Goal-directed haemodynamic therapy and gastrointestinal complications in major surgery: a meta-analysis of randomized controlled trials
1 Anaesthesia and Intensive Care Unit, Department of Emergency and Organ Transplantation and
2 General Surgery Section, Department of Application in Surgery of Innovative Technologies, University of Bari, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy
* Corresponding author. E-mail: nbrienza{at}rianima.uniba.it
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Abstract |
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Postoperative gastrointestinal (GI) dysfunction is one of the most frequent complications in surgical patients. Most cases are associated with episodes of splanchnic hypoperfusion due to hypovolaemia or cardiac dysfunction. It has been suggested that perioperative haemodynamic goal-directed therapy (GDT) may reduce the incidence of these complications in cardiac surgery, and other surgery, but clear evidence is lacking. We have undertaken a meta-analysis of the effects of GDT on postoperative GI and liver complications. A systematic search, using MEDLINE, EMBASE, and The Cochrane Library databases, was performed. Sixteen randomized controlled trials (3410 participants) met the inclusion criteria. Data synthesis was obtained using odds ratio (OR) with 95% confidence interval (CI) by random-effects model. Statistical heterogeneity was assessed by Q and I2 statistics. GI complications were ranked as major (required radiological or surgical intervention or life-threatening condition) or minor (no or only pharmacological treatment required). Major GI complications were significantly reduced by GDT when compared with a control group (OR, 0.42; 95% CI, 0.27–0.65). Minor GI complications were also significantly decreased in the GDT group (OR, 0.29; 95% CI, 0.17–0.50). Treatment did not reduce hepatic injury rate (OR, 0.54; 95% CI, 0.19–1.55). Quality sensitive analyses confirmed the main overall results. In patients undergoing major surgery, GDT, by maintaining an adequate systemic oxygenation, can protect organs particularly at risk of perioperative hypoperfusion and is effective in reducing GI complications.
Keywords: complications, hypovolaemia; fluids, i.v.; oxygen, transport; surgery, non-cardiac; surgery, postoperative period
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Introduction |
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Gastrointestinal (GI) dysfunction is a very common postoperative complication after major surgery and is associated with prolonged hospital stay in as many as 50% of patients.5 Therefore, identification of strategies that can prevent it is of paramount importance.
Organ perfusion and oxygen delivery are often impaired as a consequence of the surgery-induced alterations in the cardio-respiratory and metabolic demands.52 Episodes of reduced splanchnic perfusion and oxygenation, related to intraoperative hypotension or occult hypovolaemia, are frequent during major surgery.31 35 44 47 In cardiac surgery, an association between perioperative haemodynamic instability and postoperative GI dysfunction has been found22 and goal-directed therapy (GDT), which aims to increase oxygen delivery and avoid gut hypoperfusion, has been reported to reduce the incidence of postoperative morbidity (including GI complications).44 In non-cardiac major surgery, some trials23 46 59 suggest that GDT, by assuring a better splanchnic blood supply, contributes to a quicker recovery of the gut function. GI dysfunction ranges from mild complications (i.e. postoperative ileus and inability to tolerate enteral nutrition) to more severe surgical complications, associated with high mortality, and substantial costs and resource consumption.36 Unfortunately, all the above studies enrolled a low number of patients and were underpowered to detect any significant reduction of severe GI complications.
The gut, liver, and kidney are particularly at risk of hypoperfusion and GDT can improve renal function.10 We have conducted a meta-analysis to evaluate the relationship between perioperative haemodynamic optimization and postoperative GI and liver complications.
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Methods |
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Different search strategies (last update December 2008) were performed to retrieve relevant randomized controlled trials (RCTs) by using MEDLINE, The Cochrane Library, and EMBASE databases (see Supplementary Appendix). No date restriction was applied for MEDLINE and The Cochrane Library databases, whereas the search was limited to 2006–8 for EMBASE database.38 Additional RCTs were identified in the reference lists of previously published reviews and retrieved articles, and other data sources were hand-searched in the annual proceedings (2003–8) of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, the Society of Cardiovascular Anesthesiologists, the Royal College of Anaesthetists, and the American Society of Anesthesiologists. In order to reduce publication bias, abstracts were searched.41 Publication language was not a search criterion.
