Measurement of Pressure-Time Product during Spontaneous Assisted Breathing by Rapid Interrupter Technique

Background: Measuring the work of breathing of patients undergoing spontaneous assisted ventilation can be useful to monitor and titrate ventilatory support. The aim of this study was to obtain measurements of the pressure generated by the respiratory muscles (PMUSC) and the derived pressure-time product (PTP; a good indicator of the metabolic work of breathing), performing the rapid interrupter technique with a commercial ventilator.

Methods: A Draeger Evita 4 ventilator (Draeger Medical, Lubeck, Germany) was controlled by a personal computer to rapidly interrupt the airway flow at different times and volumes of the respiratory cycle during pressure-support ventilation. From the airway pressure tracing after the occlusion, the authors estimated the alveolar pressure and PMUSC; the integration of PMUSC values over the inspiratory time yields the measurement of PTP. Esophageal pressure measurements were used as a reference. After a bench study of the valves' performance, the authors performed 11 measurement sequences in eight patients.

Results: The closure times for the inspiratory and expiratory valves were 74 +/- 10 and 61 +/- 13 ms, respectively. The interrupter technique provided a reliable estimate of PMUSC (PMUSC, occl = 1.00 [middle dot] PMUSC, pes + 0.19; r = 0.88; 95% confidence interval for agreement, +5.49/-5.32 cm H2O). PTPoccl tightly correlated with PTPpes (PTPoccl = 0.95 [middle dot] PTPpes + 0.13; r = 0.96; 95% confidence interval, 1.94/-1.61 cm H2O [middle dot] s).     

Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma.

PURPOSE: Fenretinide (4HPR), a synthetic retinoid, induces apoptosis in neuroblastoma cells. A Phase I study in children with neuroblastoma was designed to determine maximum tolerated dose, toxicity, and pharmacokinetics. EXPERIMENTAL DESIGN: Fifty-four patients received oral 4HPR, once daily, for 28 days, followed by a 7-day interruption, for up to 6 courses. The starting dose was 100 mg/m(2)/day. At least 3 patients were entered at each escalating 4HPR dose level. Pharmacokinetic sampling was performed on days 1 and 28 of the first course. RESULTS: Fifty-four patients, of whom 53 were evaluable, received doses between 100 and 4000 mg/m(2)/day for a total of 168 courses. Additional dose escalation was precluded by capsule number intake. A total of 34 of 53 evaluable patients showed manageable, reversible toxicities, which were not dose related. One dose-limiting toxicity (nyctalopia grade 3) occurred after the 1000 mg/m(2)/day dose. Twelve patients showed grade 2 toxicity: skin xerosis (6 cases); nyctalopia (3 cases); hepatic toxicity (1 case); diarrhea (1 case); and headache (1 case). Stable disease was observed in 41 patients for a median period of 23 months (range 2-35+). After first administration, average 4HPR peak plasma levels ranged from 0.6 to 6 micro M (after 100 and 4000 mg/m(2)/day, respectively) and increased 2-fold (to 1.3 and 12.9 micro M, respectively) after the 28-day treatment. 4HPR half-life increased from 17 h after the first administration to 25 h after the 28(th) administration. Incidence of grade 2-3 toxicity was 0 of 12 (0%), 7 of 22 (31%), and 4 of 8 (50%) with peak 4HPR concentrations <3 micro M, 3-10 micro M, and >10 micro M, respectively. After repeated treatment, retinol levels decreased from 20 to 10% of pretreatment levels after all of the doses. CONCLUSIONS: In children, 4HPR administration up to 4000 mg/m(2)/day over 28 days, followed by a 7-day interruption, results in manageable toxicity and in drug plasma concentrations comparable with those that induce apoptosis in neuroblastoma cell lines.     

Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group

Background:Alveolar soft part sarcoma (ASPS) is a rare malignanttumor and little is known about its clinical features and management. Wereport on a series of 19 pediatric patients managed over 20 years. Patients and methods:Primary conservative surgery was performedin all patients and was radical in nine, non-radical in three; seven patientsunderwent biopsy alone (3 unresectable tumors, 4 metastatic disease). In twocases radical surgery was performed after primary chemotherapy. Radiotherapywas delivered to 8 patients, chemotherapy to 15. Results:After a median follow-up of 74 months, the five-yearsurvival was 80% for the whole series, 91% for patients withlocalized disease, 100% for patients with tumor 5 cm, and31% for those >5 cm; 16 of 19 patients were alive (12 of 12 withgrossly-resected tumor in first continuous remission). Chemotherapy achievedtwo partial remission among seven evaluable patients. Conclusions:Pediatric ASPS has a more favorable prognosis thanits adult counterpart. In this series, tumor size correlates with metastaticdisease at onset and is the major factor influencing survival. Surgery is themainstay of therapy. The effectiveness of adjuvant therapy remains to beestablished, though radiotherapy may be advisable in cases of inadequatesurgery.     

Neurofibromatosis and malignant childhood cancers: a survey in Italy, 1970-83

Neural tumors, Wilms' tumor, rhabdomyosarcoma and several types of leukemia have been previously described in association with neurofibromatosis (NF). In a nation-wide collection of cases in Italy, 15 children (0-14 years of age) with NF and cancer or leukemia were identified; 13 of them had been diagnosed with cancer between 1976-83. The expected number of children with cancer and NF in 1976-83 was 4.48. The distribution of tumor types was different from that found in the general population, with a higher proportion of tumors of neural crest origin as well as soft tissue sarcomas. In 7/15 the family history was positive for NF; in 5/7 the individuals affected included the mother and/or a maternal relative.     

Assessment of cerebral blood volume in schizophrenia: A magnetic resonance imaging study

Brain atrophy has consistently been observed in schizophrenia, representing a 'gross' evidence of anatomical abnormalities. Reduced cerebral blood volume (CBV) may accompany brain size decrement in schizophrenia, as suggested by prior small SPECT studies. In this study, we non-invasively investigated the hemisphere CBV in a large sample of patients suffering from schizophrenia with perfusion-weighted imaging (PWI). PWI images were obtained, following intravenous injection of paramagnetic contrast agent (Gadolinium-DTPA), for 54 DSM-IV patients with schizophrenia (mean age+/-SD=39.19+/-12.20 years; 34 males, 20 females) and 24 normal controls (mean age+/-SD=44.63+/-10.43 years; 9 males, 15 females) with a 1.5T Siemens magnet using an echo-planar sequence (TR=2160 ms, TE=47 ms, slice thickness=5mm). The contrast of enhancement (CE), a semi-quantitative parameter inversely estimating the CBV, were calculated pixel by pixel as the ratio of the maximum signal intensity drop during the passage of contrast agent (Sm) by the baseline pre-bolus signal intensity (So) (CE=Sm/Sox100) for right and left hemisphere on two axial images. Specifically, higher CE values correspond to lower CBV and viceversa Compared to normal controls, patients with schizophrenia had significantly higher bilateral hemisphere CE values (p=0.02) and inverse CE laterality index (p=0.02). This study showed abnormally reduced and inverse hemisphere CBV in a large population of patients with schizophrenia. Hypothetically, chronic low CBV may sustain neural hypoactivation and concomitant increase of free radicals, ultimately resulting in neuronal loss and cognitive impairments. Thus, altered intracranial hemodynamics may accompany brain atrophy and cognitive deficits, being a crucial factor in the pathophysiology of schizophrenia.     

Measurement of pressure-time product during spontaneous assisted breathing by rapid interrupter technique

