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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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To evaluate the effects of endotoxemia on respiratory controller
function, 12 subjects were randomized to receive endotoxin or saline; six also received ibuprofen, a cyclooxygenase inhibitor, and
six received placebo. Administration of endotoxin produced fever,
increased respiratory frequency, decreased inspiratory time, and
widened alveolar-arterial oxygen tension gradient (all p 
0.001);
these responses were blocked by ibuprofen. Independent of ibuprofen, endotoxin produced dyspnea, and it increased fractional inspiratory time, minute ventilation, and mean inspiratory flow (all p 0.025). Endotoxin altered the autocorrelative behavior of
respiratory frequency by increasing its autocorrelation coefficient at a lag of one breath, the number of breath lags with significant serial correlations, and its correlated fraction (all p < 0.05); these
responses were blocked by ibuprofen. Changes in correlated behavior of respiratory frequency were related to changes in arterial carbon dioxide tension (r = 0.86; p < 0.03). Endotoxin decreased the oscillatory fraction of inspiratory time in both the placebo (p < 0.05) and ibuprofen groups (p = 0.06). In conclusion, endotoxin produced increases in respiratory motor output and dyspnea independent of fever and symptoms, and it curtailed the freedom to
vary respiratory timing
a response that appears to be mediated
by the cyclooxygenase pathway.
Keywords: endotoxemia; respiratory center; Fourier analysis; sepsis; respiratory muscles
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Administration of intravenous endotoxin to human subjects replicates many features of sepsis, including fever, leukocytosis, release of inflammatory mediators, a hyperdynamic cardiovascular state, and reversible depression of left ventricular function (1). Several of these alterations are known to increase respiratory drive, and greater ventilatory demands increase stress on patients coping with the challenge of sepsis (2, 3). Remarkably little is known about control of breathing in this setting because of the difficulty in its assessment (4). Instrumentation involving use of a mouthpiece causes large changes in respiratory controller output (5) and is tolerated for only brief periods. These limitations can be overcome by techniques such as inductive plethysmography, which allow ventilation to be measured nonobtrusively over prolonged periods (5). Newer approaches to data analysis also yield additional insight into the mechanisms underlying controller performance (6).
The deviation of the magnitude of a breath component from its mean can be partitioned into a nonrandom (correlated/oscillatory) fraction and a random, white-noise [w(n)] fraction. Characteristic alterations in these fractions occur with mechanical and chemical stimulations (7). In healthy subjects, we showed that the relationship of a given breath component between neighboring breaths was enhanced by inhaling carbon dioxide (9). Endotoxin is known to alter arterial carbon dioxide tension (PaCO2) (3), and the change in PaCO2 might alter the correlated behavior of breath components. Endotoxin also decreases circulation time, which predisposes to a decrease in the oscillatory fraction of breath variability (1, 11, 12).
We used a human model of the systemic inflammatory response to characterize the change in breathing pattern measured nonobtrusively and continuously. We hypothesized that endotoxemia will produce an increase in respiratory motor output, accompanied by an increase in the correlated fraction and a decrease in the oscillatory fraction of variational activity of breath components. To determine the influence of the cyclooxygenase pathway in modulating respiratory controller function during endotoxemia, measurements were also obtained in the subjects after they received the cyclooxygenase inhibitor, ibuprofen.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Ten healthy men and two women (mean age, 27.5 ± 1.6 yr) were studied. The study was approved by, and performed in accordance with, the ethical standards of our institutional review board on human experimentation. Written informed consent was obtained from each subject. Data from these subjects describing changes in stress hormones, chemokines, exhaled nitric oxide, and heart rate variability have been previously published (13).
Study Design
Twelve subjects were randomized to receive endotoxin (4 ng/kg, U.S.
Standard Endotoxin, Lot EC-5 E. coli 0:113, Food and Drug Administration, Bethesda, MD) or saline (control) intravenously 1 wk apart.
