Korean J Transplant 2023; 37(4): 241-249
Published online December 31, 2023
https://doi.org/10.4285/kjt.23.0049
© The Korean Society for Transplantation
Seyed Mohammad Reza Nejatollahi1 , Yazdan Abdolmohammadi2 , Sepideh Ahmadi2 , Arman Hasanzade3 , Fatemeh Hosseini2 , Arshia Mohseni3 , Shadi Shafaghi2 , Mojtaba Mokhber Dezfuli2 , Fariba Ghorbani3
1Department of Hepato-Pancreato-Biliary and Transplant Surgery, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Correspondence to: Fariba Ghorbani
Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Shahid Bahonar Ave, Darabad, Tehran 19569, Iran
E-mail: dr.f.ghorbani@gmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Obtaining consent from potential donor families is a challenging step in the donation process and is influenced by various factors.
Methods: In this cross-sectional study, we utilized a questionnaire containing 14 questions about facilitators and barriers in the family interview process. The questionnaire was distributed in March 2023 to intensive care unit (ICU) nurses who had experience with donor family interviews. We collected the opinions of these respondents on hospital performance and drew comparisons between the studied hospitals.
Results: A total of 60 participating ICU nurses provided mean scores for hospital performance in family interviews of 2.60±0.84 for type I hospitals (those providing neurosurgery and trauma care) and 2.035±0.890 for type II hospitals (those without neurosurgery and trauma services; P=0.04). The mean scores for public and private hospitals were 1.86±0.86 and 2.59±0.85, respectively (P=0.008). Based on the findings, the most important facilitators were the availability of organ donation staff and access to a professional team for family discussions. Conversely, poor physician communication skills and limited communication capabilities among medical staff were identified as significant barriers. Implementation of a professional team for family interviews was found to be more critical for type II hospitals. Poor physician communication skills were a significant concern in public hospitals, while families’ lack of awareness of patient prognosis emerged as a key barrier in private hospitals.
Conclusions: This study highlights numerous facilitators and barriers that vary across hospitals. Addressing these issues individually and developing tailored plans to enhance hospital performance in interviewing donor families is essential.
Keywords: Organ donation, Brain death, Organ procurement system, Organ donor
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Brain death is characterized by the irreversible loss of all cortex and brain stem functions. This condition is declared based on established criteria determined through neurologic examination. Statistics indicate that brain death accounts for approximately 2% to 5% of in-hospital deaths in the United States [1] and about 2.9% in Saudi Arabia [2].
Following brain death, cardiac autonomic activity can sustain organ function only for a limited time. Therefore, to prolong the preservation of organs, mechanical ventilation and medical care are crucial [3,4]. Brain-dead patients serve as a major source of organs for transplantation, and the increased focus of donation teams on these donors has contributed to a ratio of two kidney transplantations from deceased donors for each transplantation from a living donor. Despite the importance of the organs provided by brain-dead donors, donation can only be considered when the patient’s family consents to the process [5].
Considering the substantial gap between organ supply and demand, endeavoring to convert potential to actual donors is crucial [3,6]. This conversion rate is a vital metric that helps organizations and hospitals evaluate the effectiveness of their donation processes. It is defined as the proportion of potential donors from whom at least one organ is recovered for donation. The organ procurement network (OPN) of our center reported a conversion rate of 27%–30% in 2020 [7].
Numerous factors influence the conversion rate, including the potential donors’ conditions and medical histories, the efficiency of organ donation teams, and characteristics of the hospital and the donor families [8,9]. Addressing and optimizing these factors are essential steps in improving organ donation rates and saving additional lives through transplantation.
Considering the hemodynamic instability of potential donors and the physiological changes due to brain death that can lead to cardiac arrest, limited time is available for organ donation teams to identify potential donors and initiate the necessary steps. In addition to efforts aimed at improving donation processes and increasing the conversion rate, expanding the donor pool is crucial. One effective approach is to identify potential donors in emergency wards in addition to intensive care units (ICUs) [10].
