Dopexamine and its role in the protection of hepatosplanchnic and renal perfusion in high-risk surgical and critically ill patients

M. C. Renton* and C. P. Snowden

Department of Anaesthesia and Intensive Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, UK

* Corresponding author. E-mail: mcrenton{at}doctors.org.uk

Accepted for publication November 29, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Dopexamine is increasingly being used in high-risk surgical and critically ill patients to preserve hepatosplanchnic and renal perfusion. This systematic review of randomized controlled trials was undertaken to investigate the clinical evidence for using dopexamine in this role.

Methods. Data sources included Medline, Cochrane Library, EMBASE and CINAHL and reference lists of relevant articles. Randomized controlled trials which compared dopexamine treatment with a control group, in high-risk surgical and critically ill adult patients and with primary outcome measures designed to assess hepatosplanchnic and renal perfusion were included. Articles not published in English were excluded.

Results. Twenty-one trials were selected from the literature search. The results suggest that dopexamine may protect against colonic mucosal damage in patients undergoing abdominal aortic surgery and may improve gastric mucosal pHi in general surgical patients, especially those with preoperative gastric mucosal pHi measurements <7.35 and those undergoing pancreatico-duodenectomy surgery. Dopexamine may have beneficial effects on renal perfusion in patients undergoing cardiac surgery but appears to have little or no benefit on gastric mucosal pHi in the same patient population. In critically ill patients none of the studies demonstrated a beneficial effect of dopexamine on either hepatosplanchnic or renal perfusion.

Conclusion. The evidence provided by the existing studies is both inadequate and inconsistent. There is insufficient evidence to offer reliable recommendations on the clinical use of dopexamine for the protection of either hepatosplanchnic or renal perfusion in high-risk surgical patients. Furthermore, there is no current evidence to support a role for dopexamine in protecting either hepatosplanchnic or renal perfusion in critically ill patients.

Keywords: circulation, renal ; circulation, splanchnic ; complications, critically ill patients ; review, systematic ; surgery, cardiac ; surgery, major ; surgery, vascular ; sympathetic nervous system, dopexamine


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients undergoing major surgery are at risk of developing postoperative complications resulting in increased mortality and morbidity, delayed recovery and longer duration of hospital stay. The risk is even greater in patients with multiple preoperative comorbidities, creating a subset of patients who comprise a particularly high-risk group. Similarly, critically ill patients are at increased risk of complications due to illness severity. The aetiology of these complications is multifactorial, but it has been suggested that hepatosplanchnic and renal ischaemia may be significant contributing factors.1 Attention has now focused on developing a therapeutic agent or intervention that may protect these organs by preserving perfusion and preventing the development of tissue ischaemia.

Dopexamine hydrochloride is a synthetic catecholamine with marked intrinsic agonist activity at ß2 adrenergic receptors, less agonist activity at DA1 dopaminergic receptors and weak agonist activity at ß1 adrenergic and DA2 dopaminergic receptors. In addition, dopexamine exhibits indirect sympathomimetic actions mediated by inhibition of neuronal uptake of endogenous catecholamines but it is devoid of any intrinsic action at {alpha} adrenergic receptors.2 The primary indication for dopexamine is as a positive inotrope and vasodilator for use in acute exacerbations of chronic heart failure and in heart failure associated with cardiac surgery. However, it has also been proposed that the unique receptor activity of dopexamine may make it effective in counteracting the vasoconstriction that occurs within the hepatosplanchnic and renal microcirculations during times of physiological stress. In this context, dopexamine may be the ideal agent to protect perfusion to the hepatosplanchnic and renal organs, thereby minimizing ischaemic tissue damage and subsequent organ dysfunction in these high-risk groups.

