Effect of adding dopexamine to intraoperative volume expansion in patients undergoing major elective abdominal surgery{dagger}

M. D. Stone, R. J. T. Wilson*, J. Cross and B. T. Williams

Department of Anaesthesia, York District Hospital, Wigginton Road, York YO31 8HE, UK

Corresponding author. E-mail: rjtwilson@doctors.org.uk
{dagger}This article is accompanied by the Editorial.

Accepted for publication: May 28, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The contribution of low-dose dopexamine to outcome, when given to increase cardiac output in patients already treated with fluids during major abdominal surgery, is not yet known.

Method. We carried out a randomized double-blind placebo-controlled trial. All 100 patients studied were given fluid infusions during surgery guided by stroke volume measurements made with an oesophageal Doppler probe. Patients were randomized to receive dopexamine at the rate of 0.25 µg kg–1 min–1 or saline 0.9% (control) for the first 24 h after the start of surgery. The primary outcome measure was the incidence of postoperative morbidity.

Results. There were no statistically significant differences between groups in the incidence of postoperative complications, the length of hospital stay, the incidence of morbidity and the use of critical care facilities. The patients randomized to receive dopexamine had significantly more pre-existing disease than the control patients. Mortality in both groups was significantly less than predicted by the POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) risk prediction score.

Conclusion. We could not demonstrate an advantage to using low-dose dopexamine in high-risk patients during major abdominal surgery.

Br J Anaesth 2003; 91: 619–24

Keywords: anaesthetic techniques, epidural; complications, morbidity; monitoring, intraoperative; pharmacology, agonists adrenergic; surgery, abdominal


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Dopexamine is an inotropic agent that stimulates ß2 and dopamine receptors. Studies of dopexamine in high-risk patients undergoing surgery have been inconclusive. Two trials of preoperative increased oxygen delivery (D·O2) found less mortality and morbidity,1 2 but a multicentre trial found no significant benefit.3 Where dopexamine was clinically effective, it was also found to be cost-effective, despite the apparent costs involved in preoperative admission to the intensive care unit (ICU).4 5

We chose to investigate dopexamine because fluid and dopexamine therapy reduced complications and length of hospital stay compared with a control group and a group given fluid and epinephrine.2

In our previous study of fluid and dopexamine before surgery, the median D·O2 was 604 ml min–1 m–2 in the dopexamine group after fluid administration, and the median dose of dopexamine given was small (0.125 µg kg–1 min–1). All the patients were given at least this dose, even if the target D·O2 had been achieved with fluid treatment only, so the exact role of low-dose dopexamine in high-risk surgical patients remains uncertain.

Preoperative increases in D·O2 in patients before surgery require measurements of cardiac output, usually by pulmonary artery catheter, and carried out in an ICU or high-dependency bed unit (HDU). This can be difficult if these resources are limited, as in the UK. An alternative is to give fluids and inotropes during surgery to increase stroke volume, measured by an oesophageal Doppler probe. This approach can reduce morbidity after cardiac surgery and surgery for fractured neck of femur.6 7

We examined whether low-dose dopexamine gave any additional advantage in reducing morbidity in high-risk patients undergoing major abdominal surgery, who had already received fluid therapy guided by oesophageal Doppler.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
York NHS Trust ethics committee approval for the study was granted and informed written consent was obtained from all patients.

We recruited patients about to have elective surgery for bowel resection, upper gastrointestinal surgery including pancreatic resection, and open resection of urological cancer. We excluded patients having vascular surgery or oesophageal surgery, and those aged less than 60 yr unless they had additional disease, or if formal preoperative fluid and inotrope therapy was considered necessary by the surgical or anaesthetic team.

A standardized anaesthetic technique was used for all patients. Before induction of anaesthesia an i.v. cannula was inserted into a forearm vein. A thoracic epidural was placed under local anaesthesia before induction of anaesthesia. Anaesthesia was then induced with alfentanil 20 µg kg–1 and propofol 1–2 mg kg–1 i.v., and maintained with isoflurane in oxygen-enriched air. Intraoperative analgesia was obtained using an epidural injection of diamorphine 2–3 mg and bupivacaine 0.5%, 0.1 ml kg–1, followed by an infusion of bupivacaine 0.15% and diamorphine 0.005% at 6 ml h–1, which was continued after surgery.

After induction of anaesthesia, an oesophageal Doppler probe was inserted to guide fluid therapy (Deltex Medical, Chichester, UK). After infusion of compound sodium lactate 1 litre during induction of anaesthesia, 250 ml aliquots of Haes-SterilTM 6% (Fresenius-Kabi, Runcorn, UK) were given until the stroke volume did not increase by more than 5% or until a maximum volume of 2500 ml had been given. A target blood pressure was not set; this was left to individual clinicians’ discretion. Central venous pressure monitoring was not used to guide the fluid therapy. Haemoglobin was checked when clinically indicated and red cells were given to maintain haemoglobin concentration between 90 and 110 g litre–1.

Patients were randomized to receive dopexamine or saline 0.9% (control). The hospital pharmacy department prepared the blinded drugs, using a Unix-based computer program for treatment allocation.

