Andrew C. Jackson

A method for measuring and modeling the physiological traits causing obstructive sleep apnea

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individuals set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patients physiology and guide therapy based on the traits.

A simplified method for determining phenotypic traits in patients with obstructive sleep apnea

We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure = 0 cmH(2)O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from -0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apnea-hypopnea index (r = 0.9, P < 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy.

Behavioral task-induced bronchodilation in asthma during active and passive tasks: a possible cholinergic link to psychologically induced airway changes.

This study investigated pulmonary and autonomic reactions to active and passive behavioral laboratory tasks among asthmatic subjects.It also examined the relationship between airway irritability, as measured by the methacholine challenge test (MCT), and autonomic activity and reactivity to these tasks. Fifty-one asthmatic and 37 nonasthmatic subjects were exposed to psychological laboratory tasks involving either active (mental arithmetic and reaction time) or passive (films depicting shop accidents and thoracic surgery) response. The MCT was given to asthmatics in a separate session. Active tasks reduced respiratory impedance, as measured by forced oscillation pneumography. They also increased heart rate and appeared to block vagal activity, as measured by respiratory sinus arrhythmia (RSA). Airway irritability as assessed by the MCT was positively related to amplitude of RSA and to skin conductance levels. Our data suggest that active and passive behavioral tasks may produce different pulmonary effects among both asthmatic and nonasthmatic individuals. Engaging in tasks requiring active responses may produce temporary improvements in pulmonary function. No autonomic differences were obtained between asthmatics and nonasthmatics in physiological response to stress, but greater cholinergic receptor sensitivity was suggested among high responders to methacholine.

Variations in the Pattern of Muscle Innervation by the L5 and S1 Nerve Roots

Evidence based on electrical studies is presented for the standard and anomalous patterns of innervation of muscles supplied by the fifth lumbar and first sacral nerve roots. Although considerable controversy still exists, previous work in this field suggests that the L5 nerve root supplies tibialis anterior, extensor hallucis longus, extensor digitorum brevis, and the lateral head of gastrocnemius, while the S1 nerve root innervates the medial head of gastrocnemius, soleus, and abductor hallucis. In order to confirm the reliability of this data, the L5 and S1 nerve roots of 50 patients were electrically stimulated during surgery, and distally evoked responses in the relevant muscles were recorded, using surface electrodes. The results confirm the essential reliability of the proposed table of segmental innervation and also demonstrate that most muscles have a dual innervation, with one nerve root being dominant. However, eight patients (16%) exhibited a marked departure from the normal pattern. For example, it is clear that on occasion the extensor digitorum brevis and the lateral head of gastrocnemius can be supplied by S1 and the soleus and medial head of gastrocnemius can be supplied by L5. In a prospective study of 100 patients presenting with clinical evidence of lumbosacral nerve root entrapment, the level of nerve root involvement, as predicted by electromyography, was compared with the operative findings. Correct preoperative nerve root localization was achieved in 84%. At least half the failures in prediction are thought to be due to anomalies of innervation. A further study of 12 patients with disorders of bony segmentation revealed anomalous muscle innervation in seven, so that diagnostic errors may frequently be expected in this group. In clinical practice, whenever anomalous bony segmentation is encountered, the likelihood of variable nerve root innervation should be appreciated, and we recommend that both nerve roots in question should be explored at operation.

Statistical Measures of Parameter Estimates from Models Fit to Respiratory Impedance Data: Emphasis on Joint Vanabilities

To describe respiratory mechanical impedance data, many investigators have proposed electromechanical models and then fit them to data using formal parameter estimation techniques. This approach has resulted in confusion as to how to interpret the resulting estimated values, and hence as to which model is most appropriate. A key cause of this confusion is that most studies rely on the quality of fit between the model and the data as the only measure of model validity rather than performing adequate statistical analysis of the parameter estimates themselves. This paper describes several statistical measures that should be applied to parameter estimates obtained from forced oscillation data. Specifically, we describe standard errors of the parameter estimates, confidence intervals for each parameter estimate, and the joint confidence region for the parameters. Much emphasis is placed on the joint confidence region which, unlike the interval, allows for simultaneous variations in parameters. The measures are applied to an often used six-element model for respiratory impedance data of dogs from 4 to 64 Hz. This application indicated that even when fitting data over this frequency range, parameter estimates are not well defined and the parameter estimated with least accuracy is airway resistance.

The orthopaedic management of hypophosphataemic rickets

The orthopaedic management of 19 patients with hypophosphataemic rickets was reviewed. Three groups of patients could be identified: teenagers or young adults without knee problems, those with knee problems, and adults or elderly patients with stiff joints due to mineralisation of ligaments. Osteotomies were best staged. Diaphyseal osteotomies were performed at all ages with stabilisation over an intramedullary nail; metaphyseal osteotomies were most successful at or close to maturity. Early degeneration of the knees with shedding of the articular cartilage was seen in young adults, and osteochondritis-like lesions were seen in some teenagers. Stiffness and bone pain were a feature in elderly patients.

