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Biomedical subjects

L R Sehgal

Publications and source records attributed to L R Sehgal.

At least 19 recordsLinked to original sources
PubMed1992

Oxygen extraction ratio: a valid indicator of transfusion need in limited coronary vascular reserve?

We have described whole body oxygen (O2) extraction ratio (ER) as a reliable indicator of transfusion need in acute normovolemic anemia. In normal hearts, myocardial lactate production (-LACT), indicating anaerobic metabolism, does not occur until the ER greater than 50% and Hct less than 10%. It is not known if the ER is valid in the setting of limited coronary vascular reserve. This study assesses the effect of a critical left anterior descending (LAD) coronary stenosis on the compensation to acute blood loss anemia. Adult dogs were anesthetized, paralyzed, and mechanically ventilated. A critical LAD stenosis was created in seven animals (STEN). There were seven controls (CON). Animals underwent isovolemic exchange transfusion with 6% HES until cardiac failure (CF). Catheters were placed in the aorta, pulmonary artery, and anterior interventricular coronary vein. Cardiac failure occurred at Hct = 8.6% +/- 0.4% in the CON and 17.0% +/- 0.5% in the STEN animals. Cardiac output increased in the CON, but not in the STEN animals. Blood flow in the LAD increased in the CON but not the STEN animals. -LACT began in the CON and STEN animals at Hct less than 20% and coincided with an ER greater than 50% in both groups. We conclude that CF occurs at a higher hematocrit with a critical LAD stenosis. The whole body ER greater than 50% remains a valid indicator of myocardial metabolism in anemia in the presence of limited coronary vascular reserve. The ER may be a useful guide to transfusion therapy.

Anemia↗
PubMed1992

Artificial blood: current status of hemoglobin solutions.

Attempts to develop a hemoglobin-based red cell substitute have spanned many decades, but no clinically useful product has been produced to date. The issues preventing clinical application primarily are ones of safety--not efficacy. Numerous animal studies have documented the efficacy of SFH. Although effective, the solution has limitations that have caused concern. Oncotic considerations limit the concentration of the infusate SFH to 6 to 8 g/dL, or half-normal. Owing to the loss of organic phosphate modulators of P50, such as 2,3-DPG, the P50 of SFH is typically between 12 and 14 mm Hg, which is also half the normal value. And finally, the intravascular half-life of SFH is too short, ranging only from 2 to 6 hr. Polymerization provides a means of correcting these limitations. The high oxygen affinity can be greatly diminished by covalent binding of pyridoxal-5'-phosphate to the N-terminal of the chains. Colloid osmotic pressure exerted by a protein solution is proportional to the number of discrete colloid particles. Through polymerization, the number of colloid particles is reduced, leading to a decrease in COP. Data show that this can be achieved in a reproducible fashion. The rate at which COP diminishes determines the yield of polymeric species, as well as their molecular weight distribution. Polymerization can be controlled to result in a yield of 75% to 85% polymers with a molecular weight distribution of 128 to 400 kd. The number average and the weight average molecular weights indicate that the large proportion of polymers represent the cross linking of two tetramers. The data that reflect the interaction of oxygen with poly-SFH-P indicate that the oxygen carrying function of hemoglobin has not been significantly altered by the chemical modifications. The binding coefficient of oxygen is unchanged. As anticipated, there is a loss of cooperativity (diminished Hill coefficient) between the hemoglobin chains, suggesting structural restrictions in the polymeric species because of cross linking. A reduced alkaline Bohr effect is the expected result, and data confirm this. Finally, some increase in oxygen affinity is to be expected with polymerization. This is indeed the case, although the P50 of poly-SFH-P is comparable to banked blood (18 to 22 mm Hg). To be clinically useful, a modified hemoglobin solution requires a reasonable shelf-life.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Gas Analysis↗
PubMed1991

Erythropoietin deficiency after coronary artery bypass procedures.

