peri-operative cardiovascular optimization

Peri-operative cardiovascular optimization

Owen Boyd MRCP, FRCA

Consultant in Intensive Care Medicine and AnaesthesiaThe Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, United Kingdom

Many studies show that post-operative mortality in identi®able subgroups of patients is higherthan expected. Often the cause is obscure, but tissue hypoperfusion resulting in multipleorgan dysfunction syndrome appears to be a major factor. A number of techniques areavailable to monitor and then to improve tissue perfusion by treatment with ¯uids andpharmacological agents (usually vasodilators and inotropes) to prede®ned values. Meta-analysisof 13 randomized, controlled studies enrolling 994 patients shows a signi®cant reduction inmortality in the treatment group (odds ratio 0.35, 95% con®dence interval 0.23±0.53).Implementing the proposed techniques on all suitable patients is controversial as this hasmajor service implications and some questions remain unanswered. However, peri-operativecardiovascular optimization in selected groups of patients is shown to reduce the likelihood ofmortality and morbidity for those patients and by reducing costs and hospital stay may help tostreamline care for all surgical patients.

Key words: peri-operative treatment; optimization; oxygen delivery; cardiac output; surgery;mortality rate; high-risk patients; right-heart catheter; inotropes; vasodilators; ¯uid therapy;review; meta-analysis.

Over the last two decades surgeons and anaesthetists have developed the principle ofsupporting tissue perfusion. Surgery has become shorter with less blood loss, reducedhandling of tissues and less trauma as laparoscopic techniques improve. Anaesthesiateaching emphasizes early resuscitation, improved monitoring, more responsive ¯uidtherapy, improved temperature control, better control of the stress of post-operativepain and, in certain circumstances such as aortic surgery, the use of vasodilators andinotropes speci®cally to maintain perfusion during severe cardiovascular stress. How-ever, there is little direct evidence for the e�ectiveness of any one particular measure,and most anaesthetists rely on personal preference at worst and anecdote at best.Frequently this results in the same routine being used for all patients. Speci®cally, thecardiovascular system is monitored by heart rate and blood pressure measurementswhich tell the anaesthetist little about the state of the circulation, giving noinformation on blood ¯ow and tissue perfusion. However, there is plenty of evidencethat formally assessing markers of tissue perfusion and instituting treatment toincrease perfusion if it appears low improves post-operative outcome. In this chapter Iwill explore the evidence that there may be a hidden problem with surgical mortalityrate, suggest a link between post-operative mortality and tissue hypoperfusion, reviewrandomized, controlled clinical trials that investigate the possible e�ectiveness ofincreasing tissue perfusion in the peri-operative period and consider some of theproblems and controversies that occur in general application of the result.

1521±6896/99/030267+11 $12.00/00 *c 1999 Harcourt Publishers Ltd.

BaillieÁ re's Clinical AnaesthesiologyVol. 13, No. 3, pp. 267±277, 1999

3

SURGICAL MORTALITY RATES

Before one starts to consider altering goals of therapy that have served well, and formost patients are completely adequate, it is necessary to identify that a problem reallyexists. Overall surgical mortality is low and is considered acceptable at about the 2%level. However, it is apparent that there are wide variations in mortality depending onthe operation and the underlying condition of the patient. There are a number offeatures which make the interpretation of surgical mortality rates di�cult; ®rst, ®guresare often only published from major referral centres; second, there are di�eringcriteria for analysing the causation of post-operative deaths; third, there are wide-spread variations in patients considered for di�erent operations; lastly, published®gures usually do not take into account the in¯uence of comorbidity. However, anumber of larger more general studies have been undertaken.

The National Veterans Surgical Risk Study considered 83 958 operations over a 2year period performed on patients with a mean age of 60 years; the mortality rateoverall was 3.1% at 30 days, but 17% of patient had one or more major complications.1

In a separate review of 900 patients aged 65 years and over2 patients with non-electiveadmissions (mortality rate 30% versus 5% for elective admissions), American Society ofAnesthesiologists (ASA) grade 3� (mortality rate 27% versus 8% for ASA 53), ageover 75 years (mortality rate 20% versus 11% for patients aged 65±74 years) and majorsurgery (mortality rate 25% versus 10% for non-major surgery) were associated withmuch higher mortality. Other studies on speci®c groups of surgical patients havecon®rmed the major in¯uence that age and performance status have on post-operativemortality.3

The urgency of the requirement for surgery also in¯uences outcome. In anotherpopulation-based study of colorectal surgery the overall mortality rate was 7.6% at30 days, but mortality rates of 21.7% were seen in patients undergoing urgent oremergency surgery.4 In a study of urgent and emergency laparotomy in patients agedover 65 years during a 6 month period, an overall mortality of 44% was found. Inpatients rated as ASA 3 and over the mortality rate was 53%.5 Few studies are availablein the literature which relate post-operative surgical mortality directly to the patient'smedical condition. In a study of 108 878 uses of anaesthetics between 1972 and 19776,the overall mortality rate was 2.2%, but this rose considerably when there was acoexisting medical condition: 7.0% with ischaemic heart disease, 15.8% with cardiacfailure and 5.7% with just diabetes. These mortality rates were increased signi®cantly ifthe surgery was undertaken as an emergency.

