Exercise capacity: a predictor of mobidity and mortality?

In this paper by Diller et al. (2010, European Heart Journal 31, 3073-3083), the authors report the outcomes of 321 patients that underwent the Fontan procedure from 1997-2008 in four major hospitals in Europe.

The Importance of Exercise Capacity in Patients with Congenital Heart Defects

One of the major advancements of this study was that the authors not only recorded the fate of these patients but they also measured exercise capacity of these patients to see whether it affected their probability of dying, needing a heart transplant, or risk of hospitalization. This is an important advancement because recent studies have suggested that exercise capacity for patients with congenital heart defects (including those that have undergone the Fontan procedure) can be predictive of future survival as well as future medical issues.  For example, in 335 adult patients with various congenital heart defects (average age 33 years), exercise capacity was much lower than other individuals of the same age and was actually similar to adult patients that had heart failure that was not caused by a congenital heart defect (Diller et al., 2005, Circulation). By exercise capacity, I mean maximal oxygen consumption (“VO2 maximum”) that is measured during a cardiopulmonary exercise test that takes place on treadmill. Other traits during exercise are also measured of course but VO2 maximum is thought to reflect the overall physical condition (especially cardiovascular condition) and capacity for physical exertion of an individual. For example, VO2 maximum is very high in endurance athletes like runners or cyclists. This early study by Diller et al. (2005) was surprising because many adult patients with congenital heart defects did not report to the investigators that they actually experienced limitation during exercise or other periods of physical exertion yet they clearly showed it in their depressed VO2 maximum values.

In this study by Diller et al. (2010), the authors located 321 patients from Europe with various congenital heart defects that had the Fontan procedure 1997-2009 in 4 hospitals in Europe (German Heart Center in Munich, Royal Brompton Hospital in London, University Hospital in Bologna, and Great Ormand Street Hospital in London). They performed cardiopulomonary exercise testing to measure VO2 maximum and a variety of other characteristics reflecting exercise capacity during a standardized exercise trial on a treadmill. They followed these patients for an average of 21 months after exercise testing, though some patients were followed as short as <14 months and others >42 months. They recorded whether these patients were hospitalized, died, or underwent heart transplantation.

Major Findings of this Study by Diller et al. (2010)

1) Exercise capacity (VO2 maximum) was not affected by whether patients had the lateral tunnel/intra-cardiac Fontan or the extra-cardiac Fontan. Though it is important to note that a formal statistical analysis was not presented here.

2) VO2 maximum during exercise testing was highly reduced compared to normal patients. As expected and other studies have found (see below), VO2 maximum during exercise was highly reduced compared to what would be expected for a patient at that same age without the Fontan procedure. Actually only <3% of patients had what would be considered a normal exercise capacity (VO2 maximum) based upon the calculations of the authors.

3) VO2 maximum was not significantly related to probability of death or need for heart transplantation but heart rate reserve was. Unlike previous studies (see below), VO2 maximum was not related to the probability of death or need for a heart transplant but patients with lower heart rate reserve (which is the peak heart rate during exercise minus the resting heart rate) had a higher chance of dying or needing a heart transplant during follow-up. However, it is important to note that relatively few patients died (22 patients out of 321) or needed a heart transplant (6 patients out of 321) so these comparisons might not be the best given you are comparing the physiological values of one very small group (28 patients) compared to another much larger group (283 patients). Also, when the authors compared patients that were followed for a minimum of 3 years, they found that there was no effect of exercise capacity on probability of death or need for cardiac transplantation.

4) Patients with low exercise capacity (low VO2 maximum, low heart rate reserve, etc.) were more likely to be hospitalized during follow-up. The authors found that 41% of patients were hospitalized for a heart related issue during the follow-up period. Those patients with low VO2 maximum during exercise testing and low heart rate reserve (again peak heart rate during exercise minus resting heart rate) were more likely to be hospitalized for a heart related issue during follow-up.

