High flow nasal cannula: Influence of gas type and flow rate on airway pressure and CO2 clearance in adult nasal airway replicas.

BACKGROUND: High flow nasal cannula therapy is a form of respiratory support which delivers high flow rates of heated, humidified gas to the nares via specialized cannula. Two primary mechanisms of action attributed to the therapy are the provision of positive airway pressure as well as clearance of CO2-rich exhaled gas from the upper airways. METHODS: Physiologically accurate nose-throat airway replicas were connected at the trachea to a lung simulator, where CO2 was supplied to mimic the CO2 content in exhaled gas. Cannula delivered either air, oxygen or heliox (80/20%volume helium/oxygen) to the replicas at flow rates ranging from 0 to 60 l/min. Five replicas and three cannulas were compared. Tracheal pressure and CO2 concentration were continuously measured. The lung simulator provided breaths with tidal volume of 500 ml and frequency of 18 breaths/min. Additional clearance measurements were conducted for tidal volume and breathing frequency of 750 ml and 27 breaths/min, respectively. FINDINGS: Cannula flow rate was the dominant factor governing CO2 concentration. Average CO2 concentration decreased with increasing cannula flow rate, but above 30 L/min this effect was less pronounced. Tracheal positive end-expiratory pressure increased with flow rate and was lower for heliox than for air or oxygen. A predictive correlation was developed and used to predict positive end-expiratory pressure for a given cannula size as a function of supplied flow rate and occlusion of the nares. INTERPRETATION: Compared with administration of air or oxygen, administration of heliox is expected to result in similar CO2 clearance from the upper airway, but markedly lower airway pressure.

Effects of iris pigmentation on response of ocular pressure to timolol.

Timolol ophthalmic solution effectively reduced mean intraocular pressure (IOP) in Negro and Caucasian patients with chronic open angle glaucoma and untreated IOP of 22 mm Hg or higher. No differences in pressure lowering response were observed among the races although the Negroes required somewhat higher timolol concentrations to produce similar reductions from baseline IOP. Negro patients also appeared to have a more severe disease as indicated by the number of prior antiglaucoma drugs required and the untreated (baseline) pressures. An unexpected finding was the significantly greater number of Caucasians with dark irides who were discontinued from therapy because of inadequate pressure reduction.

A soluble sustained-release ophthalmic delivery unit.

Four studies carried out in normal volunteers assessed the characteristics and acceptability of the matrix of a soluble sustained-release delivery system. Fourteen volunteers in the first study received crossover single applications of a rod- and oval-shaped soluble unit at 8 AM. Fifteen normal volunteers in the second study received soluble units at 9 PM in the inferior cul-de-sac. During the crossover phase, the units were placed into the superior cul-de-sac rather than the inferior cul-de-sac. In the third study, 15 normal volunteers received a rod-shaped unit in one eye and an oval-shaped insert in the opposite eye nightly for five successive nights. In Study 4, 24 normal volunteers subdivided into four groups of 12 eyes received an 18-mg rod, 24-mg rod, 18 mg-oval, or 24-mg oval unit at 9 PM. We concluded that the disappearance rate of these soluble units from the conjunctival sac depended on the size rather than shape and was not influenced by sleep. The soluble units were well tolerated.

Factors affecting the deposition of aerosolized insulin.

The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their efficiency (measured, for example, in terms of the amount of insulin absorbed in the blood compared to the total amount loaded into an inhalation device). A primary factor that could cause inefficiency of insulin absorption is deposition in the nonalveolated airways with subsequent removal from the lung via mucociliary clearance. Thus, a better understanding of the spatial distribution of insulin particle deposition in the lung can give guidance to the optimization of inhalation therapy. A mathematical model was used to study factors affecting the disposition of aerosolized insulin. The model calculates the trajectories of inhaled particles in the lung and has been validated by data from human subject experiments. Computer simulations were performed describing a wide range of patient breathing maneuvers. The results indicate significant variations in particle deposition patterns within lungs for different tidal volumes, inspiratory flow rates, and breath hold times. These findings indicate that particle sizes and ventilatory parameters are significant factors determining locations of particle deposition within human lungs, and thus the absorption of insulin into the blood stream via alveloated airways. Mathematical modeling is a valuable technique to complement clinical studies in the targeted delivery of inhaled insulin.

A technical problem in the calculation of laminar flow near irregular surfaces described by sampled geometric data.

The numerical simulation of fluid flow and transport near biological surfaces must take into account the natural irregularity of these surfaces if the influence of the surface geometry on the near-wall flow field is to be modeled. If the geometric description of a biological surface has a limited resolution, what impact will this have on the accuracy of a computational simulation of the near-wall flow field? It is important to emphasize here that the problem arises from the limited number of data points describing the geometry and not from any limit on the number of mesh points in any subsequent calculation. In this note we show that if every point in a geometric data set describing an axisymmetric model of a diseased coronary artery is taken as a mesh point, then a well converged and otherwise accurately calculated wall shear stress distribution contains a degree of uncertainty which is attributable wholly to the limited resolution of the original geometric model. The approach taken is to repeat the numerical calculation on a reduced resolution version of the original geometric data set, comparing the wall shear stress distribution with that obtained originally. We conclude that accurate computational modeling and simulation of transport processes near irregular biological surfaces will be highly dependent on the availability of well-resolved geometric data describing the surface under study.

Three-dimensional fluid particle trajectories in the human larynx and trachea.

