Bilateral phrenic stimulation: a simple technique to assess diaphragmatic fatigue in humans

Transdiaphragmatic pressure (Pdi) and the rate of relaxation of the diaphragm (tau) were measured at functional residual capacity (FRC) in six normal seated subjects during single-twitch stimulation of both phrenic nerves. The latter were stimulated supramaximally with needle electrodes with square-wave impulses of 0.1-ms duration at 1 Hz before and after diaphragmatic fatigue produced by resistive loaded breathing. Constancy of chest wall configuration was achieved by monitoring the diameter of the abdomen and the rib cage with a respiratory inductive plethysmograph system. During control the peak Pdi generated during the phrenic stimulation amounted to 34.4 +/- 4.2 (SE) cmH2O and represented in each subject a fixed fraction (17%) of its maximal transdiaphragmatic pressure. After diaphragmatic fatigue the peak Pdi decreased by an average of 45%, amounting to 18.1 +/- 2.7 cmH2O 5 min after the fatigue run, and tau increased from 55.2 +/- 9 ms during control to 77 +/- 8 ms 5 min after the fatigue run. The decrease in peak Pdi and the increase in tau observed after the fatigue run persisted throughout the 30 min of the recovery period studied, the peak Pdi amounting to 18.4 +/- 2.8 and 18.9 +/- 3.3 cmH2O and tau to 81.3 +/- 5.7 and 88.7 +/- 10 ms at 15 and 30 min after the end of the fatigue run, respectively. It is concluded that diaphragmatic fatigue can be detected in man by bilateral phrenic stimulation with needle electrodes without any discomfort for the subject and that the decrease in diaphragmatic strength after fatigue is long lasting.     

Adverse effects of myasthenia gravis on rat phrenic diaphragm contractile performance.

Myasthenia gravis has variable effects on the respiratory system, ranging from no abnormalities to life-threatening respiratory failure. Studies characterized diaphragm muscle contractile performance in rat autoimmune myasthenia gravis. Rats received monoclonal antibody that recognizes acetylcholine receptor determinants (or inactive antibody); 3 days later, phrenic nerve and diaphragm were studied in vitro. Myasthenic rats segregated into two groups, those with normal vs. impaired limb muscle function when tested in intact animals ("mild" and "severe" myasthenic). Baseline diaphragm twitch force was reduced for both severe (P < 0.01) and mild (P < 0.05) myasthenic compared with control animals (twitch force: normal 1,352 +/- 140, mild myasthenic 672 +/- 99, severe myasthenic 687 +/- 74 g/cm2). However, only severe myasthenic diaphragm had impaired diaphragm endurance, based on significantly (P < 0.05) accelerated rate of peak force decline during the initial period of stimulation (0.02 + 0.02, 0.03 +/- 0.01, and 0.09 +/- 0.01%/pulse for normal, mild myasthenic, and severe myasthenic, respectively, during continuous stimulation) and intratrain fatigue (up to 30.5 +/- 7.4% intratrain force drop in severe myasthenic vs. none in normal and mild myasthenic, P < 0.01). Furthermore, compared with continuous stimulation, intermittent stimulation had a protective effect on force of severe myasthenic diaphragm (force after 2,000 pulses was 31.4 +/- 2.0% of initial during intermittent stimulation vs. 13.0 +/- 2.1% of initial during continuous stimulation, P < 0.01) but not on normal diaphragm. These data indicate that baseline force and fatigue may be affected to different extents by varying severity of myasthenia gravis and furthermore provide a mechanism by which alterations in breathing pattern may worsen respiratory muscle function in neuromuscular diseases.     

Effect of fatigue on maximal inspiratory pressure-flow capacity.

