Antegrade and retrograde arterial perfusion strategy in minimally invasive mitral-valve surgery: a propensity score analysis on 1280 patients^†

Abstract

OBJECTIVES

Recent studies have suggested an increased risk of stroke in patients undergoing minimally invasive mitral-valve surgery with retrograde perfusion when compared with antegrade perfusion. The aim of the present study was therefore to evaluate the impact on early outcome of retrograde arterial perfusion (RAP) strategy vs antegrade arterial perfusion strategy in a consecutive large cohort of patients who underwent minimally invasive mitral-valve surgery through a right minithoracotomy.

METHODS

Between 2003 and 2012, 1280 consecutive patients underwent first-time minimally invasive mitral-valve surgery at our institution. A total of 167 (13%) of these patients received a retrograde perfusion, while 1113 (87%) received antegrade perfusion. Logistic analysis was used to evaluate outcomes and risk factors for stroke. Treatment selection bias was controlled by constructing a propensity score from core patient characteristics. The propensity score was the probability of receiving retrograde perfusion and was included along with the comparison variable in the multivariable analyses of outcome.

RESULTS

The overall frequency of in-hospital mortality was 1.1% (14/1280) and postoperative stroke was 1.6% (21/1280). After adjusting for the propensity score, RAP was associated with a higher incidence of stroke (5 vs 1%; P = 0.002), postoperative delirium (14 vs 5%, P = 0.001) and aortic dissection (1.7 vs 0%; P = 0.01). Multivariable regression analysis revealed that the use of retrograde perfusion was an independent risk factor for stroke [odds ratio (OR) 4.28; P = 0.02] and postoperative delirium (OR 3.51; P = 0.001).

CONCLUSIONS

Minimally invasive mitral valve procedure can be performed with low morbidity and mortality. The use of retrograde perfusion is associated with a higher incidence of neurological complications and aortic dissection when compared with antegrade perfusion. Central aortic cannulation allows the avoidance of complications associated with retrograde perfusion while extending the suitability of minimally invasive mitral procedures also to those patients who have an absolute contraindication to femoral artery cannulation.

INTRODUCTION

In recent years, minimally invasive mitral-valve surgery (MIMVS) has become the preferred approach for mitral valve procedures in most centers worldwide [1–3]. The belief that this approach leads to less pain, shorter hospital stays, faster return to normal activities, superior cosmesis and potential cost savings has driven this development. Nevertheless, concerns have been expressed in terms of an increased morbidity with MIMVS [4]. Specifically, some authors have reported an increased risk of stroke with MIMVS when compared with standard sternotomy [5]. The reason for such an increased risk of neurological complications is still not clear, but recently, some studies have demonstrated an association between the use of retrograde perfusion and stroke during MIMVS [6, 7]. At our institution, we started an MIMVS program in 2003, and from that moment, we have significantly modified our approach, moving from a pure portaccess platform to central aortic cannulation with trans-thoracic aortic clamping [8]. The aim of the present study was, therefore, to evaluate the impact on early outcome of retrograde arterial perfusion (RAP) vs antegrade arterial perfusion (AAP) in a consecutive large cohort of patients who underwent MIMVS through a right minithoracotomy at our institution, over a 9-year period.

MATERIAL AND METHODS

Patient selection and data collection

This was a retrospective, observational, cohort study of prospectively collected data from consecutive patients who underwent MIMVS through right minithoracotmy, at the G. Pasquinucci Heart Hospital between September 2003 and March 2012. The data collection forms were entered in an institutional database and included five sections that were filled in consecutively by anaesthetists, surgeons and intensive-care unit, high-dependency unit and ward nurses. The resulting base sample contained detailed clinical information on 1280 patients. No patients were excluded. The study was approved by the clinical audit committee of the G. Pasquinucci Heart Hospital, to meet ethical and legal requirements, and individual consent was waived.

Definition

Hospital mortality included all deaths within 30 days of operation irrespective of where the death occurred and all deaths in hospital after 30 days among patients who had not been discharged after the index operation. Our definition of perioperative stroke included any new temporary or permanent, focal or global neurological deficit. Postoperative delirium was defined as a transient mental syndrome of acute onset characterized by global impairment of cognitive functions, a reduced level of consciousness, attentional abnormalities, increased or decreased psychomotor activity and a disordered sleep-wake cycle. Perioperative stroke and delirium were diagnosed during clinical assessment by physicians involved in the daily care of patients, and were confirmed by computed tomography or magnetic resonance imaging whenever possible. The diagnosis of stroke was also confirmed and documented by staff neurologists. Renal complications included acute renal failure, defined as the requirement of haemodialysis or an elevated creatinine level (>200 mmol/l). A diagnosis of postoperative myocardial infarction (MI) was based on the presence of new Q waves >0.04 ms and/or a reduction in R waves >25% in at least 2 contiguous leads on electrocardiogram (ECG). Pulmonary complication included chest infection, ventilation failure, reintubation and tracheostomy.