RCTs were selected using the following inclusion criteria.
- Effects of perioperative GDT on morbidity as main research topic. GDT was defined as perioperative monitoring and manipulation of haemodynamic variables to reach normal or supranormal values by fluid alone or in combination with inotropic therapy. RCTs with no description or no difference in optimization strategy between groups, and RCTs with therapy titrated to the same goal in both groups or not titrated to predefined endpoints were excluded.
- Adult (age 18 yr or more) surgical patients undergoing non-cardiac major surgery. Major surgery was defined using the POSSUM score.14 Studies involving mixed population of critically ill, non-surgical patients, or postoperative patients with already established sepsis or organ failure and undergoing late optimization were excluded.33 49
- A definition and incidence of postoperative GI or hepatic complications. These data were searched in the study or in Supplementary Appendix or were obtained by contacting authors.
Two investigators (M.T.G. and N.B.) examined each title and abstract to exclude clearly irrelevant studies and to identify potentially relevant articles. The other two investigators (M.M. and M.T.) independently determined the eligibility of full-text articles retrieved. The names of the author, institution, journal of publication, and results were unknown to the two investigators at this time.
The Scottish Intercollegiate Guidelines Network (SIGN) checklist for RCTs51 was used to evaluate the methodological quality of RCTs. A double plus (++) denotes studies very unlikely to have bias, plus (+) studies where bias is unlikely, and minus (–) studies with high risk of bias.51 A double plus was assigned to studies that adequately described all the criteria of randomization, concealment, blinding, intention-to-treat analysis, and predefined outcomes, whereas a sign of plus was given to studies meeting only four out of the five criteria. The adequacy of these five criteria is strongly associated with bias reduction.30 32 Regarding blinding, those studies in which the outcome was explicitly predefined, the outcome assessment was blinded, or both were considered adequately masked.26 The SIGN checklist was independently filled by two investigators (M.T.G. and M.M.) and whenever different, the study was further assessed in order to reach consensus.
Data were independently collected by two investigators (M.T.G. and N.B.), with any discrepancy resolved by re-inspection of the original article. To avoid transcription errors, the data were input into statistical software and rechecked by different investigators (M.M. and M.T.). Data abstraction included patients characteristics (age and sex) and risk factors (POSSUM score, ASA physical status classification, age >60 yr, and preoperative morbidity), type of surgery (i.e. elective or emergency, abdominal, thoracic, and vascular), anaesthetic management, haemodynamic GDT (endpoints, therapeutic intervention, and monitoring tools), and definition and incidence of GI and hepatic complications.
Quantitative data synthesis
Meta-analytic techniques (analysis software RevMan, version 5.0.20 Cochrane Collaboration, Oxford, UK) were used to combine studies using odds ratios (ORs) and 95% confidence intervals (CIs). A statistical difference between groups was considered to occur if the pooled 95% CI did not include 1 for the OR. An OR <1 favoured GDT when compared with a control group. Two-sided P-values were calculated. A random-effects model was chosen for all analyses. Statistical heterogeneity and inconsistency were assessed by using the Q and I2 tests, respectively.27 28 When the P-value of the Q-test was <0.10,16 the I2 was >25%, or both, heterogeneity and inconsistency were considered significant.27
GI postoperative complications were ranked using the classification proposed by Dindo and colleagues,17 which has the advantages of minimizing subjective interpretation and graduating the clinical impact of a complication on patient outcome in the short and long term. This classification evaluates the treatment used to correct a specific complication deviating from the normal postoperative course and consists of four grades:17
- grade I (no need of pharmacological treatment, e.g. non-infectious diarrhoea);
- grade II (need of pharmacological treatment, e.g. infectious diarrhoea requiring antibiotics);
- grade III (need of surgical, endoscopic, or radiological intervention, e.g. anastomotic leakage);
- grade IV (life-threatening complications requiring intensive care unit management, e.g. necrotizing pancreatitis).
- Major GI complications—grade III or IV of postoperative GI complications.17
- Minor GI complications—grade I or II of Dindo and colleagues'17 postoperative GI complications.
