Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock: a prospective observational study.

PURPOSE: Ventricular-arterial (V-A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). METHODS: After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. RESULTS: Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l(-1)), arterial dP/dt max (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms(-1)), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg(-1) min(-1), p < 0.05). CONCLUSIONS: HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V-A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.

A cross-sectional nationwide survey on esophageal atresia and tracheoesophageal fistula.

BACKGROUND: Our study aims at disclosing epidemiology and most relevant clinical features of esophageal atresia (EA) pointing to a model of multicentre collaboration. METHODS: A detailed questionnaire was sent to all Italian Units of pediatric surgery in order to collect data of patients born with EA between January and December 2012. The results were crosschecked by matching date and place of birth of the patients with those of diagnosis-related group provided by the Italian Ministry of Health (MOH). RESULTS: A total of 146 questionnaires were returned plus a further 32 patients reported in the MOH database. Basing on a total of 178 patients with EA born in Italy in 2012, the incidence of EA was calculated in 3.33 per 10,000 live births. Antenatal diagnosis was suspected in 29.5% patients. 55.5% showed associated anomalies. The most common type of EA was Gross type C (89%). Postoperative complications occurred in 37% of type C EA and 100% of type A EA. A 9.5% mortality rate was reported. CONCLUSIONS: This is the first Italian cross-sectional nationwide survey on EA. We can now develop shared guidelines and provide more reliable prognostic expectations for our patients.

[Validity of urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) as biomarker of exposure to very low concentrations of carbon disulphide: preliminary results]. / Validiti dell'acido 2-tiotiazolidin-4-carbossilico (TTCA) urinario quale indicatore biologico dell'esposizione a concentrazioni molto basse di solfuro di carbonio: risultati preliminori.

The possibility to use urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) as biomarker of occupational exposure to very low doses of carbon disulphide (CS2) was evaluated preliminarily in 10 workers employed in a chemical plant where rubber vulcanization accelerators are produced, and in 10 workers, residents in the same geographical area and not occupationally exposed to CS2 and dithiocarbamates (DTC). Exposure to airborne CS2 was assessed, only for exposed workers, by both personal and area samplers. For the determination of TTCA, a spot urine sample was collected for each worker, exposed and non exposed, at the end of work-shift. A questionnaire probing lifestyle and dietary habits and non occupational exposure to CS2 and DTC was administered to all workers involved in the study. Environmental exposure to CS2 in 2007 ranged between 0.21 mg/m3 and 0.73 mg/m3 for personal sampling, and between 0.23 mg/m3 and 0.41 mg/m3 for area sampling. Urinary TTCA levels resulted very low and did not show any significant difference between exposed (Median: 10.8 microg/g creat; Range: 6.1-26.4 microg/g creat) and non exposed workers (Median: 9.3 microg/g creat; Range: 3.0-33.0 microg/g creat), while higher, but not significant concentrations of TTCA were observed in smokers than in non smokers (p = 0.09). No correlation was found between urinary TTCA levels and environmental exposure to CS2, age, body mass index, smoking and dietary habits. In conclusion, the low sensibility and specificity in the assessment of occupational exposure to low doses of CS2 in workers compared to general population subjects, makes urinary TTCA a biomarker with a low usefulness in biological monitoring. ACGIH, besides, should also introduce "B" (background) notation, at present not considered for the BEI indicated for urinary TTCA.

Activation pathways of 5-fluorouracil in rat organs and in PC12 cells.

Activation of the pyrimidine analogue 5-fluorouracil (5-FU) to the ribonucleotide level may occur through one of the following three pathways: 1) the 5-phosphoribosyl 1-pyrophosphate (PRPP)-mediated direct transfer of ribose 5-phosphate to 5-FU as catalysed by orotate phosphoribosyltransferase; 2) the ribose 1-phosphate (Rib1-P)-mediated addition of ribose by uridine phosphorylase, followed by the action of uridine kinase; and 3) the 2'-deoxyribose 1-phosphate (deoxyRib1-P)-mediated addition of deoxyribose, thought to be catalysed by thymidine phosphorylase, followed by the action of thymidine kinase. Many of the conclusions as to the precise pathways by which normal tissues and different cell lines activate uracil are indirectly derived from drug interactions affecting the availability of the substrates of the three pathways, or from measurement of activities of the enzymes metabolising 5-FU in normal tissues and tumours. In previous papers (Cappiello et al. Biochim Biophys Acta 1998;1425:273--81; Mascia et al. Biochim Biophys Acta 1999;1472:93--8), we assessed the molecular mechanisms by which the natural base uracil is salvaged in vitro to uracil ribonucleotides and deoxyribonucleotides in rat liver and brain. In this paper, we investigated the pathways of 5-FU activation to cytotoxic ribonucleotide and deoxyribonucleotide levels in normal rat tissues and PC12 cell extracts. The results clearly showed that normal rat tissues activated 5-FU mainly via the Rib1-P pathway, and to a lesser extent via the PRPP pathway. The deoxyRib1-P pathway was absent. PC12 cells activated 5-FU mainly via the PRPP pathway and to a lesser extent by the other two pathways.