Erythropoietin is the primary regulator of erythropoiesis. Erythropoietin has been shown to increase exponentially in response to linear decreases in hematocrit in normal, unstressed animals. However, the effect of operation, with its attendant stress, on erythropoietin levels is unknown. The purpose of this study is to evaluate the effect of surgical stress on erythropoietin. Twenty otherwise healthy patients scheduled for elective surgical procedures were studied. The cholecystectomy group included 10 patients who underwent cholecystectomy for documented stone disease. Ten patients who underwent coronary artery bypass procedures constituted the coronary artery bypass grafting group. Patients were studied preoperatively as well as on the first and second postoperative days. The hematocrit and erythropoietin levels were similar in both groups preoperatively. The hematocrit in the coronary artery bypass grafting group was lower than that of the cholecystectomy group on postoperative day 1 (0.31 versus 0.36; p less than 0.003) and postoperative day 2 (0.30 versus 0.36; p less than 0.001). During the first two postoperative days the erythropoietin levels were similar between groups. The data show that postoperative erythropoietin levels are similar after coronary artery bypass grafting, despite more severe anemia, when compared with cholecystectomy. This suggests that after coronary artery bypass grafting there is a relative deficiency of erythropoietin. Administration of recombinant human erythropoietin to patients undergoing surgical procedures could correct the erythropoietin deficiency and accelerate postoperative erythropoiesis.

Adult↗
PubMed1990

The efficacy of polymerized pyridoxylated hemoglobin solution as an O2 carrier.

A polymerized pyridoxylated hemoglobin solution (Poly SFH-P) has been prepared with a normal [Hb] of 14 g/dL, a normal COP of 20 to 25 torr, a P50 of 16 to 20 torr, and a plasma T1/2 of 40 to 46 hours. Animals underwent a total exchange transfusion with Poly SFH-P to assess its ability to support hemodynamics and oxygen transport in the absence of red cells. All animals survived the exchange transfusion. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and oxygen consumption (VO2) remained at baseline values at zero hematocrit after the exchange. The final plasma [Hb] at Hct less than 1% was 9.7 +/- 0.4 g/dL. These results are significantly better than previous data with unmodified tetrameric hemoglobin solution (SFH). Poly SFH-P supports life in the absence of red cells. In contrast to SFH, Poly SFH-P achieves a nearly normal [Hb], a longer T1/2, and maintains baseline hemodynamics and oxygen consumption at zero hematocrit. These results document that Poly SFH-P is an effective oxygen carrier that offers greater potential than previous products as a clinically useful red cell substitute.

Animals↗
PubMed1990

Erythropoietic response to acute anemia.

Reliance on a brisk erythropoietic response to untreated blood loss is an alternative to transfusion of homologous blood. Slow erythropoiesis has been observed in ICU patients who refused blood. Many of these patients received supplemental oxygen therapy and Fluosol-DA, a temporary red cell substitute. This study reports the erythropoietic response, in the baboon, to moderate (Hct 20%) and severe (Hct 10%) anemia. In addition, the effect of oxygen therapy (FIO2 0.6 for 1 wk) and fluorocarbon emulsions (Oxypherol) on erythropoiesis was evaluated. Baboons uniformly survived acute normovolemic anemia with Hct 10%. In all cases, the response to anemia was characterized by a lag period (with no change in Hct), and a nonlinear recovery period. A lag period of 3 days was observed in both moderate and severe anemia for baboons breathing room air or FIO2 0.6. The lag period was prolonged to 1 wk in the presence of Oxypherol. The recovery period exhibited a uniform and negative correlation between the rate of Hct change and the Hct, in all cases. The theoretical maximum rate of increase of Hct was 2.6%/day. In untreated blood loss, shortening the lag period and increasing the slope of the recovery period will decrease the length of time that the patient is anemic.

Acute Disease↗
PubMed1990

Effect of hemoglobin solution on compensation to anemia in the erythrocyte-free primate.

Hemoglobin solutions are undergoing clinical trials as erythrocyte substitutes. Some of these solutions have higher O2 affinities compared with normal erythrocyte hemoglobin. Also, they appear to interact with endothelial-derived smooth muscle relaxation. The purpose of this study was to evaluate the nature and limits of compensation to acute normovolemic anemia in the erythrocyte-free primate maintained with a hemoglobin solution. The experimental group consisted of six anesthetized paralyzed adult baboons (Papio anubis) that were exchange transfused (ET) with a pyridoxylated polymerized hemoglobin solution [hemoglobin concentration [( Hb]) = 14 g/dl, O2 half-saturation pressure of hemoglobin (P50) = 19.6 Torr] until a hematocrit less than 1% was achieved. They underwent a second ET with Dextran-70 until [Hb] = 1 g/dl. A control group (n = 6) underwent an ET with Dextran-70 until [Hb] = 1 g/dl. Both groups maintained O2 consumption (VO2) until [Hb] = 3 g/dl. Both groups were stable until [Hb] less than 1 g/dl, and both groups increased their cardiac output. The relation between VO2 and O2 delivery was similar for both groups. In vivo P50 and mixed venous O2 tension were significantly lower in the experimental group. The nature and limits of compensation to diminished O2 delivery due to anemia were similar in the two groups.

