Key words : Coronavirus disease 2019, Deceased donation, Severe acute respiratory syndrome coronavirus 2

Introduction

Brain death is defined as the complete and permanent loss of brain functions and brainstem reflexes.¹ Organs and tissues retrieved from donors diagnosed with brain death are crucial for treatment of diseases that can only be treated with transplant. However, despite developments in the field of intensive care, the lack of diagnosis and reporting of brain death and the associated low rate of organ donation remain serious problems for patients waiting for organ transplant.^2,3 To achieve expansion of the donation pool, early identification of potential donors, successful obtainment of family consent, and adequate management of donor organs are essential.⁴ On the other hand, inadequate care of potential donors and/or prolongment of the donation process (especially during the critical period from identifi­cation of potential donors to the procurement of organs) may result in the loss of the organs.⁵

An ongoing outbreak of pneumonia caused by a novel coronavirus, SARS-CoV-2, which is the virus that causes COVID-19 disease, was reported⁶ in late 2019 and rapidly developed into a pandemic that has changed our daily lives and also disrupted hospital functions, medical processes, and health care resources.⁷ During this ongoing pandemic, the transplant process has been negatively affected by the use of immunosuppressive treatments after transplant, the risk of organ procurement from donors with asymptomatic SARS-CoV-2 infection, and the risk of COVID-19 transmission from health care personnel with undiscovered infections.^7,8

Although the pandemic has created a serious burden on health care services, arrangements have been made in many countries to ensure that the transplant process remains undisrupted, including donor and recipient screening and perioperative management.⁹ In Turkey, new regulations have been introduced by the General Directorate of Health Services, Department of Organ, Tissue Transplantation and Dialysis, and the processes of brain death diagnosis and donor care have been managed according to the recommendations of the Scientific Advisory Board.¹⁰

Studies on the effects of COVID-19 on transplant processes have primarily focused on recipients and transplant teams. However, there are few studies that have focused on donation volume and the efficiency of the procurement process.¹¹ Moreover, there are no data in the recent literature regarding the difficulties encountered in the process of diagnosis, family consent, and donation in the midst of this pandemic. Here, we investigated the effects of SARS-CoV-2 infection on the number and frequency of brain death diagnoses among potential donors, the time from family consent to procurement, and management of donor organs.

Materials and Methods

Medical records of patients who were diagnosed with brain death at the Intensive Care Unit of Bursa City Hospital between July 15, 2019, and November 18, 2020, were retrospectively reviewed. We retrieved details of donors’ demographic characteristics, diagnoses at intensive care unit (ICU) admission, Glasgow Coma Scale scores at ICU admission, confirmatory tests performed for the determination of brain death (apnea test, ancillary tests), family consent rates, and procured organs.

The time from ICU admission to the deter­mination of brain death, the time from clinical consideration of brain death to the confirmation of the diagnosis, and the time from family consent to procurement were recorded. These variables were compared between patients diagnosed with brain death before the pandemic versus during the pandemic.

In donors, the results of C-reactive protein (CRP), procalcitonin (PCT), white blood cell count, and cultures (tracheal aspirate, urine, and blood) were evaluated at ICU admission and on the day of brain death diagnosis and ICU discharge.

During the pandemic, COVID-19 screening was performed for patients who were accepted as potential donors according to the recommendations of the Scientific Advisory Board in our country.¹⁰ According to these instructions, real-time polymerase chain reaction (RT-PCR) tests were stipulated for every potential donor whose Glasgow Coma Scale score was 6 or less, in an effort to avoid additional delay of the donation process. It was advised to investigate travel and contact history of the patients and the symptoms of COVID-19. In addition, to account for the incubation period of SARS-CoV-2, RT-PCR tests were ordered twice at 24-hour intervals from intratracheal aspirate samples before the organ transplant coordinator presented the patient data to the National Coordination Center. For the exclusion of COVID-19, all potential donors underwent chest computed tomography, according to consultation with the Department of Infectious Diseases and Clinical Microbiology and the Department of Chest Diseases.

