Is there data using alprostadil in the immediate post-liver transplant period? If so, ideal dose and duration of therapy? Any reports of apnea?

Comment by InpharmD Researcher

The use of prostaglandins including alprostadil to reduce ischemic injury after liver transplantation is currently not substantiated by clinical evidence. Some studies suggest prostaglandins might reduce the risk of acute kidney failure requiring dialysis in liver transplant patients, but there is no evidence suggesting a reduction in risk of death, primary non-function of the allograft, or liver re-transplantation. We included doses and duration of prostaglandin therapy used for the clinical studies reviewed for completeness. There were no reports of apnea in the reviewed clinical studies.
Background

Appropriate use of prostaglandins to reduce ischemic injury after liver transplantation is not well defined in liver transplant clinical guidelines.

A 2011 Cochrane review assessed the benefits and harms of prostaglandin E1 (alprostadil) or prostaglandin E2 in adult liver-transplanted patients. The review included 10 trials with the majority carrying high bias. There was no significant effect of prostaglandins on all-cause mortality (37/298[12.4%] in prostaglandin group versus 47/312[15.1%] in control group; OR 0.84, 95% CI 0.53 to 1.37; I(2) = 0%), on primary non-function of the allograft (8/238 [3.4%] versus 16/250[6.4%] ;OR 0.55, 95% CI 0.23 to 1.33; I(2) = 0%), and on liver re-transplantation (12/161[7.5%] versus 14/171[8.2%]; OR 0.99, 95% CI 0.44 to 2.25; I(2) = 0%). Prostaglandins seemed to significantly decrease the risk of acute kidney failure requiring dialysis (13/158[8.2%] versus 34/171[9.9%]; OR 0.37, 95% CI 0.18 to 0.75; I(2) = 0%). There was no significant increase in the risk of adverse events with prostaglandins. The authors concluded there is no evidence that the administration of prostaglandins to liver transplanted patients reduces the risk of death, primary non-function of the allograft, or liver re-transplantation. Prostaglandins might reduce the risk of acute kidney failure requiring dialysis, but due to the lack the quality of the evidence, is considered only moderate due to the high risk of bias in most of the included trials. [1]

The following is a summary of the usage (dose and duration) of prostaglandin E1 in clinical studies of liver transplantation more than 20 years old. For detailed clinical summaries of recent trials, please see Tables 1 and 2 in the literature review section.

Prostaglandin E1 (PGE1, Prostin-VR, Upjohn) has been given as a continuous infusion through a central venous catheter, starting at the time of surgery or immediately after its completion. Five hundred micrograms were diluted in 100 mL of 5% dextrose in water, and started at a dose of 0.2 µg/kg per hour, which was gradually increased to 0.6 µg/kg per hour and maintained there for the next 5 to 7 days unless hypotension or cardiovascular instability necessitated an adjustment. [2]

Prostin VR infusion has been used at a rate of 10 ug/h before the anhepatic phase and was increased by 10 ug/hr every 30 minutes until a maintenance level of 40 ug/h had been reached. [3], [4]

A study utilized an initial infusion rate of 25 ug/kg per hour in patients receiving PGE1. Increases in increments of 2.5 mL/h every 10 minutes up to a maximum infusion rate of 10.0 mL/h. Infusion was continued for a total of 7 days or until the patient was transferred out of the intensive care unit (ICU), whichever occurred first. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there data using alprostadil in the immediate post-liver transplant period? If so, ideal dose and duration of therapy? Any reports of apnea?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

The Use of Prostaglandins in the Immediate Postsurgical Liver Transplant Period

Design

Clinical study

N=40

Objective

To demonstrate prostaglandin's therapeutic role in which alprostadil was administered only after the appearance of posttransplant liver dysfunction

Study Groups

Group 1 (n=24)

Group 2 (n=16)

Inclusion Criteria

Liver transplant patients who showed signs of precocious liver dysfunction based on an analysis of routine laboratory data.

Exclusion Criteria

Not explicitly stated. 