Uracil salvage pathway in PC12 cells.

The salvage anabolism of uracil to pyrimidine ribonucleosides and ribonucleotides was investigated in PC12 cells. Pyrimidine base phosphoribosyl transferase is absent in PC12 cells. As a consequence any uracil or cytosine salvage must be a 5-phosphoribosyl 1-pyrophosphate-independent process. When PC12 cell extracts were incubated with ribose 1-phosphate, ATP and uracil they can readily catalyze the synthesis of uracil nucleotides, through a salvage pathway in which the ribose moiety of ribose 1-phosphate is transferred to uracil via uridine phosphorylase (acting anabolically), with subsequent uridine phosphorylation. This pathway is similar to that previously described by us in rat liver and brain extracts (Cappiello et al., Biochim. Biophys. Acta 1425 (1998) 273; Mascia et al., Biochim. Biophys. Acta 1472 (1999) 93). We show using intact PC12 cells that they can readily take up uracil from the external medium. The analysis of intracellular metabolites reveals that uracil taken up is salvaged into uracil nucleotides, with uridine as an intermediate. We propose that the ribose 1-phosphate-dependent uracil salvage shown by our in vitro studies, using tissues or cellular extracts, might also be operative in intact cells. Our results must be taken into consideration for the comprehension of novel chemotherapeutics' influence on pyrimidine neuronal metabolism.

In vitro recycling of alpha-D-ribose 1-phosphate for the salvage of purine bases.

In this paper, we extend our previous observation on the mobilization of the ribose moiety from a purine nucleoside to a pyrimidine base, with subsequent pyrimidine nucleotides formation (Cappiello et al., Biochim. Biophys. Acta 1425 (1998) 273-281). The data show that, at least in vitro, also the reverse process is possible. In rat brain extracts, the activated ribose, stemming from uridine as ribose 1-phosphate, can be used to salvage adenine and hypoxanthine to their respective nucleotides. Since the salvage of purine bases is a 5-phosphoribosyl 1-pyrophosphate-dependent process, catalyzed by adenine phosphoribosyltransferase and hypoxanthine guanine phosphoribosyltransferase, our results imply that Rib-1P must be transformed into 5-phosphoribosyl 1-pyrophosphate, via the successive action of phosphopentomutase and 5-phosphoribosyl 1-pyrophosphate synthetase; and,in fact, no adenosine could be found as an intermediate when rat brain extracts were incubated with adenine, Rib-1P and ATP, showing that adenine salvage does not imply adenine ribosylation, followed by adenosine phosphorylation. Taken together with our previous results on the Rib-1P-dependent salvage of pyrimidine nucleotides, our results give a clear picture of the in vitro Rib-1P recycling, for both purine and pyrimidine salvage.

Time-course of impairment of respiratory mechanics after cardiac surgery and cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass (CPB) is associated with abnormalities of lung function characterized by an increase in static elastance of the respiratory system. We examined the following: a) the effects of CPB on the total inspiratory volume-pressure (V-P) relationship of the respiratory system; b) the relative contribution of the chest wall and lung to the impairment of respiratory system mechanics; and c) the time-course of such impairment. DESIGN: Prospective, interventional study. SETTING: Surgical and medical intensive care units in a teaching hospital. PATIENTS: Eight adult patients scheduled for elective open heart surgery to correct valvular dysfunction. INTERVENTIONS: V-P curves (interrupter technique) of the respiratory system were partitioned between the chest wall and lung by measurements of esophageal pressure. Measurements were obtained before sternotomy (control), immediately after, 4 hrs after, and 7 hrs after separation from CPB. MEASUREMENTS AND MAIN RESULTS: Control V-P relationships of the respiratory system and lung showed lower inflection points (Pflex) at pressure values of 5.9+/-2.3 and 4.3+/-2.5 cm H2O, respectively. Immediately after and 4 hrs after separation from CPB, both curves had sigmoid shapes because of lower Pflex and formation of upper inflection (UIP) points. The pressures corresponding to the Pflex increased significantly (p < .001) by 56%+/-3% and 78%+/-4%, whereas the UIP corresponded to a pressure value of 42.34+/-8.5 and 35.6+/-7.8 cm H2O in the respiratory system and lung, respectively. A linear V-P relationship of the chest wall was observed during the control condition and after separation from CPB. Four hours later, no further increases in the pressure values corresponding to Pflex were observed on the inspiratory V-P curves of the respiratory system and lung, whereas the UIP occurred at a pressure of 35.6+/-9.1 and 29.7+/-8.4 cm H2O, respectively. A UIP was present on the V-P curve of the chest wall at a volume of 0.77+/-0.02 L. Seven hours after separation from CPB, the inspiratory V-P curves of the respiratory system, chest wall, and lung returned to normal. CONCLUSIONS: Sternotomy and CPB produced immediate changes in lung mechanics. Chest wall mechanics were affected only 4 hrs after sternotomy. Seven hours after disconnection from CPB, all mechanics had returned to normal.

