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Preoperative optimization of the high-risk surgical patient
British Journal of Anaesthesia 93 (1): 121±8 (2004)
DOI: 10.1093/bja/aeh164 Advance Access publication April 30, 2004
Preoperative optimization of the high-risk surgical patient S. J. Davies and R. J. T. Wilson* Department of Anaesthetics, York Hospital, Wigginton Road, York YO31 8HE, UK *Corresponding author. E-mail: [email protected]
Br J Anaesth 2004; 93: 121±8
After major surgery there is a signi®cant risk of major complications and even death, particularly in the elderly and patients with signi®cant cardiorespiratory disease. In the UK, recent large audits have shown a 30-day mortality rate of 5.6% for elective colorectal cancer surgery,62 19.3% for emergency colorectal surgery,62 7.3% for elective infrarenal aortic aneurysm and aorto-iliac occlusive disease surgery,4 9±15% for oesophagectomy and 13±15% for elective gastrectomy.34 Major surgery generates a strong systemic in¯ammatory response that in turn leads to an increase in oxygen requirement from an average of 110 ml min±1 m±2 at rest to an average of 170 ml min±1 m±2 in the postoperative period.43 55 This substantial increase in oxygen demand is normally met by increases in cardiac output and tissue oxygen extraction. Most patients can meet the increased oxygen demand by increasing cardiac output and will usually do well after surgery. However, there remains a group who may not have the physiological reserve to increase cardiac output to the required level and this group of patients is at higher risk of complications after surgery. Trials have identi®ed high-risk patients and implemented strategies before surgery to increase oxygen delivery (DO2) to the levels that major surgery demands.15 30 55 67 Although some of these trials have demonstrated an improvement in outcome, the strategy remains controversial. The exact mechanisms that lead to postoperative complications are not completely understood, but an understanding of the existing knowledge on the pathogenesis of postoperative morbidity and mortality will help the clinician understand the rationale for increasing DO2 and tissue perfusion in the high-risk surgical patient. In this paper we review the role of inadequate tissue perfusion and DO2 in the development of complications after major surgery, the results of trials of preoperative interventions that aim to improve cardiac function and
hence DO2, developments in the identi®cation of patients who are most likely to bene®t from these interventions and the role of ¯uids and inotropes in optimization strategies.
Why do patients get major complications after major surgery? In patients undergoing major surgery, commonly monitored physiological variables such as heart rate, arterial pressure, central venous pressure (CVP), temperature and haemoglobin concentration are poor predictors of complications after surgery. Less commonly measured variables such as cardiac index (CI), DO2, gastric intramucosal pH (pHi) and stroke volume have been shown to be better predictors of postoperative outcome.12 38 46 56 58 Survivors of major surgery and critical illness tend to have a higher CI, DO2 and oxygen consumption (VÇO2) than non-survivors. 9 10 13 15 21 28 30 48 54 55 57 67 68 Moreover, normal values for these variables are not necessarily predictive of survival: in one series, 76% of patients who died after critical illness had achieved normal values.11 The presence of an oxygen debt can be demonstrated despite normal haemodynamic and oxygen transport variables in both postoperative and critically ill patients. An observational study by Bland and colleagues13 showed that increases in cardiac output leading to a `supra-normal' DO2 of greater than 600 ml min±1 m±2 was associated with greater survival than those whose postoperative DO2 was less than 600 ml min±1 m±2, but still within an acceptable range. In a series of 253 high-risk surgical patients, Shoemaker and colleagues54 demonstrated the importance of maintaining adequate DO2 throughout the perioperative course. Patients were classi®ed retrospectively as survivors without complications, survivors with complications or nonsurvivors. VÇO2 was measured at frequent intervals before, during and after the surgical procedure, and oxygen debt
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Keywords: complications, postoperative; drug therapy; heart, cardiac output; inotropes; monitoring; surgery, postoperative period
Davies and Wilson
delivery and hence gastric pHi.50 51 64 Gastric pHi has been shown to be a good predictor of outcome after major surgery33 38 45 47 and in critically ill patients.26 Optimizing stroke volume using oesphageal Doppler monitoring during cardiac surgery to guide ¯uid therapy improved gastric pHi, reduced complications and shortened time in the intensive care unit (ICU) and hospital stay.38 In compensated shock that appears clinically normal, any inadequacy of DO2 is concentrated to the gut.25 The splanchnic circulation is sensitive to hypoperfusion and in low ¯ow states, splanchnic blood ¯ow decreases out of proportion to the overall decreases in cardiac output, and recovers last.1 3 35 It has been suggested that in nonocclusive intestinal ischaemia the enteric mucosal barrier is disrupted and translocation of endotoxin (lipopolysaccharide) and microorganisms occurs into the circulation.32 41 Translocation initiates the cytokine pathway20 (see review by Galley and Webster in this issue for further details), rendering the individual at an increased risk of sepsis and multiple organ failure; patients with proven translocation have signi®cantly more postoperative septic complications.16 40 53 The incidence of translocation increases with age, the urgency of the surgery and the presence of distal bowel obstruction.40 Endotoxin is known to be a potent activator of the pathways involved in the in¯ammatory response,36 37 66 and depressed or falling levels of circulating antibodies to endotoxin (EndoCAb) can be interpreted as exposure to endotoxin. In cardiac surgery, low levels of IgM EndoCAb are associated with poor postoperative outcome, supporting the concept that endotoxaemia has an important role in the pathogenesis of postoperative morbidity.8 27 Bacteria and endotoxin induce cytokine secretion by tissue macrophages, stimulate neutrophil migration, activate the complement and coagulation cascades and generally induce a pro-in¯ammatory state. The cytokines secreted by endotoxin-activated macrophages include interleukin (IL)1, IL-6 and tumour necrosis factor (TNF), and these can impair oxygen delivery to the gut through their actions on the microcirculation, potentiating the further translocation of endotoxin and bacteria, and also activation of the in¯ammatory system. TNF is a polypeptide that reacts with a speci®c receptor on a diverse number of cell types. Its primary role is as an in¯ammatory cytokine that recruits polymorphic nucleocytes to areas of infection and trauma, and provides the major physiological stimulus for production of IL-1 and IL6. IL-1 acts as a pyrogen, stimulates hypothalamic production of prostaglandins and stimulates the in¯ammatory cascade. IL-6 production is stimulated by IL-1 and TNF, and there is a correlation between plasma concentrations of endotoxin and IL-6.14 Prolonged elevated plasma concentration of IL-6 in trauma, burns and elective surgical patients is associated with increased morbidity and mortality.2 19 49 The high concentrations of IL-6 seen in blood from the mesenteric veins of resected colonic segments compared
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was calculated using the patients resting operative control values. Before surgery there were no differences in CI, DO2, or VÇO2 between the different outcome groups. In the 63 patients who died, mean cumulative intra-operative oxygen de®cit was 12.0 litre m±2 and maximum debt was 33.2 litre m±2 at 17.8 h after surgery. This was in contrast to the 158 survivors with no organ failure whose intraoperative oxygen de®cit was 5.7 litre m±2, with a maximum debt of 9.2 litre m±2 at 4.1 h after surgery. Essentially, the magnitude and duration of oxygen de®cit was greatest in the non-survivors, slightly less in the survivors with organ failure and least in the survivors without organ failure. In a side arm of this study, 56 patients were randomized to a control group that was maintained at normal haemodynamic and oxygen transport values, and a protocol group that was maintained at so-called `supra-normal' values of CI greater than 4.5 litre min±1 m±2, DO2 greater than 600 ml min±1 m±2 and VÇO2 greater than 170 ml min±1 m±2. The control group, who had normal values as their targets, averaged a maximal oxygen debt of 17.3 litre m±2 at 31 h after surgery, lasting for more than 48 h, whilst the protocol group with `supranormal' values had a maximal oxygen debt of 7.6 litre m±2 at 3 h after surgery, lasting an average of 13 h. Mortality in the control group was 34% with 31 organ failures, compared with a mortality of 4% in the protocol group and one organ failure. The magnitude and duration of oxygen debt correlated with the incidence of postoperative organ failure and death; minimization of these debts by augmenting CI, DO2 and VÇO2 to supra-normal levels led to a reduction in morbidity and mortality. DO2 is dependent on oxygen content of the arterial blood, and cardiac output. Timmins and colleagues63 observed the response of cardiac performance in terms of CI, left ventricular stroke work index (LVSWI), and cardiac power output (CPO) after administration of ¯uid and inotropes in critically ill patients and then looked for patterns in survivors and non-survivors. LVSWI and CPO were signi®cantly higher in survivors on admission, and all three variables were signi®cantly higher after maximal resuscitation in the surviving group. Poeze and colleagues46 showed that patients with lower stroke volumes after cardiac surgery, as measured by oesophageal Doppler, were more likely to have complications. The reduced cardiac performance seen in non-survivors suggests that the ability to increase cardiac work, and hence DO2, suf®ciently to meet the increased metabolic need of the postoperative phase is associated with increased survival. In recent years, much interest has been directed towards the role of the gut in the pathogenesis of postoperative morbidity and mortality. Low gastric pHi and increased gastric luminal carbon dioxide tension are highly predictive of postoperative complications.7 It can be shown that with increasing global oxygen delivery, splanchnic oxygen delivery increases and a parallel change is seen in splanchnic oxygen consumption, suggesting that improved systemic oxygen delivery improves splanchnic oxygen
Preoperative optimization of the high-risk surgical patient
with systemic levels indicates that the bowel is the source of the IL-6 response to surgical trauma in colorectal surgery.60 In summary it can be seen that poor outcome from major surgery is associated with a number of physiological factors including poor cardiac function and hence reduced DO2, reduced gut perfusion and a strong systemic in¯ammatory response. In theory, strategies that aim to improve these variables by optimizing haemodynamic function may improve outcome from surgery.
