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Hypothermic, Initially Oxygen-Free, Controlled Limb Reperfusion for Acute Limb Ischemia
Hypothermic, Initially Oxygen-Free, Controlled Limb Reperfusion for Acute Limb Ischemia Christian A.P. Schmidt,1,2 Zoran Rancic,1 Mario L. Lachat,1 Dieter O. Mayer,1 Frank J. Veith,1,3,4 and Markus J. Wilhelm,1 Zurich and Kreuzlingen, Switzerland, Cleveland, Ohio; and New York, New York
Background: Controlled limb reperfusion has been shown to prevent the deleterious effects of ischemiaereperfusion (IR) syndrome following revascularization of acute limb ischemia (ALI). To reduce the production of cell-toxic oxygen-free radicals, we have established a new initially oxygen-free, hypothermic, heparin-coated perfusion and hemofiltration system and report on our first results. Methods: In a retrospective single-center study, controlled limb reperfusion was applied in 36 patients (64.7 ± 15 years) with ALI of category IIA to III (33.7 ± 20.7 hr ischemic time). 52.8% had central (aortic and bifurcation) and 47.2% had peripheral (common iliac artery and distal) vascular occlusions. The common femoral artery and vein were cannulated, and a hypothermic (22 C), initially oxygen-free, potassium-free ringer’s solution was perfused using a heparincoated extracorporeal membrane oxygenation (ECMO) and hemofiltration system with lowdose heparinization. Thirty-day mortality, clinical recovery of neurological dysfunction, limb amputation, and fasciotomy rate were analyzed. Laboratory parameters associated with ischemia and IR injury were determined. Results: Average perfusion time was 94 ± 35 min. Thirty-day mortality was 27.8%. 55.5% of patients showed complete recovery of motor and sensory dysfunction. A total of 27.8% of patients developed a compartment syndrome and required fasciotomy. Lower leg amputation was necessary in 11.1% of patients. Lactate levels were reduced in ischemic limbs by 25.3% within 60 min (P < 0.05). Preoperative negative base excess of 1.96 ± 0.96 mmol/L was equalized after 12 hr (P < 0.05), while pH stayed balanced at 7.4. Serum potassium stayed within normal limits throughout 24 hr, and therefore systemic hyperkalemia was prevented and imminent metabolic acidosis was corrected. Conclusions: An initially oxygen-free, hypothermic, heparin-coated ECMO counteracts local and systemic effects of IR injury. Reduced mortality and morbidity might result from this new treatment, although this could not be conclusively proven in our study. A prospective, randomized controlled trial is needed to prove superiority of this new concept.
INTRODUCTION 1 Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland. 2
Vein Clinic Bellevue, Kreuzlingen, Switzerland.
3
The Cleveland Clinic, Cleveland, OH.
4
New York University Medical Center, New York, NY.
Correspondence to: Christian A.P. Schmidt, MD, PhD, Vein Clinic Bellevue, Br€ uckenstrasse 9, 8280 Kreuzlingen, Switzerland; E-mail: [email protected] Ann Vasc Surg 2015; 29: 560–572 http://dx.doi.org/10.1016/j.avsg.2014.09.033 Ó 2015 Elsevier Inc. All rights reserved. Manuscript received: May 29, 2014; manuscript accepted: September 14, 2014; published online: November 26, 2014.
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Acute limb ischemia (ALI) is defined as any sudden decrease in blood flow to a limb resulting in a potential threat to the viability of the extremity.1,2 As one of the most common vascular emergencies, its main causes are cardiac or arterial embolism, in situ arterial thrombosis of atherosclerotic vessels, acute graft occlusion, and aortic dissections.3,4 Depending on the severity of ischemia, 4 different categories of ALI are used today for clinical classification.5,6 Despite remarkable progress in pharmacological, interventional, and surgical therapies of ALI, the
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outcome has not considerably improved over decades.7e10 Depending on the category of ALI at presentation and on the time delay to treatment, patients still face a risk of 5e22% for amputation.10e12 Furthermore, mortality rates vary between 4% and over 40%.2,5,8,9,12,13 High morbidity and mortality rates are caused by preexisting comorbidities of mostly elderly patients, by the necessity of emergency interventions without adequate preoperative risk stratification, and especially by the ischemiaereperfusion (IR) injury which is caused by ALI and subsequent revascularization. In extensive IR injury, severe dysfunction of the affected limb or even amputation may result. In addition, multiple organ failure with lethal outcome may develop.14 In an attempt to reduce the extent of IR injury, the concept of ‘‘controlled reperfusion’’ for ALI has been introduced in 1989.15 It includes an alteration of the composition of the initial perfusate as well as a modification of the reperfusion conditions.16e21 So far, most clinical studies in humans utilized a blood perfusate enriched with oxygen. However, oxygen is thought to play a major role in the pathophysiology of IR injury.22,23 Furthermore, warm reperfusion is known to aggravate the damage to the ischemic limb, while hypothermia is supposed to reduce IR injury.22,24 Recently, an improved rodent model of ALI indicated positive effects of a flow-controlled hypothermic (15 C) limb perfusion with a crystalloid solution for 20 min.25 We have, therefore, established an initially oxygen-free, mildly hypothermic, heparin-coated extracorporeal membrane oxygenation (ECMO) and hemofiltration system. In this study, we report our experience with this perfusion technique.