The study drug was given by infusion into a peripheral or central vein. The infusion was started after induction of anaesthesia and was either dopexamine 1 mg ml–1 or normal saline 0.9%. The infusion was commenced at the rate of 0.25 µg kg–1 min–1 and maintained for 24 h after the start of surgery.

The patient’s surgical and anaesthetic teams determined most aspects of postoperative care. Patients returned to standard surgical wards unless the clinicians judged that HDU or ITU care was needed. Postoperative pain was managed by the hospital acute pain team, using preset plans. A member of the study team followed up the patients daily for the first 14 days after surgery.

The primary outcome measures were postoperative morbidity, determined by the number of patients developing one or more predefined complications, the length of hospital stay, a postoperative morbidity survey (POMS),8 standardized ratios for morbidity and mortality derived from the POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) score for predicting outcome after surgery,9 and use of critical care beds. Secondary outcome measures were the differences in intraoperative cardiovascular measurements.

We based the sample size of 50 patients per group on data from our previous study, in which the incidence of complications was 60% in the control group and 30% in the dopexamine group.2 Fifty patients per group gives 87% power of detecting a similar difference at the P=0.05 level.

Continuous data were analysed using Student’s t-test and within-group comparison of cardiovascular measurements were analysed with the paired t-test. Non-parametric data were analysed using the Mann–Whitney U-test. Incidences were analysed using the {chi}2-test. A P-value less than 0.05 was considered significant. Where appropriate, 95% confidence intervals were calculated.

Statistical analysis was performed using SPSS for Windows version 10.0 (SPSS UK, Woking, UK) and confidence interval analysis (Trevor Bryant, Southampton, UK; 2000). Analysis was performed on an intention-to-treat basis.


    Results
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 Introduction
 Methods
 Results
 Discussion
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One hundred patients were recruited over 18 months. Groups were well matched for age and surgical risk, as determined by POSSUM data, but the dopexamine group had more pre-existing disease than the control group (Table 1). These data came from records in the notes, letter from the family doctor, or records of treatment for these conditions (Table 1).


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Table 1 Patient details
 
Duration of surgery, blood loss and fluid volumes given were comparable in the groups, with no statistically significant differences (Table 2). Individual surgeons and anaesthetists were distributed equally between the groups.


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Table 2 Surgical procedures and intraoperative data
 
In both groups there were significant increases in corrected flow time, stroke volume, cardiac index and central venous pressure, final values being taken at the end of operation (Table 3). The control group had a significantly higher initial blood pressure than the dopexamine group. Final heart rate, cardiac index and corrected flow times were all significantly greater in the dopexamine group.


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Table 3 Intraoperative cardiovascular measurements: mean (SD). aP<0.001 when comparing final values with initial values within same group; bP=0.001 for between-group comparison; cP<0.05 for between-group comparison; dP=0.01 when comparing final values with initial values within same group; eP<0.01 for between-group comparison; fP<0.05 for between-group comparison. *Not all patients had central venous pressure monitoring. n=23 for control group and n=26 for dopexamine group in this analysis
 
There were no statistically significant differences between groups in the incidence of postoperative complications, the length of hospital stay, morbidity determined by the postoperative morbidity survey, and the use of critical care facilities (Table 4).


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Table 4 Patient complications
 
Five patients died in hospital. In the control group, one patient died of pulmonary embolism 15 days after surgery, and one from bacterial endocarditis after 48 days. There were three deaths in the dopexamine group, one from septic shock caused by bronchopneumonia (9 days), one from septic shock caused by an anastomotic leak (24 days), and one from disseminated malignancy (50 days).

Standardized ratios were constructed for morbidity and mortality 6 weeks after surgery to compare the actual incidences and the predicted incidences derived from the POSSUM score. Mortality was significantly less than that predicted by the POSSUM score in both groups.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We were not able to find a significant advantage of giving dopexamine to patients who had been treated with fluid therapy. This contrasts with findings from our previous work on increasing oxygen delivery before surgery, in which both mortality and morbidity were less in patients treated with fluid and either dopexamine or epinephrine.2 The control group in that study did not receive formal fluid therapy, so the possibility that fluid alone would be just as effective remained unresolved. The present study suggests that increasing circulating volume is indeed as effective; however, the surgical procedures in the previous study were different, including aortic and oesophageal surgery in addition to gastrointestinal surgery. There were two reasons for this difference. First, oesophageal Doppler is of limited value in patients undergoing oesophageal resections or aortic surgery, as measurements can only be obtained before resection in oesophageal surgery and measurements are unreliable during aortic cross-clamping. Secondly, we can only treat selected patients before surgery. Patients having oesophageal or aortic surgery are often clinically considered to require treatment using the fluid and dopexamine protocol from our previous work.