The aim of this systematic review is to evaluate the evidence for the role of dopexamine in preserving both hepatosplanchnic and renal perfusion in high-risk surgical and critically ill patients.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Relevant primary research relating to the use of dopexamine was identified by searching a number of electronic databases including Medline (1966–May 2003), the Cochrane Library, EMBASE (1980–week 21, 2003) and CINAHL. The databases were searched using dopexamine as a keyword and medical subject heading (MeSH). All citations identified by this search strategy were screened, and those considered relevant to the review were imported into the computer software program Reference Manager 10®. Finally, the reference lists of all relevant literature were reviewed to identify additional papers not indexed in the databases. Studies were selected for inclusion in the review based on the following criteria: a study population of intensive care patients or patients undergoing major surgery, dopexamine infusion as an intervention, outcome measures relating to renal and hepatosplanchnic perfusion and a randomized controlled study design. Papers that were not published in English, trials with no control group, trials with neonates or infants as the study population and articles without full journal publication were excluded. All studies were critically appraised and scored for methodological quality using a modified scoring system described by Heyland and colleagues3 (Table 1). The maximum score awardable was 11. The study designs and outcome variables were too heterogeneous to allow statistical analysis of pooled data; therefore results were compared and contrasted using descriptive analysis.


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Table 1 Criteria used to assess methodological quality

 

    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A total of 351 articles were identified using the search profile described above. Of these, 35 papers reported clinical trials investigating the effect of dopexamine on heptosplanchnic or renal perfusion in major surgical or critically ill patients. Eight of these trials were excluded because no randomization method was reported,411 and a further six were excluded because there were no control groups for comparison.1217 Of the final 21 studies included in the review, 15 investigated hepatosplanchnic perfusion in patients undergoing major surgery, three investigated hepatosplanchnic perfusion in critically ill patients, four investigated renal perfusion in patients undergoing major surgery and one investigated renal perfusion in critically ill patients. The median quality score was 6 (range 2–10). The results are summarized in Tables 2GoGoGoGo7.


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Table 2 Summary of studies investigating effect of dopexamine on hepatosplanchnic perfusion or function in vascular surgery patients

 

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Table 3 Summary of studies investigating effect of dopexamine on hepatosplanchnic perfusion in general surgery patients. ICG, indocyanine green; MOF, multi-organ failure

 

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Table 4 Summary of studies investigating effect of dopexamine on hepatosplanchnic perfusion or function in cardiac surgery patients. CABG, coronary artery bypass graft; ICG, indocyanine green

 

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Table 5 Summary of studies investigating effect of dopexamine on hepatosplanchnic perfusion or function in critically ill patients. SIRS, systemic inflammatory response syndrome

 

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Table 6 Summary of studies investigating effect of dopexamine on renal perfusion or function in surgical patients. CABG, coronary artery bypass graft

 

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Table 7 Summary of studies investigating effect of dopexamine on renal perfusion or function in critically ill patients

 
Dopexamine and hepatosplanchnic perfusion
Three studies explored the effect of dopexamine on hepatosplanchnic perfusion in patients undergoing elective infrarenal aortic surgery (Table 2). Baguneid and colleagues,18 in a sidearm to a multicentre trial, performed pre- and postoperative colonoscopy and mucosal biopsies to assess the degree of colonic mucosal inflammation and ischaemia. There was a significant increase in the number of patients with histological appearance suggestive of mucosal ischaemia and in the degree of mucosal ischaemia in the control group compared with the dopexamine-treated group. However, there were no differences in the immunohistochemical markers of inflammation between the groups. In contrast, Piper and colleagues,19 in a small study of 20 patients, reported no beneficial effect on gastric mucosal pHi following 24 h of dopexamine treatment, although three patients were excluded from analysis because of the use of additional catecholamines. This raises the possibility that dopexamine may have a differential effect on the perfusion of the intestinal mucosa, offering greater protection to colonic than to gastric mucosa in this particular patient population. McGinley and colleagues,20 in a small two-centre study, assessed postoperative gut permeability using the dual sugar absorption method and found it increased in all patients, including those randomized to receive dopexamine. Although well conducted, this trial limited the period of dopexamine treatment to the duration of surgery. This may be insufficient time for dopexamine to have any impact on mucosal integrity. Indeed, it is probable that the intestinal mucosa continues to be at risk of ischaemia well into the postoperative period and therefore would benefit from sustained protection during this time.

