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Vol. 83, Issue 5, 1654-1659, 1997
1 Department of Anesthesiology and Critical Care Medicine and 2 Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Kocis, Keith C., Peter J. Radell, Wayne I. Sternberger, Jane
E. Benson, Richard J. Traystman, and David G. Nichols. Ultrasound evaluation of piglet diaphragm function before and after fatigue. J. Appl. Physiol. 83(5):
1654-1659, 1997.
Clinically, a noninvasive measure of diaphragm
function is needed. The purpose of this study is to determine whether
ultrasonography can be used to 1)
quantify diaphragm function and 2)
identify fatigue in a piglet model. Five piglets were anesthetized with
pentobarbital sodium and halothane and studied during the following
conditions: 1) baseline (spontaneous breathing); 2) baseline + CO2 [inhaled
CO2 to increase arterial PCO2 to 50-60 Torr (6.6-8
kPa)]; 3) fatigue + CO2 (fatigue induced with 30 min
of phrenic nerve pacing); and 4)
recovery + CO2 (recovery after 1 h
of mechanical ventilation). Ultrasound measurements of the posterior
diaphragm were made (inspiratory mean velocity) in the transverse
plane. Images were obtained from the midline, just inferior to the
xiphoid process, and perpendicular to the abdomen. M-mode measures were
made of the right posterior hemidiaphragm in the plane just lateral to
the inferior vena cava. Abdominal and esophageal pressures were
measured and transdiaphragmatic pressure (Pdi) was calculated during
spontaneous (Sp) and paced (Pace) breaths. Arterial blood gases were
also measured. Pdi(Sp) and Pdi(Pace)
during baseline + CO2 were 8 ± 0.7 and 49 ± 11 cmH2O, respectively, and
decreased to 6 ± 1.0 and 27 ± 7 cmH2O,
respectively, during fatigue + CO2. Mean inspiratory velocity
also decreased from 13 ± 2 to 8 ± 1 cm/s during these
conditions. All variables returned to baseline during recovery + CO2. Ultrasonography can be
used to quantify diaphragm function and identify piglet diaphragm fatigue.
inhaled carbon dioxide; diaphragm fatigue; respiratory muscle; transvenous phrenic nerve pacing; ultrasonography
INTRODUCTION DIAPHRAGM DYSFUNCTION is a prominent cause of failure
to wean from mechanical ventilation (5, 12, 19, 22, 30). Several
clinical tools are available to indirectly evaluate diaphragm function.
Radiographic examinations (2, 4, 33-35) can be used to evaluate
diaphragm location (chest radiograph, computed tomography) or motion
(fluoroscopy). Phrenic nerve stimulation studies (8, 14, 24, 26) have
been used to assess efferent phrenic conduction. Pulmonary function
tests (41) indirectly assess diaphragm function, but results are effort
dependent, decreasing its utility in young or uncooperative children.
Inhaled CO2 has been administered
to stimulate central respiratory drive and, therefore, decrease the
variability in measures of pulmonary function in adults and children
(12, 25). Transdiaphragmatic pressure (Pdi), calculated from abdominal
and pleural pressures, is a measure of the force output of the
diaphragm. It remains the standard for diagnosing diaphragm weakness
and fatigue (3, 12, 13, 21, 40), but the requirement for invasive
catheter placement limits its utility in children. Overall, these
studies have provided incomplete information about quantitative
diaphragm function.
Ultrasonography has been used to image the diaphragm diagnostically in
adults and children (1, 6, 7, 10, 11, 15-17, 20, 29, 36).
Ultrasonography is ideal in children, because it is noninvasive,
painless, safe, and portable. Image quality is superior in children
compared with adults because of the small body size and lack of body
fat in most children. These studies have focused on measuring
superior-inferior excursion distance by two-dimensional imaging and
M-mode scanning or calculating a change in diaphragm thickness.
Problems exist in measuring absolute superior-inferior distances with
an ultrasound probe placed on the abdomen, since the diaphragm and
abdominal wall are simultaneously moving and often not in the same
superior-inferior plane. Also, measuring the change in the thickness of
an infant's diaphragm during inspiration is fraught with large error.
We therefore sought to measure other ultrasound indexes of diaphragm
function. Finally, we sought to correlate the ultrasound indexes with
classic pulmonary mechanics.
A piglet animal model has been used to simulate the infant diaphragm
(18, 27, 31, 32, 37). In this model, transvenous phrenic nerve pacing
induces diaphragm fatigue validated by a decrease in Pdi and depletion
of high-energy phosphate metabolites (8, 27, 31, 32, 37). Prior studies
have suggested that a combination of low- and high-frequency fatigue is
produced by this model (27). This well-established and controlled
animal model of diaphragm fatigue was used in this study.
