Effect of Propofol Fentanyl Anesthesia on Hepatocellular Integrity During Induced Hypotension
Sohaila H. Omar,
Abdallah M. Dessouki,
Emad S. Osman,
Abla S. El Hadidy,
Hend H. Kamel
Yasser M. Samhan
We undertook a study to evaluate the effects of propofol on hepatocellular
integrity with or without nitroglycerin-induced hypotension using specific
and sensitive markers of hepatic injury. In a randomized controlled study,
thirty adult consented patients aged 22 to 55 years old scheduled for
various urological procedures were allocated randomly to a nitroglycerin
(NTG) or a control group (control) of fifteen patients each. Anesthesia
was induced with fentanyl 2 µg kg 1 and propofol 2 mg kg 1.
For maintenance, propofol infusion 6-10 mg kg 1 h 1
and increments of fentanyl and atracurium were administered according
to the monitored hemodynamic and neuromuscular responses, respectively.
Induced hypotension was achieved in the NTG group using nitroglycerin
infusion started at a rate of 0.5-1 µg kg 1 min 1
and adjusted to maintain a mean arterial pressure (MAP) of 50-65 mm Hg.
Hepatic glutathione S-transferases ( -GST and -GST), hyaluronic acid (HA),
aspartate (AST) and alanine (ALT) aminotransferases were measured before
anaesthesia (T0), 15 min (T1), 30 min (T2),
60 min (T3) after reaching the target threshold of MAP and
24 h after the end of anesthesia (T4). The control group showed
no significant changes in plasma -GST and hyaluronic acid concentrations
while the NTG group showed significantly higher levels in hyaluronic acid
from T0 to T1 (p = 0.016), T2 (p = 0.007)
and T3 (p = 0.003). Also, -GST was increased significantly
in the NTG group from T0 to T2 (p = 0.037) and T3
(p = 0.049). Both enzymes returned back to normal range 24 h after the
procedures (T4). -GST, AST and ALT showed no significant changes
throughout the study period in both groups. Propofol fentanyl anesthesia
had no effect on plasma concentrations of GST and hyaluronate either during
or after surgery. The addition of hypotension is associated with a transient
reversible increase in these enzymes reflecting a minor degree of impaired
With the acknowledgment that almost all anesthetic techniques reduce
liver blood flow (Murray et al., 1992), it would seem wise that
during procedures performed under hypotensive anesthesia, where further
reduction of liver blood flow may be detrimental, the techniques and the
agents used should be those having the least effect on liver blood flow
and hepatocellular integrity. Renewed interest in the use of intravenous
techniques to provide balanced anesthesia has been prompted partly by
the concern of its potential to yield a compensated modulatory effects
on the cardiovascular system, including preserved baroreflex activity
(Win et al., 2007). Moreover, the use of propofol as part of a
TIVA regimen seems to have no influence on hepatocellular function during
and after surgery (Röhm et al., 2005). The measurement of
the hepatic isoenzymes glutathione S-transferases ( -GST and -GST) is
a sensitive and specific method for the detection of acute and early drug-induced
hepatocellular damage (Iwanaga et al., 2000). Serial studies demonstrated
that the endothelial cell is a more susceptible target for the immune
response than the hepatocyte. Since hyaluronic acid (HA) is utilized in
assessing sinusoidal endothelial cell function and perfusion, thus measurement
of serum hyaluronate concentration may even offer a better indicator in
the early assessment of hepatocellular damage (Tran et al., 2000).
The purpose of this study was to assess the effects of propofol fentanyl
anesthesia on hepatocellular integrity during nitroglycerin-induced hypotension
using these specific and sensitive markers of hepatic injury.