Seven trials explored the effect of dopexamine on hepatosplanchnic perfusion in patients undergoing major abdominal surgery (Table 3). Three studies measured gastric mucosal pHi and one assessed mucosal to arterial gradient. Poeze and colleagues,21 in a side-arm to a large multicentre trial, performed a retrospective analysis of the gastric mucosal pHi data from 286 patients. The results suggest that treatment with dopexamine is effective at raising gastric mucosal pHi but only in those patients with preoperative readings <7.35. Similarly, Boldt and colleagues,22 in a well-conducted trial involving patients undergoing pancreatico-duodenectomy surgery, reported a significant improvement in gastric mucosal pHi in patients treated with dopexamine, although four control patients also received treatment with dobutamine. In contrast, Byers and colleagues23 reported no significant differences in gastric mucosal pHi readings between patients treated with dopexamine and control patients, although this trial reported a high mortality rate in the control group. Muller and colleagues24 measured mucosal to arterial PCO2 gradient but found no significant difference between treatment and control patients. However, dopexamine therapy was limited to only 1 h and two patients were excluded because of difficulties in obtaining mucosal estimates. Of the final three studies, Suojaranta-Ylinen and colleagues25 found no improvement in liver blood flow between treatment and control patients, measured using indocyanine green clearance. Bellamy and colleagues,26 in a cross-over study, found a significant improvement in mucosal blood flow, measured using laser Doppler flowmetry, and Kaisers and colleagues,27 also in a cross-over study, reported similar improvements in hepatic venous oxygen saturation in the presence of dopexamine.

Five trials investigated the effect of dopexamine on hepatosplanchnic perfusion in adult patients undergoing cardiac surgery (Table 4). Of these, three assessed the effect of dopexamine on gastric mucosal pHi or mucosa to arterial gradient and reported no benefit from treatment with dopexamine. There were inconsistencies in these studies in that Berendes and colleagues28 included nine patients who received additional treatment with norepinephrine, and four patients were withdrawn from the study by Gårdebäck and Settergren29 because their mucosal was less than their arterial , suggesting errors in measurement. Interestingly, the study by Gårdebäck and colleagues30 included only those patients who developed a low postoperative gastric mucosal pHi but demonstrated no benefit. This contrasts with the work by Poeze and colleagues21 in abdominal surgery. The small cross-over trial by Thoren and colleagues31 suggested that dopexamine was effective at increasing mucosal blood flow, measured using laser Doppler flowmetry, but there was no comment on any improvement in mucosal oxygenation. Furthermore, the increase in blood flow was associated with a similar percentage increase in cardiac output, implying no specific vasodilatory effect of dopexamine on the hepatosplanchnic microcirculation. Sharpe and colleagues32 found no improvement in liver blood flow in patients treated with dopexamine at a dose of 1 µg kg–1 min–1 compared with control patients.

Three studies were identified that explored the role of dopexamine in preserving hepatosplanchnic perfusion in critically ill patients (Table 5). None of the trials reported any beneficial effect. However, this area of research is compounded by difficulties in defining what constitutes a critically ill patient, and all three studies used slightly different selection criteria that may have resulted in different study populations. The large trial by Ralph and colleagues33 included 102 patients and infused dopexamine over a prolonged period. Despite methodological flaws, the authors reported no benefit from treatment with dopexamine on gut permeability or Sequential Organ Failure Assessment (SOFA) scores. Two cross-over studies by Blunt and colleagues34 and Trinder and colleagues35 found no improvement in gastric mucosal pHi in patients treated with dopexamine; however, the identification of a time effect in the second phase of both trials means that their results must be interpreted with caution.

In summary, the evidence available to assess the role of dopexamine in protecting hepatosplanchnic perfusion in surgical patients is inadequate and inconclusive. The validity of the clinical trials is affected by difficulties in measuring hepatosplanchnic perfusion and methodological flaws in the study designs. At best, dopexamine may improve gastric mucosal pHi in general surgery patients whose preoperative gastric mucosal pHi is <7.35 or who are undergoing pancreatico-duodenectomy surgery and it may offer some protection to colonic mucosa in patients undergoing elective infrarenal aortic surgery. There is no evidence to suggest that it protects hepatosplanchnic perfusion in patients undergoing cardiac surgery. Current evidence does not support the use of dopexamine in protecting hepatosplanchnic perfusion in critically ill patients.