The rate of family consent for donation varies across centers, with our OPN demonstrating rates of 70% to 86% based on unpublished data. Enhancing the cooperation and support provided by hospital staff can substantially influence this rate. By fostering a compassionate and supportive environment within hospitals, staff can play a vital role in providing clear and accurate information to families, addressing their concerns, and offering empathetic support during this difficult time. Training hospital staff to effectively communicate with patients’ families and provide them with the necessary information about organ donation can lead to higher consent rates. Building a strong and supportive relationship with potential donor families is important, as these families are facing bereavement and grief while having to navigate a complex decision-making process during a critical situation [11]. Hospital characteristics also play an integral role in this process. Each hospital has its own regulations concerning organ donation and the support it provides. The level of staff awareness, along with their attitudes toward donation, are key factors that can influence the donation success rate [12,13].
Evaluating different hospitals with respect to facilitating factors, barriers to obtaining consent, and the procedures utilized for organ preservation is crucial for bridging the gap between organ supply and demand and to address related issues. Previous studies have examined the effects of hospital characteristics on consent rate. This research has revealed that consent rates across academic centers were 9% higher than for non-academic centers, while trauma centers exhibited higher family consent rates by 4% to 7.7% compared to non-trauma centers [14-16].
A family’s decision regarding organ donation can be influenced by a multitude of factors, including cultural values, social beliefs, religious regulations, circumstances of death, and satisfaction with the care provided by the hospital. Numerous studies have explored the impact of hospital characteristics on organ donation success rates. In a previous study, researchers examined the barriers and facilitators of potential donor identification in each hospital studied. They found that adopting a center-specific strategy was more effective in improving the identification of potential donors [12]. Therefore, the primary objective of this study was to investigate the motivations and barriers that influence the process of obtaining family consent based on hospital characteristics.
The study was approved by the ethics committee of the National Research Institute of Tuberculosis and Lung Diseases (No. IR.SBMU.NRITLD.REC.1401.124). The questionnaire was anonymous, and all participants were invited to answer the questionnaire voluntarily.
This cross-sectional study utilized a 14-item questionnaire adapted from the tool developed by Oczkowski et al. [17]. This questionnaire was designed to explore facilitating factors (seven questions) and barriers (seven questions) influencing the family consent process. Participants responses were measured using a Likert scale, with scores ranging from one to five, corresponding to “completely disagree,” “disagree,” “neutral,” “agree,” and “completely agree,” respectively. We also included an additional question asking participants to rate the performance of the hospital at which they work regarding the process of family interviewing for organ donation. Respondents were asked to provide their opinion on a scale from 1 to 5, with options of perfect (5), acceptable (4), needs improvement (3), not acceptable (2), and poor (1).
The questionnaire was translated into Persian. To assess the validity of the translated questionnaire, 10 experts evaluated its content. The content validity ratio and the minimum score of the content validity index were found to be 0.62 and 0.79, respectively, indicating acceptable content validity. The questionnaire’s reliability was evaluated through the Cronbach alpha test, yielding a result of 0.85.
The study was designed to evaluate the impact of hospital characteristics on the family consent process. These characteristics included the presence of neurosurgery and trauma care services and the funding status of the hospital. Based on these features, the 57 hospitals associated with our OPN were categorized into two types: type I hospitals were those that provided neurosurgery and trauma care, while type II hospitals were those that did not. Additionally, hospitals were classified as public or private, based on whether they received government funding or operated independently.
Data collection took place in March 2023. For this process, we sent the questionnaire via WhatsApp to the nurses working in the ICUs of the 57 connected hospitals. We asked these individuals to participate in the study by answering the questionnaire if they had previous experience in conducting family interviews. A total of 60 ICU nurses who had participated in the family interview process responded to the questionnaire and were included in the study population.
All data collected using the questionnaires were entered into SPSS ver. 21 (IBM Corp.). Quantitative information was reported as mean±standard deviation, while qualitative data were presented as percentages. To analyze proportions and categorical variables, the chi-square test was utilized. For quantitative items obtained using the Likert scale, the Mann-Whitney U-test was employed due to the non-normality of the distribution. The statistical significance level was set at a P-value of 0.05, with a confidence interval (CI) of 95%. In instances for which a significant difference was observed, the standardized mean difference was calculated using the Psychometrica calculator.