Anemia↗
PubMed1989

Treatment of acute postoperative anemia with recombinant human erythropoietin.

Risks inherent in the administration of blood products have increased efforts to avoid homologous transfusion. Although this has increased interest in autologous transfusion and intraoperative salvage, little attention has been focused on efforts to enhance endogenous erythropoiesis as a method of minimizing exposure to homologous blood. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study is to evaluate the effect of rHuEPO, administered postoperatively, on a model of acute blood loss. Eleven adult male baboons were randomized into two groups. All animals underwent a laparotomy and an exchange transfusion, with 6% hetastarch, to a final hematocrit of 15%. Group I (N = 6) received 1,000 units/kg of recombinant human erythropoietin daily for the first 14 postoperative days. Group II (N = 5) received an equivalent volume of placebo. All animals were given supplemental vitamin B12, folate and 200% of shed iron, as iron dextran IV, after exchange transfusion. Response was observed for a period of 35 days. All animals survived the protocol. There were no adverse reactions to rHuEPO or surgical complications. The hematocrits were similar between groups at baseline and after exchange transfusion. The maximal rate of erythropoiesis was significantly faster in the rHuEPO group (2.1 vs. 1.3%/day; p less than 0.01). The time required to return to hematocrits of 30% (9.9 vs. 17.4 days, p less than 0.001) and to baseline hematocrits (11.9 vs. 32.1 days, p less than 0.01) were both significantly shorter in the rHuEPO group. The data show that rHuEPO accelerates the recovery from anemia in the postoperative setting. Acceleration of erythropoiesis represents another alternative to homologous transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
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↗
PubMed1989

Perioperative recombinant human erythropoietin.

The risks of transfusion-associated infectious disease have made increased efforts to avoid homologous transfusion imperative. Little attention has been focused on efforts to accelerate erythropoiesis as a method of reducing homologous blood use. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study was to evaluate the effects of perioperative rHuEPO administration on postoperative erythropoiesis. Fifteen baboons were divided into three groups of five each. Group I received no rHuEPO. Group II received five daily preoperative doses of rHuEPO (1000 U/kg). Group III received five daily preoperative doses and 14 daily postoperative doses of rHuEPO (1000 U/kg). All animals underwent a laparotomy followed by an exchange transfusion to a final hematocrit of 15%. The time in days required to recover to hematocrits of 20% was significantly shorter in both groups that received preoperative doses of rHuEPO when compared with that of controls (3.3 vs 5.7 days, p less than 0.01). The recovery times to hematocrits of 25%, 30%, and baseline levels were all significantly shorter in the group that received both preoperative and postoperative doses of rHuEPO. The data show that perioperative dosage of rHuEPO significantly accelerates postoperative erythropoiesis. Perioperative administration of rHuEPO may reduce the requirements for homologous transfusion.

Animals↗
PubMed1988

Coronary vascular actions of stroma-free hemoglobin preparations.

The left anterior descending coronary artery was cannulated in anesthetized, open-chest dogs for use as a coronary test bed to assess the coronary vascular actions of oxygenated, unmodified and pyridoxylated, partially cross-linked (polymerized), stroma-free hemoglobin solutions (SFHS). The actions of these SFHSs were assessed in this test bed, by comparison with perfusion with whole blood. Unmodified SFHS caused significant vasoconstriction, whereas pyridoxylated, partially polymerized SFHS did not do so. The existing coronary flow during perfusion with either SFHS preparation, under basal conditions, did not increase during intracoronary infusion of adenosine. Coronary flow-autoregulation was also altered during perfusion with either SFHS, because the "normal" reactive hyperemia response, observed in the control experiments, was not seen. These findings suggest that both unmodified and pyridoxylated cross-linked (70% polymers) hemoglobin preparations possess some vascular activity when tested in the canine coronary circulation.

Animals↗
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↗
PubMed1988

Limits of cardiac compensation in anemic baboons.

The risk of homologous blood may cause physicians to withhold red cell treatment after acute blood loss. We believe that in the euvolemic patient with acute anemia, the heart is the principal organ at risk. The cardiac compensation to extreme anemia is unknown and is the purpose of this report. Fourteen adult baboons were anesthetized, paralyzed, and ventilated with room air. Left atrial and coronary sinus catheters were inserted surgically. Experimental animals (n = 7) were hemodiluted at constant left atrial pressure with 5% human serum albumin. Control animals (n = 7) underwent similar volume exchanges with fresh, cross-matched, homologous red blood cells resuspended in human serum albumin, also at constant left atrial pressure. Six of seven experimental animals survived until hematocrit levels were 4%. Adequate cardiac compensation was observed until hematocrit levels were less than 10%. Increased flow, without increases in the O2 extraction ratio, was the mechanism of compensation used by the healthy heart with patent coronary vessels.