Studies that have investigated optimization of surgical patients have varied in their approaches to both the timing of interventions, and the goals they have aimed to achieve. This article focuses on studies that have applied interventions in the preoperative phase, and are grouped according to the variables targeted by the interventions.
Preoperative optimization of oxygen delivery The strategy of preoperative optimization of DO2 developed from the observational work of Bland and Shoemaker,13 as previously discussed. In a prospective randomized controlled trial, 88 elective and emergency patients were preoperatively randomized to one of three groups.55 A CVPcontrol group (n=30) had a central venous catheter placed and were managed using the standard clinical values available by CVP measurement as therapeutic goals. The pulmonary artery ¯otation catheter (PAFC)-control group (n=30) had a PAFC placed, and were managed to achieve haemodynamic and oxygen transport variables within normal ranges. The PAFC-protocol group had a PAFC placed in order to manipulate haemodynamic and oxygen transport values to supra-normal levels of CI greater than 4.5 litre min±1 m±2, DO2 greater than 600 ml min±1 m±2, pulmonary artery occlusion pressure (PAOP) below 18 mm Hg, CVP below 15 mm Hg, systemic vascular resistance (SVR) above 1450 dyne s cm±5 and VÇO2 above 170 ml min±1 m±2. Patients were admitted to the ICU before surgery, and therapeutic `goals' were achieved using infusions of crystalloid and colloid solutions, packed red blood cells and various inotropes and vasodilators. In the PAFCprotocol group, target DO2 was achieved in two-thirds of patients using ¯uid administration alone. Before therapy was initiated, haemodynamic and oxygen transport values were comparable for the PAFCcontrol and PAFC-protocol groups. After surgery the study design ensured signi®cant increases in CI, DO2 and VÇO2 in the PAFC-protocol group compared with the PAFCcontrol group. Mortality was 4% in the PAFC-protocol group, 23% in the CVP-control group and 33% in the PAFC-control group (P<0.02). In the PAFC-protocol group there was also a signi®cant reduction in the incidence of
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Preoperative haemodynamic optimization of high-risk surgical patients
major complications and in the length of stay in the ICU. CI, DO2 and VÇO2 were within standard normal values in the PAFC-control group, suggesting that the reduction in mortality in the PAFC-protocol group was a result of a deliberate elevation of DO2 to supra-normal levels using ¯uid and inotropes. Boyd and colleagues15 studied a similar high-risk population in a randomized controlled trial of 107 patients (elective and emergency), enrolled and randomized into protocol and control groups. All patients had a PAFC inserted and were then resuscitated to a PAOP of 12±14 mm Hg, a mean arterial pressure (MAP) of 80±110 mm Hg, oxygen saturation above 94% and urine output greater than 0.5 ml kg±1 h±1. The only difference between the two groups was a therapeutic target for the protocol group of DO2 greater than 600 ml min±1 m±2, aided if required by the administration of dopexamine, a dopaminergic and beta-2 adrenergic agonist. There were no differences between the groups in baseline characteristics or baseline haemodynamic and oxygen transport variables before resuscitation and administration of dopexamine. CI and DO2 were signi®cantly increased in the treatment group before surgery as a result of the protocol. On admission to the ICU after surgery, all patients were resuscitated back to their previous goals, and in the protocol group DO2 was maintained above 600 ml min±1 m±2 by further titration of dopexamine, which was continued until two consecutive plasma lactate levels were below 1.5 mmol litre±1. Mortality was reduced from 22.2% in the control group to 5.7% in the treatment group (P=0.015), and there was a reduction in the mean number of complications per patient from 1.35 in the control group to 0.68 in the treatment group (P=0.008). Although the majority of patients did not reach their target DO2, the strategy of deliberately aiming to increase DO2 to supra-normal levels reduced mortality and complications. Twenty-six patients out of the 107 were admitted to the trial during or after surgery; however, of the 81 patients admitted to the trial before surgery (43 protocol and 38 control), survival was 7.0% vs 23.7% (P=0.04) in favour of the protocol group, and complication rates were similar, with 0.70 complications per patient in the protocol group and 1.45 in the control group (P=0.009). Wilson and Woods67 conducted a prospective randomized controlled trial with double blinding of the protocol groups in a series of 138 patients undergoing elective highrisk aortic, thoraco-abdominal or abdominal surgery. Patients were identi®ed as high risk through a combination of surgical and medical factors, and were assigned to one of three groups of 46: control, or preoptimized with either dopexamine or epinephrine (adrenaline). The control group remained on the general surgical ward with no preoperative ¯uid protocol. The protocol groups were admitted to the ICU for a minimum of 4 h before surgery, and had full monitoring instigated, including insertion of a PAFC. Both groups were initially ¯uid optimized with colloid until a
Davies and Wilson
Other preoperative haemodynamic optimization strategies Other preoptimization strategies have been employed that target end-points other than DO2, such as CI or mixed venous saturation. Berlauk and colleagues9 investigated the role and timing of preoperative optimization of haemodynamic status in 89 patients undergoing peripheral vascular surgery. The patients were randomized to receive a PAFC either 12 h (group 1) or 3 h (group 2) before the operation (group 1) or no PAFC (group 3). Those that received the PAFC were ¯uid resuscitated and given vasoactive and inotropic agents to achieve end-points of CI greater than 2.8 litre min±1 m±2, SVR below 1100 dyne s cm±5 and PAOP of 8±15 mm Hg. Those who did not meet these criteria were excluded from the study. The groups were well matched in most criteria, but 80% of the patients with angina were randomized to group 1. The mortality in the PAFC groups was 1.5%, compared with 9.5% in the control group (P=0.08). Those patients that were particularly high risk (e.g. recent myocardial infarction, severe heart failure or valvular heart disease) were excluded as it was deemed that there was evidence that this group would bene®t from PAFC placement. Patients in the PAFC groups had fewer adverse intra-operative events (hypotension, tachycardia, arrhythmia) (P<0.05), and lower postoperative cardiovascular mortality when compared with the control group (P<0.05), although the protocol group did receive transdermal glyceryl trinitrate, which may help account for this. Although this study shows bene®t from this type of intervention, the goals targeted are low, as patients could be considered optimized with a CI of 2.8 litre min±1 m±2. Further studies have used these goals as end-points, but assuming a normal haemoglobin level and oxygen saturation, a patient could be considered as `optimized' with a DO2 of 380±410 ml min±1 m±2, a normal but not supranormal value. Despite the relatively modest therapeutic targets and the exclusion of higher risk patients, there was a signi®cant reduction in morbidity during and after surgery. Valentine and colleagues65 applied the same `tune up' criteria to 120 patients scheduled for aortic reconstructive surgery and failed to show any bene®t. The protocol group had PAFC placement at least 14 h before surgery and were treated to the same protocol as that applied in Berlauk's study, whilst the control group had no preoperative interventions. Overall mortality was 5% in the protocol group and 1% in the control group, with more intra-operative complications in the PAFC group (18% vs 5%, P=0.02). All patients underwent adenosine thallium scintigraphy before surgery, and those with a reversible perfusion defect were excluded. In addition, any patient with unstable angina, recent changes in anginal symptoms, cardiac failure, severe valvular heart disease or chronic renal failure were excluded. Therapeutic targets in the PAFC group did not guarantee a DO2 of 600 ml min±1 m±2.
