Maximal Transdiaphragmatic Pressure Research Articles

Chloroquine Treatment Causes Diaphragm Muscle Denervation

Chloroquine (CQ), an antimalarial agent, inhibits autophagy by preventing the autophagosome from fusing with the lysosome, emulating the effects of aging. Autophagy is a cellular digestion process that contributes to homeostasis through degradation of cytoplasmic structures in the cell. Aging effects include autophagy impairment, leading to the accumulation of altered proteins and organelles, thus contributing to subsequent cell damage and death. Previous studies in phrenic motor neurons show an age-dependent increase in key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. In addition, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, suggesting a neuromuscular effect in aging. We hypothesized that treatment with the autophagy inhibitor chloroquine alters pre-synaptic morphology and increases the proportion of denervated diaphragm muscle fibers. Adult male and female 6-month C57BL6 mice were used to examine diaphragm muscle neuromuscular junction (NMJ) morphology and denervation. The autophagy inhibitor chloroquine (10 mg/kg/d) or vehicle was administered via daily intraperitoneal injections for 7 days. Confocal microscopy was used to compare pre- and post-synaptic morphology and denervation. There was evidence of a decrease in pre-synaptic volume without evidence of post-synaptic volume changes in chloroquine treated mice compared to vehicle. As expected, vehicle treated mice did not show evidence of substantial denervation. In contrast, chloroquine treated mice showed an increased proportion of denervated NMJs. The morphological changes observed were similar to those previously reported in the diaphragm muscles of 24-month-old mice. These findings reveal the effects at the neuromuscular junction of inhibiting autophagy and implicate impaired autophagy as a mechanism of aging effects. Supported by NIH R01 AG057052 and Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Flow-resistive loading and diaphragmatic muscle function in term and preterm infants.

We aimed to assess diaphragmatic function in term and preterm infants with and without history of bronchopulmonary dysplasia (BPD), before and after the application of inspiratory flow resistive loading. Forty infants of a median (range) gestational age of 34 (25-40) weeks were studied. BPD was defined as supplemental oxygen requirement for >28 days of life. Seventeen infants were term, 17 preterm without history of BPD, and six preterm with a history of BPD. The diaphragmatic pressure-time index (PTIdi) was calculated as the mean to maximum trans-diaphragmatic pressure ratio times the inspiratory duty cycle. The PTIdi was calculated before and after the application of an inspiratory-flow resistance for 120 s. Airflow was measured by a pneumotachograph and the transdiaphragmatic pressure by a dual pressure catheter. The median (interquartile range [IQR]) pre-resistance PTIdi was higher in preterm infants without BPD (0.064 [0.050-0.077]) compared with term infants (0.052 [0.044-0.062], p = .029) and was higher in preterm infants with BPD (0.119 [0.086-0.132]) compared with a subgroup of preterm infants without BPD (0.062 [0.056-0.072], p = .004). The median (IQR) postresistance PTIdi was higher in preterm infants without BPD (0.101 [0.084-0.132]) compared with term infants (0.067 [0.055-0.083], p < .001) and was higher in preterm infants with BPD [0.201(0.172-0.272)] compared with the preterm subgroup without BPD (0.091 [0.081-0.108],p = .004). The median (IQR) percentage change of the PTIdi after the application of the resistance was higher in preterm infants without BPD (65 [51-92] %) compared with term infants (34 [20-39] %, p < .001). Preterm infants, especially those recovering from BPD, are at increased risk of diaphragmatic muscle fatigue under conditions of increased inspiratory loading.

Diaphragmatic muscle function in term and preterm infants

We aimed to assess the determinants of diaphragmatic function in term and preterm infants. 149 infants (56 term; 93 preterm, of whom 14 were diagnosed with bronchopulmonary dysplasia—BPD) were studied before discharge. Diaphragmatic function was assessed by measurement of the maximum transdiaphragmatic pressure (Pdimax)—a measure of diaphragmatic strength, and the pressure–time index of the diaphragm (PTIdi)—a measure of the load-to-capacity ratio of the diaphragm. The Pdimax was higher in term than preterm infants without BPD (90.1 ± 16.3 vs 81.1 ± 11.8 cmH2O; P = 0.001). Term-born infants also had lower PTIdi compared to preterms without BPD (0.052 ± 0.014 vs 0.060 ± 0.017; P = 0.006). In term and preterm infants without BPD, GA was the most significant predictor of Pdimax and PTIdi, independently of the duration of mechanical ventilation and oxygen support. In infants with GA < 32 weeks (n = 30), the Pdimax was higher in infants without BPD compared to those with BPD (76.1 ± 11.1 vs 65.2 ± 11.9 cmH2O; P = 0.015). Preterms without BPD also had lower PTIdi compared to those with BPD (0.069 ± 0.016 vs 0.109 ± 0.017; P < 0.001). In this subgroup, GA was the only significant independent determinant of Pdimax, while BPD and the GA were significant determinants of the PTIdi. Conclusions: Preterm infants present lower diaphragmatic strength and impaired ability to sustain the generated force over time, which renders them prone to diaphragmatic fatigue. In very preterm infants, BPD may further aggravate diaphragmatic function.What is Known:• The diaphragm of preterm infants has limited capacity to undertake the work of breathing effectively.• The maximum transdiaphragmatic pressure (a measure of diaphragmatic strength) and the pressure–time index of the diaphragm (a measure of the load-to-capacity ratio of the muscle) have not been extensively assessed in small infants.What is New:• Preterm infants have lower diaphragmatic strength and impaired ability to sustain the generated force over time, which renders them prone to diaphragmatic fatigue.• In very preterm infants, bronchopulmonary dysplasia may further impair diaphragmatic function.

