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Combined effects of prolonged prostaglandin E1-induced hypotension and haemodilution on human hepatic function

Fukusaki, M.; Maekawa, T.; Yamaguchi, K.; Matsumoto, M.; Shibata, O.*; Sumikawa, K.*

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European Journal of Anaesthesiology: March 1997 - Volume 14 - Issue 2 - p 157-163



Several methods of reducing the costs and hazards associated with the transfusion of homologous blood have been advocated. Acute pre-operative haemodilution is used increasingly in combination with drug-induced controlled hypotension for blood conservation [1–3]. The coexistence of decreased perfusion pressure and a reduction in oxygen-carrying capacity of the arterial blood may increase the risk of tissue hypoxia. The studies on organ blood flow and tissue oxygenation during normovolaemic haemodilution combined with adenosine- or nitroprusside-induced hypotension for 60 min have been conducted in animal experiments, and it has been reported that oxygen supply to the liver is decreased [4,5]. Thus, a prolonged combination of hypotension and haemodilution may increase the risk of hepato-cellular damage.

Prostaglandin E1 (PGE1) has been used safely to induce hypotension during general anaesthesia for mastectomy [6], total hip replacement [7] and cerebral aneurysm surgery [8]. Since PGE1 maintains hepatic circulation [9] and protects hepatic cells [10], it would be instructive to examine the effect of a prolonged combination of PGE1-induced hypotension and haemodilution on the hepatic tissue metabolism. However, the subject is difficult to survey from a human bibliographic point of view.

The present study was designed to assess combined effects of prolonged PGE1-induced hypotension and haemodilution on the hepatic function in clinical settings.


The subjects of this investigation were 30 ASA Grade I or II patients without hypertension, ischaemic heart disease, cerebral infarction, hepatic disease or renal disease, aged 41–77 years and weighing 41–63 kg, who were scheduled for hip surgery (total hip arthroplasty revision or rotational acetabular osteotomy). The protocol was approved by the hospital's institutional human investigation committee, and written informed consent was obtained from each patient.

Premedication consisted of 0.5 mg atropine and 1 mg kg−1 hydroxyzine, given intramuscularly (i.m.), 1 h before the scheduled time of surgery. Anaesthesia was induced with intravenous (i.v.) thiamylal 4–5 mg kg−1 and fentanyl 2 μg kg−1, and maintained with nitrous oxide in oxygen 60% supplemented with 1.0–1.5% end-tidal isoflurane. Intravenous fentanyl 1–2 μg kg−1 and vecuronium 0.05 mg kg−1 were injected during surgery. Tracheal intubation was facilitated with i.v. vecuronium 0.1 mg kg−1. Ventilation was controlled to maintain end-tidal CO2 tension at 4.7 kPa (NELLCOR N-1000, Nellcor CMI Corp., Kyoto). A radial artery catheter was inserted for continuous monitoring of arterial pressure and to obtain blood samples. Lactated Ringer's solution containing 5% glucose was infused at 15 mL kg−1 before operation, and infusion was continued at a rate of 8 mL kg−1 h−1 during surgery. Additional, lactated Ringer's solution was infused three times the amount of blood lost. Rectal temperature was maintained between 35 and 37°C using a circulating water blanket and by adjusting room temperature.

Prior to surgery, patients were randomly divided into three groups. Group A (n = 10) received controlled hypotension alone, group B (n = 10) received haemodilution alone and group C (n = 10) received a combination of controlled hypotension and haemodilution. In group A, autologous blood (800 mL) was stored prior to surgery. The last date for pre-donation was more than 7 days pre-operation. The haemodilution in groups B and C was carried out after induction of anaesthesia by withdrawing approximately 1000 mL of blood, and with immediate replacement with an equal volume of 3% dextran (average molecular weight 40 000) solution. Controlled hypotension was induced by prostaglandin E1 (PGE1) at a rate of 0.1–0.2 μg kg−1 min−1, and mean arterial blood pressure was maintained at approximately 55 mmHg for 180 min in groups A and C.

Transfusion of autologous blood began when intra-operative blood loss exceeded 400 mL, and intra-operative and post-operative salvage of 600 mL shed blood was with an autologous blood recovery system (Cell Saver HaemoLite 2, Haemonetics Corp., MA, USA) in any group.