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PAOP of 12 mm Hg was reached (blood products were used if the haemoglobin concentration was less than 110 g litre±1). Patients then received either epinephrine 0.025 mg kg±1 min±1 or dopexamine 0.125 mg kg±1 min±1 by doubleblind infusion; these were increased by single multiples of the baseline until the target DO2 of greater than 600 ml min±1 m±2 was achieved. The infusion was continued for 12±24 h after surgery, and all patients received at least the baseline dose of inotrope even if their target DO2 had been achieved during the ¯uid administration phase. Hospital mortality in the protocol groups was 3%, compared with 17% in the control (P=0.007), and morbidity and hospital length of stay were signi®cantly reduced in the group receiving dopexamine. Lobo and colleagues30 conducted a prospective randomized controlled trial of 37 high-risk patients undergoing major elective surgery. Patients had common goals in terms of MAP, PAOP, haematocrit and arterial oxygen saturation, but were allocated to a control group in which the target DO2 was 520±600 ml min±1 m±2, or the protocol group in which DO2 was driven to supra-normal levels of greater than 600 ml min±1 m±2. All patients followed the same protocol pathway and dobutamine was used as the primary inotrope in both groups to achieve the desired targets. Mortality was reduced from 50% in the control group to 15.7% in the protocol group (P<0.05). Sandham and colleagues52 conducted a multicentre, prospective, randomized controlled trial over a 9-yr period involving 1994 patients over the age of 60 yr and of ASA grade III or IV who were due to undergo major elective or urgent surgery. Patients were allocated to either a standard care group, who received conventional therapy, or a catheter group, who received goal-directed therapy via the aid of a PAFC in order to achieve DO2 of 550±600 ml min±1 m±2 or CI of 3.5±4.5 litre min±1 m±2. Twenty-one percent of patients in the catheter group reached the DO2 target before surgery, rising to 63% after surgery. CVP catheters were placed in 77% of the non-PAFC group and mean CVP measures were identical between groups at all perioperative stages. Hospital mortality was 7.7% in the standard care group and 7.8% in the catheter group (P=0.004). In both groups, the actual mortality was half of the expected control mortality of 15% used in the sample size calculation. There are several possible reasons for this. The majority of patients (87%) were ASA III, and with relatively good cardiac function (87% were NYHA I or II). The goal set for DO2 was 550±600 ml min±1 m±2, compared with greater than 600 ml min±1 m±2 in the previous trials described, and only a minority of patients (21%) achieved this target before surgery. Although the PAFC patients received more inotropes, colloid and blood products than control patients, the identical CVP measures suggest that the ¯uid and inotrope therapy in the control group resulted in similar haemodynamic end-points. Finally, this trial took 9 yr to complete, during which there may well have been signi®cant improvements in surgical technique and perioperative care.
Preoperative optimization of the high-risk surgical patient
led to reductions in mortality and morbidity. These studies have been relatively small in size, but do show a consistent outcome bene®t.
Identifying patients likely to bene®t from preoperative optimization of oxygen delivery The principle of preoperative investigations is to gain information about patients that leads to modi®cation of their perioperative management, and to improve the outcome from major surgery. Shoemaker and colleagues57 published criteria for high-risk patients that encompassed a mixture of patient and laboratory factors, but these do not quantify the degree of cardiorespiratory disease an individual has, or stratify the risk. As mentioned previously, if a patient is unable to elevate cardiac output and DO2 to the required levels, they are more likely to have a poor outcome after major surgery. To identify the high-risk surgical patient, objective information on dynamic cardiorespiratory function is needed in order to assess perioperative needs and to provide accurate information on the risks and bene®ts of the procedure to the patient. Functional activity can be graded in terms of metabolic equivalents (METS) by the Duke Activity Status Index.29 One MET represents the resting oxygen consumption of an adult (approximately 3.5 ml kg±1 min±1), and grading of a person's ability to perform various levels of exertion provides a rough subjective surrogate for the maximal VÇO2, arguably one of the best indices of cardiorespiratory ®tness. The subjective measurement of exercise tolerance provides good positive prediction of complications, in that if an individual is unable to climb two ¯ights of stairs then they have an 89% chance of postoperative cardiorespiratory complications,23 but the actual risk of an adverse outcome is not strati®ed. Stress tests such as dobutamine stress echocardiography, exercise ECG and dypyridamole thallium scintigraphy have been used to identify high-risk patients and quantify risk. The positive prediction value of these tests for postoperative ischaemic events is poor at 20±30%, although the negative prediction value is much higher at 95±100%.18 These tests evaluate the presence of myocardial ischaemia and the limitations on heart rate, but do not give information on the extent of cardiac failure and the limitations on DO2. Cardiopulmonary exercise testing (CPX testing) examines the ability of the cardiorespiratory systems to deliver oxygen to tissues under stress, in this case the exercising limb muscles. As the work rate increases, in order to generate adequate levels of ATP, the oxygen demands of the exercising muscle increase, leading to an increase in cardiac output. Eventually the energy demands outstrip the supply of oxygen and aerobic metabolism is supplemented by anaerobic metabolism, with the consequent generation of lactate. The oxygen consumption at which this occurs is known as the anaerobic threshold (AT), and can be identi®ed easily in most individuals. Older and
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Ziegler and colleagues69 studied 72 patients undergoing aortic and limb salvage surgery. This study compared different methods of using a PAFC for managing surgical patients. All 72 patients had a PAFC inserted without complication, and patients in the protocol group were optimized with ¯uids, inotropes and vasodilators to achieve PAOP above 12 mm Hg, Hb above 100 g litre±1 and a mixed venous oxygen saturation above 65%. In the control group the PAFC was available for intra-operative and postoperative ¯uid management, but no speci®c preoperative therapy was initiated. There was no difference in mortality (9% vs 5%) or morbidity between the two groups. The physiological goals, in particular the mixed venous oxygen saturation, are relatively low. Bender and colleagues6 studied a similar group to Berlauk and randomized 103 patients undergoing elective infrarenal aneurysm and lower limb revascularization surgery to receive a PAFC before surgery and to be optimized to a CI above 2.8 litre min±1 m±2, PAOP of 8± 15 mm Hg and SVR below 1100 dyne s cm±5, or to receive standard care (n=53). In the protocol group, a combination of crystalloid solutions, dopamine and sodium nitroprusside was used to obtain the desired targets. Mortality was 2% in the protocol group (1/51) and 1.9% in the control group (1/ 53), and there was no difference in morbidity between the two groups. This low mortality, coupled with only 35% of the protocol group needing haemodynamic manipulation after PAFC insertion (compared with more than 60% in the Berlauk trial), suggests that the study population was not particularly high risk. A degree of preoperative optimization of haemodynamic variables was used in a multicentre trial examining the effects of dopexamine on outcome after major elective or emergency abdominal surgery.61 A total of 412 patients de®ned as high risk were admitted to ICUs before surgery and had PAFCs inserted. Fluid, blood products and oxygen were then given to achieve CI above 2.5 litre min±1 m±2, PAOP of 10 mm Hg, haemoglobin concentration greater than 100 g litre±1, arterial oxygen saturation above 94% and MAP of 70 mm Hg. Obtaining the minimum of all these targets would allow a patient to be considered optimized with a DO2 of 320 ml min±1 m±2. After reaching baseline targets, patients were randomly allocated to receive placebo or dopexamine 0.5 or 2.0 mg kg±1 min±1. Infusions were maintained for 24 h after surgery. There was no overall difference in mortality or morbidity. A post-hoc subgroup analysis of 51 patients who required urgent surgery revealed that mortality at 28 days was 29% in the placebo group, 11% in the group receiving dopexamine 2.0 mg kg±1 min±1 and 0% in patients receiving dopexamine 0.5 mg kg±1 min±1. In summary, studies of preoperative haemodynamic intervention that do not target supra-normal values of DO2, or that do not study the highest risk groups of patients, do not show clear bene®t in outcome. In patients who are at high risk of complications or death, a deliberate attempt to elevate DO2 to supra-normal levels (>600 ml min±1 m±2) has
Davies and Wilson
Role of ¯uids and inotropes Although some patients will achieve target DO2 with volume resuscitation alone, it seems that a variable but signi®cant proportion of the population will require inotropic support to obtain prede®ned haemodynamic goals. The use of inotropes is not without consequence, as they may alter regional blood ¯ow and cause tissue hypoxia,11 and myocardial oxygen supply and demand requirements can be mismatched, with the potential to cause myocardial ischaemia,5 39 and increased systemic VÇO2 can occur.24 31 There appears to be a difference in outcome when different inotropes are used. In the study of Wilson and colleagues,67 mortality was reduced in both groups that received ¯uid and an inotrope (dopexamine or epinephrine) but there was a marked reduction in complications and length of hospital stay only in the dopexamine group. The role of inotropes in optimization of high-risk surgical patients may encompass other factors apart from an increase in oxygen transport variables. Catecholamines inhibit TNF
secretion and alter the IL-6 to IL-10 ratio (a measure of the balance of pro- and anti-in¯ammatory cytokines), and this modulation of the cytokine response may be a mechanism that in¯uences the decreased morbidity and mortality seen in the optimization trials. As discussed above, one of the major causes of postoperative morbidity is impairment of the function of the gastrointestinal barrier. Dopexamine has been shown to preserve gut barrier function, being signi®cantly less likely to cause gastrointestinal paralysis in animal models compared with epinephrine and norepinephrine (noradrenaline),22 improves gastric pHi and therefore by inference, splanchnic oxygen delivery,59 and reduces in¯ammatory changes in the gastrointestinal mucosa after major abdominal surgery.17
Conclusion Major body cavity surgery causes a strong in¯ammatory response, which in turn causes a marked increase in oxygen requirements. To match the demand, a patient will have to be able to elevate their cardiac output accordingly. The high-risk patient is one who can't spontaneously elevate their cardiac output to the required level, and for elective cases we may be able to identify these patients through CPX testing. To successfully manage a high-risk patient it is appropriate to monitor stroke volume and CI, and to use these variables to ensure that the patient's circulation is optimally ®lled. Once optimal ®lling has been achieved, it is logical to measure indices of tissue perfusion and oxygen demand, such as base de®cit, lactate levels, mixed venous oxygen saturation or gastric pHi. If these variables indicate persistent tissue hypoperfusion, it is likely that the CI and DO2 at the point of optimal ®lling is still inadequate and will need to be improved with inotropic support.
