Robert M. Nalbandian

Sickle cell crisis terminated by intravenous urea in sugar solutions--a preliminary report.

Contrary to general opinion, sickle cell anemia is now among the best understood of diseases. There is now a molecular basis for the pathogenesis, the diagnosis, and the treatment of this lethal genetic affliction an explicit protocol and illustrative cases of the use of Intravenous urea in sugar solutions for the termination of sickle cell crisis are provided. The therapeutic principle involves the rapid establishment of a high blood urea nitrogen gradient of the order of 150–200 mg%, which is maintained by appropriate adjustment of the infusion of urea until that point in time when pain disappears and the infusion is discontinued. For several reasons including the critically important one of maintenance of hydration, the use of a central venous catheter with a Y-hookup for simultaneous Infusions of both a 30% urea (in sugar) solution as well as Ringers or Ringers lactate solutions is specified. By this therapeutic modality we have been consistently able to abort sickle cell crisis without the use of narcotics or analgesics. When the published protocol for the I.V. use of urea in sugar solutions has been faithfully followed, we have never had a therapeutic failure, a medical misadventure, or a death; 17 times in 15 patients Faithful compliance with all particulars of the protocol is essential.

Oral urea and the prophylactic treatment of sickle cell disease-a preliminary report.

The purpose of life-long oral prophylactic urea in the treatment of sickle cell disease is to arrest progress of the disease. If episodic and incremental tissue damage of various organs is to be avoided, oral urea treatment must be instituted as soon as the homozygous state for S hemoglobin can be diagnosed, i.e., at five to six months after birth. Our therapeutic regimen of a modest elevation of the blood urea nitrogen level by daily oral urea medication is a clinical application of a simple but important laboratory experiment We have shown that it requires less urea to block sickling than it does to reverse sickling. Explicit clinical protocols are provided. Advantages of oral urea in the prophylactic mode over intravenous urea in the treatment of acute sickle cell crisis include simplicity, trivial cost, safety, and promise of a functional full life-span free of injury. Our experience also indicates that oral prophylactic urea treatment may not be effective under three conditions: (1) in the presence of an unsuspected iron deficiency; (2) in sickle-thalassemia syndromes; and (3) in patient failure to maintain urea dosage schedules. In our study, to date, in 80 patients managed on oral urea therapy, it appears that the frequency of sickle cell crisis has been eliminated and parameters of hemoglobin and hematocrit plasma volume determinations done in some of our patients indicate that increased hemoglobin levels are not the result of hemoconcentration.

Consumption coagulopathy: practical principles of diagnosis and management.

Abstract Consumption coagulopathy, with its multiple etiologies, is a common mechanism of death. If the disease is properly diagnosed and managed, life can often be extended over several days, yielding sufficient time for the diagnosis and treatment of the underlying disorder. With the correction of the primary disease the threat of consumption coagulopathy will spontaneously remit. Determination of the type of coagulopathy is critical since the disease may be lethal if the wrong treatment is given. A small group of simple tests suitable for hospital laboratories periodically repeated will yield patterns of differential diagnostic and therapeutic significance. In consumption coagulopathy the central pathophysiologic result is the intravascular conversion of plasma to serum. The central principle of therapy is the intravascular reversion of serum to plasma by the titration of the patient with continuous intravenous administration of the indicated drug, dosages being determined by the response of individual coagulation parameters in a periodically repeated standard panel. The physician, and especially the pathologist because of his pivotal role in the diagnosis and management of cases of consumption coagulopathy, must have an extraordinarily clear understanding of these concepts. The practical operational approach we offer achieves these ends.

The Molecular Basis for the Treatment of Sickle Cell Crisis by Intravenous Urea.

Excerpt We show that the molecular basis for the use of intravenous urea in the treatment of sickle cell crisis is supported by molecular pathology and in vitro experiments. We have been able to in...

Embryonic, Fetal, and Neonatal Hemoglobin Synthesis: Relationship to Abortion and Thalassemia.

