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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxin is a major mediator of the life-threatening cardiovascular dysfunction that characterizes Gram-negative sepsis. In animal models of endotoxemia, pretreatment with ibuprofen or pentoxifylline attenuates some of these cardiovascular changes. To evaluate the effects of these agents on the human cardiovascular response to endotoxemia, hemodynamic variables were measured serially in 24 normal subjects who were given intravenous endotoxin. The subjects were randomized to receive oral ibuprofen (n = 9), pentoxifylline (n = 10), or no medication before endotoxin administration (n = 5). The subjects were volume loaded 3-5 h after endotoxin administration, and hemodynamic measurements were reassessed. Core temperature after endotoxin alone or endotoxin-pentoxifylline approached a maximum at 3 h (greater than or equal to 38.6 degrees C), while the endotoxin-ibuprofen group remained afebrile. At 3 and 5 h, all three groups had significant increases in heart rate, cardiac index, oxygen delivery, and oxygen consumption, while systemic vascular resistance index decreased significantly from baseline. The oxygen extraction ratio remained unchanged. After volume loading, the left ventricular ejection fraction and left ventricular end-diastolic and end-systolic volume indexes did not differ among the groups. The hyperdynamic cardiovascular response to endotoxin in humans occurs in the absence of fever and is not significantly ameliorated by oral cyclooxygenase or phosphodiesterase inhibition.
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PMID:Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. 140 57

The efficacy of the phosphodiesterase inhibitor enoximone for reversal of severe postcardiotomy low cardiac output syndrome was investigated in 13 cases of cardiogenic shock refractory to conventional treatment consisting of beta-adrenergic agonists (n = 13) combined with vasodilators (n = 7), and intra-aortic balloon counterpulsation (n = 5). Following a bolus of 1 mg/kg enoximone, cardiac and stroke volume indices increased from 1.56 +/- 0.27 l/min/m2 and 16.3 +/- 3.3 ml/m2, respectively, to 2.72 +/- 0.67 and 27.8 +/- 7.1 (both p < 0.001). Mean arterial pressure fell, from 77 +/- 11 to 68 +/- 9 mmHg (p < 0.05), as did atrial filling pressures (LAP and RAP), LAP from 21.3 +/- 5.5 to 15.9 +/- 2.9 and RAP from 16.6 +/- 2.3 to 13.7 +/- 2.1 mmHg (both p < 0.01). The heart rate rose by only 5%. Enoximone therapy was maintained by a continuous infusion (5-7.5 micrograms/kg/min) for 40.6 +/- 8.6 hours (range 14-92). All hemodynamic parameters remained stable throughout treatment. Six patients died of sepsis and/or multiorgan failure but seven were discharged from hospital. Enoximone thus improved hemodynamic performance significantly in cardiogenic shock after open-heart surgery. It also has proved valuable in cardiac failure when conventional therapy was unsuccessful.
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PMID:Efficacy of phosphodiesterase inhibitor enoximone in management of postcardiotomy cardiogenic shock. 143 45

Pulmonary hypertension, systemic vasodilation and the supply dependency of oxygen uptake are the major problems associated with sepsis. Thus, the goal of haemodynamic therapy in septic patients is an increase in cardiac output large enough to permit adequate tissue oxygenation. The purpose of this study was to establish whether the additional use of the phosphodiesterase inhibitor amrinone is useful in hypodynamic septic patients with inadequate tissue perfusion. Nine patients who had developed the clinical signs of sepsis (temperature greater than 38.5 degrees C, leukocytosis greater than 15,000/mm3, thrombopenia less than 100,000/mm3 or a drop in platelet count greater than 30%, cardiovascular shock) were given amrinone 30 micrograms.kg-1.min-1 for one hour. All patients showed mixed venous oxygen saturations below 70% and oxygen extraction rates above 30%, despite maximum catecholamine therapy. Haemodynamic parameters were measured with the help of a pulmonary artery catheter. Statistical significance was checked using the Wilcoxon signed-ranks test. During amrinone application cardiac index increased significantly from 4.6.1.81.min-1.m-2 to 5.6 +/- 1.81.min-1.m-2 (p less than 0.01), while central venous pressure was kept constant by volume supply. Mean pulmonary artery pressure remained nearly unchanged, whereas mean arterial pressure dropped significantly from 91 +/- 13 mmHg to 75 +/- 8 mmHg (p less than 0.01). The oxygen supply rose during administration of amrinone by an average of 17%, which led to a rise in oxygen uptake. Independence of oxygen uptake from oxygen supply, however, could not be attained. In septic patients, amrinone increases cardiac output via pulmonary vasodilation. However, pronounced systemic vasodilation lowers arterial blood pressure, enhancing the risk of myocardial ischaemia.
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PMID:[Amrinone for cardiovascular therapy in hypodynamic septic patients?]. 161 30