References
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1 Adar R, Franklin A, Spark RF, Rosoff CB, Salzman EW. Effect of dehydration and cardiac tamponade on superior mesenteric artery ¯ow: role of vasoactive substances. Surgery 1976; 79: 534± 43 2 Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ. Systemic cytokine response after major surgery. Br J Surg 1992; 79: 757±60 3 Bailey RW, Bulkley GB, Hamilton SR, Morris JB, Haglund UH. Protection of the small intestine from nonocclusive mesenteric ischemic injury due to cardiogenic shock. Am J Surg 1987; 153: 108±16 4 Bayly PJ, Matthews JN, Dobson PM, Price ML, Thomas DG. Inhospital mortality from abdominal aortic surgery in Great Britain and Ireland: Vascular Anaesthesia Society audit. Br J Surg 2001; 88: 687±92 5 Bekker AY, Wolk S, Rim J, Turndorf H, Ritter AB. Comparison of cardiotropic drug effects on haemodynamic and myocardial energetics in patients with heart failure: a computer simulation. J Med Eng Technol 2000; 24: 87±94
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colleagues44 measured AT in 187 elderly patients before major abdominal surgery. The overall non-surgical mortality from the cohort was 5.9%. Patients who had an AT below 11 ml kg±1 min±1 (n=55) had a mortality of 18% compared with those who had an AT above 11 ml kg±1 min±1 (n=132) whose mortality was 0.8% (P<0.001). In patients who exhibited signs of ischaemia during the testing process, the mortality was 42% for patients whose AT was below 11 ml kg±1 min±1 and only 4% for those whose AT was above 11 ml kg±1 min±1 (P<0.001). From these data it is seen that poor ventricular function, and hence poor DO2, as measured by AT, predicted a high risk for major surgery, particularly when coupled with evidence of myocardial ischaemia. In a second study of 548 consecutive patients undergoing major abdominal surgery, Older and colleagues42 used AT to stratify risk and direct perioperative interventions accordingly. Of the cohort, 153 patients (28%) with an AT below 11 ml kg±1 min±1 were admitted to ICU before surgery and had baseline haemodynamic and oxygen transport variables monitored; 115 patients (21%) with an AT above 11 ml kg±1 min±1 but with evidence of myocardial ischaemia on testing were admitted to a high-dependency unit (HDU) after surgery; those with an AT above 11 ml kg±1 min±1 with no evidence of ischaemia were cared for on a normal ward. Of the 21 patients who died, 19 had been triaged to ICU/HDU as a result of CPX testing, and the two deaths in the ward group were due to disease progression. Through pre-admission to ICU and use of PAFCs to monitor cardiac function, the mortality in the high-risk group (low AT) was reduced from 18% to 8.9%. In summary, the AT identi®es a population that is less able to mount the appropriate increase in DO2 demanded after major surgery and in which a strategy of invasive monitoring and optimization of cardiac function is more likely to improve outcome.
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25 Gutierrez G, Bismar H, Dantzker DR, Silva N. Comparison of gastric intramucosal pH with measures of oxygen transport and consumption in critically ill patients. Crit Care Med 1992; 20: 451±7 26 Gutierrez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992; 339: 195±9 27 Hamilton-Davies C, Barclay GR, Cardigan RA, et al. Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery. Chest 1997; 112: 1189±96 28 Hayes MA, Yau EH, Timmins AC, Hinds CJ, Watson D. Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome. Chest 1993; 103: 886±95 29 Hlatky MA, Boineau RE, Higginbotham MB, et al. A brief selfadministered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 1989; 64: 651±4 30 Lobo SM, Salgado PF, Castillo VG, et al. Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical patients. Crit Care Med 2000; 28: 3396±404 31 Lundholm L, Svedmyr N. Studies on the stimulating effects of adrenaline and noradrenaline on respiration in man. Acta Physiol Scand 1966; 67: 65±75 32 Marston A, Buckley GB, Fiddian-Green RG, Haglund UH. Splanchnic Ischaemia and Multiple Organ Failure. London: Edward Arnold, 1989; 339±63 33 Maynard ND, Taylor PR, Mason RC, Bihari DJ. Gastric intramucosal pH predicts outcome after surgery for ruptured abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 1996; 11: 201±6 34 McCulloch P, Ward J, Tekkis PP. Mortality and morbidity in gastro-oesophageal cancer surgery: initial results of ASCOT multicentre prospective cohort study. BMJ 2003; 327: 1192±7 35 McNeill JR, Stark RD, Greenway CV. Intestinal vasoconstriction after hemorrhage: roles of vasopressin and angiotensin. Am J Physiol 1970; 219: 1342±7 36 Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481±6 37 Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 1974; 140: 797±811 38 Mythen MG, Webb AR. Perioperative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg 1995; 130: 423±9 39 Nikolaidis LA, Hentosz T, Doverspike A, et al. Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure. Cardiovasc Res 2002; 53: 392±404 40 O'Boyle CJ, MacFie J, Mitchell CJ, Johnstone D, Sagar PM, Sedman PC. Microbiology of bacterial translocation in humans. Gut 1998; 42: 29±35 41 Ohri SK, Somasundaram S, Koak Y, et al. The effect of intestinal hypoperfusion on intestinal absorption and permeability during cardiopulmonary bypass. Gastroenterology 1994; 106: 318±23 42 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 43 Older P, Smith R. Experience with the preoperative invasive measurement of haemodynamic, respiratory and renal function in 100 elderly patients scheduled for major abdominal surgery. Anaesth Intens Care 1988; 16: 389±95 44 Older P, Smith R, Courtney P, Hone R. Preoperative evaluation
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6 Bender JS, Smith-Meek MA, Jones CE. Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery: results of a prospective, randomized trial. Ann Surg 1997; 226: 229±36 7 Bennett-Guerrero E. Automated detection of gastric luminal partial pressure of CO2. Anesthesiology 2000; 92, 38±45 8 Bennett-Guerrero E, Ayuso L, et al. Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997; 277: 646±50 9 Berlauk JF, Abrams JH, Gilmour IJ, O'Connor SR, Knighton DR, Cerra FB. Preoperative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery. A prospective, randomized clinical trial. Ann Surg 1991; 214: 289±97 10 Bishop MH, Shoemaker WC, Appel PL, et al. Prospective, randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma. J Trauma 1995; 38: 780±7 11 Bland R, Shoemaker WC, Shabot MM. Physiologic monitoring goals for the critically ill patient. Surg Gynecol Obstet 1978; 147: 833±41 12 Bland RD, Shoemaker WC. Common physiologic patterns in general surgical patients: hemodynamic and oxygen transport changes during and after operation in patients with and without associated medical problems. Surg Clin North Am 1985; 65: 793± 809 13 Bland RD, Shoemaker WC, Abraham E, Cobo JC. Hemodynamic and oxygen transport patterns in surviving and nonsurviving postoperative patients. Crit Care Med 1985; 13: 85±90 14 Boelke E, Storck M, Buttenschoen K, Berger D, Hannekum A. Endotoxemia and mediator release during cardiac surgery. Angiology 2000; 51: 743±9 15 Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients [see comments]. JAMA 1993; 270: 2699±707 16 Brooks SG, May J, Sedman P, et al. Translocation of enteric bacteria in humans. Br J Surg 1993; 80: 901±2 17 Byers RJ, Eddleston JM, Pearson RC, Bigley G, McMahon RF. Dopexamine reduces the incidence of acute in¯ammation in the gut mucosa after abdominal surgery in high-risk patients. Crit Care Med 1999; 27: 1787±93 18 Chassot PG, Delabays A, Spahn DR. Preoperative evaluation of patients with, or at risk of, coronary artery disease undergoing non-cardiac surgery. Br J Anaesth 2002; 89: 747±59 19 Damas P, Ledoux D, Nys M, et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992; 215: 356±62 20 Deitch EA. Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 1992; 216: 117±34 21 Fleming A, Bishop M, Shoemaker W, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992; 127: 1175±9 22 Fruhwald S, Scheidl S, Toller W, et al. Low potential of dobutamine and dopexamine to block intestinal peristalsis as compared with other catecholamines. Crit Care Med 2000; 28: 2893±7 23 Girish M, Trayner E Jr, Dammann O, Pinto-Plata V, Celli B. Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest 2001; 120: 1147±51 24 Green CJ, Frazer RS, Underhill S, Maycock P, Fairhurst JA, Campbell IT. Metabolic effects of dobutamine in normal man. Clin Sci (Lond) 1992; 82: 77±83
