key: cord-1021561-v85pv7tu
authors: Chew, Claire Alexandra; Iyer, Shridhar Ganpathi; Chieh Kow, Alfred Wei; Madhavan, Krishnakumar; Teng Wong, Andrea Sze; Halazun, Karim J.; Battula, Narendra; Scalera, Irene; Angelico, Roberta; Farid, Sharid; Buchholz, Bettina M.; Rotellar, Fernando; Chi-Yan Chan, Albert; Kim, Jong Man; Wang, Chih-Chi; Pitchaimuthu, Maheswaran; Reddy, Mettu Srinivas; Soin, Arvinder Singh; Derosas, Carlos; Imventarza, Oscar; Isaac, John; Muiesan, Paolo; Mirza, Darius F.; Bonney, Glenn Kunnath
title: An international multicentre study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise
date: 2020-05-23
journal: J Hepatol
DOI: 10.1016/j.jhep.2020.05.023
sha: df71d4bf0c0b0ae9d9a3ea6c04596338755203db
doc_id: 1021561
cord_uid: v85pv7tu

BACKGROUND: The outbreak of Covid-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multi-center study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the Quadripartite Equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium- sized liver transplant centers from twelve countries across four continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a “sickest-first” approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - Recipient Outcome, Donor/Graft Safety, Waiting List Mortality and Healthcare Resources for seven countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of Quadripartite Equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems to allow greater global solidarity and transparency in these austere times.

The outbreak of Covid-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources.

We performed an international multi-center study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the Quadripartite Equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources.

Seventeen large-and medium-sized liver transplant centers from twelve countries across four continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score 

This four-dimensional model of Quadripartite Equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems to allow greater global solidarity and transparency in these austere times.

There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources in the Covid-19

pandemic. We describe a four-dimensional model of Quadripartite Equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. 1 Since then, the novel coronavirus disease 2019 has rapidly spread across the world leading the World Health Organization (WHO) to declare a global pandemic on 11 March 2020. The surge in the number of people seeking medical treatment has temporarily overwhelmed health services, leading to concerns regarding the allocation of scarce resources such as intensive care facilities. 2, 3 This has immediate implications on liver transplantation worldwide. The availability of intensive care facilities is crucial, not only for the identification of donors for deceased donor transplantation, but also for the care of post-operative patients. 4 In such austere times, a balance must be achieved between the survival benefit of transplantation, waiting list mortality, risk to donors and diminishing national resources. The availability of viral testing for patients as well as healthcare workers also remains a major concern.

The aim of this study was to perform an international multi-center analysis to understand the evolution in response of major transplant centers from the initial outbreak to the declaration of a pandemic. We propose a model of Quadripartite

Equipoise to guide ethical decision-making in the context of liver transplantation in a viral pandemic.

The The triangular base of the pyramid was defined using Recipient Outcome, Donor/Graft Safety and Waiting List Mortality. These were each drawn from the centroid to the 3 vertices of the triangle at an equal angle of 120°. The vertical axis was defined using the Healthcare Resources factor. Three-dimensional modelling of the pyramid was performed using Rhinoceros 3D (Version 6; Seattle, WA, USA). The volume of each pyramid was extracted using Grasshopper, a parametric modelling plug-in for Rhinoceros 3D. Data was obtained from public registries and published literature. [8] [9] [10] [11] [12] [13] [14] [15] [16] The 5-year overall survival and annual waiting list mortality for Singapore is currently unpublished and was obtained directly from the national registry.

At the time of submission, the number of infections worldwide remains on an exponential trajectory ( Figure 1 ). It is in this context that we first aimed to survey the changes to prioritization in liver transplantation and the screening of donors and recipients for viral infections.

Seventeen large-and medium-sized liver transplant centers from twelve countries across four continents participated. The response rate of centers surveyed was 100%.

Characteristics of the transplant activity of participating centers are shown in Table 1 .

Due to the low rates of deceased donation, there was a higher waiting list mortality of 10 -20% in six out of seven Asian centers where the proportion of LDLT performed was concordantly higher, encompassing over 20% of all transplants. While all centers had a criterion for the listing of super-urgent recipients, the criteria for medical urgency was less consistently defined and included acute or acute-on-chronic liver failure, arterial thrombosis, or Model for End-Sate Liver Disease (MELD) score of > 29 ( Table 1 ).

The changes in protocols for transplant activity between centers are shown in Figure   2 . When queried on "suggested protocols" for their institution, most respondents opted to limit transplant activity and favored a "sickest-first" approach ( Figure 2) , with the allowance of other transplants on a case-by-case basis. Nearly all respondents felt that the screening of donors and recipients for Covid-19 prior to transplantation was indicated.

A detailed review of the changes in response to the pandemic was requested from seven major transplant centers ( Based on the results of the survey, the patterns of transplant activity did not appear to correspond with the burden of Covid-19 on healthcare resources, highlighting a clear need for a framework to guide the prioritization of transplant activity. Therefore, we modelled the ethical tension that arises when considering liver transplantation during a viral pandemic, to derive a QE score for seven countries as shown in Figure 3 .

