Do Miniaturized Extracorporeal Circuits Confer Significant Clinical Benefit Without Compromising Safety? A Meta-Analysis of Randomized Controlled Trials
Harling, Leanne; Warren, Oliver J.; Martin, Anna; Kemp, Paul R.; Evans, Paul C.; Darzi, Ara; Athanasiou, Thanos
From the Department of Surgery and Cancer, Imperial College London, London, UK.
Submitted for consideration September 2010; accepted for publication in revised form November 2010.
Reprint Requests: Leanne Harling, BSc (Hons), MRCS (Eng), Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Building, St. Mary's Hospital, London W2 1NY, UK. Email: email@example.com.
Miniaturized extracorporeal circulation (mECC) attempts to reduce the adverse effects of conventional extracorporeal circulation (CECC) bypass. However, the potential benefits remain unclear and safety concerns persist. A systematic literature review identified 29 studies incorporating 2,355 patients: 1,181 (50.1%) who underwent cardiac surgery with CECC and 1,174 (49.9%) with mECC. These were meta-analyzed using random effects modeling. Heterogeneity, subgroup analysis, and risk of bias were assessed. Primary endpoints were 30-day mortality, neurovascular compromise, and end organ dysfunction. Secondary endpoints were length of stay and transfusion burden. Miniaturized extracorporeal circulation significantly reduced postoperative arrhythmias (p = 0.03), but no significant difference in 30-day mortality, neurocognitive disturbance, cerebrovascular events, renal failure, or myocardial infarction was identified. Miniaturized extracorporeal circulation also significantly reduced mean blood loss (p < 0.00001) and number of patients transfused (p < 0.00001); however, duration of hospitalization, units transfused per patient, chest tube drainage, and revision for rebleeding remained unchanged. Subgroup analysis of larger studies (10 studies, n ≥ 31) showed mECC to significantly reduce ventilation period, hospital stay, and intensive care unit (ICU) stay. Similarly, a significant reduction in neurocognitive disturbance was seen in studies with closely matched demographic groups. Miniaturized extracorporeal circulation is not associated with increased cerebrovascular injury and may confer an advantage, reducing postoperative arrhythmia, blood loss, and transfusion burden.
The arrival of cardiopulmonary bypass (CPB) in 1953 revolutionized cardiac surgery,1 allowing the heart to be stopped and its chambers opened and operated on. However, it became apparent that conventional extracorporeal circulation (CECC) may produce a complex and unpredictable acute inflammatory response that may independently affect postoperative morbidity.2 The search for an alternative, more physiological system over the last decade has led to the development of miniaturized extracorporeal circulation (mECC).
Miniaturized extracorporeal circulation reduces the interface between blood and artificial surfaces by minimizing the overall size of the circuit. Coated tubing (heparin/phosphorylcholine) attempts to reduce protein adsorption and platelet activation, and a low prime volume (∼500 ml in comparison with ∼1,500 ml in conventional circuits) minimizes hemodilution. The venous cardiotomy reservoir and suction devices are removed, eradicating the blood air interface and maintaining a closed circuit. The centrifugal pump provides kinetic assist for venous drainage allowing for shortening of the venous line. Additionally, it provides the advantage of minimizing platelet aggregation and cellular damage and in some cases act as a safety net in the instance of large air bubble entrainment.3
Concerns have been raised over a loss of safety margins with the mECC circuit, in particular with respect to air entrainment and potentially higher rates of neurologic injury.4,5 However, a number of recent meta-analyses comparing mECC with CECC in coronary artery bypass grafting (CABG) have suggested that mECC may not only reduce inflammation, hemodilution, and postoperative blood transfusion requirements6,7 but also stroke rates.8,9 This has been reflected in a relatively rapid uptake of this technology in Great Britain and Ireland, with a recent survey suggesting that up to 40% of centers are now using mECC in certain clinical scenarios.10 The purpose of this article is to provide a comprehensive meta-analysis comparing mECC with CECC for all cardiac surgical procedures, not just CABG. We aim to primarily focus on the safety of mECC systems, in particular looking at postoperative morbidity and mortality potentially associated with the technique. Secondarily, we will address clinical and biochemical outcomes and perform a thorough assessment of study quality by means of subgroup and risk of bias analysis in accordance with current Cochrane guidelines.
A literature search was performed using PubMed, Ovid, Embase, Google Scholar, and Cochrane databases. The “related articles” function was used to broaden the search, and all abstracts, studies, and citations were scanned and reviewed. Studies in all languages were sought. No date restrictions were placed on articles. The last date for this search was July 1, 2010.
The databases of peer-reviewed journals focusing on cardiac surgery, artificial organs, and extracorporeal circulatory support were searched, including published conference proceedings. Searches were also made of previous reviews including cross-references. References of the acquired articles were all searched manually to identify any further studies for inclusion.