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patients. Use of sequential cardiorespiratory variables in de®ning criteria for therapeutic goals and early warning of death. Arch Surg 1973; 106: 630±6 Shoemaker WC, Pierchala C, Chang P, State D. Prediction of outcome and severity of illness by analysis of the frequency distributions of cardiorespiratory variables. Crit Care Med 1977; 5: 82±8 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 Syk I, Mangell P, Bjartell A, Jeppsson B. Systemic interleukin-6 response to colorectal surgery originates from the bowel. Dig Surg 2002; 19: 210±15 Takala J, Meier-Hellmann A, Eddleston J, Hulstaert P, Sramek V. Effect of dopexamine on outcome after major abdominal surgery: a prospective, randomized, controlled multicenter study. European Multicenter Study Group on Dopexamine in Major Abdominal Surgery. Crit Care Med 2000; 28: 3417±23 Tekkis P, Poloniecki J, Thompson M, Stamatakis J. Operative mortality in colorectal cancer: prospective national study. BMJ 2003; 327: 1196±1201 Timmins AC, Hayes M, Yau E, Watson JD, Hinds CJ. The relationship between cardiac reserve and survival in critically ill patients receiving treatment aimed at achieving supranormal oxygen delivery and consumption. Postgrad Med J 1992; 68 Suppl 2: S34±40 Uusaro A, Ruokonen E, Takala J. Splanchnic oxygen transport after cardiac surgery: evidence for inadequate tissue perfusion after stabilization of hemodynamics. Intensive Care Med 1996; 22: 26±33 Valentine RJ, Duke ML, Inman MH, et al. Effectiveness of pulmonary artery catheters in aortic surgery: a randomized trial. J Vasc Surg 1998; 27: 203±11 Williams JG. The in¯ammatory response. J Intensive Care Med 1992; 7, 53±66 Wilson J, Woods I, Fawcett J, et al. Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery. BMJ 1999; 318: 1099±103 Yu M, Levy MM, Smith P, Takiguchi SA, Miyasaki A, Myers SA. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study. Crit Care Med 1993; 21: 830±8 Ziegler DW, Wright JG, Choban PS, Flancbaum L. A prospective randomized trial of preoperative "optimization" of cardiac function in patients undergoing elective peripheral vascular surgery. Surgery 1997; 122: 584±92
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of cardiac failure and ischemia in elderly patients by cardiopulmonary exercise testing. Chest 1993; 104: 701±4 Pargger H, Hampl KF, Christen P, Staender S, Scheidegger D. Gastric intramucosal pH-guided therapy in patients after elective repair of infrarenal abdominal aneurysms: is it bene®cial? Intensive Care Med 1998; 24: 769±76 Poeze M, Ramsay G, Greve JW, Singer M. Prediction of postoperative cardiac surgical morbidity and organ failure within 4 hours of intensive care unit admission using esophageal Doppler ultrasonography. Crit Care Med 1999; 27: 1288±94 Poeze M, Takala J, Greve JW, Ramsay G. Preoperative tonometry is predictive for mortality and morbidity in high-risk surgical patients. Intensive Care Med 2000; 26: 1272±81 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 Roumen RM, Hendriks T, van der Ven Jongekrijg J, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann Surg 1993; 218: 769±76 Ruokonen E, Takala J, Kari A. Regional blood ¯ow and oxygen transport in patients with the low cardiac output syndrome after cardiac surgery. Crit Care Med 1993; 21: 1304±11 Ruokonen E, Takala J, Kari A, Saxen H, Mertsola J, Hansen EJ. Regional blood ¯ow and oxygen transport in septic shock. Crit Care Med 1993; 21: 1296±303 Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003; 348: 5±14 Sedman PC, MacFie J, Sagar P, et al. The prevalence of gut translocation in humans. Gastroenterology 1994; 107: 643±9 Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients. Chest 1992; 102: 208±15 Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176±86 Shoemaker WC, Czer LS. Evaluation of the biologic importance of various hemodynamic and oxygen transport variables: which variables should be monitored in postoperative shock? Crit Care Med 1979; 7: 424±31 Shoemaker WC, Montgomery ES, Kaplan E, Elwyn DH. Physiologic patterns in surviving and nonsurviving shock
DOI: 10.1093/bja/aeh164 Advance Access publication April 30, 2004
Preoperative optimization of the high-risk surgical patient S. J. Davies and R. J. T. Wilson* Department of Anaesthetics, York Hospital, Wigginton Road, York YO31 8HE, UK *Corresponding author. E-mail: [email protected]
Br J Anaesth 2004; 93: 121±8
After major surgery there is a signi®cant risk of major complications and even death, particularly in the elderly and patients with signi®cant cardiorespiratory disease. In the UK, recent large audits have shown a 30-day mortality rate of 5.6% for elective colorectal cancer surgery,62 19.3% for emergency colorectal surgery,62 7.3% for elective infrarenal aortic aneurysm and aorto-iliac occlusive disease surgery,4 9±15% for oesophagectomy and 13±15% for elective gastrectomy.34 Major surgery generates a strong systemic in¯ammatory response that in turn leads to an increase in oxygen requirement from an average of 110 ml min±1 m±2 at rest to an average of 170 ml min±1 m±2 in the postoperative period.43 55 This substantial increase in oxygen demand is normally met by increases in cardiac output and tissue oxygen extraction. Most patients can meet the increased oxygen demand by increasing cardiac output and will usually do well after surgery. However, there remains a group who may not have the physiological reserve to increase cardiac output to the required level and this group of patients is at higher risk of complications after surgery. Trials have identi®ed high-risk patients and implemented strategies before surgery to increase oxygen delivery (DO2) to the levels that major surgery demands.15 30 55 67 Although some of these trials have demonstrated an improvement in outcome, the strategy remains controversial. The exact mechanisms that lead to postoperative complications are not completely understood, but an understanding of the existing knowledge on the pathogenesis of postoperative morbidity and mortality will help the clinician understand the rationale for increasing DO2 and tissue perfusion in the high-risk surgical patient. In this paper we review the role of inadequate tissue perfusion and DO2 in the development of complications after major surgery, the results of trials of preoperative interventions that aim to improve cardiac function and
hence DO2, developments in the identi®cation of patients who are most likely to bene®t from these interventions and the role of ¯uids and inotropes in optimization strategies.