In summary, patients who have a worse outcome are older, have coexisting diseaseprocesses and present in more urgent circumstances. This is hardly surprising, and itslikely truth would be recognized by the most junior trainee, but the extent of the

Practice point

Surgical mortality in identi®able subgroups is higher than expected.

Research agenda

More research into the epidemiology of surgical mortality.

268 O. Boyd

mortality rate in these patients who can be quite easily identi®ed pre-operatively isnot always recognized.

TISSUE PERFUSION AND SURGICAL OUTCOME

There are a number of medical conditions that may directly in¯uence surgical outcomeand which are unrelated to the surgery itself, but often the coexisting medicalconditions are much more vague and it is not always intuitively obvious why theseconditions should contribute to surgical mortality. Data on post-operative causes ofdeath are rare despite the fact that it is known that 80% of post-operative deaths aredue to multiple organ dysfunction syndrome (MODS).7

There are a number of factors which, acting independently or in combination,trigger the onset of MODS.8 One of these factors appears to be alterations inmicrocirculatory ¯ow.9,10 There is also evidence of microvascular injury in patientsdying of MODS11 and inadequate oxygen supply to the tissues leading directly to celldeath and reperfusion may cause continuation and ampli®cation of the tissue damage.12

It has been known for some time that there are changes in a number of theparameters of tissue perfusion at the time of life-threatening illness. The measurementof actual e�ective tissue perfusion is not yet possible as a bedside technique, and mostinvestigators have used surrogate markers such as cardiac output (CO), total bodyoxygen delivery (DO2) and total body oxygen consumption (VO2). As early as 193120±25% increases in VO2 were seen in patients who sustained orthopaedic injuries andoperations.13 Further studies showed that such patients could be classi®ed by their COinto three groups: `no' shock, `mild' shock and `severe' shock, with severe shockhaving lower CO and the highest peripheral resistance.14 Importantly the classi®cationof the shock in an individual patient related to outcome, with the `severe' shock grouphaving the worst outcome.14

As techniques of invasive monitoring of cardiovascular status developed, furtherstudies were conducted. In an observational study of patients undergoing cardiacsurgery those with a cardiac index greater than 2.4 l/min/m2 had no seriouscardiovascular complications, while those who had a lower CO had a mortality rate of67%.15 Similar results were found by Clowes and coworkers studying the circulatoryresponses of patients undergoing thoracic operations16 and peritonitis.17 Other stud-ies showed that patients who survived major surgery had higher cardiac index, lowersystemic vascular resistance and higher VO2 than non-survivors.18,19 Furthermore, itwas found that the commonly monitored vital signs, heart rate, temperature, centralvenous pressure and haemoglobin, were the poorest predictors of mortality, whileperfusion-related variables, such as CO and total body DO2, were the best.20 Theactual numerical values for CO and DO2 that separate survivors from non-survivorsare slightly di�erent at di�erent ages, all values being lower at older ages.21

Recent studies to assess the impact of oxygen transport variables on post-operativemortality and morbidity show similar trends. Kusano et al22 studied patientsundergoing oesophagectomy showing that at 6 hours post-operatively DO2 and VO2

Practice point

Peri-operative tissue hypoperfusion is a major cause of post-operative mortality.

Peri-operative cardiovascular optimization 269

were signi®cantly lower in those patients who developed anastamotic leak or pneum-onia. In a separate study of 57 patients who survived repair of ruptured abdominalaneurysm those who developed multiple organ failure had signi®cantly lower DO2than those that did not, and logistic regression analysis showed this to be a betterpredictor of outcome than previously identi®ed risk factors.23

Furthermore, a mismatch between VO2 and supply, as re¯ected by a rise in theoxygen extraction ratio, was shown to be a better indicator of prolonged intensivecare than conventional risk factors in patients undergoing cardiac surgery.24

A summary of the evidence shows the following: a subgroup of surgical patientshave a high mortality; lower CO, DO2 and tissue perfusion occur in patients withhigher mortality; most post-operative deaths are caused by MODS; tissue hypoper-fusion is a major cause of MODS. How do these lines of evidence combine to in¯uenceclinical practice?

