Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients.

PURPOSE: To examine the consequences of administration of norepinephrine on muscle tissue oxygenation in severely hypotensive septic shock patients. METHODS: This was a prospective observational study conducted in a medical intensive care unit of a university hospital. We included 28 septic shock patients that received early volume resuscitation. All were eligible for receiving norepinephrine because of life-threatening hypotension and low diastolic arterial pressure. Muscle tissue oxygen saturation (StO2) and its changes during a vascular occlusion test were measured at the level of the thenar eminence using a near-infrared spectroscopy (NIRS) device. Transpulmonary thermodilution cardiac index (CI) and NIRS-derived variables were obtained before and after the mean arterial pressure (MAP) was increased by norepinephrine. The baseline StO2 and the vascular occlusion test-derived variables of 17 healthy volunteers were measured and served as controls. RESULTS: In healthy volunteers, StO2 ranged between 75 and 90% and StO2 recovery slopes ranged between 1.5 and 3.4%/s. Administration of norepinephrine, which was associated with an increase in MAP from 54 ± 8 to 77 ± 9 mmHg (p < 0.05), also induced increases in CI from 3.14 ± 1.03 to 3.61 ± 1.28 L/min/m² (p < 0.05), in StO2 from 75 ± 9 to 78 ± 9% (p < 0.05) and in StO2 recovery slope from 1.0 ± 0.6 to 1.5 ± 0.7%/s (p < 0.05). CONCLUSIONS: Norepinephrine administration aimed at achieving a MAP higher than 65 mmHg in septic shock patients with life-threatening hypotension resulted in improvement of NIRS variables measured at the level of the thenar eminence.

Androgen therapy in aplastic anaemia: a comparative study of high and low-doses and of 4 different androgens. French Cooperative Group for the Study of Aplastic and Refractory Anemias.

A prospective randomized study of androgen therapy in aplastic anaemia (AA) was performed: 2 androgens (fluoxymesterone and norethandrolone) at high (1 mg/kg/d) and low (0.2 mg/kg/d) dose were studied on 110 patients; and 4 androgens given at high doses were objectively compared in 125 other cases. When patients are matched for AA severity there is an obvious efficiency of the high-dose androgens in the survival of the less severe cases of aplastic anaemia and in their haematological improvement. The data further show that, among the 4 androgens tested, fluoxymesterone is the most efficient and stanozolol the least. We conclude that androgen therapy is truly efficient in moderately severe aplastic anaemia and that fluoxymesterone (1 mg/kg/d) for 18 months should be chosen as reference drug to any new androgen therapy assay.

In vitro CFU-E and BFU-E responses to androgen in bone marrow from children with primary hypoproliferative anaemia: a possible therapeutic assay.

The effects of natural and synthetic androgens on erythroid colony formation in children's bone marrow cultures were studied using a methylcellulose microculture assay. In an attempt to predict the clinical response to androgens in two children with Fanconi anaemia (FA) and two children with Diamond-Blackfan syndrome (DB), we tested the hormonal stimulation of testosterone, nortestosterone and etiocholanolone on CFU-E, BFU-E and uroporphyrinogen I synthase activity (UROS). We observed that colony formation and UROS activity were reduced when compared to values obtained with normal children's bone marrow cultures. The addition of steroids to the cultures significantly enhanced the numbers of CFU-E and BFU-E derived colonies and their UROS activity in marrow from patients with FA and one patient with DB. The strong depletion of marrow progenitor cells in the unresponsive marrow from child 4 with DB could explain the absence of hormonal response. Whereas the responsiveness to steroids varied according to the individual, the in vitro testing of erythroid differentiation in the presence of androgens theoretically may lead to an effective prediction of response to therapy in children with hypoplastic anaemia.

[Effects of weakly androgenic anabolic steroids on growth in Turner's syndrome]. / Effets des stéroïdes anabolisants faiblement androgéniques sur la croissance dans le syndrome de Turner.

