Role of nitrogen in transmucosal gas exchange rate in the rat middle ear

2006 ◽  
Vol 101 (5) ◽  
pp. 1281-1287 ◽  
Author(s):  
Romain E. Kania ◽  
Philippe Herman ◽  
Patrice Tran Ba Huy ◽  
Amos Ar
Keyword(s):  
Mathematical Model ◽  
Steady State ◽  
Gas Exchange ◽  
Phase Ii ◽  
Middle Ear ◽  
Phase Iii ◽  
Gas Composition ◽  
Linear Decrease ◽  
Gas Volume

This study investigates the role of nitrogen (N2) in transmucosal gas exchange of the middle ear (ME). We used an experimental rat model to measure gas volume variations in the ME cavity at constant pressure. We disturbed the steady-state gas composition with either air or N2 to measure resulting changes in volume at ambient pressure. Changes in gas volume over time could be characterized by three phases: a primary transient increase with time (phase I), followed by a linear decrease (phase II), and then a gradual decrease (phase III). The mean slope of phase II was −0.128 μl/min (SD 0.023) in the air group ( n = 10) and −0.105 μl/min (SD 0.032) in the N2 group ( n = 10), but the difference was not significant ( P = 0.13), which suggests that the rate of gas loss can be attributed mainly to the same steady-state partial pressure gradient of N2 reached in this phase. Furthermore, a mathematical model was developed analyzing the transmucosal N2 exchange in phase II. The model takes gas diffusion into account, predicting that, in the absence of change in mucosal blood flow rate, gas volume in the ME should show a linear decrease with time after steady-state conditions and gas composition are established. In accordance with the experimental results, the mathematical model also suggested that transmucosal gas absorption of the rat ME during steady-state conditions is governed mainly by diffusive N2 exchange between the ME gas and its mucosal blood circulation.

Kinetics of absorption atelectasis during anesthesia: a mathematical model

1999 ◽  
Vol 86 (4) ◽  
pp. 1116-1125 ◽  
Author(s):  
C. J. Joyce ◽  
A. B. Williams
Keyword(s):  
Mathematical Model ◽  
Gas Exchange ◽  
Main Parameter ◽  
Important Determinant ◽  
Gas Absorption ◽  
Gas Composition ◽  
Gas Uptake ◽  
Lung Compartment ◽  
Combined Models ◽  
Kinetics Of

Recent computed tomography studies show that inspired gas composition affects the development of anesthesia-related atelectasis. This suggests that gas absorption plays an important role in the genesis of the atelectasis. A mathematical model was developed that combined models of gas exchange from an ideal lung compartment, peripheral gas exchange, and gas uptake from a closed collapsible cavity. It was assumed that, initially, the lung functioned as an ideal lung compartment but that, with induction of anesthesia, the airways to dependent areas of lung closed and these areas of lung behaved as a closed collapsible cavity. The main parameter of interest was the time the unventilated area of lung took to collapse; the effects of preoxygenation and of different inspired gas mixtures during anesthesia were examined. Preoxygenation increased the rate of gas uptake from the unventilated area of lung and was the most important determinant of the time to collapse. Increasing the inspired O2 fraction during anesthesia reduced the time to collapse. Which inert gas (N2 or N2O) was breathed during anesthesia had minimal effect on the time to collapse.

scholarly journals Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure

Circulation ◽  
2018 ◽  
Vol 138 (10) ◽  
pp. 1039-1053 ◽  
Author(s):  
Stephen J. Greene ◽  
Robert J. Mentz ◽  
Mona Fiuzat ◽  
Javed Butler ◽  
Scott D. Solomon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Drug Development ◽  
Phase Ii ◽  
Temporal Trends ◽  
Lessons Learned ◽  
Phase Iii ◽  
End Points ◽  
Surrogate Outcomes ◽  
Past Experiences

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.

Theoretic Analysis of Middle Ear Gas Composition under Conditions of Nonphysiologic Ventilation

1992 ◽  
Vol 101 (5) ◽  
pp. 445-451 ◽  
Author(s):  
Ervin J. Ostfeld ◽  
Alexander Silberberg
Keyword(s):  
Steady State ◽  
Eustachian Tube ◽  
Middle Ear ◽  
Gas Flow ◽  
High Rate ◽  
Gas Flows ◽  
Gas Composition ◽  
Flow Through ◽  
Pressure Changes ◽  
Patulous Eustachian Tube

As gas flows in and out of the nasopharynx, the pressure in that region fluctuates. It drops below or rises above atmospheric pressure, which is itself not constant but is subject to changes in altitude and weather. Such pressure changes in the nasopharynx produce a pumping of gas into and out of the middle ear. The net amount of middle ear gas transferred from or to the nasopharynx will, component for component, in steady state exactly equal the amount of middle ear gas transferred to or from the microcirculation by means of diffusional absorption by (or release from) the mucosa. In the case of a permanently patulous eustachian tube, a single parameter, characteristic of the rate of ventilation through the open eustachian tube, is found to determine the gas composition in the middle ear, whereas in the case of a middle ear ventilated by tympanostomy, two rate-of-ventilation parameters, one for gas flow through the ventilation tube and one for flow through a periodically open eustachian tube, determine the steady state gas composition. A high rate of ventilation favors absorption of oxygen and venting of carbon dioxide from the middle ear in both cases.