Anaesthetic, surgical technique and postoperative management

Our surgical techniques have previously been described [8]. Our institutional surgical approach for mitral-valve surgery has been a right minithoracotomy since 2003. Perfusion practice has evolved during the past 7 years. Initially, a femoral arterial perfusion with femoral venous drainage and endoclamp placement was used. Subsequently, we abandoned the endoclamp in favour of trans-thoracic aortic cross-clamping. Finally, as familiarity with the right minithoracotomy approach increased, we shifted to direct ascending aorta cannulation with trans-thoracic aortic cross-clamping. Actually, we used central aortic cannulation with a trans-thoracic detachable aortic cross-clamp whenever possible. In those cases in which it is not possible to cannulate the ascending aorta we used a femoral artery perfusion.

Statistical analysis

Continuous data were expressed as mean ± SD, and categorical data as percentages. The Kolmogorov–Smirnov test was used to check for normality of data in the two groups before further analysis. Differences between RAP and AAP groups were compared with the use of a χ²-square test for categorical variables and t or Wilcoxon rank sum tests, as appropriate, for continuous variables. To reduce the effect of selection bias and potential confounding in this observational study, we developed a propensity score analysis. The propensity for RAP perfusion was determined without regard for outcomes by the use of a non-parsimonious multiple logistic-regression analysis. All the variables listed in Table 1 were included in the analysis. Due to concerns regarding a potential time effect on our results, the year of operation (number of days of each operation from the 1th September 2003, divided by 365) was included as a covariate in the multivariate models. A propensity score, indicating the predicted probability of receiving RAP treatment, was then calculated from the logistic equation for each patient. The model's reliability and its predictive ability were tested with the Hosmer–Lemeshow goodness-of-fit test (P = 0.43) and the C-index (c = 0.76), respectively. Once the propensity score is constructed for each patient, there are three ways of using the score for comparisons: matching, stratification and multivariable adjustment. Due to the small sample size of the RAP group compared with the AAP group, we decided to use multivariable adjustment because matching would have reduced the study size even further and stratification can be difficult to interpret. Using a propensity score as the sole means for adjusting outcomes was preferable due to the low number of events in our study and provides better adjustment for those factors driving treatment selection; the overall effect is more complete risk adjustment [9]. The propensity score was then included along with the comparison variable (RAP or AAP) in multivariable analyses of outcome producing an adjusted odds ratio (OR) with 95% confidence interval (CI). A multivariate analysis of stroke and postoperative delirium was performed with backwards stepwise logistic regression in an effort to identify independent predictors of neurological complications. A significance level of 0.05 was used for both entry and selection. Results are reported as percentage and ORs with 95% CIs. All reported P values are two-sided, and P values of <0.05 were considered to indicate statistical significance. All statistical analysis was performed with SPSS version 19.0 (SPSS, Inc., Chicago, IL, USA).

RESULTS

Patient characteristics and operative data

During the study period, 1280 consecutive patients underwent MIMVS, of these, 167 (13%) had RAP and 1113 (87%) AAP. Baseline characteristics of the study population are given in Table 1. Compared with the RAP group, patients who had AAP were more likely to have a history of smoking (P = 0.03), hypertension (P = 0.02) and to be older (P = 0.03). Operative data are reported in Table 2. Patients who had a RAP were more likely to use endoclamp (P = 0.001) while in AAP, the trans-thoracic clamp was used more frequently (P = 0.001). There were no significant differences in term of CPB time, however aortic cross-clamp time was longer in the AAP group (P = 0.002). The rates of MV repair as well as associated tricuspid procedures were similar between the two groups. AAP patients received atrial fibrillation ablation more frequently than RAP (P = 0.01).

Crude in-hospital outcomes

Crude in-hospital results are reported in Table 3. RAP was associated with a similar in-hospital mortality compared with AAP (OR = 1.11; P = 0.95) but with a higher incidence of stroke (OR = 4.25; P = 0.001) and postoperative delirium (OR = 3.05; P = 0.001). Moreover, RAP patients had a significantly higher rate of aortic dissection (OR = 1.95; P = 0.01). However, AAP patients were more likely to develop postoperative AF (OR = 0.61; P = 0.02). No significant differences between the two groups were noted for others complications.