The inspiratory muscles can be fatigued by repetitive contractions characterized by high force (inspiratory resistive loads) or high velocities of shortening (hyperpnea). The effects of fatigue induced by inspiratory resistive loaded breathing (pressure tasks) or by eucapnic hyperpnea (flow tasks) on maximal inspiratory pressure-flow capacity and rib cage and diaphragm strength were examined in five healthy adult subjects. Tasks consisted of sustaining an assigned breathing frequency, duty cycle, and either a "pressure-time product" of esophageal pressure (for the pressure tasks) or peak inspiratory flow rate (for the flow tasks). Esophageal pressure was measured during maximal inspiratory efforts against a closed glottis (Pesmax), maximal transdiaphragmatic pressure was measured during open-glottis expulsive maneuvers (Pdimax), and maximal inspiratory flow (VImax) was measured during maximal inspiratory efforts with no added external resistance before and after fatiguing pressure and flow tasks. The reduction in Pesmax) with pressure fatigue (-25 +/- 7%) was significantly greater than the change in Pesmax with flow fatigue (-8 +/- 8%, P less than 0.01). In contrast, the reductions in Pdimax (-11 +/- 8%) and VImax (-16 +/- 3%) with flow fatigue were greater than the changes in Pdimax (-0.6 +/- 4%, P less than 0.05) or VImax (-3 +/- 4%, P less than 0.05) with pressure fatigue. We conclude that respiratory muscle performance is dependent not only on the presence of fatigue but whether fatigue was induced by pressure tasks or flow tasks. The specific impairment of Pesmax and not of Pdimax or flow with pressure fatigue may reflect selective fatigue of the rib cage muscles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects and mechanism of action of terbutaline on diaphragmatic contractility and fatigue

We studied the effects of intravenously administered terbutaline on diaphragmatic force and fatigue during electrical stimulation of the diaphragm in 17 anesthetized dogs. The diaphragm was stimulated indirectly through the phrenic nerves with electrodes placed around the fifth roots and directly with electrodes surgically implanted in the abdominal side of each hemidiaphragm. Transdiaphragmatic pressure (Pdi) during direct or indirect supramaximal 2-s stimulation applied over a frequency range of 10-100 Hz was measured with balloon catheters during tracheal occlusion at functional residual capacity. In seven dogs the administration of terbutaline (0.5 mg) had no effect on Pdi at any stimulation frequency applied directly or indirectly. The effect of terbutaline (0.5 mg) on diaphragmatic fatigue was then tested in 10 other dogs. Diaphragmatic fatigue was produced by continuous 20-Hz electrical supramaxial stimulation of the phrenic nerves during 30 min. At the end of the fatigue procedure Pdi decreased by 50 +/- 5 and 30 +/- 8% of control values at 10 and 100 Hz, respectively, for either direct or indirect stimulation. The decrease in Pdi for low frequencies of stimulation (10 and 20 Hz) lasted 100 +/- 18 min, whereas it lasted only 40 +/- 10 min for the high frequencies (50 and 100 Hz). When terbutaline (0.5 mg) was administered after the fatiguing procedure, Pdi increased within 15 min by 20 +/- 4% at 10 Hz and by 12 +/- 3% at 100 Hz for either direct or indirect stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory sensation and pattern of respiratory muscle activation during diaphragm fatigue

We have examined the relationship between respiratory effort sensation (modified Borg scale) and amplitude of the integrated surface electromyogram of the diaphragm (Edi, esophageal electrode), rib cage muscles (Erc), and sternomastoid muscle (Esm) during the development of diaphragm fatigue in five normal subjects. Three conditions were studied: run A: transdiaphragmatic pressure (Pdi), 65% Pdimax; esophageal pressure (Pes), 60% Pesmax; run B: Pdi, 50% Pdimax; Pes, 60% Pesmax; and run C: Pdi, 50% Pdimax; Pes, 20% Pesmax. During all runs there was a progressive rise in sensation, which was greater in runs A and B than in run C (P less than 0.05, analysis of variance). There was no difference between runs A and B. At the end of run C subjects did not report a maximal Borg score despite their inability to generate the target Pdi. The increase in sensory score with fatigue correlated highly with Esm/Esmmax and with Erc/Ercmax. There was no correlation between sensory score and Edi/Edimax. We conclude that the increase in respiratory effort sensation that accompanies diaphragm fatigue is not due to perception of increased diaphragmatic activation. It may reflect increased overall respiratory motor output not directed to the diaphragm.     