The endotoxin and saline were injected at 0 h, and each was followed
by the infusion of 10 ml of normal saline. Six subjects received oral
ibuprofen 800 mg (Upjohn, Kalamazoo, MI), and the remaining six
received placebo at 
1.5 h, 0 h, and 3 h (total ibuprofen dose was
2,400 mg). Subjects were blinded to the ibuprofen or placebo and endotoxin or saline treatment arms. Study groups are defined as follows:
saline + placebo, endotoxin + placebo, saline + ibuprofen, and endotoxin + ibuprofen.
Measurements of Ventilation
Ventilation was measured nonobtrusively with a respiratory inductive plethysmograph (RIP; Respigraph, Non-Invasive Monitoring Systems, Inc., Miami Beach, FL) in each subject. The ribcage and abdominal sensors of the RIP were calibrated using the qualitative diagnostic calibration technique during 5 min of natural breathing with the head of the bed placed at 45 degrees (18). These calibration gains were maintained during subsequent recordings while the subjects rested on a bed in a quiet room; interruption by staff was minimized to avoid spurious alterations in the breathing pattern. Data collection began before administration of endotoxin or saline and continued over the subsequent 8 h. Posture was maintained constant during RIP calibration and data collection.
At 1 h intervals, ventilation was also measured with a pneumotachograph (Bicore Monitoring Systems, Inc., Irvine, CA) connected through a mouthpiece for 5 min, with the nose clipped, connected to
the pneumotachograph. These data were used to provide volumetric calibration of RIP data during the ensuing hour. The following variables, excluding any measurements during mouthpiece breathing, were averaged from the RIP signals into 1-h block epochs: respiratory frequency, tidal volume (VT), minute ventilation (
I), inspiratory time (TI), fractional inspiratory time (TI/TTOT) and mean inspiratory flow (VT/TI).
Respiratory Muscle Function
Esophageal pressure (Pes) was measured with a balloon catheter connected to a pressure transducer (Bicore Monitoring Systems, Inc., Irvine, CA). Proper positioning of the esophageal balloon was ensured by the occlusion technique (19). Inspiratory muscle strength was measured every hour by having subjects perform three maximal inspiratory efforts against an occluded airway at functional residual capacity; the greatest value was selected as maximal inspiratory pressure (PImax). Measurements of PImax were obtained immediately after the 5-min period of breathing through the mouthpiece.
Temperature, Dyspnea, and Arterial Blood Gas Measurements
Temperature was measured hourly with a calibrated oral thermometer (Diatek, Inc., San Diego, CA). Dyspnea was assessed every hour in each subject using a Borg scale in response to the question "How uncomfortable is your breathing?" Dyspnea measurements were made just before the placement of the mouthpiece for the pneumotachographic recordings. Arterial blood gases were obtained before giving endotoxin and every hour thereafter from an indwelling radial arterial catheter.
Data Analysis
Mean changes in breath components. Mean values of breath components throughout the entire 8-h experiment were averaged in 1-h epochs for each study group.
Variability changes in breath components. Breath components in a
breath series display breath-to-breath variability, which may consist
of correlated, oscillatory, and random components. Autocorrelation
and spectral analysis enable the determination of the relative magnitudes of these components (9). To examine the effect of endotoxin on
the variational activity of breathing in each study group, 640 consecutive breaths obtained at 3 to 4 h after the administration of endotoxin
and saline were chosen. This period was chosen because major physiological changes associated with endotoxemia in normal subjects are
known to occur within this time frame (3, 12). Because time-series
analysis requires stationary (time invariant) data, segments of data in
each of the study groups that displayed the least deviation in I on visual inspection were chosen for analysis.