Voluntary activation of the diaphragm after inspiratory pressure threshold loading.

After a bout of isolated inspiratory work, such as inspiratory pressure threshold loading (IPTL), the human diaphragm can exhibit a reversible loss in contractile function, as evidenced by a decrease in transdiaphragmatic twitch pressure (PDI,TW ). Whether or not diaphragm fatigability after IPTL is affected by neural mechanisms, measured through voluntary activation of the diaphragm (D-VA) in addition to contractile mechanisms, is unknown. It is also unknown if changes in D-VA are similar between sexes given observed differences in diaphragm fatigability between males and females. We sought to determine whether D-VA decreases after IPTL and whether this was different between sexes. Healthy females (n=11) and males (n=10) completed an IPTL task with an inspired duty cycle of 0.7 and targeting an intensity of 60% maximal transdiaphragmatic pressure until task failure. PDI,TW and D-VA were measured using cervical magnetic stimulation of the phrenic nerves in combination with maximal inspiratory pressure maneuvers. At task failure, PDI,TW decreased to a lesser degree in females vs. males (87 ± 15 vs. 73 ± 12% baseline, respectively, p=0.016). D-VA decreased after IPTL but was not different between females and males (91 ± 8 vs. 88 ± 10% baseline, respectively, p=0.432). When all participants were pooled together, the decrease in PDI,TW correlated with both the total cumulative diaphragm pressure generation (R2 =0.43; p=0.021) and the time to task failure (TTF, R2 = 0.40; p = 0.30) whereas the decrease in D-VA correlated only with TTF (R2 =0.24; p=0.041). Our results suggest that neural mechanisms can contribute to diaphragm fatigability, and this contribution is similar between females and males following IPTL.

Aging and TrkB Signaling Effects on Autophagy Flux in Cervical Spinal Cord

Autophagy maintains cellular homeostasis by the elimination of damaged proteins or organelles. Our overarching hypothesis is that autophagy contributes to aging-related neuromuscular dysfunction. The mechanisms regulating autophagy flux are promising therapeutic targets to mitigate the effects of neuromuscular dysfunction across conditions such as aging. In previous studies, we found that autophagy flux is reduced in early old age (18-month old mice; 90% survival), with progressive autophagosome accumulation in old age evident by increased LC3 and p62 protein expression in cervical motor neurons (24-month old mice; 75% survival). Neurotrophins acting through the tropomyosin-related kinase receptor subtype B (TrkB) are critical to the maintenance of neuromuscular function including neuromuscular transmission in the diaphragm muscle and generation of maximal transdiaphragmatic pressure (Pdi), both in young and aged mice. Specifically, inhibition of TrkB signaling impairs maximal Pdi generation whereas activation of TrkB signaling blunts failure in neuromuscular transmission. We hypothesize that inhibiting TrkB kinase activity reduces autophagy flux resulting in increased LC3 and p62 expression, like the aging effects at phrenic motor neurons. TrkBF616A mice at 18- and 24- months of age, harboring a mutation that induces susceptibility to 1NMPP1-mediated TrkB kinase inhibition, were randomized to receive 1-week treatment with vehicle or 1NMPP1 (n=6 per age and treatment group). Protein expression of the autophagy markers LC3 and p62 in cervical spinal cord (CSC) segments C2-C6 was analyzed by Western blotting. There was a significant effect on LC3 and p62 expression of age, but not of 1NMPP1 treatment, and no age*treatment interaction. LC3B expression increased by ~50% and p62 expression increased by ~30% in 24 month-old compared to 18 month-old mice. These results are consistent with previous reports that there is an aging-related impairment of autophagy and accumulation of autophagosomes; however, inhibiting TrkB kinase activity does not modulate autophagy in these age groups. Understanding the role of TrkB signaling in mediating changes in autophagy and age-related neuromuscular dysfunction will be important in advancing potential therapeutic applications of TrkB agonists.

Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation.

Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in TrkBF616A mice worsens neuromuscular transmission failure (NMTF). We hypothesized that acute inhibition of TrkB kinase activity will impair the ability of the diaphragm muscle to produce maximal transdiaphragmatic pressure (Pdi) without impacting the ability to generate forces associated with ventilation, consistent with the greater susceptibility to NMTF in motor units responsible for higher-force nonventilatory behaviors. Adult male and female TrkBF616A mice were injected with 1NMPP1 (n = 8) or vehicle (DMSO; n = 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs") and during maximal activation elicited by bilateral phrenic nerve stimulation. In the vehicle-treated group, Pdi increased from ~10 cmH2O during eupnea and hypoxia/hypercapnia, to ~35 cmH2O during sighs and tracheal occlusion, and to ~65 cm H2O during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (~30% reduction; P < 0.05). This reduction in maximal Pdi is generally similar to the worsening of NMTF previously reported with TrkB kinase inhibition in rodents. Accordingly, impaired TrkB signaling limits the range of motor behaviors accomplished by the diaphragm muscle and may contribute to neuromuscular dysfunction, primarily by impacting fatigable, higher force-generating motor units.NEW & NOTEWORTHY TrkB signaling plays an important role in maintaining neuromuscular function in the diaphragm muscle and may be necessary to accomplish the various motor behaviors ranging from ventilation to expulsive, behaviors requiring near-maximal forces. This study shows that inhibition of TrkB kinase activity impairs maximal pressure generation by the diaphragm muscle, but the ability to generate the lower pressures required for ventilatory behaviors is not impacted.

A growing animal model for neonatal repair of large diaphragmatic defects to evaluate patch function and outcome.

ObjectivesWe aimed to develop a more representative model for neonatal congenital diaphragmatic hernia repair in a large animal model, by creating a large defect in a fast-growing pup, using functional pulmonary and diaphragmatic read outs.BackgroundGrafts are increasingly used to repair congenital diaphragmatic hernia with the risk of local complications. Growing animal models have been used to test novel materials.Methods6-week-old rabbits underwent fiberoptic intubation, left subcostal laparotomy and hemi-diaphragmatic excision (either nearly complete (n = 13) or 3*3cm (n = 9)) and primary closure (Gore-Tex patch). Survival was further increased by moving to laryngeal mask airway ventilation (n = 15). Sham operated animals were used as controls (n = 6). Survivors (90 days) underwent chest X-Ray (scoliosis), measurements of maximum transdiaphragmatic pressure and breathing pattern (tidal volume, Pdi). Rates of herniation, lung histology and right hemi-diaphragmatic fiber cross-sectional area was measured.ResultsRabbits surviving 90 days doubled their weight. Only one (8%) with a complete defect survived to 90 days. In the 3*3cm defect group all survived to 48 hours, however seven (78%) died later (16–49 days) from respiratory failure secondary to tracheal stricture formation. Use of a laryngeal mask airway doubled 90-day survival, one pup displaying herniation (17%). Cobb angel measurements, breathing pattern, and lung histology were comparable to sham. Under exertion, sham animals increased their maximum transdiaphragmatic pressure 134% compared to a 71% increase in patched animals (p<0.05). Patched animals had a compensatory increase in their right hemi-diaphragmatic fiber cross-sectional area (p<0.0001).ConclusionsA primarily patched 3*3cm defect in growing rabbits, under laryngeal mask airway ventilation, enables adequate survival with normal lung function and reduced maximum transdiaphragmatic pressure compared to controls.

Comparison of respiratory function during TIVA and isoflurane anaesthesia in ponies Part II: breathing patterns and transdiaphragmatic pressure

