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Stretching the Cardiac Donor Ischemic Time to Beyond Six Hours: What’s the Impact?
Division of Heart and Lung Transplant, University of Alberta Hospital, Canada
Submission: March 14, 2017; Published: May 26, 2017
*Corresponding author: Rahul Chandola, Division of Heart and Lung Transplant, University of Alberta Hospital, 77 Gerrard street west, Toronto, Ontario, M5G2A1, Canada, Fax: 1 416340-4385; Email: firstname.lastname@example.org
How to cite this article: Rahul C. Stretching the Cardiac Donor Ischemic Time to Beyond Six Hours: What’s the Impact?. J Cardiol & Cardiovasc Ther 2017; 5(3): 555664. DOI: 10.19080/JOCCT.2017.05.555664. DOI:10.19080/JOCCT.2017.05.555664
An estimated 5.1 million Americans ≥20 years of age have heart failure. By 2030, the prevalence of HF is believed to increase by 25% . The International Society for Heart and Lung Transplantation (ISHLT) registers upto 3,500-4,000 heart transplants worldwide every year. The number of transplants done annually have been quite static over last 20 years despite the growing heart failure population. The shortage of donor hearts has clearly limited the number of heart transplantations . This disparity in organ (heart) demand and the ever increasing shortage of donors has led to a need to expand the donor eligibility criteria. This has led to accepting the donor organs from remote places, with the anticipated prolonged ischemic times. Although donor ischemic times up to 4-5 hours are generally acceptable, the benefits of ischemic times in excess of 240-300 minutes are still arguable . Although many studies have analyzed the impact of long ischemic times on the adult cardiac transplant outcomes in terms of survival and graft function [3-6], these studies have been limited by a relatively small number of patients with longer ischemic time ranges. As a result, the evidence evaluating the impact of prolonged ischemia time, in particular beyond 360 min in the adult population, on the heart transplant outcomes is limited. We sought to determine if prolonged ischemic times beyond 360 minutes has any impact on the short, midterm and long term survival and the postoperative outcomes of heart transplants at University of Alberta.
Data was collected from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. This database is a prospective data collection registry that collects real-time data, from three hospital sites, beginning at the patient’s referral for cardiac catheterization. Data is entered into the APPROACH registry along the patient’s clinical trajectory. The APPROACH database is a mandatory registry for all patients in all hospitals that provide cardiac catheterization, coronary revascularization and cardiac surgery in Alberta, Canada, a province of approximately 3.7 million people.
APPROACH contains demographic data as well as the presence or absence of previous myocardial infarction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, chronic pulmonary disease, elevated creatinine, renal dialysis, hyperlipidemia, hypertension, liver disease, gastrointestinal disease, and malignancy as well as indication for revascularization, extent of CAD, and procedural data including pre, peri and post operative data. Adverse events data are also recorded in the APPROACH database and reviewed through various hospital based morbidity and mortality rounds. As the data in APPROACH is used for both clinical and administrative purposes, software checks have been put into place to ensure that there are limited missing data particularly in the baseline characteristics of the patients in APPROACH. Furthermore, for the purposes of research, we annually employ a data replacement method that has been validated and ensures that the data is over 95% complete. From this database patients are followed longitudinally for the determination of short and long-term outcomes. For the purposes of this study, cardiac catheterization and/or echocardiography were used to measure EF and LVEDP.