To determine brain death, our hospital follows the guidelines of the Turkish Neurological Society.¹² Our hospital’s organ transplant coordinators conduct interviews with the potential donors’ families, present the patient data to the National Coordination Center, and prepare legal documents.

Ethics approval was received from the Bursa City Hospital Clinical Research Ethics Committee on November 18, 2020 (project number 2020-10/7; Ministry of Health approval date November 13, 2020).

Statistical analyses
The data were analyzed with SPSS software (version 20.0). The descriptive statistics are presented as number, percentage, mean ± SD, and median with interquartile range (IQR). The normal distribution of the data of the numerical variables was evaluated with the Shapiro-Wilk normality test. Comparisons between groups were performed with a t test for variables with normal distribution and the Mann-Whitney U test for variables without normal distribution. The relationships between categorical data were evaluated with the chi-square test. P < .05 was considered statistically significant.

Results

During the study period, 40 patients at our hospital were diagnosed with brain death (13 patients before the pandemic, 27 patients during the pandemic). The mean age of actual donors was 29.6 years, and 60% were men. The main cause of brain death was intracranial hemorrhage (75%). The demographic and ICU admission data of the patients are summarized in Table 1.

For the determination of brain death, apnea tests were performed in 19 patients; the test could not be completed in 1 patient because of hypoxemia. Cranial computed tomography angiography was performed as an ancillary test in 36 patients clinically diagnosed with brain death (Table 1).

In the period before the pandemic, median time from ICU admission to the diagnosis of brain death was 4 days (IQR, 5 days) and the median time from the first neurological examination to the confirmation of the diagnosis was 26 hours (IQR, 8 hours).

However, during the pandemic, the median time from ICU admission to the diagnosis of brain death was 4 days (IQR, 12 days) and the time from the first neurological examination to the confirmation of diagnosis was 29 hours (IQR, 11 hours) (P > .05) (Table 1).

The first PCR-positive case for COVID-19 in Turkey was reported on March 11, 2020.¹³ Family consent rate for donation was 15% (n = 2/13) before the pandemic and 29.6% (n = 8/27) during the pandemic. Two patients developed cardiac arrest before the family interview; 1 patient was a foreign citizen, and so the family interview could not be performed.

Restrictions during the pandemic caused difficul­ties in contacting family members, and 9 families who were asked for reconsideration conveyed their negative decisions by phone after the interviews.

Organs from 2 donors were procured before the pandemic. Organs from 8 donors were procured during the pandemic, and organs were accepted from 3 of these 8 donors. However, despite the confirmation of consent, we rejected organs for 5 of these 8 donors (during the pandemic) because of suspicion of infection, with SARS-Cov2 as the suspected pathogen in 1 of these 5 donors. Mean organ donation time was 8.5 ± 2.12 hours (minimum to maximum [min-max], 7-10 hours) in the period before the pandemic and 54 ± 11.53 hours (min-max, 45-67 hours) during the pandemic. For donors whose organs were rejected for medical reasons, the time from family consent to the rejection of organs by transplant centers was 13 ± 6.44 hours (min-max, 6-22 hours). There were 31 organs donated from 5 accepted donors, but only 14 of these organs were procured and used for transplant.

Although acute renal failure was not detected in the patients in the period before the pandemic, 11% (n = 3) of the patients during the pandemic had acute renal failure. In addition, the rate of catecholamine administration to patients was 54% (n = 7) before the pandemic and 81% (n = 22) during the pandemic.

In our hospital, CRP, PCT, and cultures were ordered for potential donor care in the period before the pandemic only when infection was suspected. During the pandemic, these tests were routinely performed, and it was found that the acute phase reactants were increased as a result of the prolonged stay in the ICU. However, only the increase in the CRP value from ICU admission to operation was statistically significant (from 31.11 ± 35.99 to 181.06 ± 154.07 mg/dL; P = .004).

