Heart transplantation outcomes in cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) is a progressive inflammatory cardiomyopathy that can lead to heart failure, arrhythmia, and death. There is limited data on Orthotopic Heart Transplantation (OHT) outcomes in patients with CS. Here we examine outcomes in patients with CS who have undergone OHT at centers throughout the United States from 1987 to 2019. METHODS: This was an analysis of 63,947 adult patients undergoing OHT captured in the United Network for Organ Sharing (UNOS) registry. Patients were characterized as cardiac sarcoidosis (CS) or Non-CS. Baseline characteristics were compared using chi-square and Kruskal-Wallis Tests. Outcomes of interest included primary graft failure, patient survival, treated graft rejection, hospitalization for infection, and post-transplant malignancy. RESULTS: During the study period 227 patients with CS underwent OHT. Patients with CS were younger, had higher proportion of non-white patients, and received transplants at more urgent statuses. After multivariable modeling there was no difference in survival (HR 0.86, CI 0.59-1.3, p = 0.446) or graft failure (HR 0.849, CI 0.58-1.23, p = 0.394) between patients with CS and Non-CS. Patients with CS had lower odds of rejection (OR 0.558, CI 0.315- 0.985, p = 0.0444). Patients with CS had similar odds of hospitalization for infection and post-transplant malignancy, as Non-CS patients. CONCLUSIONS: Patients with CS and Non-CS had similar post OHT survival, odds of graft failure, hospitalizations for infection, and post-transplant malignancy. Results of this study confirm the role of heart transplantation as a viable option for patients with CS.

A mechanism of benefit of soy genistein in asthma: inhibition of eosinophil p38-dependent leukotriene synthesis.

BACKGROUND: Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown. OBJECTIVE: To determine whether genistein blocks eosinophil leukotriene C(4) (LTC(4)) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients. METHODS: Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC(4) synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FE(NO)) and ex vivo eosinophil LTC(4) production were assessed before and after the soy isoflavone treatment period. RESULTS: Genistein inhibited eosinophil LTC(4) synthesis (IC(50) 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC(4) synthesis decreased by 33% (N=11, P=0.02) and FE(NO) decreased by 18% (N=13, P=0.03). CONCLUSION: At physiologically relevant concentrations, genistein inhibits eosinophil LTC(4) synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC(4) synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.

Differential dependence on protein kinase C of arachidonic acid metabolism stimulated by hydrogen peroxide and by zymosan in the alveolar macrophage.

The dependence on protein kinase C (PKC) of arachidonic acid (AA) metabolism stimulated by the biologically important oxidant H2O2, as compared to zymosan particles, was investigated in the rat alveolar macrophage. The PKC inhibitor staurosporine markedly reduced AA release and eicosanoid synthesis stimulated by zymosan, but only slightly inhibited AA release and metabolism induced by H2O2. Furthermore, in macrophages depleted of PKC by extended exposure to phorbol 12-myristate 13-acetate, AA release in response to zymosan was greatly inhibited, whereas that stimulated by H2O2 was attenuated to a significantly lesser degree. Thus, zymosan-stimulated AA metabolism requires active PKC, whereas H2O2-induced metabolism is largely PKC-independent. This provides direct evidence for the existence of two pathways of agonist-stimulated AA metabolism, which differ in their dependence on PKC, in the alveolar macrophage.

Glucocorticoids fail to inhibit arachidonic acid metabolism stimulated by hydrogen peroxide in the alveolar macrophage.

We have previously demonstrated that the biologically important oxidant hydrogen peroxide (H2O2) triggers release and metabolism of arachidonic acid (AA) in the alveolar macrophage (AM). In this study, we evaluated the ability of glucocorticoids to inhibit rat AM AA metabolism stimulated by H2O2, as compared to the particulate zymosan. Methylprednisolone and other glucocorticoids failed to significantly inhibit release of AA stimulated by H2O2, while markedly reducing AA release in response to zymosan. Similarly, methylprednisolone only weakly inhibited synthesis of thromboxane (Tx)B2 stimulated by H2O2, while inhibiting zymosan-induced eicosanoid synthesis to a marked degree. On the other hand, the phospholipase inhibitor mepacrine strongly inhibited AA release and TxB2 formation stimulated by both H2O2 and zymosan, indicating that H2O2 induced AA metabolism is indeed susceptible to pharmacologic inhibition. The failure of glucocorticoids to inhibit AA metabolism stimulated by H2O2 in the AM may in part explain their inability to ameliorate oxidant-mediated lung inflammation and injury.