Measurements included arterial ketone body ratio (AKBR, aceto-acetate/3-hydroxybutyrate), an index of hepatic cellular function [11], and common clinical blood chemistry, i.e. serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum lactic dehydrogenase (LDH) and total bilirubin (TB). In addition to measurement of AKBR, arterial blood gas, lactate, blood sugar and serum osmolality were measured simultaneously. AKBR was measured by method of enzymatic analysis (enzyme immunoassay kit, KETOREX, Sanwakagaku, Nagoya). Arterial lactate was measured by enzymatic analysis (enzyme immunoassay kit, Determiner LA, Kyowa Medix, Tokyo). Arterial blood gas was analysed using a blood gas analyser (ABL–4, Radiometer Corp., Copenhagen). Blood sugar, SGOT, SGPT, LDH and TB were measured by automatic blood chemistry analyser (Automatic analyser 736-20, HITACHI Corp., Tokyo). Serum osmolality was measured by osmometer (Fiske osmometer model 3400, Fiske MedScience, Inc., MA, USA). Haematocrit value was determined by centrifugation. Measurement of AKBR was made before haemodilution (T0), after haemodilution (T1), 60 min (T2), 120 min (T3), 180 min after starting hypotension (T4), 60 min after recovery of normotension (T5) and on the 1st post-operative day (POD) (T6). Measurements of SGOT, SGPT, LDH and TB were made before haemodilution (T0), 1st POD (T6), 7th POD (T7), 14th POD (T8), 21st POD (T9) and 30th POD (T10).

The data were expressed as mean ± SD. Analysis of variance and Scheffe's test were performed for statistical analysis of AKBR, haemodynamic, metabolic, blood gas and clinical hepatic function data. Student's t-test and analysis of variance were used for statistical analysis of the other data. A P-value less than 0.05 was considered statistically significant.


The three groups were similar in age, weight and operative time, but there were significant differences in intra-operative blood loss, operative infusion volume and operative urinary output (Table 1). No patient received any homologous blood.

Table 1
Table 1:
Patient group characteristics

The changes in haemodynamic, metabolic and blood gas values for group A, group B and group C are shown in Tables 2, 3 and 4, respectively. After haemodilution, haematocrit values showed a significant decrease in groups B and C, and final haematocrit values were 21 ± 2% in group B and 22 ± 2% in group C during surgery. The mean arterial blood pressure was maintained at approximately 55 mmHg for 180 min in groups A and C during PGE1-induced hypotension. Serum glucose concentrations were 150 mg dL−1 or more in each group. PaO2 values were more than 20 kPa in each group throughout the study time. There was no marked acidaemia or alkalemia in any group. Serum osmolality showed no change in any group.

Table 2
Table 2:
Changes in haemodynamic, metabolic, and blood gas parameters in group A (controlled hypotension alone)
Table 3
Table 3:
Changes in haemodynamic, metabolic, and blood gas parameters in group B (haemodilution alone)
Table 4
Table 4:
Changes in haemodynamic, metabolic and blood gas parameters in group C (controlled hypotension combined with haemodilution)

The changes in AKBR in group A, group B and group C are shown in Fig. 1. AKBR showed a significant decrease in group C at 120 min (−40%) and at 180 min (−49%) after the start of hypotension and at 60 min (−32%) after recovery of normotension, whereas it showed no change in groups A and B throughout the study. The value of lactate showed a significant increase in group C at 120 min and at 180 min after the start of hypotension and at 60 min after recovery of normotension.

Fig. 1.
Fig. 1.:
Time course of change of AKBR in group A, group B and group C. The normal range for AKBR is in excess of 0.70. AKBR showed no change in groups A and B throughout the time course, whereas it showed a significant decrease in group C at 120 min (T3) and at 180 min after the start of hypotension (T4) and at 60 min after the recovery of normotension (T5). Data are mean ± SD (n = 10 for each point).† P<0.05 compared with the values at T0.†† P<0.01 compared with the values at T0.* P<0.05 compared with the values at group A.# P<0.05 compared with the values at group B.Abbreviation: group A (controlled hypotension alone), group B (haemodilution alone), group C (a combination of controlled hypotension and haemodilution). AKBR = arterial ketone body ratio.

The changes in the biological hepatic function tests are shown in Table 5. SGOT measured at 1st, 7th and 14th POD showed a significant increase in group C only. SGPT, LDH and TB measured at 7th and 14th POD also showed significant increases in group C only. These values were unchanged in groups A and B after surgery.

