Venodila tion Contributes

Hypotension in Humans
Michael Muzi, MD, Richard A. Berens,
Thomas J . Ebert, MD, PhD
to Propofol-Media ted
MD, J ohn P. Kampine, MD, PhD, and
Department of Anesthesiology, Medical College of Wisconsin and VA Medical Center,
Milwaukee, Wisconsin
The present investigation explored the possibility
that the commonly observed hypotension that occurs
during induction of anesthesia with propofol might
be related to its ability to produce venodilation.
Thirty-six ASA I and I1 patients who received no
premedication were studied. The first 20 patients
were divided into two equal groups. Hemodynamic
measurements consisted of heart rate, arterial blood
pressure, and forearm venous compliance by occlu-
sive plethysmography. Baseline measurements were
made in awake patients while resting in a supine
position. Repeat measurements were made during
steady-state infusions of propofol (2.5 mg/kg bolus
injection, followed by a continuous infusion at
200 pg.kg-'.min-') or thiopental (4 mg/kg bolus
injection, followed by continuous infusion at
200 pg.kg-'.min- '), 10 min after tracheal intubation
while patients were artificially ventilated. Both anes-
thetics resulted in a significant ( P <0.05) and similar
tachycardia; however, propofol produced significant
decreases in systolic (-30 ? 9 mm Hg) and diastolic
(-11 ? 4 mm Hg) arterial blood pressure. Forearm
venous compliance was significantly increased dur-
ing propofol administration but unchanged in pa-
tients receiving thiopental. In four additional patients
receiving smaller consecutive infusions of propofol
(50 and 100 pg.kg-'+min-'), significant subtle in-
creases in forearm compliance were also recorded.
These increases were not observed in four patients
who received placebo infusions. Thus, one mecha-
nism promoting hypotension during propofol anes-
thesia in humans seems to be related to its direct
effects on venous smooth muscle tone and presum-
ably venous return.
(Anesth Analg 1992;74:877-83)
ropofol is a relatively new intravenous anes-
thetic that has been used for both induction and
P maintenance of general anesthesia. When
propofol has been used for induction of anesthesia, a
recurring observation has been that the hemody-
namic responses, particularly the decrease in arterial
blood pressure, are often more pronounced than
those produced by traditional drugs intravenously
administered to induce anesthesia (1-5). The precise
mechanism(s) of propofol-induced hypotension is
not known. Reductions in arterial blood pressure
have been attributed to decreases in cardiac output or
peripheral resistance, or both. These measurements
have been reported during propofol administration in
numerous studies in humans (3-7). Unfortunately,
the published data are difficult to interpret for several
reasons. First, propofol has been administered to
both healthy and unhealthy patients, and responses
Accepted for publication January 21, 1992.
Address correspondence to Dr. Ebert, VA Medical Center,
112A, 5000 West National Avenue, Milwaukee, WI 53295.
may have been influenced by underlying cardiac,
autonomic, and vascular pathology. Second, numer-
ous types of preoperative sedative/anxiolytic medica-
tions have been used before administration of propo-
fol. These could influence the hemodynamic changes
noted during anesthetic induction.
A recent study (8) in a-chlorolose anesthetized
dogs has provided insight into one mechanism me-
diating hypotension during propofol use. This study
reported that larger volumes of colloids given intra-
venously were necessary to maintain stable cardiac
filling pressures during administration of propofol
compared with thiopental. The authors concluded
that this additional fluid requirement was due, in
part, to a direct effect of propofol on venous smooth
muscle tone. In accordance with these findings, sev-
eral studies in humans (9-11) have demonstrated
large decreases in cardiac filling pressures during the
administration of propofol. Therefore, we explored
the possibility that propofol administration produced
venodilation in humans. If such an effect were
present, it could contribute substantially to the reduc-
0003-2999/92/$5.00 Anesth Analg 1992;74:877-83 877
878 MU21 ET AL.
PROPOFOL-MEDIATED VENODILATION
ANESTH ANALG
1992;74:877-83
tions in cardiac output and systemic blood pressure
often noted during administration of propofol. To
examine this question, we used venous occlusion
plethysmography to evaluate the compliance of the
veins within the forearm during anesthetic induction
with either propofol or thiopental.