CARDIOVASCULAR OPTIMISATION IN THEPERI-OPERATIVE PERIOD

The answer may appear simple: in patients who have limited tissue perfusion, tissueperfusion should be maximized. However, there are a number of unansweredquestions which make this approach controversial.

First, how are CO and DO2 maximized? Total body tissue perfusion relies onadequate arterial oxygen saturation, haemoglobin concentration and CO and is usuallyassessed generally by calculation of DO2. However, it is unclear which of the com-ponents of the equation should be speci®cally increased. Most studies have focused onan increase of CO, and indeed an increase in CO has become synonymous with theterm `optimization', but is not known which of the components that in¯uence CO,cardiac ®lling pressures, the reduction of cardiac afterload or the increasing cardiacpump power, is the most bene®cial. Furthermore, it is not yet clear when treatmentto optimize the cardiovascular system should either start or ®nish.

Second, how is tissue perfusion actually assessed? The options for assessing tissueperfusion in a clinical situation are limited, and most have concentrated on assessmentsof total body perfusion based on CO or parameters derived from it. Most studies haveused right-heart catheterization to measure CO and to derive further parameters suchas DO2, but right-heart catheters can be used to measure mixed venous oxygensaturation, and this has been used as a target for treatment in one study. Dopplerassessment of CO has been used in two studies, and other techniques such asechocardiography, lithium dye dilution and even formalized clinical estimation couldalso be employed.

Research agenda

The development of clinically appropriate techniques to monitor tissue perfusion.

Research agenda

Development of a straightforward scoring system for the identi®cation of patientsmost at risk from post-operative mortality and morbidity.

270 O. Boyd

Third, which patients will bene®t from cardiovascular optimization? It is di�cult toassess which patients may bene®t most from cardiovascular optimization, informationis lacking and there are as yet no formal scoring systems that have been shown to beuseful in this situation. Most of the studies have used a single operation type to identifypatients or a more general list of clinical characteristics. Both of these approaches areopen to criticism: the ®rst may miss some patients and include others that are at notso a high risk; the second is open to individual interpretation.Fourth, what are the resource implications if the policy is implemented? Any new

policy that is to be implemented in modern health care needs to be considered interms of its in¯uence on resources. Cardiovascular optimization will initially requiremore time, more beds, greater skill mix and suitable post-operative facilities. Thisappears to be a big commitment and although some studies have started to investigatethis point there is inadequate emphasis on the positive in¯uence that cardiovascularoptimization could have on resource use.

The studies

Despite these controversial issues there are now a number of controlled randomizedstudies in the published literature that have investigated the role of increasing DO2 tothe tissues in peri-operative patients. These have been reviewed by various authors,and a number of criticisms of the study techniques have been made.25±30 Not all ofthese criticisms are easy to remedy. A summary of the relevant points is as follows.

1. Di�erent studies have enrolled di�ering patient groups with di�ering comorbid-ities and expected mortality rates.

2. Di�erent techniques have been used to in¯uence DO2.3. The studies are not blinded; although this would be methodologically di�cult it

does lower their statistical impact.4. Some studies have limited statistical power owing to low baseline mortality rates.5. Di�erent endpoints for initial treatment and continuing treatment have been used.6. Two di�erent approaches to the measurement of CO have been used, either right-

heart catheterization or Doppler studies.7. There has been failure to analyse outcome results according to intention to treat.8. Some have based their conclusions on subgroup analysis.9. The studies vary in their control for co-intervention.

10. A `cross-over phenomenon' exists whereby patients may fail to achieve the goals ofthe group they have been randomized to or, in the case of some control patients, toachieve the goals of the treatment group which weakens the ability of the study todetect any treatment e�ect.

Thirteen randomized, controlled studies can be identi®ed in the currently availableliterature that have speci®cally aimed to increase tissue perfusion with ¯uids, vasodil-ators or inotropes. The ®rst was published in 1985 by Schultz and colleagues.31 In aclinical trial of 70 patients undergoing operative repair of hip fracture, they showedthat, compared with a control group whose mortality was 29%, a monitored grouptreated with ¯uids, inotropes and vasodilators to a previously identi®ed physiologicalpro®le including increased CO had a mortality of only 2.9%. In a series of uncontrolledstudies Shoemaker et al have shown a decreased mortality compared with non-randomized patients.32,33 Using the same approach in which CO and DO2 wereincreased with ¯uids and inotropes, Shoemaker et al then demonstrated a reduction inmortality from 33% to 4% in a randomized study of similar high-risk surgical patients.33