Inclusion and Exclusion Criteria and Study Selection
To be considered for inclusion in this study, studies had to be comparative, randomized controlled trials reporting on the evaluation of cardiac surgery performed with mECC compared with CECC. Studies with more than two study arms, comparing other interventions such as off-pump CABG (OPCAB), were included but data only extracted from the relevant patient groups. Studies were excluded from the review if 1) it was in the form of a nonrandomized study; 2) inconsistency of data did not allow valid extraction; 3) data were duplicated; and 4) the trial was carried out on animal models. Based on these criteria, three reviewers (L.H., O.J.W., and A.M.) independently selected studies for further examination by reading titles and abstracts of all identified citations. All potentially eligible studies were retrieved in full for further assessment. Any disagreement was resolved by discussion with the senior author (T.A.).
Three authors (L.H., O.W., and A.M.) independently extracted the following data from each article: first author; year of publication; study type; number of subjects; study population demographics, including method of presentation, type of cardiac surgical procedure, preoperative risk, and details on operative intervention; and variations in mECC utilization and technical approach. All laboratory, physiological, and clinical outcome measures used by the included studies were recorded. Specific outcome data were retrieved wherever possible for the following: i) primary endpoints: 30-day mortality, neurocognitive disturbance, cerebrovascular event, renal failure, postoperative myocardial infarction (MI), and all-cause sustained arrhythmia and ii) secondary endpoints: hospital stay, ventilation period, intensive care unit (ICU) stay, mean blood loss, chest tube drainage over 24 hours, number of units of packed red cells transfused, number of patients transfused, and revision for rebleeding. Data extraction was carried out independently by the same authors, using a standardized excel spreadsheet, and any discrepancy between reviewers being addressed through consensus.
The group where CECC occurred was regarded as the reference group and that in which mECC was used, the treatment group. Meta-analysis was performed in line with recommendations from the Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines.11,12 Where outcomes were continuous data, the effect measure estimated was weighted mean difference (WMD), reported with 95% confidence intervals (CIs). A WMD <0 favored the mECC group. The point estimate of the WMD was considered statistically significant at the p < 0.05 levels, if the 95% CI did not include the value 0. Statistical analysis for categoric variables was performed using the odds ratio (OR) as the summary statistic. This ratio represents the odds of an adverse event occurring in the treatment (mECC) compared with the reference (CECC) group. An OR of <1 favors the treatment group, and the point estimate of the OR is considered statistically significant at the p < 0.05 level, if the 95% CI does not include the value 1.
Pooled estimates, CIs, and tests for heterogeneity were calculated, and visual evaluation of possible publication bias was performed by the use of funnel plots and risk of bias plots.13 In the forest plots of the results, squares indicate point estimates of treatment effect (WMD or OR), and horizontal bars indicate 95% CIs. The diamond represents the summary estimate of treatment effect from the pooled studies with 95% CIs. In a fixed effect model, it is assumed that there is no heterogeneity in treatment effect between studies, whereas in a random effect model, it is assumed that there is variation between studies, and the calculated WMD or OR, therefore, has a more conservative value.13,14 In surgical research and, thus, in our study, meta-analysis using the random effect model is preferable, particularly because patients who are operated on in different centers have varying risk profiles and selection criteria for each surgical technique.
Heterogeneity was explored using the χ2 statistic, but the I2 value was calculated to quantify the degree of heterogeneity across trials that could not be attributable to chance alone. I2 provides a superior measure of heterogeneity between trials as it is independent of the number of trials included in the analysis and is not limited by power.15,16 When I2 > 50, it indicates significant heterogeneity. Three further strategies were used to quantitatively assess heterogeneity. First, data were reanalyzed by using both random-effect and fixed-effect models, and second, graphical exploration with funnel plots was used to evaluate publication bias and reanalysis performed once any outlying studies had been removed from the data.17 Third, sensitivity analysis was performed using the following subgroups: i) all studies; ii) studies including CABG only; iii) studies including aortic valve replacement (AVR) only; iv) study size (n ≥ 31); v) studies with eight or more demographic matching criteria, i.e., studies with minimal heterogeneity between control and treatment groups; and vi) higher quality studies (Jadad score ≥2). These subgroups were identified in the protocol before conducting the review and analysis.
Analysis was conducted by use of the statistical software SPSS version 12.0 for Windows (SPSS Inc., Chicago, IL) and Review Manager Version 5.0 for Windows (The Cochrane Collaboration, Software Update, Oxford, UK).
Risk of Bias Analysis
In conjunction with the aforementioned assessment of bias, a domain-based evaluation of risk of bias was performed in accordance with the guidelines outlined in the Cochrane handbook for Systematic reviews or Interventions version 18.104.22.168 Two authors (L.H. and O.J.W.) subjectively reviewed all studies included in this review and assigned a value of “yes,” “no,” or “unclear” to the following questions: i) was the allocation sequence adequately generated? ii) was allocation adequately concealed? iii) was there blinding of participants, personnel, and outcome assessors? iv) were incomplete outcome data sufficiently assessed? v) are reports in the study free of the suggestion of selective outcome reporting? and vi) were any other sources of bias identified?
“Risk of bias” plots were then performed using Review Manager Version 5.0 for Windows (The Cochrane Collaboration, Software Update, Oxford, UK).