ObjectiveTo compare breathing patterns and transdiaphragmatic pressure during total intravenous (TIVA) and isoflurane anaesthesia in ponies. Study designExperimental, cross–over study. AnimalsSix healthy ponies weighing 286 (233–388) ± 61 kg, age 13 (9–16) ± 3 years. MethodsFollowing premedication with romifidine [80 μg kg−1 intravenously (IV)], general anaesthesia was induced with midazolam (0.06 mg kg−1 IV) and ketamine (2.5 mg kg−1 IV) and maintained with either isoflurane (Fe’Iso = 1.1%) (T-ISO) or an IV combination of romifidine (120 μg kg−1 per hour), midazolam (0.09 mg kg−1 hour−1) and ketamine (3.3 mg kg−1 hour−1) (T-TIVA), while breathing 60% oxygen (FIO2). The circumference changes of the rib cage (RC) and abdominal compartment (ABD) were recorded using respiratory ultrasonic plethysmography (RUP). Balloon tipped catheters were placed in the distal oesophagus and the stomach and maximal transdiaphragmatic pressure (Pdi max) was calculated during Mueller's manoeuvre. ResultsThe breathing pattern T-ISO was more regular and respiratory rate significantly lower compared with T-TIVA. Ponies in T-TIVA showed regularly appearing sighs, which were never observed in T-ISO. Different contribution of the RC and ABD compartments to the breathing pattern was observed with a smaller participation of the RC to the total volume change during T-ISO. Transdiaphragmatic pressures (mean 13.7 ± SD 8.61 versus 23.4 ± 7.27 cmH2O, p < 0.0001) were higher in T-TIVA compared to T-ISO. The sum of the RC and ABD circumferential changes was lower during T-TIVA compared to T-ISO (6.32 ± 4.42 versus 11.72 ± 4.38 units, p < 0.0001). Conclusion and clinical relevanceMarked differences in breathing pattern and transdiaphragmatic pressure exist during inhalation- and TIVA and these should be taken into account for clinical estimation of anaesthetic depth.

Resting Cardiopulmonary Function in Paralympic Athletes with Cervical Spinal Cord Injury

The purposes of this study were to describe resting cardiopulmonary function in highly trained athletes with cervical spinal cord injury (SCI) and to compare the data with able-bodied (AB) control subjects. Twelve Paralympic wheelchair rugby players with cervical SCI (injury level = C5-C7) and 12 AB controls matched for age, stature, and body mass were assessed for pulmonary function using spirometry, body plethysmography, and maximal inspiratory and expiratory mouth pressures; diaphragm function using magnetic stimulation of the phrenic nerves; and cardiac function using transthoracic echocardiography. Total lung capacity, vital capacity, inspiratory reserve volume, and expiratory reserve volume were lower in SCI compared with AB (P < 0.01), whereas residual volume was elevated in SCI (P = 0.022). Airway resistance and maximal inspiratory mouth pressure were not different between groups (P > 0.41), whereas maximal expiratory mouth pressure, maximal transdiaphragmatic pressure, and twitch transdiaphragmatic pressure were lower in SCI (P < 0.01). Percent predicted total lung capacity was significantly correlated with maximal transdiaphragmatic pressure in SCI (r = 0.74), suggesting that the pulmonary restriction was a result of diaphragm weakness. Left ventricular mass, ejection fraction, stroke volume, and cardiac output were lower in SCI (P < 0.04), but early and late filling velocities during diastole were not different between groups (P > 0.05). Highly trained athletes with cervical SCI exhibit a restrictive pulmonary defect, weakness of the expiratory and diaphragm muscles, atrophy of the heart, and reduced systolic cardiac function.

Prediction of extubation outcome in preterm infants by composite extubation indices

To determine whether composite extubation indices can predict extubation outcome in preterm infants. Prospective observational study. Level III neonatal intensive care unit. Fifty-six preterm infants cared for in the neonatal intensive care unit of a tertiary teaching hospital during 2007 and 2008. None. The study consisted of two parts. In the first part, different extubation indices were evaluated in a group of 28 neonates (derivation group). These indices included the diaphragmatic pressure-time index, the respiratory muscle pressure-time index, the maximal transdiaphragmatic pressure, the maximal inspiratory pressure, the airway pressure generated 100 milliseconds after an occlusion/maximal transdiaphragmatic pressure ratio, the airway pressure generated 100 milliseconds after an occlusion/maximal inspiratory pressure ratio, the tidal volume, and the respiratory rate to tidal volume ratio. After exploratory analysis, the best performing indices and the optimal threshold values to predict extubation outcome were selected. In the second part of the study, these indices were validated at the predetermined threshold values in an additional group of 28 preterm neonates (validation group). Four infants (14.3%) in the derivation group and four in the validation group (14.3%) failed extubation. Receiver operator characteristic curve analysis revealed that a diaphragmatic pressure-time index of ≤0.12, a respiratory muscle pressure-time index ≤0.10, a airway pressure generated 100 milliseconds after an occlusion/maximal transdiaphragmatic pressure of ≤0.14, and a airway pressure generated 100 milliseconds after an occlusion/maximal inspiratory pressure of ≤0.09 were the most accurate predictors of extubation outcome in the derivation group. In the validation group, a diaphragmatic pressure-time index of ≤0.12 and a respiratory muscle pressure-time index of ≤0.10 both had zero false-positive results, predicting with accuracy successful extubation. Composite extubation indices such as the diaphragmatic pressure-time index and the noninvasive respiratory muscle pressure-time index can accurately predict extubation outcome in preterm neonates.