MATERIALS AND METHODS
After obtaining personal informed consent and local ethics committee
approval, 30 adult patients aged 22 to 55 years old of either sex (ASA
class I or II) scheduled for various elective urological procedures (nephrolithotomy,
nephrectomy) were studied in Theodor Bilharz Research Institute during
the period from March 2005 till September 2006. Patients with previous
liver disease, obesity, exposure to general anesthesia within the preceding
3 months, renal insufficiency (creatinine >1.5 mg dL 1),
unstable angina, severe uncontrolled hypertension or patients receiving
medications likely to interfere with liver function were excluded from
the study. When induced hypotension was believed to be beneficial, patients
were randomly allocated to a control group (control, n = 15) and a study
group (hypotension induced using nitroglycerin NTG, n = 15) using balanced
total intravenous anesthesia (TIVA) with propofol (Propofol 1%, Fresinius
Kabi Austria GmbH Graz, Austria) and fentanyl. Routine monitoring included
five leads ECG, SpO2, capnography, non invasive blood pressure,
temperature, peripheral nerve stimulator as well as continuous invasive
measurement of mean arterial blood pressure (MAP) (Infinity Kappa, Dräger,
Lübeck, Germany). In both groups, IM midazolam 0.05 mg kg 1
was administered as premedication 30 min before induction of anesthesia,
which was induced by fentanyl 2 µg kg 1, propofol 2 mg kg 1
and tracheal intubation was facilitated with atracurium 0.5 mg kg 1.
For maintenance, propofol infusion 6-10 mg kg 1 h 1
and increments of fentanyl 1 µg kg 1 and atracurium 0.15 mg
kg 1 were administered according to the monitored hemodynamic
and neuromuscular responses, respectively. Induced hypotension was achieved
in the NTG group using nitroglycerin infusion started at a rate of 0.5-1
µg kg 1 min 1 and increased by the same increments
at 2 min interval to maintain MAP of 50-65 mm Hg. A target threshold of
MAP was defined as value of 80-90 mm Hg in the control group and 50-65
mm Hg in the NTG group. Hypotensive episodes were treated by increasing
the rate of fluid administration and/or decreasing propofol infusion in
both groups and reducing the rate of nitroglycerin infusion in the NTG
group. By the end of surgery, propofol and nitroglycerin infusions were
reduced so that MAP gradually returns nearly to its normal level. After
anesthesia, patients were observed for 3 h in the post-anesthesia care
unit and thereafter on the ward. Venous blood (5 mL each) was obtained
from contra lateral antecubital vein of the infusion site before anesthesia
(T0), 15 min (T1), 30 min (T2), 60 min
(T3) after reaching the target threshold of MAP and 24 h after
the end of anesthesia (T4). Heparinized plasma was the preferred
sample matrices. Blood samples were collected in lithium heparin tubes
and centrifuged at 2500 g for ten minutes at 2-8°C within 6 h of collection.
Plasma supernatant was decanted and re-centrifuged at 6000 g for 10 min
at 2-8°C to ensure complete removal of platelets. Plasma was carefully
collected by aspiration and stored at -20°C and samples were assayed for
hepatic -GST, -GST and HA. -GST was measured using the Biotrin High Sensitivity
Alpha GST EIA Kit, Cat. No. BIO60HEPAS-96 wells. It is a quantitative
enzyme immunoassay. -GST was measured using the Biotrin Pi GST EIA-Hman
GST-Pi Kit, Cat.No. Kat.Nr/cat Nb: BIO85-96 wells, which is also a quantitative
enzyme immunoassay. HA measurement was performed using hyaluronic acid
(HA) test kit (Corgenix Inc., Denver, Colorado, USA). Activity of AST
and ALT was measured as routine hospital laboratory test analysis.
Statistical analysis was performed using SPSS software version 10. Data
were expressed as mean±standard deviation. Comparison between the two
groups in the same time was done using Mann-Whitney U-test while comparison
relative to the baseline in the same group was performed using Friedman`s
ANOVA with post-hoc Wilcoxon matched paired t-test. p<0.05 was considered
As regards the demographic data, the total dose of propofol and
the perioperative values, including the duration of anesthesia and surgery,
there was no statistical significant difference between the two groups.