A total of 423 publications were identified in the above search, 71 of which remained after title and abstract review. After exclusion of nonrandomized controlled trials, 33 studies remained. Of these, a further four studies were excluded: two duplicate studies and two studies that did not directly compare CECC and mECC. As a result, a total of 29 comparative, randomized controlled trials fulfilling all inclusion and exclusion criteria were included in this meta-analysis.4,19–46 These were then studied in detail to identify their primary and secondary outcomes and data sets. Of these, three pairs of studies were further identified, which replicated data but had other differing endpoints. Where there was replication of data for a given endpoint, the smaller of the two studies was excluded from the analysis. This enabled maximal data extraction without duplication within our meta-analysis. These 29 studies included a combined total of 2,355 patients of whom 1,181 (50.1%) underwent cardiac surgery with CECC and 1,174 (49.9%) underwent cardiac surgery with mECC.
The characteristics of the included studies are detailed in Appendix. Four of the studies looked at aortic surgery only,8,23,24,36 and two included both isolated aortic surgery and combined aortic valve and graft surgery.31,46 The remaining 23 studies looked at CABG only.4,19–21,25–30,32–35,37–45 Sixteen studies included only elective cases,4,19–21,28,35–37,39–46 one included elective and urgent cases,32 one included all cases irrespective of urgency,34 and 1122–27,29–31,33,38 did not specify. All studies performed some matching of their study groups, but the extent to which they did so varied significantly, ranging from 1 to 14 various matching criteria. All studies ensured that there was no significant difference in age between their studies groups, although six studies did not match for gender. One study looked specifically at high-risk patients only27; however, no other groups performed specific subgroup analysis for risk stratification.
Variations in Equipment and Technical Approach
Fourteen of the included studies used the Jostra MECC system,21–24,26,30,32,35–37,39–41,44 three used the CardioVention CorX system,19,20,45 three used the Sorin Synergy system,25,28,42 three used Terumo ROCSafe Hybrid perfusion system,27,31,46 three used Medtronic resting heart system,4,29,38 two used the Dideco ECCO system,34,43 and one used a custom system based on Terumo components.33 All the above mECC circuits comprised a closed circuit with the absence of a venous cardiotomy reservoir. In addition to these components, 13 studies used additional intraoperative venting systems. Of these, nine used closed venting systems22–24,28,29,31,33,34,39,45 and three used venting systems with a blood air interface, rendering the system semiclosed.36–38 One study passed vented blood through a separate roller pump before returning it to the venous line.31
Risk of Bias Analysis
In accordance with the Cochrane guidelines,18 a risk of bias analysis was performed for all studies included in this review (Figure 1). Overall, a moderate level of bias was detected, mostly because of failure to explicitly predefine outcomes in study methodology. In addition to this, only nine of the included studies adequately reported the randomization protocol, and just four of these described a method used to conceal the allocation sequence in sufficient detail. Twenty of the 29 studies did not mention blinding of either the laboratory or surgical teams (Figure 1).
Outcomes of Interest
A wide range of both clinical and biochemical endpoints were recorded by the studies included in this analysis. Endpoints common to 10 or more studies included in-hospital mortality, ventilation period, hospital stay, ICU stay, arrhythmia, stroke, mean blood loss, hematocrit, platelet count, interleukins (ILs; IL-1b, −2, −6, −8, and −10), and inotropic support.
Results From Meta-Analysis
Table 1 outlines the overall results of the meta-analysis, including all 29 studies. No statistically significant differences were seen in mean perfusion time or cross-clamp time between the mECC and CECC groups (p = 0.33 and 0.65, respectively). The use of retrograde autologous prime (RAP) was reported by 8 of the 29 studies included in this review. Of these, three used RAP in both the mECC and CECC groups,28,38,42 three used RAP in the mECC group alone,31,43,46 and two did not use RAP in either group.4,33
No significant difference in 30-day mortality was seen between the mECC and CECC groups in either overall analysis or subgroup analysis (p = 0.13, CI: 0.24–1.19, OR: 0.53).
End Organ Dysfunction.
A significant reduction in all cause, sustained arrhythmia was seen in the mECC group compared with CECC (p = 0.03, CI: 0.49–0.97, OR: 0.69), without significant heterogeneity (χ2: 10.22, I2 = 22, p = 0.25). No significant difference was seen in postoperative MI (p = 0.16, CI: 0.23–1.27, OR: 0.54) or postoperative renal failure (p = 0.60, CI: 0.18–2.68, OR: 0.60) between the two groups, and no significant heterogeneity was found within this data.
Overall analysis of all 29 studies demonstrated no statistically significant difference in the incidence of cerebrovascular events (p = 0.64) or neurocognitive disturbance (p = 0.70) between the mECC and CECC.
Length of Stay.
No statistically significant difference was seen in hospital stay (p = 0.84, CI: −1.43 to 1.17, WMD: −0.13), ICU stay (p = 0.08, CI: −9.29 to 0.46, WMD: −4.41), or ventilation period (p = 0.10, CI: −2.07 to 0.24, WMD: −0.92) between the mECC and CECC. This was associated with significant heterogeneity for all three outcomes (χ2: 206.85, I2 = 95, p < 0.00001; χ2: 287.29, I2 = 96, p < 0.00001; and χ2: 106.55, I2 = 88, p < 0.00001, respectively).
mECC was associated with a statistically significant reduction in mean blood loss (p < 0.00001, WMD: −131.32, 95% CI: [−187.87 to −74.76]) and number of patients transfused (p < 0.00001, OR: 0.35, 95% CI: [0.23–0.53]), when compared with the CECC group. Although significant heterogeneity was present in mean blood loss (p < 0.00001, χ2 = 97.96, I2 = 89), there was no evidence of heterogeneity in the number of patients transfused (p = 0.46, χ2 = 7.73, I2 = 0). No significant difference was found in the number of units of packed cells, fresh frozen plasma (FFP) or platelets transfused per patient, the 24-hour chest tube drainage, or the number of cases of revision for rebleeding.