Dyspnea and ventilatory muscle function during exercise on air and oxygen breathing in patients with chronic obstructive pulmonary disease (COPD)

Exercise performance and dyspnea in COPD patients have been shown to be improved with supplemental oxygen, although the exact mechanisms resulting in the improvement are still unclear. The purpose of the present study was to investigate a possible relationship between ventilatory muscle function and sensation of dyspnea (modified Borg Scale) during exercise on 20% O2 and 30% O2. Eight patients with COPD (FEV1 1.06 L +/- 0.30 L) exercised on a treadmill two times breathing compressed air or 30% oxygen with a one hour rest in between. The electrical activity of the diaphragm (EMGdi) was recorded with esophageal electrodes, and that of the sternomastoid muscle (EMGsm) was recorded from the fine wire electrodes. The ratio of high frequency (150 to 350 Hz) to low frequency (20 to 47 Hz) power (H/L) of EMGdi was analyzed to assess diaphragmatic fatigue, which was defined as a 20% fall of H/L ratio from the control value. Flow, volume, O2 Saturation (SaO2), esophageal pressure (Pes) and transdiaphragmatic pressure (Pdi) were measured. Tension time index (TTdi) was calculated from Pdi and the ratio of inspiratory time to total time for one cycle (Ti/Ttot). At rest, we measured maximal esophageal pressure (Pesmax), maximal transdiaphragmatic pressure (Pdimax), maximal integrated EMGdi (EMGdimax) and EMGsm (EMGsmmax). Incremental exercise was discontinued by dyspnea. The walking distance achieved was increased in all patients on 30% O2. Dyspnea and desaturation were significantly improved on 30% O2 breathing, and the onset of diaphragmatic fatigue was delayed.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of weaning success in patients with prolonged mechanical ventilation

IntroductionPhysiological determinants of weaning success and failure are usually studied in ventilator-supported patients, comparing those who failed a trial of spontaneous breathing with those who tolerated such a trial and were successfully extubated. A major limitation of these studies was that the two groups may be not comparable concerning the severity of the underlying disease and the presence of comorbidities. In this physiological study, we assessed the determinants of weaning success in patients acting as their own control, once they are eventually liberated from the ventilator.MethodsIn 30 stable tracheotomised ventilator-dependent patients admitted to a weaning center inside a respiratory intensive care unit, we recorded the breathing pattern, respiratory mechanics, inspiratory muscle function, and tension-time index of diaphragm (TTdi = Pdisw/Pdimax [that is, tidal transdiaphragmatic pressure over maximum transdiaphragmatic pressure] × Ti/Ttot [that is, the inspiratory time over the total breath duration]) at the time of weaning failure (T0). The measurements were repeated in all the patients (T1) either during a successful weaning trial (successful weaning [SW] group, n = 16) or 5 weeks later, in the case of repeated weaning failure (failed weaning [FW] group, n = 14).ResultsCompared to T0, in the FW group at T1, significant differences were observed only for a reduction in spontaneous breathing frequency and in TTdi (0.21 ± 0.122 versus 0.14 ± 0.054, P = 0.008). SW patients showed a significant increase in Pdimax (34.9 ± 18.9 cm H2O versus 43.0 ± 20.0, P = 0.02) and decrease in Pdisw/Pdimax (36.0% ± 15.8% versus 23.1% ± 7.9%, P = 0.004).ConclusionsThe recovery of an inadequate inspiratory muscle force could be the major determinant of 'late' weaning success, since this allows the patients to breathe far below the diaphragm fatigue threshold.

The cortico-diaphragmatic pathway involvement in amyotrophic lateral sclerosis: Neurophysiological, respiratory and clinical considerations

Cortico-diaphragmatic pathway was investigated by means of transcranial magnetic stimulation (TMS), in 14 patients affected by definite amyotrophic lateral sclerosis (ALS) without clinical signs of respiratory impairment. Spirometry, gas analysis, and measurement of static inspiratory and expiratory pressures were performed in all patients. Forced vital capacity, forced expiratory volume at the first and second peak expiratory flow, sniff effort from FRC level (SNIP), maximal inspiratory and expiratory pressure at mouth (MIP/MEP), maximal transdiaphragmatic pressure (Pdimx) were considered. TMS was performed, recording by surface electrodes from hemidiaphragm, bilaterally. Latency of cortical and spinal motor-evoked potentials (Cx-MEP/Sp-MEP) and central motor conduction time (CMCT) were measured. None of the patients showed altered spirometry and gas levels. Seven patients showed decreased Pdimx and eight of MEP values. Four patients showed a delayed Sp-MEP. In one patient the Cx-MEP was abolished while the mean values of both Cx-MEP and CMCT were significantly increased (19.2 ± 4.1 ms, P < 0.0001; 10.8 ± 4.8 ms, P < 0.0001). Cx-MEP and CMCT did not show significant correlations with any of the respiratory measures. The patients with prolonged Sp-MEP, showed longer disease duration, lower Norris score, lower Pdimx and MEP values. In conclusion, cortico-diaphragmatic study is a sensitive measure to reveal subclinical diaphragmatic impairment although not correlated to respiratory measures.

