Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary resuscitation in pigs

BACKGROUND: It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold between 20 and 30 mm Hg that renders defibrillation successful. METHODS AND RESULTS: After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg, respectively; n=6) or epinephrine (early epinephrine: 45, 45, and 200 microg/kg, respectively; n=6). Another 12 animals were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive, every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n=6), or epinephrine (late epinephrine: 45 and 200 microg/kg, respectively; n=6). Defibrillation was attempted after 22 minutes of cardiac arrest. Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after early vasopressin compared with early epinephrine (50+/-4 versus 34+/-3 mm Hg, P<0.02; 42+/-5 versus 15+/-3 mm Hg, P<0.0008; and 37+/-5 versus 11+/-3 mm Hg, P<0. 002, respectively). Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after late vasopressin compared with late epinephrine (40+/-3 versus 22+/-4 mm Hg, P<0.004, and 32+/-4 versus 15+/-4 mm Hg, P<0.01, respectively). All vasopressin animals survived 60 minutes, whereas no epinephrine pig had return of spontaneous circulation (P<0.05). CONCLUSIONS: Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.     

Endocrine effects of acute and chronic cimetidine administration

In normal men, acute oral administration of 300 mg cimetidine or intravenous injection of 50 mg of the drug had no effect on prolactin release. In contrast, intravenous injection of 150 or 300 mg led to substantial increments in serum prolactin. Peptic ulcer patients were randomly assigned to treatment with either cimetidine or antacid. Serial blood sampling until ulcer healing showed no significant changes in serum prolactin, testosterone, free testosterone, estradiol, LH, or FSH in either group. It is likely that the impotence and breast changes occasionally seen during cimetidine therapy are due to peripheral antagonism of androgen action rather than to alterations in circulating hormone levels.Supported by funds from the Medical Research Service of the Veterans Administration and Smith, Kline and French Laboratories.     

Prenatal and neonatal exposure of male rat pups to cimetidine but not ranitidine adversely affects subsequent adult sexual functioning

Cimetidine, ranitidine, or water was administered to pregnant rats from the 12th day of pregnancy through weaning at 21 days of age. The effects of such treatments upon the male progeny were evaluated. Anogenital distance and indices, measures of masculinity, were found to be reduced (p less than 0.05) in pups of cimetidine-exposed dams but not in the pups obtained from either the ranitidine or water controls. In addition, at 55 days and 110 days of age, the testes and ventral prostate-seminal vesicles (androgen-responsive tissues) of the rats exposed to cimetidine were smaller (p less than 0.05) than those of the other two groups. Moreover, at both 55 and 110 days of age, the testosterone levels were reduced (p less than 0.05) in these same pups. Despite the fact that the cimetidine-exposed animals had reduced testosterone levels compared with the levels of the other two groups, the luteinizing hormone levels did not differ among the three groups. Finally, both before and after exogenous androgen replacement, the sexual behavior of the cimetidine-exposed animals was diminished when compared with that of the other two groups.     

Activation of tuberoinfundibular but not tuberohypophysial dopaminergic neurons following intracerebroventricular administration of alpha-melanocyte-stimulating hormone

The effect of alpha-melanocyte-stimulating hormone (alpha MSH) on the activity of different central dopaminergic neurons in the male rat was determined by measuring the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following the administration of a decarboxylase inhibitor in brain regions that contain terminals of nigrostriatal (striatum), mesolimbic (nucleus accumbens), tuberoinfundibular (median eminence) and tuberohypophysial (neural and intermediate lobe of the pituitary) dopaminergic neurons. Intracerebroventricular (i.c.v.) administration of alpha MSH caused a prompt (within 30 min) increase in the concentration of DOPAC and the accumulation of DOPA in the median eminence, but was without effect in the other brain regions. The alpha MSH-induced increase in tuberoinfundibular dopaminergic neuronal activity was temporally related to a decrease in circulating concentrations of prolactin. Twelve hours after the i.c.v. administration of prolactin DOPA accumulation increased in the median eminence but not in the neural or intermediate lobes of the pituitary. DOPA accumulation was not altered in any brain region 12 h after the i.c.v. administration of alpha MSH. These results suggest that alpha MSH acts acutely to selectively activate tuberoinfundibular dopaminergic neurons and thereby cause the secretion of prolactin from the anterior pituitary to decrease.     