The standard deviation (SD), viz., the square root of the variance, for each breath component was calculated in each subject as a measure of gross breath-to-breath variability. Autocorrelation analysis was employed to determine what fraction of variational activity is correlated on a breath-to-breath basis (9, 20, 21). Power spectral analysis was employed to determine what fraction of the variational activity is oscillatory at a particular frequency on a breath-to-breath basis (9). The power spectrum expresses the variance of a signal as a function of frequency (6, 8, 9). Total variational activity was then modeled as a compound consisting of both random and nonrandom fractions (6). The correlated and oscillatory fractions are quantified using autocorrelation and spectral analysis, and the random (white-noise) fraction is derived as the remainder of the total variance (6, 8, 9).
General statistical analysis. Data of the entire study were analyzed using a four-way analysis of variance (ANOVA) based on administration of endotoxin, treatment with ibuprofen, subjects nested within treatment, and time (22). Two- and three-way interactions among endotoxin, ibuprofen, and time were included in the model. All interactions involving subjects were pooled to produce the residual error term. For analysis of respiratory variables, 40-50 min of quiet breathing (500-800 breaths) were used each hour. Residuals from the ANOVA were analyzed using a Shapiro-Wilk test to check for normality (23). When endotoxin had fundamentally similar effects on a variable both in the presence and absence of ibuprofen, the endotoxin + placebo and endotoxin + ibuprofen data were pooled and compared with data obtained under control conditions, that is, saline + placebo and saline + ibuprofen. Data were also analyzed by computing the maximum change for each individual and analyzing the four groups using a Kruskal-Wallis test (24). Summary statistics are given as mean ± SE.
For analysis of the variability changes of each breath component during the 3- to 4-h epoch, paired t tests were used to compare responses in the placebo group (endotoxin + placebo versus saline + placebo); a similar analysis was performed in the ibuprofen group (i.e., endotoxin + ibuprofen to saline + ibuprofen). To ensure that the data approximated a Gaussian distribution, they were logarithmically transformed if appropriate before t tests were performed. Analysis of the variability changes of breath component are expressed as mean ± SD.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Systemic Responses to Endotoxin
Endotoxin + placebo produced an increase in temperature in each subject (p = 0.001), which was maximal at 3 h and blocked by ibuprofen (Figure 1, upper panel, p = 0.005). All subjects receiving endotoxin + placebo developed headache and chills, and some developed arthralgias, myalgias, and nausea; these symptoms were blocked by ibuprofen. Compared with subjects who did not receive endotoxin, dyspnea increased in all subjects given endotoxin (n = 12, p = 0.025) and was maximal at 2 h (Figure 1, lower panel).
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Arterial Blood Gas Values and Respiratory Muscle Function
Endotoxin widened A-a DO2 (p = 0.0001), which was maximal at 4 h (Figure 2, lower panel). The increase in A-a DO2 was blocked by ibuprofen (p = 0.025). Although pH, PaCO2, or PO2 did not change significantly over the entire 8 h of endotoxin (Table 1), the values changed significantly at the 4 h point: PaCO2 decreased from 43.7 ± 1.1 mm Hg after saline to 41.5 ± 1.0 mm Hg after endotoxin (p < 0.004); the respective values for PaO2 were 101.7 ± 1.2 and 93.6 ± 2.0 mm Hg (p < 0.007); and the respective values for pH were 7.38 ± 0.01 and 7.37 ± 0.01 (p = 0.76). In the ibuprofen group, PaCO2 decreased from 42.0 ± 0.3 mm Hg after saline to 39.0 ± 1.1 mm Hg after endotoxin (p = 0.06); the respective values for PaO2 were 98.1 ± 3.5 and 98.3 ± 4.7 mm Hg (p = 0.93); the respective values for pH were 7.38 ± 0.01 and 7.39 ± 0.01 (p = 0.09).
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Neither PImax nor the swings in Pes during tidal breathing were altered by endotoxin in any group (Table 1).