The study was performed in 57 hospitals connected to our OPN. Among these hospitals, 37 were type I, and 25 were private. In all but three of the 57 hospitals, at least one nurse participated in this study by answering our questionnaire. The roles of facilitating and barrier factors were compared between type I and II hospitals and between public and private hospitals.
The response rate of the questionnaire was 80%, and of the 60 nurses who participated, 53 answered all questions. The average age of these 53 nurses was 35.5±10.0 years, and 52.8% were women (n=28). Most nurses (73.6%) were employed by public hospitals. The average length of work experience among all participants was 14.6±5.9 years. Regarding ICU experience, approximately 30.3% of the participants had worked in the ICU for 1 to 5 years, while most of the participants had more than 5 years of ICU experience.
Table 1 presents participant opinions regarding the factors facilitating the process of obtaining consent for organ donation. Approximately 47% of the participants agreed that the current methods used in hospitals were effective in facilitating consent.
Table 1. Participant opinions on factors facilitating consent for organ donation
Factor | Final score | Min–max | Strongly disagree | Disagree | Neither agree nor disagree | Agree | Strongly agree |
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Presence or immediate availability of organ donation unit staff for discussion of organ donation | 4.15±0.85 | 2–5 | 0 | 2 (3.7) | 10 (18.5) | 20 (37.0) | 22 (40.7) |
Use of a professional team for discussion with the family | 4.69±0.63 | 2–5 | 0 | 0 | 5 (9.3) | 7 (13.0) | 42 (77.8) |
Bedside nurse attendance of discussions about organ donation | 3.50±1.20 | 1–5 | 4 (7.7) | 8 (15.4) | 10 (19.2) | 18 (34.6) | 12 (23.1) |
Separating discussions about brain death from organ donation | 4.11±1.14 | 1–5 | 3 (5.6) | 2 (3.7) | 8 (14.8) | 14 (25.9) | 27 (50.0) |
In-services and staff education | 4.06±1.07 | 2–5 | 0 | 6 (11.1) | 5 (9.3) | 19 (35.2) | 24 (44.4) |
Pamphlets and educational booklets | 3.67±1.10 | 1–5 | 3 (5.6) | 7 (13.0) | 11 (20.4) | 17 (31.5) | 16 (29.6) |
Clearly explaining the issue to the patient’s family | 3.92±1.10 | 1–5 | 2 (3.7) | 4 (7.4) | 10 (18.5) | 17 (31.5) | 20 (37.0) |
Values are presented as mean±standard deviation, range or number (%).
Among the facilitating factors, “the availability of organ donation staff” was considered important or very important by 80.7% of the participants, with an average score of 4.15±0.85. “Use of a professional team for discussion with the family” received the highest score, with an average value of 4.69±0.63. Nearly all participants regarded this factor as an important or very important facilitator. “Bedside nurse attendance of discussions about organ donation” was also viewed as an effective factor according to 57.7% of participants. This factor obtained a score of 3.5±1.2.
Table 2 displays participant opinions regarding the barriers inhibiting consent for organ donation. “Poor physician communication skills” was considered important or very important by 79.2% of the participants, earning the highest score among the barriers (4.25±0.91). Likewise, 75% of the participants identified “limitations in communication skills among medical staff” as an important or very important barrier. Additionally, “insufficient time for discussing organ donation with the family” was considered a notable deterrent by 77.8% of participants.
Table 2. Participant opinions on barriers hindering consent for organ donation
Factor | Final score | Min–max | Strongly disagree | Disagree | Neither agree nor disagree | Agree | Strongly agree |
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Poor physician communication skillsa) | 4.25±0.91 | 2–5 | 0 | 3 (5.7) | 8 (15.1) | 15 (38.3) | 27 (50.9) |
Limitations in communication skills among medical staffb) | 4.06±1.07 | 1–5 | 1 (1.9) | 5 (9.6) | 7 (13.5) | 16 (30.8) | 23 (44.2) |
Insufficient time for discussing organ donation with the family | 4.04±0.96 | 1–5 | 2 (3.8) | 1 (1.9) | 8 (15.4) | 23 (44.2) | 18 (34.4) |
Family’s emotional unpreparedness to address organ donation | 4.02±0.92 | 2–5 | 0 | 3 (5.6) | 10 (19.2) | 21 (40.4) | 18 (34.6) |
Lack of awareness about the patient’s prognosis | 4.07±1.10 | 1–5 | 3 (5.6) | 2 (3.7) | 9 (16.7) | 14 (25.9) | 26 (48.1) |
Lack of awareness of the importance of organ donation | 4.06±1.03 | 1–5 | 1 (1.9) | 4 (7.7) | 8 (15.4) | 17 (32.7) | 22 (42.3) |
Differences between patient and family desires for organ donation | 3.57±1.20 | 1–5 | 3 (5.7) | 8 (15.1) | 14 (26.4) | 12 (22.6) | 16 (30.2) |
Values are presented as mean±standard deviation, range or number (%).