The effect of oral cimetidine on total and unbound serum lidocaine concentrations in patients with suspected myocardial infarction

In this study, we prospectively evaluated the effect of oral cimetidine on serum lidocaine concentrations in 6 patients with suspected myocardial infarction. Compared to baseline lidocaine levels, total lidocaine concentrations increased by 8.2 +/- 7.8% at 6 hours, 16.4 +/- 9.0% at 12 hours and 27.9 +/- 9.4% at 24 hours after two doses of oral cimetidine. Unbound lidocaine concentrations increased by 14.3 +/- 4.1% at 6 hours, and 18.3 +/- 10.3% at 24 hours after cimetidine. In patients with myocardial infarction (3), total lidocaine concentrations increased by 24.2 +/- 10.4%, whereas unbound lidocaine increased by 8.9 +/- 10.2% at 24 hours. Therefore, increases in total lidocaine concentrations after cimetidine administration were considerably less than those previously reported and empiric dosage reductions of lidocaine in patients receiving cimetidine may not be appropriate.     

Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins

Tissue factor pathway inhibitor (TFPI) is released to circulating blood after intravenous (i.v.) and subcutaneous (s.c.) injections of heparins, and may thus contribute to the antithrombotic effect of heparins. We have recently shown that total TFPI activity, plasma free TFPI antigen, and heparin releasable TFPI were partially depleted during repeated and continuous i.v. infusion of unfractionated heparin (UFH), but not during s.c. treatment with a low molecular weight heparin (LMWH). The difference may be attributed to a different mode of action or the different mode of administration. In the present randomized cross-over study, s.c. administration of therapeutic doses of UFH was compared with s.c. administration of two LMWHs. 12 healthy male volunteers were treated for 3 d with UFH, 250 U/kg twice daily, dalteparin, 200 U/kg once daily, and enoxaparin, 1.5 mg/kg once daily. Six participants were also treated with UFH, 300 U/kg once daily. On day 5 a single dose of either drug was given. Peak levels of total TFPI activity and free TFPI antigen were detected 1 h after injection, whereas maximal prolongation of activated partial thromboplastin time (APTT) and peak levels of anti-factor Xa activity and anti-factor IIa activity were detected after 4 h. On UFH administered twice daily, free TFPI antigen decreased by 44% from baseline level before the first injection on day 1 to pre-injection level on day 5. On UFH administered once daily, basal free TFPI antigen decreased by 50%, 56% and 27% on day 2, 3 and 5 respectively, compared with day 1. Minimal depletion of TFPI was detected during treatment with LMWHs. The study demonstrates the different modes of action of LMWHs and UFH and may help to explain the superior antithrombotic efficacy of LMWHs.     

Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings

Intranasal administration of insulin has been shown to influence neuroendocrine functions via an effect on central nervous mechanisms. Because insulin, in particular when infused into cerebral arteries, induces blood pressure (BP) elevation by an unknown mechanism, we investigated whether insulin exerts similar effects on BP after intranasal administration. To evaluate the immediate effects of insulin on BP, 20 IU of human insulin was intranasally administered every 10 minutes over a 2-hour period. Blood pressure, heart rate, and muscular sympathetic nervous activity (MSNA) were continuously monitored. For evaluating the effects of subchronic administration of insulin, changes during and after 8 weeks of treatment with 160 IU insulin/d on BP were monitored. Compared with placebo, the immediate nasal administration of insulin raised diastolic BP (12.21% +/- 5.10%; P < .05), mean arterial BP (10.81% +/- 4.32%; P < .04), and systolic BP (9.53% +/- 4.66%; P < .08), whereas MSNA and heart rate were unaffected. In contrast, prolonged intranasal insulin administration did not affect BP (P > .62 for all comparisons). The immediate increase in BP in the face of an unsuppressed MSNA after insulin suggests that intranasal insulin transiently changes the baroreflex set point. Thus, data suggest that intranasal insulin administration affects BP regulatory centers in the brain. However, the effect is not observed with prolonged administration of the hormone, suggesting the emergence of counterregulatory processes.     

N-acetylcysteine reduces contrast-associated nephropathy but not clinical events during long-term follow-up

Background

Contrast-associated nephropathy (CAN) is associated with increased morbidity and mortality following percutaneous coronary intervention (PCI). N-acetylcysteine (NAC) has been shown to reduce the risk of nephropathy; however, the impact of NAC on long-term clinical outcomes has not been assessed.

Methods

This randomized, double-blind, placebo-controlled trial enrolled 180 patients with moderate renal dysfunction undergoing PCI or coronary angiography with a high likelihood of ad hoc PCI; 171 patients completed the clinical follow-up. Patients received oral NAC (2000 mg/dose, n = 95) or placebo (n = 85) twice a day for 3 doses if randomized the night prior to the procedure, and 2 doses if randomized the day of the procedure. The primary end point was the incidence of a ≥25% increase in serum creatinine level 48 to 72 hours after PCI. Secondary end points were the inhospital incidence of death, nonfatal myocardial infarction, or urgent dialysis, and the 9-month incidence of death, nonfatal myocardial infarction, need for dialysis, or repeat hospitalization for cardiac reasons.