BACKGROUND: Measuring the work of breathing of patients undergoing spontaneous assisted ventilation can be useful to monitor and titrate ventilatory support. The aim of this study was to obtain measurements of the pressure generated by the respiratory muscles (PMUSC) and the derived pressure-time product (PTP; a good indicator of the metabolic work of breathing), performing the rapid interrupter technique with a commercial ventilator. METHODS: A Draeger Evita 4 ventilator (Draeger Medical, Lubeck, Germany) was controlled by a personal computer to rapidly interrupt the airway flow at different times and volumes of the respiratory cycle during pressure-support ventilation. From the airway pressure tracing after the occlusion, the authors estimated the alveolar pressure and PMUSC; the integration of PMUSC values over the inspiratory time yields the measurement of PTP. Esophageal pressure measurements were used as a reference. After a bench study of the valves' performance, the authors performed 11 measurement sequences in eight patients. RESULTS: The closure times for the inspiratory and expiratory valves were 74 +/- 10 and 61 +/- 13 ms, respectively. The interrupter technique provided a reliable estimate of PMUSC (PMUSC, occl = 1.00 . PMUSC, pes + 0.19; r = 0.88; 95% confidence interval for agreement, +5.49/-5.32 cm H2O). PTPoccl tightly correlated with PTPpes (PTPoccl = 0.95 . PTPpes + 0.13; r = 0.96; 95% confidence interval, 1.94/-1.61 cm H2O . s). CONCLUSION: The rapid interrupter technique can be performed by means of a commercial ventilator, providing reliable measurement of PMUSC and PTP.     

Risk factors for treatment failure in patients with severe acute cardiogenic pulmonary oedema

Intubation is necessary in 7 to 20% of patients with severe acute cardiogenic pulmonary oedema despite optimal treatment. This study evaluated the usefulness of parameters largely available in clinical practice to predict the need for intubation in a population of acute cardiogenic pulmonary oedema patients treated with medical therapy and continuous positive airway pressure. The present retrospective cohort study involved 142 patients with severe acute cardiogenic pulmonary oedema who were admitted to coronary care or the intensive care unit of a university hospital and were treated by an in-hospital protocol. Physiological measurements and blood gas samples were evaluated at 'baseline' (just after admission), 'early' (one to three hours after beginning treatment) and 'late' (eight to 10 hours after beginning treatment). Twenty-two patients (15.5%) required intubation. A systolic blood pressure at admission lower than 140 mmHg was significantly associated with a higher risk for intubation, while hypercapnic patients or those with a reduced left ventricular ejection fraction at admission did not show a worse prognosis. A simple score based on largely available parameters (1 point for each: age >78 years, systolic blood pressure <140 mmHg at admission, arterial blood gas acidosis and heart rate >95 bpm at early time) is proposed. The rate of intubation according to this score ranged from 0% (score of 0) to 90% (score of 3). Our study found that simple parameters available in clinical practice are significantly associated with the need for intubation in acute cardiogenic pulmonary oedema patients treated with continuous positive airway pressure and medical therapy. A simple score to evaluate the need for endotracheal intubation is proposed.     

Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury

Background: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident.

Methods: The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI.

Results: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone.     

Head helmet versus face mask for non-invasive continuous positive airway pressure: a physiological study

Objective To assess selected physiological effects of non-invasive continuous positive airway pressure delivered by head helmet (CPAP_H), a special interface device designed to completely contain the head of the patient, compared to face mask (CPAP_M).Design Randomized physiological study.Setting University research laboratory.Patients Eight healthy volunteers.Intervention Continuous positive airway pressure delivered by face mask and CPAP_H in random order. Three gas flow rates (20-30-40 l/min and 30-45-60 l/min, respectively, for CPAP_M and CPAP_H) and four CPAP levels (0-5-10-15 cmH₂O) were employed in a randomized sequence.Measurements and results In each patient we monitored airway pressure, esophageal pressure, expiratory flow, and inspiratory and expiratory CO₂ concentration. End-expiratory lung volume changes from CPAP 0 were measured by inductance plethysmography. The application of increased levels of CPAP resulted in a significant increase in end-expiratory lung volume, similar for CPAP_H and CPAP_M. Inspiratory changes of airway pressure were comparable for the two CPAP modes. Inspiratory CO₂ concentration was higher during CPAP_H (significantly decreased at increased gas flow rates), compared to CPAP_M.Conclusions Continuous positive airway pressure delivered by head helmet is as effective as CPAP_M in increasing end-expiratory lung volume and in compensating for airway pressure changes without the need of a reservoir bag. Higher gas flow rates are necessary to maintain a relatively low inspiratory CO₂ concentration.