Should perioperative management target oxygen delivery?

S. J. Mackenzie1

1 Department of Anaesthetics, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 5SA, UK E-mail: simon.mackenzie{at}luht.scot.nhs.uk

Several strategies have been proposed to improve outcome after surgery. One of these is the use of fluids and catecholamines to achieve ‘supra-normal’ oxygen delivery, an approach variously termed ‘goal directed therapy’, ‘pre-optimization’, and ‘haemodynamic optimization’. This attractive concept is the basis of the study by Stone and colleagues,1 published in this issue of the journal. In this placebo controlled trial, patients who were given dopexamine at a rate of 0.25 µg kg–1 min–1 during surgery and for 24 h thereafter had a significantly higher cardiac index than patients given placebo, but morbidity and mortality were unaffected. Fluid therapy was used to increase stroke volume, measured using an oesophageal Doppler, before commencing the dopexamine. Oxygen delivery was not measured but the authors’ estimate, that it would have been between 500 and 550 ml min–1 m2 in the placebo group and over 600 ml min–1 m2 in the dopexamine group, is likely to be accurate. The mortality rate in both groups was less than the rate predicted using the POSSUM scoring system, an observation that the authors consider significant and suggest is likely to be attributable to the targeting of stroke volume. What does this study add to our understanding of the role of dopexamine and of attempts to target oxygen delivery?

Dopexamine

With regard to the specific role of dopexamine, the results of Stone and colleagues support those of a previous study,2 which found no benefit from the use of doses of 0.5 µg kg–1 min–1 or 2 µg kg–1 min–1 in patients undergoing abdominal surgery. It appears that the theoretical attractions of dopexamine, particularly with regard to hepatosplanchnic blood flow, do not translate into better outcomes for patients. There is a parallel with the once widespread use of prophylactic dopamine to prevent renal failure. This has now been shown not to be effective, and concerns have arisen about potentially harmful endocrine effects.3 Although dopexamine has a different dopaminergic receptor profile from dopamine, it has similar potential for adverse effects, particularly at higher doses.4 Dopexamine is licensed for the treatment of exacerbations of chronic heart failure, or heart failure associated with cardiac surgery.5 The use of fixed dose ‘prophylactic’ dopexamine in general surgery seems inadvisable on present evidence, however.

Oxygen delivery

Deliberately increasing cardiac output in order to raise oxygen delivery is a different issue. The study by Stone and colleagues1 largely presumes its value, but adds little new evidence, as mortality is compared with a statistical model rather than a control group. It is now accepted that haemodynamic optimization is not of benefit once organ failure has developed,68 but it remains of interest in the early stages of critical illness,9 and has been strongly advocated in the perioperative situation.10 A recent meta-analysis8 concluded that it was effective when started early in studies where the control group mortality was more than 20%. In contrast, mortality was not reduced if the control group mortality was less than 15%, if the goals were ‘normal values’, or when treatment did not improve oxygen delivery. It is unfortunate that this analysis used control group mortality, which is actually an outcome measure, as an indicator of severity of illness. Four of the six studies cited with control group mortality greater than 20% were related to surgery,1114 although in one of these14 the control group mortality was actually 17%. The case for targeting oxygen delivery in high-risk surgery is largely based on these studies and so their reliability is a key issue. All aimed for a cardiac index of 4.5 litre min–1 m–2 and oxygen delivery of 600 ml min–1 m–2. They had similar entry criteria, based on combinations of co-morbidities and the nature of surgery, but the actual patients recruited differed markedly. The study by Shoemaker and colleagues11 was the first prospective trial in this field and is also the weakest methodologically. The results appear impressive (control mortality 38%, protocol 4%) but could be because of chance.15

In two studies,12 13 all patients were admitted to intensive care unit (ICU) and had their oxygen delivery measured. Boyd and colleagues12 found that 28-day mortality was 22% in the control group and 5.7% in the treatment group. A mixture of elective and emergency patients was included, and there does not appear to be any difference in outcome between the 81 patients enrolled preoperatively and the 26 enrolled postoperatively. Surgeons and anaesthetists, but not the ICU staff, were blinded to patient allocation. Although there was a statistically significant difference in oxygen delivery between the groups, only 23 of the 43 patients in the protocol group actually reached the target value before surgery and most did not do so afterwards. Lobo and colleagues13 studied 37 patients undergoing elective cancer or aortic aneurysm surgery. These patients were mechanically ventilated for a median of 2.5 days postoperatively, which would be unusual in UK practice. The probability of cardiac complications (Goldman index) was lower in the protocol group. No difference was found in 28-day mortality. The mortality rate at 60 days was lower in the protocol group (15.7 vs 50%) because of three late deaths in the control group. Again, the differences between the groups in terms of oxygen delivery were not great. The difference was only statistically significant at one point during the 24 h studied, and the targets were achieved by 28% of the control group as well as by 42% of the protocol group. The authors suggested that it might be the use of dobutamine rather than differences in oxygen delivery that affected the outcome.