After establishment of brain death, donor was matched with recipient for ABO blood compatibility and body weight matching. We accept donors within 20% of the recipient weight. Prospective human leukocyte antigen (HLA) matching was not used but the patients with high levels of panel reactive anti-HLA antibodies underwent a prospective cross-match. The donors are accepted preferably under age 60, especially if long ischemic times are expected. The echocardiogram should not reveal any structural heart disease, shunts (except patent foramen ovale), more than mild left ventricular hypertrophy and no significant wall motion abnormalities. Other factors
to be considered include hemodynamic stability and not more
than small to moderate doses of isotropic support. We prefer
to have coronary angiograms for patients >45 years. Coronary
angiogram should not reveal anything more than mild
coronary artery disease. The donor should not have a history
of heart disease, sepsis; known malignancy (some primary
brain tumors can be accepted). Serologies should be negative
for HIV, hepatitis B (hepatitis B s Ag), hepatitis C, HTLV and
Donors with ABO incompatibility, body weight and size
mismatch and those who do not meet brain death criteria as
outlined under policies, are excluded. Other exclusion criteria
are HIV positivity, Hepatitis B surface antigenemia, Hepatitis
C positivity, evidence of significant infection or sepsis, any
structural cardiac deformity, ventricular arrhythmias, more
than mild coronary artery disease on angiogram, poor left
and/or right ventricular function that does not responds
to relevant isotropic, preload and after load manipulations
and/or ejection fraction <45% or fractional shortening
<25%, echocardiographic evidence of significant valvular
abnormality, any acute malignancy (except some primary
brain tumors), carbon monoxide poisoning as the cause of
death and history of intravenous drug use.
Goal at this juncture is the effective treatment of potential
cardiac arrhythmias, hemodynamic instability, metabolic
acidosis and diabetes insipidus. Methyl prednisolone 10-
15mg/kg bolus, Triiodothyronine (T3) 3mcg/hr, Thyroxin
(T4) 10mcg/hr, vasopressin 0.5-4 units/hr is started and
titrated to keep SVR 850- 1250. Insulin infusion is run at
1 unit/hr and titrated to keep blood glucose levels to 120
-180mg/dl. Donor hearts were harvested from heart-beating,
brain-dead individuals. Donor hearts were perfused with 2
litres of Celsior solution at a constant pressure of 60mmHg
over a 7-10 min period and were transported immersed in
hypothermic celsior solution with normal saline at 4-8C.
Biatrial technique described by Lower and Shum way was
utilized for transplantation before year 2000 and we changed
to bicaval anastomosis technique since then [5,6].
The use of routine induction therapy is the current
standard of care for all patients undergoing cardiac
transplant at the University of Alberta, with one exception:
anti-HCV positive patients do not receive induction. Primary
agent used for induction is Rabbit anti-thymocyte globulin
(Thymoglobulin®) given at a dose of 0.75mg/kg IV in 250ml of
NS via central line to run over 12 hours twice a day for 3 days.
The daily dose is continued to maintain absolute lymphocyte
count (ALC) ≤0.2x109/L x >2 days. Tacrolimus is started every12 hours once the renal function stabilizes with the dose to
be adjusted in response to serum drug levels. Tacrolimus is
usually administered orally q12hrs (8 am and 8 pm) beginning
post-operatively when bowel sounds are present and renal
function is stable (optimally when it is approaching baseline).
The initial oral dose is 0.075mg/kg/day administered in two
divided doses. At 0-3 months, tacrolimus levels are maintained
at 8-12ug/L, at 3-6 months in the range of 6-10ug/L and 6
months onwards at 5-8ug/L.
Since 2000, azathioprine was replaced by mycophenolate
mofetil (MMF). Usual dose is 500-1500mg po BID for MMF.
Individual dosage adjustments are made according to patient
response (GI tolerance) and WBC’s. Methylprednisolone (2mg/
kg) IV is given perioperatively every 12 hours for 3 doses. First
dose is started within four hours of patient arrival in CVICU.
Prednisone is started at 1mg/kg NG/PO daily, after third dose
of methylprednisolone, if bowel sounds are present. The dose
is tapered per day to achieve 0.3mg/kg/day by 30 days posttransplant.
Tapering doses of prednisone are calculated for
each patient individually to achieve the following: 1-month
post-op: 0.3mg/kg daily, 2-months post-op: 0.2mg/kg daily,
3-months post-op: 0.1mg/kg daily and further weaning to
discontinue prednisone by 6 months.
Exclusion criteria for cardiac transplantation were
factors that adversely impact long-term survival (e.g.
cancer), increase perioperative morbidity and mortality
(e.g. pulmonary hypertension, recent pulmonary embolus,
active infection), or affect a patient’s ability to care for himor
herself (eg, untreated major psychiatric illness, recent
substance abuse). Pretransplant pulmonary hypertension,
defined as greater than 6 Woods units, was also considered
to be a relative contraindication to transplantation. Many of
these comorbidities, however, are being reevaluated, given our
favorable experience in transplanting patients once perceived
to be high risk (eg. diabetics).