MATERIALS AND METHODS Patients Thirty-six consecutive patients (28 men and 8 women, mean age 64.3 ± 15 years; range 27e 91 years) presenting within an 8-year period with acute and persistent lower limb ischemia were included in the study (Tables I and II). Inclusion criteria in this prospectively planned, retrospectively analyzed study were a history of at least 6 hr of acute ischemia and ischemia-related neurological dysfunction (sensory, motor, or both). In cases of referrals from nearby hospitals, no treatment was started before which would have a major influence on our diagnostic work-up and treatment. According to the Rutherford classification of ALI, 13 patients (36.1%) presented with grade IIA, 10
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patients (27.8%) with grade IIB, and 13 patients (36.1%) with grade III. Nineteen patients (52.8%) had central (aortic and bifurcation) vascular occlusions (Table I), of whom 13 (36.1% of all) had acute distal aortic occlusion above the bifurcation (Leriche syndrome), 3 (8.3% of all) had aortic dissection Stanford type B, 2 (5.5% of all) had aortic dissection type A, and 1 (2.7%) had ALI because of a ruptured abdominal aortic aneurysm. Seventeen patients (47.2%) had peripheral (common iliac artery and distal) vascular occlusions (Table II), of whom 13 (36.1% of all) had iliaco-femoral and 4 (11.1% of all) had femoro-crural acute thrombotic or embolic occlusions. Study Protocol All patients underwent preoperative, 64-line angiocomputed tomography scan (Sensation 16; Siemens, Erlangen, Germany) and/or a selective angiography. To assess the severity of local ischemia and muscle necrosis as well as the systemic consequences and to evaluate the effectiveness of initially oxygenfree, mildly hypothermic limb perfusion (22 C), several laboratory parameters were obtained at different time points. Lactate was measured in the femoral venous drainage from the ischemic limb during reperfusion at 0, 30, and 60 min, as well as in systemic serum before and after reperfusion (2, 1, 6, 12, and 24 hr). Creatine kinase (CK), myoglobin, lactate dehydrogenase (LDH), potassium, creatinine, pH, and base excess were analyzed in systemic serum before start of reperfusion, 1 hr after end of reperfusion, and thereafter at 6, 12, 24, 48, 96, and up to 144 (CK) hr. The time course of the laboratory parameters was determined. The attending vascular surgeon or intensive care doctor assessed recovery of motor or sensory neurologic dysfunction clinically on a daily basis. After being discharged home, patients were seen on an outpatient basis at our institution 30 days after surgery. In case of a postoperative referral to another hospital, we received a discharge letter in all cases. Patient records were retrospectively analyzed with respect to all-cause hospital mortality, recovery of neurological dysfunction of the ischemic limb, limb amputation, and intraoperative or postoperative fasciotomy. All patients gave informed consent to the study, which was approved by the University of Zurich ethics committee. Controlled Reperfusion All surgical procedures were performed by 2 senior vascular surgeons under local or general anesthesia with invasive arterial blood pressure and central
DOI (hr) ALICat
Procedure
Outcome
48 IIa
Embolectomy, femoro-femoral bypass
Complete recovery
24 III
Bilateral iliaco-femoral embolectomy, left lower leg fasciotomy, left below-knee amputation on POD 4
Complete recovery of right leg
13 IIa
Replacement of ascending aorta and hemiarch, iliaco-femoral crossover bypass Bilateral iliaco-femoral thrombectomy, aorto-bifemoral 14- 7-mm graft, left profundaplasty, and left metatarsal IeV amputation Bilateral iliaco-femoral thrombectomy, right lower leg fasciotomy 8-mm right subclavio-external iliac bypass plus right external iliaco-femoral left common femoral bypass Open thoraco-abdominal aortic replacement with reimplantation of celiac trunk, SMA, and both renal arteries Open thoraco-abdominal aortic replacement with aorto-femoral/iliac Y graft plus reimplantation of celiac trunk, SMA, and right renal artery Thrombectomy Y graft and femoropoliteal bilaterally, neo-anastomosis of Y graft to bilateral common femoral artery Fenestration of dissection membrane, tube graft reconstruction of infrarenal aorta Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y graft, open fenestration of dissection membrane of perirenal aorta
Intraoperative stroke with right-sided hemiplegia sensory recovery impossible to assess because of psychotic syndrome Complete recovery of both legs
Gen-der
Age
Diagnosis
1
F
90
5
M
74
7
M
70
TEO of left leg after EVAR of ruptured AAA Leriche syndrome, bilateral ALI because of embolization from infrarenal aortic tube graft with subsequent left femorocrural bypass occlusion Acute type A aortic dissection with ALI of right leg
8
M
72
Leriche syndrome
48 IIa
10
M
68
Leriche syndrome
13 III
14
M
58
Acute type B aortic dissection
48 III
15
M
73
TEO because of TAAA Crawford III
48 IIa
16
M
55
TEO of both common iliac arteries plus occlusion of celiac trunk and IMA because of TAAA
48 IIa
17
M
58
Leriche syndrome because of TEO of an aorto-bifemoral Y graft implanted 2 years before
10 IIb
18
M
68
10 IIa
19
M
75
Acute type A aortic dissection with Leriche syndrome, paraplegia, and mesenterial infarction Subacute type B aortic dissection with Leriche syndrome and ruptured AAA
36 III
Died due to reperfusion MOF on POD 1 Recovery of lower extremity perfusion Complete recovery
Sensory deficit below L5, incomplete paraplegia below L2 (because of spinal ischemia) Recovery of leg perfusion Died because of malignant cerebral edema on POD 1
Bilateral lower leg fasciotomy on POD 1, complete bilateral motor recovery, remaining sensory deficit of right lower leg Died intraoperatively because of untreatable mesenteric ischemia before replacement of ascending aorta Complete recovery
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Table I. Central vascular occlusions: characteristics, diagnosis, treatment, and outcome of 19 patients receiving ECMO therapy for acute limb ischemia because of central vascular occlusions
72
Leriche syndrome because of infrarenal TEO of AAA
48 III
21
M
72
Leriche syndrome
12 IIa
23
M
62
Leriche syndrome
48 III
25
M
56
Leriche syndrome
20 IIb
26
F
60
Subacute Leriche syndrome
48 IIa
28
M
59
TEO of left common iliac artery, partially thrombosed thoracic and abdominal aorta