Dopexamine and renal perfusion
Four studies explored the effect of dopexamine on renal haemodynamics and function in adult patients undergoing elective high-risk surgery (Table 6). Three trials involved patients undergoing cardiac surgery and one involved patients undergoing infrarenal abdominal aortic aneurysm repair. In those studies taking creatinine clearance as the primary outcome measure of interest, only one, by Berendes and colleagues,28 showed a significant benefit from treatment with dopexamine in patients undergoing cardiac surgery. Three of the four trials only included patients with normal preoperative renal function. However, Dehne and colleagues36 specifically included patients with preoperative renal impairment, an important patient group at risk of developing postoperative renal failure and in which a protective agent would be beneficial. This study failed to show any significant difference in creatinine clearance between treatment and control patients, with or without renal impairment. One potential reason for this negative result is that treatment was terminated at the end of surgery despite the likelihood that the renal organs continue to be at risk of ischaemia into the postoperative period and may benefit from ongoing protection during this time. One study37 measured the renal vascular resistance index and found no difference between patient groups, but the clinical implications of this are not known. The trial involving vascular surgical patients showed no improvement in creatinine clearance with dopexamine treatment.38

Only one study investigated the effect of dopexamine on renal function in critically ill patients (Table 7). However, this trial provides no evidence that dopexamine protects renal function in the population investigated, even following prolonged infusion over several days.33

In summary, one well-conducted study suggests that dopexamine may protect renal function in patients undergoing cardiac surgery with normal preoperative renal function. There is no current evidence to suggest a protective role in either vascular surgery patients or critically ill patients.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There are sound theoretical reasons as to why dopexamine hydrochloride might be effective in maintaining adequate perfusion to both the hepatosplanchnic and renal organs in high-risk surgical patients and critically ill patients. The aims of this review were to evaluate the clinical evidence for this theory. A comprehensive literature search was conducted to identify relevant studies and those satisfying the explicit selection criteria were analysed and discussed. The results suggest that dopexamine may protect colonic mucosa in patients undergoing abdominal aortic surgery and may improve gastric mucosal pHi in high-risk surgical patients, specifically those whose preoperative gastric mucosal pHi is <7.35, and in those undergoing pancreatico-duodenectomy surgery. It may also protect renal perfusion in patients undergoing cardiac surgery but appears to have little or no benefit on gastric mucosal pHi in the same patient population. None of the studies suggested a beneficial effect of dopexamine on either hepatosplanchnic or renal perfusion in critically ill patients. Variations in outcome measures, study populations, treatment protocols and methodological quality created difficulties in combining study results. As a consequence the supporting information is inadequate to provide evidence-based clinical recommendations for the use of dopexamine.

Clinical measurement of the effect of treatment in this area of research is difficult. The hepatosplanchnic and renal circulations are complex systems comprising a number of vascular beds that react in different ways to physiological stresses and pharmacological interventions, in addition to being relatively inaccessible. For these reasons measuring hepatosplanchnic and renal perfusion is technically challenging. Furthermore, the splanchnic organs and kidneys have a great capacity to adapt to reduced blood flow, and therefore reductions in absolute blood flow do not necessarily equate with tissue ischaemia. It is likely to be the adequacy of perfusion, encompassed in the oxygen supply–demand ratio at the cellular level, which is more important. The techniques currently available measure different aspects of organ blood flow, function and oxygenation. All methods have limitations in their reliability and the clinical implications have to be made by extrapolation from association alone. In the studies reviewed the outcome variable used most frequently to assess hepatosplanchnic perfusion was gastric mucosal pHi. This has the advantages that it assesses adequacy of mucosal perfusion and may have some prognostic value in both surgical and critically ill patients,39 but it suffers from poor repeatability and reliability.40 Amongst the many outcome variables used to assess renal function, creatinine clearance was considered the most sensitive. Although there are inherent limitations with this investigation in that creatinine is both secreted and reabsorbed by the renal tubules, endogenous creatinine clearance is easy to measure in the clinical situation and provides a useful index of renal function.41