As part of a quantitative assessment of heterogeneity, we performed sensitivity analysis using subgroups. The following subgroups were isolated: i) “CABG only,” ii) Jadad score ≥2 (i.e., high-quality studies), iii) matching criteria >8 (i.e., studies with minimal heterogeneity between mECC and CECC groups), and iv) larger studies, where total number of patients included in the each group (N ≥ 31).
Sensitivity analysis revealed no significant difference between mECC and CECC for any subgroups with no effect on heterogeneity.
Analysis of studies with >8 matching criteria revealed a significant reduction in neurocognitive disturbance with mECC (p = 0.04, OR: 0.47, CI: [0.23–0.98]), without significant heterogeneity. No significant difference in cerebrovascular events was observed between mECC and CECC in any subgroup.
A significant reduction in the incidence of postoperative arrhythmia was identified in the mECC group when patients undergoing CABG only were isolated (number of studies: 6, p = 0.05, OR: 0.71, CI: [0.51–1.00]). This was not associated with significant heterogeneity. A loss of significance was observed in comparison with the overall data in the matching criteria >8, Jadad score ≥2 and N ≥31 subgroups.
A significant reduction in the incidence of postoperative MI was seen with mECC when larger studies (N ≥ 31) were analyzed (p = 0.03, CI: [0.08–0.88], OR: 0.26), without significant heterogeneity. Although it must be noted that only two studies fitted these criteria and were included in this analysis. No significant difference was observed between mECC and CECC in other subgroups or in the overall analysis.2
Length of Stay.
No significant difference was seen between the mECC and CECC when subgroup analysis was performed for CABG only, Jadad score ≥2, or matching criteria >8. Further to this isolating, these three subgroups did not affect heterogeneity. However, on analysis of larger studies (N ≥ 31), a significant reduction in hospital stay (p = 0.02, CI: [−0.67 to 0.05], WMD: −0.45), ICU stay (p < 0.00001, CI [−6.79 to 4.33], WMD: −5.56), and ventilation period (p = 0.03, CI: [−2.46 to 0.10], WMD: −1.28) was seen with mECC without significant heterogeneity.
Mean blood loss and number of patients transfused remained significant, without a change in the significance of the heterogeneity, in all subgroups. A trend toward a reduction in chest tube drainage over 24 hours (p = 0.09, WMD: −103.35, CI: [−222.44 to 15.73]) was identified when studies with >8 matching criteria were analyzed, which was not present in the overall analysis (p = 0.74, WMD: −25.21, CI: [−176.36 to 125.93]). However, this was associated with the emergence of significant heterogeneity of the data (χ2: 9.75, p = 0.02, I2 = 69). In addition, we performed a subgroup analysis of mean blood loss in studies using the antifibrinolytic aprotinin. No significant difference was seen in mean blood loss when only studies using aprotinin were analyzed (four studies; n = 80 CECC, 79 mECC; p = 0.10). Similarly, no difference was detected between mECC and CECC in the nonaprotinin group (three studies; n = 307 CECC, 312 mECC; p = 0.15).
The results of our overall meta-analysis show that mECC is associated with a significant reduction in postoperative arrhythmias, mean blood loss, and the number of patients transfused, when compared with conventional techniques of extracorporeal circulation. We did not show any significant difference in mortality, hospital stay, ICU stay, postoperative ventilation period, revision for rebleeding, units transfused per patient, renal dysfunction, MI, neurocognitive deficit, or cerebrovascular events between the two groups. As some of the studies included in this review are small, we performed a sensitivity analysis of patients undergoing isolated CABG, higher quality studies (Jadad score ≥2), larger studies (n ≥ 31), and studies with closely matched study groups (matching criteria >8). Of particular interest, analysis of larger studies (N ≥ 31) revealed a significant reduction in hospital stay, ICU stay, and ventilation period in the mECC group. Further to this, analysis of studies matching mECC and CECC groups for >8 demographic criteria revealed a significant reduction in postoperative neurocognitive disturbance.
When performing meta-analysis, it is important to explain the causes of heterogeneity and not to focus solely on calculating the overall estimates for the outcomes of interest.47 Our overall analysis shows significant heterogeneity in all length of stay (LOS) endpoints (hospital stay, ICU stay, and ventilation period) and several transfusion parameters (mean blood loss, number of units transfused per patient, and 24-hour chest tube drainage). We hypothesized that this may be in part due to the inclusion of a number of smaller, lower quality studies, and as such, we performed sensitivity analysis to further investigate these effects. Heterogeneity was reduced in the LOS endpoints when only larger studies (N ≥ 31) were included. Sensitivity analysis did not, however, reduce the heterogeneity in the mean blood loss, number of units transfused per patient, or 24-hour chest tube drainage endpoints, possibly reflecting genuine differences in surgical practice between centers.