Why do patients get major complications after major surgery? In patients undergoing major surgery, commonly monitored physiological variables such as heart rate, arterial pressure, central venous pressure (CVP), temperature and haemoglobin concentration are poor predictors of complications after surgery. Less commonly measured variables such as cardiac index (CI), DO2, gastric intramucosal pH (pHi) and stroke volume have been shown to be better predictors of postoperative outcome.12 38 46 56 58 Survivors of major surgery and critical illness tend to have a higher CI, DO2 and oxygen consumption (VÇO2) than non-survivors. 9 10 13 15 21 28 30 48 54 55 57 67 68 Moreover, normal values for these variables are not necessarily predictive of survival: in one series, 76% of patients who died after critical illness had achieved normal values.11 The presence of an oxygen debt can be demonstrated despite normal haemodynamic and oxygen transport variables in both postoperative and critically ill patients. An observational study by Bland and colleagues13 showed that increases in cardiac output leading to a `supra-normal' DO2 of greater than 600 ml min±1 m±2 was associated with greater survival than those whose postoperative DO2 was less than 600 ml min±1 m±2, but still within an acceptable range. In a series of 253 high-risk surgical patients, Shoemaker and colleagues54 demonstrated the importance of maintaining adequate DO2 throughout the perioperative course. Patients were classi®ed retrospectively as survivors without complications, survivors with complications or nonsurvivors. VÇO2 was measured at frequent intervals before, during and after the surgical procedure, and oxygen debt
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2004
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Keywords: complications, postoperative; drug therapy; heart, cardiac output; inotropes; monitoring; surgery, postoperative period
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delivery and hence gastric pHi.50 51 64 Gastric pHi has been shown to be a good predictor of outcome after major surgery33 38 45 47 and in critically ill patients.26 Optimizing stroke volume using oesphageal Doppler monitoring during cardiac surgery to guide ¯uid therapy improved gastric pHi, reduced complications and shortened time in the intensive care unit (ICU) and hospital stay.38 In compensated shock that appears clinically normal, any inadequacy of DO2 is concentrated to the gut.25 The splanchnic circulation is sensitive to hypoperfusion and in low ¯ow states, splanchnic blood ¯ow decreases out of proportion to the overall decreases in cardiac output, and recovers last.1 3 35 It has been suggested that in nonocclusive intestinal ischaemia the enteric mucosal barrier is disrupted and translocation of endotoxin (lipopolysaccharide) and microorganisms occurs into the circulation.32 41 Translocation initiates the cytokine pathway20 (see review by Galley and Webster in this issue for further details), rendering the individual at an increased risk of sepsis and multiple organ failure; patients with proven translocation have signi®cantly more postoperative septic complications.16 40 53 The incidence of translocation increases with age, the urgency of the surgery and the presence of distal bowel obstruction.40 Endotoxin is known to be a potent activator of the pathways involved in the in¯ammatory response,36 37 66 and depressed or falling levels of circulating antibodies to endotoxin (EndoCAb) can be interpreted as exposure to endotoxin. In cardiac surgery, low levels of IgM EndoCAb are associated with poor postoperative outcome, supporting the concept that endotoxaemia has an important role in the pathogenesis of postoperative morbidity.8 27 Bacteria and endotoxin induce cytokine secretion by tissue macrophages, stimulate neutrophil migration, activate the complement and coagulation cascades and generally induce a pro-in¯ammatory state. The cytokines secreted by endotoxin-activated macrophages include interleukin (IL)1, IL-6 and tumour necrosis factor (TNF), and these can impair oxygen delivery to the gut through their actions on the microcirculation, potentiating the further translocation of endotoxin and bacteria, and also activation of the in¯ammatory system. TNF is a polypeptide that reacts with a speci®c receptor on a diverse number of cell types. Its primary role is as an in¯ammatory cytokine that recruits polymorphic nucleocytes to areas of infection and trauma, and provides the major physiological stimulus for production of IL-1 and IL6. IL-1 acts as a pyrogen, stimulates hypothalamic production of prostaglandins and stimulates the in¯ammatory cascade. IL-6 production is stimulated by IL-1 and TNF, and there is a correlation between plasma concentrations of endotoxin and IL-6.14 Prolonged elevated plasma concentration of IL-6 in trauma, burns and elective surgical patients is associated with increased morbidity and mortality.2 19 49 The high concentrations of IL-6 seen in blood from the mesenteric veins of resected colonic segments compared
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was calculated using the patients resting operative control values. Before surgery there were no differences in CI, DO2, or VÇO2 between the different outcome groups. In the 63 patients who died, mean cumulative intra-operative oxygen de®cit was 12.0 litre m±2 and maximum debt was 33.2 litre m±2 at 17.8 h after surgery. This was in contrast to the 158 survivors with no organ failure whose intraoperative oxygen de®cit was 5.7 litre m±2, with a maximum debt of 9.2 litre m±2 at 4.1 h after surgery. Essentially, the magnitude and duration of oxygen de®cit was greatest in the non-survivors, slightly less in the survivors with organ failure and least in the survivors without organ failure. In a side arm of this study, 56 patients were randomized to a control group that was maintained at normal haemodynamic and oxygen transport values, and a protocol group that was maintained at so-called `supra-normal' values of CI greater than 4.5 litre min±1 m±2, DO2 greater than 600 ml min±1 m±2 and VÇO2 greater than 170 ml min±1 m±2. The control group, who had normal values as their targets, averaged a maximal oxygen debt of 17.3 litre m±2 at 31 h after surgery, lasting for more than 48 h, whilst the protocol group with `supranormal' values had a maximal oxygen debt of 7.6 litre m±2 at 3 h after surgery, lasting an average of 13 h. Mortality in the control group was 34% with 31 organ failures, compared with a mortality of 4% in the protocol group and one organ failure. The magnitude and duration of oxygen debt correlated with the incidence of postoperative organ failure and death; minimization of these debts by augmenting CI, DO2 and VÇO2 to supra-normal levels led to a reduction in morbidity and mortality. DO2 is dependent on oxygen content of the arterial blood, and cardiac output. Timmins and colleagues63 observed the response of cardiac performance in terms of CI, left ventricular stroke work index (LVSWI), and cardiac power output (CPO) after administration of ¯uid and inotropes in critically ill patients and then looked for patterns in survivors and non-survivors. LVSWI and CPO were signi®cantly higher in survivors on admission, and all three variables were signi®cantly higher after maximal resuscitation in the surviving group. Poeze and colleagues46 showed that patients with lower stroke volumes after cardiac surgery, as measured by oesophageal Doppler, were more likely to have complications. The reduced cardiac performance seen in non-survivors suggests that the ability to increase cardiac work, and hence DO2, suf®ciently to meet the increased metabolic need of the postoperative phase is associated with increased survival. In recent years, much interest has been directed towards the role of the gut in the pathogenesis of postoperative morbidity and mortality. Low gastric pHi and increased gastric luminal carbon dioxide tension are highly predictive of postoperative complications.7 It can be shown that with increasing global oxygen delivery, splanchnic oxygen delivery increases and a parallel change is seen in splanchnic oxygen consumption, suggesting that improved systemic oxygen delivery improves splanchnic oxygen
Preoperative optimization of the high-risk surgical patient
with systemic levels indicates that the bowel is the source of the IL-6 response to surgical trauma in colorectal surgery.60 In summary it can be seen that poor outcome from major surgery is associated with a number of physiological factors including poor cardiac function and hence reduced DO2, reduced gut perfusion and a strong systemic in¯ammatory response. In theory, strategies that aim to improve these variables by optimizing haemodynamic function may improve outcome from surgery.
Studies that have investigated optimization of surgical patients have varied in their approaches to both the timing of interventions, and the goals they have aimed to achieve. This article focuses on studies that have applied interventions in the preoperative phase, and are grouped according to the variables targeted by the interventions.
