Stewart B. Gottfried

Proportional assist ventilation may improve exercise performance in severe chronic obstructive pulmonary disease.

PURPOSE Exercise tolerance is impaired in chronic obstructive pulmonary disease (COPD), in part because of a reduction in ventilatory capacity and excessive dyspnea experienced. The authors reasoned that proportional assist ventilation (PAV), a ventilator mode in which the level of support varies proportionately with patient effort, could be used during exercise to assist ventilation. The purpose of this study was to evaluate the efficacy of PAV to improve exercise endurance and related physiologic parameters in COPD. METHODS In 8 patients (age = 62.8 years mean, +/- 6.9 standard deviation) with severe COPD (forced expiratory volume in 1 second = 0.70 +/- 0.21 L) flow, volume, dyspnea, leg fatigue, arterial blood gases, and gas exchange were measured during constant workrate exercise (37 +/- 18 watts; i.e., 80% previously determined maximum oxygen consumption). Crossover exercise trials were performed in random order: while spontaneously breathing through the experimental circuit without assistance (control trial) and with PAV (using 9.8 +/- 2.1 cm H2O/L and 3.3 +/- 1.0 cm H2O/L/sec of volume assist and flow assist, respectively). RESULTS The application of PAV during exercise was well tolerated by each subject. Compared with the control measurement at equivalent time during exercise, PAV improved breathing pattern and arterial blood gases while dyspnea was reduced. Consequently, there was a significant increase in exercise duration with PAV (323 +/- 245 seconds during the control trial compared with 507 +/- 334 seconds with PAV, P = 0.02). CONCLUSIONS Proportional assist ventilation can improve performance during constant workrate exercise in severe COPD.

Regulation of myosin heavy chain gene expression after short-term diaphragm inactivation

Although prolonged diaphragm denervation (DNV) produces myofiber atrophy and a loss of type I myosin heavy chain (MHC) expression, short-term DNV leads to significant diaphragm hypertrophy. The purpose of this study was to explore the regulation of MHC isoform expression and muscle remodeling during DNV hypertrophy of the diaphragm. Both unilateral and bilateral DNV led to similar changes, with a significant increase in total RNA content and muscle mass but no change in dry-to-wet weight ratio. Sarcomere number was also increased in diaphragm myofibers after DNV ( approximately 20%), suggesting an adaptive response to muscle stretch. There was hypertrophy of type I myofibers and increased coexpression of type I and type II MHCs within single myofibers by immunocytochemistry as well as increased type I MHC (25-46%) and decreased type IIb MHC (14-39%) by SDS-PAGE. Contractility parameters were also consistent with a type II-to-type I MHC phenotype transformation. Importantly, DNV-induced modulation of MHC isoform mRNA transcript levels did not correspond to changes in their cognate proteins, suggesting a major degree of posttranscriptional control. We conclude that DNV hypertrophy of the diaphragm is associated with reciprocal changes in type I and type II MHC isoforms that are directly opposed to the type I-to-type II MHC phenotype transformation reported in the diaphragm DNV atrophy model. Furthermore, in contradistinction to most hypertrophy models, control of MHC gene expression and myofibrillar remodeling after short-term DNV appears to entail major involvement of posttranscriptional regulatory mechanisms.Although prolonged diaphragm denervation (DNV) produces myofiber atrophy and a loss of type I myosin heavy chain (MHC) expression, short-term DNV leads to significant diaphragm hypertrophy. The purpose of this study was to explore the regulation of MHC isoform expression and muscle remodeling during DNV hypertrophy of the diaphragm. Both unilateral and bilateral DNV led to similar changes, with a significant increase in total RNA content and muscle mass but no change in dry-to-wet weight ratio. Sarcomere number was also increased in diaphragm myofibers after DNV (∼20%), suggesting an adaptive response to muscle stretch. There was hypertrophy of type I myofibers and increased coexpression of type I and type II MHCs within single myofibers by immunocytochemistry as well as increased type I MHC (25-46%) and decreased type IIb MHC (14-39%) by SDS-PAGE. Contractility parameters were also consistent with a type II-to-type I MHC phenotype transformation. Importantly, DNV-induced modulation of MHC isoform mRNA transcript levels did not correspond to changes in their cognate proteins, suggesting a major degree of posttranscriptional control. We conclude that DNV hypertrophy of the diaphragm is associated with reciprocal changes in type I and type II MHC isoforms that are directly opposed to the type I-to-type II MHC phenotype transformation reported in the diaphragm DNV atrophy model. Furthermore, in contradistinction to most hypertrophy models, control of MHC gene expression and myofibrillar remodeling after short-term DNV appears to entail major involvement of posttranscriptional regulatory mechanisms.

Effects of sodium cyanide and nicotine on upper airway resistance in anesthetized dogs

The purpose of this study was to determine whether pharmacologic interventions which increase respiratory drive could also reduce flow resistance in the upper airway. Studies were performed in twelve anesthetized supine dogs. In six animals breathing spontaneously through the intact upper airway, intravenous administration of respiratory stimulants (sodium cyanide and nicotine) produced a dose-related decrease in upper airway. In nine animals, upper airway resistance was measured across the isolated upper airway. The stimulants produced a dose-related decrease in upper airway resistance. In both preparations inspiratory resistance fell at lower doses than expiratory resistance. Eventually a dose could be given which resulted in comparable, minimal values of resistance during both inspiration and expiration. Mechanisms for changes in resistance were clarified using lateral radiographs of the neck and transbronchoscopic views of the upper airway. Pharmacologic challenge resulted in a change in the route of airflow (from nose only to nose-and-mouth breathing) as well as a change in caliber of the airway at the level of the naso-pharynx and hyoid apparatus. In anesthetized dogs, respiratory stimulants will decrease upper airway resistance by increasing activation of upper airway muscles which may enlarge the airway, change the route of flow, and thus overcoming collapsing forces produced by increased chest wall muscle activation.

Repetitive magnetic stimulation of the phrenic nerves for diaphragm conditioning: a normative study of feasibility and optimal settings

Electrical stimulation can enhance muscle function. We applied repetitive cervical magnetic phrenic stimulation (rCMS) to induce diaphragm contractions in 7 healthy subjects (800 ms trains; transdiaphragmatic pressure (Pdi) measurements; tolerance ratings). Each rCMS train produced a sustained diaphragm contraction. Sixty-five percent of the maximal available output at 15 Hz proved the best compromise between Pdi and discomfort with nonfatiguing contractions. rCMS appears feasible and should be investigated for diaphragm conditioning in appropriate clinical populations.