Is mECC a Safe Alternative to CECC?
One major concern with the use of the mECC circuit is that the risk of neurologic injury may be higher. It was originally thought that the combination of active venous drainage and removal of the cardiotomy reservoir in mECC would result in a loss of safety margins and may increase the risk of air entrainment into the circuit. Subsequently, this would potentially result in the production of gaseous micro emboli and higher rates of neurologic injury in the mECC group.32,34 Contrary to this, recent meta-analyses by both Zangrillo et al.48 and Biancari and Rimpilainen8 found a significant reduction in stroke in patients undergoing open-heart surgery with mECC rather than CECC. Elsewhere, reduced levels of air microemboli in patients supported by mECC compared with CECC have been reported.32 Our results show equivalent rates of neurocognitive disturbance and cerebrovascular injury with mECC and CECC. However, sensitivity analysis of studies with >8 matching criteria did reveal a significant reduction in neurocognitive disturbance in the mECC group (p = 0.04) without significant heterogeneity. This is most likely to be a reflection of the multifactorial etiology of intra- and postoperative neurologic injury after cardiac surgery. Although microemboli undoubtedly have an important role, macroemboli, cerebral hypoperfusion, and reperfusion injury all contribute to neurologic injury. In particular, it is likely that by reducing the inflammatory response to bypass in addition to reducing transfusion rates, mECC may reduce postoperative neurocognitive disturbance. Our results may bring reassurance to those clinicians who have previously avoided mECC, believing it to carry too higher risk of neurologic injury.
New onset atrial fibrillation (AF) after cardiac surgery is also associated with a number of deleterious outcomes including an increased incidence of stroke, renal failure, and gastrointestinal complications, as well as an increase in duration of hospital stay.49 The published rate of postoperative AF after cardiac surgery varies widely from an estimated 11%–40% patients undergoing CABG alone to up to 60% of patients undergoing valvular surgery.50 Our results show a significant reduction in all cause, sustained postoperative arrhythmia with mECC, without significant heterogeneity. The explanation for this, however, is not entirely clear as the pathogenesis of postoperative arrhythmia is multifactorial, and the factors attenuated by mECC are not yet fully established. A reduction in the systemic inflammatory response with mECC is a likely contributing factor. Increases in serum inflammatory mediators such as C-reactive protein (CRP), ILs (IL-1 and IL-6), tumor necrosis factor (TNF-α), and complement have been associated with the development of AF secondary to both structural and electrical remodeling. 51 Furthermore, a reduction in the incidence of postoperative AF has been proposed to occur through a reduction in the inflammatory response associated with postoperative blood transfusion.52 We have demonstrated mECC to be associated with a significant reduction in the number of patients transfused compared with CECC and may, therefore, indirectly contribute to a reduction in postoperative arrhythmias. However, only the study by Svitek et al.42 reported similar transfusion rates and data on the incidence of AF. In this study, no difference in the incidence of AF was seen (CECC, 10/36 and mECC, 10/39; p = not significant [NS]), and as such, no further conclusions can be drawn. Another important observation is that none of the studies included in this review used a standardized protocol for the diagnosis and reporting of AF, in accordance with the Heart Rhythm Society Consensus guidelines.
A Reduction in Transfusion Burden
The need to maintain higher oxygen carrying capacity and correct coagulopathy translates to high transfusion rates in cardiac surgery.53 Although the deleterious effects of infection, immunosuppression, end organ dysfunction, and adverse transfusion reactions have been greatly minimized by newer methods of donor screening, handling, and administration of blood products, transfusion still confers a significant risk, and appropriate measures should be undertaken to minimize the need for transfusion.54,55 The use of autologous blood by cell-saving devices can reduce the volume of allogenic blood transfusion,56 but methods enabling an overall reduction of blood loss should still be paramount in reducing transfusion burden. Our data support that of other recent meta- analyses6,8,9,48 showing a significant reduction in mean blood loss in the mECC group, when compared with CECC. This also held true for all subgroups included in the sensitivity analysis. The rationale is most likely a combination of a number of factors; first, the coated, minimal prime volume mECC circuit reduces hemodilution, protein adsorption, and platelet activation. Second, by replacing the traditional roller pump system with a centrifugal pump, mECC reduces mechanical damage to both blood components and platelet aggregation.3,12 Of note, however, significant heterogeneity is present in both the overall analysis and in all categories of the sensitivity analysis. We think that this is most likely a reflection of the differing anticoagulation strategies used both pre- and postoperatively across the institutions included within this review. Of note, none matched groups for preoperative usage of antiplatelet agents, anticoagulants, or inherited or acquired coagulopathies. Several studies did exclude patients on this basis, although this was not uniform throughout this review. Only five4,21,31,38,39 studies excluded patients with hematological disease/coagulopathies, one study38 excluded those who had undergone thrombolysis within 5 days, and five studies4,21,28,38,39 excluded patients who were on anticoagulants preoperatively. Seven studies reported specific protocols to initiate blood transfusion; however, there was significant variation within these: four centers used transfusion trigger hematocrit <25%,23,24,29,36 one used hematocrit <28%,32 two transfused when hemoglobin (Hb) < 8 g · dl−1,38,46 and one center if Hb < 6 mmol · L−1.28 In addition to this, emergency cases and those with left main-stem or proximal three-vessel disease are more likely to experience higher rates of postoperative bleeding due to the use of antiplatelet agents preoperatively. Interestingly, our results also show a statistically significant reduction in the number of patients transfused in the mECC group, when compared with the CECC group without significant heterogeneity.
