Our search identified 17,877 records and we assessed 54 full-text articles for exclusion by screening of titles, duplicates and abstracts. Twenty-two RCTs were included in the final analysis (PRISMA, Fig. 1). Twenty-one studies were published in English, and one French study was translated by a native speaking researcher (DM).
The 22 RCTs included a total of 3432 donors. Details of the included studies are shown in Table 1. Twenty-one RCTs were conducted in high income countries across Europe and North America, with one study conducted in Iran (12, 13). Five RCTs evaluated systemic thyroid hormone therapy, four used systemic steroids and two studies used a combination of steroids and thyroid hormone. Further systemic treatments included albuterol, desmopressin, dopamine, protocolised fluid therapy, therapeutic hypothermia, naloxone, phentolamine, simvastatin, vitamin C or a protocolised ventilation strategy and were studied by one trial each. Almost one third (7/22) of all studies focused primarily on kidney transplantation and a further of eight studies were aimed at optimising donor factors in critical care. Four studies primarily studied lung transplantation, two studied liver transplantation and only one study was primarily aimed at heart transplantation.
Table 1
Details of included studies, sorted by year of publication
Year of publication
|
Author
|
Primary organ of Interest
|
Intervention
|
Number of randomised donors
|
Specified primary end point
|
Also published in as follow up /nested or substudy
|
1991
|
Mariot (19)
|
Donor stability
|
(1) T3 1 mcg/ml and hydrocortisone 50 mg/ml; (2) placebo
|
40
|
Haemodynamic stability
|
|
1998
|
Guesde (48)
|
Kidney
|
(1) Desmopressin 1 mcg bolus every 2 hours; (2) Desmopressin only
|
97
|
Serum Creatinine, Delayed Graft Function
|
|
2000
|
Polyak(49)
|
Kidney
|
6 arms :
(10 mg phentolamine/50kg of phentolamine mesylate vs. 20 mg H/50 kg hydralazine vs. standard care) with cold stage vs. machine perfusion
|
150
|
(1) renal flow characteristics, (2) DGF
|
|
2005
|
Perez-Blanco(20)
|
Donor stability
|
(1) 1 mcg/kg T3 intravenous bolus, followed by 0.06 mcg/kg per hour for 270 min, to max of 100 mcg ;
(2) Usual care
|
52
|
Donor stability and organ biochemistry
|
|
2008
|
Kotsch (50)
|
Liver
|
(1) 250 mg Methylprednisolone bolus and 100 mg/h afterwards;
(2) Usual care
|
100
|
Liver biochemistry, cytokine levels
|
Pratschke 2006(18)
|
2008
|
Venkateswaran (51)
|
Lung
|
(1) Methylprednisolone 15 mg/kg (1g);
(2) T3 0.8 mcg/kg bolus following by infusion (0.113 mcg/kg/hr);
(3) Methylprednisolone + T3;
(4) (4) Placebo
|
80
|
Difference between PaO2 and FiO2 prior to organ retrieval (2008);
Difference in cardiac index (2009)
Expression of mRNA on T3 responsive genes (2010)
|
Venkateswaran 2009(52)
James 2010(22)
|
2009
|
Schnuelle (53)
|
Kidney
|
(1) Dopamine 4 mcg/kg/min;
(2) No dopamine
|
264
|
Delayed Graft Function
|
Benck 2011(54)
Benck 2018(55)
Schnuelle 2017(56)
|
2010
|
Kainz (57)
|
Kidney
|
(1) 1 g Methylprednisolone; (2) 0.9 % Saline
|
306
|
DGF (Kainz 2010) and 5-year graft survival (Reindl-Schwaighofer 2019)
|
Reindl-Schwaighofer 2019 (14)
|
2010
|
Mascia(23)
|
Lung
|
(1) conventional ventilatory strategy;
(2) protective ventilatory strategy
|
118
|
Number of potential donors meeting eligibility
|
|
2012
|
Amatschek(25)
|
Liver
|
(1) single injection of 1000 mg methylprednisolone;
(2) placebo (0.9% saline) injection between 6 and 3 h before organ recovery
|
90
|
Concentration slope of transaminase within 1st week after transplant
|
|
2013
|
Sharpe(16)
|
Donor factors
|
(1) Oral T4 (2 mcg/kg); (2) intravenous