We therefore propose to use ultrasonography to quantitate diaphragm
function in a piglet model of diaphragm fatigue. We hypothesize that
ultrasonography can be used in a piglet model to
1) quantify diaphragm function and
2) identify diaphragm fatigue.
METHODS
Pes. These measurements were made during spontaneous breathing
[Pdi(Sp)] and brief periods of phrenic nerve pacing
[Pdi(Pace)] at end expiration with the airway occluded.
Pdi(Pace) represents the maximum force output of the diaphragm for the
preset pacing conditions and is independent of the piglet's
respiratory drive. Diaphragm fatigue was defined as a 20% decrease in
Pdi(Pace) from baseline after 30 min of transvenous phrenic nerve
pacing. Airway pressure (Paw) was measured via a needle-tipped catheter
inserted into the endotracheal tube. Transpulmonary pressure (Ptp) was
calculated as Paw Pes. A constant Ptp at end expiration during
the study periods was considered evidence of constant lung volume.
Transvenous pacing catheters were placed into the external
jugular veins bilaterally. Catheter position was adjusted to achieve
maximum phrenic nerve pacing of the diaphragm. Brachial plexus
stimulation was avoided. The pacing catheters were connected to a
stimulator (model S8, Grass Medical Instruments, Quincy, MA). Pacing
parameters were 2,000-ms train duration at 30 Hz, duty cycle of
0.33, and 15-25 V.
Fig. 1.
Animal preparation. n, Nerve; ext jug, external jugular vein.
[View Larger Version of this Image (36K GIF file)]
From the M-mode trace (Fig. 4) obtained in the transverse plane, the mean velocity of the right posterior hemidiaphragm during inspiration and expiration was measured. The inspiratory mean velocity (VI) was calculated by dividing the distance (D) the right posterior hemidiaphragm moves during inspiration by the inspiratory time. Similarly, the expiratory mean velocity was calculated using D and the time for expiration. A first-order time constant (T) represents the time in which ~63% of inspiration (or expiration) occurs. This value (T) was then divided by the total duration of inspiration (or expiration), resulting in the inspiratory (or expiratory) time-corrected time constant (Tc). This was done to correct for varying inspiratory (or expiratory) time in the piglets. From imaging in the right lateral sagittal plane (Fig. 3), the radius of curvature of the right posterior hemidiaphragm at end inspiration and end expiration was calculated by identifying three points on the diaphragm that defined a circle of radius r.
All images were recorded on videotape in super VHS format for later off-line analysis. The recordings were played through a computer with video-image capturing and digitizing capabilities (SNAPSHOT, Cardinal Technologies, Lancaster, PA). Individual images were captured, coded, and enhanced using Photo Paint (Corel, Ottawa, ON, Canada) graphics software. From the enhanced images, unique algorithms were developed within the engineering software MATLAB (Mathworks, Natick, MA) to perform the individual measurements and calculations. All measurements were recorded as the mean of three respiratory cycles and made by an investigator blinded to the individual piglet and study condition. Study protocol. Pressure measurements during spontaneous and paced breaths, arterial blood-gas values, and ultrasound measurements were obtained during the following conditions (Fig. 5): 1) baseline-spontaneous breathing; 2) baseline + CO2, in which piglets inhaled a CO2 mixture to increase PaCO2 to 50-60 Torr (6.6-8 kPa); 3) fatigue + CO2, in which fatigue was induced with 30 min of phrenic nerve pacing while the animals inhaled the CO2 mixture; and 4) recovery + CO2, in which the animals recovered after 1 h of mechanical ventilation while inhaling the CO2 mixture.
Statistical analysis. All data were analyzed using the Statistical Analysis System (SAS, Cary, NC). Analysis was performed using the paired Student's t-test, with P < 0.05 considered significant. Values are means ± SE. A priori, the primary outcome was the comparison of measurements in conditions baseline + CO2 and fatigue + CO2. Other comparisons were secondary outcomes performed to strengthen the validity of the study.
RESULTS
The hemodynamic, respiratory, abdominal and esophageal pressures, and ultrasound results for the four study conditions are shown in Table 1. The piglets' heart rate, blood pressure, and arterial blood gases did not change throughout the experiment, except for the expected increase in PaCO2 and secondary decrease in pH when CO2 was added to the inspired gas. Paw, Pes(Sp), and Ptp did not change for all experimental conditions, indicating constant lung volume. Pdi(Sp) decreased with fatigue + CO2 compared with baseline + CO2, despite nonsignificant changes in the individual components, Pab(Sp) and Pes(Sp). Pdi(Sp) normalized during recovery + CO2. Pes(Pace), Pab(Pace), and Pdi(Pace) decreased as expected with fatigue + CO2 compared with baseline + CO2 and normalized during recovery + CO2. In addition, there was a significant decrease in Pes(Pace) after CO2 was added to the inspired gas. The only ultrasound index to significantly change during the experimental conditions was VI, which decreased during fatigue + CO2 compared with baseline + CO2 and normalized during recovery + CO2.