- Hepatic complications—hepatic postoperative dysfunction, defined as liver SOFA score >2 (total bilirubin
2 mg dl–1),58 as an elevation of amino-transferases 80 U litre–1 and total bilirubin 2 mg dl–1, as an elevation of amino-transferases 200 U litre–1, or as an elevation of total bilirubin (3 mg dl–1).18
For major GI complications, subgroup analyses were planned for studies which included abdominal surgery and studies which included high-risk patients. Studies were included in this subgroup analysis if the authors defined patients as at high risk of morbidity/mortality based on need of emergency surgery, elective major surgery, or both in patients with risk criteria defined by perioperative scoring system (POSSUM),14 ASA physical status classification, age >60 yr, and preoperative morbidity.
Statistical power with 
error of 0.05 was calculated for each analysis and it was considered adequate if 80%.
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Results |
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The search strategies identified 2230 (MEDLINE), 7955 (Cochrane Library), and 729 (EMBASE) articles. After initial screening and subsequent more detailed selection, a pool of 50 potentially relevant RCTs was identified. The subsequent eligibility process (Fig. 1) excluded 34 articles and, therefore, 16 articles,4 6 7 12 13 19 23 39 40 46 48 50 53 57 59 60 enrolling a total of 3410 patients, were included in the analysis. Eight studies were performed in Europe, five in the USA, two in Brazil, and one in Canada, from 1991 to 2007.
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All selected articles evaluated the effects of GDT on GI and liver morbidity, as primary or secondary outcome, and had a population sample of adult patients undergoing major non-cardiac procedures. Out of 16 studies, 15 included abdominal surgery; of these, 11 studies also included abdominal aortic, urological, gynaecological, or orthopaedic surgery. One study included only vascular surgery. Eleven studies enrolled high-risk patients. Nine studies received a SIGN evaluation equal or higher than + (Table 1).
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PP, arterial pulse pressure variation; LiDCO, lithium indicator dilution cardiac output. For risk definition, see text. A double plus (++) describes studies with very unlikely bias, a sign of plus (+) describes studies with unlikely bias, and a sign of minus (–) describes studies with high risk of biasThe incidence of major GI complications was reported or retrieved in 11 out of 16 RCTs, the incidence of minor ones in 6 and the incidence of hepatic postoperative dysfunction in 5 (Table 2).
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Quantitative data synthesis
Major GI complications
In 11 RCTs, 106 patients developed major GI complications: 69/533 (13%) had been randomized to the control group and 37/546 (6.8%) to perioperative GDT. Pooled OR for the development of major GI complications was 0.42 and 95% CI was 0.27–0.65 (statistical power 91%). No statistical heterogeneity and inconsistency were detected. The quality sensitive analysis confirmed the beneficial effect of GDT in studies with low risk of bias (OR, 0.34; 95% CI, 0.19–0.62; 524 patients; statistical power 90%) (Fig. 2).
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Subgroup analysis of patients having abdominal surgery revealed that major GI complications were significantly reduced by GDT (OR, 0.37; 95% CI, 0.16–0.87; 321 patients; 4 RCTs; P=0.02). No statistical heterogeneity and inconsistency were detected (Q statistic P=0.95; I2=0%).
Subgroup analysis of high-risk patients demonstrated that GDT significantly reduced major GI complications (OR, 0.40; 95% CI, 0.24–0.65; 687 patients; 7 RCTs; P<0.001). No statistical heterogeneity and inconsistency were detected (Q statistic P=0.50; I2=0%). No difference between GDT and control groups was observed on major GI complications in low-risk patients (OR, 0.50; 95% CI, 0.18–1.34; 392 patients; 4 RCTs; P=0.17). No statistical heterogeneity and inconsistency were detected (Q statistic P=0.64; I2=0%).