Before the pandemic, cultures were obtained from tracheal aspirate from 4 of 13 patients, while blood and urine samples were obtained from 6 of 13 patients. During the pandemic; blood samples were obtained from all 27 patients, tracheal aspirate samples from 25 patients, and urine samples from 26 patients. The origins of the positive bacterial cultures are presented in Table 2. Acinetobacter baumannii (n = 6) was the most frequently isolated bacteria in tracheal aspirate samples, whereas Staphylococcus epidermidis (n = 4) was the most frequently isolated bacteria in blood cultures. The values for CRP, PCT, and white blood cell count and the culture results of the donors with family consent are summarized in Table 3 and Table 4.

Discussion

Organ transplant is a life-saving medical intervention that offers the only therapeutic option for terminal organ failure. The first case of COVID-19 in Turkey was reported on March 11, 2020, and the number of cases has dramatically increased. The subsequent demand for ICU beds and ventilator support for the treatment of patients with COVID-19 compelled hospitals to make changes to accommodate this need.

As a result, this epidemic has negatively affected rates of deceased organ donation and transplant in our country as in other countries.^8,11,13 In 2019 in Turkey, there were 2309 patients diagnosed with brain death, 619 families gave consent for organ donation, and the number of accepted organs was 2504. By comparison, in 2020, there were 1385 patients diagnosed with brain death, 263 families gave consent for donation, and the number of accepted organs was 1059.¹⁴ When we compared the data of 2019 versus 2020, there was a dramatic decrease of 40.01% in the diagnosis of brain death, a 57.5% decrease in the frequency of family consent, and a 57.8% decrease in the number of accepted organs. Because our hospital is a referral center for COVID-19, 65% (n = 156/239) of the adult ICU beds were allocated for the management of COVID-19 patients, and only 27 diagnoses of brain death were made in our hospital during the pandemic. In our country, the General Directorate of Health Services, Department of Organ, Tissue Transplantation and Dialysis is assigned to improve the rate of brain death notifications and thereby increase the deceased donor organ pool, with a goal to report at least 1 diagnosis of brain death per ventilated intensive care bed per year.¹⁵ The low frequency of brain death diagnoses in our hospital and throughout Turkey may be the result of (1) loss of undiagnosed potential donors due to the workload of health care workers and (2) underreporting to organ transplant coordinators by ICU staff of potential donors with unconfirmed criteria.

During the pandemic, the goal of the Science Board of our country was to design a new national approach for organ transplant and donation.¹⁰ With consideration for the broad clinical course of COVID-19, potential donors may be asymptomatic or mildly symptomatic during donation, for which universal screening is needed.⁸ However, the new initiatives for care of potential donors have considerably extended the overall time for the donation process. The time to operation after the interview with the family was 8.5 hours before the pandemic and 54 hours during the pandemic. Although there were few patients in our study, it is evident that the donation process has become longer than before the pandemic. The extension of this critical period has led to a greater focus on the management of donor care in an effort to maximize the number of organs presented for donation, and infection management among potential donors has become a specific priority in response to this prolonged donation period. In our study, the reason for rejection of 5 donors (17 organs) was diagnosis of SARS-CoV-2 infection in 1 patient and suspected infection in 4 other patients. Before the pandemic, samples from blood, tracheal aspirate, urine, and other biological fluids were cultured only in cases of clinical suspicion of infection; however, during the pandemic, culture screening has become routine for all cases, and CRP and PCT levels were followed up at regular intervals. Further studies are needed to clarify the role of routine culture-based screening in donor care.