All pre-operative, peri-operative and post-operative
categorical variables were compared among the two groups
by χ2 test for independence, and continuous variables (age
and body mass index) were compared by one-way analysis of
variance (ANOVA) with post-hoc Bonferroni correction. Longterm
survival after heart transplantation was estimated using
Kaplan-Meier actuarial log rank statistics for the two groups.
Multi-variate regression using Cox proportional hazards
modeling was used to determine independent risk factors for
death for all patients analyzed in the cohort.
From January 1992 through January 2012, 475 patients
underwent cardiac transplantation at University of Albertahospital. The recipients were separated into the two groups
based on length of ischemic time in minutes: group 1, moderate
Ischemic Time (MIT), 120-359 minutes (n=382); group 2
prolonged Ischemic Time (PIT), >360 minutes (n=93). All 475
recipients were included in the analysis, including patients
who died in the early postoperative period. Ischemic time was
defined as the interval from application of donor aortic cross
clamp to release of the recipient cross clamp.
The PIT group, had 69 males (74.2%) 24 females (25.8%),
had a mean age at transplantation of 50.9 years, mean BMI at
transplantation of 29.5, and a median waiting time of 19.3 days
(3.4 to 260.8 days). The MIT group, 303 males (79.3%) and 79
females (20.7%), had a mean age at transplantation of 51.4 yrs
(SD -12.8), mean BMI at transplantation of 27.2 (SD -15.3) and a
median waiting time for an organ of 10.3 days (0.8 to 57.5days).
There were no statistically significant differences between
the groups in terms of recipient gender, age, mean BMIs or
median waiting time (Table 1). The significant demographic
differences were in terms of relatively younger donors in the
MIT group (27.5% vs 12.2% donors <21 years and 23.8% vs
37.8% donors >47 years, p value-.003), frequency of prior
PCI (with recipients in MIT group having a lower incidence
of previous PCI) (18.8% vs 28.7%, p value-0.04), PIT group
having higher number of patients who were being treated
with dialysis (16.1 vs 5.1 p value-0.001.) and higher number
of patients with liver disease (11.8% vs 2.5%, pvalue-<0.001).
As would be expected, the PIT group had significantly longer
pump times (355.4 vs 194.8 minutes, p value <0.001.) and
associated cross clamp times.
The incidence of postoperative bleeding was significantly
higher in PIT group (13.8% vs 7.8%, p value.05) (Table 2).
Neurological complications were also quite higher in the PIT
group (18.4% vs 7.6%, p value-0.002). Specifically 6.5% of
the patients in PIT group had permanent stroke as opposed
to 0.8% in the MIT group (p value-<0.001). 2.2% patients in
the PIT group had transient stroke as compared to 0.8% in
the MIT group (p value <0.001). 3.2% of the patients stayed
in continuous coma as opposed to 0.8% of the patients in
MIT group (p value <0.001). Incidence of sternal wound
infection, duration of ventilation, incidence of postoperative
renal dysfunction, incidence of dialysis requirement, cardiac
tamponade, cardiac rejection during primary hospitalization
were similar between both the groups.
Univariate analysis, identified a significant difference
between PIT and MIT groups in 30 day (23.7% and 8.6%,
p<0.001) and 6 month mortality (24.7% and 9.9% p <0.001).
Long term survival between groups was also significantly
different (p=0.04) between both groups (Figure 1) Cox
proportional hazards models were used to test the independent
effect of ischemic time on mortality while controlling for pre,
peri and post operative variables that were significantly
associated with ischemic time (Table 3).
In model 2, following adjustment for donor age and pump
time in minutes, the hazard ratio was 1.19 (95% upper and
lower CI 0.76 & 1.85.) (p value=0.45).
Finally in model 3, we adjusted for neurological
complications. The hazard ratio was 1.13 with 95% upper and
lower CI of 0.72 and 1.77(p value-0.60) (Table 4).
