laboratory and animal investigations
Continuous Negative Extrathoracic
Pressure and Positive End-Expiratory
Pressure*
A Comparative Study in Escherichia coli
Endotoxin-Treated Neonatal Piglets
Thomas G. Mundie, PhD; Kuuleialoha Finn, PhD;
Venkataraman Ralaraman, MRRS; Sneha Sood, MD; and
David Easa, MD
Recent clinical studies have suggested that improve¬
pulmonary gas exchange with the use of
continuous negative extrathoracic pressure (CNEP) in
conjunction with intermittent mandatory ventilation
ment in
(IMV) may be due to increased pulmonary blood flow.
Accordingly, we investigated the effects of CNEP vs
positive end-expiratory pressure (PEEP) in ventilated
neonatal piglets after Escherichia coli endotoxin was
administered to induce pulmonary hypertension. Two
experimental groups of piglets with six in each, were
subjected to three 30-min alternating periods.6 cm
H20 CNEP with 6 cm H20 PEEP, beginning 2 h after
endotoxin infusion. End-expiratory lung volume (EELV)
increased similarly from baseline (13 ±2 mL/kg) with
both CNEP (28 ± 2 mL/kg) and PEEP (29 ± 2 mL/kg). In
addition, the increase in PaC>2 from baseline with CNEP
(106 ± 9 to 135 ± 7 mm Hg) was similar to that with PEEP
(114 ±11 to 132 ±6 mm Hg). Further, no differences
were found in dynamic lung compliance, EELV, lung
resistance, blood gas indexes, or hemodynamics, includ¬
Administered either by continuous negative extrathoracic pressure (CNEP) or positive end-ex¬
^**
piratory pressure (PEEP), end-expiratory pressure is
used in conjunction with mechanical ventilation to
normal lung volume. In addi¬
surface area for gas exchange,
restoration of lung volume with end-expiratory pres¬
sure decreases pulmonary vascular resistance (PVR)
restore and maintain
tion to increasing the
*From the Department of Clinical Investigation Tripler Army
Medical Center (Dr. Mundie), and Department of Pediatrics
Medical Center for Women and Children John A.
Kapiolani
Burns School of Medicine (Drs. Finn, Balaraman, Sood, and
Easa), Honolulu.
Supported
by the US Army Health Services Command and Ka¬
Medical Center for Women and Children. The opinions
piolani
or assertions contained herein are the private views of the authors
and are not to be construed as official or as reflecting the views
of the Department of the Army or the Department of Defense.
Manuscript received September 20, 1993; revision accepted May
6, 1994.
Kapiolani Medical Center,
Reprint requests: Dr. Easa,
Punahou St., Honolulu, HI 96826
1319
ing transmural pulmonary artery pressure and pulmo¬
nary vascular resistance between CNEP and PEEP.
With transpulmonary pressure and transrespiratory pres¬
sure equal, CNEP in tandem with IMV is physiologi¬
cally equivalent to PEEP and IMV.
(Chest 1995; 107:249-55)
Cdyn=dynamic lung compliance; CNEP=continuous neg¬
ative extrathoracic pressure; CO=cardiac output;
EELV=end-expiratory lung volume; Fl02=fraction of in¬
spired oxygen; IMV=intermittent mandatory ventilation;
MAP=mean arterial pressure; Ptp=transpulmonary pres¬
sure; Ptr=transrespiratory pressure; PAP=pulmonary ar¬
tery pressure; PAPtm=transmural PAP; Pao=airway open¬
ing pressure; PEEP=positive end-expiratory prsesure;
Pes=esophageal pressure; PVR=pulmonary vascular resis¬
tance; Rl= lung resistance; SVR=systemic vascular resis¬
tance; Vt= tidal volume; ZEEP=zero end-expiratory pres¬
sure
negative extrathoracic pressure;
end-expiratory lung volume; pulmonary hypertension
Key words:
continuous
to stinting of extra-alveolar pulmonary blood
vessels.1 However, recent reports of improvement in
oxygenation after substituting CNEP for PEEP in
due
mechanically ventilated infants with pulmonary dis¬
have suggested that there may be some intrin¬
sic differences between the two modes of distending
pressure.2"4 Proposed mechanisms include a more
uniform lung expansion as well as improvement in
pulmonary blood flow with CNEP.2"4 Other clinical
reports of using CNEP in infants and children also
have suggested or demonstrated improvement in
pulmonary blood flow.5"7 Experimental evidence for
pulmonary hemodynamic differences between
CNEP and PEEP has been reported by Adams et al,
8 who showed that when referenced to
atmospheric
pressure, pulmonary artery pressure (PAP) decreases
in spontaneously breathing piglets subjected to .8
cm H20 CNEP as compared with +8 cm H20 PEEP.