Determination of Maximal Diaphragm Strength in Chronic Obstructive Pulmonary Disease: Cervical Magnetic Stimulation Versus Traditional Sniff Maneuver

Magnetic stimulation of the diaphragm allows its strength to be assessed. The clinical applications of this technique are becoming more widespread given that the patient's cooperation is not required. The aim of the present study was to compare this inhalation technique with traditional voluntary forced inspiration (sniff test) in a group of patients with chronic obstructive pulmonary disease (COPD). Sixteen men with moderate-to-severe COPD were studied (mean [SD] forced expiratory volume in 1 second, 35% [15%] of the reference value). For all patients, the maximal transdiaphragmatic pressure (a measure of the contractility of the muscle) was determined at peak inspiration and during cervical magnetic stimulation. A moderate correlation between measurements with the 2 techniques was observed. The value obtained with stimulation was approximately 20% of that obtained with the sniff maneuver (22 [7] cm H2O vs 97 [27] cm H2O, respectively). The stimulation technique yielded an intraindividual coefficient of variability of 12% (7%) and an interindividual one of 33% (6%). Very similar values for these coefficients were obtained with the sniff maneuver. Qualitative analysis of the stimulation technique showed it to have a high sensitivity (89%) for diagnosing muscle weakness, with few false negatives. In contrast, specificity was very low (43%), and false positives for muscle weakness were relatively common. The overall effectiveness of the prediction was acceptable (69%). Cervical magnetic stimulation appears to be a good clinical option for ruling out diaphragm weakness. It is particularly indicated in patients with limited capacity for understanding instructions or those unable to cooperate.

Olprinone/dopamine combination for improving diaphragmatic fatigue in pentobarbital-anesthetized dogs

Background: Diaphragmatic fatigue might contribute to the development of respiratory failure. In particular, the spontaneous, natural rate of phrenic nerve discharge occurs mainly in low-frequency ranges making low-frequency fatigue clinically important in both humans and animals. Olprinone, a phosphodiesterase 3 inhibitor, improves contractility in fatigued diaphragm, but is also associated with hypotension. Dopamine might be used concomitantly for treating related hypotension. Objective: The purpose of the study was to assess the effect of olprinoneplus dopamine on diaphragmatic fatigue in pentobarbital-anesthetized dogs. Methods: This nonblinded study was conducted at the Department ofAnesthesiology, Institute of Clinical Medicine, Tsukuba, Japan. Diaphragmatic fatigue (assessed by a decrease in diaphragmatic contractility) was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 minutes. Immediately after the fatigue-producing period, groups 2, 3, and 4 received an initial 10 μg/kg dose of olprinone. Group 2 then received maintenance olprinone of 0.3 μg/kg · min; group 3 received maintenance olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min; and group 4 received maintenance olprinone 0.3 μg/kg · min plus dopamine 5 μg/kg · min. Group 1 received no study drug. Olprinone and dopamine were administered IV for 30 minutes. Diaphragmatic contractility was assessed by measuring the maximal transdiaphragmatic pressure (Pdi) generated by test stimuli after airway occlusion at functional residual capacity. Hypotension induced by the study drugs was defined as a >10 mm Hg decrease in mean arterial pressure (MAP), calculated by diastolic pressure plus ⅓ pulse pressure, from baseline. Results: Twenty-eight mongrel dogs (18 males and 10 females, weighing 10-15 kg)were used in the study; 7 dogs were randomly assigned to each treatment group. When fatigue was established in each group, mean (SD) Pdi at low-frequency (20 Hz) stimulation decreased significantly from baseline in all groups (group 1: 15.6 [2.2] vs 11.7 [2.4] cm H 2O, P = 0.008; group 2: 15.4 [1.5] vs 11.6 [1.3] cm H 2O, P= 0.005; group 3:15.5 [2.0] vs 11.6 [1.8] cm H 2O, P= 0.006; group 4: 15.7 [1.4] vs 12.0 [1.4] cm H 2O, P= 0.008), while no significant change existed in Pdi at high-frequency (100 Hz) stimulation ( P = NS). After study drug administration, Pdi in groups 2, 3, and 4 increased significantly from fatigued values at both 20 Hz stimulation (group 2: 11.6 [1.3] vs 21.8 [2.0] cm H 2O, P = 0.001; group 3: 11.6 [1.8] vs 22.2 [1.8] cm H 2O, P = 0.001; group 4: 12.0 [1.4] vs 25.9 [1.9 ] cm H 2O, P = 0.001) and 100 Hz stimulation (group 2: 22.0 [2.2] vs 29.0 [1.9] cm H 2O, P = 0.002; group 3: 22.1 [2.0] vs 29.3 [2.2] cm H 2O, P = 0.002; group 4: 21.8 [2.2] vs 31.7 [2.4] cm H 2O, P= 0.001). The increase in Pdi was significantly larger in group 4 compared with the other 3 groups (all, P < 0.05). Hypotension was not observed in group 4. MAP did not change significantly in group 1 or group 4 compared with baseline or fatigued MAP values ( P = NS). Groups 2 and 3 had significant decreases in MAP with treatment compared with values in group 1 and with baseline and fatigued MAP values (all, P < 0.05). The MAP of group 4 was significantly greater than the MAP of groups 2 and 3 with treatment (both, P < 0.05). Conclusions: Olprinone 0.3 μg/kg sd min plus dopamine 5 μg/kg · min improved contractility in fatigued diaphragms and was not associated with hypotension in these pentobarbital-anesthetized dogs. Olprinone monotherapy and olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min might improve contractility significantly. However, it was also associated with significant decreases in MAP.