Critical oxygen tension in rat brain: a combined (31)P-NMR and EPR oximetry study

The relationship between cerebral interstitial oxygen tension (Pt(O(2))) and cellular energetics was investigated in mechanically ventilated, anesthetized rats during progressive acute hypoxia to determine whether there is a "critical" brain Pt(O(2)) for maintaining steady-state aerobic metabolism. Cerebral Pt(O(2)), measured by electron paramagnetic resonance oximetry, decreased proportionately to inspired oxygen fraction. (31)P-nuclear magnetic resonance measurements revealed no changes in P(i), phosphocreatine (PCr)/P(i) ratio, or intracellular pH when arterial blood oxygen tension (Pa(O(2))) was reduced from 145.1 +/- 11.7 to 56.5 +/- 4.4 mmHg (means +/- SE). Intracellular acidosis, a sharp rise in P(i), and a decline in the PCr/P(i) ratio developed when Pa(O(2)) was reduced further to 40.7 +/- 2.3 mmHg. The corresponding Pt(O(2)) values were 15.1 +/- 1.8, 8.8 +/- 0.4, and 6.8 +/- 0.3 mmHg. We conclude that over a range of decreasing oxygen tensions, cerebral oxidative metabolism is not sensitive to oxygen concentration. Oxygen becomes a regulatory substrate, however, when Pt(O(2)) is decreased to a critical level.     

Increased fatigue of isovelocity vs. isometric contractions of canine diaphragm

A comparison of fatigue as a loss of force with repeated contractions over time was performed in canine respiratory muscle by isometric (nonshortening) and isovelocity (shortening) contractions. In situ diaphragm muscle strips were attached to a linear ergometer and electrically stimulated (30 or 40 Hz) via the left phrenic nerve to produce either isometric (n = 12) or isovelocity (n = 12) contractions (1.5 s) from optimal muscle length (Lo = 8.8 cm). Similar velocities of shortening between isovelocity experiments [0.19 +/- 0.02 (SD) Lo/S] were produced by maximizing the mean power output (Wmax = 210 +/- 27 mW/cm2) that could be developed over 1.5 s when displacement was approximately 0.30 Lo. Initial peak isometric tension was 1.98 kg/cm2, whereas initial peak isovelocity tension was 1.84 kg/mc2 (P less than 0.01) or 93% of initial isometric tension. Fatigue trials of 5 min were conducted on muscles contracting at a constant duty cycle (0.43). At the end of the trials, peak isovelocity tension had fallen to 50% of initial isometric tension (P less than 0.01), whereas peak isometric tension had only fallen by 27%. These results indicate that muscle shortening during force production has a significant influence on diaphragm muscle fatigue. We conclude that the effects of shortening on fatigue must be considered in models of respiratory muscle function, because these muscles typically shorten during breathing.     