Ventilatory Response to Endotoxin
Endotoxin produced an increase in respiratory frequency (p = 0.0001), commencing during the first hour and reaching its maximum at 4 h (Figure 3, upper panel, and Table 2). TI decreased after endotoxin + placebo (p = 0.0006, Figure 3, middle panel ), reaching its nadir at 4 h. Ibuprofen blocked the increase in frequency (p = 0.0001, Figure 3, upper panel) and the decrease in TI (p = 0.05, Figure 3, middle panel ). Endotoxin produced an increase in TI/TTOT (p = 0.018), which was maximal at 4 h (Figure 3, lower panel, and Table 2); the absolute increase in TI/TTOT was similar whether or not ibuprofen was administered in conjunction with endotoxin (n = 12, p = 0.016) and it was maximal at 2 h.
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An increase in VT/TI was seen in all subjects after giving
endotoxin (n = 12, p = 0.01), reaching a peak at 2 h for endotoxin + ibuprofen and at 4 h for endotoxin + placebo (Figure
2, upper panel, and Table 2). Endotoxin produced an increase
in I (p = 0.003) with the maximum change at 4 h (Figure 2,
middle panel, and Table 2). An increase in I was likewise observed when endotoxin was given with and without ibuprofen
(n = 12, p = 0.0001) and was maximal at 2 h for endotoxin + ibuprofen and at 4 h for endotoxin + placebo (Figure 2, middle panel).
Variational Activity of Breathing
Gross variability of breath components, quantified in terms of standard deviation, was unaltered with endotoxin in either the placebo or ibuprofen group (Table 3).
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Time series plots of respiratory frequency and the respective autocorrelograms after administration of saline and endotoxin in a subject from the placebo group are shown in Figure 4. In the placebo group, endotoxin caused increases in the
autocorrelation coefficient at a lag of one breath for frequency
and the number of breath lags with significant serial correlations for frequency (Table 3). In the ibuprofen group, endotoxin caused a decrease in the autocorrelation coefficient at a
lag of one breath for I (p < 0.03) (Table 3); in this group, endotoxin did not change the number of serially correlated
breath lags for any breath component.
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In the placebo group, the number of subjects displaying a significant peak for any breath component was not altered with endotoxin. In the ibuprofen group, three subjects had significant peaks in TE after endotoxin compared with six subjects after saline (p < 0.04; chi-square analysis). Neither the frequency nor the corresponding power of these significant peaks was altered by endotoxin in either the placebo or the ibuprofen groups.
In the placebo group, fractionation of variational activity of
breathing showed that the correlated fraction for frequency increased from 5.76 ± 5.42 (SD) during saline to 9.87 ± 8.58% during endotoxin (p < 0.03), whereas the random fractions for frequency tended to decrease from 93.81 ± 5.39% during saline to 89.93 ± 8.56% during endotoxin (p = 0.06) (Figure 5).
The oscillatory fraction of TI decreased from 0.34 ± 0.38%
during saline to 0.20 ± 0.29% during endotoxin (p < 0.03); the
respective values for the oscillatory fraction of VT were 0.49 ± 0.46 and 0.08 ± 0.11% (p = 0.07). The fractions of I and TE
were unaltered by endotoxin. In the ibuprofen group, the oscillatory fraction of TI decreased from 1.49 ± 1.63% during saline to 0.42 ± 0.64% during endotoxin (p = 0.06); no other
fraction was altered by endotoxin.
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In the placebo group, the change in the random fraction of
frequency after the administration of endotoxin displayed a
negative correlation with the change in PaCO2 (r = 0.87, p < 0.02); the change in the correlated fraction of frequency also
showed a positive correlation with the change in PaCO2 (r = 0.86; p < 0.03) (Figure 6). In other words, the greater the decrease in random behavior of frequency after endotoxin, the
less the change in PaCO2; conversely, the greater the increase
in correlated behavior of frequency after endotoxin, the greater
the change in PaCO2. The same relationships were observed in
the ibuprofen group.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The systemic inflammatory response induced by endotoxin was accompanied by an increase in respiratory drive (primarily mediated through changes in respiratory timing) and dyspnea. Endotoxin increased the correlated fraction of respiratory frequency and decreased the oscillatory fraction of TI. Ibuprofen suppressed the development of fever and the mean and correlated behavior of frequency, but it did not prevent the increase in respiratory drive, the decrease in oscillatory behavior of TI, or the development of dyspnea. These observations suggest that endotoxin has a direct effect on respiratory controller function, independently of its effect on symptoms and fever, and that this effect is partly mediated through the cyclooxygenase pathway.