Summary of Effects of Exercise Capacity on Survival and Health of Patients with Congenital Heart Defects

This study by Diller et al. (2010) adds to the growing number of studies showing that patients with congenital heart defects that ALSO exhibit low capacity for aerobic exercise tend to fare poorly. For example, in separate studies using different patients, Diller et al. (2005) found that adult patients with low exercise capacity (low VO2 maximum) tended to be more likely to be hospitalized or die in the year following exercise capacity testing (see also Dimopoulos et al., 2006 Circulation 113, 2796-2802). In a later study but with a longer follow-up time after testing of exercise capacity (28 months after testing), those with low exercise capacity (again low VO2 maximum) had a higher probability of dying in the subsequent 28 months (Diller et al., 2006 J American Coll of Cardiology 48, 1250-1256). In this same study by Diller et al. (2006), the authors also found that patients whose heart rates didn’t respond appropriately to exercise (i.e., dramatically increase immediately following the start of exercise) had a higher probability of dying in the subsequent 28 months. These studies along with the results from Diller et al. (2010) that I discussed above strongly link the  inability of the heart to perform properly during exercise for patients with congenital heart defects is unfortunately linked with an increased risk of future medical complications (reflected in increased hospitalization rates for heart related issues) or death.

Obviously these results don’t suggest that a low VO2 maximum or low heart rate reserve or other marker of exercise capacity is equivalent to an increased risk of death for ALL patients. One question that I have based upon these studies is what is known about the effects of preventative care for patients with congenital heart defects? For example, to conclusively test that exercise capacity does in fact contribute itself to increased risk of death or hospitalization rather than simply reflecting overall poor condition, future studies would need to identify groups of patients with variable exercise capacity. If half of these patients did moderate and regular exercise like walking that might increase exercise capacity, would they fare better than the other half that did not engage in such moderate exercise? I don’t know but that would be interesting to identify if we can improve outcomes by increasing exercise capacity. The major goal here would be to see how we can increase exercise capacity and that has beneficial outcomes in the short- and long-term. Interestingly, recent studies where patients with the Fontan physiology were provided with sildenafil (viagra) showed increased exercise capacity (e.g., Giardini et al., 2008 European Heart Journal 29, 1681-1687). Obviously this needs much more study to understand the costs and benefits of administering sildenafil to patients with Fontan physiology. However, this is currently a promising and interesting start to understanding if increasing exercise capacity lowers the risk of hospitalization or probability of death.

Lateral tunnel versus extracardiac conduit Fontan procedure: a concurrent comparison

In this paper by Kumar et al. (2003, Ann Thorac Surg 76, 1389-1397), the authors compare the outcomes of patients that underwent the Fontan procedure either using the intra-cardiac (lateral tunnel) or extra-cardiac conduit method. I have previously discussed the differences of these two types of the Fontan procedure here. and how the use of each type has changed over time here. In brief, the intra-cardiac or lateral tunnel method is the ‘older’ method (introduced in 1987) and the extra-cardiac method was more recently developed (1990). The lateral tunnel/intra-cardiac method involves sewing a piece of plastic inside the right atrium to route all blood from the lower part of the body (via the inferior vena cava) to the lungs whereas the extra-cardiac method involves placing a tube (either a tissue graft or plastic) outside the heart so that all blood from the lower part of the body (again via inferior vena cava) goes to the lungs. Regardless, some hospitals still perform the intra-cardiac method is the preferred option (see here).

The first thing to point out that this study was published over 10 years ago and uses data from patients that underwent the Fontan procedure from 1995-2002. As I have discussed elsewhere, there have been significant improvements in patient care and outcomes from the Fontan procedure. The other issue that these authors indicate is that most institutions only use one of the types of Fontan or they have suddenly changed over time. As such, it is hard to compare the outcomes of a lateral tunnel vs. extra-cardiac Fontan at a single hospital over the same time period. This study presents data where they performed both lateral tunnel (37 patients) and extra-cardiac (33 patients)  Fontan procedures at the same institution (Medical University of South Carolina) at the same time period.

