Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some conditions that predispose to ventilatory failure increase the work of breathing (chronic obstructive pulmonary disease [COPD], obesity, kyphoscoliosis), whereas others cause severe respiratory muscle weakness. Specific reasons for muscle weakness include critical illness (electrolyte imbalance, acidemia, shock, sepsis), chronic illness (poor nutrition, cachexia), and neuromuscular diseases. Inspiratory muscle weakness from mechanical disadvantage to the diaphragm is characteristic of asthma and COPD. The increased work of breathing combined with muscle weakness increases the pressure needed to inspire a breath and decreases maximal inspiratory pressure. When this pressure exceeds 0.4, dyspnea and inspiratory muscle fatigue ensue. One way to lower this pressure and avert fatigue is to lower the tidal volume. Ventilatory drive is high, not low, in ventilatory failure. Concomitant shortening of inspiration and breath duration cause the small tidal volume and increased respiratory rate. Gas exchange is compromised by ventilation/perfusion imbalance, and the ratio of dead space to tidal volume is also increased by rapid, shallow breathing. Reduction in tidal volume minimizes dyspnea, but the small tidal volume is inadequate for gas exchange. Acute treatment of respiratory muscle failure involves respiratory muscle rest through mechanical ventilation and removal of noxious influences (infection, metabolic disarray), whereas chronic treatment involves rebuilding the contractile apparatus by nutritional repletion and training.
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PMID:Respiratory muscles and ventilatory failure: 1993 perspective. 850 1

Granulocyte transfusions may be beneficial in neutropenic patients with progressive infections despite appropriate antibiotics. In order to evaluate both the feasibility of granulocyte collection in normal donors receiving granulocyte colony-stimulating factor (G-CSF) and the efficacy of infusing these cells into neutropenic patients with progressive sepsis, four donors received between 5-10 micrograms/kg G-CSF per day and underwent leucapheresis within a day of the first dose. Different red cell sedimenting agents and interface settings were evaluated to determine the optimal method of granulocyte collection. The number of granulocytes collected, the peripheral blood granulocyte level in the recipient at various time points after infusion, and the clinical response were evaluated. Results showed that G-CSF and the leucaphereses caused mild to moderate fatigue in two donors and profound fatigue and a brief episode of hypoxia in one donor. Efficient granulocyte collections were only obtained using dextran 40 or dextran 70 as the sedimenting agent and a deep interface setting which extended sampling into the upper red cell layer. Infusion of granulocytes obtained with this technique resulted in a sustained increase in circulating granulocyte numbers in three recipients, one of whom gained significant clinical benefit. In conclusion, granulocyte transfusions from donors given G-CSF are feasible and may be clinically beneficial, particularly if given early in the course of infection in neutropenic patients.
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PMID:G-CSF stimulated donor granulocyte collections for neutropenic sepsis. 853 1

Thirty-four patients with advanced malignant melanoma were treated with recombinant alpha-interferon (IFN) and chemotherapy consisting of carboplatin, vinblastine, and bleomycin (CVB). CVB was given for four cycles and IFN for 1 year or until progression. Of the 34 analyzed patients, 17 (50%) achieved an objective response, including two complete (6%) and 15 partial responses (44%). Responses were noted in cutaneous, lymph node, and pulmonary sites, with a median time to disease progression of 5 months (range, 3-20 months). The median survival from onset of therapy was 8 months (range, 1-22 months) for the 34 patients. Ninety-four percent of the patients experienced flu-like symptoms and 82% fatigue or weakness. Leukopenia grade 3-4 was observed in four patients (12%). There were two toxicity-related deaths (6%); one from bleomycin-induced pneumonitis and one from neutropenic sepsis. It is concluded that the addition of IFN to CVB regimen, in this study, showed no apparent advantage on response rates, disease-free interval, or survival. The observed treatment-related mortality was unacceptably high. IFN administered as maintenance therapy following CVB conferred no survival benefit.
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PMID:Recombinant interferon ALFA-2A in combination with carboplatin, vinblastine, and bleomycin in the treatment of advanced malignant melanoma. 863 45

