Actions and Uses

• Prostaglandins (PGs) belong to an ubiquitous class of chemicals known as eicosanoids. They are found in virtually every tissue in the body and have a very wide spectrum of biological activities.
• Eicosanoids are derivatives of arachidonic acid, a polyunsaturated fatty acid with 20 carbon atoms). The term eicosanoids includes the family of prostaglandins (PGs), prostacyclin, thromboxanes, and leukotrienes. The PGs are divided in different families depending on their structure, each designated by a letter (A, E, F, G, H, or I). In addition to this letter, each individual prostaglandin carries a digit that indicates the number of double bonds in its fatty acid side chain. For example, alprostadil (PGE1) belongs to the E family and has only one double bond in its side chain.
• PGs play an important role in platelet aggregation and hemostasis (blood clotting).
• Most PGs have a marked vasodilator effect.
• PGs act as local chemical messengers and modulate the release and the action of hormones and neurotransmitters.
• PGs play an important role in multiple reproductive processes.
• PGs are somehow involved in the immune system's response to injury and infection.
• Some PGs including PGE₁ are thought to inhibit T cell mediated cytotoxicity and interleukin 2 (IL-2) driven T cell proliferation. These actions may help in the prevention of acute allograft rejection (see Moran et al NEJM '90; 322:1183).

Alprostadil (PGE₁) is a strong vasodilator, and inhibits leukocyte adhesion and platelet aggregation. It is also thought to have a direct cytoprotective effect, presumably by suppressing production of the proinflammatory cytokines (IL-6 and IL-8)⁷.

Based on this wide array of actions, PGs have been tried in solid organ transplantation. Specifically, it is hoped that the administration of PGE₁ to the liver transplant recipient in the immediate posttransplant period would help prevent or ameliorate:

• Ischemic reperfusion injury of the liver.
• Primary non-function (PNF).
• Renal hypoperfusion /dysfunction.
• Acute hepatocellular rejection?

Clinical Studies

There have been four significant studies that dealt with PGE1 in liver transplantation:

• Greig et al¹ (neither randomized nor controlled):

• 10 pts received PGE₁ within 4 -34 hrs of transplantation, titrated up to a max of 0.6 µ g/kg/hr, and continued for 4-7 days.
• 8 of the 10 pts had decreases in AST, PT, aPTT, and increases in coagulation factors V & VII.
• Graft survival was 80% in treated grp (n=10) and 17% in untreated grp (n=6).
• Patient survival was 90% in treated grp (n=10) and 33% in untreated grp.
• Henley et al² (double-blind, randomized, placebo-controlled)

• 78 pts received PGE₁ immediately after restoration of blood flow. titrated up to a max of 40 µ g/hr, and continued for 21 days.
• There were no significant differences in the incidence of acute rejection or PNF. However the treated grp spent 40% fewer days in the ICU and 23% less time in the hospital during transplant admission. There was also reduced need for dialysis in this grp.
• Klein et al³ (double-blind, randomized, placebo-controlled)

• 58 pts received PGE₁ immediately after restoration of blood flow. titrated up to a max of 1 µ g/kg/hr, and continued for 7 days.
• There were no significant differences in graft or pt survival.
• There were no significant differences in the incidence of PNF.
• There were no significant differences in the incidence of severe renal dysfunction (Scr twice baseline and urine flow < 0.5 mL/kg/hr for 12 hrs. However, Scr and BUN were significantly lower in the treated grp.
• The median length of ICU stay was markedly shorter in the treated grp (4 vs 10 days).
• Giostra et al⁴ (neither randomized nor controlled)

• 21 pts received PGE₁ immediately after restoration of blood flow. titrated up to a max of 0.6 µ g/kg/hr, and continued for 4 days.
• There were no significant differences in overall graft or pt survival.
• The treated grp had significantly lower AST levels.
• The treated grp had significantly lower incidence of steroid-resistant rejection

Available As

Injectable: 500 µg/mL (1 mL)

Dose & Administration

• Alprostadil (PGE₁) is prepared as 500 µg/100mL of D5W (final concentration = 5 µg/mL). However, it is also compatible with normal saline, and if necessary it can diluted in a larger volume.
• Infusion begins shortly after reperfusion of the donor liver.
• Initial rate (continuous infusion) = 0.1 µg/kg/hr (based on pre-op body wt).
• Every hour, increase rate by 0.2 µg/kg/hr up to a maximum rate of 1 µg/kg/hr. However, we normally aim for final rate 0.6 µg/kg/hr.
• PGE₁ infusion is continued throughout ICU stay unless discontinued because of hemodynamic instability, persistant fever, or thrombocytopenia. It should be noted that PGE₁ does not known to cause throbocytopenia, but it does interfere with platelet function (òaggregation).
• PGE₁ therapy is discontinued shortly before the patient leaves the ICU.
• Blood pressure, heart rate, body temperature, and platelet count should be closely monitored during PGE₁ infusion.
• Here is a more detailed protocol.

Pharmacokinetics

• Protein binding = 80%
• Metabolized in the lungs (75% in a single pass); elimination half-life = 7 minutes (hence the need for continuous infusion). Metabolites are excreted in the urine.

Main Side Effects

• Cardiovascular: flushing (10%), hypotension, tachycardia, and cardiac arrest.
• Hematologic: Disseminated intravascular coagulation, thrombocytopenia, anemia
• CNS: persistent fever; headache, dizziness, seizures;
• Respiratory: apnea; cough, nasal congestion
• GI: Diarrhea

References

1. Kawamura et al. Crit Care Med 2000; 28:2201
2. Greig PD. et al. Transplantation 1989; 48:447-453.
3. Henley KS et al. Hepatology 1995; 21:366372.
4. Klein AS. et al. Gastroent 1996; 111:710-715.
5. Giostra E. et al. Transplant Proc 1997; 29:2381-2384.
6. Merion et al Adv Exp Med Bio 1997; 433:13-18.
7. Schafer and Sorrel. Ganstroenterology '96; 11:819
8. Candela-Toha AM et al. Transplantation 1999; 15;68(1):166-7.