LOS and Economic Viability
An additional important consideration when evaluating mECC is its impact on LOS, as any improvement in this confers both clinical and economic benefits.35 Subgroup analysis of the larger studies (N ≥ 31) has shown mECC to be associated with a significant reduction in hospital stay, ICU stay, and ventilation period. There are a number of reasons why this might be the case, including reduced fluid imbalance, reduced postoperative inflammation, and reduced transfusion. All these may expedite recovery and subsequent discharge from both the ICU and hospital. It should, however, be noted that there is significant heterogeneity present for the ventilation period outcome. Although the exact reason for this remains unclear, one possible explanation is a difference in individual hospital protocols, with variability in the criteria for extubation. Neither extubation nor hospital/ICU discharge protocol was specified by any of the studies included within this review.
The aim of meta-analysis is to describe the overall effect outlined in a number of different clinical trials and to use these results to provide evidence-based recommendations for further research.57 Among the pitfalls of meta-analytical techniques, there is documented concern regarding exaggeration of insignificant effects produced by a number of small and poorly designed studies. To this end, we excluded all nonrandomized controlled trials and have performed sensitivity analysis of larger and higher quality studies.
There has been a relative increase in popularity of mECC in recent years, but we think there is still significant uncertainty surrounding its usage and, as a result, reluctance in its global uptake. The reasons for this are likely to be multifactorial, including concerns over its air handling capabilities, a paucity of high-quality randomized controlled trials, and the higher cost incurred with use of the mECC system. However, recent studies have not incurred the same air handling problems as described by Nollert et al.4 in 2005, and the potential benefits of the mECC system on reducing postoperative arrhythmias, neurocognitive disturbance, transfusion rates, and ultimately hospital stay are likely to have significant economic benefit, potentially outweighing this additional expense. Despite this, a large number of studies in this review are underpowered due to small sample size, and, as no cost analysis of mECC has yet been performed, we are presently unable to provide quantitative data in this regard.
The primary aim of this review is to provide an evidence base to guide preoperative planning while further work is carried out. We have, therefore, highlighted limitations to the current research and formulated several recommendations based on the “EPICOT” guidelines.58 Although 29 randomized controlled studies were included in this meta-analysis, a number of these were small (only 10 studies include N ≥ 31) or of poor quality (only 14 studies with Jadad score ≥2). Subgroup analysis of larger studies (N ≥ 31) removed the heterogeneity present in both hospital- and ICU-stay outcomes, highlighting the need for larger studies to produce a more homogenous data set. In addition, poor detailing of study methodology resulted in a moderate overall risk of bias in the studies included in this review. Future research should aim to reduce potential sources of bias by paying specific attention to sequence generation, allocation concealment, blinding, and the reporting of outcome data.
Other limitations of this meta-analysis include the significant variation in the technical details of the mECC systems, variations in anticoagulation strategies, inclusion of emergency patients, and the lack of preoperative risk stratification.
The present data dispel many of the safety concerns associated with mECC, as no difference in 30-day mortality or adverse neurologic outcomes is identified between mECC and CECC. Additionally, we have shown that mECC may in fact confer an advantage over CECC by reducing the incidence of postoperative arrhythmia. Our data also confirm that of previous meta-analyses showing mECC to be associated with a reduction in both blood loss and transfusion burden. The data presented are subject to a number of confounding factors including varying mECC circuits and anticoagulation protocols. It is also clear that further large, randomized controlled trials are required to produce more homogeneous data, in particular focusing not only on CABG but also on isolating valvular surgery.
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1. Gibbon J: Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med
37: 171–185, 1954.
2. Warren OJ, Smith AJ, Alexiou C, et al
: The inflammatory response to cardiopulmonary bypass: Part 1—Mechanisms of pathogenesis. J Cardiothorac Vasc Anesth
23: 223–231, 2009.
3. Nishinaka T, Nishida H, Endo M, et al
: Less blood damage in the impeller centrifugal pump: A comparative study with the roller pump in open heart surgery. Artif Organs
20: 707–710, 1996.
4. Nollert G, Schwabenland I, Maktav D, et al
: Miniaturized cardiopulmonary bypass in coronary artery bypass surgery: Marginal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg
80: 2326–2332, 2005.
5. Norman MJ, Sistino JJ, Acsell JR: The effectiveness of low-prime cardiopulmonary bypass circuits at removing gaseous emboli. J Extra Corpor Technol
36: 336–342, 2004.
6. Benedetto U, Angeloni E, Refice S, et al
: Is minimized extracorporeal circulation effective to reduce the need for red blood cell transfusion in coronary artery bypass grafting? Meta-analysis of randomized controlled trials. J Thorac Cardiovasc Surg
138: 1450–1453, 2009.