Thirty-six patients with advanced epithelial ovarian cancer received epirubicin as second-line therapy after primary treatment with carboplatin and cyclophosphamide. Thirty-four patients were evaluatable for response, 36 for toxicity. There were 9 responses (response rate 26.4%, 95% CI = 12.9-44.4), 2 complete and 7 partial. Median duration of response was 149 days (range 42-183); 4 patients with partial remission are still on study. Toxicity consisted of fatal cardiac failure and paravenous injection (1 patient), fatal leukopenia and sepsis (1 patient), and severe loss of appetite, nausea and vomiting, fatigue, and general malaise in 3 patients. Platelet nadir grade 4 (WHO) was observed in 2 patients while leukocyte nadir grade 4 was seen in 3 patients. The present study showed a high response rate from standard-dose epirubicin. Toxicity was acceptable in most patients, but 2 patients died from treatment complications which gives a treatment-related mortality rate of 6%. Response was primarily seen in patients with minor tumor load and in good general condition.
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PMID:A phase 2 study with epirubicin as second-line treatment of patients with advanced epithelial ovarian cancer. 891 Jun 29

Impaired pulmonary gas exchange can result from lung parenchymal failure inducing oxygenation deficiency and fatigue of the respiratory muscles, which is characterized by hypercapnia or a combination of both mechanisms. Contractility of and coordination between the diaphragm and the thoracoabdominal respiratory muscles predominantly determine the efficiency of spontaneous breathing. Sepsis, cardiac failure, malnutrition or acute changes of the load conditions may induce fatigue of the respiratory muscles. Augmentation of spontaneous breathing is not only achieved by the application of different technical principles or devices; it also has to improve perfusion, metabolism, load conditions and contractility of the respiratory muscles. Intermittent mandatory ventilation (IMV) allows spontaneous breathing of the patient and augments alveolar ventilation by periodically applying positive airway pressure tidal volumes, which are generated by the respirator. Potential advantages include lower mean airway pressure (PAW), as compared with controlled mechanical ventilation, and improved haemodynamics. Suboptimal IMV systems may impose increased work and oxygen cost of breathing, fatigue of the respiratory muscles and CO2 retention. During pressure support ventilation (PSV), inspiratory alterations of PAW or gas flow (trigger) are detected by the respirator, which delivers a gas flow to maintain PAW at a fixed value (usually 5-20 cm H2O) during inspiration. PSV may be combined with other modalities of respiratory therapy such as IMV or CPAP. Claimed advantages of PSV include decreased effort of breathing, reduced systemic and respiratory muscle consumption of oxygen, prophylaxis of diaphragmatic fatigue and an improved extubation rate after prolonged periods of mechanical ventilation. Minimum alveolar ventilation is not guaranteed during PSV; thus, close observation of the patient is mandatory to avoid serious respiratory complications. Continuous positive airway pressure breathing (CPAP) maintains PAW above atmospheric pressure throughout the respiratory cycle, which may increase functional residual capacity and decrease the effort of breathing. CPAP has been conceptually designed for the augmentation of spontaneous breathing and requires the intact central and peripheral regulation of the respiratory system. Airway pressure release ventilation (APRV) improves alveolar ventilation by intermittent release of PAW, which is kept above atmospheric pressure by means of a high-flow CPAP system. The opening of an expiratory valve for 1-2 s induces a decreased PAW and lung volume, which increases rapidly to pre-exhalation values after closure of the valve due to the high gas flow within the circuit (90-100 1/min). APRV may improve haemodynamics and VA/Q distribution as compared with conventional mechanical ventilation. Biphasic positive airway pressure (BIPAP) is characterized by the combination of spontaneous breathing and time-regulated, pressure-controlled mechanical ventilation. During the respiratory cycle the ventilator generates two alternating CPAP levels, which can be modified with regard to time and pressure. As with APRV, alveolar ventilation is maintained even if the spontaneous breathing efforts of the patient cease, which improves the safety of both modes of respiratory therapy. The contribution of spontaneous breathing to total minute ventilation may be important, since a decreased shunt and improved VA/Q relationship have been observed in experimental non-cardiogenic lung oedema. These data give support to the concept that spontaneous breathing should be maintained and augmented in the setting of acute respiratory failure.
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PMID:[Augmented spontaneous breathing]. 896 3

The combination of abnormally low plasma cystine and glutamine levels, low natural killer (NK) cell activity, skeletal muscle wasting or muscle fatigue, and increased rates of urea production defines a complex of abnormalities that is tentatively called "low CG syndrome." These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue syndrome, and to some extent in overtrained athletes. The coincidence of these symptoms in diseases of different etiological origin suggests a causal relationship. The low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting. Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass, 3) the cyst(e)ine-mediated regulatory circuit is compromised in various catabolic conditions, including old age, and 4) cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.
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PMID:Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. 936 43