Wilson and colleagues14 randomized 138 patients undergoing elective surgery. In two groups they aimed to achieve an oxygen delivery of 600 ml min–1 m–2 using either epinephrine or dopexamine. These patients were admitted to ICU or high dependency unit (HDU) before surgery, and returned there afterwards. In the control group, who had ‘standard management’, oxygen delivery was not measured and 30% of patients returned to a general ward postoperatively. Mortality was 17% in the control group and 3% in the treatment groups. Clearly, the study design precluded blinding and the different location of postoperative care is a potential confounding factor. The goals were relatively easily met in many patients in this study. This, and the observation that morbidity appeared less in the dopexamine group, stimulated the study by the same group published in this issue.1

A large study of 1994 patients by the Canadian Critical Care Clinical Trials Group,16 has been published since Kern and Shoemaker’s meta-analysis.8 The patients studied were over 60 yrs old, ASA class III or IV, having urgent or elective surgery. These criteria differ from those used by Shoemaker, but the median Goldman cardiac risk index was 8, which is greater than in the study by Lobo.13 The intervention group had pulmonary artery catheters inserted before surgery and therapy aimed for an oxygen delivery of 550–600 ml min–1 m–2, which was reached in 63% of patients. All patients were managed in ICU for at least 24 h after surgery. The groups were well matched and very similar to those patients screened but not randomized, suggesting that selection bias was unlikely. The number of patients, the universal use of ICU, and the multi-centre nature make this a robust study, despite the long recruitment period. There was no difference in mortality at hospital discharge (control 7.7%, protocol 7.8%), or at 6- and 12-month follow-up.

In several studies, many patients given active treatment were unable to achieve an oxygen delivery of 600 ml min–1 m–2. It is worth asking whether this is the correct target, and whether the lower mortality rate associated with this treatment plan in some studies is caused by other factors.

A target of 600 ml min–1 m–2 is based on the median of values achieved by survivors in observational studies,11 so not all patients would be expected to achieve this value. Kern and Shoemaker8 suggest that this goal was not intended to apply to all patients, although it is difficult to see what other practical guidance could be given to clinicians as they found no benefit in trials that did not set ‘supra-normal’ values. Their proposal to calculate goals for individual patients is certainly not possible at present. The lack of benefit in the Canadian trial16 might be because a slightly lower target was set, but this seems unlikely. Other studies have used different goals such as Doppler derived values or mixed venous oxygen saturations.

There are other possible causes for the apparent treatment effect. There could be a specific drug effect of dobutamine13 or dopexamine,14 but we have seen that prospective studies1 2 do not support this hypothesis. The benefit in some studies could relate to ICU admission,14 but other studies have admitted all patients to ICU and still found a difference.12 13 ICU staff were not blinded to treatment allocation, however, and this may affect the results, particularly where the investigators believe strongly in the hypothesis. Such bias is less likely in a multi-centre trial and the failure of the Canadian trial16 to show a difference is important.

Implications for clinical practice

The limitations of the evidence mean that it is premature to suggest that the time has come to implement goal-directed therapy for large numbers of high-risk surgical patients.10 Not only are the advantages of doing so uncertain, but also the patients who might benefit are not clearly defined. The recognition that the majority of postoperative complications occur in a relatively small group of high-risk patients was key to the initial development of this approach. This means that if efficacy is uncertain even for high-risk patients, then there can be even less confidence for lower risk groups,8 despite suggestions that morbidity may be reduced. There are few groups of patients with a greater than 20% mortality rate, the threshold suggested by Kern and Shoemaker. Mortality after surgery for upper gastrointestinal malignancy17 or aortic aneurysm repair,18 precisely the types of operation often included in these trials, is around 3–7%, although there are certainly sub-groups with poorer outcomes. Studies from Australia argue persuasively19 that a low anaerobic threshold on an exercise test before surgery is much more predictive of operative risk than myocardial ischaemia. More widespread use of this test might help in identifying high-risk patients, but clearly this is only practicable for planned surgery.