With the ever expanding heart failure population in need of
heart transplantation and a shortage of donor organs, cardiac
centers often have to accept organs from far off places in an
effort to increase the donor pool, leading to prolonged ischemic
times. There has been a lot of confusion in regards to effect
of donor ischemic times on transplant outcomes. Some of the
studies did not find any relationship between ischemic time
and survival [7-9]. Some multi-institutional studies, on the
other hand, found early mortality after transplantation to be
affected by prolonged donor ischemic times [10-12]. There were
few other studies that found an inverse relationship between
donor ischemic times and survival outcomes . Mullen et
al.  from our institution compared the groups with donor
ischemic times lesser and greater than 4h and did not find any
difference in the 30-day, 90-day or actuarial survival between
the groups. The use of allograft with ischemia times greater
than 4-5h has been reported by some investigators with prolonged ventilation, prolonged ICU stay, prolonged hospital
stay, increased graft dysfunction, and higher morbidity and
early mortality [15-20]. It was interesting to find, contrary to
previous studies, there wasn’t significant difference between
the two groups in terms of need for prolonged ventilation
(40.3% in MIT vs 46.2% in PIT, p value-0.30), length of ICU
stay (11.4 vs 11.1 days, p value-0.88) or duration of hospital
stay (26.3 vs 26.7 days, p value-0.92). Interestingly, the length
of isotropic support also did not differ significantly between
both the groups. The incidence of renal failure and the number
of patients requiring dialysis were also not statistically
different. 30 day biopsy-proven acute cellular rejection grade
3A or greater was not statistically different in both the group.
15.7% of the patients in MIT group had grade 3A or greater
acute cellular rejection compared to 12.9% in the PIT group
(p value-0.50). There was a difference in the incidence of
postoperative bleeding in both the groups. We found 7.4%
incidence of take backs for postoperative bleeding in MIT
group as compared to 13.8% in the PIT group (p value-.05).
This is possibly a result of increased cardiopulmonary bypass
times in PIT group (mean of 355.4 minutes vs 194.8 minutes,
p<.001) leading to coagulopathy and platelet dysfunction,
accounting for increased take backs in this group.
We also found a significantly high incidence of neurological
adverse events in the PIT group (18.4% vs 7.6%, p value-0.02).
Specifically 6.5% of the patients in PIT group had permanent
stroke as opposed to 0.8% in the MIT group (p value-<0.001).
2.2% patients in the PIT group had transient stroke as compared
to 0.8% in the MIT group (p value <0.001). 3.2% of the patients
stayed in continuous coma as opposed to 0.8% of the patients
in MIT group (p value <0.001). Interestingly, the majority of
patients with permanent stroke had ischemic cardiomyopathy
as the etiology of heart failure. It is known that patients with
ischemic cardiomyopathy have significant atherosclerotic
disease and it is possible there was a preexisting burden of
cerebrovascular atherosclerotic disease that could have led
to increased incidence of strokes in this group as suggested
by some earlier studies . We could not find any other
specific differences between the two groups of patients with
strokes because of the relatively small number of patients with
On univariate analysis, survival outcomes were quite
significantly different between both the groups. In PIT group,
the 30 day mortality was 23.7% vs 8.6% for the MIT group.
The 6 month mortality was 24.7 for PIT group and 9.9% for the
MIT group (p value <0.001). We then used the Cox proportional
hazards models to test the independent effect of ischemic time
on mortality while controlling for pre, peri and post operative
variables that were significantly associated with ischemic time.
Both the groups (MIT and PIT) were adjusted for heart failure,
prior PCI, preoperative dialysis, preexisting liver disease and
donor age in four quartiles. After adjusting the donor ischemic
time for these variables, the survival outcomes were not statistically significant (The hazard ratio was 1.19 with 95%
upper and lower CI of 0.76 and 1.85, p value-0.45, model 2).
When both groups were further adjusted for postoperative
neurological outcomes, the hazard ratio decreased further
1.13, p value-0.60.