Methods

Group 1 is comprised of patients with macroscopic signs of hypoperfusion or lacking bile production at the end of the operation, whereas Group 2 is of patients with an increase in transaminases and fall in biliary production in the first 24 hours postsurgery. Each group was administered alprostadil (PGE1; 0.01 µg/kg/min to the maximum plateau of 0.06 µg/kg/ min). PGE1 was administered intravenously starting at 0.01 µg/kg/min and increasing the dosage progressively by 0.01 to 0.03 µg/kg/min until a maximum of 0.06 µg/kg/min was reached over a span of 6 hours as tolerated. 

Duration

Overall treatment = 6 hours

Follow-up: every 6 hours for 48 hours (T0 - T8)
Outcome Measures

Mean values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), activated thromboplastin time-ratio (aPTT-r), international normalized ratio (INR), bilirubin, creatinine and plasma nitrogen, PaO2/FiO2 at the start of the treatment and every 6 hours for 48 hours, and daily diuresis. 

Baseline Characteristics

  

Liver transplant patients

(n=40)

                

Age, years

 50.8                

Male

 28 (70%)                

Clinical baseline characteristics between the groups were not provided.

Results

 

Liver transplant patients^

(n=40)
  T0 T1 T2 T3 T4 T5 T6 T7 T8

AST (UI/L)

 1641±1470 1621±1597* 1437±1487** 1307±1482* 1374±1583* 1218±1376** 1098±1640** 871±1120** 642±699**

ALT (UI/L)

 1300±1070 1400±1161 1488±1377 1541±1580 1633±1738 1589±1630 1460±1395 1394±1321 1291±1238

Bilirubin (mg/dL)

 6.2±4.2 6.1±4.1 5.7±4.3 5.9±4.5 6.1±4.4 6.4±4.6 6.5±4.8 6.7±4.8 6.8±4.6

INR

 1.95±0.81 1.93±1.05* 1.82±0.86** 1.77±0.7** 1.79±0.81** 1.74±0.78** 1.64±0.61** 1.59±0.5** 1.56±0.45**

aPTT ratio

 1.23±0.21 1.14±0.17** 1.10±0.17** 1.10±0.16** 1.09±0.15** 1.08±0.13** 1.08±0.15** 1.07±0.18** 1.07±0.17**

Creatinine (mg/dL)

 1.23±0.62  1.26±0.58 1.22±0.6 1.17±0.61* 1.15±0.62** 1.15±0.64 1.11±0.65* 1.10±0.62** 1.10±0.61**

Urea (mg/dL)

 70±39 75±41** 81±44** 82±47** 88±50** 92±54** 97±59** 99±62** 102±65**

PaO2/FiO2 ratio

 459±203 406±148 386±159* 356±133* 346±159** 352±170* 315±123** 321±124* 356±158**

^Given the trends in the mean values of the outcome measures observed in groups 1 and 2 were not significantly different, the two cohorts were considered as a single population of treated patients.

* P< 0.05

** P< 0.001 

Adverse Events

Common Adverse Events: Not disclosed.

Serious Adverse Events: Not disclosed.

Percentage that Discontinued due to Adverse Events: Not disclosed.

Study Author Conclusions

Prostaglandins used in the manner in our study showed a significant efficiency to improve liver dysfunction after transplantation.

InpharmD Researcher Critique

The results showed a significant decrease in AST, INR, aPTT-r, and creatinine clearance (P< 0.05), while there was a significant rise in the blood urea nitrogen (P< 0.001). The PaO2/FiO2 ratio showed a significant decrease (P< 0.001) in pulmonary vasodilatation. Even though this study evaluates the use of alprostadil during an immediate postsurgical liver transplant period, this study has several limitations including a lack of an internal control group, a small sample size, and a potentially underrepresented population. The study is likely to be underpowered to detect the true difference given its small sample size. 
References:

Gatta A, Dante A, Del Gaudio M, et al. The use of prostaglandins in the immediate postsurgical liver transplant period. Transplant Proc. 2006;38(4):1092-1095. doi: 10.1016/j.transproceed.2006.03.046.

 

Perioperative Prostaglandin e1 Infusion in Living Donor Liver Transplantation: A Double-Blind, Placebo-Controlled Randomized Trial

Design

Randomized, double-blind, placebo-controlled trial

N=99

Objective

To evaluate the role of perioperative PGE1 infusion in Live Donor Liver Transplantation (LDLT)

Study Groups

Perioperative PGE1 infusion (n=49)

Placebo (n=50)

Inclusion Criteria

All consenting patients over 18 years of age undergoing LDLT during the recruitment period.