Hemodynamic response after intravenous and oral administration of a new phosphodiesterase inhibitor, CI-914, was studied in 13 patients with severe congestive heart failure. Comparable significant increases in cardiac index of 26% (p less than 0.01) and 19% (p less than 0.02) after intravenous and oral administration were observed. Systemic vascular resistance, right atrial and pulmonary artery wedge pressure decreased significantly after intravenous drug administration. Although similar changes occurred after oral administration, they were not statistically significant. Peak CI-914 plasma concentration occurred 2.3 +/- 2.2 hours after oral drug administration and exhibited measurable hemodynamic effects for up to 10 to 12 hours. Seven of the 13 patients received long-term oral CI-914 for as long as 12 weeks and exhibited an improvement in New York Heart Association functional class and exercise capacity. Five patients died with progressive heart failure, 1 patient died suddenly and 1 died of sepsis. The drug was well tolerated and appears to have potential as a cardiotonic agent.
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PMID:Hemodynamic effects of a new type III phosphodiesterase inhibitor (CI-914) for congestive heart failure. 351 61

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
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PMID:TNF modulates endothelial properties by decreasing cAMP. 776 2

Paediatric cardiac transplantation (pHTX) has gained widespread acceptance as a therapy in end-stage myocardial failure and some forms of congenital heart disease, particularly hypoplastic left heart syndrome (HLHS). The major problems to the anaesthesiologist in these patients are induction of anaesthesia in infants with HLHS and treatment of pulmonary hypertension in the early post-bypass period. PATIENTS AND METHODS. Anaesthesia for pHTX was performed in 15 children < 1 year of age (4-237 days); 12 suffered from HLHS, 2 from endocardial fibroelastosis, and 1 from dilatative cardiomyopathy. Induction of anaesthesia in patients with HLHS IS a challenge to the anaesthesiologist, as he has to maintain the delicate balance between pulmonary and systemic blood flow. Anaesthesia was induced with fentanyl (10-15 micrograms/kg) and pancuronium (0.2-0.4 mg/kg) and maintained with fentanyl (total dosage 70-100 micrograms/kg). Modification of ventilatory parameters such as FiO2, PaCO2, and airway pressure (PEEP, I:E ratio) was used to influence systemic and pulmonary blood distribution in the pre-bypass period according to changes in haemodynamics (target: O2 saturation approximately 75%-80%, PaCO2 45-50 mmHg). Treatment of pulmonary hypertension in the weaning and early post-bypass period consisted of respiratory (PaCO2 < 30 mmHg) and metabolic alkalinisation (pH 7.45-7.55, BE > +3 mmol/l), the use of prostaglandin E1 (3-6-12 micrograms/kg.h), and the phosphodiesterase inhibitor enoximone (10-15 micrograms/kg.min). Additional positive inotropic support was achieved with dobutamine (5-10 micrograms/kg.min), adrenaline (0.1-0.5 micrograms/kg.min), and/or orciprenaline (0.1-0.2 micrograms/kg.min) and calcium chloride (25-100 mg/kg). RESULTS. Two children died intraoperatively and 1 on the 1st postoperative day from overwhelming pulmonary vascular resistance and right ventricular failure. Three children died between 3 and 4 weeks postoperatively, 1 from cytomegalovirus infection, 1 from sepsis, and 1 from acute rejection. Nine patients survived and are well up to 5.5 years after transplantation. CONCLUSION. Pulmonary hypertension in the weaning and early post-bypass period is the main anaesthesiological problem of pHTX, particularly in children with HLHS. A polypragmatic approach to this problem consisting of alkalinisation, pulmonary vasodilatation, and inotropic support is presented and seems to be effective. Further improvements in concepts of pHTX are limited by the lack of donor organs. Though the experience with pHTX in neonates and infants is growing slowly, it might be a routine procedure from the anaesthesiological point of view within a few years in some selected centres.
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PMID:[Anesthesia for heart transplantation in newborn and suckling infants. Special aspects of the hypoplastic left heart syndrome]. 778 53

At toxic doses, cardiotropic drugs may compromise cardiac output leading to circulatory shock. Specific treatment varies depending on the nature and the dose of the drugs ingested as well as causal mechanism including vasopegia, hypovolaemia, cardiogenic effects and sepsis. Progress in our understanding of the pharmacodynamic aspects of intoxication and the development of specific antidotes has led to reduced morbidity and mortality. In addition to the classical inotropes, mainly catecholamines and phosphodiesterase inhibitors, other therapeutic agents may have specific inotrope effects in such ad hoc situations. These include hypertonic alkaline saline solution, calcium, glucagon, hydroxocobalamine and other cobalt salts, oxygen and immunotoxicotherapy. Together with volum replacement, dobutamine at the dose of 7 to 20 micrograms/kg/min can usually restore cardiac performance in cases of carbamate-induced circulatory shock. In case of tricyclic antidepressant overdose, treatment should include respiratory assistance and infusion of alkaline sodium solutions to both reverse the extracellular acidosis and correct sodium balance. Catecholamines may be necessary in cases with severe hypotension. Major vasoplegia and impaired intraventricular conduction may be induced by overdoses of chloroquine and class I antiarrhythmic drugs. Signs of gravity are: ingested dose above 4 g, QRS > or = 0.12 s or systolic arterial pressure < or = 80 mmHg. Treatment with epinephrine, respiratory assistance and diazepam has been proven effective during the acute phase, but right catheterism is often required due to major haemodynamic instability during the first 72 first hours. Beta-blockers have both a bronchoconstrictor and respiratory depressor effects favouring cardiovascular failure by hypoemia. Symptoms occur in 30-40% of the cases of overdose. Shock results from the reduction in blood pressure and cardiac inotropism. Glucagon, isoprenaline and epinephrine, prescribed in that order, can considerably reduce mortality to less than 4%. Despite the development of specific molecules, the risk of mortality due to toxic shock caused by antiarrhythmics, chloroquine, colchicine, calcium inhibitors and paraquat remains high.
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PMID:[Shock caused by poisoning. Use of cardiotropic agents]. 797 61

