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Sizing strategies in heart and lung transplantation: you cannot manage what you do not measure
“...utilizing refined estimates of organ size ... would allow us to better measure, better understand, better control and, ultimately, improve the important donor to recipient size matching process in heart and lung transplantation.” Robert M Reed*,1 & Michael Eberlein2 “Measurement is the first step that leads to control and eventually to improvement. If you can’t measure something, you can’t understand it. If you can’t understand it, you can’t control it. If you can’t control it, you can’t improve it.” – H James Harrington [1] . When my 7-year-old daughter asked me to explain to her what it was that I was working on, I tried to explain to her how better regression models allow better estimation of heart size, and that a too-small heart doesn’t do as well. I did not think she would understand. “Like the Grinch?” she asked, clearly thinking of the Dr Seuss character whose heart was “two sizes too small” [2] . She understood perfectly. The significance of recipient to donor organ size matching in heart transplantation has long been under-appreciated, likely reflecting failure to measure (and thus appreciate) true differences in size. Current practice utilizes recipient and
donor weights as the principal surrogate of organ size in the matching process. Recipients are most often listed for acceptable donor weight ranges between 30% higher or lower than the recipient’s weight [3] . Unfortunately, body weight is an imperfect predictor of cardiac size and this weight-based approach is of questionable value. A series of investigations have shown that donor to recipient weight discrepancies are not associated with differential survival after cardiac transplantation [3–5] . So, we may ask – in the presence of good data showing no effect – why do we continue the practice? Is it simply because there has been no better alternative proposed? Another curiosity of cardiac transplantation that has been poorly explained, again due to failure to adequately estimate size differences, is the observation that a donor to recipient sex mismatch correlates with worse survival [4] . Particularly notable is the excess risk associated with a female donor heart transplanted into a male recipient.
KEYWORDS
• Grinch effect • heart transplantation • lung transplantation • organ size mismatch • sex mismatch
University of Maryland School of Medicine, Division of Pulmonary & Critical Care Medicine, 110 South Paca Street, 2nd Floor. Baltimore, MD 21201, USA 2 University of Iowa School of Medicine, Division of Pulmonary & Critical Care Medicine, Iowa City, IA 52242, USA *Author for correspondence: Tel: +1 410 328 8141; Fax: +1 410 328 0177;
[email protected] 1
10.2217/FCA.14.17 © 2014 Future Medicine Ltd
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Editorial Reed & Eberlein
“In the current system, undersizing is largely occult. One cannot manage what one does not measure.”
Prior studies have not been able to adequately examine size differences due to the lack of normalized values for heart size. The assumption has again been that weight is a valid estimate for heart size. Recent advancements in cardiac imaging have now allowed for the development of normal values of cardiac size. Specifically, we now have refined regression equations predicting left and right ventricular mass, which incorporate not only weight, but also sex, height and age [6,7] . An estimate of cardiac size can be generated by adding the predicted left ventricular and the predicted right ventricular mass as the predicted total heart mass: ●● Predicted left ventricular mass = a · height0.54 · weight0.61 a = 6.82 for women and 8.25 for men. Mass measured in grams, height in meters and weight in kilograms. ●● Predicted right ventricular mass
= a · age-0.32 · height1.135 · weight0.315 a = 10.59 for women and 11.25 for men. Mass measured in grams, height in meters and weight in kilograms. When we consider cardiac size in light of these normalized values, it becomes apparent that weight is a particularly poor predictor of cardiac size differences in the setting of a sex mismatch. As a rule of thumb, organs from females are roughly 20% smaller than organs from otherwise similar males. Thus, the current practice of matching a donor heart to a recipient by body weight fails to discriminate substantial organ size mismatches in the setting of sex mismatches. In a retrospective analysis of more than 31,000 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplant registry, we evaluated donor to recipient heart size matching based on the predicted heart mass [3] . There were several notable findings: ●● We reconfirmed that differences in donor–