Summary of Major Points of this Paper:

1) Theoretical advantages of extra-cardiac method. The lateral tunnel or intra-cardiac method requires placing a piece of plastic (“baffle”) inside of the atrium. The lateral tunnel/intra-cardiac method has had good early, medium, and long-term outcomes as well in previous follow-up studies. However, this requires sewing the piece of plastic (Gore Tex) inside the heart, which may increase the risk of atrial arrhythmias. The extra-cardiac method avoids having to sew this piece of plastic inside of the heart and so a theoretical advantage is that this method may decrease risk of future heart rhythm issues. However, note that this generally requires that the surgery be performed later in life because you are placing a piece of plastic in the heart that will not grow with the patient. Another possible advantage of the extra-cardiac method is that it can allow surgeons to perform the procedure without aortic cross-clamping (where they prevent the blood from leaving the heart) and even without cardiopulmonary bypass, which may have some advantages for short- and long-term outcomes (discussed here). For example, in this study, aortic cross clamping was always used for the lateral tunnel/intra-cardiac method but used in ~51% of patients for the extra-cardiac method.

2) No difference in time on cardiopulmonary bypass between intra-cardiac and extra-cardiac method but patients undergoing intra-cardiac method were on aortic cross clamping longer than those using extra-cardiac method. Patients undergoing the lateral tunnel/intra-cardiac method were on bypass (mean = 134 min) nearly the same amount of time as those undergoing the extra-cardiac method (mean = 145 min). However, 100% of patients undergoing the lateral tunnel/intra-cardiac method had aortic cross-clamping and for a longer period of time (mean = 55 min) than those that had the extra-cardiac method (52% of patients, mean = 26 min).

3) No difference in time on ventilator, time in intensive care unit, duration of chest tube drainage, and hospital stay between those having the lateral tunnel/intra-cardiac method vs. those undergoing the extra-cardiac method. This is an interesting result given that the lateral tunnel/intra-cardiac method is theoretically supposed to improve short-term outcome (that soon after the surgery) because of decreased chest tube drainage, etc. However, here they didn’t find any differences between the two methods.

4) No difference in type or frequency of medications given to patients that underwent intra-cardiac vs. extra-cardiac Fontan ~3 years previous. Though this probably attributable to the hospital itself and how they treat their patients, most of the patients were on asprin (94%) and there were no other differences between the type of frequency of medications taken between patients that underwent intra-cardiac or extra-cardiac method ~3 years previous.

5) No difference in heart rhythm problems between patients that had underwent intra-cardiac vs. extra-cardiac Fontan at ~3 years after the surgery. This is somewhat surprising that 15% of patients that had underwent the intra-cardiac Fontan ~3 years previous had heart rhythm issues (sinus node dysfunction) whereas MORE (28%) of patients that had underwent the extra-cardiac Fontan had heart rhythm issues ~3 years previous. Although this is not statistically different, this is opposite than what would be expected. Two patients underwent permanent pacemaker implantation (1 lateral tunnel and 1 extra-cardiac method) and in one case for slow junctional rhythm.

6) No difference in the post-operative blood pressure in various parts of the atrium and in the Fontan pathway (“Fontan pressure” and transpulmonary gradient) between patients that underwent the intra-cardiac vs. extra-cardiac Fontan. The authors provide brief discussion how these pressures can be predictive of early Fontan failure but they found no difference between these two methods in the first 24 hours after the Fontan.

Summary: This study highlights the lack of any real differences between the intra-cardiac/lateral tunnel vs. extra-cardiac Fontan in both the short- and long-term. This study also highlights the low rates of mortality or Fontan takedown (4.3%) around and soon after the actual surgery and high rates of survival 3-5 years after the Fontan for both the intra-cardiac (97%) and extra-cardiac (91%) methods.