Lethal circulatory shock during microbial sepsis is thought to be initiated by early molecular events, including production of tumor necrosis factor (TNF) and cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The phosphodiesterase inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and modulates PMN function, and has been shown to improve outcome in experimental sepsis. We hypothesized that PTX would attenuate gram-negative and fungal septic shock by different mechanisms: reduced TNF production in Escherichia coli (EC) sepsis vs. enhanced PMN-mediated defense during Candida albicans (CA) fungemia. Conscious chronically catheterized rats received PTX (25 mg/kg, i.v.) before i.v. challenge with 10(10) viable EC (serotype 055:B5), 10(9) viable serotype A yeast-phase CA (each the LD100 in < 24 hr in naive rats), or normal sterile saline (NSS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment controls received NSS before and after challenge. Serum TNF peaked 1.5 hr after EC infection in NSS-treated animals (1654 +/- 390 U/ml, mean +/- SE), and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), but PTX did not improve 24 hr survival. PTX also aggravated systemic hypotension after EC, and did not modify neutropenia, thrombocytopenia, or microvascular permeability assessed by organ wet/dry weight (W/D) ratios. Peak serum TNF in CA + NSS animals (130 +/- 45 U/ml) was delayed 8 hr compared to EC animals, and were not reduced by PTX (67 +/- 25 U/ml, P = NS). Moreover, PTX did not alter CA-induced mortality, hypothermia, hypotension, neutropenia, increased lung W/D, or interstitial and alveolar hemorrhage. We conclude that PTX-induced suppression of endogenous TNF production does not prevent gram-negative shock in this model, possibly due to impaired TNF-mediated antibacterial host defense. Since fungal septic shock with acute disseminated candidiasis evolves prior to significant increases in circulating TNF, PTX also appears ineffective in its treatment.
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PMID:Effects of pentoxifylline on tumor necrosis factor production and survival during lethal E. coli sepsis vs. disseminated candidiasis with fungal septic shock. 848 22

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.
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PMID:The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity. 870 44

1. This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP levels were determined in the effluate and bile by radio immunoassay methods. 2. After endotoxin treatment, infusion of enoximone at three concentrations (1 microM, 10 microM) resulted in an increased glucose output from -1.4 +/- 0.9 to 7.8 +/- 2.5 mumol l-1 20 min-1. Bile acid-independent bile flow increased also, in a dose-dependent manner. 3. In untreated livers, cyclic AMP release increased in the effluate from 1000 +/- 73 fmol g-1 min-1 to 1710 +/- 143 fmol g-1 min-1 when enoximone (10 microM) was administered. In bile from untreated livers, the level of cyclic AMP was also significantly increased by enoximone. After endotoxin treatment, the enoximone (10 microM) effect on cyclic AMP levels in effluate and bile was greatly reduced. Levels of cyclic GMP in the effluate and bile appeared unchanged in the presence of enoximone. 4. During co-infusion of glucagon (1 nM) and enoximone (10 microM), cyclic nucleotide levels in the effluate and bile of livers after endotoxin treatment were determined. In the effluate, cyclic AMP release increased from 827 +/- 144 fmol g-1 min-1 to 17802 +/- 2821 fmol g-1 min-1 when glucagon was administered. The presence of enoximone enhanced cyclic AMP further to 41696 +/- 920 fmol g-1 min-1. The same changes in cyclic AMP release were found in bile. Levels of cyclic GMP in the effluate and bile were not significantly affected by the administration of glucagon and the PDI. 5. Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to glucagon increased glucose release by 8.2 +/- 2.8 mumol g-1 20 min-1, without alteration of lactate balance. The PDI enhanced the glycogenolytic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production. 6. Enoximone significantly enhanced the bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was unaffected by the PDI. The vasoconstrictor effect of nerve stimulation was reduced by the PDI. 7. We conclude that endotoxin treatment reduces the ability of the PDI, enoximone, to increase cyclic AMP release in the perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 is involved in the degradation of cyclic AMP in the liver after exposure to endotoxin. Additionally, the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.
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PMID:Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment. 876 9

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