collected from 3 untreated and 3 thymol-corncob-treated pens (15 x 150 m; fifty 400-kg cattle/pen), 3 times per week for 8 wk. Samples were analyzed for thymol concentration, total VFA, branched-chain VFA, aromatic compounds, and the number of Escherichia coli and total coliform bacteria. Over the 8 wk, with the exception of wk 7, the desired thymol concentration of 15 to 20 micromol/g DM was maintained in the manure. Concentrations of VFA and branched chain-VFA increased over time in untreated and treated pens. However, the rate of VFA accumulation in treated pens (7.5 +/- 1.3 micromol.g DM(-1).wk(-1)) was less (P < 0.01) than the rate of accumulation in untreated pens (18.0 +/- 2.1 micromol.g DM(-1).wk(-1)). Likewise, the rate of branched-chain VFA accumulation in treated pens (0.31 +/- 0.04 micromol.g DM(-1).wk(-1)) was less (P < 0.01) than in untreated pens (0.55 +/- 0.06 micromol.g DM(-1).wk(1)). The concentrations of E. coli in treated pens (2.9 +/- 1.2 x 10(5) cfu.g DM(-1)) were 91% less (P < 0.04) than in untreated pens (31.1 +/- 4.0 x 10(5) cfu.g DM(-1)). Similarly, concentrations of coliforms in treated pens (3.7 +/- 1.3 x 10(5) cfu.g DM(-1)) were 89% less (P < 0.04) than those of untreated pens (35.3 +/- 4.2 x 10(5) cfu.g DM(-1)). These results indicate that odor emissions and total coliforms can be reduced in feedlot manure with a once per week application of thymol incorporated in a granular form. However, corncobs are bulky, and other granular carriers with a greater carrying capacity for thyme oil should be explored.

Animal Husbandry↗
PubMed1985

Weanling pigs under sublethal concentrations of atmospheric carbon monoxide.

Atmospheric carbon monoxide at 200 ppm for 21 d had no adverse effect on any performance or behavioral characteristic measured in weanling pigs. The pigs tended to compensate for carboxyhemoglobin-induced reduction in oxygen-carrying capacity of their blood by increasing total hemoglobin concentration. Pigs exposed to carbon monoxide at 300 ppm had a 31% reduction in body-weight gain (.20 vs .29 kg/d) and a 20% reduction in feed conversion efficiency (gain/feed = .48 vs .60) at d 10. Over the 21-d exposure period, rate of gain was reduced by 21% (.31 vs .39 kg/d), feed conversion efficiency by 8% (.47 vs .51). There appeared to be a threshold concentration between 200 and 300 ppm above which atmospheric carbon monoxide reduced weanling pigs' performance.

Animals↗
PubMed1981

Changes in cerebral blood flow relating to haematocrit and viscosity.

Evidence suggests that haematocrit and viscosity are important factors in the control of cerebral blood flow (CBF). Conditions in which the haematocrit is raised, such as polycythaemia rubra vera and relative polycythaemia are associated with a low CBF. Following reduction in haematocrit, there is a significant rise in CBF. It is likely that two factors are responsible for this. Firstly there is a fall in oxygen carrying capacity with venesection. Secondly there is a marked fall in whole blood viscosity. Both these changes tend to result in a rise in CBF. Further studies in patients with paraproteinaemias suggest that oxygen carriage and blood viscosity are independent variables in the control of CBF.

Animals↗
PubMedDate not supplied

Primary benign erythrocytosis with high erythropoietin levels and an early erythropoietin-sensitive population in the peripheral blood.

Primary erythrocytosis diagnosed in a 10-month-old female and followed for 12 years is described. The erythrocytosis was associated with an abnormally elevated set point of erythropoietin production in which the sensitivity fluctuated independently, but corresponded to the alterations in the oxygen-carrying capacity of the blood, when the hematocrit was lowered by phlebotomies. Extensive work for secondary erythrocytoses failed to demonstrate a recognizable cause for this abnormal erythropoietin production. Erythroid cell cultures from peripheral blood mononuclear cells showed the existence of at least two populations: one consistent with dramatic expansion of the erythron in keeping with enhanced sensitivity to endogenous erythropoietin, and the other consistent with the features of typical colonies derived from burst-forming units-erythroid (BFU-Es), seen in normal peripheral blood on days 12 to 14 of culture. The expanded population was characterized by the appearance of single colonies on days 4 to 6 and enormous response to the increasing amounts of erythropoietin, which enhanced their number, size, and maturation. The combination of clinical and in vitro data as well as the absence of any abnormality in the erythropoiesis of the parents and sibling suggest that the erythrocytosis in this child represents a new form with a benign course.