The authors discuss their results in light of other studies that were contemporary at the time of this publication (2003). There results are similar to those of Gaynor et al. (2001, J Thorac Cardiovasc Surg 121, 28-41) who reported results from patients undergoing either intra- or extra-cardiac Fontan at Children’s Hospital of Philadelphia (1992-1999) and who again found no real differences between the methods. However, in another previous study that did a similar comparison between patients that underwent the intra-cardiac or extra-cardiac method at the Hospital for Sick Children in Toronto (data from 1994-1998), there was a significantly higher incidence of heart rhythm problems for patients undergoing the lateral tunnel/intra-cardiac method (45%) than those that underwent the extra-cardiac method (15%) at the post-operative period. Why the differences? The authors indicate that it may come from how the Fontan procedure was staged. The second surgery prior to the Fontan is either the hemi-Fontan procedure or the bidirectional Glenn shunt. The authors indicate that they selectively perform the hemi-Fontan for patients that were to undergo the lateral tunnel/intra-cardiac Fontan and perform the bidirectional Glenn shunt for patients that are due to undergo the extra-cardiac Fontan. In contrast, the patients at the hospital in Toronto were all staged with the bidirectional Glenn shunt regardless of whether they were to undergo the intra-cardiac or extra-cardiac Fontan (well, all patients except 1). The authors discuss how the hemi-Fontan (2nd surgery) prior to the lateral tunnel Fontan is a preferred option than doing the bidirectional Glenn shunt prior to the lateral tunnel Fontan (as the surgeons in Toronto did) because the latter involves making incisions in the same area where the previous incisions for the bidirectional Glenn shunt were made. Cutting into the same places where previous incisions were made in the sinus node region is probably not a preferable option. Interesting result. These findings confirm other studies that the risk of heart rhythm issues is higher for patients that underwent the bidirectional Glenn shunt prior to the lateral tunnel/intra-cardiac Fontan than if they had underwent the hemi-Fontan prior to the lateral tunnel/intra-cardiac Fontan. I wonder if all hospitals now always do the hemi-Fontan before the lateral tunnel/intra-cardiac method now?

Finally, the authors discuss how sometimes one method has to be done over another because of other issues with the heart anatomy. In other words, the choice of an intra-cardiac vs. extra-cardiac Fontan is not randomized among patients. For example, the lateral tunnel Fontan is often done for patients with hypoplastic left-heart syndrome but the extra-cardiac method is preferred for patients with heterotaxy syndrome. This makes it difficult to assess whether the short-, medium, or long-term outcomes are a result of the surgical procedure itself (i.e., which Fontan method) or the actual underlying condition.

Link to this paper:


Intra- or extracardiac Fontan operation? A simple strategy when to do what

In this paper, Kuroczynski et al. (Arch Med Sci 2013) reviewed the records of patients that had undergone intra-cardiac or extra-cardiac Fontan after the bidirectional Glenn surgery (the second one in staged surgeries). It is a relatively small dataset (72 patients) from one institution/hospital in Germany over a number of years (1995-2008) but I think this question is interesting and important. Understanding the potential risks and benefits of both an intra-cardiac or extra-cardiac Fontan is important. We should expect that medical science should improve outcomes and sometimes this requires paradigm shifts. For example, if an institution/hospital only performs intra-cardiac Fontan procedure, if presented with overwhelming evidence that the extra-cardiac route is “better” in the long-term (which this study does not necessarily show!), they should reconsider their methods.

Here are the major points:

As I have discussed before, two routes are commonly used in the Fontan procedure. Remember that the Fontan procedure is the 3rd step for a univentricular heart and generally comes after a 2nd open heart surgery (often the bidirectional Glenn).

1) What is the intra-cardiac Fontan method? The first potential Fontan method is to use the intra-cardiac route (also called ‘lateral tunnel’) where the blood from the lower part of the body (inferior vena cava) is routed directly to the pulmonary arteries through a ‘tunnel’ in  the atrium (generally the right atrium), which involves sewing a patch (‘baffle’) inside the heart. As its name implies (‘intra-cardiac’), this happens inside the heart. One potential caveat of the intra-cardiac Fontan is that it requires aortic cross-clamping (preventing blood from leaving the heart to the rest of the body) and stopping the heart so the surgical procedure can be completed. The intra-cardiac method also typically involves placing a fenestration in the baffle, which I have discussed in other blogs. Here is a diagram of the intra-cardiac method from Khairy et al. (2007, Circulation 115, 800-812):

Screen shot 2013-03-19 at 7.09.48 AM

2) What is the extra-cardiac Fontan method? The extra-cardiac method differs from the intra-cardiac method mostly in that it happens outside of the heart. Outside of the heart, a tunnel made of polytetrafluroethylene (type of plastic also used in non-stick cookware) connects the blood flow from the lower part of the body (again the inferior vena cava) directly to the right pulmonary artery. Here is an image of the extra-cardiac method from the Boston Children’s Hospital


