Frank P. Primiano

Course of cystic fibrosis in 95 patients

The course of 95 patients with cystic fibrosis is presented. Survivors have a mean follow-up period of over 14 years (minimum: 13 years). Of 45 patients diagnosed prior to extensive irreversible pulmonary involvement, only one has died and none is disabled. In contrast, of the other 50 patients diagnosed after substantial irreversible pulmonary disease was present, 26 have died. Mortality and morbidity has been greater in females. Possible factors contributing to the improving prognosis include early diagnosis, aggressive management with comprehensive care, easy access to specialized care, and improved antimicrobial therapy.

Theoretical analysis of chest wall mechanics.

A mathematical model of the chest wall partitioned into rib cage, diaphragmatic and abdominal components is developed consistent with published experimental observations. The model describes not only the orthodox chest wall movements (rib cage and abdomen expand together during inspiration) of the quietly breathing standing adult, but also Mueller maneuvers (inspiration against an occluded airway opening) and the paradoxical breathing patterns (rib cage contracts while abdomen expands during inspiration) observed in quadriplegia and in the newborn. The abdomen is inferred to act as a cylinder reinforced by the abdominal muscles functioning similarly to bands around a barrel. The rib cage and abdominal wall are inferred to act not as though they were directly attached to one another, but as though they were being pressed together by the skeleton. Furthermore, transabdominal pressure is visualized as acting, not across the rib cage isolated from the diaphragm, as has been suggested previously, but instead, across the combined rib cage and diaphragm acting as a deformable unit containing the lungs.

A Nonlinear Model Combining Pulmonary Mechanics and Gas Concentration Dynamics

To elucidate the various mechanisms by which pulmonary mechanics affect the distribution of gas species throughout the lungs, a multicompartment model relating pressure differences, flows, volumes, and gas species concentrations has been developed. The alveolar regions of the model are nonlinearly elastic and the pressure-flow relation of their associated small airways is volume dependent. Various combinations of parameter values were chosen, including cases in which the model was mechanically uniform (normal) and nonuniform (obstructive). Computer solutions of model equations were obtained for both piecewise-exponential and sinusoidal transpulmonary pressure inputs. Clinical measures of mechanical uniformity and gas concentration homogeneity were evaluated along with unobservable indexes. Results indicate how the distribution of mechanical variables affects the distribution of gas species concentration within the lungs. For the nonuniform (obstructive) model, the gas is distributed more inhomogeneously at higher frequencies and lower lung volumes. The distribution of initial dead space gas to the compartments as well as pendelluft tend to decrease this inhomogeneity. Dynamic compliance for the non-uniform model was frequency dependent at each of the three volume operating points investigated, whereas the semilog nitrogen washout curve was essentially linear for some frequencies and volumes while nonlinear for others. Consequently, inferences about distributions of mechanical parameters and intrapulmonary gas may require that clinical measurements be obtained together at several frequencies and volume operating points.

Ventilation inhomogeneity: Alveolar mechanics and gas distribution

The effects of regional lung differences in alveolar mechanics on the transpulmonary pressure-volume (Ptp-V) relationship and the single-breath washout (SBW) of nitrogen were investigated by mathematical modeling and postmorten human lung experiments. Regional nonuniformity in alveolar collapse and re-opening were associated with differences in gravitational stress or elasticity. Model simulations predict that neither type of regional nonuniformity qualitatively affects the shape of the Ptp-V curve, but does affect the terminal (or small-volume) portion of the SBW. Comparisons of characteristics of the Ptp-V and SBW curves indicate that regional nonuniformity in alveolar collapse is an important mechanism associated with ventilation inhomogeneity.

Engineers and the respiratory system: a perspective.

The respiratory system has so many diverse aspects that its function can be studied with the tools of almost any of the engineering disciplines. These tools include mathematical modeling, data analysis techniques, instrumentation, and methods of hardware and software design. Thus, engineers can contribute not only to the understanding of basic respiratory processes, but also to the delivery of health care. Too often, however, they are familiar with only a very specialized area, which may limit the scope of their activities or cause a misdirection of effort. In contrast, medical scientists usually have a broad understanding of the physiological system and knowledge of practical problems associated with clinical applications. Thus, the activities of engineers and medical scientists are complementary and can lead to fruitful collaborations. However, more often than not, the medical scientist takes responsibility for defining problems and setting goals, even though, in many areas of respiratory research, engineers can, and should, play the leading role. But to be able to assume this role, the engineer must be as familiar with the respiratory system as with theoretical principles, experimental approaches, and advanced technology. Investigators trained in engineering and the physical sciences who at tempt to understand respiratory system function are confronted by a major obstacle: translating the verbal explanations of complicated phenomena, so prevalent in the life science literature, into more precise mathematical descriptions of the type with which they are familiar. A lack of a rigorous formal framework for the ideas of mechanics, mass transport, control and

A conceptual framework for pulmonary function testing.