We recently reported on the pulmonary function
ease
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249
fluid-filled esophageal catheter was placed into the lower third of
the esophagus for measurement of esophageal pressure (Pes).
Catheter placement was validated using the occlusion technique
of Beardsmore et al.13
Vascular catheters were inserted as previously described.9,11,12
A femoral artery catheter was used for blood sampling and mea¬
surement of mean arterial pressure (MAP), while a femoral vein
catheter was used for infusion of normal saline solution, 100
mL/kg/d. A thermodilution catheter measured PAP, pulmonary
arterial wedge pressure and was used for CO determination. Fi¬
nally, a right atrial catheter was used to inject cold dextrose for
CO determinations and to monitor central venous pressure (CVP).
The PVR and systemic vascular resistance (SVR) were calculated
using standard formulas.11 All vascular pressures were reported as
transmural by subtracting end-expiratory Pes.
Lung mechanics were calculated and monitored throughout
the experiment as previously described.9,12 In summary, respira¬
tory flow was measured with a low dead space pneumotachometer (Hans Rudolph, 8131, Kansas City, Mo). The flow signal was
electronically integrated to obtain tidal volume (Vt) and minute
ventilation. In order to provide a measure of pressure across the
lung, we measured Ptp at end-expiration, calculated as the
difference between airway opening pressure (Pao), measured just
proximal to the endotracheal tube, and Pes. Similarly, in order to
provide a measure of pressure across the lung at end-inspiration,
Ptr was calculated as the difference between Paw and body sur¬
face pressure at end-inspiration.9 Values for Vt, dynamic lung
compliance (Cdyn), and lung resistance (Rl) were calculated
from the mean of five breaths. The EELV was measured using the
helium dilution technique (Equilibrated Bio Systems, Melville,
and hemodynamics of anesthetized neonatal piglets;
these piglets were ventilated, had lung lavage with
saline solution, and were treated with either incre¬
mental CNEP or PEEP. No differences were found
in any parameter with the exception of EELV at
certain distending pressures.9 In that study, among
the effects of saline lavage were significant increases
in both cardiac output (CO) and transmural pulmo¬
nary artery pressure (PAPtm), although the increase
in PAPtm was only modest. Since pulmonary hyper¬
tension is a common and serious disorder of the
newborn infant,10 an accurate understanding of the
effects of various ventilator strategies designed to
restore EELV
on
pulmonary hemodynamics is es¬
sential. Thus, we were interested in comparing the
effects of CNEP and PEEP in an animal model of
acute lung injury associated with a more severe form
of pulmonary hypertension. In this study, an infusion
of Escherichia coli endotoxin was utilized to induce
pulmonary hypertension in two groups of piglets
subsequently treated with alternating periods of
CNEP and PEEP. We hypothesized that at equiva¬
lent transpulmonary pressure (Ptp) and transrespiratory pressure (Ptr), there would be no differences
in the effects of CNEP and PEEP on PAPtm and
PVR.
Materials
Animal Preparation
and
Methods
This study was approved by the Institutional Animal Use and
Tripler Army Medical Center and was in
compliance with the Animal Welfare Act. Eighteen neonatal
piglets of either sex, 6 to 11 days old, weighing 2.6 ±0.5 kg, were
anesthetized with pentobarbital as previously described.1112 Af¬
ter intubation with a 3.0- to 4.0-mm cuffed endotracheal tube, the
lungs were slowly inflated once with 100 mL of air to reduce the
effects of pulmonary atelectasis and to standardize lung inflation
history. Mechanical ventilation was initiated at baseline settings:
Care Committee of
peak inspiratory pressure,
12 to 14
cm
H2O; PEEP, 0 cm H2O;
rate, 35 to 45 breaths per minute; inspiratory time, 0.35 s; and
fraction of inspired oxygen (FI02), 0-21. An end-tidal CO2 mon¬
itor was used during animal preparation to maintain PaCC>2 be¬
tween 35 and 45 mm Hg by adjusting ventilator settings. An 8F
Surgery
NY).