Confidence bounds on respiratory mechanical properties estimated from transfer versus input impedance in humans versus dogs

A sensitivity analysis is used to determine whether and why the six-element model of A.B. Dubois et al. (1956) could be applicable to lower-frequency (<64 Hz) transfer impedance, Z/sub tr/, data in humans, but not input impedance, Z/sub in/, data over any frequency range. The joint parameter uncertainty bounds are predicted, assuming a fit to either 2-32-Hz Z/sub in/ or Z/sub tr/ data created from literature-based mean parameter values. It was predicted that the estimates will be very unreliable if obtained from Z/sub in/ data for humans or dogs, or from Z/sub tr/ data from dogs. Surprisingly, however, the reliability of several parameter estimates from human Z/sub tr/ data from only 2-32 Hz are reasonable. The variability in 2-62-Hz-based Z/sub tr/ parameter estimates is evaluated by comparing experimental variability in two healthy human subjects to theoretical and Monte Carlo numerical predictions based on a single trial. Again, the Z/sub tr/ parameters were reliable. A simulation study was used to describe the reasons for enhanced reliability when using human Z/sub tr/ data.<<ETX>>

Interpretation of respiratory input impedance in healthy infants.

Respiratory input impedance (Zin) is a potentially informative test of pulmonary function in infants who are unable to perform standard tests commonly performed in children and adults. Analysis of Zin in dogs using the six‐element model of DuBois et al. (J Appl Physiol 8:587, 1956) provides estimates of airways resistance separate from tissue resistance, as well as an estimate of thoracic gas volume. However, reliable estimates of these parameters can only be obtained when Zin displays a distinct antiresonance that is associated with the tissue inertance and alveolar gas compression compliance. To determine whether infants have such an antiresonance, Zin was measured in nine healthy infants (4 < f < 160 Hz). An antiresonance was found at 112.8 ± 10.4 Hz, and the six‐element model fit these data well, but the resulting parameters were physiologically unrealistic. We hypothesized that the antiresonance in the measured Zin is the result of a shunt compliance proximal to alveolar gas compression compliance. Gas compression in the face mask and nonrigid upper airway walls could provide such a shunt compliance. We investigated another model with four parameters, a single shunt compliance (Cfm) representing gas compression in the face mask in parallel with the infants total respiratory resistance (Rrs), inertance (Irs), and compliance (Crs). This model fits the data well, and the estimated Rrs (19.3 ± 4.2 cmH2O/L/s) was physiologically reasonable. However, Crs (Crs = 1.03 · 0.58 mL/cmH2O) was one order of magnitude smaller than reported Crs. The value for Cfm was slightly larger than that based on the estimated volume of gas in the face mask, suggesting an additional influence of upper airway wall shunting. Computer simulations using a model that includes the face mask and upper airway walls confirmed that Cfm and the upper airway wall properties significantly influence Zin data over this frequency range. Nevertheless, these simulations suggest that the Rrs estimated from the four‐element model is related to airway resistance. Pediatr Pulmonol. 1996; 22:364–375.

A deep breath bronchoconstricts obese asthmatics.

Background: Asthma is characterized by the loss of a deep breath (DB)-induced bronchodilation and bronchoprotection. Obesity causes lung restriction and increases airway resistance, which may further worsen the capacity of a DB to induce bronchodilation; however, whether increasing BMI impairs the bronchodilatory response to a DB in asthmatics is unknown. Methods: The population consisted of 99 subjects, 87 with moderate to severe persistent asthma and 12 obese control subjects. Using transfer impedance we derived airway resistance (Raw). Participants breathed for 1 minute and took a slow DB followed by passive exhalation to functional residual capacity (FRC) and tidal breathing for another minute. Results: After a DB, obese asthmatics had the largest percent increase in Raw (median 9.8% interquartile range [IQR] 3.1–15.1), compared with overweight (6.5% IQR −1.3, 12.1) and lean (0.7% IQR −3, 7.9) asthmatics and obese controls (2.5% IQR –.6, 11) (p for trend = 0.008). The association between the percent increase in Raw after a DB and BMI as a continuous variable was significant (p = 0.02). Conclusions: In obese, moderate to severe and poorly controlled asthmatics, a DB results in increased Raw. This phenomenon was not observed in leaner asthmatics of similar severity or in obese control subjects.

The Reciprocal Relationship Between Thoracic and Spinal Deformity and Its Effect on Pulmonary Function in a Rabbit Model : A Pilot Study

Study Design. Investigate the association between growth of the spine and thorax under conditions that create symmetric or asymmetric growth disturbances of the spine or thorax in a growing rabbit. Objective. Prove growth of the spine and growth of the thorax are directly related. Summary of Background Data. Understanding the association between growth of the thorax and growth of the spine may explain the occurrence of thoracic insufficiency in patients with congenital scoliosis. Methods. Symmetric or asymmetric growth disturbances of the spine or thorax were established in 5-week-old rabbits. During growth of the rabbits, structural changes in the spine, thorax, and lung volume were assessed using serial CT scans. Measures of pulmonary function, spine, and thoracic deformity were related to one another across groups. Results. The mean Cobb angle and distortion of the thoracic cage were significantly greater for the unilateral tethered rib group. There were no significant differences in total lung volume among the experimental groups. However, the left/right lung volume ratio was significantly different for the unilateral tethered rib group compared with the control group. Conclusions. Unilateral deformity of the spine or thorax induces both a scoliosis and thoracic cage deformity with asymmetric lung volumes.