‘Controlled Reperfusion’ Fails to Improve Outcomes in Critical Limb Ischemia

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Patients undergoing surgical revascularization for critical limb ischemia do not benefit from a ‘controlled reperfusion’ strategy aimed at minimizing reperfusion injury, according to data from a randomized trial published online July 23, 2013, ahead of print in Circulation: Cardiovascular Interventions.

For the CRAIL trial, investigators led by Claudia Heilmann, MD, of Heart Center Freiburg University (Freiburg, Germany), randomized 174 patients with acute limb ischemia (Rutherford class IIA-III) at 14 centers to standard thromboembolectomy with (n = 88) or without (n = 86) controlled reperfusion between October 2002 and March 2008.

Rationale for Controlled Reperfusion

According to the authors, the adjunctive technique is designed to control the flow, pressure, and duration of reperfusion as well as enhance the reperfused blood with agents that limit tissue damage by reactive oxygen species and help restore cellular energy and substrate metabolism.

After thromboembolectomy and before restoration of blood flow, a cannula is connected to the blood inflow line, and oxygenated blood is drawn into a blood bag, where it is mixed with a reperfusion solution containing 9 protective compounds—including the buffering agent dihydrogen phosphate, the free radical scavenger allopurinol, and the calcium chelator sodium citrate—at a ratio of 6:1.

Next, the blood-reperfusion solution is transferred to a second blood bag and reperfusion is initiated via a distal cannula under continuous control to maintain a maximal pressure of 60 mm Hg. The procedure is repeated for 30 ± 3 minutes. Then the incision is closed and normal blood flow is reestablished.

No Hint of Benefit

Rates of amputation-free survival at 4 weeks (primary efficacy endpoint) were virtually identical between the surgery-alone and controlled reperfusion groups (82.4% vs. 82.6%; P = 1.00). In addition, 15 patients in each group (approximately 17.5%) underwent amputation or died (8 each of cardiovascular causes) within the first month.

Also at 4 weeks, rates of amputation and death were markedly reduced among the subgroup of patients with unilateral ischemia, treatment per protocol, and successful revascularization (n = 104) compared with the overall study population (8% vs. 33%). Even when analysis was limited to per-protocol patients, however, no difference was seen between the surgery-only and controlled reperfusion groups (8.5% vs. 6.7%; P = 0.75).

At 1 year, rates of amputation-free survival remained similar between surgery and controlled reperfusion (62.1% vs. 63.1%), with no differences between the treatments for amputation or death individually, or for the causes of death, either in the intention-to-treat analysis (table 1) or the per-protocol cohort.

Table 1. Risk of Death or Amputation at 1 Year: Controlled Reperfusion vs. Surgery Alone



95% CI

P Value

Amputation-Free Survival












Overall Survival




Cardiovascular Death




Noncardiovascular Death




Amputation or Cardiovascular Death




Analysis of various patient subgroups defined by prognostic factors including age, sex, duration of ischemia, Rutherford stage, and extent of vascular obliteration showed no difference between the treatments for amputation-free survival, time to amputation, length of overall survival, or time to amputation or cardiac death.

In the safety population (defined by unilateral ischemia, treatment per protocol, and successful revascularization), rates of at least 1 serious adverse event were similar between the conventional treatment and controlled reperfusion groups (26.2% and 25.3%, respectively).

The extent of ischemia had a strong impact on 1-year outcomes, with amputation-free survival twice as high for unilateral compared with bilateral ischemia (65.7% vs. 27.3%; P = 0.002) and amputation two-thirds less frequent (15.4% vs. 45.5%; P = 0.003). On multivariable analysis of patients with unilateral ischemia, older age (≥ 80 years) predicted higher 1-year amputation-free survival (HR 2.06; P = 0.004) while occlusions located either at or below the femoral bifurcation (each HR 0.48; P = 0.028) had lower odds of 1-year amputation-free survival than those located centrally or above the femoral bifurcation. Intraoperative successful revascularization reduced the risk of amputation and death after adjustment for age and extent of obliteration (HR 0.49; P = 0.010).

Better Understanding of Mechanisms May Improve Therapy

“It seems possible that a meticulous surgical technique and the setting of a clinical trial, especially for these emergency patients, leaves not much room for further improving the outcome by [controlled reperfusion],” Dr. Heilmann and colleagues assert, adding that “[f]urther investigations on the mechanisms of local and systemic reperfusion injury are necessary to achieve a better outcome [in] these severely ill patients.”

Translation to Clinical Benefit Challenging

In a telephone interview with TCTMD, Robert A. Kloner, MD, PhD, of Good Samaritan Hospital (Los Angeles, CA), said the concept of controlled reperfusion has long been controversial. For example, he noted, in the form of ‘stuttering’ reperfusion (aka postconditioning) in the heart, it has clearly prevented arrhythmia but yielded mixed results in terms of reducing infarct size.

Use of various chemicals to minimize reperfusion injury has likewise had an uneven record, Dr. Kloner observed. For example, some free radical scavengers have worked in experimental models but not in clinical trials. A noted limitation of this approach is that many antioxidants cannot enter the cell, he pointed out, adding that a new experimental agent called Bendavia that penetrates and protects mitochondria has shown promise in reducing no-reflow.

Another possible reason for the checkered history of attempts to translate experimental approaches to reperfusion injury into clinical benefit is that the therapy appears to need to be onboard during at least part of the ischemic period as well as during reperfusion, Dr. Kloner commented. He noted that hypothermia for acute MI reduces infarct size only if it is present during the ischemic phase.

As to why the study protocol failed to produce a clinical benefit, Dr. Kloner suggested that the particular cocktail of agents may need refinement or that reperfusion injury may simply play a smaller role in leg skeletal muscle than it does in cardiac muscle.

“But after these results, I would not be enthusiastic about moving forward with this particular protocol, at least in the leg,” he concluded.

Study Details

Ischemia lasted > 6 hours in 81% of patients and > 24 hours in 27%. A total of 88% of the cohort had Rutherford stage IIB or III lesions, and the occlusion was located at or above the femoral bifurcation in 63%. Vascular obliteration occurred due to arterial embolism in 56%, and 11 patients presented with bilateral acute ischemia. 


Heilmann C, Schmoor C, Siepe M, et al. Controlled reperfusion versus conventional treatment of the acutely ischemic limb: Results of a randomized, open-label, multicenter trial. Circ Cardiovasc Interv. 2013;Epub ahead of print.



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‘Controlled Reperfusion’ Fails to Improve Outcomes in Critical Limb Ischemia

Patients undergoing surgical revascularization for critical limb ischemia do not benefit from a ‘controlled reperfusion’ strategy aimed at minimizing reperfusion injury, according to data from a randomized trial published online July 23, 2013, ahead of print in Circulation Cardiovascular Interventions. For
  • The study was supported by grants from Dr. Franz Köhler Chemie and HP-Medica.
  • Dr. Heilmann reports no relevant conflicts of interest.
  • Dr. Kloner reports receiving research grants from and serving as a consultant to Stealth Peptides, maker of Bendavia.