Experimental Design
The experimental design is shown in Figure 1. After instru¬
mentation and 30 min of stabilization, piglets were treated with
pancuronium, 0.1 mg/kg (Astra Pharmaceutical Products, Westborough, Mass) prior to taking control values. Paralysis was
maintained throughout with intermittent doses of pancuronium.
Next, E coli endotoxin, 12 Mg/kg (Serotype 055:B5, Sigma
Chemical Co., St. Louis) was administered intravenously over 30
min. For the piglets, an FI02 of 0.5 was maintained for the
remainder of the experiment. Following endotoxin administra¬
tion, they were observed for a 2-h period before application of
distending pressure (CNEP or PEEP) in order to avoid the early
phase of endotoxin-induced pulmonary hypertension character¬
ized by wide fluctuations in PAP (Fig 2). At that time, two
experimental groups of piglets were exposed to three periods of
6 cm H20 distending pressure, either CNEP-PEEP-CNEP (n=6)
or PEEP-CNEP-PEEP (n=6). A third group (zero end-expiratory
Sick
Control
CNEP-PEEP-CNEP
PEEP-CNEP-PEEP
ZEEP-ZEEP-ZEEP
12 jjg/kg
Endotoxin
1.>-
-60
-30
-1.1.1-
30
60
90
120
150
180
210
240
Time (min)
Figure 1.
Experimental design. After piglets were instrumented on ZEEP, initial measurements were
taken (Control), followed by endotoxin infusion. Two hours later, measurements were repeated (sick),
followed by one of three sequences. Two experimental groups (each n 6) were subjected to alternat¬
ing sequences of distending pressure with -6 cm H20 CNEP or +6 cm H20 PEEP, while a third con¬
trol group (n=6) continued on ZEEP.
=
250
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CNEP and PEEP in E coli Endotoxin-Treated Neonatal Piglets (Mundie et al)
Figure 2. Effects of endotoxin in ZEEP control
group. Mean values for pulmonary function and he¬
modynamics in ZEEP control group (n=6) during
and 4 h after endotoxin infusion (solid rectangles).
For clarity, standard error bars have been omitted.
Values for Cdyn given in milliliters per centimeter of
water; Pa02 values given in millimeters of mercury;
CO PVR and SVR values given in millimeters of
mercury /liters per minute per kilogram.
pressure ([ZEEP], control; n=6) was maintained on ZEEP through¬
the experiment. We kept Vt constant by adjusting peak in¬
spiratory pressure settings on the positive-pressure ventilator.
were
Hemodynamic and pulmonary function measurements
taken every 30 min in the two experimental groups and every 15
min in the ZEEP control group. The ZEEP control group was
out
monitored more frequently to accurately describe the effects of
endotoxin. The CNEP was administered in a body-enclosed two-
compartment negative-pressure chamber.4,12,14
Data
Analysis
The experimental design allowed us to compare the effects of
6 cm H20 PEEP with -6 cm H20 CNEP using within group
(one-way analysis of variance for repeated measures) and betweenIn
group (two-way analysis of variance) statistical comparisons.
addition, the effects of CNEP or PEEP in endotoxin-treated pig¬
lets were compared with the ZEEP control group by two-way
was used for multi¬
analysis of variance. Duncan's post hoc test
at p<0.05. Data
ple comparisons. The level of significance was set
in figures and tables are expressed as mean ± SEM. Statistical
analysis was performed using a computer software package
(NCSS, Kaysville, Utah).
When no differences were found between respective data sets,
Time (hr)
Time (hr)
results presented later on represent a combined mean ± SEM
from all three periods of CNEP or PEEP taken from both exper¬
imental groups or all three periods in the ZEEP control group.
