Major surgery is associated with a significant systemic inflammatory response and this in itself is associated with an increase in oxygen demand. In health, DO₂ is augmented by increasing CO and tissue oxygen extraction. If a patient is unable to achieve this due to cardiopulmonary disease, then there will be a degree of tissue dysoxia, which in the face of increased metabolic demand can lead to cellular dysfunction and ultimately organ dysfunction, failure and death. Complications and death following surgery have been shown to be associated with reduced DO₂ and VO₂ or a surrogate, the central venous oxygen saturation (ScvO₂) 1920. Reduced perfusion of the gut has also been implicated in post-operative organ dysfunction, due to disruption of the gut endothelial barrier with leakage of endotoxin into the circulation, activating multiple inflammatory pathways 21. From the equation above, increasing DO₂ is achieved by increasing CO and/or CaO₂. As dissolved oxygen is small, CaO₂ is increased by increasing the arterial oxygen saturation and/or the haemoglobin concentration. This should occur as a matter of course in intensive care. CO is therefore the variable that is most readily manipulated in order to increase DO₂, and this is usually performed using fluids and inotropes to improve blood flow. It is worth mentioning that DO₂ commonly measured is a global measurement whereas it is probable that regional, organ-specific or microcirculatory areas are the ones with compromised oxygenation. Nevertheless, it has been shown repeatedly that augmenting global DO₂ is beneficial 8922.

There is considerable evidence to demonstrate the benefits of augmenting oxygen delivery in high-risk surgical patients during the peri-operative period 23. In 1988 Shoemaker and colleagues 8 showed that morbidity and mortality of high-risk patients, a population that had a mortality of 30 to 40% following surgery, could be significantly reduced by using goal directed therapy (GDT) to meet the increased metabolic requirements following surgery. Therapeutic targets were based on physiological values that they had themselves observed in survivors after surgery 22242526. These perfusion-related targets included cardiac index (CI), DO₂ and VO₂. In the early studies these variables and the associated therapy were monitored and guided with a pulmonary artery catheter (PAC) with targets of CI >4.5 l/minute/m², oxygen delivery index (DO₂I) >600 ml/minute/m² and VO₂l >170 ml/minute/m². With this approach the mortality was substantially reduced in comparison to standard care using commonly measured parameters such as heart rate, arterial blood pressure and central venous pressure. This led to the concept that this group of patients could be optimised to so-called 'supranormal' values compared to resting values in the peri-operative period in order to improve their outcome. In 1993 Boyd and colleagues 27 conducted a randomised controlled trial (RCT) in which the same treatment goals were targeted pre- and post-operatively by means of supplemental oxygen, fluid and blood products. A 75% reduction in mortality was shown together with less post-operative complications. Wilson and colleagues 28, again targeting DO₂I >600 ml/minute/m², but also a haemoglobin of ≥11 g/dl and pulmonary artery occlusion pressure ≥12 mmHg, subsequently confirmed that preoperative optimisation of oxygen delivery significantly reduced hospital mortality with fewer complications and reduced length of stay. Other groups have reported similar favourable results in cardiac surgical patients 29, general surgical patients 30 and trauma patients 31. It has also been demonstrated that goal-directed administration of intravenous fluid improves gut perfusion and reduces major complications 3031. Donati and colleagues 32 conducted a prospective RCT of 135 high-risk surgical patients scheduled for major abdominal surgery and found a significantly lower length of hospital stay and number of organ failures in patients randomised to receive GDT starting intra-operatively and in whom the OER was maintained at <27%. The finding that peri-operative augmentation of DO₂ through GDT is associated with improved outcome has now been demonstrated in a number of meta-analyses by Kern and Shoemaker 33, Boyd 34 and more recently by Poeze and colleagues 35 and the Cochrane group 36. What is clear is that pre-optimisation before and during surgery 2627283037 and post-optimisation in ICU 38 in a protocolised GDT manner improves patient outcomes in high-risk surgical patients (Figure 1).

Despite these promising results, this practice has not been widely embraced for a number of reasons. Firstly, there may be confusion in identifying patients who may benefit from this therapy. Secondly, all the initial trials utilized the PAC. When this technique ran into controversy 39, the therapies associated with it were also debated. Even though there are now many alternatives, the concept of GDT is still considered to be synonymous with the PAC. Furthermore, there is some conflicting evidence. The largest and perhaps most controversial trial to date purporting to provide GDT for surgical patients was published by Sandham and co-workers 4041. Despite this controversy, the meta-analysis, even when including all available studies, confirms an improvement in mortality 36.

There has also been confusion inadvertently extrapolating results from other trials providing GDT to different patient groups. For instance, Gattinoni and colleagues 42 demonstrated that aggressive GDT is not effective for patients once organ failure is established in the critically ill. Hayes and colleagues demonstrated a worse outcome 43, although this study involved very high levels of dobutamine that would not nowadays be considered reasonable to meet these goals. Benefit has not been seen in patients who are not considered as high-risk 29, or if supranormal DO₂ targets were not used 4445. Individual variations of critical oxygen delivery or anaerobic thresholds may be a major reason for the heterogeneity of some of these studies and patient populations.