The efficacy of dopexamine appeared to vary between study populations with surgical patients generally showing greater benefit than critically ill patients. The nature and duration of physiological stresses may be sufficiently dissimilar between these two patient groups to impact on hepatosplanchnic and renal perfusion in different ways, thereby affecting response to treatment. Alternatively, the timing of treatment in relation to the physiological insult is likely to be an important factor. It is known that reperfusion following ischaemia is a major contributing factor in tissue damage1 and the prevention of ischaemia may be more important than reversing it once it has occurred. In surgical patients it is possible to initiate dopexamine therapy before any insult threatens hepatosplanchnic and renal perfusion, whereas in critically ill patients it is inevitably commenced after the physiological insult has occurred. This may partially explain the disappointing results seen in critically ill patients.

Surprisingly, there appeared to be no dose–effect relationship, but duration of therapy may be an important factor in the treatment response. It should be sufficiently long to allow time for improved splanchnic and renal perfusion to have an impact on tissue oxygenation. Poeze and colleagues21 found that 6 h of treatment with dopexamine was required before any significant impact on gastric mucosal pHi was seen, suggesting that this should be the minimum duration. In addition, it would seem logical that treatment should be continued until the perfusion of hepatosplanchnic and renal organs is no longer at risk of compromise. Therefore the optimum treatment regime remains far from clear.

Dopexamine causes vasodilation and this may unmask covert hypovolaemia, necessitating the use of additional volume expansion to maintain blood pressure. Therefore it is possible that patients receiving treatment may also have received excess fluids compared with control patients, and this could potentially explain some of the beneficial effects attributed to dopexamine. Despite the importance of fluid management, only eight out of 21 studies reported the volume and type of fluids given. However, all of these eight studies reported fluid volumes to be comparable between groups, suggesting that, in this context, fluids did not influence the results significantly. Similarly, comparison with other vasodilators did not reveal any consistencies in results, suggesting that vasodilation and additional fluids alone cannot explain the potential benefits offered by dopexamine. More recent work suggests that dopexamine possesses anti-inflammatory properties and may potentially have a role to play in the modulation of the systemic inflammatory response syndrome (SIRS).23 42 However, whether this is due to a direct anti-inflammatory effect or is secondary to protection of gut perfusion and function remains far from clear.

Encouragingly, there was a low incidence of adverse effects associated with dopexamine treatment in the studies reviewed, with very few patients withdrawn from trials because of drug intolerance. The most common reason for terminating treatment was sinus tachycardia, although this was rarely associated with evidence of myocardial ischaemia. Other literature suggests that dopexamine treatment is associated with only limited increases in myocardial oxygen demand and a low risk of cardiac arrhythmias.2 43 Even so, tachycardia is generally considered undesirable in high-risk patients, particularly those with a history of heart disease, and this must be taken into consideration when deciding whether to use dopexamine in individual patients.

Flaws in study methodology further compound interpretation of results. There are many sources of bias that can threaten the internal validity of a clinical trial. Most can be minimized by appropriate randomization, use of control groups and blinding of treatment options; hence only randomized controlled trials were included in this review. Unfortunately, although studies stated that patients were randomized, the method used was often not adequately described and therefore appropriateness could not be ascertained. There is no proven alternative treatment for the protection of hepatosplanchnic and renal organs against which to compare dopexamine, thereby necessitating the use of a placebo control group. Several studies failed to include a control group and were therefore omitted from the review. Blinding of the investigator to treatment option is important in order to minimize assessment bias. Despite this, several trials were non-blinded and others did not make it clear whether or how blinding was achieved. Finally, many of the trials used small sample sizes with a median size of 30 subjects (range 5–286). Only two trials involved more than 50 subjects. Most studies did not justify the initial sample sizes used and several studies were underpowered.