Table 5
Table 5:
Changes in clinical hepatic function parameters in group A, group B and group C


In the present study, moderate haemodilution, to a haematocrit of ≈21–23%, was induced by acute haemodilution, and the mean arterial blood pressure was lowered to 55 mmHg. The degree of haemodilution and hypotension was adopted using previously published values, used to reduce surgical blood loss [1,12,13]. The duration of hypotension was about 180 min, which was the time necessary for surgery.

The compensatory mechanisms for haemodilution, i.e. an increase in flow and O2 extraction in the tissues, depends on an increase in cardiac output, and thus, hypovolaemia should be avoided. Oxygen transport and tissue oxygenation are well maintained by cardiac compensation in spite of a decrease in haematocrit close to 20% provided normovolaemia is maintained in man [13,14]. In groups B and C, haemodilution with normovolaemia was maintained because serum osmolalities were within normal range during surgery.

The liver, at least in a pig model, is claimed to compensate for anaemia exclusively by an increased oxygen extraction [15]. In a rat haemodilution model, it has been reported that haemodilution exerts no influence on the energy status of the liver provided the haematocrit is maintained above 20% as judged using the results of the arterial ketone body ratio (AKBR) and the hepatic energy change [16]. Levine et al.[17] showed no effect of prolonged anaemia in baboons, the number of subjects was small, and no other pertubations such as hypotension occurred.

It has been reported that cardiac output, hepatic blood flow and hepatic function were well maintained during sodium nitroprusside or adenosine-induced hypotension in experimental animals [4,5]. Chauvin et al.[18] demonstrated that hepatic blood flow did not decrease, despite a decrease in blood pressure of 20–60% when cardiac index is maintained during sodium nitroprusside hypotension in humans. Thus, cardiac output is the main factor controlling hepatic circulation.

In the present study, AKBR was measured as a metabolic indicator of liver function because it is the least invasive. It has been reported that AKBR is closely correlated with the ketone body ratio in hepatic tissue, reflecting the mitochondrial ratio of NAD+ to NADH [16]. Since the mitochondrial ratio of NAD+ to NADH is an index of mitochondrial oxidative phosphorylation, AKBR has been reported to reflect the hepatic energy state [11]. Thus, a decrease in AKBR (less than 0.70) indicates the damage of the hepatic mitochondrial energy status as a result of cellular damage [11,16]. Although hypoxaemia and hypoglycaemia have also been reported to decrease AKBR. In this study, blood sugar and PaO2 were maintained at levels more than 150 mg dL−1 and 20 kPa, respectively.

AKBR and biological hepatic function tests were unchanged in groups A and B throughout the study. It seemed that hepatic function was well maintained during haemodilution alone or PGE1-induced hypotension alone for 180 min because cardiac output and hepatic circulation were well maintained by normovolaemic haemodilution and PGE1. AKBR showed a significant decrease in group C at 120 min and 180 min after starting hypotension and at 60 min after recovery of normotension. The values of 3-hydroxybutyrate and lactate showed a significant increase at 120 min and at 180 min after the start of hypotension. Significant increases in the SGOT, SGPT and LDH were shown on the 7th and 14th POD in group C. The changes in transaminases and LDH were small and might well be just the reflection of surgical trauma. However, surgical stress was similar in the three groups, but the changes in biological hepatic function tests were increased significantly in group C only. It appears that as the hepatic mitochondrial energy status was suppressed by the impaired hepatic circulation, 3-hydroxybutyrate showed a significant increase and AKBR consequently showed a significant decrease.

PGE1 has been reported to maintain cardiac output [19] and perfusion in the liver [9], and to protect the hepatic cells, i.e. the stabilizing effects on cellular membranes [20]. However, hepatic oxygen delivery might not be maintained during a prolonged fall in perfusion pressure and a reduction in the oxygen-carrying capacity of arterial blood. Lejus et al.[21] reported that whole body oxygen delivery becomes inadequate below a wide range of haemoglobin levels during haemodilution and deliberate hypotension in the dog, and in such a situation, oxygen delivery was uninfluenced by changes in cardiac output because of hypotension. The study indicates the protective role of anaesthesia, i.e. decreased oxygen demand.

The results suggest that a prolonged combination of more than 120 min of PGE1-induced hypotension and moderate haemodilution would cause a mild impairment of hepatic cellular function.


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Controlled Hypotension, haemodilution; Pre-operative, prostaglandins, prostaglandin E1; Surgery, orthopaedic

© 1997 European Academy of Anaesthesiology