Effect of abdominal compression on maximum transdiaphragmatic pressure

Transdiaphragmatic pressure (Pdi) is lower during maximum inspiratory effort with the diaphragm alone than when maximum inspiratory and expulsive efforts are combined. The increase in Pdi with expulsive effort has been attributed to increased neural activation of the diaphragm. Alternatively, the increase could be due to stretching of the contracted diaphragm. If this were so, Pdi measured during a combined maximum effort would overestimate the capacity of the diaphragm to generate inspiratory force. This study determined the likely contribution of stretching of the contracted diaphragm to estimates of maximum Pdi (Pdimax) obtained during combined inspiratory and expulsive effort. Three healthy trained subjects were studied standing. Diaphragmatic Mueller maneuvers were performed at functional residual capacity and sustained during subsequent abdominal compression by either abdominal muscle expulsive effort or externally applied pressure. Measurements were made of changes in abdominal (Pab) and pleural (Ppl) pressure, Pdi, rib cage and abdominal dimensions and respiratory electromyograms. Three reproducible performances of each maneuver from each subject were analyzed. When expulsive effort was added to maximum diaphragmatic inspiratory effort, Pdimax increased from 86 +/- 12 to 148 +/- 14 (SD) cmH2O within the 1st s and was 128 +/- 14 cmH2O 2 s later. When external compression was added to maximum diaphragmatic inspiratory effort, Pdimax increased from 87 +/- 16 to 171 +/- 19 cmH2O within the 1st s and was 152 +/- 16 cmH2O 2 s later.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preferential fatigue of the rib cage muscles during inspiratory resistive loaded ventilation

Because the inspiratory rib cage muscles are recruited during inspiratory resistive loaded breathing, we hypothesized that such loading would preferentially fatigue the rib cage muscles. We measured the pressure developed by the inspiratory rib cage muscles during maximal static inspiratory maneuvers (Pinsp) and the pressure developed by the diaphragm during maximal static open-glottis expulsive maneuvers (Pdimax) in four human subjects, both before and after fatigue induced by an inspiratory resistive loaded breathing task. Tasks consisted of maintaining a target esophageal pressure, breathing frequency, and duty cycle for 3-5 min, after which the subjects maintained the highest esophageal pressure possible for an additional 5 min. After loading, Pinsp decreased in all subjects [control, -128 +/- 14 (SD) cmH2O; with fatigue, -102 +/- 18 cmH2O; P less than 0.001, paired t test]. Pdimax was unchanged (control, -192 +/- 23 cmH2O; fatigue, -195 +/- 27 cmH2O). These data suggest that 1) inability to sustain the target during loading resulted from fatigue of the inspiratory rib cage muscles, not diaphragm, and 2) simultaneous measurement of Pinsp and Pdimax may be useful in partitioning muscle fatigue into rib cage and diaphragmatic components.     

Cardiovascular failure and apnea in shock

A model of shock was developed in anesthetized dogs by limiting venous return with a balloon inflated in the right atrium. The change in ventilation (VE) in response to a sustained decrease in arterial pressure (Pa) to 50-60 Torr was studied by recording transdiaphragmatic pressure (Pdi) and diaphragm (Edi) and parasternal intercostal (Eic) electrical activity. Four dogs died of cardiac arrest after 20-60 min. In 11 dogs, VE, after an initial increase, decreased progressively until apnea occurred after 103 +/- 24 min, after 60% reductions in breathing frequency, Pdi, and Eic and a 30% fall in Edi. No decrease in diaphragm contractility was found in response to artificial phrenic nerve stimulation. The cardiocirculatory function deteriorated during shock until it became irreversible at apneic time. No recovery from apnea occurred without a recovery of Pa. We conclude that the fall in VE and ensuing apnea in this model resulted from a decrease in central respiratory neural output associated with a progressive deterioration of the cardiocirculatory function.     

Diaphragmatic function during hypoxemia: neonatal and developmental aspects

The effect of acute hypoxemia on diaphragmatic force output was studied in five young (age 4-8 days, wt 1.3-2.2 kg) and five older (age 16-19 days, wt 2.8-3.3 kg), anesthetized, spontaneously breathing piglets. Diaphragmatic force output was assessed by analysis of the transdiaphragmatic pressure (Pdi) generated during an occluded inspiratory effort, at end-expiratory lung volume, triggered by supramaximal transvenous stimulation of both phrenic nerves at frequencies of 20, 30, 50, and 100 Hz. During pressure measurements, the piglets were fitted with a rigid plaster cast covering the abdomen and lower third of the chest to ensure a consistency in diaphragmatic shortening during phrenic nerve stimulation. Pdi was measured under base-line conditions [inspired O2 fractional concentration (FIO2) = 0.50] and after 10 min of hypoxemia induced by breathing 12-14% FIO2. Pdi was significantly less than base line during acute hypoxemia at all frequencies of stimulation in both young and older piglets. The decline in the older piglets' Pdi during hypoxemia was significantly greater than that seen in younger piglets. We conclude that acute hypoxemia impairs the capacity of the developing piglet diaphragm to generate force. Furthermore, our data suggest that the young piglet is more resistant to the depressant effects of hypoxemia when compared to its older counterpart.     