Methods
Thirty-six healthy (ASA I and 11) patients (range,
36-65 yr) participated in this investigation. The study
protocol was approved by the Human Research Re-
view Board of the institution, and informed consent
was obtained from each participant. Only patients
scheduled for elective surgery participated in this
research. Patients were not receiving vasoactive med-
ications, and each abstained from oral intake for at
least 8 h before the testing session. All preoperative
medications were withheld. On arrival in the operat-
ing room, an 18-gauge intravenous catheter was
inserted into the right arm, and 10 mL/kg of normal
saline solution was administered over 20 min. Pa-
tients were recumbent, with their left elbow slightly
flexed and resting on a sandbag, and the wrist was
suspended above the heart level at an angle of 80"
from the horizontal. A double-stranded, mercury-in-
Silastic, temperature-compensated strain gauge was
placed around the forearm at its greatest girth. An
18-gauge cannula was inserted into a superficial vein
of this forearm, and the tip of this catheter was
positioned under the strain gauge at midforearm
level to record vein pressure. Venous pressure was
monitored with a transducer placed at the horizontal
level of the catheter tip and connected to a storage
oscilloscope, ink writing recorder, and a computer.
Forearm venous pressure was increased by inflating
an upper arm cuff. In study 1, three different occlud-
ing pressures were used (20, 30, and 40 mm Hg), and
each was maintained for 90-120 s while the circum-
ferential expansion of the forearm (strain gauge) was
recorded. Measurements of arm girth and forearm
vein pressure were taken approximately 30-40 s be-
yond the point at which superficial vein pressure
stabilized (Figure 1). At this time, superficial, deep,
and other small vessels were assumed to be fully
distended and stable. The venous occluding cuff was
then released until forearm girth and vein pressure
returned to baseline, at which time a new inflation
pressure was applied. Venous compliance was calcu-
lated at each inflation pressure as the change in arm
volume (mL) per change in vein pressure (mm Hg),
as previously described (12). Compliance curves were
obtained by plotting the relationship between vein
pressure and forearm volume (Figure 2). Whenever
time permitted, each intensity of cuff inflation was
repeated, and the data from duplicate trials were
averaged. Heart rate was monitored from lead I1 of
the electrocardiogram, and blood pressure was mea-
sured at 2-min intervals by a noninvasive automated
oscillometric blood pressure device.
In study 1, after awake baseline compliance data
were obtained, patients were randomized to receive
either thiopental (4 mg/kg bolus injection, followed
by a continuous infusion of 200 pg.kg-'.min-') or
propofol (2.5 mg/kg bolus injection, followed by a
continuous infusion of 200 pg.kg-'.min-'). Vecuro-
nium (0.1 mL/kg) was used for neuromuscular block-
ade before intubation. Controlled ventilation with
70% nitrogen and 30% oxygen was used in a semicir-
cle system, End-tidal CO, (mass spectrometer) was
maintained between 35 and 40 mm Hg. Ten minutes
after tracheal intubation, venous occlusion trials were
repeated.
In a separate group of eight patients randomized
to receive thiopental ( n =4) and propofol ( n =4) in
an identical fashion to those described above, the
spectral edge was recorded from a four-lead lifescan
system (Neurometrics, San Diego, Calif.). The spec-
tral edge represented the frequency below which 95%
of the electroencephalographic power was located.
These recordings served as an index of anesthetic
depth to aid in our assertion that the chosen anes-
thetic doses and infusion rates were probably equi-
potent.