Preoperative optimization of oxygen delivery The strategy of preoperative optimization of DO2 developed from the observational work of Bland and Shoemaker,13 as previously discussed. In a prospective randomized controlled trial, 88 elective and emergency patients were preoperatively randomized to one of three groups.55 A CVPcontrol group (n=30) had a central venous catheter placed and were managed using the standard clinical values available by CVP measurement as therapeutic goals. The pulmonary artery ¯otation catheter (PAFC)-control group (n=30) had a PAFC placed, and were managed to achieve haemodynamic and oxygen transport variables within normal ranges. The PAFC-protocol group had a PAFC placed in order to manipulate haemodynamic and oxygen transport values to supra-normal levels of CI greater than 4.5 litre min±1 m±2, DO2 greater than 600 ml min±1 m±2, pulmonary artery occlusion pressure (PAOP) below 18 mm Hg, CVP below 15 mm Hg, systemic vascular resistance (SVR) above 1450 dyne s cm±5 and VÇO2 above 170 ml min±1 m±2. Patients were admitted to the ICU before surgery, and therapeutic `goals' were achieved using infusions of crystalloid and colloid solutions, packed red blood cells and various inotropes and vasodilators. In the PAFCprotocol group, target DO2 was achieved in two-thirds of patients using ¯uid administration alone. Before therapy was initiated, haemodynamic and oxygen transport values were comparable for the PAFCcontrol and PAFC-protocol groups. After surgery the study design ensured signi®cant increases in CI, DO2 and VÇO2 in the PAFC-protocol group compared with the PAFCcontrol group. Mortality was 4% in the PAFC-protocol group, 23% in the CVP-control group and 33% in the PAFC-control group (P<0.02). In the PAFC-protocol group there was also a signi®cant reduction in the incidence of
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major complications and in the length of stay in the ICU. CI, DO2 and VÇO2 were within standard normal values in the PAFC-control group, suggesting that the reduction in mortality in the PAFC-protocol group was a result of a deliberate elevation of DO2 to supra-normal levels using ¯uid and inotropes. Boyd and colleagues15 studied a similar high-risk population in a randomized controlled trial of 107 patients (elective and emergency), enrolled and randomized into protocol and control groups. All patients had a PAFC inserted and were then resuscitated to a PAOP of 12±14 mm Hg, a mean arterial pressure (MAP) of 80±110 mm Hg, oxygen saturation above 94% and urine output greater than 0.5 ml kg±1 h±1. The only difference between the two groups was a therapeutic target for the protocol group of DO2 greater than 600 ml min±1 m±2, aided if required by the administration of dopexamine, a dopaminergic and beta-2 adrenergic agonist. There were no differences between the groups in baseline characteristics or baseline haemodynamic and oxygen transport variables before resuscitation and administration of dopexamine. CI and DO2 were signi®cantly increased in the treatment group before surgery as a result of the protocol. On admission to the ICU after surgery, all patients were resuscitated back to their previous goals, and in the protocol group DO2 was maintained above 600 ml min±1 m±2 by further titration of dopexamine, which was continued until two consecutive plasma lactate levels were below 1.5 mmol litre±1. Mortality was reduced from 22.2% in the control group to 5.7% in the treatment group (P=0.015), and there was a reduction in the mean number of complications per patient from 1.35 in the control group to 0.68 in the treatment group (P=0.008). Although the majority of patients did not reach their target DO2, the strategy of deliberately aiming to increase DO2 to supra-normal levels reduced mortality and complications. Twenty-six patients out of the 107 were admitted to the trial during or after surgery; however, of the 81 patients admitted to the trial before surgery (43 protocol and 38 control), survival was 7.0% vs 23.7% (P=0.04) in favour of the protocol group, and complication rates were similar, with 0.70 complications per patient in the protocol group and 1.45 in the control group (P=0.009). Wilson and Woods67 conducted a prospective randomized controlled trial with double blinding of the protocol groups in a series of 138 patients undergoing elective highrisk aortic, thoraco-abdominal or abdominal surgery. Patients were identi®ed as high risk through a combination of surgical and medical factors, and were assigned to one of three groups of 46: control, or preoptimized with either dopexamine or epinephrine (adrenaline). The control group remained on the general surgical ward with no preoperative ¯uid protocol. The protocol groups were admitted to the ICU for a minimum of 4 h before surgery, and had full monitoring instigated, including insertion of a PAFC. Both groups were initially ¯uid optimized with colloid until a
Davies and Wilson
Other preoperative haemodynamic optimization strategies Other preoptimization strategies have been employed that target end-points other than DO2, such as CI or mixed venous saturation. Berlauk and colleagues9 investigated the role and timing of preoperative optimization of haemodynamic status in 89 patients undergoing peripheral vascular surgery. The patients were randomized to receive a PAFC either 12 h (group 1) or 3 h (group 2) before the operation (group 1) or no PAFC (group 3). Those that received the PAFC were ¯uid resuscitated and given vasoactive and inotropic agents to achieve end-points of CI greater than 2.8 litre min±1 m±2, SVR below 1100 dyne s cm±5 and PAOP of 8±15 mm Hg. Those who did not meet these criteria were excluded from the study. The groups were well matched in most criteria, but 80% of the patients with angina were randomized to group 1. The mortality in the PAFC groups was 1.5%, compared with 9.5% in the control group (P=0.08). Those patients that were particularly high risk (e.g. recent myocardial infarction, severe heart failure or valvular heart disease) were excluded as it was deemed that there was evidence that this group would bene®t from PAFC placement. Patients in the PAFC groups had fewer adverse intra-operative events (hypotension, tachycardia, arrhythmia) (P<0.05), and lower postoperative cardiovascular mortality when compared with the control group (P<0.05), although the protocol group did receive transdermal glyceryl trinitrate, which may help account for this. Although this study shows bene®t from this type of intervention, the goals targeted are low, as patients could be considered optimized with a CI of 2.8 litre min±1 m±2. Further studies have used these goals as end-points, but assuming a normal haemoglobin level and oxygen saturation, a patient could be considered as `optimized' with a DO2 of 380±410 ml min±1 m±2, a normal but not supranormal value. Despite the relatively modest therapeutic targets and the exclusion of higher risk patients, there was a signi®cant reduction in morbidity during and after surgery. Valentine and colleagues65 applied the same `tune up' criteria to 120 patients scheduled for aortic reconstructive surgery and failed to show any bene®t. The protocol group had PAFC placement at least 14 h before surgery and were treated to the same protocol as that applied in Berlauk's study, whilst the control group had no preoperative interventions. Overall mortality was 5% in the protocol group and 1% in the control group, with more intra-operative complications in the PAFC group (18% vs 5%, P=0.02). All patients underwent adenosine thallium scintigraphy before surgery, and those with a reversible perfusion defect were excluded. In addition, any patient with unstable angina, recent changes in anginal symptoms, cardiac failure, severe valvular heart disease or chronic renal failure were excluded. Therapeutic targets in the PAFC group did not guarantee a DO2 of 600 ml min±1 m±2.
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PAOP of 12 mm Hg was reached (blood products were used if the haemoglobin concentration was less than 110 g litre±1). Patients then received either epinephrine 0.025 mg kg±1 min±1 or dopexamine 0.125 mg kg±1 min±1 by doubleblind infusion; these were increased by single multiples of the baseline until the target DO2 of greater than 600 ml min±1 m±2 was achieved. The infusion was continued for 12±24 h after surgery, and all patients received at least the baseline dose of inotrope even if their target DO2 had been achieved during the ¯uid administration phase. Hospital mortality in the protocol groups was 3%, compared with 17% in the control (P=0.007), and morbidity and hospital length of stay were signi®cantly reduced in the group receiving dopexamine. Lobo and colleagues30 conducted a prospective randomized controlled trial of 37 high-risk patients undergoing major elective surgery. Patients had common goals in terms of MAP, PAOP, haematocrit and arterial oxygen saturation, but were allocated to a control group in which the target DO2 was 520±600 ml min±1 m±2, or the protocol group in which DO2 was driven to supra-normal levels of greater than 600 ml min±1 m±2. All patients followed the same protocol pathway and dobutamine was used as the primary inotrope in both groups to achieve the desired targets. Mortality was reduced from 50% in the control group to 15.7% in the protocol group (P<0.05). Sandham and colleagues52 conducted a multicentre, prospective, randomized controlled trial over a 9-yr period involving 1994 patients over the age of 60 yr and of ASA grade III or IV who were due to undergo major elective or urgent surgery. Patients were allocated to either a standard care group, who received conventional therapy, or a catheter group, who received goal-directed therapy via the aid of a PAFC in order to achieve DO2 of 550±600 ml min±1 m±2 or CI of 3.5±4.5 litre min±1 m±2. Twenty-one percent of patients in the catheter group reached the DO2 target before surgery, rising to 63% after surgery. CVP catheters were placed in 77% of the non-PAFC group and mean CVP measures were identical between groups at all perioperative stages. Hospital mortality was 7.7% in the standard care group and 7.8% in the catheter group (P=0.004). In both groups, the actual mortality was half of the expected control mortality of 15% used in the sample size calculation. There are several possible reasons for this. The majority of patients (87%) were ASA III, and with relatively good cardiac function (87% were NYHA I or II). The goal set for DO2 was 550±600 ml min±1 m±2, compared with greater than 600 ml min±1 m±2 in the previous trials described, and only a minority of patients (21%) achieved this target before surgery. Although the PAFC patients received more inotropes, colloid and blood products than control patients, the identical CVP measures suggest that the ¯uid and inotrope therapy in the control group resulted in similar haemodynamic end-points. Finally, this trial took 9 yr to complete, during which there may well have been signi®cant improvements in surgical technique and perioperative care.
Preoperative optimization of the high-risk surgical patient
led to reductions in mortality and morbidity. These studies have been relatively small in size, but do show a consistent outcome bene®t.