Minor GI complications
In 6 RCTs, 87 patients developed minor GI complications: 64/304 (21%) had been randomized to the control group and 23/274 (8.4%) to perioperative haemodynamic optimization. The OR and 95% CI for the development of minor GI complications in each trial and the pooled estimate (OR, 0.29; 95% CI, 0.17–0.50; P<0.001; statistical power 99%) are shown in Figure 3. No statistical heterogeneity and inconsistency were detected. The quality sensitive analysis confirmed the main result (OR, 0.25; 95% CI, 0.14–0.43; 453 patients; 4 RCTs; P<0.001, statistical power 99%) (Fig. 3).
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Liver complications
GDT did not reduce hepatic injury rate (OR, 0.54; 95% CI, 0.19–1.55; P=0.25, statistical power 78%). A high statistical heterogeneity and inconsistency were observed. One study57 reported no liver complications in either group. A re-analysis of the results, adding a nominal value of 0.5 in all 2x2 cells to enable calculation of OR and retesting of heterogeneity, yielded similar result. The quality sensitive analysis confirmed the main result (OR, 0.55; 95% CI, 0.15–2.06; 2116 patients; 3 RCTs, P=0.37, statistical power 20%) (Fig. 4).
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Discussion |
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This meta-analysis supports the ability of GDT to reduce major and minor GI complications in the perioperative period. No benefit was observed in hepatic postoperative injury rate.
Although the pathogenesis of GI complications is multifactorial,43 gut hypoperfusion, secondary to hypovolaemia or cardiac dysfunction, plays a key role. Healthy subjects tolerate a 25–30% decrease in blood volume without changes in systemic arterial pressure or heart rate, yet splanchnic perfusion is compromised after 10–15% reduction in intravascular volume.25 Selective vasoconstriction of mesenteric arterioles, mediated primarily by the renin–angiotensin system, contributes to the maintenance of systemic arterial pressure and the perfusion of non-mesenteric organs.55 This response occurs at the expense of splanchnic hypoperfusion that often outlasts the period of the hypovolaemic insult or low-flow state, promoting abdominal organ damage. GI dysfunction presents with clinical signs and symptoms ranging from impaired motility43 and inability to tolerate enteral diet to ischaemic injury.55 The type of surgery is important. For example, in abdominal surgery, poor oxygen delivery is significantly associated with anastomotic leak,35 especially in GI segments highly dependent on oxidative phosphorylation.56 Strategies to maintain oxygen delivery and minimize splanchnic hypoperfusion have been advocated to improve postoperative morbidity,15 and our analysis demonstrates that GDT is able to reduce major GI complications in non-cardiac major surgery. Our subgroup analyses identify high-risk patients and abdominal surgery as areas that may potentially benefit from GDT. As major GI complications are associated with high mortality, and substantial costs and resource consumption,36 the prevention or the prompt reversal of an inadequate perfusion may be much more effective than treating an already established damage.2
Our findings on the effect of GDT on GI complications appear to conflict with studies of restrictive fluid regimens. Such strategies, based on prefixed volume infusion, regardless of any specific monitoring and target, have been shown to reduce postoperative GI complications.8 45 This standardized approach does not consider individual differences, preoperative hydration, and duration or severity of surgical insult, and therefore, some patients may receive too much and others too little fluid. Interestingly, more postoperative complications have been reported to occur in some restrictive groups.29 In this context, an individualized, timely fluid ‘replacement’ therapy with or without inotropic support, aimed at physiological flow-related endpoints with appropriate monitoring, may be a more rational choice during major surgery and our results support this approach.
Our analysis also shows that minor abdominal complications (mainly including nausea and emesis) were reduced by GDT. Two recent meta-analyses, focusing on a Doppler-guided fluid loading strategy in low-risk patients, have already noted this benefit.1 11 Our analysis strengthens this and may allow extension of the evidence to other patient categories, surgical procedures, and optimization and monitoring strategies. The reduction in minor GI complications supports the benefit on bowel function obtained by GDT. However, the risk to benefit ratio and the cost of perioperative optimization should be taken into account. The clinical utility of GDT is often questioned, since it is perceived as a costly strategy. This may not necessarily be true, as GDT can result in net cost savings due to the reduced costs of treating complications and a shorter hospital stay.21 24 Evidence-based information with evaluation of benefit/risk ratio and related cost should help clinicians to choose the best therapy for individual patients.