In study 2, arm compliance readings were obtained
at lower propofol infusion rates in an additional four
patients who were awake and breathing spontane-
ously. Each received a 12-min infusion of propofol at
50 pg.kg-'.min-', followed by an 8-min infusion of
100 pg.kg-'.min-'. Vein compliance measurements
at cuff inflation pressures of 20 mm Hg were obtained
before and at the 12th and 20th minute after initiating
the propofol infusion. Four volunteers served as time
controls and received saline infusions (single-blinded
study design). Heart rate and blood pressure (by aus-
cultation of Korotkoff sounds) were obtained at these
respective time points as well. End-tidal CO, measure-
ments were monitored from modified nasal prongs.
Group data are expressed as mean values ? SEM.
Analysis of variance was used to determine differ-
ences between group responses. Two-way analysis of
variance for repeated measures was used to deter-
mine whether responses differed during awake and
anesthetized situations. Post hoc testing to determine
significance at individual points on the compliance
curves were done with Dunnett's t-testing. Re-
sponses were considered significant if P <0.05.
Results
The age, height, weight, and ASA classification of the
patients did not differ between groups in study 1 or
ANESTH ANALG
1992;74:877-83
Awake
I
MU21 ET AL. 879
PROPOFOL-MEDIATED VENODILATJ ON
Anesthetized
(propofol)
I
A
forearm
girth,
mm
forearm 4
vein
pressure,
mm Hg
J.
40 1
L
O t - L
t
cuff inflation
to 40 mm Hg
t
cuff
release
t
cuff inflation cuff
to 40 mm Hg release
Figure 1. An original tracing from one patient that demonstrates forearm girth and forearm vein pressure changes (A) during upper arm
venous occlusion at 40 mm Hg. This tracing demonstrates that venous occlusion produces a gradual increase in forearm vein pressure in
this subject while awake. Ten minutes after tracheal intubation, during propofol anesthesia (200 pg.kg '.min - I ) , the same venous
occlusion produced a more rapid increase in forearm vein pressure and a greater absolute change in forearm girth (right half of diagram).
The downward arrow in each diagram represents the point at which absolute changes in forearm vein pressure and forearm girth were
derived. This point was taken 40 s after stabilization of forearm vein pressure.
study 2. Baseline hemodynamics recorded from 20
patients while awake and 10 min after tracheal intu-
bation are shown in Table 1. There were no differ-
ences between groups in awake resting heart rate or
blood pressures. Propofol produced a more profound
reduction in both systolic and diastolic pressure com-
pared with individuals receiving thiopental.
Figure 1 is a representative recording from one
patient while awake and after induction of anesthesia
with propofol. Changes in forearm vein pressure
were similar under both situations; however, the
rapidity and magnitude of changes in forearm girth
were markedly enhanced after the administration of
propofol. Figure 2 summarizes the changes in the
compliance curves produced by thiopental (left) and
propofol (right) and illustrates a significant augmen-
tation in the compliance curve (upward shift) during
the administration of propofol.
In the subset of eight patients in which the spectral
edge of the electroencephalogram was recorded, the
awake spectral edge averaged 19.1 ? 2 in the group
scheduled to receive propofol, whereas the awake
spectral edge of the group scheduled to receive
thiopental averaged 18.7 * 2.2. Ten minutes after
tracheal intubation while continuous infusions of
these drugs were being administered, patients receiv-
ing propofol had an average spectral edge of 11.6 ?
0.6, whereas those receiving thiopental had a mean
spectral edge of 11.2 & 0.7. These changes were not
significantly different.
In patients receiving sedative infusion doses of
propofol in study 2, end-tidal CO, and respiratory
rate did not change. Systolic and diastolic blood
pressure decreased significantly in the group receiv-
ing propofol, whereas these variables were un-
changed in the time control group (Figure 3). In
addition, sedative doses of propofol produced a 28%-
34% increase in the forearm volume compared with
the baseline (before propofol) conditions. This con-
trasted markedly with the stable response in the
forearm of the time control group (Figure 3).