a)Here, a physician is defined as the treating medical professional responsible for the patient’s care, including specialists such as neurosurgeons, neurologists, trauma surgeons, and others. This clarification was provided in the questionnaire; b)The term “medical staff” encompasses nurses and other personnel who interact with patients and their families, excluding the treating physician. This clarification was provided in the questionnaire.
Another barrier was “the family’s emotional unpreparedness to address organ donation,” with 75% of participants considering this an important or very important factor. Participants also highlighted “lack of awareness of the patient’s prognosis” as a major obstacle, with 74% agreement, while “lack of awareness of the importance of organ donation” was considered a barrier by 75% of the participants. Additionally, “lack of awareness of the deceased person’s desires” was considered an obstacle in 52.8% of the responses.
From the perspective of the nurse participants, “differences between patient and family desires for organ donation” constituted the least important barrier in the process of converting a potential donor into an actual donor, with a score of 3.57±1.20.
The performance of different hospitals in the organ donation process was assessed based on participant responses. For the family interview process, the participants gave average scores of 2.60±0.84 to type I hospitals and 2.05±0.89 to type II hospitals, constituting a statistically significant difference (P=0.04). Similarly, the score for public hospitals was 1.86±0.86, while that for private hospitals was 2.59±0.85, indicating a significant difference in hospital performance (P=0.008). In short, type I hospitals and private hospitals were perceived to have superior performance by the ICU nurses in this study.
Regarding facilitators, the use of a professional donation team for communication with families received scores of 4.540±0.741 for type I hospitals and 4.940±0.236 for type II hospitals, constituting a statistically significant difference (standard mean difference [SMD], 0.64; 95% CI, 0.03–1.24; P=0.03). Type II hospitals were found to place a greater emphasis on employee in-service training compared to type I hospitals (SMD, 0.58; 95% CI, −0.02 to 1.19; P=0.03). However, no significant differences were noted in facilitators between public and private hospitals (Table 3).
Table 3. Factors facilitating consent for organ donation across hospitals
Facilitating factor | Trauma and neurosurgery care | Public hospital vs. private hospital | |||||||
---|---|---|---|---|---|---|---|---|---|
Type I | Type II | P-value | 95% CI of SMD | Public | Private | P-value | 95% CI of SMD | ||
Presence or immediate availability of organ donation unit staff for discussion of organ donation | 4.11±0.91 | 4.18±0.72 | 0.90 | −0.51 to 0.67 | 4.38±0.74 | 4.08±0.88 | 0.63 | –1.08 to 0.30 | |
Use of a professional team for discussion with the family | 4.54±0.74 | 4.94±0.23 | 0.03 | 0.03 to 1.24 | 4.75±0.46 | 4.70±0.64 | 0.71 | −0.78 to 0.58 | |
Bedside nurse attendance of discussions about organ donation | 3.37±1.28 | 3.69±1.07 | 0.40 | −0.33 to 0.85 | 3.75±1.28 | 3.37±1.23 | 0.28 | −0.29 to 0.58 | |
Separating discussions about brain death from organ donation | 4.03±1.24 | 4.22±0.94 | 0.70 | −0.43 to 0.76 | 4.38±0.91 | 4.10±1.19 | 0.64 | −1.32 to 0.82 | |
In-services and staff education | 3.83±1.12 | 4.44±0.85 | 0.03 | −0.02 to 1.19 | 4.25±1.03 | 4.05±1.07 | 0.70 | −0.19 to 0.55 | |
Pamphlets and educational booklets | 3.63±1.21 | 3.72±1.22 | 0.70 | −0.52 to 0.66 | 3.87±0.99 | 3.57±1.29 | 0.69 | −0.02 to 0.58 | |
Clearly explaining the issue to the patient’s family | 3.89±1.18 | 3.94±0.96 | 0.90 | −0.54 to 0.63 | 3.87±1.12 | 3.92±1.17 | 0.90 | −0.64 to 0.73 |
Values are presented as mean±standard deviation.
