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Maintaining Tissue Perfusion in High-Risk Surgical Patients

A Systematic Review of Randomized Clinical Trials

Gurgel, Sanderland T., MD; do Nascimento, Paulo Jr., MD, PhD

doi: 10.1213/ANE.0b013e3182055384
Critical Care, Trauma, and Resuscitation: Research Reports
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BACKGROUND: Surgical patients with limited organic reserve are considered high-risk patients and have an increased perioperative mortality. For this reason, they need a more rigorous perioperative protocol of hemodynamic control to prevent tissue hypoperfusion. In this study, we systematically reviewed the randomized controlled clinical trials that used a hemodynamic protocol to maintain adequate tissue perfusion in the high-risk surgical patient.

METHODS: We searched MEDLINE, Embase, LILACS, and Cochrane databases to identify randomized controlled clinical studies of surgical patients studied using a perioperative hemodynamic protocol of tissue perfusion aiming to reduce mortality and morbidity; the latter characterized at least one dysfunctional organ in the postoperative period. Pooled odds ratio (POR) and 95% confidence interval (CI) were calculated for categorical outcomes.

RESULTS: Thirty-two clinical trials were selected, comprising 5056 high-risk surgical patients. Global meta-analysis showed a significant reduction in mortality rate (POR: 0.67; 95% CI: 0.55–0.82; P < 0.001) and in postoperative organ dysfunction incidence (POR: 0.62; 95% CI: 0.55–0.70; P < 0.00,001) when a hemodynamic protocol was used to maintain tissue perfusion. When the mortality rate was >20% in the control group, the use of a hemodynamic protocol to maintain tissue optimization resulted in a further reduction in mortality (POR: 0.32; 95% CI: 0.21–0.47; P < 0.00,001). Monitoring cardiac output with a pulmonary artery catheter and increasing oxygen transport and/or decreasing consumption also significantly reduced mortality (POR: 0.67; 95% CI: 0.54–0.84; P < 0.001 and POR: 0.71; 95% CI: 0.57–0.88; P < 0.05, respectively). Therapy directed at increasing mixed or central venous oxygen saturation did not significantly reduce mortality (POR: 0.68; 95% CI: 0.22–2.10; P > 0.05). The only study using lactate as a marker of tissue perfusion failed to demonstrate a statistically significant reduction in mortality (OR: 0.33; 95% CI: 0.07–1.65; P > 0.05).

CONCLUSIONS: In high-risk surgical patients, the use of a hemodynamic protocol to maintain tissue perfusion decreased mortality and postoperative organ failure. Monitoring cardiac output calculating oxygen transport and consumption helped to guide therapy. Additional randomized controlled clinical studies are necessary to analyze the value of monitoring mixed or central venous oxygen saturation and lactate in high-risk surgical patients.

Published ahead of print December 14, 2010

From the Department of Anesthesiology, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Dr. Paulo do Nascimento, Jr., Department of Anesthesiology, Universidade Estadual Paulista, UNESP, Distrito de Rubião Jr, s/n, PO Box 530, Botucatu, SP, Brazil, 18.618-970. Address e-mail to pnasc@fmb.unesp.br.

Accepted October 4, 2010

Published ahead of print December 14, 2010

The mortality rate in some subgroups of surgical patients is much higher than expected for most surgical procedures.1 Despite the multifactorial causes of death and organ failure in these patients, a persistent inadequacy of tissue perfusion seems to be the pivotal factor for the development of perioperative organ failure.2 With respect to risk identification, there seems to be a tendency toward the occurrence of a postoperative cardiac event in the surgical patient, but for most high-risk patients, the main cause of death is more often related to tissue perfusion dysfunction than to a cardiac problem.3

Thus, even if it seems obvious that surgical patients with a risk of tissue hypoperfusion should be monitored and treated during a perioperative period with fluids, blood, and drugs, there are some unanswered questions about this approach. Who, when, and how to maintain tissue perfusion, but mainly, what is the best goal to guide tissue perfusion? In this systematic review, we analyzed the methodological quality of randomized controlled clinical trials of high-risk surgical patients whose tissue perfusion was monitored and maintained perioperatively, and evaluated the influence of treatment on postoperative organ failure and mortality. Furthermore, the role of individual markers of tissue perfusion as the goal for treatment in the perioperative period to establish information for clinical practice and guidelines for the future was also analyzed.