Cells, Cultured↗
PubMed1988

Characteristics of polymerized pyridoxylated hemoglobin.

Polymerization of SFH-P currently provides the only approach that leads to a hemoglobin solution that approximates the O2 carrying capacity of whole blood and can be infused without altering the COP of plasma. It appears to have an adequate O2 loading and unloading characteristic and a greatly improved intravascular half-life. In addition, stable shelf-life at 4 degrees C of greater than five months, makes it a prime candidate for future pre-clinical and clinical investigations.

Animals↗
PubMed1989

Liposome-encapsulated hemoglobin as an artificial red blood cell: characterization and scale-up.

Encapsulation methods using high pressure extrusion and homogenization were developed which produce hemoglobin-containing liposomes, approximately one micron or less in diameter with an oxygen-carrying capacity of more than half that of red blood cells (RBCs). These methods were developed for scaling-up liposome-encapsulated hemoglobin (LEH) production. Previously, the lack of adequate scale-up methods has been a serious barrier to full scale efficacy and toxicity testing for all the researchers engaged in such investigations. The scale-up methods and characterization of the resulting LEH preparations are presented.

Blood Substitutes↗
PubMed1992

Relationship between chemical properties and biological properties of pyridoxalated hemoglobin-polyoxyethylene.

Pyridoxalated hemoglobin-polyoxyethylene (PHP) is a conjugate of human hemoglobin with alpha-carboxymethyl, omega-carboxymethoxypolyoxyethylene(POE). This conjugate is selected as an oxygen carrier for blood substitute because it can survive for a long time in the circulation and also it can transport the same amount of oxygen as red cell. Optimization of PHP has been done by changing the degree of the modification and reaction procedures in order to adjust viscosity and colloid osmotic pressure to physiological values. The oxygen carrying capacity was physically evaluated by oxygen equilibrium curves and biologically by an ATP content in perfused isolated liver. Structural relationship of PHP to the binding properties to haptoglobin was studied and the effect of the POE modification on the binding properties was observed when the number of POE per one hemoglobin molecule is over six. Based on the comparative study of solubility of met-PHP and met-SFH, the POE modification was suggested to reduce the toxicity of hemoglobin against organs. Finally physical properties of PHP at low temperature was discussed in relation to organ preservation.

Animals↗
PubMed1992

A potential blood substitute from carboxylic dextran and oxyhemoglobin. II. Physicochemical and physiological assessments. Preliminary results on guinea pig.

The hemoglobin solution covalently linked to dextran benzene tetracarboxylate (dex-BTC) described in Part I, offered the following characteristics: [Hb] = 70 g/l, non modified Hb less than 15%, metHb less than 5%, P50 close to blood value, viscosity and oncotic pressure near to physiological values (37 degrees C). It was biocompatible, stable in plasma, non hypotensive in rat model, non pyrogenic and did not present abnormal toxicity (on mice, according to the french Pharmacopea). Nevertheless, on account of the presence of dextran in the conjugate and due to the literature, we observed an anaphylactoïd reaction in rats consecutive to the injections: absence of hypotension but presence of a massive oedema resulting from an important increase in the capillary permeability with harmful consequences to the vascular retention and survival time. As guinea pigs are insensitive to dextran, we are beginning to assess this conjugate solution in this animal. The first results are very promising: a lack of mortality after large injection, an almost complete vascular retention, a weak urinary loss (only non conjugated Hb), and a plasmatic half-disappearance time close to 7h. Results from haemorrhagic shocks to a final hematocrit less than 0.10 l/l and total and isovolemic exchange transfusions seem to prove a real oxygen-carrying capacity of this new Hb solution.

Animals↗
PubMed1992

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.

Animals↗