Key words : Age, Donor goals, Hemodynamic monitoring schedule, Utilized donors

Introduction

Management of potential organ donors is crucial in the donation process, considering that hemodynamic instability is quite common (up to 70%) among donors after brain death (BD), and this instability is a risk factor for organ loss.^1-5

Donor management goals (DMG) are endpoints that guide the bedside critical care management of organ donors after brain death, and the achievement of these goals has been associated with an increased number of organs transplanted per donor.^4,5-7

According to the Italian law, death by neurologic criteria is certified after a 6-hour observation period. Since 2019, a monitoring schedule has been imple-mented by the Tuscany Transplant Authority to strictly record DMG during the observation period and, consequently, to tailor hemodynamic mana-gement for each BD donor.

We aimed to assess the achievement of DMG during the 6-hour observation period for BD donors consecutively admitted to our intensive care unit (ICU) (a high-volume organ-procurement center). We further assessed whether the achievement of DMG was influenced by donor age.

Materials and Methods

In the present single-center observational study, we included 87 utilized BD donors consecutively admitted to our ICU from January 1, 2019, to December 31, 2022. The study was approved by the Institutional Review Board of Regional Authority for Transplantation and performed in accordance with the Helsinki Declaration of 1975.

Study population
Diagnosis of death was confirmed by strict adherence to standardized clinical, neurologic, and electroencephalogram criteria in accordance with the Italian law and related guidelines. According to the Italian law, death by neurologic criteria is certified after a 6-hour observation period.

Time 1 refers to the beginning of this period, and time 2 refers to the end of this period. Clinical data included age, sex, risk factors (hypertension, diabetes mellitus, and known previous coronary artery disease), and cause of death. Data were prospectively recorded and retrospectively analyzed.

Donor management
All potential donors were managed as previously described.8-10 The DMG for our study were as follows: mean arterial pressure (MAP) >70 mm Hg, central venous pressure (CVP) 6 to 10 mm Hg, urine output of 1.2 mL/kg/h, and partial pressure of oxygen ?90 mm Hg.8,10,11 Hemodynamic management also included replacement therapy with cortisone and thyroid hormone.10 Antidiuretic hormone and intravenous insulin (target glucose values <180 mg/dL) were considered on a case-by-case basis.

In 2019 the Tuscany Transplant Authority implemented the use of a monitoring schedule for which systolic and diastolic blood pressure, heart rate, CVP, and diuresis were reported by the transplant coordinator during the 6-hour observation period. Partial pressure of oxygen is also recorded.

In the presence of a reduction in blood pressure, the following changes are made according to our protocol: (1) volume replacement (crystalloid) whenever CVP is <6 cm H2O and (2) increase in norepinephrine dose up to 0.2 ?g/kg/min. If this dose is not sufficient to restore perfusion (MAP >70 mm Hg), then vasopressin is added.

Hemodynamic instability is defined as (1) the need for an incremental dose of vasoactive agents after adequate volume replacement and (2) the need for vasopressin.

We aimed to assess the achievement of DMG during the observation period in our series through the study period. We also evaluated whether the achievement of DMG differed between younger and older donors. We chose an arbitrary age cutoff of 65 years.

Statistical analyses
Data were analyzed with the use of SPSS statistical software (version 20). P < 0.05 (was considered statistically significant. Categorical variables are repor-ted as frequencies and percentages, and continuous variables are reported as mean values ± SD or median values (with 25th-75th IQR). For continuous variables, between-group comparisons were made with analysis of variance (followed by Bonferroni posttests, if the overall P value was significant) or by the Kruskal-Wallis H test. Categorical variables were compared by chi-square tests.

Results

Our series comprised 87 consecutive BD donors in whom at least 1 organ was utilized (Table 1). Female donors were prevalent (66%), and the most prevalent cause of brain death was stroke (54%). The organ-per-donor ratio was 2.3 in our population. The most frequent cause of death in younger BD donors (<65 years) was trauma, whereas stroke was more frequent in older BD donors.

As shown in Table 2, the number of DMG significantly increased during the 6-hour observation period (P < .001), and all DMG were achieved in most donors (84/87) at the end of the observation period (time 2) with no changes in the use and dose of vasoactive drugs.

With respect to age, the number of DMG was significantly higher in older donor at time 1, but the number significantly increased in both age subgroups of donors at the end of the 6-hour observation period.

Discussion

The main findings of the present investigation, performed in 87 utilized BD donors, were as follows: (1) the implementation of a monitoring schedule resulted in the achievement of all DMG at the end of the 6-hour observation period in most BD donors; (2) in younger BD donors all DMG were achieved at time 2, different from older BD donors, which indicated that hemodynamic management is more challenging in younger BD donors.