Results

CAN occurred in 9.6% of patients assigned to NAC and 22.2% of patients assigned to placebo (P = .04); 1 patient receiving NAC required urgent dialysis. The inhospital composite end point occurred in 7 (7.4%) NAC-treated and 3 (3.5%) placebo-treated patients, P = NS. At 9 months, the composite end point occurred in 23 (24.2%) NAC-treated patients and 18 (21.2%) placebo-treated, P = NS.

Conclusion

Although high-dose NAC prevented periprocedural CAN, this benefit did not translate into a decrease in adverse outcomes over 9 months. Further studies to determine the clinical utility of this drug are required.     

Suppression of Plasmodium falciparum infections during concomitant measles or influenza but not during pertussis.

In tropical countries, concomitant infections are a continuous problem. In the Rufiji Delta, an area of Tanzania that is holoendemic for malaria, there were outbreaks of influenza A, measles, and pertussis in 1986 and 1987. Significantly lower parasitic prevalences and mean densities of malaria parasites were found in children up to nine years of age who had measles or influenza than in asymptomatic control children. In contrast, children with pertussis had a higher prevalence and mean density than controls. The clinical courses of measles, influenza, or pertussis infections did not appear to be significantly affected by concomitant malaria infections. The reasons for the suppression of Plasmodium falciparum parasitemia during these viral infections are unclear. This effect could not be explained by the presence of fever.     

Interferon-gamma mediates suppression of erythropoiesis but not reduced red cell survival following CpG-ODN administration in vivo

OBJECTIVE: Cytokines released during inflammatory processes have been proposed to play a central role in mediating mechanism(s) leading to anemia. Here, we used CpG-ODN to investigate the effects of a pro-inflammatory response on the pathophysiological processes leading to anemia. METHODS: Na?ve and erythropoietin (EPO)-treated mice were injected for 2 days with 100 microg CpG-ODN or control ODN and the effects on the course of red blood cell (RBC) and reticulocyte counts, RBC turnover, and EPO-stimulated maturation of erythroid cells were analyzed. To study the effect of CpG-ODN on erythroid cell maturation in vitro, we obtained primary EPO-responsive cells by treating mice with thiamphenicol (15 mg/g body weight). RESULTS: CpG-ODN-treated mice developed anemia, which persisted for 5 days and was associated with a 50% reduction in EPO-stimulated differentiation of EPOR+ cells to TER119+ erythroblasts. CpG-ODN-induced suppression required accessory cells, including antigen presenting cells, which activated other cells to produce pro-inflammatory cytokines. In vitro neutralization of IFN-gamma, but not IL-12, TNF-alpha, IFN-alpha, IL-1alpha, or IL-1beta, abrogated the erythropoietic suppression induced by CpG-ODN. The anemia observed in CpG-ODN-treated mice was also associated with reduced RBC survival in vivo, as demonstrated by a sevenfold to eightfold higher turnover of biotinylated RBC compared to control ODN-treated mice. In vivo IFN-gamma neutralization confirmed that IFN-gamma contributed to erythropoietic suppression but not reduced RBC survival. CONCLUSIONS: Together, these results demonstrate that CpG-ODN anemia is associated with suppressed erythropoiesis and decreased RBC survival. Importantly, CpG-ODN-induced IFN-gamma was found to be the major factor mediating erythropoietic suppression but not decreased RBC survival.     

Invasive candidiasis does not complicate short-term cimetidine treatment of duodenal ulcer

The purpose of this study was to record the frequency of invasive candidiasis of duodenal ulcer and to determine whether or not it is enhanced by cimetidine treatment. Our multicenter prospective trial involved 99 patients with endoscopically proven duodenal ulcer who were undergoing a 4- or 8-week cimetidine (800 mg/day) treatment program. At the endoscopic examination, performed before and after the 4- or 8-week treatment, three biopsy samples were taken from the ulcer edge or from the healed tissue. Ulcer infiltration by Candida was presumed by the presence of mycetes in stained tissue samples. Healing rate was 76% at 4 weeks and 89.9% at 8 weeks. Candida infiltration was not seen in any biopsy specimen. Short-term treatment with cimetidine does not promote invasion of mycetes into the duodenal ulcer lesion.