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METHODS

This article is a systematic review of randomized controlled clinical trials of surgical patients with a limited physiological organic reserve who were submitted to a hemodynamic protocol to maintain adequate tissue perfusion compared with patients who had standard care in the perioperative period. The impact of the treatment on postoperative organ failure and mortality was analyzed. MEDLINE, Embase, LILACS, and Cochrane databases were searched up to November 2009 with the following terms: end point, optimization, goal-directed therapy, hemodynamic optimization, global tissue hypoxia, multiple organ failure, multiple organ dysfunction, surgery, high-risk patients, postoperative period, perioperative period, trauma, shock, burns, critical care, intensive care, oxygen delivery, oxygen transport, oxygen consumption, cardiac output, dobutamine, fluid therapy, blood lactate, central venous oxygen saturation (ScvO2), mixed venous oxygen saturation (Sv[Combining Macron]O2), and oximetry.

The criteria of inclusion were as follows: randomized controlled clinical studies, blinded or not; patients older than 18 years submitted to major surgery with high likelihood of development of complications in the postoperative period, according to the presence of ≥1 high-risk criteria defined by Shoemaker et al.4 in 1988 (Table 1); presence of a well-defined hemodynamic protocol to maintain tissue perfusion with either/both fluids or/and vasoactive and inotropic drugs with therapeutic goals well defined (primary end points for treatment involving variables of tissue perfusion: cardiac output, oxygen delivery/consumption, ScvO2/Sv[Combining Macron]O2, lactate); presence of a control group with patients treated according to standard of care; and reduction of mortality rate (defined as the total mortality rate within the first 28 postoperative days or in-hospital mortality, if postoperative days were not reported in the articles), and/or postoperative organ dysfunction, as defined by Donati et al.5 (Table 2), as the main outcomes. The measured variables as the result of hemodynamic control, i.e., death and organ dysfunction, were validated and categorized as postoperative complications by Dindo et al.6 in a cohort study of 6336 patients.

Table 1

Table 1

Table 2

Table 2

Studies of patients with sepsis or septic shock or with patients presenting evidence of organ dysfunction or failure before surgery were excluded from the analysis. Analysis of the outcome of postoperative organ dysfunction was conducted in the form of a dichotomous variable, that is, the number of patients who had at least 1 organ dysfunction versus the number of patients without any organ dysfunction.

Selected studies were analyzed according to their methodological quality, using a scoring system previously evaluated (Table 3).7 Considering possible differences in clinical outcomes according to the scientific rigor of the trials, we chose to separate the trials in 2 distinct analyses according to the methodological quality score, one with the score between 0 and 9 and another with a score between 10 and 16.

Table 3

Table 3

Based on the possible influence of patients' clinical conditions on mortality, the selected clinical trials were also divided in 3 subgroups according to the mortality rate of the control group: 0% to 10%, 11% to 20%, and >20%.

For statistical evaluation, the MetaView module of Review Manager 5.0 (RevMan) computer software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) was used. Odds ratio (OR) and 95% confidence interval (CI) with a model of fixed effect for dichotomy variables were calculated with the Mantel-Haenszel method. χ2 with P > 0.05 for homogeneity was used, and I2 was calculated for a heterogeneity test, considering values between 0% and 30% of little importance, values between 31% and 50% of moderate importance, values between 51% and 75% of high importance, and values ≥76% of extreme importance.

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RESULTS

A total of 4607 potentially relevant references were identified and screened for retrieval. Sixty-six studies were selected, and 32 randomized controlled trials with 5056 patients met the eligibility criteria (Fig. 1).