The shape and size of the triangular base characterizes the transplant activity of each country. As previously described, Donor/Graft Safety was fixed at a maximal value of 1.000. Differences in the triangular base between countries were determined by the The QE score of Italy on 1 March was 11.6, which was smaller than the score of several countries later into the pandemic. This was contributed to by both fewer ICU beds and the relatively low waiting list mortality of 5.1%. Respondents from Italy also reported a decrease in referrals for cadaveric donors, likely a reflection of both social restriction measures as well as an overwhelmed healthcare system. The computed QE score on 24 March for Italy was 0.0.

Since the outbreak of Covid-19 in January 2020, healthcare systems worldwide have become overwhelmed by rising numbers of infected patients. 19 It is no longer an option but rather a priority to set consistent ethical frameworks to manage this burden on our healthcare systems. In a pandemic, maximizing societal benefit is a necessary approach towards managing scarce resources such as intensive care facilities. 20 However, the democratization of these resources for lifesaving procedures such as organ transplantation adds a further layer of complexity. Unlike other organs with potential alternative or bridging therapies, liver transplantation is the only option for patients with end-stage liver failure.

To our knowledge, this is the largest study to date to catalogue the changes in the prioritization of transplant activity and viral screening in response to the Covid-19

outbreak. In response to the declaration of the pandemic, ten out of 17 centers worldwide reduced their transplant activity by employing a "sickest-first" approach.

Paradoxically, the transplantation of such patients may intensify the burden on ICUs and compromise access for Covid-19 patients with severe respiratory compromise, 21 thereby reducing the overall societal benefit. Of the seven centers that transplant less than 50 livers a year, only one did not reduce their transplant activity, while of those transplanting over 100 livers a year, four out of six also opted not to do so. On first glance this may reflect greater accessibility to resources in bigger centers (Figure 2 ), however, this was not supported by the number of ICU beds per capita in their respective countries. 15, 16 Upon surveying respondents for their "suggested" response to the pandemic, nearly all respondents called for viral screening of both donors and recipients ( Figure 2 Worldwide, organ allocation by MELD score or the "sickest-first" approach is modelled on the principle of justice, where fairness is determined by urgency. 24 However, other scores that consider the impact of donor factors draw on the principle of utility, which prioritizes maximizing the overall survival benefit from transplantation. 25 However, a crucial point to note is that current best evidence suggests approximately 10% of Covid-19 patients require intensive care. 32 The proportion of active Covid-19 patients with respiratory compromise requiring ICU admission is a function of the viral pathology and is unlikely to vary significantly between countries. This effectively renders the burden on ICU facilities a relatively fixed fraction of the total number of active cases. It is with this in mind that the authors have chosen the most robust available data, the number of active cases by country, for estimating the burden on health care resources. As more data becomes available, this axis may be further refined to more accurately measure the operational burden caused by the pandemic.

The ethical tension between the burden of disease and need for transplantation arises from the shortage of resources, in particular the shared resource of ICU facilities. The

Centers for Disease Control and Prevention (CDC) has issued guidance for the allocation of ventilators in which they emphasize the need to apply "an ethical framework that focuses on saving as many lives as possible". 33, 34 While this affects policymakers, who decide on the supply of ventilators to hospitals, crucially it affects clinicians who are now pressed to make extremely difficult decisions to triage ventilators in ICUs. 35 In the context of the diminishing availability of such resources, the transplant community is faced with a similar dilemma in considering the prioritization of liver transplantation during a pandemic.

In our study, we modelled these four ethical considerations in a pyramidal structure and a QE score was calculated using the volume of the model (Figure 3 ). While the absolute value of the score remains nominal, the expansion or contraction of the model reflects the need to either pursue or limit transplant activity.

In South Korea, minimal variation in QE score (16.1 to 13.6) (Figure 3 ) was concordant with the continuation of standard activity described by the survey ( Figure   2 ). Singapore instituted early changes to decrease transplant activity and the need for where living donation is an option, the Donor/Graft Safety score can be adjusted depending on the morbidity associated with the donor operation, which would be comparatively lower for kidney transplantation than for liver. 36, 37 In the case of deceased donor transplantations, the axis can be calculated using organ-specific risk scoring systems that predict graft safety. 38, 39 Recipient Outcome and Waiting List

Mortality can be similarly modified using organ-specific outcomes. However, unlike end-stage liver disease, other organs have potential bridging alternatives to transplantation -the left ventricular assist device for the heart, hemodialysis for kidneys and insulin supplementation for the pancreas. As such, a reduction in transplant activity may not affect the waiting list mortality as significantly as in liver transplantation. In addition, the degree of strain on ICU facilities will also vary depending on the organ-specific need for ICU support in the peri-operative period. 

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The authors have no conflicts of interest to declare.

The authors have no financial support to declare.

All authors contributed to data curation, formal analysis and manuscript review/editing. AW contributed to software and visualization. CC, IS, and GB contributed to conceptualization and methodology. CC and GB contributed to writing of the original draft.

We thank Dr Richard W. Laing, Dr David C. Bartlett, and Dr Thiagarajan Srinivasan for collating data from their respective centers.

• Increased operational burden on healthcare systems worldwide from Covid-19 outbreak • Frameworks to balance need for liver transplant against limited resources needed• International multi-center study of policies for transplant prioritization conducted• Novel four-dimensional model of Quadripartite Equipoise to balance ethical tensions • Fluctuation of model over time guides need to pursue or limit transplant activity