A major and more realistic limitation to the adoption of GDT is that of limited critical care resources. Many units are unable to admit high-risk patients pre-operatively to institute GDT and, similarly, many high-risk patients do not return to a critical care environment following surgery. Currently, only a small proportion (fewer than 15%) of high-risk patients are admitted to intensive care 4. Numerous trials have shown that length of hospital stay and complications can be reduced by instituting GDT. As critical care resources are slowly expanding, it can be argued that it is not only better for the patient but also economically sound to justify this. Encouragingly, it has been shown that it is possible to select patients who would most likely benefit from pre-operative intensive care admission based on high-risk criteria 46. Pearse and colleagues 38 showed that initiation of GDT post-operatively and after ICU admission confers significant benefit, which is reassuring considering the potential difficulties of implementing it pre- or peri-operatively. Paradoxically, nearly all of the studies that have assessed GDT have demonstrated a reduced incidence of complications following surgery with a subsequent decreased need for critical care services. It will take a paradigm shift in many clinicians (and their managers) thinking though to convert a rationale of reacting to problems to one of preventing them happening in the first place, even though this may reduce the overall demand for this expensive resource.

The concept of targeting a specific goal is not new and is done every day in intensive care, be it mean arterial pressure, arterial blood gases or haemoglobin. Several authors have demonstrated that the standard parameters of heart rate, blood pressure, central venous pressure and urine output are neither predictive nor able to be routinely manipulated to improve outcome. Indeed, a recent meta-analysis has proven that the central venous pressure is not able to identify which patients require more fluid 47. Although manipulating haemodynamics is certainly beneficial using goals of stroke volume and/or CI, if one accepts the concept of avoiding tissue oxygen debt in high-risk surgical patients, then the most important parameters that are associated with improved survival relate to oxygen flux. The most commonly used oxygen transport goals have been DO₂I and tissue oxygen consumption index (VO2I). GDT traditionally has been associated with targeting the DO₂I to a supranormal value of >600 ml/minute/m². Although this is perhaps the best studied endpoint for the resuscitation, it is by no means clear that it is the 'best' marker; rather, it is the only level of DO₂ that has been repeatedly studied. Others may yet prove to be better still. The use of supranormal goals, although controversial, has been shown in many studies to be beneficial since Shoemaker and colleagues' original work. Donati and colleagues 32 used OER, aiming for a goal of <27% (shown to be a predictor of survival in high risk surgical patients 22), using fluids and dobutamine. The OER is based on arterial and central venous saturation measurements and flow monitoring was not required in their study. In the intra-operative setting, where DO₂ is less easy to measure and target, a variety of other goals have been used. These include the corrected flow time (FTc) from the oesophageal Doppler trace (for example, targeting >0.35 s 48) or pulse pressure variation. Other goals studied that may be useful include serum lactate and mixed venous saturations (SvO₂) 29. Regional measures of DO₂ such as gastric intramucosal pH (pHi) 49 and near infrared spectroscopy (NIRS) are promising but have not been formally evaluated in a GDT manner.

The first and most common step in GDT is to ensure that the circulating volume is at an optimal level. The identification of the ideal preload, or patients who are likely to respond to a fluid challenge (preload responsiveness), has been extensively studied. It is quite clear that none of the traditional parameters are useful to accurately detect the volaemic status of patients. In order to overcome this problem, all studies have utilized some sort of blood flow monitoring and various different technologies have been used to measure cardiac output or stroke volume. Most of the earlier work was using the PAC, but with the advancement of technology this can now be done with less invasive techniques. Many subsequent studies have involved a single proprietary flow monitoring device. Current flow monitoring techniques that are used include Doppler technologies or arterial pressure waveform analysis, thereby measuring changes in stroke volume or cardiac output. These can be used either to predict a patient likely to respond to a volume challenge or to carefully monitor the response to a fluid bolus. This therefore provides a sophisticated and sensitive mechanism for titrating intravenous fluids to complex patients. Benefit has been demonstrated with fluid loading alone to maximize stroke volume, using these technologies 4850. Targeting of the pulse pressure variation in mechanically ventilated patients to a value of less than 10% with fluid challenges has been demonstrated to improve post-operative outcome and reduce length of hospital stay 51.

Fluid therapy as guided by the oesophageal Doppler (Deltex Medical Ltd, Chichester, UK) reduces mortality and hospital stay 315253. The oesophageal Doppler is well tolerated and can be used throughout the entire peri-operative period. It has little bias and high clinical agreement when compared with the PAC for monitoring changes in cardiac output 54. FTc is inversely proportional to systemic vascular resistance and is sensitive to changes in left ventricular preload 55. It may also be a more sensitive indicator of cardiac filling than pulmonary artery occlusion pressure 56. Improved outcome as demonstrated by faster return of gastrointestinal function, a reduction in post-operative complications and shortened hospital stay was demonstrated when using the oesophageal Doppler for goal-directed fluid administration (that is, targeting stroke volume and FTc to maximize CI) during major surgery 48. A meta-analysis of five RCTs of 420 patients undergoing major abdominal surgery showed fewer complications, less requirement for inotropes, faster return of gastro-intestinal function, fewer ICU admissions and shorter hospital stay in patients who received oesophageal Doppler-guided haemodynamic management 50.