Pulmonary function (PF) testing is traditionally depicted as a sequence of separate activities in which a “test” is performed producing “results” which are subsequently “interpreted.” An alternative view of PF testing is presented which identifies two problems that must be solved: an inductive problem and a deductive problem. Solving the inductive problem yields two sets of models both of which are needed for the solution of the deductive problem. One set of models, called physiology models, describes physical processes in the respiratory system. The second set, termed pathology models, relates parameters of the physiology models and clinical measures to functional status category, treatment and prognosis. A key component of the deductive problem is the PF test, itself, which is the test of the hypothesis that a subject belongs to a particular functional category specified by a given pathology model. Since this hypothesis is formulated before pulmonary function (physiology model) parameters are evaluated, knowledge of the implications (interpretation) of any observed parameter values (results) is an integral part of the “test” and therefore must be understood before “results” are obtained. Even though this framework is described in the context of PF testing, it can be applied to medical decision making in general.Pulmonary function (PF) testing is traditionally depicted as a sequence of separate activities in which a “test” is performed producing “results” which are subsequently “interpreted.” An alternative view of PF testing is presented which identifies two problems that must be solved: an inductive problem and a deductive problem. Solving the inductive problem yields two sets of models both of which are needed for the solution of the deductive problem. One set of models, called physiology models, describes physical processes in the respiratory system. The second set, termed pathology models, relates parameters of the physiology models and clinical measures to functional status category, treatment and prognosis. A key component of the deductive problem is the PF test, itself, which is the test of the hypothesis that a subject belongs to a particular functional category specified by a given pathology model. Since this hypothesis is formulated before pulmonary function (physiology model) parameters are evaluated, knowledge of the implications (interpretation) of any observed parameter values (results) is an integral part of the “test” and therefore must be understood before “results” are obtained. Even though this framework is described in the context of PF testing, it can be applied to medical decision making in general.

Microprocessor-Based Blood Gas Analyzer

An automatic blood gas analyzer based on the Intel 8080 microprocessor has been designed, built, and is in use in a clinical laboratory. Commercially available blood gas electrodes and amplifiers serve as the input devices. The microprocessor system, utilizing less than 2 1/4K words of memory stored in PROM, consists of a set of subroutines and utility programs which utilize a floating point math package which contains, besides the four basic functions, log10 X and 10x functions. The subroutines enable the microprocessor to monitor the reaction in the electrode chamber, compensate the measured blood gas values for abnormal body temperature, and calculate three additional parameters: HCO-3 concentration, base excess, and percent O2 saturation of hemoglobin. The only steps left to the medical personnel are to clean and calibrate the electrodes, introduce the blood into the electrode chambers, and distribute the printed results.

ASSOCIATION OF CHILDHOOD OBESITY-HYPOVENTILATION SYNDROME AND FAMILIAL DECREASED VENTILATORY RESPONSE TO HYPERCAPNIA

Subnormal ventilatory response to hypercapnia is accepted as part of the obesity-hypoventilation syndrome in adults, but ventilatory control has not been studied in children with the obesity-hypoventilation syndrome. We studied ventilatory response to hypercapnia in the families of 2 obese 13-year-old girls with the Prader-Willi Syndrome, one of whom had recovered from the obesity hypoventilation syndrome, and one of whom had never hypoventilated. Siblings and parents were not obese.The response to hypercapnia, measured as the slope (S) of ventilation (L/min) vs. alveolar carbon dioxide tension (mmHg) during rebreathing, was decreased in the patient with the obesity-hypoventilation syndrome (S=1.0) and in 3 family members (mean S=1.1, range .7-1.4). The other Prader-Willi patient (S=3.6) and her family (mean S=2.2, range 1.6-3.6) had considerably greater responses. Young adult controls (mean S=3.3, range 2.8-4.2) fell within published normal ranges (S=1.5 - 5.0).Respiratory failure in the child with the obesity-hypoventilation syndrome is probably related to two independent factors: obesity and a familial diminished response to hypercapnia. The familial factor may explain why only a small percentage of obese patients develop the obesity-hypoventilation syndrome.

Analysis of Plethysmographic Estimation of Alveolar Pressure

Relationships between the change in a representative alveolar pressure in a pulmonary system which acts as a single mechanical compartment and changes in measurable variables are derived for several plethysmographic systems. Derivations considering air as a one-component gas are presented for the pressure and flow-displacement plethysmographs in which the subject exchanges respired gas with air in the box, and for a plethysmograph from which the subject breathes gas from outside the box using a tube through the box wall. A set of assumptions and approximations which can be invoked to develop the standard differential plethysmographic equations is explicitly stated. The analysis is extended to include multicomponent gas mixtures and mass exchange between alveolar gas and blood for a generalized plethysmographic configuration. Some practical requirements on experimental conditions arising from the derived relationships and the assumptions and approximations used in the derivations are considered.