Figure 1

Figure 1

The average methodological system score was 9.5 from a range of 0 to 16, corresponding to 59.3% of the top score. The average score was close to the median (equal 9) and the mode (equal 10), suggesting a normal distribution.

Figures 2 through 4 show pooled ORs for mortality according to the control group mortality rate. Table 4 shows characteristics of selected clinical trials, including intervention, methodological quality score, and treatment goals to maintain tissue perfusion. Table 5 shows ORs and 95% CIs, level of heterogeneity, and overall effect for mortality and organ failure incidence according to the methodological score of the studies, mortality rate of control groups, use of pulmonary artery catheter, and variables used for hemodynamic control.

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Table 4

Table 4

Table 5

Table 5

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DISCUSSION

There is a subgroup of patients during some surgical procedures that have a high potential for complications during the perioperative period. To explore the possible interventions that might reduce the incidence of complications in these patients, a substantial number of randomized controlled clinical trials on perioperative hemodynamic stabilization are necessary. A systematic review of these clinical trials would be considered the highest level of evidence and guide for interventions that improve outcome.8 There is still a need to explore perioperative hemodynamic control in high-risk surgical patients, considering not only the diverse markers of tissue perfusion, but also the targets for treatment. We focused on those trials comprising high-risk surgical patients with no evident organ dysfunction before surgery and submitted to an early protocol of hemodynamic treatment, trying to prevent occult tissue hypoperfusion.

There are several previous systematic reviews on high-risk surgical patients studied using a hemodynamic protocol to maintain adequate tissue perfusion during the perioperative period.

Boyd1 identified 17 randomized controlled clinical trials that had investigated perioperative therapies designed to increase tissue perfusion in surgical patients, many of them with limited cardiovascular reserve. A total of 1974 patients were enrolled in the studies and the OR for reduction in mortality was 0.45, with 95% CIs ranging from 0.33 to 0.60. The author suggested that outcome could be improved preoperatively by increasing tissue oxygen delivery in such patients.

Heyland et al.9 may have been the first to systematically review randomized clinical trials designed to achieve supranormal values of cardiac, oxygen delivery, and consumption indexes in critically ill patients. They rigorously selected 7 articles of 64 potentially identified, and did not find a significant reduction in mortality rate (relative risk 0.86, 95% CI from 0.62 to 1.20). Nonetheless, their analysis of 2 studies with preoperative increase of tissue perfusion showed significant reduction in mortality rate, suggesting that hemodynamic preoperative control could benefit the high-risk surgical patient.

Kern and Shoemaker10 reviewed 21 randomized controlled studies with hemodynamic protocols for acutely ill, high-risk elective surgery, trauma, and septic patients, using either normal or supranormal values for therapy, the latter described as cardiac index >4.5 L · min−1 · m−2, oxygen transport index (DO2I) >600 mL · min−1 · m−2, and oxygen consumption (V[Combining Dot Above]O2I) >170 mL · min−1 · m−2. They found that in severely ill patients (control group mortality >20%), 6 studies showed a significant (23%) mortality difference between the control and protocol groups with early treatment. However, in 7 studies in which hemodynamic stabilization was performed after the development of organ failure, there was not a significant reduction in mortality rate.

Poeze et al.11 selected 30 randomized clinical trials of high-risk clinical and surgical patients hemodynamically treated and analyzed the methodological quality of the studies. The methodological quality of the studies was considered moderate and the outcomes of the randomized clinical trials were not related to their quality. In the studies that included patients with sepsis or organ dysfunction, no benefits were seen in outcome with hemodynamic control, but those with perioperative interventions aimed at maintaining tissue perfusion of high-risk surgical patients significantly reduced mortality.

