[Animal experiment studies on hemodynamics following partial and total blood exchange with a pyridoxalated polyhemoglobin solution]. / Tierexperimentelle Untersuchungen zur Hämodynamik nach partiellem und totalem Blutaustausch mit einer pyridoxalierten Polyhämoglobinlösung.

The effects of a pyridoxalated polyhaemoglobin (SFH-PLP)n-solution on haemodynamics were investigated in a model of partial (hct = 12%) and total blood exchange (hct less than 1%) in 7 dogs. Partial blood exchange resulted in a slight increase in right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) and in a marked decrease in heart rate (HR). Cardiac output (CO) did not increase as would be expected from haemodilution. After total blood exchange, arterial pressure, HR, RAP, PCWP and CO were unchanged compared to the pre-exchange values during the 90 minutes of observation. However, pronounced pulmonary vasoconstriction was observed in 4 dogs. The beneficial effects on haemodynamics are due to the long intravascular persistance of the polymerized haemoglobin molecules (plasma half-disappearance time = 36 hours) and the addition of albumin supplying a sufficient colloid-osmotic pressure of the solution. These characteristics and the good oxygen unloading capacity of the pyridoxalated polyhaemoglobin resulted in longterm survival of three dogs. These results demonstrate a better haemodynamic efficacy of the (SFH-PLP)n-solution compared to previous investigations with unmodified haemoglobin solutions. However, there are still many problems, which have to be clarified prior to its clinical application.

Hemodynamics and oxygen transport after partial and total blood exchange with pyridoxalated polyhemoglobin in dogs.

The effects of a pyridoxalated polyhemoglobin solution (SFH-PLP)n-solution) on cardiovascular hemodynamics and oxygen transport were investigated in a model of partial and total blood exchange in seven dogs. Cardiac output, mean arterial pressure and heart rate were essentially unchanged, even after total blood exchange, due to the long plasma half-disappearance time of (SFH-PLP)n (36 h) and due to the addition of albumin to the solution. The oxygen-binding capacity of (SFH-PLP)n was 1.1 to 1.2 ml O2/g hb. Oxygen availability was reduced to about 50%, resulting from the low hemoglobin concentration and the decreased oxygen-binding capacity of (SFH-PLP)n. Since cardiac output did not increase, O2-consumption was maintained by an increase in O2-extraction from 21 to about 50%. However the decrease in mixed venous PO2 to values not below 30 mmHg (4.00 kPa) proves the sufficient unloading capacity of (SFH-PLP)n. The adequate tissue oxygenation of (SFH-PLP)n could be demonstrated by the lack of a metabolic acidosis, the essentially unchanged PO2-histograms of the skeletal muscle and the only moderate decrease in mixed venous PO2. Four dogs survived for more than 3 days; three of them were long-term survivors. This suggests that oxygen supply was maintained by (SFH-PLP)n until red blood cells were restored.

Oxygen-transporting fluids and oxygen delivery with hemodilution.

The hemodynamic effectiveness and the oxygen characteristics of stroma-free hemoglobin (SFH) solutions were studied in 11 dogs. the animals were bled two-thirds of the estimated blood volume or until cardiac arrest. The shed blood was immediately replaced by equivalent amounts of either SFH or polyhemoglobin (SFH-PLP). Sixty min later, Ringer's lactate was given iv for 180 min to maintain right atrial pressure at the initial value. In a second set of experiments, the intravascular persistence of SFH-PLP was investigated in 5 dogs by withdrawal of blood (7 ml/kg bw) and immediate replacement with 131I-labeled SFH-PLP. Hemodynamic disorders after severe blood loss could be reversed by infusion of hemoglobin solutions. Due to the short intravascular persistence, cardiac output did not increase as one would expect from the degree of hemodilution. Pyridoxalation of the hemoglobin molecule reduced oxygen affinity and improved oxygen unloading at the tissue level. The short intravascular half-time of this compound could be overcome by crosslinking of the pyridoxalated hemoglobin molecules. Further studies must prove whether this polyhemoglobin can be used as a long-term oxygen-carrying blood substitute.