Dependence of Middle Ear Gas Composition on Pulmonary Ventilation

1997 ◽  
Vol 106 (4) ◽  
pp. 314-319 ◽  
Author(s):  
Haya Mover-Lev ◽  
Moshe Harell ◽  
Dalia Levy ◽  
Amos Ar ◽  
Michal Luntz ◽  
...  
Keyword(s):  
Steady State ◽  
Middle Ear ◽  
Pulmonary Ventilation ◽  
Venous Blood ◽  
Blood Gases ◽  
Mixed Venous Blood ◽  
Gas Composition ◽  
Blood Gas ◽  
Ventilation Perfusion Ratio ◽  
Mixed Venous

The middle ear (ME) steady state gas composition resembles that of mixed venous blood. We changed arterial and venous blood gases by artificially ventilating anesthetized guinea pigs and measured simultaneous ME gas changes during spontaneous breathing, hyperventilation, and hypoventilation. During hyperventilation, PaCO2 and PvCO2 (a = arterial, v = venous) decreased from 46.0 and 53.0 mm Hg to 17.9 and 37.5 mm Hg, respectively, while PaO2 and PvO2 (85.6 and 38.2 mm Hg) did not change. This was accompanied by an ME PCO2 decrease from 70.4 to 58.8 mm Hg and a PO2 decrease from 36.8 to 25.4 mm Hg. During hypoventilation, PaCO2 and PvCO2 increased to 56.8 and 66.4 mm Hg, while PvO2 decreased to 21.8 mm Hg. The ME PCO2 increased simultaneously to 88.8 mm Hg and the ME PO2 decreased to 25.4 mm Hg. The ME PO2 decrease during hyperventilation may be explained by a 33% decrease in ME mucosa perfusion, calculated from the ME ventilation-perfusion ratio. This study shows that ME gas composition follows fluctuations of blood gas levels and thus may affect total ME pressure.

Phase I/II Pharmacodynamic Study of the P-Glycoprotein (Pgp) Inhibitor Zosuquidar Administered by Continuous Infusion (CIV) with Daunorubicin (DNR) and Cytarabine (ARA-C) as Primary Therapy in Older Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 422-422 ◽  
Author(s):  
Jeffrey Lancet ◽  
Maria R. Baer ◽  
Larry D. Cripe ◽  
Alan F. List ◽  
John F. Marcelletti ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Phase Ii ◽  
Older Patients ◽  
Phase Ii Trial ◽  
Plasma Concentrations ◽  
Phase Iii ◽  
Functional Assay ◽  
Primary Therapy ◽  
Functional Inhibition

Abstract Pgp expression in AML increases with age and adversely affects treatment response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Previous studies established that plasma concentrations > 170 ng/mL achieve complete functional inhibition of Pgp. Prolonged Pgp blockade is necessary to optimize antineoplastic sensitization in resistant cells in vitro, but was not applied previously. Specifically, the 72-hour CIV schedule of zosuquidar in this trial differs from the 6-hour infusion employed in the E3999 Phase III trial of this agent. We initiated a Phase I/II trial of zosuquidar as a 72-hr CIV in older patients with newly diagnosed AML. Objectives of the Phase I study were to establish safety and determine the dose necessary to achieve a sustained zosuquidar plasma level > 170 ng/mL with in vivo validation of Pgp functional inhibition. Eligibility included ages 55–75, ECOG PS 0–2, adequate end-organ function, and Pgp activity by functional assay (Phase II only). Phase II objective is to determine the complete remission rate (CR) in Pgp+ patients. Planned zosuquidar dose levels of 700 mg/d and 800 mg/d were based upon PK modeling predicting achievement of plasma inhibitory concentrations [> 170 ng/mL] in 93% and 97% of patients, respectively, within 4 hours. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Patients who achieved a CR received up to 2 cycles of consolidation with the same agents using an abbreviated schedule. The Phase I portion of the trial has been completed with 16 patients: 10 patients received 700 mg/d of zosuquidar and 6 patients, 800 mg/d. The median age was 66; M/F was 9/7; cytogenetics: adverse (6), intermediate (7), favorable (1) and unknown (2); de novo/secondary AML: 8/8; Pgp+ by functional assay (11). Phase I DLTs included one death due to respiratory failure on Day 8 of induction (700 mg/d); one patient with delayed bone marrow recovery and one patient with Grade 3 reversible delirium (800 mg/d). Early death (< 30 days) occurred in 1 patient. Other adverse events attributed to zosuquidar include reversible tremor (48%), dizziness (15%) and confusion (11%). Mean zosuquidar steady-state concentrations were 220±57 ng/mL (700 mg/d) and 462±222 ng/mL (800 mg/d), with a median of 49–52 hours above 170 ng/mL. Pharmacodynamic studies using circulating NK cells as an index of Pgp activity showed near complete inhibition (>90%) by 4 hours that was sustained throughout the infusion in all patients tested. Based upon these data, the recommended Phase II dose of zosuquidar by 72-hr CIV is 700 mg/d. An additional 9 Pgp+ patients have been enrolled to the Phase II trial. Among the total 20 evaluable Pgp+ patients, 10 (50%) have achieved CR or CRp. Zosuquidar 700 mg/d administered by CIV with DNR/ARA-C is well tolerated and achieves rapid and sustained Pgp inhibition at steady state plasma levels, with preliminary evidence of clinical benefit in Pgp+ patients. Accrual to the Phase II trial is ongoing.