Blood loss as well the amount of crystalloid and colloid fluids given
during the study period were significantly higher in the control as compared
to the NTG group (Table 1). The MAP in the NTG group
was significantly decreased by 15, 30 and 60 min compared with T0
(p<0.05) as well as to the control group at the same timing whereas
no difference was seen in other hemodynamic variables. These changes were
reverted by the end of the procedure until 24 h afterwards (Table
2). Baseline values of -GST, -GST and HA concentrations were within
normal range in all patients and comparable between both groups (Table
3). The control group showed no changes in plasma -GST, -GST and HA
concentrations. -GST increased significantly in the NTG group from T0
(2849.0±642.4 ng L 1) to T2 (3171.0±914.6
ng L 1; p = 0.037) and T3 (3673.0±1623.7
ng L 1; p= 0.049). HA in the NTG group showed also significantly
higher levels from T0 (19.9±3.96 ng mL 1) to T1
(21.6±4.77 ng mL 1; p = 0.016), T2 (24.7±4.97
ng mL 1; p = 0.007) and T3 (27.8±4.83 ng
mL 1; p = 0.003). Both enzymes returned back to normal range
24 h after the procedure (T4). -GST, AST and ALT showed no
significant changes throughout the study period in both groups. No clinical
signs or symptoms of hepatic disorders, gastroenterologic problems or
systemic inflammatory disease were observed in any patient.
||Patient demographics, perioperative data and fluid therapy
|Data are expressed as mean±SD unless otherwise noted,
Control = Control group (n = 15), NTG = Induced hypotension group
(n = 15), *p<0.05, Intergroup comparison
||Mean Arterial Pressure (MAP) and Heart Rate (HR)
Data are expressed as mean±SD, Control = Control
group (n = 15), NTG = Induced hypotension group (n = 15), MAP =
Mean arterial Pressure, HR = Heart rate, T0 = Before
anesthesia, T1 = 15 min, T2 = 30 min, T3
= 60 min after reaching the target threshold of mean arterial pressure,
T4 = 24 h after the end of anesthesia, *p<0.01 versus
the baseline value (T0), ap<0.01 versus
the control group at the same time
||Plasma -GST, -GST, HA, AST and ALT concentrations in
the study groups
|Data are expressed as mean±SD, -GST = -glutathione S-transferase,
-GST = -glutathione S-transferase, HA = Hyaluronic acid, AST = Aspartate
aminotransferase, ALT = Alanine aminotransferase, T0 =
Before anesthesia, T1 = 15 min, T2 = 30 min,
T3 = 60 min after reaching the target threshold of mean
arterial pressure, T4 = 24 h after the end of anesthesia,
Control = Control group (n = 15), NTG = Induced hypotension group
(n = 15), *p<0.05; **p<0.01 versus the baseline value (T0)
centration of GST either during or after surgery (Murray et al.,
1994). The significant increasing hyaluronan level in the NTG group indicates
an undesirable reduction in effective sinusoidal perfusion as previously
stated by Gibson et al. (1993). A static or decreasing level would
permit a more extensive clinical evaluation to proceed with greater confidence
as shown in the control group. No significant changes in aminotransferases
were recorded either in the control group or the NTG group which goes
in accordance with Robinson and Patterson (1985) as well as Fukusaki et
al. (1997), respectively. Furthermore, when propofol was infused at
a rate of 2.1 mg kg 1 h 1 with fentanyl for postoperative
infant sedation in ICU for 48 h, it did not cause any hemodynamic disturbances
and the hepaticen Results from the present study suggest that propofol
per se is not inclined to cause any distortion in the hepatocellular integrity
whereas hepatocellular insult occurred only with superadded hypotension.
Standard biochemical tests of liver function have limited use in the detection
of minor degrees of anaesthetic-related liver dysfunction. In contrast,
measurement of GST concentration in plasma provides a highly specific
test of hepatocellular damage and their results correlate better with
histological changes than do the aminotransferases (Sherman et al.,
1983). Periportal hepatocytes contain the largest concentration of aminotransferases,
but centrilobular hepatocytes, which are relatively deficient in ALT and
AST, are more susceptible to damage from hypoxia (Redick et al.,
1982). GST are readily and rapidly released into the circulation after
hepatic injury; their short half-life (T½< 90 min) allow
earlier detection of hepatic damage than AST (T½ 17 h) and
ALT (T½ 47 h) (Murray et al., 1994). Present results
in the control group where hypotension was not elicited show no significant
changes in -GST throughout the study period as previously reported by
Röhm et al. (2005) while using propofol-remifentanil anesthesia.