72 IIa
30
M
53
Acute type B aortic dissection with Leriche syndrome, paraparesis
8 III
32
F
62
Leriche syndrome because of TEO of aorto-bifemoral Y graft implanted 23 years before
14 III
Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y graft, bypass revascularization of right internal iliac artery plus bilateral profundaplasty 10-mm axillo-bifemoral graft implantation Bilateral iliaco-femoral thrombectomy, aorto-bifemoral graft implantation Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y-graft implantation, right lower leg fasciotomy Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y-graft implantation Open thoraco-abdominal aortic replacement, reimplantation of celiac trunk, SMA, both renal arteries plus aorto-bifemoral graft implantation TEVAR, PTA, and stent implantation of right renal artery, right common iliac, and common femoral artery Replacement of aorto-bifemoral Y graft and right femoro-popliteal thrombectomy
Bilateral motor recovery, remaining sensory deficit, died on POD 30 because of sepsis Bi-iliacal thrombectomy on POD 1 because of graft occlusion, incomplete bilateral motor and sensory recovery Complete recovery Complete recovery, resuscitation on POD 2 because of MI, emergency CABG Incomplete bilateral motor and sensory recovery (preexisting since 2 weeks before operation) Complete recovery
Right lower leg fasciotomy on POD 1, died on POD 2 because of ventricular fibrillation and cardiomyopathy Recovery of leg perfusion Complete recovery, died on POD 4 because of massive small bowel infarction due to TEO of SMA
AAA, abdominal aortic aneurysm; ALICat, acute limb ischemia category; CABG, coronary artery bypass grafting; CMP, cardiomyopathy; DOI, duration of ischemia; DVT, deep vein thrombosis; EVAR, endovascular aortic repair; F, female; GSV, greater saphenous vein; HTX, heart transplantation; IABP, intra-aortic balloon pump; IMA, inferior mesenteric artery; M, male; MI, myocardial infarction; MOF, multiorgan failure; PE, pulmonary embolism; POD, postoperative day; PTA, percutaneous transluminal angioplasty; SMA, superior mesenteric artery; TAAA, thoraco-abdominal aortic aneurysm; TEO, thromboembolic occlusion; TEVAR, thoracic endovascular aortic repair; VAD, ventricular assist device.
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M
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20
563
DOI (h) ALICat
Gen-der
Age
Diagnosis
2
M
45
12 IIb
3
M
53
4
M
42
6
M
77
Acute cardioembolic occlusion of left common femoral artery Thrombotic occlusion of left common iliac artery Bilateral ALI because of suicidal neuroleptic intoxication Dissection of left common femoral artery after ECMO implantation post CABG
9
F
91
Embolic occlusion of left external iliac artery
22 III
Embolectomy of left external iliac, common femoral, and superficial femoral artery
11
M
73
48 IIb
12
M
88
13
F
54
TEO of left external iliac, common femoral and superficial femoral artery TEO of right common iliac artery 3 weeks after aorto-biiliac Y-graft implantation TEO of both common iliac arteries because of partially thrombosed suprarenal AAA
22
M
80
TEO of right leg of aorto-bifemoral Y graft implanted 8 years before
48 IIb
24
M
68
48 IIb
27
M
64
TEO of left axillo-femoral bypass, implanted in 1997 after aorto-bifemoral Y-graft occlusion (implanted in 1982) Thrombosed right popliteal aneurysm
29
M
80
Acute cardioembolic occlusion of left external iliac artery
8 III
31
M
49
7 III
33
F
46
TEO of right common femoral artery because of IABP insertion before CABG TEO of right common iliac artery because of paraneoplastic syndrome because of metastasizing lung cancer
Left profundaplasty, 8-mm femorofemoral crossover bypass Thromboembolectomy of right common iliac artery Bilateral iliac thrombectomy, aortobifemoral Y graft with reimplantation of SMA, celiac trunk, and both renal arteries Thromboembolectomy of right leg of Y graft and additional bypass grafting to right profunda femoris artery Axillo-femoral bypass graft thromboembolectomy, left lower leg fasciotomy GSV femoro-popliteal bypass, right lower leg fasciotomy Embolectomy of left external iliac and common femoral artery, left lower leg fasciotomy Thrombectomy of right common femoral artery, CABG Thromboembolectomy of right common iliac and superficial femoral artery
48 IIa 30 III 48 IIb
10 III 48 IIa
96 IIa
48 IIb
Procedure
Outcome
Embolectomy, lower leg fasciotomy on POD 1 Iliac thrombectomy, aorto-bifemoral 18- 9-mm graft Left through-knee amputation, right lower leg fasciotomy Embolectomy, left profundoplasty, and 6mm femoro-popliteal bypass
Complete recovery Complete recovery Incomplete sensory and motor recovery of right leg Died of cardiac tamponade on POD 6, motor recovery of left leg, sensory recovery impossible to assess Incomplete sensory and motor recovery, difficult to assess because of symptomatic transitory psychotic syndrome Complete recovery Incomplete sensory and motor recovery of right leg Complete recovery
Complete recovery, died on POD 11 because of DVT and subsequent PE Left below-knee amputation on POD 3
Complete recovery Complete recovery
Complete recovery Right below-knee amputation on POD 3, died on POD 10 because of cancer
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Table II. Peripheral vascular occlusions: characteristics, diagnosis, treatment, and outcome of 17 patients receiving ECMO therapy for acute limb ischemia because of peripheral vascular occlusions
30 IIb Thrombotic occlusion of right external iliac artery after resection of the sacroiliac joint for osteosarcoma F 36
36
21 IIa Acute cardioembolic occlusion of left common iliac artery F 35
85
24 IIb Occlusion of right common femoral artery because of ECMO implantation after resuscitation for restrictive CMP 27 M 34
AAA, abdominal aortic aneurysm; ALICat, acute limb ischemia category; CABG, coronary artery bypass grafting; CMP, cardiomyopathy; DOI, duration of ischemia; DVT, deep vein thrombosis; EVAR, endovascular aortic repair; F, female; GSV, greater saphenous vein; HTX, heart transplantation; IABP, intra-aortic balloon pump; IMA, inferior mesenteric artery; M, male; MI, myocardial infarction; MOF, multiorgan failure; PE, pulmonary embolism; POD, postoperative day; PTA, percutaneous transluminal angioplasty; SMA, superior mesenteric artery; TAAA, thoraco-abdominal aortic aneurysm; TEO, thromboembolic occlusion; TEVAR, thoracic endovascular aortic repair; VAD, ventricular assist device.