Abstract : In the embryo and fetus, the events and genetic mechanisms regulating the production of the five different globin chains account for several molecular species of intrauterine and neonatal hemoglobins. Strikingly intricate, synchronized correlations with reference to onset, peak level, and disappearance of: (1) five distinct globin chains; (2) five molecular species of hemoglobin; (3) three distinct intrauterine erythropoietic cell lines; ad (4) erythropoiesis in three specific embryonic and fetal organs are noted and result in new insights and findings. It is shown on the basis of correlated published data in the literature that under normal conditions of embryonic and fetal hemoglobin synthesis: (1) the erythroblasts in the yolk sac in the first trimester synthesize alpha and epsilon globin chains and so produce hemoglobins Gower-1 and Gower-2; (2) the erythroblasts in the liver in the second trimester synthesize alpha and gamma globin chains predominantly and so produce hemoglobin F; and (3) the erythroblasts in the bone marrow in the second trimester initially and in the third trimester more intensely synthesize alpha, beta, and delta globin chains and so produce hemoglobins A and A2 predominantly. Important clinical insights are gained by an understanding of these genetic, biochemical, and embryologic correlations of intrauterine erythropoiesis, including the basis: (1) for the well-known but presently unexplained peak incidence of abortions at the end of the first trimester; (2) for the delayed postnatal morphologic expression of S hemoglobin; (3) for the appearance of hemoglobinopathies Barts and H; and (4) for the thalassemia syndromes. (Author)

Sickling Crisis Treated Successfully by Urea in Invert Sugar.

Excerpt The use of urea in invert sugar for the treatment of sickling crisis has a molecular basis and is implicit in Murayamas recently modified hypothesis for the molecular mechanism of sickling...

Urea, Urease, Cyanate and the Sickling of Hemoglobin S.

Abstract : The hypothesis suggested recently that urea in sugar solutions interferes with the sickling event by ionization to cyanate and subsequent carbamylation of the hemoglobin S molecule was tested. Controlled studies in oxygen-free atmospheres have shown that SS cells, protected from sickling by urea-sugar solutions at clinically effective concentrations, were sickled subsequent to the addition of urease. The urea molecule per se interferes with sickling; cyanate has no role in this action of urea. UREA: (1) blocks and reverses sickling; (2) protected sickle cells become sickled when incubated with urease; (3) effects are reversible; (4) effects are immediate; and (5) effects are apparent in the deoxygenated state. CYANATE: (1) blocks but does NOT reverse sickling; (2) treated cells are unaffected by urease; (3) effects are permanent; (4) effects require time; and (5) initially hemoglobin S must be oxygenated before carbamylation will occur. Thus, it is apparent that urea and cyanate interfere with sickling by distinctly separate molecular mechanisms. The blocking and desickling action of urea is urea-dependent. Possible molecular mechanisms for the action of urea are discussed. (Author)

Restoration of phagocytosis and oxidative metabolism by Piracetam in failing human neutrophils: A qualitative assessment

By the use of immunobeads, a convenient clinical laboratory test is available which detects, in metabolically stressed leukocytes, failing or absent phagocytosis and/or impaired to absent oxidative metabolic activity. Furthermore, it has been demonstrated that Piracetam, 2-oxo-pyrrolidine acetamide, will restore such compromised neutrophils to normal functional status. In 4 of 19 patients, all with a variety of serious diseases, a range from impaired to total failure of neutrophilic phagocytic and metabolic oxidative activities was detected by the test. Piracetam, as shown by qualitative methods, restored to optimal activity the two impaired neutrophil functions in these 4 patients. Quantitative techniques are available currently to establish the beneficial effect of Piracetam on such defective neutrophils. Piracetam merits additional study to determine its efficacy in enhancement of restorative effects on compromised neutrophils which have been observed. The clinical promise of this investigation offers benefit to some patients now jeopardized by certain stressful diseases in part due to agonal failure of neutrophils.

Sickle Cell Screening

To the Editor.— We are gratified that Uddin et al (227:1405, 1974) have found the automated dithionite test ( Clin Chem 17:1033, 1971) so reliable in sickle cell hemoglobin screening. Because of the closing caveat about screening civilian populations, emphasis on several points is offered. The use of the automated dithionite test (ADT) as the initial method of screening, and the reservation of hemoglobin electrophoresis (HE) for those cases that are ADT-positive or that require genetic counseling, is an eminently satisfactory procedure, yielding requisite data at lowest cost. Not all newly found cases of hemoglobin S will require or demand genetic counseling; when the ADT gives positive findings, the HE should be performed on such specimens in that sequence to get the essential data. Electrophoresis does not need to be done on all specimens in any given test population. Exaggerated preoccupation with hemoglobin C has led to the expensive and redundant

Urea Therapy in Sickle-Cell Disease

Excerpt To the editor: The recent letter of Drs. Rudders and Pisciotta (Ann Intern Med77:659-660, 1972) sets forth their understandable demurral on urea therapy in sickle-cell disease. Our views ca...