In a multicentre study, Takala’s group3 found that dopexamine did not decrease the mortality, morbidity or length of ICU stay of patients when compared with fluid-resuscitated control patients. However, there were many low-risk patients in that study and a post hoc analysis of the higher-risk patients in the study found a trend to reduced mortality in the low-dose (0.5 µg kg–1 min–1) dopexamine group. We tried to exclude patients at low risk of complications from the present study, and the mortality predicted by the POSSUM score suggests we achieved this. Although the POSSUM scores of the groups were equal, the dopexamine group contained more patients with pre-existing comorbidity, with greater than three times more recorded ischaemic heart disease compared with control. More comorbidity is associated with more postoperative complications and unfavourable outcomes.10 The complication rate in the dopexamine group was less (not significantly so) than that in the control group despite greater comorbidity. The results of this study have to be interpreted with this in mind. Because postoperative complications were less than expected in both groups, a type 2 error is possible because of the small sample size. More than 250 patients per group would be needed to give a study power of 80%, given the complication rates found in this study.

As with the Takala study, we used a fixed dose of dopexamine and did not aim to increase oxygen delivery to a specific value. A fixed dose regime has limitations, but was used to keep the protocol simple and easily applied. Assuming that the benefit of dopexamine found in previous work was from increases in oxygen delivery, we chose a dose of 0.25 µg kg–1 min–1 because our previous work found that most patients achieved oxygen delivery values greater than 600 ml min–1 m–2 with this dose or less. Because stroke volume was increased by colloid infusion, both groups had an increased cardiac index during surgery. Although the increase in the dopexamine group was significantly greater, the mean oxygen delivery in the control group would still have been in the region of 500–550 ml min–1 m–2 assum ing postoperative haemoglobin concentrations of about 100 g litre–1.

The dose of dopexamine that causes clinically important anti-inflammatory effects is not clear because most of the anti-inflammatory effects have been found in the laboratory, with a dose of up to 2 µg kg–1 min–2.11 The dose we used was less (see above). Anti-inflammatory effects include attenuation of cytokine production,11 decreased white cell aggregation at the site of injury,12 decreased intestinal vascular permeability13 and a decrease in inflammatory changes in the bowel after major abdominal or vascular surgery.14 15 If the beneficial effect seen in previous studies were caused by an anti-inflammatory effect, dopexamine could be more effective if given before surgery and the start of inflammation. This remains to be formally tested.

All patients in this study received standard care, consisting of fluid administration guided by stroke volume measurements, a standardized general anaesthetic technique, and postoperative epidural analgesia. This care was associated with less mortality than that predicted by POSSUM scores. The use of the POSSUM score to predict outcome in patients undergoing major surgery should be justified. The POSSUM score was originally developed from a general surgical population in hospitals in the north of England,9 and it is a useful risk-adjustment method of comparing surgical outcomes between different surgeons and surgical units.16 17 The original POSSUM method can overpredict patient mortality, particularly in low-risk patients who are expected to survive surgery.18 In the original POSSUM report, patients were followed up for 6 weeks after surgery, and the algorithms were based on observations during this period. In our previous study the control group had an actual mortality at 6 weeks of 13%, which was exactly that predicted by POSSUM, and thus it appears that POSSUM can predict outcome in patients undergoing high-risk surgery with no formal fluid therapy.

If we assume that POSSUM is a satisfactory prediction tool for our patients, we should consider which parts of the present treatment improved outcome. As mentioned above, increasing stroke volume led to a significant increase in cardiac output, and therefore oxygen delivery, by the end of surgery. Intraoperative fluid therapy guided by flow measurement can also reduce postoperative complications in cardiac surgery and surgery for fractured neck of femur.6 7 The oesophageal Doppler probe is a validated measure of aortic flow,19 but its use is not without problems. It may be less accurate when used with epidurals,20 but the absolute values are less important when assessing specific responses to fluid therapy. To use the oesophageal Doppler requires the patient to be anaesthetized or heavily sedated, and therefore stroke volume monitoring usually has to stop at the end of the procedure. In cardiac surgery, postoperative haemodynamic optimization may further improve outcome, even in a relatively low-risk population.21 Our complication rate may have been reduced further if stroke volume monitoring was continued after surgery.

All the patients in this study received a thoracic epidural for analgesia during and after surgery. Although epidural techniques give better analgesia than systemic opioids,22 23 it is not clear whether outcome for high-risk general surgical patients is improved. In a recent large randomized trial of high-risk patients having major abdominal surgery, thoracic epidural analgesia reduced respiratory complications, but did not affect morbidity or mortality.24 In patients having aortic surgery, postoperative ischaemia and morbidity were no less with thoracic epidural analgesia.25 26 It is unlikely that epidural analgesia alone affected the overall estimated benefit in this study.

More use of critical care facilities improves outcome after major surgery.28 29 The postoperative care of the patients in this study was determined purely by the clinicians responsible for their care. The admission rate to the HDU or ITU was 25%, with a planned admission rate of 9%. Most of the patients studied were in standard postoperative wards. There were no statistically significant differences between those admitted to critical care areas and those managed in standard wards.

In conclusion, we found no advantage of treatment with low-dose dopexamine for patients receiving intraoperative fluid treatment guided by stroke volume measurement. Obtaining a maximum stroke volume is probably the important part of the treatment that reduces mortality to less than that predicted by the POSSUM score. Further studies are needed of the timing of fluid treatment, the value of measurement of the circulation after surgery, and to define patients in whom inotropic support may be beneficial.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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