In this study, higher proportions of patients in PIT group
have had coronary intraluminal stenting procedures in the past
(28.7 vs 18.8, p value-0.04). This could be because this group
had more advanced cardiac disease and ischemic burden. The
PIT group also had significantly more number of patients on
dialysis (16.1 vs 5.1, p value<0.001) and Pretransplant liver
dysfunction (11.8 vs 2.5, p value <0.001) suggesting that they
were in advanced stages of cardiomyopathy with multiorgan
dysfunction, thereby implying more sicker patients comprising
this group. We also had older donors in the PIT group. This
was statistically significant (12.2% in PIT vs 27.5% donors
in MIT <21 years and 37.8 PIT vs 23.8% MIT donors >47
years, p value-.003). This is probably because even the older
donors were accepted for sicker recipients, considering the
urgently required donor organ in the PIT group. The duration
of cardiopulmonary bypass was longer in patients receiving
a graft with long ischemic time (mean of 355.4 minutes
for PIT vs 194.8 minutes for MIT group, p<.001). This was
because of planned longer reperfusion time in patients with
prolonged ischemic times. Although univariate analysis did
show significant mortality differences, when we controlled
both the groups for these above discussed variables(prior PCI,
pretransplant dialysis, pretransplant liver dysfuction, donor
age and duration of cardiopulmonary bypass), there were no
significant differences in survival outcomes between the two
groups [( hazard ratio was 1.19(model 2)]. The decision to
accept the donor hearts from far off places with anticipated
long ischemic times should be a thoughtful process based on
detailed evaluation of recipient and donor specific factors.
Variables such as recipient co morbidities specially renal
dysfunction and hepatic dysfunction, donor age, donor
isotropic use and left ventricular function should be considered
in the decision making process.
Prolonged donor ischemic time in itself should not be
the deciding factor in not accepting the donor heart, as the
postoperative and survival outcomes are not much different
in patients with prolonged ischemic times. Our series also
indicate that donor hearts with prolonged ischemic times
should not be implanted to patients with advanced UNOS
status and sicker hearts along with other organ system
dysfunction, as indicated by some of the other studies [10-12].
In our series, the difference in survival outcomes in univariate
analysis was evident because of more sick patients with
multiorgan dysfunction in the PIT group but as both the groups
were controlled for other variables associated with prolonged
ischemic times, the survival outcomes were no different
between the groups.
The largest single-center series to evaluate the effect
of prolonged donor ischemic times on transplant outcomes
(in adult population) evaluated donor ischemic time up to
approximately 5 hours (295.5±37.1 minutes). Prolonged DIT
was evaluated for up to 5 hours in a cohort of 17 patients
. This study did not analyze whether or not DIT >6 hours
adversely affected survival. The evidence evaluating the
impact of prolonged ischemia time in particular beyond
360min, on the short and long term outcomes after heart
transplantation, is limited and to our knowledge, has not been
tested in adult cardiac transplantation. In our study, we have
shown that even extending DIT beyond 6hrs did not result
in statistically significant differences in survival outcomes.
Although univariate analysis did show mortality differences,
there were no differences in survival outcomes between the
two groups after controlling for other pre, intra and post
operative variables that were significantly associated with
ischemic time. This study signals that in view of the current
donor shortage, donor hearts associated with anticipated
prolonged ischemic times should be considered as an option to
expand the donor pool.
A limitation of this study is that the data were collected
in a clinical prospective registry and were observational in
nature. However we believe that our study given the size of
the sample and the extent of the data collected on all patients
adds to the literature in this area. Another limitation is the use
of death as the only long-term outcome for hazards modeling,
other surrogate end-points including rates of re-admission to
hospital, and progression of symptoms would all be valuable
outcomes to measure.
In summary, we can conclude that with the current
techniques of myocardial preservation, modified reperfusion
and the detailed evaluation of recipient and donor factors on a
case by case basis, donor hearts with ischemia time greater than
6 hours provide comparable postoperative outcomes and short,
intermediate and long term survival results. The prolonged
ischemic times, in itself, should not be a contraindication for
OHT. Rather a thoughtful donor and recipient matching should
be done and consideration should be given to the recipient
UNOS status and comorbidities specially renal and hepatic
dysfunction, donor age, donor cardiac function and stability.