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DISCUSSION
A piglet model has been developed that simulates the human infant diaphragm (8, 27, 31, 32, 37). The protocol was modified by addition of CO2 to raise PaCO2 to 50-60 Torr (6.6-8 kPa) in an effort to increase the piglet's central respiratory drive. This should decrease the variability in the effort-dependent measurements [Pdi(Sp) and ultrasound indexes]. In comparing baseline with baseline + CO2 conditions, pH decreased and PaCO2 increased, as expected. Although a decrease in Pes(Pace) occurred, there was no decrease in Pdi(Pace) during these two conditions. There were no changes in the ultrasonographic measurements after the addition of CO2.
Transvenous phrenic nerve pacing of the diaphragm has been shown to decrease force output [Pdi(Pace)] and deplete high-energy phosphate metabolites in a piglet model (8, 27, 31, 32, 37). After 30 min of pacing (fatigue + CO2), there was a 34% decrease in maximal force output [Pdi(Pace)] compared with baseline + CO2. Force output of the diaphragm during spontaneous breaths [Pdi(Sp)] also decreased by 25%. Only one ultrasound index, inspiratory mean velocity, was found to have decreased during these conditions. The remaining ultrasound indexes, expiratory mean velocity, inspiratory and expiratory time constants (T), inspiratory and expiratory time-corrected time constants (Tc), and radius of curvature during inspiration and expiration did not change.
In the recovery phase (recovery + CO2), Pdi(Pace), Pdi(Sp), and VI normalized to levels found at baseline + CO2. This agrees with previous work in this piglet model showing resolution of fatigue and return of high-energy phosphate metabolites after full mechanical ventilatory support and diaphragm rest (18, 27, 32).
There have been only isolated reports in animals and no studies in humans measuring the velocity of shortening of the diaphragm. The maximal velocity of shortening has been measured in isolated rat diaphragm strips under resting conditions (23). In this study the authors also found a decrease in the length of diaphragm shortening with fatigue, but the velocity was not measured under this condition (23). The association between reduced force output and reduced velocity has been described in skeletal muscle (38). Both changes may reflect altered cross-bridge function secondary to increased inorganic phosphate, increased ADP, or decreased phosphocreatine concentrations (39). We have demonstrated previously increased inorganic phosphate production and phosphocreatine consumption during fatiguing diaphragmatic contractions in this model (32).
There were several limitations of this study. First, the sample size was small (n = 5), resulting in relatively small power, and therefore type II errors may occur. The sample size was estimated from previous results, which showed that the effects we were measuring were large. Second, our model is an acute preparation for diaphragm fatigue and not weakness. We in part attribute our inability to demonstrate a change in the diaphragm radius of curvature to this, since the diaphragm has had little time to remodel and alter its resting position. Third, central input to the diaphragm may influence the VI but was not directly measured. Instead, the possible influence of central input on VI was controlled for by addition of CO2 to maximize respiratory drive and by addition of a recovery phase to the experimental protocol. Finally, we have not validated the VI to an absolute rate of diaphragm shortening in the anterior-posterior direction. Additional experiments are required to measure simultaneously the velocity of the diaphragm in the anterior-posterior direction and the VI. Until these data are acquired, we are unable to state that VI was an actual velocity or whether it only positively correlated with the velocity of shortening of the diaphragm in the anterior-posterior direction.
In summary, quantitative ultrasound measurements, specifically VI, can be used to evaluate diaphragm function in a piglet model of diaphragm fatigue. We speculate that these techniques could be applied to the evaluation of the diaphragm in children. If these techniques are successful, we expect that this tool will enable investigators to better evaluate the function of the diaphragm. By quantifying diaphragm function, one might be able to predict the timing for successful extubation from mechanical ventilation, evaluate diaphragm function during drug therapy, and assess mechanical ventilation strategies designed to strengthen the diaphragm.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge Daniel J. Kocis, Jr., for assistance with the statistical analyses and the Acuson Corporation for ultrasound equipment support.
FOOTNOTES
Address for reprint requests: K. C. Kocis, Dept. of Pediatrics and Surgery, Childrens Hospital Los Angeles, 4650 Sunset Blvd., MS 66, Los Angeles, CA 90027.
Received 20 March 1996; accepted in final form 27 June 1997.
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