Threshold effects of respiratory muscle work on limb vascular resistance

The purpose of this study was to determine whether the human diaphragm, like limb muscle, has a threshold of force output at which a metaboreflex is activated causing systemic vasoconstriction. We used Doppler ultrasound techniques to quantify leg blood flow (Q(L)) and utilized the changes in mouth twitch pressure (DeltaP(M)T) in response to bilateral phrenic nerve stimulation to quantify the onset of diaphragm fatigue. Six healthy male subjects performed four randomly assigned trials of identical duration (8 +/- 2 min) and breathing pattern [20 breaths/min and time spent on inspiration during the duty cycle (time spent on inspiration/total time of one breathing cycle) was 0.4] during which they inspired primarily with the diaphragm. For trials 1-3, inspiratory resistance and effort was gradually increased [30, 40, and 50% maximal inspiratory pressure (MIP)], diaphragm fatigue did not occur, and Q(L), limb vascular resistance (LVR), and mean arterial pressure remained unchanged from control (P > 0.05). The fourth trial utilized the same breathing pattern with 60% MIP and caused diaphragm fatigue, as shown by a 30 +/- 12% reduction in P(M)T with bilateral phrenic nerve stimulation. During the fatigue trial, Q(L) and LVR were unchanged from baseline at minute 1, but LVR rose 36% and Q(L) fell 25% at minute 2 and by 52% and 30%, respectively, during the final minutes of the trial. Both LVR and Q(L) returned to control within 30 s of recovery. In summary, voluntary increases in inspiratory muscle effort, in the absence of fatigue, had no effect on LVR and Q(L), whereas fatiguing the diaphragm elicited time-dependent increases in LVR and decreases in Q(L). We attribute the limb vasoconstriction to a metaboreflex originating in the diaphragm, which reaches its threshold for activation during fatiguing contractions.     

Human muscle fatigue after glycogen depletion: a 31P magnetic resonance study.

To differentiate the effects of high energy phosphates, pH, and [H2PO4-] on skeletal muscle fatigue, intracellular acidosis during handgrip exercise was attenuated by prolonged submaximal exercise. Healthy human subjects (n = 6) performed 5-min bouts of maximal rhythmic handgrip (RHG) before (CONTROL) and after prolonged (60-min) handgrip exercise (ATTEN-EX) designed to attenuate lactic acidosis in active muscle by partially depleting muscle glycogen. Concentrations of free intracellular phosphocreatine ([PCr]), adenosine triphosphate ([ATP]), and orthophosphate ([P(i)]) and pH were measured by 31P nuclear magnetic resonance spectroscopy and used to calculate adenosine diphosphate [ADP], [H2PO4-], and [HPO4(2-)]. Handgrip force output was measured with a dynamometer, and fatigue was determined by loss of maximal contractile force. After ATTEN-EX, the normal exercise-induced muscle acidosis was reduced. At peak CONTROL RHG, pH fell to 6.3 +/- 0.1 (SE) and muscle fatigue was correlated with [PCr] (r = 0.83), [P(i)] (r = 0.82), and [H2PO4-] (r = 0.81); [ADP] was 22.0 +/- 5.7 mumol/kg. At peak RHG after ATTEN-EX, pH was 6.9 +/- 0.1 and [ADP] was 116.1 +/- 18.2 mumol/kg, although [PCr] and [P(i)] were not different from CONTROL RHG (P greater than 0.05). After ATTEN-EX, fatigue correlated most closely with [ADP] (r = 0.84). The data indicate that skeletal muscle fatigue 1) is multifactorial, 2) can occur without decreased pH or increased [H2PO4-], and 3) is correlated with [ADP] after exercise-induced glycogen depletion.     