|
32
|
Percentage of study time donors required inotropic support
|
|
2014
|
Ware (42)
|
Lung
|
(1) Aerosolized albuterol (5 mg 4-hourly);
(2) Placebo
|
506
|
Change in oxygenation from enrolment to organ procurement
|
|
2015
|
Niemann(58)
|
Kidney
|
(1) Hypothermia (34–35 degrees) for 4 hours;
(2) Normothermia (36.5–37.5) for 4 hours
|
370
|
Delayed Graft Function
|
|
2015
|
Orban(12)
|
Kidney
|
(1) 600mg of IV N-Acetylcysteine (1 hr prior to and 2 hours post cerebral angiography);
(2) No N-Acetylcysteine
|
217
|
Delayed Graft Function
|
|
2015
|
Kazemi (13)
|
Donor factors (2015), liver (2016)
|
(1) 100 mg/kg dose of vitamin C 6 hours before procurement followed by vitamin C infusion (100 mg/kg) over the 6 hours;
(2) standard care
|
40
|
(1) donor IL-6, donor TNF-alpha gene expression; (2) recipient liver function (2015)
Inflammatory cytokine levels (2016)
|
Sisakth 2016(26)
|
2015
|
Al-Khafaji(59)
|
Donor factors
|
(1) Protocolised fluid therapy;
(2) Usual care
|
556
|
Number of organs transplanted per donor
|
|
2018
|
Jafari(60)
|
Kidney
|
(1) Methylprednisolone 15 mg/kg day;
(2) Methylprednisolone 15 mg/kg/day + 100 mg 2-hourly;
(3) Usual care
|
51
|
Expression of inflammatory mediators and toll-like receptors
|
|
2018
|
Holmstrom (61)
|
Heart
|
(1) 80 mg simvastatin; (2) Control
|
84
|
Recipient TnT (or Trop-I, or CK-MB)
|
Nykanen 2019(27)
|
2019
|
Dhar(17)
|
Donor factors
|
(1) T3 4mcg bolus then 2 mcg/h;
(2) T4 20mcg bolus, then 10 mcg/h
|
37
|
LVEF (Echocardiogram)
|
|
2019
|
Dhar(62)
|
Lung
|
(1) Naloxone 8 mg;
(2) 0.9% Saline
|
199
|
Change in fraction of inspired oxygen ratio from baseline to final arterial gas
|
|
2019
|
Frenette(62)
|
Donor factors
|
(1) Levothyroxine 20 mcg bolus followed by 20 mcg/hr infusion;
(2) Placebo
|
15
|
Feasibility outcomes
|
|
2020
|
Dhar(28)
|
Donor factors
|
(1) Levothyroxine 20 mcg bolus followed by 10 mcg/hr infusion;
(2) Placebo
|
28
|
LVEF (Echocardiogram)
|
|
|
|
|
total number of donors
|
3432
|
|
|
Overview of included 22 RCTs including year of publication, primary target of each RCT, details of intervention and comparator and number of randomised donors. For each RCT the listed primary outcome as reported by each study is given. Information about nested, follow-up and/or sub-studies referring to the same donor cohort is also provided. |
Risk of bias in included studies
All twenty two trials were assessed for risk of bias, with eight at high risk of bias (Fig. 2). Only one trial was at low risk of bias(14). Approximately a quarter of all studies were at high risk of reporting and performance bias. Further details of risk of bias assessments can be found in Additional file 3.
Synthesis of results
Multitude of reported outcomes across studies
Eight RCTs (36.3%) aimed to study the effects of the intervention on outcomes directly relevant during the donor management period in ICU. Amongst this group, named outcomes included: vasopressor/inotrope requirements, echocardiography parameters, number of transplanted organs, routine biochemical (e.g. thyroid function) or inflammatory (e.g. TNF-alpha) markers, or an assessment of haemodynamic stability. The remaining fourteen studies identified one transplanted organ as their main target, with the kidney (n = 7) as the most studied graft, followed by lungs (n = 4), liver (n = 2) and heart (n = 1). Amongst each of these, there was variation of the exact outcomes measured. Effects of treatments on pancreas were only studied in one trial (15), whilst simultaneous kidney and pancreas and intestinal transplants were not studies in any of the trials.