Risk-adjusted in-hospital outcomes

Risk-adjusted in-hospital outcomes are reported in Table 3. After adjusting for the propensity score, RAP was still associated with a higher incidence of stroke (adjusted OR 4.24; P = 0.002) and postoperative delirium (adjusted OR 3.60, P = 0.001). Although no longer statistically significant, there was still a trend suggesting that RAP had a lower incidence of postoperative AF (adjusted OR 0.68; P = 0.09).

Multivariable regression analysis revealed that the use RAP was an independent risk factor for stroke (OR 4.28; P = 0.02) and postoperative delirium (OR 3.51; P = 0.001). Other independent predictors of stroke and delirium are reported in Table 4.

DISCUSSION

Minimally invasive approaches have been used with increasing frequency for heart-valve repair and replacement surgery over the past 10 years [1–3]. This transition towards a less-invasive approach has been characterized by the development of new, innovative arterial and venous cannulation techniques and actually two perfusion strategies are available to the surgeon who performs MIMVS: the retrograde route with femoral artery cannulation and the antegrade route with direct ascending aorta cannulation. Despite good results having been reported for both perfusion techniques [2–3, 10], recently some retrospective studies have raised the suspicion that retrograde perfusion strategy during MIMVS could be associated with an increased risk of neurological complications, when compared with antegrade perfusion [6, 10–11]. In 2011, Gammie et al. [12] retrospectively analysed the STS database comparing 4322 MIMVS operations with 23.821 standard sternotomy mitral procedures [12]. The authors reported similar mortality but a doubled risk of neurological complications with MIMVS as opposed to sternotomy (OR = 1.96; P = 0.001). However, their results were significantly hampered by the fact that at the time of the study the STS database data specification did not include the type of incision used and therefore the authors identified MIMVS procedures as those performed ‘with a femoral arterial and femoral/jugular venous cannulation’. This imprecise definition of the MIMVS procedure raised the suspecion that femoral artery perfusion, rather then incision locations, was associated with neurological complications. In response to this study, Grossi et al. [10], retrospectively analysed 3180 isolated, non-reoperative aortic and mitral operations performed through a minimally invasive incision (2291;72%) or a standard sternotomy (889;28%). The authors identify the use of RAP as an independent predictor of stroke (OR = 1.8; P = 0.004). However, in patients 50-year old or younger, retrograde perfusion had no significant impact on neurological events. Subsequently, the same group performed a similar analysis [11] in a more homogenous cohort of 1282 patients who underwent first-time isolated MIMVS at the New York University Medical School, over a 12-year period. The authors identify a clear association between the use of RAP and an increased risk of stroke in high-risk patients with peripheral vascular disease or disease of the aorta. In their reports, the authors also emphasize the role of preoperative evaluation of the aorta and distal vasculature to reduce the incidence of stroke.

At our institution, we have been conducting a minimally invasive cardiac surgery program since 2003, and over our 9-year experience, we have seen progress in our techniques [8]. Early description in the literature of MIMVS techniques predominantly involved peripheral arterial cannulation through the femoral artery [13], and at the beginning of our experience, right thoracotomy with femoral artery cannulation and endoaortic ballon occlusion was our preferred approach. Subsequently, similarly to what was reported by many other institutions [6, 10], our approach has evolved to femoral artery cannulation with trans-thoracic aortic clamping and finally we have moved to direct ascending aorta cannulation with trans-thoracic aortic clamping. It is extremely interesting to note that our results are very similar to those reported by Grossi and Galloway in their studies [7, 11]. In our analysis on a large cohort of homogeneous patients, we found that RAP was associated with a greater incidence of stroke and postoperative delirium when compared with AAP, even after adjusting results for the propensity score. The negative impact of femoral perfusion was also confirmed in the multivariable analysis, where the use of RAP was an independent risk factor for stroke and delirium. The finding of smoking (OR = 1.30) and dislypidemia (OR = 1.34) as adjunctive independent predictors of neurological complications may also be a result of their close association with atherosclerotic disease burden. Despite the use of RAP in patients with peripheral vascular disease having been recognized as a predictor of stroke in several studies, we did not find a similar association. However, it should be noted that in our study, RAP in patients with known extra-cardiac arteriophaty was rarely used and therefore our study may not be statistically powerful enough to detect this association.