Died on POD 4 because of pulmonary and renal failure Complete recovery of leg Complete recovery
Hypothermic, oxygen-free acute ischemic limb reperfusion
8-mm graft interposition of bilateral common femoral artery, direct closure of venotomies, central ECMO implantation of right atrium/ascending aorta for bridging to VAD Embolectomy of left common and external iliac and superficial femoral artery Thrombectomy of right external iliac artery
Complete recovery, patient on VAD (Berlin Heart Excor), listed for HTX Successfully bridged to HTX
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venous pressure monitoring. In patients with central vascular occlusions, a pulmonary artery catheter was inserted and transesophageal echocardiography was performed. After induction of anesthesia and systemic low-dose heparinization (bolus of 80 IU/kg body weight), common, superficial, and deep femoral arteries and veins were exposed through a standard groin incision. The common femoral artery was clamped and a transverse arteriotomy was performed to insert a 10e18F FemFlex II cannula (Edwards Lifesciences, Irvine, CA) into the superficial femoral artery. In patients with peripheral occlusions, a standard embolectomy or thrombectomy using a Fogarty catheter, in some cases combined with local thrombolytic therapy with 4000 IU/min of Urokinase (Urokinase HS medac; Pharma Consulting Marion, Senn GmbH, Basel, Switzerland), preceded the cannulation. In patients without the need for evacuation of embolic/thrombotic material, a longitudinal common femoral artery incision was performed. In 1 patient with an additional lower limb embolic occlusion, an additional access through the popliteal artery was performed. For venous drainage, the common femoral vein was clamped and a 16e24F Fem-Flex II cannula was inserted into the superficial femoral vein. The venous cannula was then connected with the corresponding ECMO tubing passing the venous blood through the hemofilter on to the centrifugal pump and returning it through an oxygenator via the arterial cannula (Fig. 1). Controlled limb reperfusion was performed using a heparin-coated tip-to-tip perfusion and hemofiltration tubing system (Bioline; Jostra AG, Hirrlingen, Germany). For peripheral occlusions, a children’s minimal extracorporeal circulation (MECC) system consisting of an oxygenator (Minimax plus membrane oxygenator; Medtronic Cardiopulmonary, Anaheim, CA) and a centrifugal pump (BP-50 BioMedicus; Medtronic Bio-Medicus, Eden Prairie, MN) was used to limit priming volume. Standard 300 mL of priming volume (perfusate) consisted of 250 mL potassium-free Ringer’s solution, 20 mL of glucose 50%, 20 ml of Mannitol 20%, as well as 20 mmol of sodium bicarbonate 8.4% (all Braun Medical AG, Sempach, Switzerland), and 300 mg of allopurinol (Allopurinol; Teva Pharma AG, Basel, Switzerland) dissolved in 10 mL NaCl 0.9% (Table III). For central occlusions, a conventional cardiopulmonary bypass (St€ ockert S III; St€ ockert, Munich, Germany) including an oxygenator (Avant Physio; Dideco St€ ockert, Munich, Germany) with a priming volume of 1500 mL with the same relative amounts and concentrations of pharmaceuticals was used. A hemofilter (BC 60 Plus, Jostra AG) was installed in
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Table III. Reperfusate composition (300 mL priming volume) Potassium-free Ringer’s solution Glucose 50% Mannitol 20% Sodium bicarbonate 8.4% Allopurinol
250 mL 20 mL 20 mL 20 mmol 300 mg in 10 mL NaCl 0.9%
Additionally, heparin 80 IU/kg body weight was given intravenously.
Table IV. Conditions of reperfusion Temperature Oxygen
Flow rate Perfusion pressure Total perfusion time Hemofiltration
Fig. 1. Schematic diagram of the cannulation technique and ECMO therapy for peripheral occlusions. A 10e18F Fem-Flex II cannula was inserted into the superficial femoral artery. For venous drainage, a 16e24F FemFlex II cannula was inserted into the superficial femoral vein. A heparin-coated tip-to-tip perfusion system was used (Bioline; Jostra AG). An MECC system consisting of an oxygenator (Minimax plus membrane oxygenator) and a centrifugal pump (BP-50 Bio-Medicus) was used. A hemofilter (Jostra BC 60 plus) was installed in the venous ECMO line.
the venous ECMO line to prevent fluid overload and to filtrate potassium, hydrogen ions, and creatinine from the venous effluent. Ischemic limbs were perfused pressure controlled (not exceeding 70 mm Hg) under initially oxygen-free (FiO2 of ECMO set to 0.21, which provides no external oxygenation) and mild hypothermic conditions (perfusate at room temperature 22 C) for 20 min. Thereafter, the oxygen content in the perfusate was increased to an FiO2 of 0.44 ± 0.13 (Table IV). Because only the pressure was controlled by the MECC or the cardiopulmonary bypass, the flow followed passively dependent on the local vascular resistance of the ischemic limb. After termination of reperfusion, the cannulae were removed and venotomies and arteriotomies were closed with
Hypothermic (reperfusate at room temperature 22 C) Initially oxygen free (FiO2 set to 0.21) for 20 min After 20 min, normoxic (FiO2 set to 0.44 ± 0.13) 504 ± 222 mL/min (range 200e1000 mL/min) 68.5 ± 9.9 mm Hg 94 ± 35.3 min (range 45e170 min) 678.9 ± 724.6 mL (range 270 to 3000 mL)
5-0 prolene running sutures and single stitches, respectively. In 13 patients, bilateral perfusion was necessary because of acute ischemia in both legs; and in 23 patients a unilateral perfusion was performed. In total, 49 ischemic lower limbs were perfused.