A computational fluid dynamics software package (FIDAP) has been employed to obtain three-dimensional flow data, which are used herein to calculate the trajectories of fluid particles. Our computations have demonstrated that the flow fields inside the larynx are very complex including eddies in the lumen and reverse motion along the surface. The effects of such flow fields will be to increase the residence times of entrained drug particles. Our computations have also demonstrated that the larynx has pronounced effects on the motion of air in the trachea.

beta-Blockers and the eye: an overview.

Some beta-adrenoceptor blocking drugs are exciting new ocular hypotensive compounds. Unlike pilocarpine, the mainstay of glaucoma treatment for the last 100 years, beta-blocking agents do not contract the pupil nor interfere with vision even in patients with central lens opacities. They also do not cause spasm of the ciliary muscle producing transient myopia and disturbance of accommodation. Paradoxically, one of these agents, timolol, causes a fall in intraocular pressure when administered locally even in patients responding to beta-agonists with a reduction in intraocular pressure. Concomitant administration of timolol with epinephrine seems to enhance its ocular hypotensive effect in many patients. The exact mode of action of beta-blockers in reducing intraocular pressure is unknown but appears to primarily reduce aqueous production. This new class of drugs seems destined to play an important role in the treatment as well as in the understanding of glaucoma.

[Efficacy and safety of long-term maintenance treatment with timolol ophthalmic solution in chronic open-angle glaucoma (author's transl)]. / Wirksamkeit und Sicherheit der Langzeitbehandlung mit Timolol-Augentropfen beim chronischen Offenwinkelglaukom.

Timoptol Ophthalmic Solution (timolol maleate, MSD) is a topical beta-adrenergic receptor blokking agent which lowers elevated intraocular pressure when applied once or twice daily. It represents a major advance in topical therapy for glaucoma and elevated intraocular pressure. It is more effective in reducing elevated intraocular pressure and produces fewer side effects than pilocarpine and epinephrine. It does not alter pupil size or affect visual acuity. Timoptol maintained satisfactory reductions in intraocular pressure in long-term maintenance studies treating over 100 patients for up to 16 months. The drug was well tolerated and without serious adverse effects. In general, reductions in intraocular pressure for non-white patients (predominantly Blacks) were similar to the Whites.

Deposition patterns of aerosolized drugs within human lungs: effects of ventilatory parameters.

A mathematical model for inhaled aerosolized drugs is validated by comparisons of predicted particle deposition values with experimental data from adult subject inhalation exposure tests. The model is subsequently used to study the effects of ventilatory parameters on particle deposition patterns within the human lung. By altering breathing profiles, deposition values can be affected regarding quantity delivered and spatial location. Increased tidal volumes and breath-holding times increase deposition in the pulmonary region, while increased inspiratory flow rates increase deposition in the tracheobronchial region. Based upon fluid dynamics considerations (Reynolds numbers), an original method of partitioning the lung is also presented. The model has implications with regard to aerosol therapy, indicating that the efficacies of inhaled pharmacological drugs in the prophylaxis and treatment of airway diseases can be improved by regulating breathing profiles to deposit particles selectively at prescribed sites within the lung.

Trimolol: effect on intraocular pressure in chronic open-angle glaucoma.

Timolol maleate is an effective agent of reducing intraocular pressure in patients with chronic open-angle glaucoma. To date, there are no adverse side effects demonstrable with use of this medication. Its mechanism of action is not clearly delineated but preliminary data suggest an effect on outflow facility.

A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies.

Nonhuman primates may be used as human surrogates in inhalation exposure studies to assess either the (1) adverse health effects of airborne particulate matter or (2) therapeutic effects of aerosolized drugs and proteins. Mathematical models describing the behavior and fate of inhaled aerosols may be used to complement such laboratory investigations. For example, the optimal conditions, in terms of ventilatory parameters (e.g., breathing frequency and tidal volume) and aerosol characteristics (e.g., geometric size and density), necessary to target drug delivery to specific sites within the respiratory tract may be estimated a priori with models. In this work a mathematical description of the rhesus monkey (Macaca mulatta) lung is presented for use with an aerosol deposition model. Deposition patterns of 0.01- to 5-microm-diameter monodisperse aerosols within lungs were calculated for 3 monkey lung models (using different descriptions of alveolated regions) and compared to human lung results obtained using a previously validated mathematical model of deposition physics. Our findings suggest that there are significant differences between deposition patterns in monkeys and humans. The nonhuman primates had greater exposures to inhaled substances, particularly on the basis of deposition per unit airway surface area. However, the different alveolar volumes in the rhesus monkey models had only minor effects on aerosol dosimetry within those lungs. By being aware of such quantitative differences, investigators can employ the respective primate models (human and nonhuman) to more effectively design and interpret the results of future inhalation exposure experiments.

Slow-release artificial tears and the treatment of keratitis sicca.

The slow-release artificial tear (SRAT) is a biodegradable, cellulosic polymer without preservative which is inserted beneath the tarsus of the lower lid, and which provides continuous lubrication and tear film stability to the eye. The SR-AT has been shown to reduce both subjective symptoms and objective signs in patients with keratitis sicca, and is a valuable adjunct to therapy in patients with this disease.

Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution.

Timolol ophthalmic solutions 0.5 per cent, 1.0 per cent, and 1.5 per cent lowered intraocular pressures significantly in normal human volunteers. Maximum lowering of the intraocular pressures was reached at two hours with the 0.5 per cent solution of timolol and at one hour with the 1.0 per cent and 1.5 per cent timolol ophthalmic solutions. The effect lasted the full seven hours of observations. No objective or subjective evidence of ocular irritation could be attributed to the drug. A single dose of timolol applied topically to the eyes of normal human volunteers had no effect on pupillary size, visual acuity, blood pressure, or pulse rate.