[Hydroxyethyl starch (HAS 450/0.7) in human plasma and liver. Course of concentration and histological changes]. / Hydroxyäthylstärke (HAS 450/0,7) in Plasma und Leber Konzentrationsverlauf und histologische Veränderungen beim Menschen.

In 12 patients 1,000 ml hydroxyethyl starch (Mw 450,000, degree of substitution 0.7) was infused intravenously. A liver biopsy was performed in 10 patients undergoing abdominal surgery 30 minutes to 28 days after the infusion. The liver tissue was investigated by light and electron microscopy. The plasma level of hydroxyethyl starch decreased to 4.8% of the initial concentration 28 days after the infusion (Anthron method). Single intracellular vacuoles were shown by electron microscopy 30 minutes after the end of infusion in Kupffer's cells only. However, 6 to 28 days after infusion intracellular vacuoles were demonstrated in parenchymal liver cells, Kupffer's cells, interstitial histiocytes and to a lesser degree in the cells of the small bile ducts. The pathogenic importance of the portracted elimination from the plasma and the liver storage is unknown.

Tissue PO2 during reanimation with hemoglobin solutions.

Solutions of conventional stoma-free hemoglobin (SFH) and of pyridoxylated stoma-free hemoglobin (SFH-PLP) were compared in a dog model of reanimation from severe arterial blood loss. SFH and SFH-PLP restored central hemodynamics after infusion without yielding significant differences between the experimental groups. To cope with the developing hypovolemia, Ringer's lactate load amounted to about 120 ml/kg, edema formation was not encountered. Skeletal muscle oxygenation was studied by means of a multiwire platin electrode. The infusion of SFH-PLP was associated with a shift to the right of the cumulative PO2-distribution curve, indicating better tissue oxygenation. Oxygen was not unloaded from SFH in plasma unless the oxygen extraction from red cell hemoglobin exceeded 40%. Oxygen unloading was, however, improved when SFH-PLP with low oxygen affinity was used. Thus, SFH-PLP merits further consideration as a short-term oxygen-carrying blood substitute.

[Hypothermic circulatory arrest after total blood exchange in dogs (author's transl)]. / Hypothermer Kreislaufstillstand nach totalem Blutaustausch beim Hund.

Total body washout (hct less than 1%) in hypothermia was performed in 31 dogs using either a crystalloidal or a colloidal perfusate. Blood exchange and cooling was achieved by means of partial bypass and heat exchanger. Short lasting blood exchange for crystalloids without cardiac arrest resulted in 66% survival of the animals. When in addition circulatory arrest was established for 30 min at 14 degrees C oesophageal temperature blood exchange for crystalloids was not tolerated. All four animals of this group died within 19 hours presenting massive interstitial edema. Replacement of the crystalloidal perfusate by a colloidal solution (2.5 g% Dextran 60 at Ringer's Lactate) and establishing circulatory for 30 or 60 min resulted in survival rates of 71% and 50% respectively. The use of the colloidal perfusate effectively prevented edema formation. Death could not be correlated with the parameters controlled.

[Blood volume replacement and hemodilution with hydroxyethyl starch]. / Volumenersatz und Hämodilution durch Hydroxyäthylstärke.

For high molecular hydroxyethylstarch (MW 450000, DS 0.7-0.8) an adequate volume effect has been demonstrated in numerous experimental and clinical studies; this colloid is, therefore, suitable for primary volume replacement as well as for preoperative normovolemic hemodilution. In contrast to colloids hitherto known HES infusion results in hyperamylasemia of probably non-pathogenic importance but significance for differential diagnosis in the post-operative period. Anaphylactoid reactions to HES are infrequent (0.08%). With regard to the manifestation and the degree of severity these reactions are not different from those observed after infusion of other colloids. Since the pathomechanism of anaphylactoid reactions to HES is still unknown prophylactic measures are not available. The elimination of HES from the circulation follows a protracted course, therefore accumulation of HES in tissues may occur after repeated infusions presenting a clear disadvantage of HES. There is, however, evidence that starch-preparations will be available in the future presenting an adequate volume effect while the elimination from the organism occurs rapidly. Low molecular hydroxyethylstarch (HES 450000, DS 0.5-0.55) yields inadequate volume effects; for this, low molecular HES can neither be recommended for long-lasting volume replacement nor for preoperative hemodilution.