Mechanical limitation during CO2 rebreathing in young patients with cystic fibrosis

The aim of the study was to determine whether a decrease in the ventilatory response to carbon dioxide (CO2) in children with cystic fibrosis (CF) is related to a mechanical limitation of the respiratory muscle capacity. The ventilatory response during CO2 rebreathing was performed in 15 patients (mean forced expiratory volume in 1 s (FEV1): 37 +/- 21% predicted, mean arterial CO2: 41+/- 5 mmHg). The slope of the minute ventilation normalised for weight per mmHg CO2 increment correlated negatively with respiratory muscle output, assessed by the oesophageal (p = 0.002), the diaphragmatic pressure time product (p = 0.01), and the tension time index (p = 0.005). In addition, this slope was correlated with dynamic lung compliance (p < 0.0001) and FEV1 (p = 0.03) but not with airway resistance and maximal transdiaphragmatic pressure. Therefore, an excessive load imposed on the respiratory muscles explains the blunting of the ventilatory response to CO2 in young patients with CF.

Respiratory Effects of Combined Truncal and Abdominal Support in Patients With Spinal Cord Injury

Hart N, Laffont I, Perez de La Sota A, Lejaille M, Macadou G, Polkey MI, Denys P, Lofaso F. Respiratory effects of combined truncal and abdominal support in patients with spinal cord injury. Objective To determine whether a custom girdle, designed to provide truncal stability and abdominal support, will improve pulmonary function, enhance inspiratory muscle activity, and reduce the sensation of respiratory effort in patients with spinal cord injury (SCI). Design Pulmonary function, transdiaphragmatic pressure time product (PTP di), twitch (Tw Pdi) and maximal transdiaphragmatic pressures (Pdi), and perception of respiratory effort (Borg Rating of Perceived Exertion score) were measured with and without an abdominal girdle in a seated position. Setting Rehabilitation hospital. Participants Ten patients with posttrauma SCI (injury level, C5–T6). Intervention Application of the abdominal girdle. Main Outcome Measures Borg score and measures of lung volumes, dynamic abdominal compliance, and Tw Pdi and maximal Pdi. Results Wearing of the girdle was associated with a lower Borg score ( P=.002) and reduced functional residual capacity ( P=.006) but increased inspiratory capacity ( P=.02) and forced vital capacity ( P=.02). Although there was a decrease in dynamic abdominal compliance ( P<.001) and an increase in PTP di ( P=.02), this was accompanied by an increase in both Tw Pdi ( P=.02) and maximal Pdi ( P=.03). Conclusions The custom girdle reduced the sensation of respiratory effort in patients with SCI by optimizing the operating lung volumes and decreasing abdominal compliance, which enhanced diaphragm performance.