recipient body weight are not associated with any differences in survival; ●● We demonstrated that differences in predicted
heart size do predict outcomes, with the most undersized septile experiencing a 25% increased risk of death at 1 year; ●● We showed that the worse survival in female-
donor to male-recipient sex mismatch appears completely related to size differences;
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●● We showed that the worse survival in male-
donor to female-recipient mismatch is attributable to some factor other than size. These findings bear a remarkable similarity to findings from our prior work in lung transplantation, showing that undersizing portends worse outcomes. Analogous to heart transplant, lung transplant organ allocation utilizes donor and recipient heights as a surrogate of lung size, and height correlates only crudely to lung size. We have shown that application of predicted total lung capacity as a more refined estimate of organ sizing is a strong predictor of various meaningful outcomes, including survival after lung transplantation [8–15] . Similar to our findings in heart transplants, the worse outcomes associated with a female-donor to male-recipient sex mismatch were not observed after adjusting for organ size differences. Based on our data, it would seem logical to consider a change to the method of thoracic organ allocation to incorporate better estimates of organ size. Rather than height range for lung and weight range for heart, it would be fairly simple to express sizing preferences in terms of percentage difference from the recipient predicted organ size values. While distinct thresholds of risk are lacking, the risk of death was clearly higher when the donor heart’s predicted mass fell below 10–15% under the predicted mass of the recipient’s heart. As such, a heart transplant practitioner might choose to express donor sizing preference as between 15% undersized to 50% oversized. Setting preferences for lung transplant would be more complex, as upper and lower limits would need to take diagnosis into greater consideration. A concern that may initially seem valid is that the proposed changes could reduce access to organs that are in scarce supply. This argument breaks down, however, when we consider that all organs suitable for transplant are generally utilized and would continue to all be utilized. The change would not affect the number of organs used for transplantation at all, but rather would improve the assignment of organs to recipients in whom the organ is likely to function best. In the current system, undersizing is largely occult. One cannot manage what one does not measure. The sizing preference would be at the discretion of the practitioner and could be tailored to the clinical scenario. The difference would be that the tailoring would be informed by measures
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Sizing strategies in heart & lung transplantation that are meaningfully associated with outcomes that matter. For example, it may be appropriate to avoid undersizing in a relatively stable patient and appropriate to liberalize size preferences in patients who are less stable. In patients awaiting heart transplantation who are less stable, an increasingly utilized strategy is to consider extended criteria, or marginal, donor heart offers [16,17] . However, an area that will require further investigation is: what is the interaction between extended criteria donor hearts and size matching? It is conceivable that accepting an extended criteria donor heart that is also very undersized confers significant additive risk. Another issue that warrants mention is patient preference. After all, transplant practitioners are required to discuss the CDC’s ‘high risk’ donor preferences with patients and many patients elect to refuse to accept these organs, largely because of the frightening sounding term. ‘High risk’ certainly sounds like something to avoid, but the actual risk associated with these organs is far less than that associated with undersizing [18] . In summary, refined estimates of organ size in thoracic transplantation uncover the otherwise occult ‘Grinch’ effect of undersizing. Although the investigations demonstrating References 1
Mobilizing the right lean metrics for success. www.qualitydigest.com/may06/articles/02_ article.shtml
2
Dr Seuss. How the Grinch Stole Christmas! Random House, NY, USA (1957).
3
Reed RM, Netzer G, Hunsicker L et al. Cardiac size and sex-matching in hearttransplantation size matters in matters of sex and the heart. JACC Heart Fail. 2(1), 73–83 (2014).