Results
Effects of Endotoxin
Figure
2 shows
a
composite of the pulmonary
function and hemodynamic responses to E coli
endotoxin in ZEEP control piglets. Data were col¬
lected at Control, during endotoxin infusion, and for
4 subsequent hours. During and immediately after
the endotoxin infusion (time, 0.5 h), there was a de¬
crease in Cdyn, EELV, PaO2, pH, and CO and an
increase in Rl, transmural MAP, PAPtm, SVR, and
PVR. During a period lasting 1 h following endotoxin
administration, either stabilization or an improve¬
ment in the parameters occurred, except for pH
which continued to decrease. From 1 h after endo¬
toxin infusion (time, 1.5 h), Rl, blood gas indexes, and
CHEST /107 /1 / JANUARY, 1995
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251
o
.
oCM -5
x
350
CNEP-PEEP-CNEP
PEEP-CNEP-PEEP
300-1
a Control
^4
250
^ 2.5 H
rr
> 200
Q.
21
150
o
E
O
100
1.5
50
250
J
1
35
^200 4
30 H
25
E
>
_j
UJ
UJ
150
O 100
15
o
10
50
Sick
Period 1 Period 2 Period 3
Figure 4. Values for PVR and CO before endotoxin infusion
Control
5
160-,
140
w
(Control), after endotoxin infusion (sick), and after three 30-min
periods (periods 1 to 3) in the 3 study groups. Values are mean ±
SEM. Asterisks represent values different from ZEEP control
group (p<0.05). Values for PVR given in millimeters of mercu¬
ry/liters per minute per kilogram.
of three 30-min periods of exposure to alternating
distending pressure with CNEP or PEEP, or in the
ZEEP control group (Fig 1, 3, 4, Table 1).
With appropriate adjustments in peak inspiratory
H
120
O
°^
4
20
10080
60
Control
Sick Period 1 Period 2 Period 3
Figure 3. Cdyn, EELV, and Pa02 before endotoxin infusion
(Control), after endotoxin infusion (sick), and after three 30-min
periods (periods 1 to 3) in the 3 study groups. Control values were
taken in an FI02 setting of 0.21; piglets were then maintained at
an FI02 setting of 0.5 for the remainder of the experiment. Val¬
ues are mean ± SEM. Asterisks represent values different from
ZEEP control group (p <0.05); Pa02 values given in millimeters
of mercury.
hemodynamic parameters began to worsen. The ex¬
perimental sequences with CNEP and PEEP were
started 2 h after endotoxin infusion (time, 2.5 h).
Ventilator Variables-Indexes of Gas Exchange
The data sampling periods are described as fol¬
lows: control, representing sampling after surgery
and stabilization prior to endotoxin infusion; sick,
representing sampling 2 h after endotoxin infusion;
periods 1,2, and 3, representing data taken after each
pressure (ZEEP control, 23.5 ± 1.0 cm H20; CNEP,
20.2 ±0.6 cm H20; PEEP, 26.4 ±0.4 cm H20), Vt
remained constant during the experimental periods
of alternating distending pressure (ZEEP control,
10.3 ±0.3 mL/kg; CNEP, 9.9 ±0.3 mL/kg; PEEP,
9.9 ± 0.3 mL/kg). Values for Ptp are reported only at
end-expiration and for Ptr, only at end-inspiration. In
the ZEEP control group, Ptp was 0, while Ptr
increased significantly from Control (13.3 ±0.9 cm
H20) after endotoxin infusion (23.8 ±1.6 cm H20),
then remained unchanged for the remaining 4 h. In
the experimental groups, Ptp was 0 until subjected to
distending pressure with CNEP (3.0 ±0.1 cm H20)
or PEEP (3.2 ±0.2 cm H20). The Ptr increased sim¬
ilarly after endotoxin infusion (before distending
pressure), as in the ZEEP control group. However,
unlike the ZEEP control group, Ptr increased further
during CNEP (26.2 ±0.6 cm H20) and PEEP
(26.4 ±0.4 cm H20). No differences were found in
Table 1.Transmural Pulmonary Artery Pressure in Three
CNEP-PEEP-CNEP (n=6)
PEEP-CNEP-PEEP (n=6)
ZEEP-ZEEP-ZEEP (n=6)
Groups of Piglets Treated With Endotoxin*
Control
Sick
Period 1
Period 2
Period 3
17±lf
18±0f
16±lf
34 ±2
32±3
34±2
27±lt
27±2f
25±lf
25±3f
34±3
30±3
24±2f
24±2f
27±3f
*Values are mean ± SEM. No differences were found among groups,
f Values different from respective sick period measurement (p<0.05).