There is no universal agreement on each DMG. For instance, mean blood pressure targets of 60 to 70 mm Hg are not based on evidence from rando-mized controlled trials (RCTs). In the Monitoring Organ Donors to Improve Transplantation Results (MOnIToR) RCT, which was stopped prematurely because of lack of resources, management based on blood pressure, pulse pressure variation, and cardiac index targets was not superior to conventional therapy with regard to increasing the number of organs transplanted per donor.12 Regarding goal-directed fluid management (as monitored by CVP), 1 RCT was prematurely stopped because goal-directed fluid management did not prove to be superior to conventional therapy.12 Historically, DMG were developed to maintain physiological homeostasis. An early series of goals was the so-called series of 100, ie, systolic pressure >100 mm Hg, urine output >100 mL/h, partial pressure of oxygen >100 mm Hg, and hemoglobin concentration >100 mg/dL.13 In the subsequent years, guidelines for donor treatments and other goals were introduced, despite worldwide variations in management strategies.14,15

Donor management continues critical care but with different and specific therapeutic goals. In some centers,16,17 donor management goals are adopted as clusters of 9 critical endpoints. Several previous investigations examined whether fulfillment of predefined DMG influences the number of organs accepted for transplant. In a prospective observational study17 including 961 donors, after controlling for donor age, sex, and body mass index, both hemodynamic (MAP, left ventricular ejection fraction, and CVP) and endocrine (serum sodium and glucose) critical care endpoints were associated with increased liver graft use. In 2014 Pavel and colleagues1 prospectively reported the effect of DMG fulfillment at several time points in the donation process on the number of organs transplanted per donor from expanded criteria donors. After adjustment for age and creatinine levels, fulfillment of DMG prior to organ recovery was associated with achievement of 3 or more organs transplanted per expanded criteria donor. In standard donor criteria, DMG were measured when a catastrophic brain injury was recognized and after brain death was declared and authorization for organ donation was obtained in 10 organ procurement organizations across United Network for Organ Sharing regions 4, 5, and 6. The fulfillment of a DMG bundle was defined as achievement of any 7 of 9 goals. A positive status change for a DMG bundle during DH management is associated with a 2-fold increase in success (?4 organs transplanted per donor).5

In Italy, death by neurologic criteria is certified after a 6-hour observation period. With respect to the clinical importance of BD donor management, the Tuscany Transplant Authority implemented a monitoring schedule to strictly record DMG during the observation period. The novelty of our present investigation was that a strict hemodynamic monitoring schedule and active vigilance proved to be an efficacious clinical tool, because it allowed the achievement of all DMG in most BD donors and a tailored hemodynamic management in younger BD donors with respect to older BD donors.

Although the topic of DMG has been addressed in previous studies,1,5,16,17 this is the first investi-gation to specifically address this topic in Italy, a country where a period of 6 hours is required for death certification by neurologic criteria. Here, we documented that an active, serial hemodynamic monitoring schedule is associated with the achieve-ment of DMG in most donors.

Epidemiological changes in clinical characteristics of BD donors have been documented in various countries.18,19 During a 15-year period in a cohort of 1286 potential heart donors aged ?60 years in the Tuscany Region (Italy), we observed an increase in donor age and in the incidence of risk factors (hypertension, diabetes mellitus, and coronary artery disease), as well as a reduction in the incidence of traumatic brain injury and an increase in postanoxic encephalopathy.9 In a consecutive series of 1702 BD donors (2001-2016), we confirmed a progressive increase in donor age and incidence of donor comorbidities (diabetes mellitus and hypertension).20

In the present study, although the monitoring schedule and hemodynamic goals in older BD donors did not differ from younger BD donors, we documented that hemodynamic management is more challenging in younger BD donors, because the number of fulfilled DMG was lower in younger BD donors versus older BD donors at the beginning of the observation period. We hypothesize that this phenomenon may be due to the higher incidence of trauma in younger BD donors.

Our data strongly suggest that a strict hemodyna-mic monitoring schedule allows the achievement of DMG both in older and in younger BD donors . We confirm our previous findings that hemodynamic management in BD donors is influenced by age. A strict hemodynamic monitoring schedule of BD donors is useful to reach a constant achievement of DMG.

Limitations
There are some limitations in this study. This is a single-center investigation. All BD donors were managed by the same ICU team in a high-volume center. The present investigation assessed the effect of a hemodynamic monitoring schedule during the 6-hour observation period (accordingly to the Italian law). In our opinion the results of the present investigation can be extended to other countries, because we documented the need of a strict hemodynamic monitoring schedule for BD donors to reach a consistent achievement of DMG and the effect of age on hemodynamics in BD donors.

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