In conclusion, the evidence provided by these studies is inadequate and inconsistent. As a result there is insufficient evidence to offer reliable clinical recommendations on the use of dopexamine for the protection of either hepatosplanchnic or renal perfusion in high-risk surgical patients. There is no current evidence to support a role for dopexamine in protecting either hepatosplanchnic or renal perfusion in critically ill patients.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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6 Smithies M, Yee TH, Jackson L, Beale R, Bihari D. Protecting the gut and the liver in the critically ill: effects of dopexamine. Crit Care Med 1994; 22: 789–95[ISI][Medline]

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17 MacGregor DA, Butterworth JF, Zaloga CP, Prielipp RC, James R, Royster RL. Hemodynamic and renal effects of dopexamine and dobutamine in patients with reduced cardiac output following coronary artery bypass grafting. Chest 1994; 106: 835–41[Abstract]

18 Baguneid MS, Welch M, Bukhari M, et al. A randomized study to evaluate the effect of a perioperative infusion of dopexamine on colonic mucosal ischemia after aortic surgery. J Vasc Surg 2001; 33: 758–63[CrossRef][ISI][Medline]

19 Piper SN, Boldt J, Schmidt CC, Brosch C, Maleck WH, Berchtold C. Influence of dopexamine on hemodynamics, intramucosal pH, and regulators of the macrocirculation and microcirculation in patients undergoing abdominal aortic surgery. J Cardiothorac Vasc Anesth 2000; 14: 281–7[CrossRef][ISI][Medline]

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24 Muller M, Boldt J, Schindler E, et al. Effects of low-dose dopexamine on splanchnic oxygenation during major abdominal surgery. Crit Care Med 1999; 27: 2389–93[CrossRef][ISI][Medline]

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28 Berendes E, Mollhoff T, Van Aken H, et al. Effects of dopexamine on creatinine clearance, systemic inflammation, and splanchnic oxygenation in patients undergoing coronary artery bypass grafting. Anesth Analg 1997; 84: 950–7[Abstract]

29 Gardeback M, Settergren G. Dopexamine and dopamine in the prevention of low gastric mucosal pH following cardiopulmonary by-pass. Acta Anaesthesiol Scand 1995; 39: 1066–70[ISI][Medline]

30 Gardeback M, Settergren G, Ohquist G, Tiren C. Effect of dopexamine on calculated low gastric intramucosal pH following valve replacement. Acta Anaesthesiol Scand 1995; 39: 599–604[ISI][Medline]

31 Thoren A, Elam M, Ricksten SE. Differential effects of dopamine, dopexamine, and dobutamine on jejunal mucosal perfusion early after cardiac surgery. Crit Care Med 2000; 28: 2338–43[CrossRef][ISI][Medline]

32 Sharpe DA, Mitchel IM, Kay EA, McGoldrick JP, Munsch CM, Kay PH. Enhancing liver blood flow after cardiopulmonary bypass: the effects of dopamine and dopexamine. Perfusion 1999; 14: 29–36[Medline]

33 Ralph CJ, Tanser SJ, Macnaughton PD, Sinclair DG. A randomised controlled trial investigating the effects of dopexamine on gastrointestinal function and organ dysfunction in the critically ill. Intensive Care Med 2002; 28: 884–90[CrossRef][ISI][Medline]

34 Blunt M, Young P, Ridley S. A comparison of the effects of dopexamine and prostacyclin in systemic inflammatory response syndrome. Anaesthesia 1999; 54: 313–19[CrossRef][ISI][Medline]

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36 Dehne MG, Klein TF, Muhling J, Sablotzki A, Osmer C, Hempelmann G. Impairment of renal function after cardiopulmonary bypass is not influenced by dopexamine. Ren Fail 2001; 23: 217–30[CrossRef][ISI][Medline]

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43 Boyd O, Bennett ED. Effects of dopexamine hydrochloride in a porcine sepsis model and in high-risk peri-operative surgical patients. Clin Intensive Care 1992; 3: 32–7





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