Impairment of lung and chest wall mechanics in patients with acute respiratory distress syndrome: role of abdominal distension.

Recent data have suggested that the elastic properties of the chest wall (CW) may be compromised in patients with ARDS because of abdominal distension (4). We partitioned CW and lung (L) mechanics, assessed the role of abdominal distension, and verified whether the underlying disease responsible for ARDS affects the impairment of respiratory mechanics. Volume-pressure (V-P) curves (interrupter technique) were assessed in nine patients with surgical ARDS and nine patients with medical ARDS. Relative to nine patients undergoing heart surgery, V-P curves of the respiratory system (rs) and L of patients with surgical or medical ARDS showed a rightward displacement. V-P curves of the CW and the L showed an upward concavity in patients with medical ARDS and a downward concavity in patients with surgical ARDS. Although the CW and the abdomen (abd) V-P curves in patients with medical ARDS were similar to those obtained in patients undergoing heart surgery, they showed a rightward shift and a downward flattening in patients with surgical ARDS. In five of these patients, a reduction in static end-inspiratory pressure of the abd (69+/-4%), rs (30+/-3%), CW (41+/-2%), and L (27+/-3%) was observed after abdominal decompression for acute bleeding. Abdominal decompression therefore caused an upward and leftward shift of the V-P curves of the respiratory system, chest wall, lung, and abdomen. In conclusion we showed that impairment of the elastic properties of the respiratory system may vary with the underlying disease responsible for ARDS. The flattening of the V-P curve at high pressures observed in some patients with ARDS may be due to an increase in chest wall elastance related to abdominal distension. These observations have implications for the assessment and ventilatory management of patients with ARDS.

Transcranial cytokine gradients in patients requiring intensive care after acute brain injury.

After acute brain injury there may be increased intracranial production of cytokines, with activation of inflammatory cascades. We have sought to determine if a transcranial cytokine gradient was demonstrable in paired sera of 32 patients requiring intensive care after acute brain injury. The difference between concentrations of IL-1 beta, IL-6, IL-8 and TNF alpha in jugular venous and arterial serum was measured on admission, and at 24, 48 and 96 h after the primary injury. There were no differences in IL-1 beta, IL-8 or TNF alpha, but median gradients of 6.7 and 11.5 pg ml-1 for IL-6 were demonstrated in the traumatic brain injury (n = 22) and subarachnoid haemorrhage (n = 10) groups, respectively (normal values in serum < 4.7 pg ml-1; P < 0.001 both groups). This suggests that there is significant production of IL-6 by intracranial cells after acute brain injury. Therapy directed towards combatting the negative effects of IL-6 may potentially benefit patients who have sustained an acute brain injury.

Usefulness of pyridinium crosslinks and CA 15-3 as markers in metastatic bone breast carcinoma.

Numerous tumor markers such as CEA, MCA, CA 15-3 have been assayed in breast cancer patients to detect relapse at a preclinical stage and most of all to monitor the treatment of the advanced disease. Since they are not site-specific, pyridinium crosslink dosage has recently been reported as a specific bone resorption marker in several non neoplastic diseases. The aim of this study was to evaluate the urinary pyridinium crosslink levels in breast cancer with or without osseous involvement, and to correlate it with serial doses of CA 15-3. 285 breast cancer patients (226 free of disease and 59 with bone metastases) were measured for both pyridinoline and CA 15-3. In the metastatic patients the mean values of the two markers were significantly higher than in non evident disease patients (P = < 0.01 and p = < 0.001 respectively). Abnormal values over the normal were found in 22% for pyridinoline and 11% for CA 15-3 in patients free of disease while the normal values observed in patients with bone metastases were 22% for pyridinoline and 39% for CA 15-3. Tandem dosage of CA 15-3, was highly sensitive but site-aspecific, and pyridinoline, which is bone specific, may be useful chiefly in the monitoring of breast cancer treatment, since many physiological conditions such as age, menopausal status and variation over 24 hours, and cost effectiveness will influence the use of pyridinoline during follow-up.