Muscle catabolism is a characteristic metabolic response to sepsis, severe infection, and injury. In patients with severe and protracted sepsis, the catabolic response results in muscle wasting and fatigue, which may adversely affect the outcome in these patients. An understanding of the regulation of muscle protein breakdown during sepsis and the mechanisms involved is important from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in septic patients and experimental animals have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis. Among the factors that regulate muscle protein breakdown during sepsis, the proinflammatory cytokines tumor necrosis factor and interleukin-1, together with glucocorticoids, are the principal mediators. Intracellular protein breakdown is regulated by multiple proteolytic pathways. Among these, the energy-ubiquitin-dependent pathway accounts for a major portion of muscle protein breakdown during sepsis. The development of specific proteasome inhibitors may make it possible in the future to target the molecular mechanisms of sepsis-induced increase in muscle proteolysis. Such treatment may prove an important avenue to reduce the metabolic cost in patients with severe infection or sepsis.
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PMID:Sepsis: stimulation of energy-dependent protein breakdown resulting in protein loss in skeletal muscle. 945 37

From October 1995 to June 1997, 19 chemotherapy-naive patients with pathology-proven locally advanced or metastatic biliary tract carcinomas (BTC) were enrolled. The regimen consisted of 5-fluorouracil (5-FU) 2600 mg/m2 and leucovorin (LV) 150 mg by weekly 24 h infusion for 6 weeks and followed by a 2 week break. The treatment was terminated if disease progressed, the patient refused or unacceptable toxicity occurred. All patients required a Port-A catheter insertion and were treated at outpatient clinics by portable infusion pumps. There were 12 males and seven females with a median age of 62 years (range 45-77). The primary tumor sites were nine intrahepatic cholangiocarcinomas (CC), three perihilar CC, one distal BTC and six gallbladder cancers. A total of 179 chemotherapy sessions were given with a mean of 9.5 (range 2-18). Eighteen patients were evaluable for response. The response rates were: 33% (six of 18) partial response (PR), 39% (seven of 18) stable disease (SD) and 28% (five of 18) progressive disease (PD). All of the patients were evaluable for toxicity. The most common toxicities were mild fatigue (nine of 19, 47%), loss of appetite (nine of 19, 47%), skin hyperpigmentation (five of 19, 26%) and diarrhea (two of 19, 11%). Only one patient had grade IV myelotoxicity with sepsis but without treatment-related death. The median time to progression was 4 months. The overall median survival time was 7.0 months. The median survival time of the PR was not reached, SD was 8.0 months and PD 3.5 months. In conclusion, weekly high-dose 5-FU with LV by 24 h infusion in an outpatient setting for patients with BTC is effective, only mildly toxic and deserves further study.
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PMID:Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. 966 May 35

A 54-year-old man was admitted to the hospital because of fever and general fatigue. A chest roentgenogram on admission showed lobular opacities and ill-defined opacities in both lower lobes. The pneumonia was successfully treated with antibiotics. The acquired immunodeficiency syndrome was diagnosed because ELISA and PCR tests for antibodies to the human immunodeficiency virus were positive and the CD 4+ lymphocyte count was 39 per cubic millimeter. Examination of bronchoalveolar lavage fluid revealed no Pneumocystis carinii. Trimethoprim and sulfamethoxazole were given prophylactically, but were withdrawn because of a rash. The patient began to receive aerosolized pentamindine and was discharged. On the next day, he was readmitted to the hospital because of a high fever. A chest roentgenogram showed diffuse miliary opacities. Chest CT scan also showed diffuse small nodular opacities in both lungs. Examination of a transbronchial biopsy specimen revealed well-defined, noncaseating granulomas with pneumocystis organisms in their centers. Cultures for tuberculosis and fungi were all negative. We diagnosed granulomatous pneumonia caused by Pneumocystis carinii, which is an atypical manifestation of Pneumocystis carinii pneumonia. The patient died of sepsis and cardiac tamponade. Microscopically, the lung tissue was found to have foamy intra-alveolar exdates, which is a typical histological feature of Pneumocystis carinii pneumonia.
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PMID:[Pneumonia caused by granulomatous Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome]. 984 88

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers.
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PMID:Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer. 1003 77


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