7. Ranucci M, Castelvecchio S: Management of mini-cardiopulmonary bypass devices: Is it worth the energy? Curr Opin Anaesthesiol
22: 78–83, 2009.
8. Biancari F, Rimpilainen R: Meta-analysis of randomised trials comparing the effectiveness of miniaturised versus conventional cardiopulmonary bypass in adult cardiac surgery. Heart
95: 964–969, 2009.
9. Rimpilainen R, Biancari F, Wistbacka JO, et al
: Outcome after coronary artery bypass surgery with miniaturized versus conventional cardiopulmonary bypass. Perfusion
23: 361–367, 2008.
10. Warren OJ, Wallace S, de Wit KL, et al
: Variations in the application of various perfusion technologies in Great Britain and Ireland–a national survey. Artif Organs
34: 200–205, 2010.
11. Moher D, Cook DJ, Eastwood S, et al
: Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. Quality of reporting of meta-analyses. Lancet
354: 1896–1900, 1999.
12. Alderson P, Green S, Higgins JPT. Cochrane Reviewers' Handbook 4.2.1 [updated December 2003].
Chichester: John Wiley & Sons, 2004.
13. Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ
315: 629–634, 1997.
14. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials
7: 177–188, 1986.
15. Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med
21: 1539–1558, 2002.
16. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ
327: 557–560, 2003.
17. Egger M, Smith GD: Misleading meta-analysis. BMJ
311: 753–754, 1995.
18. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [Updated September 2009]: The Cochrane Collaboration, 2009. Available at: www.cochrane-handbook.org
. Accessed in August 2010.
19. Abdel-Rahman U: The use of minimized extracorporeal circulation system has a beneficial effect on hemostasis—A randomized clinical study. Heart Surg Forum
9: E543–E548, 2006.
20. Abdel-Rahman U, Ozaslan F, Risteski PS, et al
: Initial experience with a minimized extracorporeal bypass system: Is there a clinical benefit? Ann Thorac Surg
80: 238–243, 2005.
21. Beghi C, Nicolini F, Agostinelli A, et al
: Mini-cardiopulmonary bypass system: Results of a prospective randomized study. Ann Thorac Surg
81: 1396–1400, 2006.
22. Bical OM, Fromes Y, Gaillard D, et al
: Comparison of the inflammatory response between miniaturized and standard CPB circuits in aortic valve surgery. Eur J Cardiothorac Surg
29: 699–702, 2006.
23. Castiglioni A, Verzini A, Colangelo N, et al.
Comparison of minimally invasive closed circuit versus standard extracorporeal circulation for aortic valve replacement: A randomized study. Interact Cardiovasc Thorac Surg
9: 37–41; 2009; discussion 41.
24. Castiglioni A, Verzini A, Pappalardo F, et al
: Minimally invasive closed circuit versus standard extracorporeal circulation for aortic valve replacement. Ann Thorac Surg
83: 586–591, 2007.
25. Farneti PA, Sbrana S, Spiller D, et al
: Reduction of blood coagulation and monocyte-platelet interaction following the use of a minimal extracorporeal circulation system (Synergy) in coronary artery bypass grafting (CABG). Perfusion
23: 49–56, 2008.
26. Fromes Y, Gaillard D, Ponzio O, et al
: Reduction of the inflammatory response following coronary bypass grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg
22: 527–533, 2002.
27. Gunaydin S, Sari T, McCusker K, et al
: Clinical evaluation of minimized extracorporeal circulation in high-risk coronary revascularization: Impact on air handling, inflammation, hemodilution and myocardial function. Perfusion
24: 153–162, 2009.
28. Huybregts RA, Morariu AM, Rakhorst G, et al
: Attenuated renal and intestinal injury after use of a mini-cardiopulmonary bypass system. Ann Thorac Surg
83: 1760–1766, 2007.
29. Kamiya H, Kofidis T, Haverich A, Klima U: Preliminary experience with the mini-extracorporeal circulation system (Medtronic resting heart system). Interact Cardiovasc Thorac Surg
5: 680–682, 2006.
30. Kofidis T, Baraki H, Singh H, et al
: The minimized extracorporeal circulation system causes less inflammation and organ damage. Perfusion
23: 147–151, 2008.
31. Kutschka I, Skorpil J, El Essawi A, et al
: Beneficial effects of modern perfusion concepts in aortic valve and aortic root surgery. Perfusion
24: 37–44, 2009.
32. Liebold A, Khosravi A, Westphal B, et al
: Effect of closed minimized cardiopulmonary bypass on cerebral tissue oxygenation and microembolization. J Thorac Cardiovasc Surg
131: 268–276, 2006.
33. Ohata T, Mitsuno M, Yamamura M, et al
: Beneficial effects of mini-cardiopulmonary bypass on hemostasis in coronary artery bypass grafting: Analysis of inflammatory response and hemodilution. ASAIO J
54: 207–209, 2008.
34. Perthel M, El-Ayoubi L, Bendisch A, et al
: Clinical advantages of using mini-bypass systems in terms of blood product use, postoperative bleeding and air entrainment: An in vivo clinical perspective. Eur J Cardiothorac Surg
31: 1070–1075, 2007; discussion 1075.