Addressing the unanswered questions

Preliminary results of another meta-analysis, performed under the auspices of the Cochrane collaboration,20 were presented to the Intensive Care Society in December 2002. These also appear to favour the targeting of oxygen delivery or some flow measurement. The full results will be of interest, but are unlikely to settle the debate, because a meta-analysis can only be as good as the constituent studies and there is, inevitably, considerable overlap with Kern and Shoemaker.8 Meta-analysis may not in fact be the most appropriate tool for several reasons. There is great heterogeneity in patients and protocols. It is unlikely to consider how this approach can fit with other strategies such as perioperative beta block,21 avoidance of hypothermia, and even calls for a return to fluid restriction in perioperative management.22 Perhaps flow measurements can help rationalize fluid therapy to avoid both hypovolaemia and fluid overload.23 Whether postoperative deaths are a result of cardiac ischaemia or cardiac failure remains in dispute,19 and both cause and response may depend on the patient populations studied, which frequently differ.24

The recognition that perioperative management can have a positive effect on long-term outcome is welcome, and the concept of ensuring adequate organ perfusion remains appealing, but we should not allow enthusiasm to lead us into error. A properly convened consensus conference could consider the different approaches, the different patients, and the different timing of interventions more effectively than a meta-analysis. It would also help raise awareness of the issues. Such a conference would now be an appropriate step, accepting that the outcome might well be a more focussed research agenda rather than a final conclusion.

References

1 Stone MD, Wilson RJT, Cross J, Williams BT. Effect of adding dopexamine to intraoperative volume expansion in patients undergoing major elective abdominal surgery. Br J Anaesth 2003; 91: 619–624[Abstract/Free Full Text]

2 Takala J, Meier-Hellman A, Eddleston J, Hulstaert P, Srameck V. Effect of dopexamine on outcome after major abdominal surgery: a prospective, randomised, controlled multicenter study. Crit Care Med 2000; 28: 3417–23[ISI][Medline]

3 Galley HF. Renal-dose dopamine: will the message now get through? Lancet 2000; 356: 2112–3[CrossRef][ISI][Medline]

4 Schilling T, Strang CM, Wilhelm L, et al. Endocrine effects of dopexamine vs dopamine in high-risk surgical patients. Intensive Care Med 2001; 27: 1908–15[CrossRef][ISI][Medline]

5 Dopacard Summary of Product Characteristics. http://emc.vhn.net accessed 28 March 2003

6 Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds C, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330: 1717–22[Abstract/Free Full Text]

7 Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 collaborative group. N Engl J Med 1995; 333: 1025–32[Abstract/Free Full Text]

8 Kern JW, Shoemaker WC. Meta-analysis of hemodynamic optimisation in high-risk patients. Crit Care Med 2002; 30: 1686–92[ISI][Medline]

9 Rivers E, Nguyen B, Havstad S, et al. early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368–77[Abstract/Free Full Text]

10 Treasure T, Bennet D. Reducing the risk of major elective surgery. BMJ 1999; 318: 1087–8[Free Full Text]

11 Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee T-S. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176–86[Abstract]

12 Boyd O, Grounds RM, Bennett ED. A randomised clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993; 270: 2699–707[Abstract]

13 Lobo SMA, Salgado PF, Castillo VGT, et al. Effect of maximising oxygen delivery on morbidity and mortality in high-risk surgical patients. Crit Care Med 2000; 28: 3396–404[ISI][Medline]

14 Wilson J, Woods I, Fawcett J, et al. Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of organ delivery. BMJ 1999; 318: 1099–103[Abstract/Free Full Text]

15 Heyland DK, Cook DJ, King D, Kernerman P, Brun-Buisson C. Maximising oxygen delivery in critically ill patients: a methodologic appraisal of the evidence. Crit Care Med 1996; 24: 517–24[ISI][Medline]

16 Sandham JD, Hull RD, Grant RF, et al. A randomised, controlled trial of the use of pulmonary artery catheters in high-risk surgical patients. N Engl J Med 2003; 348: 5–14[Abstract/Free Full Text]

17 Bittner R, Butters M, Ulrich M, Uppenbrink S, Beger HG. Total gastrectomy: updated mortality and long-term survival with particular reference to patients older than 70 years of age. Ann Surg 1996; 224: 37–42[CrossRef][ISI][Medline]

18 Bayly PJM, Matthews JNS, Dobson PM, Price ML, Thomas DG. In-hospital mortality from abdominal aortic surgery in Great Britain and Ireland: vascular Anaesthesia Society Audit. Br J Surg 2001; 88: 687–92[CrossRef][ISI][Medline]

19 Older P, Hall A, Hader R. Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly. Chest 1999; 116: 355–62[Abstract/Free Full Text]

20 Grocott M, Hamilton M, Bennett D, Rowan K. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 12003. Oxford: Update Software

21 Howell SJ, Sear JW, Foex P. Perioperative beta-blockade: a useful treatment that should be greeted with cautious enthusiasm. Br J Anaesth 2001; 86: 161–4[Free Full Text]

22 Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison P. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002; 359: 1812–18[CrossRef][ISI][Medline]

23 Holte K, Sharrock NE, Kehlet H. Pathophysiology and clinical implications of perioperative fluid excess. Br J Anaesth 2002; 89: 622–32[Abstract/Free Full Text]

24 Juste RN, Lawson AD, Soni N. Minimising cardiac anaesthetic risk: the tortoise or the hare? Anaesthesia 1996; 51: 255–62[ISI][Medline]