Identifying patients likely to bene®t from preoperative optimization of oxygen delivery The principle of preoperative investigations is to gain information about patients that leads to modi®cation of their perioperative management, and to improve the outcome from major surgery. Shoemaker and colleagues57 published criteria for high-risk patients that encompassed a mixture of patient and laboratory factors, but these do not quantify the degree of cardiorespiratory disease an individual has, or stratify the risk. As mentioned previously, if a patient is unable to elevate cardiac output and DO2 to the required levels, they are more likely to have a poor outcome after major surgery. To identify the high-risk surgical patient, objective information on dynamic cardiorespiratory function is needed in order to assess perioperative needs and to provide accurate information on the risks and bene®ts of the procedure to the patient. Functional activity can be graded in terms of metabolic equivalents (METS) by the Duke Activity Status Index.29 One MET represents the resting oxygen consumption of an adult (approximately 3.5 ml kg±1 min±1), and grading of a person's ability to perform various levels of exertion provides a rough subjective surrogate for the maximal VÇO2, arguably one of the best indices of cardiorespiratory ®tness. The subjective measurement of exercise tolerance provides good positive prediction of complications, in that if an individual is unable to climb two ¯ights of stairs then they have an 89% chance of postoperative cardiorespiratory complications,23 but the actual risk of an adverse outcome is not strati®ed. Stress tests such as dobutamine stress echocardiography, exercise ECG and dypyridamole thallium scintigraphy have been used to identify high-risk patients and quantify risk. The positive prediction value of these tests for postoperative ischaemic events is poor at 20±30%, although the negative prediction value is much higher at 95±100%.18 These tests evaluate the presence of myocardial ischaemia and the limitations on heart rate, but do not give information on the extent of cardiac failure and the limitations on DO2. Cardiopulmonary exercise testing (CPX testing) examines the ability of the cardiorespiratory systems to deliver oxygen to tissues under stress, in this case the exercising limb muscles. As the work rate increases, in order to generate adequate levels of ATP, the oxygen demands of the exercising muscle increase, leading to an increase in cardiac output. Eventually the energy demands outstrip the supply of oxygen and aerobic metabolism is supplemented by anaerobic metabolism, with the consequent generation of lactate. The oxygen consumption at which this occurs is known as the anaerobic threshold (AT), and can be identi®ed easily in most individuals. Older and
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Ziegler and colleagues69 studied 72 patients undergoing aortic and limb salvage surgery. This study compared different methods of using a PAFC for managing surgical patients. All 72 patients had a PAFC inserted without complication, and patients in the protocol group were optimized with ¯uids, inotropes and vasodilators to achieve PAOP above 12 mm Hg, Hb above 100 g litre±1 and a mixed venous oxygen saturation above 65%. In the control group the PAFC was available for intra-operative and postoperative ¯uid management, but no speci®c preoperative therapy was initiated. There was no difference in mortality (9% vs 5%) or morbidity between the two groups. The physiological goals, in particular the mixed venous oxygen saturation, are relatively low. Bender and colleagues6 studied a similar group to Berlauk and randomized 103 patients undergoing elective infrarenal aneurysm and lower limb revascularization surgery to receive a PAFC before surgery and to be optimized to a CI above 2.8 litre min±1 m±2, PAOP of 8± 15 mm Hg and SVR below 1100 dyne s cm±5, or to receive standard care (n=53). In the protocol group, a combination of crystalloid solutions, dopamine and sodium nitroprusside was used to obtain the desired targets. Mortality was 2% in the protocol group (1/51) and 1.9% in the control group (1/ 53), and there was no difference in morbidity between the two groups. This low mortality, coupled with only 35% of the protocol group needing haemodynamic manipulation after PAFC insertion (compared with more than 60% in the Berlauk trial), suggests that the study population was not particularly high risk. A degree of preoperative optimization of haemodynamic variables was used in a multicentre trial examining the effects of dopexamine on outcome after major elective or emergency abdominal surgery.61 A total of 412 patients de®ned as high risk were admitted to ICUs before surgery and had PAFCs inserted. Fluid, blood products and oxygen were then given to achieve CI above 2.5 litre min±1 m±2, PAOP of 10 mm Hg, haemoglobin concentration greater than 100 g litre±1, arterial oxygen saturation above 94% and MAP of 70 mm Hg. Obtaining the minimum of all these targets would allow a patient to be considered optimized with a DO2 of 320 ml min±1 m±2. After reaching baseline targets, patients were randomly allocated to receive placebo or dopexamine 0.5 or 2.0 mg kg±1 min±1. Infusions were maintained for 24 h after surgery. There was no overall difference in mortality or morbidity. A post-hoc subgroup analysis of 51 patients who required urgent surgery revealed that mortality at 28 days was 29% in the placebo group, 11% in the group receiving dopexamine 2.0 mg kg±1 min±1 and 0% in patients receiving dopexamine 0.5 mg kg±1 min±1. In summary, studies of preoperative haemodynamic intervention that do not target supra-normal values of DO2, or that do not study the highest risk groups of patients, do not show clear bene®t in outcome. In patients who are at high risk of complications or death, a deliberate attempt to elevate DO2 to supra-normal levels (>600 ml min±1 m±2) has
Davies and Wilson
Role of ¯uids and inotropes Although some patients will achieve target DO2 with volume resuscitation alone, it seems that a variable but signi®cant proportion of the population will require inotropic support to obtain prede®ned haemodynamic goals. The use of inotropes is not without consequence, as they may alter regional blood ¯ow and cause tissue hypoxia,11 and myocardial oxygen supply and demand requirements can be mismatched, with the potential to cause myocardial ischaemia,5 39 and increased systemic VÇO2 can occur.24 31 There appears to be a difference in outcome when different inotropes are used. In the study of Wilson and colleagues,67 mortality was reduced in both groups that received ¯uid and an inotrope (dopexamine or epinephrine) but there was a marked reduction in complications and length of hospital stay only in the dopexamine group. The role of inotropes in optimization of high-risk surgical patients may encompass other factors apart from an increase in oxygen transport variables. Catecholamines inhibit TNF
secretion and alter the IL-6 to IL-10 ratio (a measure of the balance of pro- and anti-in¯ammatory cytokines), and this modulation of the cytokine response may be a mechanism that in¯uences the decreased morbidity and mortality seen in the optimization trials. As discussed above, one of the major causes of postoperative morbidity is impairment of the function of the gastrointestinal barrier. Dopexamine has been shown to preserve gut barrier function, being signi®cantly less likely to cause gastrointestinal paralysis in animal models compared with epinephrine and norepinephrine (noradrenaline),22 improves gastric pHi and therefore by inference, splanchnic oxygen delivery,59 and reduces in¯ammatory changes in the gastrointestinal mucosa after major abdominal surgery.17
Conclusion Major body cavity surgery causes a strong in¯ammatory response, which in turn causes a marked increase in oxygen requirements. To match the demand, a patient will have to be able to elevate their cardiac output accordingly. The high-risk patient is one who can't spontaneously elevate their cardiac output to the required level, and for elective cases we may be able to identify these patients through CPX testing. To successfully manage a high-risk patient it is appropriate to monitor stroke volume and CI, and to use these variables to ensure that the patient's circulation is optimally ®lled. Once optimal ®lling has been achieved, it is logical to measure indices of tissue perfusion and oxygen demand, such as base de®cit, lactate levels, mixed venous oxygen saturation or gastric pHi. If these variables indicate persistent tissue hypoperfusion, it is likely that the CI and DO2 at the point of optimal ®lling is still inadequate and will need to be improved with inotropic support.
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colleagues44 measured AT in 187 elderly patients before major abdominal surgery. The overall non-surgical mortality from the cohort was 5.9%. Patients who had an AT below 11 ml kg±1 min±1 (n=55) had a mortality of 18% compared with those who had an AT above 11 ml kg±1 min±1 (n=132) whose mortality was 0.8% (P<0.001). In patients who exhibited signs of ischaemia during the testing process, the mortality was 42% for patients whose AT was below 11 ml kg±1 min±1 and only 4% for those whose AT was above 11 ml kg±1 min±1 (P<0.001). From these data it is seen that poor ventricular function, and hence poor DO2, as measured by AT, predicted a high risk for major surgery, particularly when coupled with evidence of myocardial ischaemia. In a second study of 548 consecutive patients undergoing major abdominal surgery, Older and colleagues42 used AT to stratify risk and direct perioperative interventions accordingly. Of the cohort, 153 patients (28%) with an AT below 11 ml kg±1 min±1 were admitted to ICU before surgery and had baseline haemodynamic and oxygen transport variables monitored; 115 patients (21%) with an AT above 11 ml kg±1 min±1 but with evidence of myocardial ischaemia on testing were admitted to a high-dependency unit (HDU) after surgery; those with an AT above 11 ml kg±1 min±1 with no evidence of ischaemia were cared for on a normal ward. Of the 21 patients who died, 19 had been triaged to ICU/HDU as a result of CPX testing, and the two deaths in the ward group were due to disease progression. Through pre-admission to ICU and use of PAFCs to monitor cardiac function, the mortality in the high-risk group (low AT) was reduced from 18% to 8.9%. In summary, the AT identi®es a population that is less able to mount the appropriate increase in DO2 demanded after major surgery and in which a strategy of invasive monitoring and optimization of cardiac function is more likely to improve outcome.
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