Nonoliguric acute renal failure after captopril therapy.

In a patient with severe renovascular hypertension, nonoliguric acute renal failure developed after she received captopril treatment. We believe this to be a previously unreported complication. Urine volume ranged from 1,640 to 2,260 mL/24 hr, and serum creatinine level rose from 2.3 to 8.3 mg/dL. There was no evidence of renal hypoperfusion or interstitial nephritis. Acute renal failure most likely was secondary to the nephrotoxic effect of captopril on chronically hypoperfused kidneys. Renal function improved rapidly after withdrawal of the drug therapy.

Reduced superoxide dismutase in lung cells of patients with asthma.

Lung cells recovered from symptomatic patients with asthma generate increased amounts of reactive oxygen species (ROS). Animal and in vitro studies indicate that ROS can reproduce many of the features of asthma. The ability of ROS to produce the clinical features of asthma may depend on an individual's lung antioxidant defenses. Patients with asthma are reported to have reduced antioxidant defenses in peripheral blood, but little is known about the antioxidant defenses of their lung cells. To define lung cell antioxidant defenses in asthma, the glutathione concentration and the glutathione reductase, glutathione peroxidase, catalase, and superoxide dismutase (SOD) activities were measured in cells recovered by bronchoalveolar lavage (BAL cells) and by bronchial brushing (bronchial epithelial cells, HBEC) from normal subjects and patients with asthma. Superoxide dismutase activity was reduced 25% in BAL cells (p < .05) and nearly 50% in HBEC (p < .02) from patients with asthma. Alterations in the other antioxidants were not identified. A direct relationship was found between airway reactivity to methacholine, measured as PC(20)FEV(1), and HBEC SOD activity (r2 = 89; p < .005), but not between airway reactivity and the other antioxidants. The finding of reduced SOD activity in lung cells of patients with asthma suggests that diminished SOD activity serves as a marker of the inflammation characterizing asthma. Alternatively, it may play a role in the development or severity of the disease.

Effect of large volume replacement with balanced electrolyte solutions on extravascular lung water in surgical patients with sepsis syndrome.

We investigated the effect of large volume replacement with balanced electrolyte solutions on extravascular lung water (EVLW) in 16 adult surgical patients with sepsis syndrome. Patients entered the study within the 24 h period following surgical interventions for acute necrotizing pancreatitis, intra-abdominal abscesses, and/or peritonitis. Sequential measurements (n = 108) were made at intervals of 6-12 h over a 48 h period. There were no significant differences between initial and final values of thermal-dye EVLW (5.0 +/- 1.1 vs. 5.7 +/- 1.1 ml/kg), plasma colloid osmotic pressure (COP, 13.3 +/- 2.5 vs. 13.2 +/- 2.9 mmHg), pulmonary artery wedge pressure (PAWP, 9.2 +/- 3.0 vs. 10.8 +/- 3.0 mmHg), and COP-PAWP gradient (4.0 +/- 3.5 vs. 2.4 +/- 3.9 mmHg). All results expressed as (mean +/- SD). The EVLW did not correlate with plasma COP, PAWP, or COP-PAWP gradient. We conclude that large volume replacement with balanced electrolyte solutions with the secondary decrease in plasma COP and COP-PAWP gradient do not necessarily contribute to a substantial increase in EVLW. This study fails to show any causal relationship between decrease in plasma COP or COP-PAWP gradient and oedema formation in the lung.

The effects of norepinephrine on hemodynamics and renal function in severe septic shock states.