Discussion
The present study has documented in healthy ASA
class I and I1 individuals that anesthetic induction
880 MU21 ET AL.
PROPOFOL-MEDIATED VENODILATION
ANESTH ANALG
199274:877-83
during thiopental
A
f or ear m
vol ume,
mi
I awake
-.-.*.-. during propofol
0 10 20 30 40
venous distending pressure, mm Hg
Figure 2. Average compliance curves generated from patients while awake and anesthetized. The left panel demonstrates that thiopental
administration (4 mglkg bolus injection, followed by infusion at 200 pg.kg-'.min-') does not alter the compliance curve. The right panel
demonstrates that propofol (2.5 mg/kg bolus injection, followed by infusion at 200 pg.kg-'.min-') produces a significant upward shift in
the compliance curve. *P <0.05.
Table 1. Hemodynamic Responses to Induction of Anesthesia (Study 1)
Thiopental infusion Propofol infusion
Awake Awake
baseline baseline
value Anesthetized' A value Anesthetized" A
Heart rate 61.2 2 3.1 73.2 ? 4.4 12.0 2 3.2" 58.6 2 3.9 67.7 t 3.2 9.1 2 3.5'
(beatslmin)
Systolic pressure 145.0 t 9.8 138.0 ? 6.9 -7.1 2 5.2 140.0 2 7.2 110.0 * 8.1" -30.0 * 9.8"'d
(mm Hg)
(mm Hg)
Diastolic pressure 72.7 t 5.9 77.5 ? 3.9 4.8 2 4.1 73.9 2 2.9 62.8 ? 4.2l -11.1 t 4.7."
Sample size 14 14 14 14
Data are expressed as mean values 2 SEM.
'Anesthetized data obtained 10 min after tracheal intubation
bP <0.01, significant change (A) fromawake baseline value.
' P <0.05, significant change (A) fromawake baseline value.
dP <0.05, differences between groups.
and maintenance with propofol produces larger de-
creases in arterial blood pressure than with thiopen-
tal. Ten minutes after tracheal intubation, systolic
blood pressure had declined by 21%, and diastolic
blood pressure had declined by 15% in patients
receiving propofol. This contrasts markedly with
those receiving thiopental in whom neither systolic
nor diastolic pressure was significantly changed from
awake baseline values. One mechanism whereby
propofol produced hypotension has been docu-
mented in the present study. We have demonstrated
a propofol-mediated augmentation in venous compli-
ance. It is estimated that approximately 70% of the
circulating blood volume is contained within the
venous system (13). Thus, it is conceivable that if the
significant changes noted in the forearm veins occur
throughout the vascular system during propofol ad-
ministration, then decreases in cardiac filling pres-
sures and, presumably, decreases in cardiac output
would occur.
The observed changes in the forearm veins pro-
duced by propofol could be due to several mecha-
nisms: (a) direct effects of propofol that alter the
viscoelastic properties of the vascular smooth muscle;
(b) indirect effects of propofol that lead to reductions
in sympathetic outflow and sympathetically medi-
ated venomotor tone; or (c) indirect effects of propo-
fol to reduce circulating humoral substances involved
in maintaining basal levels of venomotor tone. Sev-
eral lines of evidence provide insights that help
clarify these possible mechanisms. Goodchild and
Serrao (8) studied chloralose-anesthetized dogs in
which all neurogenic cardiovascular reflexes were
abolished. The authors estimated changes in capaci-
ANESTH ANALG
1992;74:877-83
6
5
A
MUZI ET AL. 881
PROPOFOL-MEDIATED VENODILATION
0 mntml (baseline) response
H durlng propotol50 p@@hnin ci pkebo
-m c t u r i ~ p o p o ~ i w ~ r n l n w ~
-xsp I150 140. 125. 116 112 112
XDP - 62 78' 71' 67 67 85
vol ume, "
ml
2
1
0
propofol time control
group (placebo) group
Figure 3. The changes (A) in forearm volume recorded in study 2
(during venous occlusion of 20 mrn Hg) in four patients receiving
propofol and in four patients serving as a time control and
receiving only placebo (saline infusion) are depicted. Propofol
caused a significant increase in forearm volume (*P <0.05)
compared with responses recorded in the control (before propofol)
condition and compared with responses recorded in the time
control group. Propofol also caused a significant decrease in
average ( x ) systolic and diastolic blood pressure.