Boyd and colleagues34 reported the results of a study in which high-risk surgicalpatients had a deliberate increase of DO2 towards 600 ml/min per m2 using dop-examine hydrochloride infusion. Results showed a signi®cant reduction in post-operative complications and mortality was reduced from 22.2% to 5.7%. The costimplications were explored in a retrospective study which showed an overall reductionof costs in patients in the treatment group with signi®cant reduction in costs oftreating complications.35 More recently some work has attempted to elucidate themechanisms of action of dopexamine hydrochloride used in this way. Byers andcolleagues36 studied 23 patients undergoing abdominal surgery randomized to receiveperi-operative dopexamine or placebo and showed that those in the dopexaminegroup had a lower incidence of acute gastritis. Furthermore, gastrointestinal per-meability following cardiac surgery is reduced by dopexamine infusion compared withdobutamine infusion.37 The reason for this may be improved gastric mucosal oxygen-ation which has been shown to occur with dopexamine hydrochloride infusion38, andthis might indicate an improvement in organ perfusion generally and might partlyexplain a reduction in MODS in these patients.

There are a number of studies that have enrolled patients undergoing vascularsurgery. In 1991 Berlauk and colleagues published the results of a randomized trial ofpatients undergoing limb-salvage arterial surgery.39 There was no signi®cant di�erencein mortality, which was 9.5% in the control group and 1.5% in the protocol group.However, the protocol group, in which ¯uids and inotropes were given to pre-de®nedtargets, had fewer adverse intraoperative events, less post-operative cardiac morbidityand less early graft thrombosis than the control group. Using very similar protocols,Valentine et al studied patients undergoing aortic operations.40 Statistical analysisshowed no di�erence in the protocol and control groups, although the overall mort-ality rate was low. Bender et al41 studied patients undergoing elective vascular surgerywith low risk of mortality (52%). In this study no signi®cant di�erences in outcomewere noted between patients managed to optimize their cardiovascular and thecontrol group. In a similar group of patients having elective aortic reconstruction orlower-limb salvage procedures Ziegler and colleagues42 targeted mixed venous oxygensaturation as their measure of adequate total body perfusion. They used ¯uids, redblood cell transfusions, inotropes and vasodilators to achieve only a modest SvO2 ofgreater than 65% in the protocol group. Although the statistical analysis of the studyhas been questioned43, it failed to show any di�erence in mortality rate or morbiditybetween the protocol group and the control group. However, in patients undergoingsurgery for resection of hepatocellular carcinoma, Ueno et al44 showed a signi®cantreduction in liver failure and hyperbilirubinaemia post-operatively in patients treatedto raise cardiac index and DO2, although in this study other morbidity rates andmortality rates were not di�erent.

Trauma patients have also been studied at an early point in their illness. In a pilotstudy of trauma patients, mortality was reduced from 44% to 24% and there was asigni®cant reduction in morbidity when CO and DO2 were increased to pre-de®nedtargets.45 A follow-up study was conducted to increase statistical power. This showed,in 115 patients with similar characteristics and a mortality rate of 37% in the controlgroup, that both mortality and morbidity were reduced.46 However, in the controlgroup, a longer time was taken to reach the operating room (86+14 min versus56+10 min) and there were more prolonged periods of systolic hypotension (82+15versus 59+10). In a much lower-risk group of patients, with control group mortalityof 10%, Durham et al47 failed to show any improvement in either mortality ormorbidity in trauma patients with massive blood loss, sepsis, hypotension or

272 O. Boyd

respiratory failure. There was no signi®cant di�erence between the groups withrespect to the mean haemodynamic and oxygen transport parameters after 24 hoursof resuscitation, but patients who achieved the goals with ¯uids alone were youngerand had a lower mortality that those who required inotropes.All of the studies so far discussed have used information derived from right-heart

catheterization and the doubts concerning the safety of the technique48 and its beinglimited to use in intensive care areas have prompted investigation of other techniques.Two studies have utilized pulsed Doppler measurement of CO. Mythen and Webb49

studied the e�ect of plasma volume expansion with 6% hydroxyethyl starch infused tomaximum stroke volume on outcome in elective cardiac surgical patients, but onlythose with ejection fraction450% were included. Although overall mortality was low,as would be expected in this group of patients, and was not signi®cantly reduced,patients in their protocol group did have a signi®cantly reduced number of post-operative complications and hospital stay. More recently, Sinclair et al50 reported theresults of a randomized study of patients undergoing repair of proximal femoralfracture. As with the previous work the patients were treated with intravenous ¯uidboluses to maximize stroke volume. The treatment group had a signi®cantly reducedhospital stay, with the implication that they also had fewer post-operative comp-lications, but once again mortality was low and not signi®cantly reduced by theintervention.