Concomitant Surgical Procedures Associated preceding procedures were as follows: open replacement of the abdominal aorta in 10 patients (27.8%); thoraco-abdominal aorta in 3 patients (8.3%); ascending aorta and hemiarch in 1 patient (2.7%); endovascular aortic repair in 1 patient (2.7%); iliaco-femoral, femoro-femoral, or femoro-popliteal bypasses in 8 patients (22.2%); thrombo embolectomy of iliac or femoral arteries, bypass grafts, or bypass limbs in 24 patients (66.7%); axillo-bifemoral bypass in 1 patient (2.7%); subclavio-iliac bypass in 1 patient (2.7%); profundaplasty in 4 patients (11.1%); percutaneous transluminal angioplasty and stent implantation in peripheral arteries in 1 patient (2.7%); coronary artery bypass grafting in 1 patient (patient 31, 2.7%); and implantation of a central ECMO in 1 patient (patient 34, 2.7%) (Table II).
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Hypothermic, oxygen-free acute ischemic limb reperfusion
Statistical Analysis
first 2 postoperative days (PODs) (4/36). Ten patients developed a lower leg compartment syndrome (27.8%), of whom 5 (13.9%) required intraoperative and 5 (13.9%) postoperative fasciotomy. Fasciotomy was performed during reconstructive surgery when a lower leg compartment syndrome was present or expected to develop, as well as postoperatively in case of clinical evidence of a compartment syndrome at a later stage. According to our standard, all 4 compartments were released using an anterolateral and a posteromedial double incision technique. Six of these 10 patients showed complete (4) or partial (2) recovery of preoperative motor and sensory dysfunction. Two of the fasciotomized patients required lower leg amputation on POD 3 and 4, respectively, because of massive myonecrosis and 2 patients died on POD 1 and 2 because of cardiac failure. Four patients (11.1%) had severe limb ischemia which made a ‘‘through-knee’’ (n ¼ 1) or a ‘‘below-knee’’ (n ¼ 3) lower limb amputation necessary. A detailed description of each patient’s functional and overall outcome is shown in Tables I and II.
All data are given as mean ± standard error of the mean or as median and range in case of nonparametric distribution of variables. We used Student’s 2-sided t-test to evaluate significant changes in serum lactate, myoglobin, CK, LDH, potassium, creatinine, pH, and base excess within the same group. A P value of <0.05 was considered statistically significant.
RESULTS Perfusion Data Ischemic limbs were perfused at a mean arterial perfusion pressure of 68 ± 9.9 mm Hg. This resulted in a flow rate of 504 ± 222 mL/min (range 200e 1000 mL/min) (Table IV). Average total perfusion time was 94 ± 35.3 min (range 45e170 min). Mean hemofiltration was 678.9 ± 724.6 mL (median 500 mL, range 270 to 3000 mL). Mean duration of lower limb ischemia from onset of symptoms to start of perfusion was 33.7 ± 20.7 hr (range 7e96 hr).
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Mortality In-hospital mortality was 27.8% (10 of 36 patients) (Tables I and II). One patient presenting with acute aortic dissection Stanford type A (patient18) died intraoperatively, and 2 other patients presenting with central occlusions because of distal aortic occlusion (patient 10) and a thoraco-abdominal aortic aneurysm (patient 16) died from procedure-related causes within the first 48 hr. The other 7 patients died within 30 days postoperatively because of cardiac failure (2), mesenteric ischemia (1), pulmonary embolism (1), metastatic lung cancer (1), sepsis (1), or multiorgan failure (1). About 22.2% of patients (8 of 36 patients) developed postoperative renal failure and required temporary continuous venovenous hemofiltration. Functional Outcome Twenty patients (55.6%) showed complete recovery of motor and sensory dysfunction, and 2 patients (5.6%) had complete recovery of the motor dysfunction with remaining sensory deficits. Five patients (13.9%) showed incomplete recovery of motor and sensory dysfunction with resulting paresis or paralysis and hypesthesia of the affected legs. In the remaining 9 patients (25%), recovery could not be determined because of poor general condition in the intensive care unit (3/36), because of early amputation of the reperfused limb (2/36), or because patients died intraoperatively or within the
Laboratory Parameters Laboratory parameters reflected the severity of ischemia as well as the efficiency of counteracting IR injury by controlled limb reperfusion. The severity of ischemia leading to cellular damage and myonecrosis was reflected by massive elevations of cellular enzymes such as serum CK up to 22,989 U/L (norm 0e80 U/L), serum myoglobin up to 20,078 U/L (norm 20e100 U/L), and serum LDH up to 1514 U/L (norm 50e150 U/L), which all culminated at 12e24 hr after start of perfusion. Using controlled limb perfusion, the massively elevated end product of anaerobic glycolysis, namely lactate of the leg measured from the venous effluent, was reduced within 60 min from 8.65 to 5.45 mmol/L (norm 0.7e2.1 mmol/L). The elimination of the metabolic waste products lactate and potassium from the ischemic leg by controlled perfusion resulted in only temporary elevation of systemic serum lactate to 3.54 mmol/L 1 hr after end of perfusion returning to the almost normal value of 2.86 mmol/L after 12 hr. Serum potassium stayed within normal range in serum all the time. Imminent metabolic acidosis reflected by the negative base excess of 1.96 mmol/L was corrected and pH remained within the normal range. Serum creatinine levels stayed at a slightly elevated level without a significant increase. A detailed illustration of laboratory parameters is shown in Figure 2.