tance by quantitating the amount of intravenous
volume necessary to maintain venous pressure and
pulmonary artery occlusion pressure at control values
during propofol administration. They demonstrated
that lower blood concentrations of propofol selec-
tively produced venodilation, whereas higher con-
centrations produced both venous and arteriolar di-
lation. They concluded that in the absence of
neurogenic tone, propofol had direct actions on vas-
cular smooth muscle. A second study (14) examined
the vascular effects of propofol on isolated rat veins
and arteries that were preconstricted with potassium.
Propofol caused a direct relaxation of both venous
and arterial smooth muscle, and the venous effects
occurred at lower propofol concentrations than the
arterial effects.
Finally, several previous studies in humans have
demonstrated that neurogenically mediated forearm
venous tone is minimal: venous tone in the extremi-
ties of resting supine patients is not altered by ad-
ministration of a ganglionic blocking drug or by
regional anesthesia (15). Moreover, the muscle veins
of the forearm appear to react minimally to sympa-
thetic stimuli (16,17). These observations, along with
the previous in vivo and in vitro data, suggest that
the effect of propofol on venous smooth muscle of the
forearm is for the most part direct.
Unfortunately, there is not a good routine clinical
indicator of changes in venous tone during anesthetic
induction. Some investigators have demonstrated
reductions in cardiac filling pressures and central
venous pressure during anesthetic induction with
propofol (9-11). However, these changes could be
due to a reflection of decreases in myocardial func-
tion, changes in the resistance ratio between precap-
illary and postcapillary vessels, or venodilation.
Another finding of interest in this study was the
lack of a change in venous compliance in patients
receiving sodium thiopental. This is in contrast to a
previous study by Eckstein et al. (15) in 1961, in
which a water plethysmograph was used to deter-
mine pressure-volume curves in the forearm veins of
relatively healthy surgical patients. The authors dem-
onstrated a significant increase in forearm vein com-
pliance during administration of thiopental. Patients
received no premedication, as in the present study;
however, measurements were made in the forearm
after thiopental was titrated in doses sufficient to
reduce mean arterial pressure by 10-15 mm Hg. The
total dose of thiopental varied from 400 to 900 mg
over periods that ranged from 20 to 40 min. Thus, it
is possible that if higher doses of thiopental were
used in the present study (sufficient to lower systemic
blood pressure), an enhanced compliance of the
forearm veins might have been evident. However,
the present study design used more clinically rele-
vant doses of thiopental to compare with propofol.
The validity of the method used in this study is
based on the likelihood that alterations in the forearm
pressure-volume relationship are strictly due to
changes in postcapillary constriction or dilation. In-
creases in arterial inflow to the forearm will increase
the rapidity of the stabilization of forearm vein pres-
sure during each venous occlusion (as noted in Figure
1) but should not influence the absolute change in
forearm volume. The increased rate of filling of the
forearm veins during propofol administration is
strong evidence for arterial vasodilation. We do not
wish to exclude this mechanism as an additional
contributor to the hypotension noted during admin-
istration of propofol. For example, administration of
propofol clearly reduces peripheral arterial resistance
in patients undergoing cardiopulmonary bypass (9)
and in patients on a J arvik-7 artificial heart (18).
Moreover, in several studies (3,5-7,19) propofol has
been shown to reduce myocardial function, although
in some cases these changes in myocardial function
could be attributed to reductions in cardiac preload.