DISCUSSION

There have recently been a number of articles reviewing studies on the e�ectiveness ofspeci®c treatment designed to increase tissue perfusion.25±30 However, some of thereviews have primarily addressed issues concerning the e�ectiveness of right-heartcatheterization27,29, and others have included studies enrolling patients at a later stageof their illness28,30, although separating those in the peri-operative period for thepurposes of analysis.30 As in previous work the data from the peri-operative studiespresented in this review can be summarized. In the 13 studies discussed 994 patientshave been enrolled. Figure 1 shows the odds ratios and con®dence intervals for thedata in these studies.30 In the total series the overall odds ratio for improvement inoutcome is 0.35 (95% con®dence interval (CI) 0.23±0.53). However, further conclusionsmay be possible if it is assumed that the control group mortality rate represents theoverall severity of illness of the patient group being studied. It can be seen that thestudies with higher mortality rate show improvement in outcome, whereas those withthe lowest mortality rates do not. The odds ratios can be recalculated using anarbitrary division taken at the median of the mortality rates of the studies. The sixstudies with mortality rates greater than 10% have a combined 451 patients and oddsratio of 0.25 (95% CI 0.15±0.43). Conversely, the seven studies with mortality rates lessthan 10% include 543 patients and provide an odds ratio of 0.88 (95% CI 0.39±2.00).

Practice point

Meta-analysis of studies on peri-operative cardiovascular optimization in 994patients in 13 studies shows a signi®cant reduction in mortality.


SUMMARY

Many studies show that post-operative mortality in identi®able subgroups of patients ishigher than expected, particularly in patients who are more elderly, have signi®cantcomorbidity and present for more urgent surgery. The direct cause for this is oftenobscure, but tissue hypoperfusion which may result in MODS appears to be a majorfactor and may account for most post-operative deaths. A number of techniques areavailable to improve tissue perfusion and to monitor this improvement, but in practicemost studies have used right-heart catheters to monitor CO and the derived value oftotal body DO2. Other techniques include Doppler assessment of cardiac output andmixed venous saturation measurement. Once baseline values have been obtained,individual patients are treated with ¯uids and pharmacological agents to pre-de®nedtargets for these parameters. Meta-analysis of 13 randomized, controlled studiesenrolling 994 patients shows a signi®cant reduction in mortality in the treatment

Research agenda

Further studies on the role of cardiovascular optimization in surgical patients,re®nement of the techniques to be used.

Figure 1.Graph showing the odds ratio and 95% CIs for the 13 studies identi®ed as investigating the e�ect ofoxygen transport goals of treatment on patients prior to the onset of organ failure plotted against thecontrol group mortality for each study: a,45; b,46; c, control versus pulmonary artery catheter (PA) targetedgroup33; d,31; e,34; f, schematically represented as odds ratio 044; g,50; h,47; i,39; j,42; k, schematicallyrepresented as odds ratio 049; l,41; m.40 Adapted from Boyd and Hayes.30

274 O. Boyd

group (odds ratio 0.35, 95% CI 0.23±0.53). Implementing the proposed techniques onall suitable patients is controversial as this has major implications for peri-operativeservice provision and some questions remain unanswered such as the methods for theearly identi®cation of at-risk patients, the endpoints for treatment and the exacttreatment technique used. However, peri-operative cardiovascular optimization inselected groups of patients has been shown to reduce the likelihood of mortality andmorbidity for those patients and by reducing costs and hospital stay may help tostreamline care for all surgical patients.

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37. Sinclair DG, Houldsworth PE, Keogh B et al. Gastrointestinal permeability following cardiopulmonarybypass: a randomised study comparing the e�ects of dopamine and dopexamine. Intensive Care Medicine1997; 23: 510±516.

38. Temmesfeld-Wollbruck B, Szalay A, Mayer K et al. Abnormalities of gastric mucosal oxygenation inseptic shock: partial responsiveness to dopexamine. American Journal of Respiratory and Critical CareMedicine 1998; 157: 1586±1592.

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42. 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. Surgery1997; 122: 584±592.

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44. Ueno S, Tanabe G, Yamada H et al. Response of patients with cirrhosis who have undergone partialhepatectomy to treatment aimed at achieving supranormal oxygen delivery and consumption. Surgery1998; 123: 278±286.

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*48. Connors AF, Spero� T, Dawson NV et al. The e�ectiveness of right heart catheterization in the initialcare of the critically ill. Journal of the American Medical Association 1996; 276: 889±897.

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peri-operative cardiovascular optimization

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