Ventilatory Response to Endotoxin
Early studies in healthy volunteers given endotoxin revealed a
26% increase in I (2)an increase remarkably similar to the
30% increase in our subjects. That the hyperventilatory response to endotoxin was not abolished by ibuprofen indicates
that it was not mediated by the cyclooxygenase pathway. The
latter finding differs from observations of Revhaug and coworkers (25), who noted that ibuprofen attenuated the hyperventilatory response to endotoxin in healthy volunteers. The
discrepancy between the studies may in part be related to the
different methods for measuring ventilation. Instrumentation
requiring the use of a mouthpiece and noseclips, as employed
by Revhaug and coworkers (25), is known to produce marked
alterations in the pattern of breathing (5); in contrast, ventilation was measured nonobtrusively in the present study. Revhaug
and coworkers (25) measured ventilation intermittently (at 2 h,
4 h, and 6 h) and fed their subjects after 4 h, whereas we obtained continuous breath-by-breath recordings throughout the
experiment and our subjects fasted.
The increase in mean inspiratory flow (VT/TI) secondary to endotoxin was not suppressed by ibuprofen. The latter observation suggests that the effect of endotoxin on the respiratory centers is mediated independently of its effect on symptoms, fever, and cyclooxygenase products. An increase in respiratory drive typically results in increased swings in intrathoracic pressure and combined with the increase in TI/TTOT could contribute to the development of respiratory muscle fatigue in patients with underlying respiratory compromise. An increase in TI/TTOT is of equal importance to the degree of inspiratory effort as a determinant of respiratory muscle fatigue (26, 27). As such, the increase in TI/TTOT with endotoxin is maladaptive, especially in that increases in respiratory effort are common in many critical illnesses.
Although the change in PaCO2 after endotoxin was not significant over the entire 8-h period in either the placebo or ibuprofen group, it was decreased significantly (p < 0.004) at the
4 h pointthe time of the maximal increase in respiratory motor output. The total variational activity of breathing did not
change with endotoxin despite the development of a decrease
in PaCO2. Corfield and coworkers (28) reported that hypocapnia produced an increase in the gross variability of breath components; the extent of hypocapnia (28), however, was much
greater than in our subjects: 24 versus 41 mm Hg. We are not
aware of other studies of gross variability of breath components during endotoxemia in healthy subjects with which to
compare our results.
Variational Activity of Breathing
An increase in correlated behavior of frequency was observed during endotoxin administration. Of the factors modulating the correlated behavior of a breath component, chemical feedback loops are especially important (29, 30). In healthy volunteers, we have observed that hyperoxic hypercapnia strengthened the interrelationship between breath components in neighboring breaths (9). Modarrasezadeh and Bruce (31) also found that variation in PaCO2 was a determinant of breath-to-breath variability. In the present study, the change in the correlated fraction of frequency during endotoxemia was related to the change in PaCO2 (Figure 6), providing further support for the importance of PaCO2 as a determinant of breath variability.
The dependence of frequency on the characteristics of the
preceding respiratory cycle may also be influenced by activation of afterdischargethat is, ventilatory augmentation that
persists after cessation of a primary stimulus (32). Afterdischarge can be activated by stimulating the carotid bodies, for
example, by brief exposure to hypoxia or exercise (33, 34). The
carotid bodies are also activated by catecholamines, which are
released by endotoxin (25, 35). Accordingly, the increase in
correlated behavior of frequency after endotoxin may have
arisen in part through activation of afterdischarge secondary
to peripheral chemoreceptor stimulation (Figures 4 and 5 and
Table 3).