OBJECTIVE: To investigate the effect of norepinephrine (NE) on hemodynamics, oxygen metabolism and renal function in patients with severe septic shock. DESIGN: Prospective study. SETTING: Post-operative ICU in a municipal general hospital. PATIENTS: The study included 56 patients with extreme low resistance states due to abdominal sepsis, who remained hypertensive (MAP < 60 mmHg) despite optimal fluid therapy and dopamine > 20 micrograms/kg/min and cumulative doses of dopamine and dobutamine > 30 micrograms/kg/min, respectively. INTERVENTIONS: After registration of baseline values dopamine was reduced to 2.5 micrograms/kg/min, and norepinephrine was administered starting at a dose of 0.05 micrograms/kg/min until a mean arterial pressure of more than 60 mmHg could be maintained. MEASUREMENTS AND RESULTS: During norepinephrine infusion (dosage ranging between 0.1-2 micrograms/kg/min, mean dose rate: 0.4 micrograms/kg/min) mean arterial pressure and systemic vascular resistance index increased significantly (p < 0.001). After 8 h a significant increase in stroke volume (p < 0.05) and decrease in heart rate (p < 0.05) could be observed. There was no significant change in cardiac index (CI), oxygen delivery (O2AVI) and oxygen consumption (VO2I). Creatinine clearance increased significantly (p < 0.005) from a control value of 75 +/- 37 ml/min to 102 +/- 43 ml/min after 48 h NE-treatment. CONCLUSION: Our results suggest that norepinephrine can be used safely in the treatment of severe septic shock states. Mean arterial pressure and glomerular filtration rate improved markedly without deleterious effects on CI, O2AVI and VO2I.

Does reoperation for abdominal sepsis enhance the inflammatory host response?

OBJECTIVE: To determine the effect of reoperation for severe abdominal sepsis on the course of proinflammatory mediators and hemodynamic factors. DESIGN: Inception cohort. SETTING: A university hospital and a secondary care hospital. PATIENTS AND METHODS: Fifteen patients suffering from severe peritonitis due to intestinal perforation or infected necrotizing pancreatitis were studied following 19 subsequent operations. Plasma samples were obtained immediately before and after reoperation, as well as at 1, 3, 6, 12, and 24 hours after operation to determine endotoxin, tumor necrosis factor alpha, and interleukin-6 levels. Clinical factors and therapeutic support were recorded at the corresponding times. MAIN OUTCOME MEASURES: Postoperative hemodynamic instability as defined by changes of the mean arterial pressure, pulmonary capillary wedge pressure, and vasopressor support. Courses of proinflammatory mediators were correlated to the hemodynamic findings. RESULTS: Mean arterial pressure decreased from 94 mm Hg postoperatively to 80 mm Hg at 3 hours (P = .006) and 81 mm Hg at 6 hours postoperatively (P = .005). Pulmonary capillary wedge pressure dropped from 14 mm Hg postoperatively to 12 mm Hg at 1 hour (P = .05). Vasopressor support significantly increased from 1 to 6 hours postoperatively (P = .02). Neither endotoxin nor tumor necrosis factor alpha levels showed significant changes in the postoperative course. Interleukin-6 levels continously increased from 586 pg/mL preoperatively to 910 pg/mL at 1 hour (P = .02) and 931 pg/mL at 3 hours postoperatively (P = .04). Overall interleukin-6 levels (R = -0.38, P = .003) and especially early postoperative interleukin-6 levels inversely correlated with postoperative mean arterial pressure. CONCLUSIONS: Reoperation for abdominal sepsis frequently causes substantial hypotension, and is, thus, potentially harmful to the patient. Reoperative trauma may induce an early postoperative increase in interleukin-6 levels. Because this increase occurs before the development of hypotension, a relationship between the kinetics of this cytokine and the observed hemodynamic instability may be present.

Discontinuation of mechanical ventilation.