Similar results have also been reported during and after 10 h of anesthesia
with propofol (Murray et al., 1994). In vitro studies also
showed that propofol did not exhibit significant inhibition of GST activity
at concentrations less than 1.0 mmol L 1 (Chen et al.,
2000). There are several possible explanations. GST activity is relatively
low among phase-II enzymes in human liver making significant inhibition
more difficult to detect (Chen et al., 2000). It may bind to a
number of anions, such as bile salts, which might inhibit enzymic activity
(Singh et al., 1980). Being a phenolic substitute, propofol might
participate in the conjugation reactions as a hydrogen provider (functional
anion) and bind with GST to reduce its conjugation ability (Deegan, 1992).
Propofol has also been shown to decrease the grade of histopathologic
injury to rat liver by decreasing apoptosis after gut ischemia/reperfusion
through scavenging of reactive oxygen species and peroxynitrite as well
as inhibiting lipid peroxidation (Kaplan et al., 2007). In contrast
to present results, Tiainen et al. (1995), using a propofol infusion
rate of 19 mg kg 1 h 1 without narcotic or muscle
relaxant supplementation, reported a significant increase in -GST from
3.1 to 10 µg L 1. This increase is probably attributed to the
use of such high infusion rate of propofol as a sole anesthetic. Additionally,
Anand et al. (2001) reported a case of hepatocellular injury in
a 17-year-old girl after propofol administration for 1 h 20 min. Liver
biochemistries were performed 6 months before her admission with no clear
preoperative data. Her previous general anesthetics had been associated
with severe postoperative nausea and vomiting as well as a history of
multiple drug allergies. As for -GST in the control group, there was also
no significant change. Being located in the cytoplasm of intrahepatic
bile duct cells (Mattew et al., 1992), this might suggest that
propofol does not have any effects on bile duct cell integrity. The serum
hyaluronate concentration is influenced by the hepatic blood flow as a
result of the delivery of hyaluronic acid to the liver (Arvidsson et
al., 1989). Since no hemodynamic changes were noted in the control
group, this might explain such lack of changes in plasma hyaluronate.
Where literature on impact of different anesthetic agents on hepatic integrity
is rather abundant, yet literature on their impact during hypotensive
technique is rather scarce, especially when using GSTs as biomarkers.
In accordance with our results, Suttner et al. (1999) reported
a similar significant rise of -GST during hypotensive anesthesia with
sodium nitroprusside 90 min after anesthesia induction and returning back
to normal 24 h after surgery. They reported a sustained significant rise
2 h postoperatively which might be related to the use of isoflurane. Moreover,
their duration of hypotension appears to be a key factor in such changes
since its rapid correction during spinal anesthesia (Ray et al.,
2002) caused no disturbance of hepatocellular function as assessed by
plasma GST. Autoregulation persists in vital organs such as the brain
and the myocardium at MAP of 50 mm Hg, while in the gastrointestinal tract
(GIT) and the liver; it exists only to a minor extent. Thus, systemic
hypotension may lead to a decreased splanchnic perfusion and, subsequently,
to a decreased oxygen delivery to the superficial mucosal lining of the
GIT and the liver (Suttner et al., 1999). Maintaining a MAP at
80 mm Hg during prolonged anesthesia with propofol had no effects on the
conzymes, AST, ALT and GGT did not increase significantly (Martin et
al., 1997). Elevated serum levels of aminotranferase activity might
be suggestive of hepatocellular damage. However, measurement of these
enzymes lacks specificity, since a variety of organs other than the liver
contain aminotransferases, which limit the usefulness of these enzymes
as indicators of mild ischemic liver damage (Suttner et al., 1999).
We conclude that propofol fentanyl anesthesia had no effect on plasma
concentrations of -GST and HA either during or after surgery. The addition
of hypotension is associated with transient reversible increase in these
enzymes reflecting a minor degree of impaired hepatocellular integrity.
Further studies would be recommended for assessing the margin of safety
of propofol fentanyl anesthesia in patients with various degree of pre-existing
hepatic dysfunction by serial measurements of -GST and hyaluronic acid.
This study was supported by G. No. T71 from Internal Project Department,
Theodor Bilharz Research Institute. The authors gratefully appreciate
Dr. Tarek M. Diab MD, Assistant Professor of Parasitology, Theodor Bilharz
Research Institute for statistical consultation.
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