Endotoxin decreased the oscillatory fraction of TI and it tended to have the same effect on VT. The decrease in oscillatory behavior could have resulted from a decrease in the gain of the respiratory control system, secondary to a decrease in circulation time between the lung and the chemoreceptors (11). Such a mechanism is plausible because endotoxin is known to increase cardiac output (1, 3, 12). Of note, the endotoxin-induced decrease in the oscillatory fraction of TI was not abolished by ibuprofen. Previously, we noted that endotoxin-induced alterations in cardiovascular function were likewise not abolished by ibuprofen (12). That ibuprofen did not modulate endotoxin-induced alterations in oscillatory behavior or cardiac output adds support to the notion that the changes in oscillatory behavior in our subjects resulted, in part, from a decrease in circulation time.
Ibuprofen, a cyclooxygenase inhibitor, did not abolish the
endotoxin-mediated increase in respiratory motor output. Ibuprofen did, however, reverse the endotoxin-mediated change
in the correlated behavior of frequency (Table 3). Compared
with endotoxin alone, ibuprofen plus endotoxin decreased the
autocorrelation coefficient for I at a lag of one breath (Table
3). These findings suggest that the cyclooxygenase pathway
may be important in modulating the variational activity of
breathing during endotoxemia.
Dyspnea
The increase in dyspnea after endotoxin followed the time
course of the increases in VT/TI and both were unaltered by
ibuprofen. Respiratory effort and dyspnea are coordinated at
different levels of ventilatory loading and volumes (36). In exercising healthy subjects, another cyclooxygenase inhibitor,
indomethacin, reduced dyspnea in relation to the level of I
(37), an effect not observed in patients with diffuse parenchymal lung disease (38). These data suggest that cyclooxygenase-independent pathways may contribute to the development of
dyspnea during experimental endotoxemia. One such pathway
may be the kallikrein-kinin system, which is known to be activated within 2 h of endotoxin. It is conceivable that the release
of local autocoids, such as bradykinin, can activate unmyelinated nociceptive vagal fibers and produce dyspnea (3, 39, 40).
Another contributing factor to the development of dyspnea may have been the inability of the respiratory controller to vary breath components following infusion of endotoxin. Chonan and coworkers (41) found that subjects became dyspneic when they voluntarily constrained their breathing through tracking various ventilatory patterns. The observed reduction in the random fraction of variational activity of frequency following infusion of endotoxin (Figures 4 and 5 and Table 3) may likewise have contributed to dyspnea in our subjects. These data are the first to suggest that naturally occurring alterations in variational activity of breathing may play a role in the pathogenesis of dyspnea.
In summary, endotoxin increased respiratory drive and
dyspnea independently of symptoms and fever. Endotoxin increased the mean and correlated behavior of frequency, while
decreasing its random behaviorchanges that were abolished
by ibuprofen. The endotoxin-induced changes in the fractions
of variational activity of frequency were a function of the
change in PaCO2. In conclusion, endotoxin produced alterations in respiratory motor output, and the cyclooxygenase
pathway, in part, mediated these alterations.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Anthony Suffredini, M.D., Critical Care Medicine Department, Bldg. 10, Room 7043, National Institutes of Health, 10 Center Drive; MSC 1662, Bethesda, MD 20892-1662. E-mail: asuffredini{at}nih.gov
(Received in original form March 7, 2000 and in revised form February 23, 2001).
Acknowledgments:
Supported by NIH intramural funding and a Merit Review grant from the Veterans Affairs Research Service.
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References |
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REFERENCES
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1. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321: 280-287 [Abstract].
2. Moser KM, Perry RB, Luschinger PC. Cardiopulmonary consequences of pyrogen-induced hyperpyrexia in man. J Clin Invest 1963; 42: 626-634 .