Some medical conditions, such as the presence of an active infection in the potential donor, may be a critical obstacle to organ donation.^16-18 The inequality between supply and demand has led most transplant centers to develop new strategies to increase the number of donors. Advanced patient age, prolonged length of ICU stay, and hemodynamic instability are no longer considered standard contraindications for organ donation.¹⁸ However, the presence of bacterial infection in the donor remains a point of concern in the discussion of contraindications. Although many transplant centers have been reluctant to consider patients with bacteremia as potential donors, some centers have recently been evaluating cases of documented bacteremia among potential donors who have received adequate antibiotic therapy.^4,16-20 Donors with suspected bacterial infection should be evaluated in detail during the pandemic period, especially for patients on the urgent wait list.²¹ In addition, cost-effective microbiological surveillance protocols could be established to closely monitor potential donors and best ensure adequate antibiotic and antifungal prophylaxis treatments when needed.

Brain death causes an inflammatory condition characterized by excessive release of cytokines, which can lead to a sudden increase of catecholamines.²² Schwarz and colleagues²² reported that plasma cytokine levels of patients with brain death were similar to the values observed in sepsis and that the systemic inflammatory response caused by brain death was triggered mainly by the brain injury itself rather than other injuries during a critical illness. Rangeard and colleagues²³ also found that, as an infection marker, PCT was increased in patients with brain death and that the mean PCT values were similar in patients with or without infection. The authors suggested that PCT values above 9 ng/mL had a specificity for infection prediction over 80%. In our study, the mean CRP and PCT values were high for the patients diagnosed with brain death during the pandemic. When 3 patients who were not used because of medical reasons were evaluated, it was found that 1 patient had elevated PCT levels but had negative cultures, whereas 2 patients had positive tracheal aspirate cultures and PCT values of >4 ng/mL. Organ procurement is rejected by medical centers for potential donors with elevated PCT levels. The high risks of infection (eg, mechanical ventilation, urinary catheterization, central venous catheterization) and the pathophysiology of brain death warrant the consideration of a multidis­ciplinary approach to prevention and control of infection, which would be more standard in these patients.^18,24

There are screening and transplant procedures for many viral infections (eg, hepatitis C virus, hepatitis B virus, HIV) in our country, but there is no committee assigned to examine unexpected potential donor-derived transmission events such as infection or malignancy. The Disease Transmission Advisory Committee of the United States, which was established in 2006 to examine potential donor-derived disease transmission events, is an active advisory group to the Organ Procurement and Transplantation Network committee of the US Department of Health and Human Services.^21,25 In light of increasing shortages of donor organs in Turkey, there is a need for establishment of advisory committees in our country to examine unexpected donor-derived transmission events during the pandemic, to work in coordination with disease control and prevention centers, and a need to evaluate collective data of events across the country to improve patient safety.

In addition, because of the restrictions during the pandemic (eg, the ban of visitors to the ICUs, ban of quarantined family members from family visits), ICU staff and the organ transplant coordinators may be unable to establish close contact with families during the process of diagnosis. Observation of the psychosocial status of the family in the process of donation inquiry, as well as the establishment of effective communication with the family during the process, is essential in the donation decision.²⁶ The interview between the coordinator and the family is a particularly difficult part of the donation process because of ethical, legal, and emotional aspects.^26,27 We believe that the challenge to conduct an effective interview process with the family was another factor that negatively affected our donor rates in our study. Nine of the families reported their negative responses by phone. During the pandemic, to reduce negative results that may occur during communi­cation with families of potential donors, we deemed it necessary to escalate our efforts to enhance public awareness of brain death and improve community confidence toward organ transplant coordinators and health care workers.

The limitations of our study are the low number of patients and the focus on a single center. In addition, there were few cases during the period before the pandemic because our hospital was newly opened in late 2019, not long before the start of the COVID-19 pandemic. Despite the small sample size, our study showed not only did the number of donors significantly decrease in our country and in our hospital during the pandemic, but also the duration of donor care was prolonged. Moreover, strategies to improve productivity of the processes for organ care and donation, including infection control, became a critical focus.

Conclusions

Increasing the deceased donor organ pool during and after the pandemic has been a vital issue that needs to be carefully addressed. However, larger national and international studies are needed to further understand the present and future effects of the COVID-19 pandemic on organ transplant programs and wait lists.

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