Neurological complications, after MIMVS surgery, including delirium, are associated with increased morbidity and mortality, as well as prolonged hospital stays. MIMVS has been shown to have a similar mortality and morbidity when compared with standard sternotomy procedures [1–3]. However, some studies have reported a particularly greater incidence of neurological complications with a minimally invasive approach [4, 5]. In our series, the incidence of stroke was 2% and it has progressively declined during the study period. Indeed, from 2005 we have developed a structured protocol to reduce the incidence of neurological complications in MIMVS. Our strategy consists in avoiding RAP whenever possible, restricting femoral artery cannulation only to circumstances where a direct ascending aorta cannulation is prohibitive. In those cases where a central aortic cannulation is deemed prohibitive, we routinely evaluate the whole thoracic aorta and the iliac arteries with a CT scan in patients older than 75 years and in patients younger than 75 years who have two or more risk factors for vascular disease. In addition, we always use CO₂ insufflation in the surgical field to reduce the amount of intra-cardiac air, and we leave the aortic root vent in place until the heart is fully beating and no more bubbles are seen on transoesophageal echocardiography. Another important finding of our study was the higher incidence of perioperative aortic dissection in the RAP group. We speculate that cannulation of the femoral artery leads to increased risk of aortic injury which, with retrograde aortic flow, can predispose to aortic dissection. Interestingly, in the 2 patients who had an aortic dissection, the aorta was clamped with an endoaortic balloon.

The study has several limitations, which are important to consider when interpreting the results. The possibility of selection bias, as for all non-randomized studies, is the main limitation of our study. For this reason, in an effort to reduce this bias, we decided to use a propensity score analysis. Another limitations of our study is that the incidence of stroke was higher at the beginning of our experience, partially reflecting the course of the learning curve associated with MIMVS. For this reason, we have inserted the time as a variable in the propensity score. Also, the fact that the two groups differed significantly in terms of aortic clamping strategy could be seen as a limitation. It is known that the endoaortic balloon can migrate and obstruct the innominate artery, leading to temporary malperfusion of the brain. However, in our study, the use of endoaortic clamping did not emerge as an independent predictors of stroke.

In conclusion, the use of RAP during MIMVS is associated with an increased risk of stroke and postoperative delirium. Despite central aortic cannulation representing a more challenging procedure than femoral artery cannulation, it allows the avoidance of complications associated with retrograde perfusion while extending the suitability of MIMVS also to those patients who have an absolute contraindication to femoral artery cannulation. Finally, MIMVS with antegrade perfusion can be performed safely with a very low incidence of neurological complications.

Conflict of interest: none declared.

REFERENCES

APPENDIX. CONFERENCE DISCUSSION

Dr G. Wimmer-Greinecker(Bad Bevensen, Germany): As a matter of fact, about 15 years ago I wrote my thesis on a similar topic where we compared use of the old Heartport system in mitral surgery with a conventional approach. And in those days, we actually were treating only younger patients, so we did not see any clinical impact. But we also measured the S100B enzyme, and we found an almost tenfold increase of this cerebral marker, and we also attributed this to the retrograde perfusion and not to the balloon. So I would completely agree with you there. There is also a meta-analysis by the consensus group of ISMICS (the International Society for Minimally Invasive Cardiothoracic Surgery) which actually shows similar results.

You have already shown the limitations of your study, and I would agree that the learning curve has played a role, and you have incorporated time as a variable in the propensity score. Another downside is that during the development over time you changed the regimen. And if you change the regimen, it is not only the things you do, but it is also the awareness of the problem which might affect your outcomes.

I have three short questions. First, you have not shown this here, but in your manuscript you write about CO2 insufflation. Have you done this in the retrograde group as well as in the antegrade?

Dr Murzi: Absolutely.

Dr Wimmer-Greinecker: The second thing is, your aortic cross-clamp time is long in the antegrade group; is this due to the bulkiness of the arterial cannula, and does this make the procedure more difficult? Does this also have an effect on the length of your incision? Is your antegrade incision longer than your retrograde incision? And, finally, I would be interested in your contraindications to date for any minimally invasive right-sided approach.

Dr Murzi: Concerning the first question on the CO2 insufflation in the operative field, we have a protocol to reduce the neurological complications. From 2005 we have adopted this structured protocol. Every time we use a CO2 insufflation, we leave the aortic root vent until the end of the procedure when we are absolutely sure that no bubbles are present on the transoesophageal echocardiogram. This is very important because in minimally invasive procedures, you cannot handle the heart, so this is extremely important. We use the same technique with antegrade and retrograde arterial perfusion.