Three recent reviews involving a few series of randomized controlled studies explored different aspects of hemodynamic stabilization. Bundgaard-Nielsen et al.12 identified 9 studies in which a goal-directed therapeutic strategy was used to maximize flow-related hemodynamic variables in surgical patients, intra- and postoperatively. They verified that the treatment strategy reduced gastrointestinal complications and hospital length of stay. Abbas and Hill13 analyzed the use of esophageal Doppler on hemodynamic control with fluids in major abdominal surgery, selecting 5 studies comprising 420 patients, and demonstrated that there was a reduction in hospital stay in the intervention group. Giglio et al.14 selected 16 studies involving perioperative monitoring and manipulation of hemodynamic variables to reach normal or supranormal values and also concluded that goal-directed hemodynamic therapy reduces gastrointestinal complications after major surgery, as tissue perfusion is maintained.

This review differs from previously published reviews on hemodynamic monitoring and control because it focuses on surgical patients with no organ failure before surgery, with a high risk of complications and death, and submitted to a specific protocol to maintain tissue perfusion involving cardiac output, oxygen delivery/consumption, and its derived variables, such as S|v[Combining Macron]O2. With these filters, 32 randomized clinical trials were recovered with >5000 patients, the largest number of individuals in a review on this topic.

In the present review, we found that in high-risk surgical patients with no evident organ dysfunction before surgery, the use of a protocol to maintain adequate hemodynamic status and tissue perfusion reduced the mortality rate and the possibility of organ failure in the postoperative period (Table 5). Therefore, strategies to ensure adequate perioperative tissue perfusion should be adopted. It is surprising that in a recent publication, Pearse et al.15 showed a different outcome in the United Kingdom, where the high-risk surgical population accounted for 12.5% of surgical procedures but for >80% of deaths. Despite the high mortality rates, fewer than 15% of these patients were admitted to intensive care. It could be that the care providers did not focus on tissue perfusion management for many of those patients.

When analyzing the methodological quality of the trials, we found that a significant percentage of the randomized controlled clinical studies involving therapeutic interventions that aimed at hemodynamic control had some methodological deficiency. Our results showed that, independent of the methodological quality score, perioperative hemodynamic control significantly reduced the incidence of organ failure. However, the methodological score influenced mortality in overall effect. Studies classified as 10 to 16 according to Chalmers score7 did not result in a significant reduction in mortality, even though there was a tendency toward a reduction (OR: 0.79; 95% CI: 0.64–0.99; moderate heterogeneity; P > 0.05) (Table 5). Additional well-designed randomized controlled studies are necessary to clarify this discrepancy and ultimately to determine whether mortality can be reduced through the maintenance of perioperative tissue perfusion in high-risk surgical patients.

The analysis of the subgroup whose control group had a higher mortality rate (>20%) showed that perioperative hemodynamic control significantly reduced mortality (Table 5). From this finding, we understand that the higher the risk involved, the more benefit patients have with a protocol to maintain tissue perfusion. In this highest-risk subgroup, there were probably more patients submitted to more complex operations, more elderly patients, and probably more patients with some limitation in physiological reserves. In the other 2 subgroups whose control groups had mortality rates of <20%, specific hemodynamic control protocols did not significantly reduce mortality. A lower mortality rate in the control group probably indicates selection of individuals with better clinical conditions having less-complex elective operations. The probability of a state of tissue hypoperfusion in these patients then seems to be greatly reduced. However, maintaining tissue perfusion perioperatively significantly reduced the incidence of organ dysfunction in all groups of patients (Table 5).

Even though the work of Sandham et al.,16 involving a considerable number of patients, has met the criteria for inclusion in this meta-analysis, the study's therapeutic intervention did not necessarily cause an increase in tissue perfusion compared with the control group. Most likely, the protocol used for the intervention did not allow uniform hemodynamic management among the randomized patients. A meta-analysis conducted without the inclusion of this study would decrease the OR and 95% CI for the event mortality from 0.67 (0.55–0.82) to 0.53 (0.41–0.68).