Physiological effects of intravenous fructose 1.6-diphosphate on diaphragmatic function in malnourished patients with COPD

A low body mass index is one of the strongest predictors of mortality in Chronic Obstructive Pulmonary Disease (COPD) patients. Under-nutrition is often associated with skeletal muscle wasting and hypophosphatemia. In a pilot, randomised, double-blind placebo-controlled study, we assessed the physiological effects of phosphorous administration in 17 stable undernourished COPD patients, on diaphragmatic function, breathing pattern, neuromuscular drive (P0.1) and dyspnea score. Fructose 1.6-diphosphate (FDP) or placebo was administered i.v. for 7 consecutive days. FDP administration was associated with a marked increase in inspiratory time (Ti) that induced a significant rise (p < 0.05) in the Pressure Time Product of the diaphragm per breath (PTPdi/b). However, since breathing frequency also decreased, the Pressure Time Product per minute of the diaphragm (PTPdi/min), index of diaphragmatic energy expenditure was markedly reduced. The efficiency of the respiratory pump in clearing CO2 was also improved, although not significantly, in the FDP group (p = 0.09) as well as the maximal transdiaphragmatic pressure during the sniff manoeuvre (Pdi,sniff). This pilot physiological study showed that phosphorus replacement in undernourished, stable COPD patients, may be associated with a complex modification in respiratory pattern and diaphragmatic functions, leading to a marked although not significant reduction in PTPdi/min.

Effect of Lung Volume Reduction Surgery on Diaphragmatic Neuromechanical Coupling At 2 Years

We previously reported that patients with emphysema show an increase in diaphragmatic neuromechanical coupling at 3 months after lung volume reduction surgery. Diaphragmatic neuromechanical coupling was quantified as the quotient of tidal volume (normalized to total lung capacity) to tidal change in transdiaphragmatic pressure (normalized to maximal transdiaphragmatic pressure). As such, neuromechanical coupling estimates the fraction of diaphragmatic capacity used to generate tidal breathing. The present investigation was conducted to determine whether benefit is maintained at 2 years. Fifteen patients with severe COPD, 8 of whom completed the 2-year study. Lung volumes, exercise capacity (6-min walking distance), diaphragmatic function (maximal transdiaphragmatic pressure and twitch transdiaphragmatic pressure elicited by phrenic nerve stimulation), and diaphragmatic neuromechanical coupling were recorded before surgery, and at 3 months and 2 years after surgery. Two years after surgery, lung volumes deteriorated to preoperative values, but patients showed persistent improvements in 6-min walking distance (p < 0.05). Three months after surgery, maximal transdiaphragmatic pressure (p < 0.05), twitch transdiaphragmatic pressure (p < 0.01), and diaphragmatic neuromechanical coupling (p < 0.01) had increased over preoperative values. The improvements in neuromechanical coupling resulted from improvements in diaphragmatic strength and, to a lesser extent, from a decrease in transdiaphragmatic pressure required to maintain tidal breathing. The change in respiratory muscle function at 2 years varied among patients: diaphragmatic contractility was > 10% of preoperative value in half of the patients who concluded our study, and neuromechanical coupling was > 10% of preoperative value in three fourths of the patients who concluded our study. Patients who maintained their gains in neuromechanical coupling also maintained their gains in 6-min walking distance. Patients undergoing lung volume reduction surgery can maintain early gains in neuromechanical coupling and exercise capacity 2 years later.

Respiratory muscle strength training with nonrespiratory maneuvers.

The diaphragm and abdominal muscles can be recruited during nonrespiratory maneuvers. With these maneuvers, transdiaphragmatic pressures are elevated to levels that could potentially provide a strength-training stimulus. To determine whether repeated forceful nonrespiratory maneuvers strengthen the diaphragm, four healthy subjects performed sit-ups and biceps curls 3-4 days/wk for 16 wk and four subjects served as controls. The maximal transdiaphragmatic pressure was measured at baseline and after 16 wk of training. Maximum static inspiratory and expiratory mouth pressures and diaphragm thickness derived from ultrasound were measured at baseline and 8 and 16 wk. After training, there were significant increases in diaphragm thickness [2.5 +/- 0.1 to 3.2 +/- 0.1 mm (mean +/- SD) (P < 0.001)], maximal transdiaphragmatic pressure [198 +/- 21 to 256 +/- 23 cmH2O (P < 0.02)], maximum static inspiratory pressure [134 +/- 22 to 171 +/- 16 cmH2O (P < 0.002)], maximum static expiratory pressure [195 +/- 20 to 267 +/- 40 cmH2O (P < 0.002)], and maximum gastric pressure [161 +/- 5 to 212 +/- 40 cmH2O (P < 0.03)]. These parameters were unchanged in the control group. We conclude that nonrespiratory maneuvers can strengthen the inspiratory and expiratory muscles in healthy individuals. Because diaphragm thickness increased with training, the increase in maximal pressures is unlikely due to a learning effect.