The effects of weakly androgenic steroids at minimal doses (norethandrolone 2.5 to 10 mg/day or methandienone 1 mg/day, administered 2 months every trimester) have been studied in 67 patients with Turner syndrome: 37 with 45 XO karyotype and 30 with mosaicism or partial X deletion. Mean bone age at the onset of treatment was 10 4/12 +/- 1 8/12 years, and the mean height retardation, adjusted to parents' height, was 3.7 +/- 1.2 standard deviations. Growth velocity was very significantly increased during the first 3 semesters of treatment. The ratio of bone age to height age, evaluated after 2 years of treatment, did not increase. The adult height reached by 37 treated patients was at the average 1.96 cm higher than that of a control group of 25 adult untreated Turner cases, this difference being not significant. The results varied greatly between individuals, without relation to the type of chromosomal abnormality or the kind and dose of steroid received. The psychological evolution of the treated patients was studied accordingly to their school and/or professional accomplishments. It was satisfactory in most of them. The anabolic treatment and/or the gain in growth velocity during treatment seemed to have positive psychological effect. No side-effects were noticed.

[Treatment of pituitary nanism: is it necessary to treat adrenal androgen deficiency?]. / Traitement du nanisme hypophysaire: faut-il traiter le déficit des androgènes surrénaux?

In 17 hypopituitary prepubescent children (14 males and 3 females), aged 14.5 +/- 2.1 years, treated for more than 2 years with human growth hormone (hGH), with bone ages of 10.4 +/- 1.4 years and plasma dehydroepiandrosterone (DHA and/or DHA-S) levels lower than the normal values for bone age, low dose androgen therapy (norethandrolone 0.25 mg/kg/day 2 of 3 months) was added to the previous treatment. The speed of growth doubled during the first six months of associated treatment. For 15 patients so treated for one year,the height gain was 7.5 +/- 1.56 cm versus 4.47 +/- 1.2 cm the preceding year. During this first year of treatment, bone age, on an average, progressed less quickly than height. The combination of hGH and low grade androgenic steroid therapy allows for the acceleration of the growth in height without increasing the doses of hGH. A prolonged controlled trial of this therapy in hypopituitary prepubescent children with bone age of at least 8 years and known deficiency of androgenic secretion by the adrenal glands is suggested.

[Acquired aplastic anemia in children. Therapy using androgens and antilymphocyte gamma globulin]. / Anemia aplástica adquirida en niños. Terapéutica con andrógenos y con gammaglobulina antilinfocítica.

Authors describe initial characteristics, clinical course and response to treatment of 13 children, aged from eight months to nine years, with acquired aplastic anaemia. Six of the children had been exposed to products with potential bone-marrow toxicity: chloranphenicol (1), pirazolones (3) and insecticides (2). Pancytopenia was severe in twelve and moderate in one. Five patients with severe aplastic anaemia were given antilymphocytic (2) or antithymocytic (3) (ATG) gammaglobulins; two of those treated with ATG responded after two and five months respectively and there was no response in the other three. Twelve patients were given androgen treatment (oxymetholone or nandrolone decanoate): four, two of whom previously had received ATG, followed a favorable course. None of the severe initial pancytopenic patients responded to androgen single agent treatment. No marrow transplant was performed in any of the children. Eight of the thirteen patients died one to 37 months after onset (median, 6 months) and five (38%) are alive after 21 months to 10 years, corresponding to two patients with moderate and three with severe initial pancytopenia. Importance of an appropriate supportive treatment during initial stages of the disease and the probable efficacy or immunosupressive treatment in certain patients must be underlined.

A study of the efficacy of 5 alpha- and 5 beta-androstanes in chronic experimental aplastic anemia in mice.

The efficacy of in vivo administration of a 5 alpha-androstane and two 5 beta-androstanes (3 alpha and 3 beta) on CFU/GM and CFU/E mouse bone marrow stem cells was compared. The subjects were two groups of Swiss Webster mice: one normal group and one group in whom chronic aplastic anemia was induced by irradiation followed by mesenteric node lymphocyte grafting from C57/Bl donor mice. In normal animals, the two types of androgens (5 alpha and 5 beta) had the same efficacy, and the injection of 5 beta-androstane, before that of 5 alpha, significantly increased its efficacy. In aplastic mice, 5 alpha and 5 beta-androstanes had the same efficacy on CFU/E but 5 beta-androstanes were more efficient on the granulopoietic committed stem cells. The efficacy of the association of the two compounds in aplastic mice was not superior to that of each drug alone, which can be explained by the depletion of the stem cell compartment induced by the stimulating effect of the first androgen.

[Pure megaloblastic refractory anemia. Prolonged complete remission following androgenotherapy]. / Anémie réfractaire pure mégaloblastique. Rémission complète prolongée après androgénothérapie.