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DISCUSSION Acute lower limb ischemia because of arterial embolism, thrombosis, or dissection remains a limb and life-threatening condition despite recent advances in operative and interventional management.8,9 In bilateral limb ischemia, mortality rates increase up to 50%26 and can reach even over 80% in case of extensive rhabdomyolysis because of acute distal aortic occlusion (Leriche syndrome).27 Among several factors which contribute to the poor outcome, such as the comorbidities of the mostly elderly patients and the necessity for emergency interventions, the IR injury has the most important impact. Ischemia alone creates a depletion of intracellular energy-rich phosphates because mitochondrial oxidative phosphorylation ceases.28 However, in acute ischemia, capillary permeability and increased filtration does not occur immediately28 and even after 4 hr of warm ischemia, cellular viability is preserved and ultrastructural changes are reversible.29 Nevertheless, with sudden restoration of blood flow at systemic arterial pressure, as seen in traditional revascularization, IR injury is likely to occur. Ischemic tissues transform xanthine, which has been accumulated through the depletion of adenosine triphosphate, to uric acid and the superoxide radical which is subsequently converted to the hydroxyl radical.30e32 These oxygen-derived free radicals are extremely short lived, but trigger peroxidation of membrane lipids (including endothelial cells) which results in increased capillary permeability and filtration. Furthermore, leucocytes are activated which leads to increased leucocyteeendothelial cell interaction, leucocyteeplatelet aggregation, and activation of the complement system.22,33 This leads
=Fig. 2.
Laboratory parameters. (A) Blood lactate levels in the ischemic limbs as determined in the venous effluent were significantly reduced by 37% from 8.65 ± 0.93 mmol/L (range 1.7e21 mmol/L) to 5.45 ± 0.48 mmol/L (range 1.9e13.2 mmol/L) within 60 min (*P ¼ 0.003, as indicated by *). (B) Systemic serum lactate levels peaked 1 hr after beginning of perfusion at 3.54 ± 0.52 mmol/L (range 0.8e13.6 mmol/L), which was not significantly different from preoperative values (P > 0.05), and almost returned to preoperative levels within 12 hr (2.86 ± 0.56 mmol/L, P > 0.05 as compared with preoperative levels). (C) Serum CK levels peaked at 12e24 hr at values of 22,340 ± 6506 U/L (P ¼ 0.008 compared with preoperative levels, as indicated by *) and 22,998 ± 7493 U/L (P ¼ 0.02 compared with preoperative levels, as indicated by *), respectively, and declined later. (D) Serum myoglobin levels peaked at
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to calcium influx into cells and ultimately cell death. Morphological changes include endothelial cell swelling, increased vascular permeability, and microthrombi formation which clinically causes the ‘‘no-reflow phenomenon’’ with local thrombosis, edema development, tissue acidosis, and muscle necrosis.34 The washout of lactate, potassium, and myoglobin into the systemic circulation following reperfusion, also known as ‘‘postreperfusion syndrome’’, can lead to renal, cardiac, pulmonary, and multiorgan failure and eventually death.14 The concept of ‘‘controlled reperfusion,’’ first described for myocardial ischemia in 1986 and adopted for ALI in 1989,15 is characterized by an altered composition of the perfusate and modified conditions of the initial blood flow and perfusion pressure.16 Studies on animals as well as in humans have indicated that limitation of the initial reperfusion pressure and modification of the perfusate composition can prevent edema development, preserve muscle contractility and structural integrity, and thus reduce the incidence of death and complications such as fasciotomies and amputations. Perfusion pressure was kept below 60e70 mm Hg, and the perfusate consisted of a potassium-free 4:1 to 6:1 blood:crystalloid oxygenated solution with addition of glucose, buffer, amino acids, and free radical scavengers.15,17e21,35 However, a bloodbased oxygenated perfusion solution induces the production of oxygen-derived free radicals following reestablishment of oxidative metabolism during reperfusion, and thus promotes the development of IR injury.22,23,31 Therefore, in this study including 36 patients presenting with ALI, our group used a crystalloid, initially oxygen-free perfusate at room temperature (22 C). Positive
6e12 hr with a maximum of 20,078 ± 7598 U/L (at 12 hr, P ¼ 0.04 compared with preoperative levels, as indicated by *) followed by a decline to 1559 ± 849 U/L after 4 days. (E) Serum LDH levels peaked at 12 hr at values of 1514 ± 275 U/L (P > 0.05 compared with preoperative levels), declining to nearly preoperative levels within 48 hr. (F) Serum potassium did not change significantly and stayed within normal range throughout 24 hr (P > 0.05). (G) Preoperative negative base excess of 1.96 ± 0.96 mmol/L was equalized after 12 and 24 hr (P ¼ 0.02, as indicated by *), while pH stayed balanced at 7.4. (H) Serum creatinine remained at slightly elevated levels (normal: <106 mmol/L) throughout the study period without a significant increase (P > 0.05). However, 8 of the 36 patients (22.2%) developed postoperative renal failure and required continuous venovenous hemofiltration.