Adaptation, Physiological↗
PubMed1988

Recombinant human erythropoietin and autologous blood donation.

Risks of transfusion are minimized with autologous blood. However, autologous donation programs require 2 to 5 weeks to yield only 2.2 units per patient. Recombinant human erythropoietin (r-HuEPO) has been shown to increase erythropoiesis. This study evaluated the effects of r-HuEPO on an aggressive autologous donation program. Twelve adult male baboons were randomized into two groups of six. All animals were studied three times per week for 5 weeks. A unit of blood was donated when on any study day the hematocrit was greater than 30%. Animals received intravenously either 750 units/kg of r-HuEPO (n = 6) or placebo (n = 6) on each study day. Iron dextran was given intravenously to replace 150% of shed iron. The r-HuEPO group had an earlier onset of reticulocytosis (2.7 vs 5.5 days, p less than 0.01) and donated 35% more blood (13.5 vs 10.0 units, p = 0.01) than the control group. No adverse reactions to r-HuEPO were observed. The data show that an aggressive autologous donation program can yield 10 units of blood over a 5-week period. Further, r-HuEPO increases that yield by an additional 35%. This aggressive autologous donation program with r-HuEPO may significantly reduce the need for homologous transfusion and its attendant risks.

Animals↗
PubMed1987

Oxygen extraction ratio: a valid indicator of myocardial metabolism in anemia.

We have shown that primates adequately compensate for acute normovolemic anemia to hematocrits (HCT) of 10%. We have described a whole-body extraction ratio (O2 consumption/O2 delivery; ER) of 50% as a reliable physiologic indicator of transfusion need. There is concern that whole-body ER may not accurately reflect impaired myocardial metabolism. The onset of significant lactate production by the left ventricle is an indicator of anaerobic metabolism. Our purpose is to compare left ventricular lactate metabolism (arterial-coronary sinus lactate; delta [L]) to ER in acute normovolemic anemia. Fourteen adult baboons were anesthetized, paralyzed, and ventilated on room air. Left atrial, coronary sinus, aortic, and Swan-Ganz catheters were inserted. Experimental animals (N = 7) were hemodiluted, at constant left atrial pressure (LAP), with 5% human serum albumin (HSA) to a HCT below 4%. Control animals (N = 7) underwent similar volume exchanges, also at constant LAP, with homologous RBCs resuspended in HSA. Whole-body extraction ratio and left ventricular lactate production were measured at baseline and at hematocrits of 20, 10, 6, and 4% in the experimental group. Data were obtained at similar volume exchange points in the control group. Significant lactate production occurred only in the experimental animals (P less than 0.05) when extraction ratio exceeded 50%. Significant lactate production does not occur before the whole-body ER exceeds 50%. ER appears to be a valid indicator of myocardial metabolism in anemia, in this setting.

Anemia↗
PubMed1986

Fluosol-DA as a red-cell substitute in acute anemia.

We assessed the safety and efficacy of Fluosol-DA as a red-cell substitute in acute anemia. Twenty-three surgical patients with blood loss and religious objections to receiving blood transfusions were evaluated. Fifteen moderately anemic patients with a mean hemoglobin level (+/- SE) of 7.2 +/- 0.5 g per deciliter had no evidence of a physiologic need for increased arterial oxygen content and did not receive Fluosol-DA. Eight severely anemic patients with a mean hemoglobin level of 3.0 +/- 0.4 g per deciliter met the criteria of need and received the drug until the physiologic need disappeared or a maximal dose of 40 ml per kilogram of body weight was reached. We observed no adverse reactions to Fluosol-DA. The average peak increment in arterial oxygen content with the drug was only 0.7 +/- 0.1 ml per deciliter. There were no appreciable beneficial effects of Fluosol-DA, perhaps because of the small increase in arterial oxygen content, the brief half-life of the drug (24.3 +/- 4.3 hours), and the limited total dose. Six of the eight patients receiving Fluosol-DA died. One of the survivors received red-cell transfusions against his wishes, under a court order, after his total Fluosol-DA dose. Fourteen of the 15 moderately anemic patients survived. The data in this select group of patients refusing blood products suggest that, after blood loss, Fluosol-DA is unnecessary in moderate anemia and ineffective in severe anemia.

Acute Disease↗