3) Do the extra-cardiac and intra-cardiac methods differ in their short- and long-term outcomes? The authors suggest that the extra-cardiac method has become the method of choice more recently because i) improved blood flow, ii) less risk of thrombosis (blood clots), iii) lower chance of heart rhythm problems in the short- and long-term, iv) surgically speaking, it is easier and requires less aortic clamping, which may be advantageous (see my other posts). However, this is actually narrow view and, while the extra-cardiac method is preferred at some pediatric cardiology hospitals, the intra-cardiac method is preferred at others. Furthermore, this is definitely not all pediatric cardiologists agree that the extra-cardiac method is preferred over the intra-cardiac method based upon follow-up studies such as this one (Khairy et al., 2012 Circulation 126, 2516-2525).

4) What do the data show presented in this study? Although the sample sizes were extremely small (e.g., for patients with tricuspid atresia, they performed 9 intra-cardiac Fontan and 10 extra-cardiac Fontan), the results are still interesting. However, keep these small sample sizes in mind as well as the fact that these data were collected from 1995-2008 and the type and level of treatment has likely improved for patients undergoing the Fontan procedure over that time period.

5) Patients undergoing the intra-cardiac method spend MORE time on cardiopulmonary bypass than patients undergoing the extra-cardiac method. The amount of time spent on cardiopulmonary bypass for the intra-cardiac Fontan was greater (median = 170 min, range = 50-399 min) than the extra-cardiac Fontan (median 104 min, range = 53-247 min). Most studies (including this one) generally show that spending more time on bypass is not good in the short- and long-term. However, it is again hard to identify cause and effect here given that patients with more complex heart defects will necessarily spend more time on bypass.

6) Patients undergoing the intra-cardiac method (median = 39 hours) spend MORE time on a ventilator after the Fontan procedure than patients undergoing the extra-cardiac method (median = 21 hours). These numbers (the median # of hours spent on ventilator) seem crazy high. A predictor of the length of time spent on the ventilator was the amount of time with aorta cross-clamped (which might reflect a more complicated surgical procedure so not surprising longer time on ventilator). Age and weight at which the Fontan was performed did not impact amount of time on ventilator.

7) Patients undergoing the intra-cardiac method (median = 19.5 days) spent MORE time in the intensive care unit recovering from the Fontan than patients undergoing the extra-cardiac method (median = 14 days). Again, it would be important to know how these values changed over the years as this may have gone down from what it was in the mid 1990’s. Age and weight at which the Fontan was performed did not impact amount of time in intensive care unit.

8) Patients undergoing the intra-cardiac method (median = 48 hours) had to receive greater inotropic support with catecholamines (basically how long they received drugs like dopamine to help their heart beat properly) than patients undergoing the extra-cardiac method (median = 10 hours).

Summary: Taken together, this study shows that there were major advantages for performing the extra-cardiac method over the intra-cardiac method. Patients that underwent the intra-cardiac method spent MORE time i) on cardiopulmonary bypass, ii) on a ventilator, iii) on drugs that helped heart contract, iv) in the intensive care unit. All of this is interesting but it doesn’t prove that intra-cardiac method is worse than extra-cardiac method as this is one study with a small sample size of patients from one institution over a long period of time where how patients needing the Fontan procedure are treated has changed.

Caveats: Why the authors did not report presence/absence of heart rhythm problems is unknown but would have been interesting. Although they found that age and weight at Fontan completion didn’t affect the outcomes, the authors also discuss that they prefer to do the Fontan at a later age (median patient age of Fontan completion was 3.2 years in this study). Using the extra-cardiac method generally requires patients to be older so that changing the length of the conduit (extra-cardiac tunnel) can be avoided as the patient gets older and grows. However, this has to be balanced with the fact that performing the Fontan at a later age can damage the normal ventricle (Mair et al., 2001).

Link to this paper:http://www.termedia.pl/Clinical-research-Intra-or-extracardiac-Fontan-operation-A-simple-strategy-when-to-do-what,19,20334,0,1.html