Exclusion Criteria

Patients undergoing ABO-incompatible liver transplantation, Deceased Donor Liver Transplantation (DDLT) or Auxiliary Partial Orthotopic Liver transplantation (APOLT); and patients with acute liver failure (ALF) who were already on PGE1 infusion at the time of transplantation.

Methods

Eligible patients were randomized to receive either 10 mcg/ml PGE1 (Alprostadil) at the rate of 0.25 mcg/kg/hour or normal saline one hour after reperfusion. The dosage of the infusion could be reduced if there was progressive hypotension requiring the initiation of vasopressors of an increase in the dose of existing vasopressors. The infusion was terminated at 96 hours after initiation, irrespective of the number of cessations. 

Duration

Recruitment period: January 2012 to December 2013 (24 months)

Infusion duration: 96 hours

Outcome Measures

Primary endpoint: Early Allograft Dysfunction (EAD).

Secondary endpoints: Postoperative liver function and renal function parameters, Acute Kidney Injury (AKI), hepatic artery thrombosis, postoperative bleeding, overall mortality and posttransplant hospital stay. 

Baseline Characteristics

  

Perioperative PGE1 infusion

(n=49)

Placebo

(n=50)

 p-Value

Recipient age, years

 42.69 ± 11.78 43.68 ± 12.47 p=0.94 

Male

41 (83.67%) 47 (94.00%) p=0.19

Etiology

Chronic liver disease (CLD)

Acute liver failure (ALF)

 

42 (85.71%)

7 (14.28%)

 

47 (94.00%)

3 (6.00%)

 p=0.20 
Serum bilirubin, mg/dl 11.49 ± 10.79 8.42 ± 7.71 p=0.18 
Serum Creatinine, mg/dl 1.046 ± 0.31 1.045 ± 0.26 p=0.98 
INR 2.83 ± 1.73 2.68 ± 1.47 p=0.57
MELD 24 (14-44) 21.5 (9-41) p=0.50

Graft type

Right lobe (with MHV)

Left lobe

 

47 (95.92%)

2 (4.08%)

 

48 (96.00%)

2 (4.00%)

 -

Intraoperative blood loss, ml

 4081.63 ± 1677.38 4084.00 ± 2450.68 p=0.54

Duration of surgery, min

 641.02 ± 75.25 637.24 ± 83.87 p=0.81

Results

Endpoint

Perioperative PGE1 infusion

(n=49)

Placebo

(n=50)

p-Value

EAD

 11 (22.4%)  18 (36%) p=0.21

Overall mortality 

 5 (10.1%) 10 (20%)  p=0.28

AKI

 4 (8.2%) 14 (28%) p=0.02

Need for renal replacement therapy

2 (4.08%) 7 (14.00%) p=0.17
Hepatic artery thrombosis 1 (2.0%) 1 (2.0%) p=1.00
Primary non-function 1 (2.0%) 2 (4.0%) p=1.00
Postoperative bleeding 4 (8.2%) 7 (14.0%) p=0.55
Post transplant in-hospital stay, days 20.81 ± 5.22 20.82 ± 6.72 p=0.52

Adverse Events

No noticeable adverse effects are attributable to the infusion.

Study Author Conclusions

Perioperative PGE1 infusion reduces the incidence of post-transplant renal dysfunction in patients undergoing LDLT; thus, the routine perioperative use of PGE1 in patients undergoing LDLT is recommended. 

InpharmD Researcher Critique

The incidence of EAD was lower in the PGE1 arm, but the difference did not reach statistical significance. The incidence of AKI was significantly lower in the PGE1 arm; however, it is merely a secondary endpoint that is truly exploratory. Generalizability may be limited given its small sample size pooled from a single institution located in India. 
References:

Bharathan VK, Chandran B, Gopalakrishnan U, et al. Perioperative prostaglandin e1 infusion in living donor liver transplantation: A double-blind, placebo-controlled randomized trial. Liver Transpl. 2016;22(8):1067-1074. doi: 10.1002/lt.24479.