252
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CNEP and PEEP in E coli Endotoxin-Treated Neonatal Piglets (Mundie et al)
either Ptp or Ptr between experimental groups at any
point; as expected, some differences were found be¬
tween experimental groups as compared with the
ZEEP control group. Blood pH was similar in the
experimental groups at Control, decreased after en¬
dotoxin infusion, but remained stable during CNEP
(7.29 ±0.01) and PEEP (7.29 ±0.01). No differences
in pH were found between experimental groups.
However, pH was lower in the ZEEP control group
during periods 1 to 3 (7.18 ±0.03), as compared with
the experimental groups. The PaC02 levels increased
from control values in all groups after endotoxin in¬
fusion, remained stable in the ZEEP control group,
but decreased with CNEP (36 ± 1 mm Hg) and PEEP
(36 ± 1 mm Hg). There were no differences in PaC02
between groups. The Pa02 data in Figure 3 showed
no differences between experimental groups; there
were differences between experimental groups and
the ZEEP control group during periods 1 to 3.
Pulmonary Function
The results in this and the following section sum¬
only differences between and within groups
during periods 1 to 3 when piglets were subjected to
CNEP and PEEP. In addition to Pa02, Figure 3
shows changes in Cdyn and EELV. There were no
between or within group differences found in EELV
or Cdyn in the experimental groups during periods
1 to 3. Further, no differences in Cdyn were found
between experimental and ZEEP control groups.
However, EELV was significantly increased in the
marize
experimental groups at 6 cm H20 distending pres¬
sure (periods 1 to 3), as compared with the ZEEP
control groups. Changes in Rl were more variable
(data not shown); no differences were found between
any groups.
Hemodynamic Parameters
Figure 4 shows changes in PVR and CO. There
were no between or within group differences found
with these parameters in the experimental groups
during periods 1 to 3. The only difference found be¬
tween experimental and ZEEP control piglets was
with PVR during period 2; both experimental groups
had lower values than the ZEEP control group. There
were no differences between groups in either PAPtm
(Table 1), SVR, transmural MAP, or heart rate (data
not
shown).
Discussion
Our previous study9 and the results of the present
investigation suggest that from a physiologic point of
view, there is no difference between CNEP in
tandem with IMV and PEEP with IMV when Ptp and
Ptr are equivalent. Both CNEP and PEEP increased
EELV equally, resulting in similar reductions in PAP
and PVR and increases in Pa02. This study offered
the opportunity to explore potential differences in
these forms of ventilation in an animal model char¬
acterized by endotoxin-induced pulmonary hyper¬
tension. In addition to the degree of pulmonary hy¬
pertension, other differences in endotoxin effect, such
as decreased CO, were seen in contrast to the effects
after lavage of the lung with saline solution.9 Our
findings are in accord with previous conclusions re¬
garding negative pressure lung inflation utilizing a
body-enclosed device.15"17 The situation may be dif¬
ferent from a physiologic point of view when the
negative pressure device used is limited to the chest,
as with a cuirass appliance, since this local application
of negative pressure may create a pressure gradient
to encourage venous return and preserve CO.817
The use of CNEP in various respiratory disorders
has been supported by the belief that CNEP is more
physiologic than PEEP. In contrast to PEEP, which
transmits pressure from the proximal airway, CNEP
would seem to more closely approximate the me¬
chanical effects of normal respiration. The combi¬
nation of an internally applied positive and exter¬
nally applied negative pressure may more evenly
distribute the applied forces across both airways and
peripheral lung tissue, leading to uniform lung
expansion.3 However, this potential advantage of
negative pressure has not been confirmed physiolog¬
ically.