The LiDCOplus system (LiDCO Ltd, Cambridge, UK) is also well validated 57. In 2005 Pearse and colleagues 38 conducted a RCT of post-operative GDT in high-risk general surgical patients using colloid and dopexamine to achieve a 2 or conventional management DO₂I of 600 ml/minute/m using the LiDCOplus to measure CO. There were fewer complications in the control group (44% versus 68%), less complications per patient and a shorter hospital stay, although there was no difference in 28- or 60-day mortality.

Several studies have shown that the PiCCO system (PULSION Medical Systems, Munich, Germany) is also a reliable method of assessing cardiac preload and may actually be more sensitive than the PAC 585960. Goepfert and colleagues 61 devised a GDT algorithm based on targeting global end-diastolic volume index, an indicator of cardiac preload as measured by PiCCO to achieve a goal of >640 ml/m² and CI >2.5 l/minute/m² in patients undergoing elective coronary artery bypass grafting surgery. This therapy was instituted immediately after induction of anaesthesia and continued in the ICU post-operatively. These patients benefited from reduced vasopressor and inotrope requirement, reduced duration of mechanical ventilation and were ready for ICU discharge earlier than the control group 61.

The Flotrac (Edwards, Irving, USA) is a blood flow sensor needing no calibration that attaches to the patient's existing arterial line and, in conjunction with the processing and display unit (Vigileo monitor), provides non-invasive cardiac output monitoring that derives its values from the arterial blood pressure signal. Comparisons with other reference techniques have been inconsistent and, to date, it remains untested in a GDT algorithm 37.

The aim of GDT is to prevent tissue oxygen debt by maintaining tissue perfusion. Many studies have tried to achieve this by augmenting DO₂. CO should be optimised in reference to preload, afterload, contractility and stroke volume whilst maintaining an adequate coronary perfusion pressure. There is an optimal haematocrit that is sufficient for oxygen transport but does not compromise rheology and, in general, haemoglobin should be kept above 7 g/dl (aiming higher in patients with ischaemic heart disease) 62. In all studies patients have been kept well oxygenated and there is some evidence that the use of continuous positive airways pressure in the post-operative period is beneficial 63. Fluid boluses alone may be sufficient to achieve goals of CO and DO₂, and GDT using just fluids has been shown to improve outcome in certain groups of surgical patients 314849. Often fluids may not be sufficient to achieve these goals and, in addition, a positive inotrope or vasodilator is necessary. Lobo and co-workers 64 compared the use of fluids and dobutamine or fluids alone to achieve the goal of DO₂I >600 ml/minute/m² in high-risk surgical patients. The use of fluid and dobutamine conferred better post-operative outcomes with less cardiovascular complications than the fluid alone group. Those patients given dobutamine were more likely to achieve the goals. Dobutamine is also a positive inotrope and peripheral vasodilator. Dopexamine is a dopamine analogue with actions at beta adrenoreceptors and also at peripheral dopamine receptors. It is a positive inotrope and peripheral vasodilator that improves microcirculatory flow and splanchnic perfusion and oxygenation, which may reduce inflammation secondary to the tissue hypoxia and translocation of bacterial products or endotoxin. This is probably the most extensively studied drug in this setting and a recent meta-analysis has demonstrated it to be of considerable use, with low-dose infusion (≤1 μg/kg/minute) associated with survival benefit and reduction in hospital stay. A survival benefit has not been seen with doses higher than this 65. Wilson compared dopexamine and adrenaline and found that although an adequate was DO₂ achieved with adrenaline, only dopexamine conferred a reduction in morbidity and length of hospital stay 28. Evidence shows that the use of dobutamine or dopexamine confers significant benefits in GDT. These drugs should be used with caution in patients with a high risk of peri-operative ischaemic cardiovascular events where excessive beta stimulation may be undesirable. Such patients have usually been excluded from GDT studies.

Once a high-risk patient is identified, any acute organ dysfunction or physiological abnormality should be managed as usual. Optimal control of any chronic illness should be ensured. This includes severe and active ischaemic heart disease, which should mandate appropriate medical treatment prior to surgery. GDT should be started as soon as possible before or after surgery as resources allow. Adequate oxygenation and haematocrit should be ensured. A variety of metabolic endpoints are surrogate flow measurements, such as lactate, SvO₂, ScvO₂, which may be useful during resuscitation, but CO (CI 4.5 l/minute/m²) and oxygen trans-600 ml/minute/m²) so direct port goals are important (DO₂I ≥600 ml/minute/m² flow monitoring should be implemented. Fluids should be given to increase CO and inodilators such as dopexamine and dobutamine added once the patient is no longer fluid (preload) responsive or not achieving the goals. Evidence suggests that GDT should continue for 8 hours 38, although many intra-operative studies show benefit with much shorter time courses.