Naloxone alters the early response to an inspiratory flow-resistive load

In a previous study in unanesthetized goats, we demonstrated that cerebrospinal fluid levels of beta-endorphin were significantly elevated after 2.5 h of inspiratory flow-resistive loading. Naloxone (NLX) (0.1 mg/kg) administration partially and transiently reversed the tidal volume depression seen during loading. In the current study, we tested the hypothesis that endogenous opioid elaboration results in depression of respiratory output to the diaphragm. In six studies of five unanesthetized goats, tidal volume (VT), transdiaphragmatic pressure (Pdi), diaphragmatic electromyogram (EMGdi), and arterial blood gases were monitored. A continuous NLX (0.1 mg/kg) or saline (SAL) infusion was begun 5 min before an inspiratory flow-resistive load of 120 cmH2O.l-1.s was imposed. Our data show that the depression of VT induced by the load was prevented by NLX as early as 15 min and persisted for 2 h. At 2 h, Pdi was still 294 +/- 45% of the base-line value compared with 217 +/- 35% during SAL. There was no difference in EMGdi between the groups at any time. However, the augmentation of Pdi was associated with a greater increase in end-expiratory gastric pressure in the NLX group. We conclude that the reduction in VT and Pdi associated with endogenous opioid elaboration is not mediated by a decrease in neural output to the diaphragm, but it appears to be the result of a decrease in respiratory output to the abdominal muscles.     

Changes in rate of relaxation of sniffs with diaphragmatic fatigue in humans

The rate of relaxation of the diaphragm after stimulated (4 subjects) and voluntary (8 subjects) contractions was compared in normal young men. Stimulated contractions were induced by supramaximal unilateral phrenic nerve stimulation and voluntary contractions by short, sharp sniffs of varying tensions against an occluded airway. The rate of relaxation of the diaphragm was calculated from the rate of decline of transdiaphragmatic pressure (Pdi). In both conditions the maximum relaxation rate (MRR) was proportional to the peak transdiaphragmatic pressure (Pdi), whereas the time constant (tau) of the later exponential decline in Pdi was independent of Pdi. The mean +/- SE rate constant of relaxation (MRR/Pdi) was 0.0078 +/- 0.0002 ms-1 and the mean tau was 57 +/- 3.8 ms for stimulated contractions. The rate of relaxation after sniffs was not different, and it was not affected by either the lung volume at which occluded sniffs were performed (in the range of residual volume to functional residual capacity + 1 liter) or by the relative contribution gastric pressure made to Pdi. After diaphragmatic fatigue was induced by inspiring against a high alinear resistance there was a decrease in relaxation rate. In the 1st min postfatigue MRR/Pdi decreased (0.0063 +/- 0.0003 ms-1; P less than 0.005) and tau increased (83 +/- 5 ms; P less than 0.005). Both values returned to prefatigue levels within 5 min of the end of the studies. We conclude that the sniff may prove to be clinically useful in the detection of diaphragmatic fatigue.     