Renal outcomes included post-transplant serum creatinine levels, presence of delayed graft function (DGF, defined as need for dialysis in first week post-transplant), primary non-function or biopsy-proved graft failure. Similar variability in organ outcomes was seen for studies focusing on the liver (post-transplant biochemical assessment versus record of graft function) or heart (echocardiogram assessment versus record of graft function) transplantation. All four studies of lung outcomes chose graft function before retrieval as their main outcome measure, whether by recording the number of lungs available for transplant or by reporting pre-specified outcomes such as final arterial blood gas or FiO2 prior to organ procurement (14, 16–18). One study of lung transplants reported one year survival of recipients of other organs, although no record of graft function or survival was made (16). The duration of follow up also significantly varied: ranging from reporting only outcomes before procurement (during duration of donor management) to trials with 5-year follow up, often published separately.
Outcomes by studied intervention
All included RCTs administered systemic treatment(s) to the randomised donor. Eleven studies studied the effects of steroids and/or thyroid hormone. The reported outcomes were grouped into outcomes affecting the major transplanted organs (kidney, liver, heart, lungs) or donor factors (such as factors haemodynamic stability or number of organs accepted for procurement). Figure 3 demonstrates that nearly all studies (21/22) of systemic treatments do not report outcome data across all the outcome domains. Only one study comparing ventilation strategies of the donor covered all outcome groups, albeit only reporting the recipient survival for each of the major transplanted organs (14). Overall, the kidney or donor factor outcome groups were most often included, with each contributing to seven intervention types. DGF was the most common reported renal outcome (6/7 studies), whilst donor factors included a variety of different outcomes such as number of transplanted organs, inotrope or vasopressor requirement, left ventricular ejection fraction or cardiac index.
Outcomes by studied primary organ
Many of the selected outcomes depended on the primary target, e.g. kidney or physiological measurements in ICU. Studies focusing on kidney or heart transplantation were more likely to provide a more comprehensive assessment of other organs, as displayed in Fig. 4. Early outcomes – defined as within 30 days of transplantation – more commonly reported surrogate outcomes such as changes in laboratory markers or echocardiographic function. Trials of interventions aimed at donor stability only rarely assessed organ specific function or outcomes – such as pre-transplant lung function, biochemical liver function assessment or mention of primary graft dysfunction for cardiac allografts. Furthermore, none of the donor stability RCTs assessed any long-term recipient or graft outcomes; therefore the long term effects of systemic treatment administered to nearly a quarter of all donors (23.3%, 800/3432) have not been collected by included trials. Organ-focused trials included long-term follow up of either one, three or five years of graft survival and between six months and three years of recipient survival as shown in Fig. 5. Only one study reported the incidence of long term post-transplant complications relating to immunosuppression, such as post-transplant lymphoproliferative disease (15). More specific measures of long term graft function after transplantation (such as creatinine or liver function tests) were only assessed in two studies (19, 20). Organ specific rejection at 30 days and 3 months was studied in two trials aimed at the kidney (21, 22). Rejection episodes within 6 or 3 years follow up were reported in both trials aimed at the liver (20, 23). No studies reported on health-related quality of life in recipients of transplanted organs.
Exploratory analysis - Donor and recipient age, sex and ethnicity
In the UK, the NHS Blood and Transplant 2018-19 report describes the characteristics of 962 donors during that period: on average 51 +/- 16 years of age, mostly white (865/962, 90%) with an equal distribution of male (49%) and female (51%) donors. Only a minority of donors were reported as Asian (4%), Black (2%) or ‘other ethnicity’ (4%) (3). All included studies provide the age of the included donors, however the trial donor population is on average a decade younger than the average UK donor; In eight studies the average donor age was below 40 years and in 12 studies the average age was under 50 years. Donor sex information is available for n = 2669 donors in total (20 studies) with 1596 (59.8%) male and 1073 (40.2%) female donors. Some individual studies, however, had groups more heavily skewed towards male donors (15, 17, 24, 25). Donor ethnicity was reported by three studies only(16, 17, 26), with two further studies (27, 28) reporting the percentage of Afro-American donors in the two groups. The three studies which provide a breakdown of donor ethnicity describe a study population of between 60–80% white donors. Nine studies provide sex or age information for the recipients of the donated organs, whilst information on recipient ethnicity is not reported by any of the included trials.