35. Prasser C, Abbady M, Keyl C, et al
: Effect of a miniaturized extracorporeal circulation (MECC System) on liver function. Perfusion
22: 245–250, 2007.
36. Remadi JP, Rakotoarivello Z, Marticho P, et al
: Aortic valve replacement with the minimal extracorporeal circulation (Jostra MECC System) versus standard cardiopulmonary bypass: A randomized prospective trial. J Thorac Cardiovasc Surg
128: 436–441, 2004.
37. Remadi JP, Rakotoarivelo Z, Marticho P, Benamar A. Prospective randomized study comparing coronary artery bypass grafting with the new mini-extracorporeal circulation Jostra System or with a standard cardiopulmonary bypass. Am Heart J
151: 198, 2006.
38. Sakwa MP, Emery RW, Shannon FL, et al
: Coronary artery bypass grafting with a minimized cardiopulmonary bypass circuit: A prospective, randomized trial. J Thorac Cardiovasc Surg
137: 481–485, 2009.
39. Schottler J, Lutter G, Boning A, et al
: Is there really a clinical benefit of using minimized extracorporeal circulation for coronary artery bypass grafting? Thorac Cardiovasc Surg
56: 65–70, 2008.
40. Skrabal CA, Choi YH, Kaminski A, et al
: Circulating endothelial cells demonstrate an attenuation of endothelial damage by minimizing the extracorporeal circulation. J Thorac Cardiovasc Surg
132: 291–296, 2006.
41. Skrabal CA, Steinhoff G, Liebold A: Minimizing cardiopulmonary bypass attenuates myocardial damage after cardiac surgery. ASAIO J
53: 32–35, 2007.
42. Svitek V, Lonsky V, Mandak J, et al
: No clear clinical benefit of using mini-invasive extracorporeal circulation in coronary artery bypass grafting in low-risk patients. Perfusion
24: 389–395, 2009.
43. Valtonen M, Vahasilta T, Kaila-Keinanen T, Kuttila K: New mini-extracorporeal circulation system (ECC.O) is a safe technique in coronary surgery. Scand Cardiovasc J
41: 345–350, 2007.
44. van Boven WJ, Gerritsen WB, Driessen AH, et al
: Myocardial oxidative stress, and cell injury comparing three different techniques for coronary artery bypass grafting. Eur J Cardiothorac Surg
34: 969–975, 2008.
45. Wippermann J, Albes JM, Hartrumpf M, et al
: Comparison of minimally invasive closed circuit extracorporeal circulation with conventional cardiopulmonary bypass and with off-pump technique in CABG patients: Selected parameters of coagulation and inflammatory system. Eur J Cardiothorac Surg
28: 127–132, 2005.
46. El-Essawi A, Hajek T, Skorpil J, et al
: A prospective randomised multicentre clinical comparison of a minimised perfusion circuit versus conventional cardiopulmonary bypass. Eur J Cardiothorac Surg
38: 91–97, 2010.
47. Blettner M, Sauerbrei W, Schlehofer B, et al
: Traditional reviews, meta-analyses and pooled analyses in epidemiology. Int J Epidemiol
28: 1–9, 1999.
48. Zangrillo A, Garozzo FA, Biondi-Zoccai G, et al
: Miniaturized cardiopulmonary bypass improves short-term outcome in cardiac surgery: A meta-analysis of randomized controlled studies. J Thorac Cardiovasc Surg
139: 1162–1169, 2010.
49. Kalavrouziotis D, Buth KJ, Ali IS: The impact of new-onset atrial fibrillation on in-hospital mortality following cardiac surgery. Chest
131: 833–839, 2007.
50. Shantsila E, Watson T, Lip GY: Atrial fibrillation post-cardiac surgery: Changing perspectives. Curr Med Res Opin
22: 1437–1441, 2006.
51. Kourliouros A, Savelieva I, Kiotsekoglou A, et al
: Current concepts in the pathogenesis of atrial fibrillation. Am Heart J
157: 243–252, 2009.
52. Koch CG, Li L, Van Wagoner DR, et al
: Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg
82: 1747–1756, 2006.
53. Stover EP, Siegel LC, Parks R, et al
: Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology
88: 327–333, 1998.
54. Ferraris VA, Ferraris SP, Saha SP, et al.
Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg
83(suppl 5): S27–S86, 2007.
55. Whitson BA, Huddleston SJ, Savik K, Shumway SJ: Risk of adverse outcomes associated with blood transfusion after cardiac surgery depends on the amount of transfusion. J Surg Res
158: 20–27, 2010.
56. Niranjan G, Asimakopoulos G, Karagounis A, et al
: Effects of cell saver autologous blood transfusion on blood loss and homologous blood transfusion requirements in patients undergoing cardiac surgery on- versus off-cardiopulmonary bypass: A randomised trial. Eur J Cardiothorac Surg
30: 271–277, 2006.
57. Smith GD, Egger M, Phillips AN: Meta-analysis: Beyond the grand mean? BMJ
315: 1610–1614, 1997.
58. Brown P, Brunnhuber K, Chalkidou K, et al
: How to formulate research recommendations. BMJ
333: 804–806, 2006.
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