A well-defined protocol with explicit goals is important for the results, which tend to be better than in studies comparing the use of a pulmonary artery catheter with standard care (Sandham et al.16). For example, Lobo et al.17 randomized high-risk surgical patients, and with a defined goal (DO2I >600 mL · min−1 · m−2) and a specific algorithm for treatment (fluids, drugs) were capable of considerably and significantly reducing the mortality rate (OR: 0.19; 95% CI: 0.04–0.88), as compared with Sandham et al. (OR: 1.01; 95% CI: 0.73–1.41).

In addition, we found that the use of a pulmonary artery catheter as a guide for hemodynamic treatment in the high-risk surgical patient significantly reduced the mortality rate (Table 5), contradicting those who found an increase in mortality rate with its use.18 High-risk surgical patients with no evident signs of preoperative tissue hypoperfusion and those without any kind of organ failure may benefit from pulmonary artery catheterization and hemodynamic control, which differs from many critically ill patients, some with multiple organ failure, who have progressive and nonreversible tissue damage and will not benefit from any kind of monitoring and treatment.

Studies for analysis were selected in which perioperative hemodynamic control was guided by cardiac index, DO2I, and V[Combining Dot Above]O2I, where we found a significant reduction in the incidence of both mortality and organ failure (Table 5). The literature has shown the insensitivity of using clinical variables such as arterial blood pressure, heart rate, consciousness level, urinary volume, and perfusion of extremities to determine the presence of tissue hypoperfusion in both clinical and stable surgical patients.19 We recommend use of tools that clearly help to recognize and maintain tissue perfusion and can significantly contribute to the final result: reduction in mortality rate and organ failure incidence. In the present review, 18 of the 31 selected studies had hemodynamic control guided by cardiac index, DO2I, and V[Combining Dot Above]O2I and a significantly reduced incidence of postoperative complications.

However, in the 3 studies that used Sv[Combining Macron]O2 or ScvO2 as goals to hemodynamically treat high-risk surgical patients, there was no significant reduction in either mortality or organ failure. In other specific conditions such as cardiac failure,20 respiratory insufficiency,21 sepsis,22 and cardiac surgery,23 low values of Sv[Combining Macron]O2 or ScvO2 were significantly related to increased mortality. Additional studies are necessary to gain a better understanding of the role of these markers in the perioperative period, because anesthesia and reduction of metabolism may make it difficult to interpret variations in Sv[Combining Macron]O2 or ScvO2.

In this meta-analysis, we found just one study in which lactate was used as a specific marker for perioperative hemodynamic control. There was no significant reduction in mortality, but organ dysfunction was significantly reduced. Similar to Sv[Combining Macron]O2 and ScvO2, in high-risk surgical patients, additional studies will be necessary to better understand the role of lactate as a guide for perioperative hemodynamic management.

In summary, the present meta-analysis suggests that, in high-risk surgical patients with no evident organ dysfunction before surgery, maintaining tissue perfusion perioperatively according to a specific protocol reduces postoperative mortality and morbidity. Furthermore, the higher the risk, the more benefit there is from hemodynamic control. The use of the pulmonary artery catheter, and cardiac index, DO2I, and V[Combining Dot Above]O2I as targets for hemodynamic control reduces postoperative mortality and organ dysfunction in this group of patients. Additional studies with Sv[Combining Macron]O2, ScvO2, and lactate as markers of tissue perfusion in the high-risk surgical patient should be performed to clarify their potential as goals for perioperative hemodynamic control and reduction of postoperative complications and mortality. Finally, methodological trial quality seems to influence mortality analysis in perioperative patients more than in other subsets of patients, such as those with sepsis and organ failure.

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DISCLOSURES

Name: Sanderland T. Gurgel

Contribution: Study design, data analysis, and manuscript preparation.

Conflicts of Interest: Dr. Gurgel received a grant from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).

Name: Paulo do Nascimento, Jr., MD, PhD

Contribution: Study design, data analysis, and manuscript preparation.

Conflicts of Interest: Dr. do Nascimento has no conflicts to declare.

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