570 Schmidt et al.
effects of an oxygen-free perfusate were recently published in a rodent model of ALI.25 In addition, we added allopurinol to the perfusate because it is known to inhibit the enzyme xanthin oxidase which is predominantly involved in the production of oxygen-free radicals.23,30,32 Because hypothermia has been described to reduce postreperfusion skeletal muscle edema and to diminish IR injury,22,24,36 we perfused at 22 C. The perfusion pressure was adjusted to values below 70 mm Hg, as suggested by others.15,19,21 Despite the application of several measures to reduce the extent of IR injury, as outlined above, the overall mortality of our patients was not markedly reduced as compared with that in other studies. This might be because of the large number of complex vascular lesions in our patients with 52.8% central vascular occlusions including 36.1% Leriche syndrome, 13.9% aortic dissections, and 2.7% ruptured abdominal aortic aneurysms. Less than half of the patients (47.2%) had peripheral vascular occlusions. With the exception of the study published by Vogt et al. (19.5% mortality, 86% neurological recovery),19 who reported on 56% distal aortic occlusions (23 of 41 patients), all other studies describe mainly unilateral peripheral vascular occlusions. Beyersdorf et al.37 reported on 14 patients, only one of whom had distal aortic occlusion (14.3% mortality, 78% complete limb recovery). Bayersdorf et al. published 1996 on controlled limb reperfusion in 19 patients after cardiac operations, 3 of whom (15.8%) exhibited distal aortic occlusions.17 They found an 84% complete limb recovery rate, a 16% mortality rate (33% mortality in patients with distal aortic occlusions), and a 63% fasciotomy rate. Defraigne reported on 2 cases.18 One patient had a unilateral and one a bilateral occlusion. There were no amputations and no death, and in both patients prophylactic fasciotomy was performed. The results appear to be better in patients with only peripheral occlusions. The only randomized controlled study, so far, reported on 14 patients in the treatment arm with unilateral, peripheral occlusions, of whom 8 patients presented with chronic limb ischemia (no mortality, 2/14 ¼ 14.3% amputations).20 Using a simplified perfusion system, Wilhelm et al. reported on 7 patients presenting with unilateral ALI (iliac and femoral occlusions). In 6 patients, full neurologic recovery (85.7%) was achieved and no patient underwent amputation or died.21 Taking into account the severity of vascular disease in our patients, the rate of complete neurologic recovery in 20 of the 36 patients (55.6%) and the
Annals of Vascular Surgery
rate of predominant motor recovery in 2 of the 36 patients (5.6%) compare well in accordance with those reported in the literature. Blaisdell and Thompson reported on 17.6% and 16% rate of nonfunctional limbs after embolectomy for peripheral occlusions.27,38 In our patient cohort with over 50% central occlusions, 5 of the 36 patients (13.9%) had incomplete motor and sensory recovery. Similarly, the rate of fasciotomy performed in 10 of the 36 patients (27.8%), as well as the need for amputation in 4 of the 36 patients (11.1%) matches well with the results of other groups.17,20 In addition, the exceptionally long duration of acute ischemia of 33.7 hr (range 7e96 hr) may have had a major impact on outcome. Apart from the importance of a remaining collateral circulation, time delay from onset of acute ischemia to treatment has been shown to affect clinical outcome directly. If treatment was initiated within 12 hr after onset of acute ischemia, limb salvage rate was reported to be 93% and mortality amounted to 19%.11 If treatment started after 12 hr, however, limb salvage decreased to 78% and mortality increased to 31%.11 There seems to be a linear relationship between time delay and increased risk for limb loss and death.39 The question of venous drainage remains controversial. In only 2 human studies it was reported that the venous efflux was eliminated from the ischemic limb, which was associated with reduced mortality rates and improved functional results as compared with controls.19,20 Walker et al.20 used a specially designed drainage/occlusion catheter, which was inserted into the common femoral vein. A mean drainage volume of 775 mL was achieved passively by gravity in 6 patients. Because a total volume of 1835 mL reperfusion solution was administered, a volume challenge of more than 1 L remained in the patients. In other studies, volume challenges of between 500 and 1500 mL were reported with resulting increase in central venous pressure.18,21 In ALI patients who mostly have a considerable preoperative cardiac morbidity, strict intravascular volume control seems to be of great importance. Therefore, we used a circuit including venous drainage and in-line serial hemofiltration. Hereby, not only was a volume overload prevented, but a negative balance could be achieved by a mean filtration rate of more than half a liter (687 mL, median 500 mL). As an additional effect and maybe the most important benefit of ischemic limb isolated perfusion, the washout of large amounts of muscular waste products including potassium and hydrogen ions into the systemic circulation was prevented by hemofiltration. Systemic washout of muscle
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waste products has been shown to be responsible for the systemic reperfusion syndrome leading to multiorgan failure and death.33 Systemic lactate did not rise significantly, potassium remained stable, kidney function was preserved in most patients, and metabolic acidosis did not develop. Lethal cardiac arrhythmias, which are known to occur following reperfusion because of changes in serum potassium, were seen in only 1 patient. Systemic complications, however, could not be prevented completely in this high risk group of patients. The idea of using a heparin-coated perfusion system is to allow administration of lower dosages of heparin. This reduces the extent of bleeding during surgery and the potential need for blood products. However, this effect could not be demonstrated in our study because the respective data were not documented quantitatively. As a study limitation, we do not have a control group without controlled reperfusion of the ischemic limb. Therefore, we can only report observational, retrospective data with all their limitations. Another limitation of our study is the heterogeneity of pathologies in our patients resulting in very different surgical treatment regimes. However, our report on 36 patients presenting with ALI and treated by controlled limb reperfusion is the largest case series published so far. Certainly, a prospective, randomized study would be necessary to prove the advantage of the perfusion system described in this study.
CONCLUSIONS The application of an initially oxygen-free, mildly hypothermic, heparin-coated perfusion and hemofiltration system might potentially limit mortality and complication rate in ALI patients despite the severe underlying vascular lesions and the long ischemia time. Prospective, randomized studies comparing this perfusion technique with the conventional blood-based reperfusion system are necessary to prove the concept. Because of the relatively small number of patients over time, a multicenter trial would be desirable to increase the validity of the study. REFERENCES 1. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31(1 Pt 2):S1e296. 2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5e67.