Increased fatigue resistance of respiratory muscles during exercise after respiratory muscle endurance training

Respiratory muscle fatigue develops during exhaustive exercise and can limit exercise performance. Respiratory muscle training, in turn, can increase exercise performance. We investigated whether respiratory muscle endurance training (RMT) reduces exercise-induced inspiratory and expiratory muscle fatigue. Twenty-one healthy, male volunteers performed twenty 30-min sessions of either normocapnic hyperpnoea (n = 13) or sham training (CON, n = 8) over 4-5 wk. Before and after training, subjects performed a constant-load cycling test at 85% maximal power output to exhaustion (PRE(EXH), POST(EXH)). A further posttraining test was stopped at the pretraining duration (POST(ISO)) i.e., isotime. Before and after cycling, transdiaphragmatic pressure was measured during cervical magnetic stimulation to assess diaphragm contractility, and gastric pressure was measured during thoracic magnetic stimulation to assess abdominal muscle contractility. Overall, RMT did not reduce respiratory muscle fatigue. However, in subjects who developed >10% of diaphragm or abdominal muscle fatigue in PRE(EXH), fatigue was significantly reduced after RMT in POST(ISO) (inspiratory: -17 +/- 6% vs. -9 +/- 10%, P = 0.038, n = 9; abdominal: -19 +/- 10% vs. -11 +/- 11%, P = 0.038, n = 9), while sham training had no significant effect. Similarly, cycling endurance in POST(EXH) did not improve after RMT (P = 0.071), while a significant improvement was seen in the subgroup with >10% of diaphragm fatigue after PRE(EXH) (P = 0.017), but not in the sham training group (P = 0.674). However, changes in cycling endurance did not correlate with changes in respiratory muscle fatigue. In conclusion, RMT decreased the development of respiratory muscle fatigue during intensive exercise, but this change did not seem to improve cycling endurance.     

Diaphragmatic function during hypercapnia: neonatal and developmental aspects

The effect of acute hypercapnia on diaphragmatic force output was studied in 6 young (4-8 days) and 6 older (16-20 days) anesthetized, spontaneously breathing piglets. Diaphragmatic force output was assessed by analysis of the transdiaphragmatic pressure (Pdi) generated during phrenic nerve stimulation. Pdi was measured under base-line conditions (50% O2-50% N2) and after 10 min of hypercapnia induced by breathing 5, 10, or 15% CO2 balanced with N2 and 50% O2. Pdi was significantly less than base line during the 10 and 15% hypercapnic conditions in the young (P less than 0.05) but not the older piglets. End-expiratory lung volume was noted to decrease during 15% CO2 hypercapnia. Force output augmentation occurred at this lower end-expiratory lung volume and was significantly greater in the older piglet compared with its younger counterpart (P less than 0.05). When the effects of lung volume on Pdi were corrected for, there was no age-related difference in the response to 15% CO2 hypercapnia. We conclude that severe hypercapnia has a depressant effect on diaphragmatic force output in both young and older piglets, and a differential augmentation in diaphragmatic force-output gain occurs at lower end-expiratory lung volume between young and older piglets, with the greater output occurring in the more mature animal.     

Respiratory muscle blood flows during physiological and chemical hyperpnea in the rat.

Whether the diaphragm retains a vasodilator reserve at maximal exercise is controversial. To address this issue, we measured respiratory and hindlimb muscle blood flows and vascular conductances using radiolabeled microspheres in rats running at their maximal attainable treadmill speed (96 +/- 5 m/min; range 71-116 m/min) and at rest while breathing either room air or 10% O(2)-8% CO(2) (balance N(2)). All hindlimb and respiratory muscle blood flows measured increased during exercise (P < 0.001), whereas increases in blood flow while breathing 10% O(2)-8% CO(2) were restricted to the diaphragm only. During exercise, muscle blood flow increased up to 18-fold above rest values, with the greatest mass specific flows (in ml. min(-1). 100 g(-1)) found in the vastus intermedius (680 +/- 44), red vastus lateralis (536 +/- 18), red gastrocnemius (565 +/- 47), and red tibialis anterior (602 +/- 44). During exercise, blood flow was higher (P < 0.05) in the costal diaphragm (395 +/- 31 ml. min(-1). 100 g(-1)) than in the crural diaphragm (286 +/- 17 ml. min(-1). 100 g(-1)). During hypoxia+hypercapnia, blood flows in both the costal and crural diaphragms (550 +/- 70 and 423 +/- 53 ml. min(-1). 100 g(-1), respectively) were elevated (P < 0.05) above those found during maximal exercise. These data demonstrate that there is a substantial functional vasodilator reserve in the rat diaphragm at maximal exercise and that hypoxia + hypercapnia-induced hyperpnea is necessary to elevate diaphragm blood flow to a level commensurate with its high oxidative capacity.     