3. Suffredini AF, Shelhamer JH, Neumann RD, Brenner M, Baltaro RJ, Parrillo JE. Pulmonary and oxygen transport effects of intravenously administered endotoxin in normal humans. Am Rev Respir Dis 1992; 145: 1398-1403 [Medline].
4. Tobin MJ, Gardner WN. Monitoring of the control of breathing. In: Tobin MJ, editor. Principles and practice of intensive care monitoring. New York: McGraw-Hill, Inc.; 1998. p. 415-464.
5.
Perez W,
Tobin MJ.
Separation of factors responsible for change in
breathing pattern induced by instrumentation.
J Appl Physiol
1985;
59:
1515-1520
6.
Modarreszadeh M,
Bruce EN,
Gothe B.
Nonrandom variability in respiratory cycle parameters of humans during stage 2 sleep.
J Appl Physiol
1990;
69:
630-639
7. Brack T, Jubran A, Tobin MJ. Effect of elastic loading on variational activity of breathing. Am J Respir Crit Care Med 1997; 155: 1341-1348 [Abstract].
8.
Brack T,
Jubran A,
Tobin MJ.
Effect of resistive loading on variational
activity of breathing.
Am J Respir Crit Care Med
1998;
157:
1756-1763
9.
Jubran A,
Grant BJ,
Tobin MJ.
Effect of hyperoxic hypercapnia on variational activity of breathing.
Am J Respir Crit Care Med
1997;
156:
1129-1139
10.
Jubran A,
Tobin MJ.
Effect of isocapnic hypoxia on variational activity
of breathing.
Am J Respir Crit Care Med
2000;
162:
1202-1209
11.
Khoo MC,
Kronauer RE,
Strohl KP,
Slutsky AS.
Factors inducing periodic breathing in humans: a general model.
J Appl Physiol
1982;
53:
644-659
12.
Martich GD,
Parker MM,
Cunnion RE,
Suffredini AF.
Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal
humans to endotoxin.
J Appl Physiol
1992;
73:
925-931
13. Bornstein SR, Preas HL, Chrousos GP, Suffredini AF. Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. J Infect Dis 1998; 178: 887-890 [Medline].
14. Bornstein SR, Wolkersdorfer GW, Tauchnitz R, Preas HL 2nd,, Chrousos GP, Suffredini AF. Plasma dehydroepiandrosterone levels during experimental endotoxemia and anti-inflammatory therapy in humans. Crit Care Med 2000; 28: 2103-2106 [Medline].
15. Godin PJ, Fleisher LA, Eidsath A, Vandivier RW, Preas HL, Banks SM, Buchman TG, Suffredini AF. Experimental human endotoxemia increases cardiac regularity: results from a prospective, randomized, crossover trial. Crit Care Med 1996; 24: 1117-1124 [Medline].
16. O'Grady NP, Tropea M, Preas HL 2nd,, Reda D, Vandivier RW, Banks SM, Suffredini AF. Detection of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta during experimental endotoxemia and human sepsis. J Infect Dis 1999; 179: 136-141 [Medline].
17.
Vandivier RW,
Eidsath A,
Banks SM,
Preas HL 2nd,,
Leighton SB,
Godin PJ,
Suffredini AF,
Danner RL.
Down-regulation of nitric oxide
production by ibuprofen in human volunteers.
J Pharmacol Exp Ther
1999;
289:
1398-1403
18.
Sackner MA,
Watson H,
Belsito AS,
Feinerman D,
Suarez M,
Gonzalez G,
Bizousky F,
Krieger B.
Calibration of respiratory inductive plethysmograph during natural breathing.
J Appl Physiol
1989;
66:
410-420
19. Baydur A, Behrakis PK, Zin WA, Jaeger M, Milic-Emili J. A simple method for assessing the validity of the esophageal balloon technique. Am Rev Respir Dis 1982; 126: 788-791 [Medline].