The vast majority of patients who undergo mechanical ventilation are able to discontinue ventilatory assistance within a few days. Typically, patients who require only short-term mechanical ventilation do not have severe underlying lung disease, and the problem for which they require ventilatory support is most commonly rapidly reversible. In these patients on short-term ventilatory support, parameters of spontaneous ventilatory requirements and respiratory muscle strength, including minute ventilation, maximal voluntary ventilation, vital capacity, and maximal inspiratory pressure, are useful in predicting the success of discontinuation of mechanical ventilation. Ventilatory support can generally be discontinued by a variety of techniques in these patients without the need for weaning from the ventilator per se. The smaller group of patients in whom it is not possible to discontinue mechanical ventilation within less than 7 days comprises individuals who frequently have severe acute or chronic lung disease, multisystem extrapulmonary disease, or neuromuscular disease. After a period of prolonged mechanical ventilatory support, these complicated patients require a process of progressive weaning in which they gradually become able to support spontaneous ventilation. Spontaneous ventilatory parameters do not correlate well with weaning ability in patients on long-term ventilatory support. A systematic and comprehensive approach in which attention is focused on optimizing pulmonary and nonpulmonary factors that affect the weaning process provides the best chance for successful withdrawal of ventilatory support after long-term mechanical ventilation. Inadequate ventilatory drive, respiratory muscle weakness and fatigue, increased work of breathing, excessive CO2 production, and cardiac failure are potential mechanisms that may play a role in inhibiting successful weaning. Adverse factors relevant to each of these mechanisms must be addressed and corrected to whatever extent possible. Studies have not demonstrated the superiority of either classic T-piece weaning or IMV weaning methods in difficult-to-wean patients on long-term ventilatory support. Both techniques may be used successfully as long as all patient variables that may adversely affect weaning ability are corrected or optimized and close care and attention to the details of the weaning process itself are provided.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of 5-lipoxygenase activity in mononuclear phagocytes: characterization of an endogenous cytosolic inhibitor.

The proinflammatory leukotrienes (LT) play important roles in host defense and disease states. However, no endogenous mechanisms to downregulate 5-lipoxygenase (5-LO), the enzyme catalyzing LT synthesis, have been described. We observed that the cytosolic fraction of rat alveolar macrophages (AMs) and peritoneal macrophages (PMs), and of peripheral blood monocytes (PBMs) contain substantial amounts of 5-LO protein, but little detectable 5-LO activity. We therefore examined these mononuclear phagocyte (MNP) cytosolic fractions for inhibitory activity against 5-LO. MNP cytosol dose-dependently reduced the 5-LO activity in neutrophil (PMN) cytosol and AM membrane. Furthermore, MNP cytosol dose-dependently prolonged the lag phase of soybean lipoxygenase (LO) without affecting the rate of product formation. This effect was overcome by subsequent addition of 13(S)-hydroperoxy-9-cis-11-trans-octadecadienoic acid (13-HpOD), suggesting that the active factor scavenges hydroperoxides. Inactivation by boiling and roteinase K suggest that is a protein. We speculate that this cytosolic factor(s) may serve as an endogenous means for the down-regulation of 5-LO in macrophages.

Increased 5-lipoxygenase metabolism in the lungs of human subjects exposed to ozone.

The environmental pollutant ozone, at sufficiently high levels, is known to induce pulmonary inflammation with resultant airway obstruction in normal subjects. Eicosanoids comprise one group of mediators released from alveolar macrophages which are involved in the pathogenesis of inflammatory lung diseases. We compared the effects of 2-h exposures to 0.4 ppm ozone and filtered air on pulmonary function and eicosanoid levels in bronchoalveolar lavage fluid in 11 normal healthy volunteers. Subjects were exposed to a 6-fold increase in minute ventilation using an adjusted work load on a cycle ergometer. All subjects complained of cough and dyspnea, and demonstrated increased airway obstruction, and increased specific airway resistance following ozone exposure as compared to air exposure. Bronchoalveolar lavage cell count demonstrated a 9-fold increase in the number of neutrophils with a lesser reduction in the number of alveolar macrophages following ozone exposure. Notably, bronchoalveolar lavage fluid leukotriene (LT) C4 (8-fold) and to a lesser extent LTB4 (1.5-fold) levels were higher following ozone exposure compared to air control, with no change in prostaglandins. In a subset of four subjects, alveolar macrophage arachidonic acid metabolism was studied in vitro following separate in vivo exposures to both ozone and air. Alveolar macrophages obtained following ozone exposure released more 5-lipoxygenase (1.5-fold) metabolites, with no change in cyclooxygenase metabolites, than did cells obtained following air exposure. These observations document activation of the 5-lipoxygenase pathway in the lung following ozone exposure, and suggest that alveolar macrophages may participate in the generation of LT, whose actions promote airway inflammation and obstruction.

Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle.

The metabolic profiles of 14 patients with prolonged abdominal sepsis were analysed on the second day after laparotomy. The profiles of survivors were compared with those of non-survivors who died one to five days after the time of evaluation due to uncontrollable multiple organ failure. In the non-surviving patients plasma glucose and glucagon levels were significantly higher than in surviving patients. The plasma concentrations of phosphoserine, cysteine, valine, phenylalanine, and 3-methylhistidine were found to be significantly increased in non-survivors and their muscle tissue showed significantly decreased concentrations of glutamine, proline and lysine with increases in valine and leucine. A correct classification of non-survivors and survivors could be obtained from the plasma and muscle amino acid concentrations, the highest discriminant power being from muscle glutamine. In severe sepsis metabolic changes correlate with the outcome of the patients, and amino acid metabolism seems to be characterised by low concentrations of muscle glutamine and high levels of the branched chain amino acids possibly indicating an inhibited intracellular glutamine formation in muscle tissue.

[The effect of propanidid in patients with an increased tendency to cerebral convulsions (author's transl)]. / Zur Wirkung von Propanidid bei Patienten mit erhöhter zerebraler Krampfbereitschaft

In view of the observation of tonic-clonic convulsions after the use of Propanidid in certan patients, a study was undertaken of the effects of this drug (7 mg/kg) on the EEG of 2 volunteers with a known history of epilepsy. Both subjects developed tonic-clonic convulsions and showed typical alterations of the EEG pattern even before the onset of hyperventilation. These EEG alterations were producible also during complete relaxation. The convulsions were easily stopped by the administration of short-acting barbiturates. Similar observations reported in the literature are briefly discussed. The conclusion is drawn that Propanidid should not be given to patients with a known history of epilepsy or any other convulsive disease.

[Regional results of human liver transplantation in Vienna]. / Regionale Ergebnisse der humanen Lebertransplantation in Wien.

21 cases of transplantation of the liver are analysed for indication, anaesthesia, operative management, anhepatic period, immunological therapy and specific post-operative problems (jaundice and rejection episodes). Causes of death are noted and prediction of survival gives a rate of 55%/1st year in the 17 patients operated on since 1982 under a standardised management schedule. The transplantation programme in Vienna provides routine treatment for otherwise untreatable primary (57% cases) and secondary metastatic (14%) tumours of the liver, and, in the second place, for end-stage hepatic cirrhosis (14%) and certain rare liver diseases (14%).

Anesthesia in malignant hyperthermia susceptible patients.

The intra- and postoperative course of 30 general and 3 regional anesthetics in 27 MH-carriers verified by in vitro contracture tests is reported. None of the patients received dantrolene prophylactically. Disposable tubings were used for ventilation, vaporizers and soda lime were removed. ECG, esophageal temperature, blood pressure, oxygen saturation, and end tidal pCO2 were monitored. Minor tranquilizers were offered for premedication. Fentanyl, thiopentone, nitrous oxide, non depolarizing relaxants, neuromuscular antagonists and naloxone were used. In three patients, surgery was performed during epidural or spinal anesthesia with the use of amide local anesthetics. Neither MH-related changes in perioperative heart rates, body temperatures, and CK levels nor any other symptoms of MH were observed in any patient. The anesthetic techniques used seem to be safe and reliable; the anesthetic management of known MHS patients is discussed in detail.