CI, confidence interval; SMD, standard mean difference.
Regarding type I hospitals, “lack of awareness of the importance of organ donation” was considered a greater barrier than in type II hospitals (SMD, −0.74; 95% CI, −1.35 to −0.12; P=0.04). No significant differences were found in other barriers between hospital types.
“Poor physician communication skills” was considered a stronger barrier in public hospitals than in private hospitals (SMD, −0.28; 95% CI, −0.96 to 0.41; P=0.02), while “the family’s lack of awareness of the patient’s prognosis” was found to be a greater barrier in private hospitals (SMD, 0.32; 95% CI, 0.36–1.02; P=0.03). However, no significant differences were observed in other barriers between public and private hospitals (Table 4).
Table 4. Barriers hindering consent for organ donation across hospitals
Barrier | Trauma and neurosurgery care | Public hospital vs. private hospital | |||||||
---|---|---|---|---|---|---|---|---|---|
Type I | Type II | P-value | 95% CI of SMD | Public | Private | P-value | 95% CI of SMD | ||
Poor physician communication skills | 4.29±0.77 | 4.20±0.94 | 0.94 | −0.70 to 0.48 | 4.25±0.88 | 4.01±0.81 | 0.02 | −0.96 to 0.41 | |
Limitations in communication skills among medical staff | 4.12±1.16 | 4.00±1.04 | 0.53 | −0.70 to 0.48 | 4.13±1.12 | 4.16±0.97 | 0.29 | −0.66 to 0.71 | |
Insufficient time for discussing organ donation with the family | 3.94±1.12 | 4.06±0.90 | 0.87 | −0.48 to 0.70 | 4.43±0.53 | 4.05±0.90 | 0.32 | −1.31 to 0.07 | |
Family’s emotional unpreparedness to address organ donation | 4.31±0.79 | 3.86±0.97 | 0.14 | −1.13 to 0.07 | 4.14±0.69 | 3.90±0.99 | 0.14 | −1.01 to 0.37 | |
Lack of awareness of the patient’s prognosis | 4.33±0.84 | 3.91±1.26 | 0.31 | −1.02 to 0.17 | 4.00±1.41 | 4.45±1.16 | 0.03 | 0.36 to 1.02 | |
Lack of awareness of the importance of organ donation | 4.50±0.73 | 3.86±1.11 | 0.04 | −1.35 to –0.12 | 4.00±1.15 | 4.00±1.07 | 0.59 | −0.68 to 0.68 | |
Differences between patient and family desires for organ donation | 3.76±1.20 | 3.49±1.26 | 0.33 | −0.81 to 0.37 | 3.88±0.99 | 3.62±1.22 | 0.34 | −0.94 to 0.43 |
Values are presented as mean±standard deviation.
CI, confidence interval; SMD, standard mean difference.
In this study, our main objective was to assess the performance of different hospitals and investigate the facilitating and inhibiting factors influencing the process of obtaining consent from potential donors’ families. Based on the opinions of the ICU nurses who participated in this study, type I hospitals and private hospitals demonstrated superior performance in the organ donation process. Regarding facilitating factors, the use of a professional team to conduct family interviews emerged as the most crucial, scoring the highest among possible facilitators. Interestingly, this factor was found to be more important in type II hospitals than in type I institutions. Additionally, we observed substantially greater emphasis on employee in-service training in type II hospitals. Conversely, poor communication skills among medical staff emerged as the greatest barrier, as indicated by the highest score. Overall, this study provides valuable insights into the dynamics influencing family consent for organ donation. Identifying key facilitators and barriers can aid healthcare institutions in devising targeted strategies to enhance their consent processes. By focusing on improving communication skills and investing in professional teams, hospitals can better support potential donor families during this critical decision-making time. Ultimately, addressing these factors can lead to increased organ donation rates, bridging the gap between organ supply and demand and saving more lives through transplantation.