The second question, I am sorry, is on the learning curve, is it not?

Dr Wimmer-Greinecker: No. The second one was on the cross-clamp time that is longer, whether this is due to the cannula and if so does this affect the size of your incision.

Dr Murzi: It was just a little bit surprising that we found a longer cross-clamp time in the antegrade group, but this is not due to a technical problem. This is due to the fact that in the other series the endoclamp was used also in a redo patient, and we do not have redo patients. And basically because maybe at the beginning of our experience we made a sort of patient selection, so the first patients were just a little bit less fragile, with fewer problems, the mitral valve maybe was just a little bit less diseased. This could be the reason why we found such a difference. The third question?

Dr Wimmer-Greinecker: Size of the incision.

Dr Murzi: At the beginning of our experience, and Dr Glauber can confirm this, our incisions were just more medial, because the ascending aorta cannulation is more challenging than femoral artery cannulation. If you have a problem, it can be hard to repair the ascending aorta. After a few cases when we became proficient with ascending aorta cannulation, we just started to move laterally, and for the last four or five years we have been doing a complete lateral 4 or 5 cm thoracotomy. However, the length of the incision was not the problem. The incision was, more or less, the same. It is just the position that has changed.

Dr Wimmer-Greinecker: And, finally, your contraindications to date?

Dr Murzi: Our contraindication to antegrade perfusion?

Dr Wimmer-Greinecker: To any kind of mini thoracotomy.

Dr Murzi: Well, basically this year we have used a minimally invasive approach in 99 percent of patients who underwent a mitral repair or replacement. So our contraindications are just the presence of severe pleural adhesions or previous right chest surgery.

Dr M. Glauber(Massa, Italy): Just some comments. Contraindications can be severe pulmonary hypertension in which, even in the case of single-lung ventilation, the cannulation of the aorta is not tolerated haemodynamically. That can be one contraindication. Another contraindication is a severe lung emphysema.

And about the longer cross-clamping time, I have to comment that I taught at least six other surgeons in my department, and this obviously takes a certain academic time, and I never hurry up in teaching people. So six surgeons in this analysis is surely something important that may justify this prolongation of time.

Dr C. Alhan(Istanbul, Turkey): I just want to make a comment and ask you a question. We look at the arterial diameter with ultrasound before the operation and the size of the cannula, and when we open the artery, it is generally constricted. And if you do not measure it before the operation, you choose a smaller size cannula. And probably in retrograde perfusion, the cannula size is much less than the arterial antegrade perfusion cannula size. Did you look at this, and what is your mean arterial cannula size? And do you think that it has any impact on results?

Dr Murzi: Basically when we think preoperatively that we cannot do an ascending aorta cannulation in the patient, we do a scan of the femoral artery to check for the diameter. And I agree with you, that sometimes during manipulation, the artery can have a spasm. And this is another reason why we always try to go antegrade. Dr Glauber can correct me if I am wrong. We believe that antegrade perfusion is more physiological. It is more conventional for the surgeon and so whenever it is possible, we go antegrade without any doubts.

However, if we had to do retrograde perfusion, we always perform an echo evaluation or maybe a CT scan of the femoral vessels. It depends on the condition of the patient. And regarding the size of the arterial perfusion cannula, we use a specifically designed cannula, and the size is 23 French.

Dr M. Glauber(Massa, Italy): The concept is that with antegrade perfusion, you do exactly the same as you are doing in a full sternotomy, so there is no selection of patients. And if you need a peripheral cannulation for any reason and you have a spasm in a small artery, what you can do is to dilate the artery with a smooth gentle dilation, increasing the size of the dilators progressively. That is what you can do.

Dr A. Lichtenberg(Düsseldorf, Germany): I have a little problem with your data. In one group, you have 33% of endoclamp patients, in the other group, nothing. Did you consider that maybe that is a reason for the strokes?

Dr Murzi: Well, we put this issue in the limitations of the study. This is a clear limitation. We cannot move from this. However, in our multivariable analysis, the endoclamp did not come out as a predictor of stroke. So based on what the data tell us, I say no. And also, the study which has been cited previously clearly showed that maybe the endoclamp can be associated with more risk of aortic dissection, but not with stroke. So basically in our opinion it is the retrograde perfusion which makes the difference.

Author notes