In a case of pure megaloblastic refractory anemia, a complete remission is reported. This remission has been obtained by prolonged high dose androgenotherapy and has now lasted for more than 5 years. The practical therapeutic consequences are discussed.

Prognostic factors in acquired aplastic anemia. A study of 352 cases.

The prognostic factors of short- and long-term survival have been studied in 352 patients with aplastic anemia of all grades of severity. This group was homogeneous with regard to the clinical and laboratory survey, and the treatment used [high-dose androgen therapy]. The "hierarchy" of the individual prognostic parameters has been established: current severe infection, granulocyte count, percentage of the nonmyeloid cells on the bone marrow slides, platelet count, reticulocyte count, 59Fe utilization, and stromal disorganization on the bone marrow biopsy specimen. As these parameters are interrelated, a multiparametric analysis enables us to define groups of patients with different short-term evolution and to derive a prognostic index from these data. The use of such an index, however, allows a correct prediction in only 73 per cent of the cases, better in the milder than in the more severe cases. It is possible that the short-term evolutive tendency (improvement or worsening during the first six weeks of therapy) may contribute supplementary information useful for prognosis and the choice of treatment. After the first three months critical period, the mortality rate no longer depends on the initial severity of the disease but exclusively on the clinical and hematologic improvement. Thus, comparing the hematologic data obtained initially and after three months of androgen therapy allows us to correctly predict the long-term evolution.

[Immunosuppression, bone marrow infusion and low dose androgens, successful therapy of severe aplastic anemia]. / Immunosupression, Knochenmarkinfusion und niedrig dosierte Androgene, eine erfolgreiche Therapie der schweren aplastischen Anämie.

18 patients with severe aplastic anemia (SAA) but without an HLA-identical sibling were treated by antilymphocyte globulin (ALG) followed by infusion of marrow cells from a semi-compatible family donor. 13 of these received low dose androgens after ALG: 11 (85%) achieved stable remission without transfusion requirement. One patient relapsed after 4 months, one patient with only partial remission died from infection. None of the 4 patients who did not receive androgens after ALG achieved remission. ALG, marrow and low-dose androgens represent a promising therapy for SAA and can be favorably compared with allogeneic bone marrow transplantation.

Androgen therapy of aplastic anaemia--a prospective study of 352 cases.

A prospective study of 352 patients with aplastic anaemia on androgen therapy has been performed. The following main observations have been obtained: The actuarial mortality rate at the 20th month is 52%, half the deaths being observed during the first 3 months; these figures are similar to those previously published, from smaller series of androgen-treated patients, and lower than those of non-androgen-treated cases. Differences in survival and improvement were observed between groups of patients treated for more than 3 months with either alkylated or non-alkylated drugs. Signs of liver damage were observed no matter which was the drug used. Continous improvement can be observed even in the 2nd year of treatment indicating that full-dose androgen therapy should be continued up to 20 months in not fully improved patients. The degree of initial disease activity is a clear prognostic parameter for the mortality in the first quarter of the course. In case of survival of severe cases, improvement can be obtained to the same extent as in milder cases. This stress the need for adequate maintenance therapy in all types of patients. Addition of glucocorticoids harms the prognosis, mainly in most granulocytopenic patients. Glucocorticoids have no effect upon the liver damage induced by androgens.

Testosterone rebound therapy: a neglected modality.

A summary of the literature and a 20-year review of our own experience with testosterone rebound therapy is presented. Of 225 patients followed, 52% rebounded to fertile levels followed by pregnancy in the wives of 25%. Pregnancy occurred in 3 wives (8%) of the 38 initially azoospermic patients. There was only a 4% incidence of failure to return to at least the pretreatment sperm count following therapy, and no persistent azoospermia was observed. These results are consistent with other recent reports of several large series of patients. Proper screening and selection of patients is mandatory. Testosterone rebound is a neglected form of therapy meriting consideration in selected patients.

[Cytogenetic studies in four cases of Fanconi's anemia (author's transl)]. / Anomalies chromosomiques et anémie de Fanconi. Etude de 4 cas

In two sibships, four patients with Fanconi's anaemia were studied cytogenetically. Interfamilial variations of the frequency of chromosome breakage and rearrangements were found, suggesting the heterogeneity of the disease. Variations of chromosomal abnormalities have also been found during the course of the disease. An abnormal 47 chromosomes clone has been observed in the bone marrow cells from one patient. A mechanism of somatic segregation is probably involved in the constitution of that clone.