Following the death of Manu Cauchy earlier this year, we are celebrating his life by describing some of his most important contributions to frostbite research. Last month we focused upon how Manu developed a way of predicting, at a very early stage, those who would go on to need surgery. Today we take a closer look at Manu's 2011 study that examined the role of iloprost and recombinant tissue plasminogen activator (rt-PA) in the treatment of the condition*.
Let’s begin with some background. Frostbite is often described as, “the freezing and crystalizing of fluids in the interstitial and cellular spaces as a consequence of prolonged exposure to freezing temperatures”. The damage caused by ice crystals triggers an inflammatory response that eventually leads to widespread vasoconstriction and platelet aggregation. Cauchy argued that these responses were responsible for tissue damage and a combination of iloprost (a vasodilator) and rt-PA (a thrombolytic) could minimize the need for surgical intervention.
Cauchy recruited 47 patients with 407 frostbitten digits. These patients had frostbite that ranged in extent from Grade 2 (distal phalanx) to Grade 4 (metacarpal/metatarsal and carpal/tarsal bones). Following rapid rewarming the patients were all given two drugs - aspirin (250mg) and the vasodilator buflomedil (400mg). The patients were then randomly assigned to one of three treatment groups:
Group 1: no further treatment
Group 2: iloprost (0.5-2ng/kg/min for 6 hours)
Group 3: iloprost (0.5-2ng/kg/min for 6 hours) and rt-PA (single dose of 100mg)
Treatment continued for 8 days. Eventually, 47 of the 407 (12%) digits were amputated. Whilst 42 of these were from Group 1, those who received iloprost did much better:
Group 1: 42/106 (40%)
Group 2: 0/142 (0%)
Group 3: 5/159 (3%)
Yes - those figures are right - only five digits needed amputating if iloprost alone or in combination with rt-PA were used!
Importantly, Cauchy also found that a delay in receiving treatment increased the risk of amputation. Those experiencing a delay were almost six times more likely to need amputation than those who presented for treatment within 12 hours.
On the basis of these results, Cauchy recommended that after rapid rewarming, a combination of aspirin, buflomedil and prostacyclin should be quickly used to treat those with significant frostbite. Since the success of iloprost made it impossible to show any further benefit from adding rt-PA, Cauchy concluded that the thrombolytic agent should only be used, “on a case by case basis, depending on the severity of injury, the presence of trauma (especially head trauma), any medical contraindications and the amount of time passed since rewarming”. For the first time, Cauchy had demonstrated that a safe and effective treatment option was available to frostbite victims and the risk of amputation could be reduced.
For a fascinating account of frostbite its worth watching this short film...
*Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of prostacyclin and rt-PA in the treatment of severe frostbite. N Eng J Med 2011;364(2):189-190.
For a copy of the study please get in touch!