[Septic shock in the urologic patient. IV. monitoring and therapy (author's transl)]. / Urosepsis bis septischer Schock. IV. Monitoring und Therapie.

The high mortality from septic shock in urologically ill patients can only be diminished by early diagnosis and treatment of the sepsis. However, there is no defined, steady sign from which the precise diagnosis septic shock can be established. Therefore the critical patient has to be controlled by a system that covers numerous signs that contribute to the diagnosis. Once septic shock is established its outcome depends on how early the failure of the microcirculation can be eliminated. The therapeutic approach is based on an improved cardiac output achieved by adequate volume therapy and positive inotropic drugs. For this reason the actual circulatory failure has to be defined and each therapeutic step has to be controlled using the Swan Ganz thermodilution catheter. The microcirculatory failure can be treated directly with dextran 40 and with specifically chosen vasoactive drugs. Disorders of the blood gases and base excess have to be corrected immediately. Treatment of acute renal and respiratory failure is mentioned.

Sodium nitroprusside induced hypotension and isovolemic hemodilution in dogs.

Hypotension at 70 mm Hg was induced with sodium nitroprusside in 6 hemodiluted and 6 control dogs. In contrast to the control dogs, the reduction in mean arterial pressure was not primarily due to the peripheral resistance reduction, but the result of a hazardous fall in cardiac output.

[Correction of tetralogy of Fallot and its influence to oxygen transport and lung changes. Part I. Oxygen transport (author's transl)]. / Der Einfluss der Korrektur einer Fallotschen Tetralogie auf Sauerstofftransport und Lungenveränderungen). Teil I: Sauerstofftransport

30 patients with tetralogy of Fallot were examined before and after correction. 10 of whom had previous procedures including 13 Blalock-Taussig shunts, 1 Cooley anastomosis and 6 pulmonary valvulotomies (Brock) with a dilator. Hemoglobin and blood gases were measured in 22 patients pre- and postoperatively on the 7th respectively 14th day and finally after 12 months. In 8 children the concentration of 2,3-DPG was accessed (pre-, postoperatively, immediately in ICU, on the 1st, 7th, 14th day and after 21 months). Hypoxia of various degrees was found at any time of the investigation, verified by a low venous oxygen saturation, high 2,3-DPG concentration and an erythrocytosis. The 2,3-DPG concentration was always elevated (preoperatively 18.2 +/- 1.8 muMol/g Hb; postoperatively 1st till 14th day 19.0 +/- 2.2; after 21 months 16.3 +/- 1.2 muMol/g Hb). Preoperatively hypoxia was correlated to the degree of the heart disease expressed by the hight of the Hb-concentration. In contrary after the correction signs of hypoxia (decreased venous oxygen saturation, increased 2,3 DPG-concentration) appeared with a low Hb as found in patients with anemia. The long term check-ups are indicative for slight cardiac residual disorders as there are hypoxic myocardial damage, residual gradients over the right ventricular outlet, reopened VSD's, and ventriculotomy scar tissue. Though the elevated 2,3-DPG-concentration and the consecutive rightward shift of the oxygen saturation curve obviously compensate these cardiac handi-caps as the excellent physical condition of the children shows.

Anaphylactoid reactions due to non-immune complex serum protein aggregates.

The infusion of aggregate-containing i.v. human gamma-globulin as well as human serum albumin can lead to severe anaphylactoid reactions with decrease in mean arterial pressure, increase in pulmonary artery pressure and decrease in cardiac output in unsensitized dogs, while the deaggregated solutions are well tolerated. During these anaphylactoid reactions, no significant changes in the serum complement activity of the dogs were observed. In clinical human serum albumin incompatibility, stimulation with albumin aggregates led to a high response in the lymphocyte culture, whereas deaggregated albumin had no stimulatory effect. By deaggregation of horse anti-human lymphocyte globulin prior to clinical administration, the compatibility of ALG therapy was improved.