Effects of inspiratory flow on diaphragmatic motor output in normal subjects.

Increasing inspiratory flow (V) has been shown to shorten neural inspiratory time (TI(n)) in normal subjects breathing on a mechanical ventilator, but the effect of V on respiratory motor output before inspiratory termination has not previously been studied in humans. While breathing spontaneously on a mechanical ventilator, eight normal subjects were intermittently exposed to 200-ms-duration positive pressure pulses of different amplitudes at the onset of inspiration. Based on the increase in V above control breaths (DeltaV), trials were grouped into small, medium, and large groups (mean DeltaV: 0.51, 1.11, and 1.65 l/s, respectively). We measured TI(n), transdiaphragmatic pressure (Pdi), and electrical activity (electromyogram) of the diaphragm (EMGdi). Transient increases in V caused shortening of TI(n) from 1.34 to 1.10 (not significant), 1.55 to 1.11 (P < 0.005), and 1.58 to 1.17 s (P < 0. 005) in the small, medium, and large DeltaV groups, respectively. EMGdi measured at end TI(n) of the pulse breaths was 131 (P < 0.05), 142, and 155% (P < 0.05) of the EMGdi of the control breaths at an identical time point in the small, medium, and large trials, respectively. The latency of the excitation was 126 +/- 42 (SD) ms, consistent with a reflex effect. Increasing V had two countervailing effects on Pdi: 1) a depressant mechanical effect due primarily to the force-length (11.2 cmH(2)O/l) relation of the diaphragm, and 2) an increase in diaphragm activation. For the eight subjects, mean peak Pdi did not change significantly, but there was significant intersubject variability, reflecting variability in the strength of the excitation reflex. We conclude that increasing inspiratory V causes a graded facilitation of EMGdi, which serves to counteract the negative effect of the force-length relation on Pdi.     

Diaphragmatic contractility after upper abdominal surgery

Postoperative dysfunction of the diaphragm has been reported after upper abdominal surgery. This study was designed to determine whether an impairment in diaphragmatic contractility was involved in the genesis of the diaphragmatic dysfunction observed after upper abdominal surgery. Five patients undergoing upper abdominal surgery were studied. The following measurements were performed before and 4 h after surgery: vital capacity (VC), functional residual capacity (FRC), and forced expiratory volume in 1 s. Diaphragmatic function was also assessed using the ratio of changes in gastric pressure (delta Pga) over changes in transdiaphragmatic pressure (delta Pdi). Finally contractility of the diaphragm was determined by measuring the change in delta Pdi generated during bilateral electrical stimulation of the phrenic nerves (Pdi stim). Diaphragmatic dysfunction occurred in all the patients after upper abdominal surgery as assessed by a marked decrease in delta Pga/delta Pdi from 0.480 +/- 0.040 to -0.097 +/- 0.152 (P less than 0.01) 4 h after surgery compared with preoperative values. VC also markedly decreased after upper abdominal surgery from 3,900 +/- 630 to 2,060 +/- 520 ml (P less than 0.01) 4 h after surgery. In contrast, no change in FRC and Pdi stim was observed 4 h after surgery. In contrast, no change in FRC and Pdi stim was observed 4 h after upper abdominal surgery compared with the preoperative values. We conclude that contractility of the diaphragm is not altered after upper abdominal surgery, and diaphragmatic dysfunction is secondary to other mechanisms such as possible reflexes arising from the periphery (chest wall and/or peritoneum), which could inhibit the phrenic nerve output.