20. Chatfield C. The analysis of time series; theory and practice. London: Chapman and Hall; 1989.
21. Tobin MJ, Yang KL, Jubran A, Lodato RF. Interrelationship of breath components in neighboring breaths of normal eupneic subjects. Am J Respir Crit Care Med 1995; 152: 1967-1976 [Abstract].
22. Scheffe H. The analysis of variance. New York: John Wiley & Sons; 1959.
23.
Shapiro SS,
Wilk MB.
An analysis of variance test for normality (complete samples).
Biometrika
1965;
52:
591-611
24. Siegel S. Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill; 1956.
25.
Revhaug A,
Michie HR,
Manson JM,
Watters JM,
Dinarello CA,
Wolff SM,
Wilmore DW.
Inhibition of cyclo-oxygenase attenuates the metabolic response to endotoxin in humans.
Arch Surg
1988;
123:
162-170
26.
Bellemare F,
Grassino A.
Effect of pressure and timing of contraction
on human diaphragm fatigue.
J Appl Physiol
1982;
53:
1190-1195
27. Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997; 155: 906-915 [Abstract].
28. Corfield DR, Morrell MJ, Guz A. The nature of breathing during hypocapnia in awake man (published erratum appears in Respir Physiol 1996;104:89). Respir Physiol 1995; 101: 145-159 [Medline].
29. Khatib MF, Oku Y, Bruce EN. Contribution of chemical feedback loops to breath-to-breath variability of tidal volume. Respir Physiol 1991; 83: 115-127 [Medline].
30. Bruce EN, Daubenspeck JA. Mechanisms and analysis of ventilatory stability. In: Dempsey JA, Pack AI, editors. Regulation of breathing. New York: Marcel Dekker, Inc.; 1995. p. 285-313.
31.
Modarreszadeh M,
Bruce EN.
Ventilatory variability induced by spontaneous variations of PaCO2 in humans.
J Appl Physiol
1994;
76:
2765-2775
32. Cherniack NS, Longobardo GS. Abnormalities in respiratory rhythm. In: Cherniack NS, Widdicombe JG, editors. Handbook of physiology. Bethesda, MD: American Physiological Society; 1986. p. 729-749.
33.
Georgopoulos D,
Bshouty Z,
Younes M,
Anthonisen NR.
Hypoxic exposure and activation of the afterdischarge mechanism in conscious
humans.
J Appl Physiol
1990;
69:
1159-1164
34.
Fregosi RF.
Short-term potentiation of breathing in humans.
J Appl
Physiol
1991;
71:
892-899
35. Heistad DD, Wheeler RC, Mark AL, Schmid PG, Abboud FM. Effects of adrenergic stimulation on ventilation in man. J Clin Invest 1972; 51: 1469-1475 .
36.
Killian KJ,
Summers E,
Basalygo M,
Campbell EJ.
Effect of frequency
on perceived magnitude of added loads to breathing.
J Appl Physiol
1985;
58:
1616-1621
37. O'Neill PA, Stark RD, Morton PB. Do prostaglandins have a role in breathlessness? Am Rev Respir Dis 1985; 132: 22-24 [Medline].
38. O'Neill PA, Stretton TB, Stark RD, Ellis SH. The effect of indomethacin on breathlessness in patients with diffuse parenchymal disease of the lung. Br J Dis Chest 1986; 80: 72-79 [Medline].
39. DeLa Cadena RA, Suffredini AF, Page JD, Pixley RA, Kaufman N, Parrillo JE, Colman RW. Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers. Blood 1993; 81:3313-3317.
40. Coleridge HM, Coleridge JC. Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu Rev Physiol 1994; 56: 69-91 [Medline].
41.
Chonan T,
Mulholland MB,
Cherniack NS,
Altose MD.
Effects of voluntary constraining of thoracic displacement during hypercapnia.
J Appl
Physiol
1987;
63:
1822-1828
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