Our results suggest that GDT does not reduce liver complications. Although major surgery plays a role in liver dysfunction,9 liver perfusion is, in contrast to gut perfusion, relatively protected by the hepatic arterial buffer response, at least in early stages of low-flow states.3 This and the multifactorial pathogenesis (including haemolysis and reabsorption of haematomas after trauma or blood transfusions, perioperative drugs, and upper abdominal surgery per se)20 of postoperative liver dysfunction may explain the absence of any significant difference in our analysis and the high statistical heterogeneity and inconsistency. In addition, in one large study50 dealing with liver complications, only 62% of the GDT group achieved haemodynamic goals and this may have contributed to the absence of any significant difference between groups.
Studies with high risk of bias often overestimate the true effect and may reduce the clinical significance of any result.42 We evaluated the risk of bias for each study and classified studies in low and high risk of bias according to the SIGN checklist. Out of 16 studies, 9 reached a low risk of bias evaluation (++ or +). Paradoxically, the trials with a high risk of bias had non-significant results. In contrast, the significant effect of GDT in reducing both minor and major GI complications was driven by the low bias trials, suggesting reliable and consistent evidence-based results. In addition, despite the methodological heterogeneity of studies using GDT, such as timing, monitoring, and protocols, it is reassuring that a strong statistical homogeneity and consistency (even by using conservative cut-off values) was still observed in the main, and also in the sensitive, analyses.
Limitations
The main limitations of all meta-analyses include reporting bias and clinical and methodological heterogeneity of the included studies. In order to reduce the reporting bias, an attempt was made to identify, retrieve, and include all reports, grey and published41 that met predefined inclusion criteria, and to retrieve unpublished data by contacting the authors of the included studies. Although we were able to get unpublished results from authors, no abstract was retrieved. Therefore, we cannot exclude any publication bias and available statistical tests are not enough to accurately detect it.37
Although splanchnic hypoperfusion is one of the most widely proposed mechanisms of pathogenesis, there are specific additional risk factors for GI dysfunction.43 Surgery and surgical manipulation of the gut can cause postoperative ileus and are a major pro-inflammatory stimulus.54 All anaesthetic drugs, especially the opioids, potentially contribute to decreased bowel motility and function.43 Moreover, acid–base, glucose, and electrolyte imbalance and hypothermia may affect GI function. We cannot really comment on how these conditions, co-morbidities and iatrogenic intervention, interact with GI complications in the postoperative period.
Clinical heterogeneity between studies of GDT cannot be ignored, in relation to type of surgery, patient's characteristics, therapeutic goals, methods for achieving these goals, and monitoring. Although we tried to control some covariates such as type of surgery or patient surgical risk by subgroup analyses, we were not able to adjust our analyses for all confounding factors. Given this heterogeneity, individual clinically relevant differences could have been missed in our aggregate data meta-analyses.
To clarify their effective role in the protection of gut function after surgery, we recommend that future studies should have hepato-splanchnic dysfunction as a main outcome, should have clear definitions of major and minor complications, should be performed in a well-defined group of patients, and should have a protocol for perioperative fluid and inotropic strategies.
In conclusion, GI dysfunction occurs in as many as 50% of surgical patients.5 Identification of strategies that prevent this frequent postoperative complication is of paramount importance. This meta-analysis, within the limitations of existing data and of the analytic approaches used, shows that GDT is an effective tool in the reduction of the incidence of GI complications. GDT, by the maintenance of adequate systemic oxygenation, can protect organs particularly at risk of perioperative hypoperfusion, decrease the incidence of postoperative complications, and may contribute to improve survival after major surgery.34
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Supplementary material |
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Supplementary material is available at British Journal of Anaesthesia online.
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Funding |
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This work was supported only from departmental sources.
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The authors wish to express their sincere gratitude to Drs R. Pearse (London, UK), A. Horgan (Newcastle upon Tyne, UK), I. Chytra (Plzen, Czech Republic), R. Venn (Worthing, UK), W.C. Shoemaker (Los Angeles, USA), P. Malhotra (New Delhi, India), and A. Donati (Ancona, Italy) for having supplied unpublished personal data.
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References |
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