Another rationale for the use of extrathoracic
negative pressure originated from the notion that
lung inflation with negative pressure has a beneficial
effect on pulmonary blood flow dynamics. In general,
it was concluded that lung inflation with negative
pressure reduced PVR, while lung inflation with
pressure increased PVR.18"21 These studies
utilized exteriorized1819 or isolated lungs20'21 and
various experimental setups to compare the static
effects of positive- and negative-pressure inflation of
the lung at varying lung volumes and Ptp. Rather
than reflecting differences between negative- and
positive-pressure lung inflation, these results may
have been due to differences in experimental condi¬
tions.119,22 Whereas the positive-pressure lung infla¬
tion setup included the vascular perfusion system at
the same atmospheric pressure,18"20 this system was
located outside of the chamber with negative-pres¬
sure inflation.2021 With negative-pressure lung infla¬
tion, the pressure surrounding the lung was decreased
by a suction device connected to the enclosed cham¬
ber housing the excised lung. Since the perfusion
setup was located outside the chamber, the driving
pressure in the pulmonary circulation and the trans¬
mural pressure across the pulmonary microvasculature both increased, favoring increased blood flow.
Including the perfusion system within the negative-
positive
CHEST /107 /1 / JANUARY, 1995
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253
pressure chamber has been shown to result in iden¬
tical effects on pulmonary hemodynamics to those
obtained with positive-pressure inflation.22
Thus, some of the confusion regarding the effects
of positive- vs negative-pressure lung inflation may
have originated from the failure to properly refer¬
ence vascular and airway pressures.15'23 Since the
lung is composed of two compartments, one poten¬
tially filled with air and the other with blood, the
reporting of any vascular pressure must take into
account the changing positive or negative ambient
fusion. Both -6 cm H20 CNEP and 6 cm H20 PEEP
similarly increased EELV and Pa02 due to the ben¬
eficial effects of distending pressure. Since both forms
of therapy were equally effective, the use of either
CNEP or PEEP may be considered for any individ¬
ual clinical situation. However, in contrast to PEEP,
the administration of CNEP currently requires the
use of cumbersome equipment that limits access to
patient care. We feel that further studies with CNEP
should be focused on improving the design of the
CNEP equipment as well as on issues of clinical util¬
pressure
ity.
generated by
our
experimental
interven¬
tions.1'9'23 Failure to account for this effect may lead
to erroneous conclusions.9'23 For example, comparing
CNEP with PEEP after lung lavage with saline
solution, PAP was similar only when reported as
PAPtm, while uncorrected values (referenced to at¬
mospheric pressure) were different at the higher
distending pressures studied.9 Similarly in this study,
all pressure measurements were reported as trans¬
mural by subtracting end-expiratory Pes. Although
we did not specifically confirm the relationship of Pes
to pleural pressure, other studies have shown a good
correlation, even with increased lung volume.24 Also,
as previously described,9 we used Ptp and Ptr to
compare more accurately the effects of negative and
positive pressure interventions. This was accom¬
plished by subtracting Pes from Pao at end-expira¬
tion as a measure of pressure across the lung at endexpiration (Ptp); subtracting body surface pressure
from Pao at end-inspiration was a measure of pres¬
sure across the lung at end-inspiration (Ptr). By per¬
forming these calculations, it is evident that driving
pressure can be expressed as a positive number with
both positive- and negative-pressure lung inflation.15
A striking effect of endotoxin was the reproducible
biphasic elevation in PAPtm seen during the 4-h pe¬
riod. This was considerably greater in magnitude
than that induced by lung lavage with saline solution
(PAP in mm Hg, low 20s).9 Indeed, the elevation in
PAP demonstrated at the time of the sick period
measurements (PAP in mm Hg, low to mid 30s) was
even greater than after exposure to a hypoxic gas
mixture (FIo2,0.15 [PAP in mm Hg, high 20s]).11 The
other hemodynamic and pulmonary function effects
of endotoxin demonstrated in this study were consis¬
tent with previous studies in swine.25"29 These are due
to the direct effects of endotoxin and the stimulation
or the release of numerous cellular and humoral
mediators, making it an accepted model of adult
respiratory distress syndrome 30
In summary, our results show that by properly
referencing pressures, CNEP or PEEP in tandem
with IMV results in equivalent effects on pulmonary
function and hemodynamics in piglets with pulmo¬
nary hypertension secondary to E coli endotoxin in¬
254
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ACKNOWLEDGMENTS: The authors thank David P. Southall,
MD, MRCP, and Martin P. Samuels, MB, MRCP, for their
help¬
ful suggestions and advice in designing this study, Glenn Hashiro, MS, and Wayne Takenaka, RRT, for technical assistance, and
Kenneth T. Nakamura, MD, and Susan Pelke, RN, for preparing
and reviewing this manuscript.
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