Although this study is one of the first studies in
humans to investigate the hemodynamic conse-
quences of propofol without any other sedative/
anxiolytic premedication or coadministered inhaled
or intravenous anesthetic and has provided clear
evidence that propofol can increase compliance of the
veins in humans, precise interpretation of our data
has some inherent limitations. We cannot be certain
that the infusion doses of thiopental and propofol
chosen for this study were equipotent. Our initial
882
MUZl ET AL.
PROPOFOL-MEDIATED VENODILATION
intent was to provide a dose-response relation with
propofol and vein compliance. In preliminary stud-
ies in two patients, induction of anesthesia with
2.5 pg.kg-'.min-' of propofol and maintenance at
100 pgkg-'.rnin-' was insufficient to maintain anes-
thetic depth. In these patients, signs of lightening of
anesthesia were noted 5 min after tracheal intubation
(tachycardia, hypertension, and lacrimation). The
ED,, for propofol has been shown to be achieved
with an infusion rate of 108 pg.kg-'.min-'; however,
this was determined while N,O was coadministered
(6). Wearbitrarily doubled the dose of propofol and
found that it maintained a level of anesthesia of
sufficient depth to complete the arm measurements.
Although quantification of the spectral edge of the
electroencephalogram is not a precise indicator of
anesthetic depth, it may be reasonable. The spectral
edge has been shown to be progressively reduced
with increasing plasma concentrations of thiopental
(20) and is transiently increased during periods when
anesthetized patients have awareness (21). Thus, we
believe that this measurement provides reasonable
estimates of anesthetic depth in unstimulated pa-
tients with normal cerebral perfusion and autoregu-
lation. Both thiopental and propofol reduced the
spectral edge to the same extent, suggesting that
anesthetic depth was similar during the thiopental
and propofol infusions.
To provide some insight as to whether lower doses
of propofol could cause venodilation, a second series
of studies was carried out in eight subjects, four of
whom received sequential infusions of propofol at 50
and 100 pg.kg-'.min-' and four who served as time
controls and received placebo infusions. It was ap-
parent that propofol produced venodilation even in
sedative doses, which did not result in loss of con-
sciousness. Associated with this augmentation in
venous compliance was a significant reduction in
arterial blood pressure in the patients receiving
propofol. These additional data raise the possibility
that small doses of propofol produce near maximal
changes in vein compliance. This issue could not be
precisely addressed in our study because of problems
in obtaining well-controlled dose-response relations
(i.e., comparing low-dose infusion data in awake,
spontaneous breathing patients with higher dose
data in anesthetized, ventilated patients). However,
the change in venous volume produced by a 20-mm
Hg occlusion pressure was augmented by 28%-34%
in patients receiving 50 and 100 pg.kg-'.min-' infu-
sions of propofol. This augmentation was only
slightly larger (37% 5 6%) in patients who were
anesthetized with a 2.5-mg/kg bolus in'ection, intu-
bated, and maintained on a 200-pg.kg-'-rnin-' infu-
sion of propofol. These data suggest that a large
ANESTH ANALG
1992;74:877-83
proportion of the venodilating effect of propofol
occurs at lower concentrations of the drug.
In summary, we have demonstrated that sedative
and anesthetic doses of propofol increase the compli-
ance of the forearm veins in humans. Based on this
study and the existing literature, we speculate that
this effect is due to a direct influence of propofol on
venous smooth muscle. If the change noted in the
forearm bed occurs throughout the venous system,
then it is likely that increases in venous capacitance
contribute in an important way to the hypotension
noted during the administration of propofol. These
findings support the recommendations that judicious
administration of intravenous fluids to replace fluid
deficits and supplement intravascular volume could
minimize the hypotension noted during the admin-
istration of propofol anesthesia (9-11).
We acknowledge the assistance of Deanne Trzcinko and Toni
Denahan in all phases of this research.
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