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Khush KK, Kubo JT, Desai M. Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the International Society for Heart and Lung Transplantation Registry. J. Heart Lung Transplant. 31(5), 459–466 (2012). Patel ND, Weiss ES, Nwakanma LU et al. Impact of donor-to-recipient weight ratio on survival after heart transplantation: analysis of the United Network for Organ Sharing Database. Circulation 118(14 Suppl.), S83–S88 (2008). Bluemke DA, Kronmal RA, Lima JA et al. The relationship of left ventricular mass and geometry to incident cardiovascular events:
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the ‘Grinch’ effect are based on retrospective analyses of thoracic transplantation databases and carry the limitations associated with this, it will likely be impossible to obtain higher level evidence. Furthermore, adjustments to the thoracic organ allocation mechanism have previously been implemented based on comparable levels of evidence [19] . Such implementation would be a big first step forward in improving size matching in thoracic organ allocation by utilizing refined estimates of organ size, rather than continuing to rely on weight and height as flawed surrogates. This advance would allow us to better measure, better understand, better control and, ultimately, improve the important donor to recipient size matching process in heart and lung transplantation. Financial & competing interests disclosure RM Reed is funded in part by the Flight Attendant Medical Research Institute (FAMRI). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
the MESA (Multi-Ethnic Study of Atherosclerosis) study. J. Am. Coll. Cardiol. 52(25), 2148–2155 (2008). 7
Kawut SM, Lima JA, Barr RG et al. Sex and race differences in right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis – Right Ventricle study. Circulation 123(22), 2542–2551 (2011).
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Dezube R, Arnaoutakis GJ, Reed RM et al. The effect of lung-size mismatch on mechanical ventilation tidal volumes after bilateral lung transplantation. Interact. Cardiovasc. Thorac. Surg. 16(3), 275-81 (2012).
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Eberlein M, Permutt S, Chahla MF et al. Lung size mismatch in bilateral lung transplantation is associated with allograft function and bronchiolitis obliterans syndrome. Chest 141(2), 451–460 (2011).
10 Eberlein M, Reed RM, Permutt S et al.
Parameters of donor-recipient size mismatch and survival after bilateral lung transplantation. J. Heart Lung Transplant. 31(11), 1207–1213 (2011). 11 Eberlein M, Arnaoutakis GJ, Yarmus L et al.
The effect of lung size mismatch on complications and resource utilization after
bilateral lung transplantation. J. Heart Lung Transplant. 31(5), 492–500 (2012). 12 Eberlein M, Bolukbas S, Reed RM.
eComment. Gender mismatching in lung transplantation: lung size mismatch is the issue! Interact. Cardiovasc. Thorac. Surg. 16(4), 435–436 (2013). 13 Eberlein M, Reed RM, Bolukbas S et al. Lung
size mismatch and survival after single and bilateral lung transplantation. Ann. Thorac. Surg. 96(2), 457–463 (2013). 14 Eberlein M, Diehl E, Bolukbas S, Merlo CA,
Reed RM. An oversized allograft is associated with improved survival after lung transplantation for idiopathic pulmonary arterial hypertension. J. Heart Lung Transplant. 32(12), 1172–1178 (2013). 15 Eberlein M, Reed RM, Maidaa M et al.
Donor–recipient size matching and survival after lung transplantation: a cohort study. Ann. Am Thorac. Soc. 10(5), 418–425 (2013). 16 Forni A, Luciani GB, Chiominto B, Pizzuti
M, Mazzucco A, Faggian G. Results with expanded donor acceptance criteria in heart transplantation. Transplant. Proc. 43(4), 953–959 (2011).
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system for heart transplantation and the impact on patient survival. J. Heart Lung Transplant. 31(4), 387–397 (2012).
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18 Arnaoutakis GJ, Sodha NR, Tedford RJ,
Merlo CA, Milano CA, Shah AS. Centers for disease control high-risk donors and thoracic organ transplantation: expanding the donor pool. J. Heart Lung Transplant. 32(4), S123 (2013).
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19 Eberlein M, Garrity ER, Orens JB. Lung
allocation in the United States. Clin. Chest Med. 32(2), 213–222 (2011).
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