Immunological properties of a high molecular weight component from yeast cell autolysate in dogs and evaluation of its potential role in human dextran reactions.

A high molecular weight component (HMC) of autolysate from Saccharomyces cerevisiae yeast cells was prepared. HMC was found to be immunogenic in dogs, inducing hemagglutinating antibody formation. Upon HMC challenge of immunized dogs, systemic anaphylactoid reactions were observed in 4/5 animals. The most prominent symptom was decreased cardiac output. Decrease in mean arterial pressure and increase in pulmonary arterial pressure were also observed. Consumption of total serum complement activity amounted to 22% of initial values. HMC also exhibited mitogenic activity in lymphocyte cultures from nonimmunized and immunized dogs. Since yeast autolysate is used as nitrogen source for Leuconostoc mesenteroides in the production of clinical B 512 dextran it is a theoretically possible trace contaminant of such solutions. Therefore, dogs hyperimmunized with HMC were also challenged with clinical dextran. No anaphylactoid signs were observed. These data suggest a negligible causal role of macromolecular contaminants derived from yeast cell autolysate in rare human anaphylactoid reactions following infusion of clinical dextran.

Intravascular persistence of hydroxyethyl starch in man.

In two groups, each consisting of five healthy volunteers, 7 ml blood/kg body weight were exchanged with equal amount of hydroxyethyl starch (HES) and dextran 60 solutions, respectively. Dextran 60 plasma levels, determined by the anthrone method, were undetectable after 4 weeks. The elimination of HES from the blood, determined by an immunological technique and by the anthrone method, had a very protracted course. Two weeks after infusion the HES plasma concentrations were 9% of the initial value and after 17 weeks they were still above the 1% level. The prolonged intravascular persistence of HES in its commercially available preparation, and the possibility of tissue accumulation after repeated HES infusions were considered undesirable. The hypothesis that HES infusion causes and augmentation of serum alpha-amylase concentrations in man was confirmed. This effect should be borne in mind when HES solutions are given to patients in whom the diagnosis of acute pancreatitis might be considered.

Oxygen transport and hemodynamics of stroma-free hemoglobin solutions.

The intravascular persistence of hb-W is significantly longer than of pyridoxylated hb (hb-PLP), however, no significant differences in BV were observed after isovolemic exchange of 20 ml/kg b.w. Even though the oxygen affinity of hb-PLP in vitro was reduced when compared to the affinity of hb-W significant differences in vivo were lacking. The development of hypovolemia and thus the lack of an adequate increase in cardiac output have been recognized as the most relevant causes to explain the changes observed. Neither of the solutions is yet to be recommended for clinical blood replacement therapy.

[Myocardial contractility in dogs in hemorrhagic shock and after volumn replacement (author's transl)]. / Die Kontraktilität des linken Ventrikels des Hundes im hämorrhagischen Schock und nach Volumenersatz

Myocardial contractility was evaluated in 8 out of 14 anaesthetized mongrel dogs during haemorrhagic shock and after volume replacement with Dextran 60 using the force-velocity relation of the contractile elements at zero load (Vmax). 7 animals received 50,000 or 20,000 KIE respectively of a proteinase inhibitor after bleeding and immediately before and one hour after the infusion of Dextran 60. The release of the lysosomal enzymes acid phosphatase and beta-glucuronidase was inhibited significantly (p less than 0.05) in the animals treated with Trasylol. However, the inhibition of the lysosomal enzymes seems not to have a decisive influence on the dynamic of the macro- and microcirculation and the myocardial contractility.

[Resuscitation with stroma-free hemoglobin solution after acute blood loss]. / Reanimation nach akutem Blutverlust mit stromafreier Hämoglobinlösung.

Resuscitation and volume replacement after acute blood loss is possible for a short duration by means of 6% stroma-free hemoglobin solution (SFH). Despite transcapillary loss of SFH, pulmonary edema is not provoked after massive infusion of cristalloid solution. The oxygen supply to the tissues is maintained by a compensatory rise in cardiac output and O2-extraction, mainly from the remaining red cell hemoglobin.