Estimation of cardiac output by analysis of respiratory gas exchange

1975 ◽  
Vol 39 (1) ◽  
pp. 159-165 ◽  
Author(s):  
L. D. Homer ◽  
B. Denysyk
Keyword(s):  
Mathematical Model ◽  
Cardiac Output ◽  
Standard Deviation ◽  
Gas Exchange ◽  
Simultaneous Estimation ◽  
Gas Composition ◽  
Central Venous ◽  
Blood Samples ◽  
Arterial Blood ◽  
Spontaneously Breathing

Cardiac output is estimated by least squares fitting of a model of pulmonary gas exchange to measurements of respiratory gas composition obtained with a mass spectrometer during a rebreathing maneuver. This new technique estimates cardiac output on spontaneously breathing subjects at rest and requires neither central venous nor arterial blood samples. Principal features of the technique are the use of multiple gases simultaneously in the analysis, the use of a mathematical model for breath-to-breath evaluation of gas exchange, and simultaneous estimation of gas exchange and alveolar gas tensions with the same instrumentation. The technique is compared with thermal dilution estimates in dogs before and during hemorrhagic shock. Two-thirds of these estimates were within 20% of one another. The standard deviation of replication was 15%. Shortcomings, possibilities for improvement, and possible applications are discussed.

Ventilatory and gas exchange kinetics during exercise in chronic airways obstruction

1982 ◽  
Vol 53 (6) ◽  
pp. 1594-1602 ◽  
Author(s):  
L. E. Nery ◽  
K. Wasserman ◽  
J. D. Andrews ◽  
D. J. Huntsman ◽  
J. E. Hansen ◽  
...  
Keyword(s):  
Gas Exchange ◽  
Phase I ◽  
Phase Ii ◽  
Cardiovascular Response ◽  
Phase Iii ◽  
Slow Phase ◽  
Initial Increase ◽  
O2 Pulse ◽  
Exchange Kinetics ◽  
Gas Exchange Kinetics

The influence of chronic obstructive pulmonary disease (COPD) on exercise ventilatory and gas exchange kinetics was assessed in nine patients with stable airway obstruction (forced expired volume at 1 s = 1.1 +/- 0.33 liters) and compared with that in six normal men. Minute ventilation (VE), CO2 output (VCO2), and O2 uptake (VO2) were determined breath-by-breath at rest and after the onset of constant-load subanaerobic threshold exercise. The initial increase in VE, VCO2, and VO2 from rest (phase I), the subsequent slow exponential rise (phase II), and the steady-state (phase III) responses were analyzed. The COPD group had a significantly smaller phase I increase in VE (3.4 +/- 0.89 vs. 6.8 +/- 1.05 liters/min), VCO2 (0.10 +/- 0.03 vs. 0.22 +/- 0.03 liters/min), VO2 (0.10 +/- 0.03 vs. 0.24 +/- 0.04 liters/min), heart rate (HR) (6 +/- 0.9 vs. 16 +/- 1.4 beats/min), and O2 pulse (0.93 +/- 0.21 vs. 2.2 +/- 0.45 ml/beat) than the controls. Phase I increase in VE was significantly correlated with phase I increase in VO2 (r = 0.88) and HR (r = 0.78) in the COPD group. Most patients also had markedly slower phase II kinetics, i.e., longer time constants (tau) for VE (87 +/- 7 vs. 65 +/- 2 s), VCO2 (79 +/- 6 vs. 63 +/- 3 s), and VO2 (56 +/- 5 vs. 39 +/- 2 s) and longer half times for HR (68 +/- 9 vs. 32 +/- 2 s) and O2 pulse (42 +/- 3 vs. 31 +/- 2 s) compared with controls. However, tau VO2/tau VE and tau VCO2/tau VE were similar in both groups. The significant correlations of the phase I VE increase with HR and VO2 are consistent with the concept that the immediate exercise hyperpnea has a cardiodynamic basis. The slow ventilatory kinetics during phase II in the COPD group appeared to be more closely related to a slowed cardiovascular response rather than to any index of respiratory function. O2 breathing did not affect the phase I increase in VE but did slow phase II kinetics in most subjects. This confirms that the role attributed to the carotid bodies in ventilatory control during exercise in normal subjects also operates in patients with COPD.

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