Comparing organ donation outcomes across hospitals and investigating the underlying reasons can be instrumental in identifying the strengths and weaknesses of each organ donation team. In a study conducted by Pilcher et al. [18], the proportion of actual donors among intubated patients who died in ICUs in Australia was found to be 8.1. Furthermore, their evaluation revealed that certain hospitals, such as private and tertiary hospitals, had a higher number of actual donors than was estimated [18].
Family refusal of organ donation is influenced by various factors, including dissatisfaction with the hospital staff, difficulty accepting brain death as an equivalent of death, inappropriate encounters between staff and the family, and religious beliefs [19,20]. Hospital characteristics play an important role in understanding these barriers. In the present study, nurses at type I hospitals demonstrated a greater appreciation for organ donation compared to those at type II hospitals, leading to a higher success rate in obtaining consent and identifying brain-dead potential donors [12].
Supporting our findings, a study by Ali et al. [16] revealed that small academic trauma centers had significantly higher consent rates than large, nontrauma, or nonacademic centers. Another previous study similarly demonstrated that both nontransplant and nonurban centers had higher conversion rates [15]. Additionally, Salim et al. [14] found that trauma centers had a 4% higher family consent rate compared to nontrauma hospitals. Rios-Diaz et al. [21] evaluated various hospital characteristics and reported that while small, nonacademic centers and hospitals that were not trauma centers had lower volumes of potential donors, they were more likely to convert a potential organ donor into an actual donor. Each hospital may have specific limitations that require a tailored strategy for organ donation. By identifying the obstacles present in individual hospitals, we can develop a targeted plan to address these limitations during the organ donation and family interview processes.
Generally, hospital characteristics such as academic status, availability of transplant services and neurosurgery services, hospital size, number of ICU beds, financial funding (public or private), and urban or nonurban location can influence the hospital authorization rate. Additionally, the medical team’s approach and communication skills play a key role in influencing the decisions of potential donor families. Therefore, in line with our findings, Manzari et al. [22] emphasized the importance of establishing a specialized team of physicians and nurses in each ICU. These teams should be well-trained in communication skills and equipped to provide appropriate support to the families of potential donors during the challenging decision-making process [22].
In this study, the involvement of a qualified team in family interviews and poor physician communication skills were the most significant facilitator and barrier, respectively. Interestingly, at Hamilton General Hospital, an academic and type I hospital, “the availability of organ donation staff for discussions of organ donation” and “lack of understanding by family/substitute decision-makers of the patient’s prognosis” played more substantial roles [17].
To our knowledge, this study is one of the first to evaluate the facilitators of and barriers to obtaining family consent based on hospital characteristics. However, our study does have several limitations. First, it was challenging to ensure accurate questionnaire responses from nurses, and we did not obtain opinions from other medical staff. Second, participants may have responded to the questionnaire in a biased manner based on their personal views about organ donation. Third, the study did not assess the impact of other potential influential factors that participants may have considered more effective, as the data were collected using predetermined questions in the questionnaire. Moreover, as a cross-sectional study, this research has the potential for selection, information, and confounding bias. Finally, nurses with positive attitudes may have been particularly willing to participate in the study, potentially affecting the results.
Based on our findings, we recommend the implementation of a professional team of organ donation coordinators in the family interview process for type II hospitals. Additionally, providing training courses for medical staff in private hospitals to enhance their communication skills is advisable, along with clarifying patient prognoses to their families.
In public hospitals, improving communication between physicians and family during the interview process is essential, as it may lead to a higher consent rate. These targeted approaches address specific challenges faced by each hospital type and can help narrow the gap between organ supply and demand, ultimately saving additional lives through successful organ transplantation.
Conflict of Interest
No potential conflict of interest relevant to this article has been reported.
Authors Contributions
Conceptualization: YA, AH. Formal analysis: FG SMRN. Methodology: FG, MMD. Project administration: SMRN. Supervision: SA. Validation: AH. Visualization: FH. Writing–original draft: SH, AH, FG. Writing–review & editing: all authors. All authors read and approved the final manuscript.