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3. Earnshaw JJ. Demography and etiology of acute leg ischemia. Semin Vasc Surg 2001;14:86e92. 4. Campbell WB, Ridler BM, Szymanska TH. Current management of acute leg ischaemia: results of an audit by the Vascular Surgical Society of Great Britain and Ireland. Br J Surg 1998;85:1498e503. 5. Ouriel K. Acute limb ischemia. In: Rutherford RB ed. Vascular Surgery. Philadelphia, PA: Elsevier, 2005. pp 959e71. 6. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517e38. 7. Berridge DC, Kessel D, Robertson I. Surgery versus thrombolysis for acute limb ischaemia: initial management. Cochrane Database Syst Rev 2002;(3):CD002784. 8. Ljungman C, Holmberg L, Bergqvist D, et al. Amputation risk and survival after embolectomy for acute arterial ischaemia. Time trends in a defined Swedish population. Eur J Vasc Endovasc Surg 1996;11:176e82. 9. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. N Engl J Med 1998;338:1105e11. 10. Earnshaw JJ, Whitman B, Foy C. National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome. J Vasc Surg 2004;39: 1018e25. 11. Abbott WM, Maloney RD, McCabe CC, et al. Arterial embolism: a 44 year perspective. Am J Surg 1982;143:460e4. 12. Antusevas A, Aleksynas N. The surgical treatment of acute ischemia of the lower limb. Medicina (Kaunas) 2003;39: 646e53. 13. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463e654. 14. Haimovici H. Arterial embolism with acute massive ischemic myopathy and myoglobinuria: evaluation of a hitherto unreported syndrome with report of two cases. Surgery 1960;47:739e47. 15. Beyersdorf F, Matheis G, Kruger S, et al. Avoiding reperfusion injury after limb revascularization: experimental observations and recommendations for clinical application. J Vasc Surg 1989;9:757e66. 16. Allen BS, Okamoto F, Buckberg GD, et al. Immediate functional recovery after six hours of regional ischemia by careful control of conditions of reperfusion and composition of reperfusate. J Thorac Cardiovasc Surg 1986;92(3 Pt 2): 621e35. 17. Beyersdorf F, Mitrev Z, Ihnken K, et al. Controlled limb reperfusion in patients having cardiac operations. J Thorac Cardiovasc Surg 1996;111:873e81.
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18. Defraigne JO, Pincemail J, Laroche C, et al. Successful controlled limb reperfusion after severe prolonged ischemia. J Vasc Surg 1997;26:346e50. 19. Vogt PR, Lutz HJ, Akint€ urk HI, et al. Prevention of postischemic tissue injury by controlled reperfusion: a preliminary study. Int J Angiol 2003;12:172e7. 20. Walker PM, Romaschin AD, Davis S, et al. Lower limb ischemia: phase 1 results of salvage perfusion. J Surg Res 1999;84:193e8. 21. Wilhelm MP, Schlensak C, Hoh A, et al. Controlled reperfusion using a simplified perfusion system preserves function after acute and persistent limb ischemia: a preliminary study. J Vasc Surg 2005;42:690e4. 22. Khalil AA, Aziz FA, Hall JC. Reperfusion injury. Plast Reconstr Surg 2006;117:1024e33. 23. Walker PM, Lindsay TF, Labbe R, et al. Salvage of skeletal muscle with free radical scavengers. J Vasc Surg 1987;5: 68e75. 24. Wright JG, Araki CT, Belkin M, et al. Postischemic hypothermia diminishes skeletal muscle reperfusion edema. J Surg Res 1989;47:389e96. 25. Dick F, Li J, Giraud MN, et al. Basic control of reperfusion effectively protects against reperfusion injury in a realistic rodent model of acute limb ischemia. Circulation 2008;118:1920e8. 26. Panetta T, Thompson JE, Talkington CM, et al. Arterial embolectomy: a 34-year experience with 400 cases. Surg Clin North Am 1986;66:339e53. 27. Thompson JE, Sigler L, Raut PS, et al. Arterial embolectomy: a 20 year experience with 163 cases. Surgery 1970;67: 212e20. 28. Paaske WP, Sejrsen P. Microvascular function in the peripheral vascular bed during ischaemia and oxygen-free perfusion. Eur J Vasc Endovasc Surg 1995;9:29e37.
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29. Beyersdorf F, Unger A, Wildhirt A, et al. Studies of reperfusion injury in skeletal muscle: preserved cellular viability after extended periods of warm ischemia. J Cardiovasc Surg (Torino) 1991;32:664e76. 30. Korthuis RJ, Granger DN, Townsley MI, et al. The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability. Circ Res 1985;57:599e609. 31. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159e63. 32. Parks DA, Granger DN. Ischemia-induced vascular changes: role of xanthine oxidase and hydroxyl radicals. Am J Physiol 1983;245:G285e9. 33. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002;10:620e30. 34. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation 2002;105:656e62. 35. Mitrev Z, Beyersdorf F, Hallmann R, et al. Reperfusion injury in skeletal muscle: controlled limb reperfusion reduces local and systemic complications after prolonged ischaemia. Cardiovasc Surg 1994;2:737e48. 36. Mowlavi A, Neumeister MW, Wilhelmi BJ, et al. Local hypothermia during early reperfusion protects skeletal muscle from ischemia-reperfusion injury. Plast Reconstr Surg 2003;111:242e50. 37. Beyersdorf F, Sarai K, Mitrev Z, et al. New surgical treatment for severe limb ischemia. J Invest Surg 1994;7:61e71. 38. Blaisdell FW, Steele M, Allen RE. Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery 1978;84:822e34. 39. Elliott JP Jr, Hageman JH, Szilagyi E, et al. Arterial embolization: problems of source, multiplicity, recurrence, and delayed treatment. Surgery 1980;88:833e45.
Background: Controlled limb reperfusion has been shown to prevent the deleterious effects of ischemiaereperfusion (IR) syndrome following revascularization of acute limb ischemia (ALI). To reduce the production of cell-toxic oxygen-free radicals, we have established a new initially oxygen-free, hypothermic, heparin-coated perfusion and hemofiltration system and report on our first results. Methods: In a retrospective single-center study, controlled limb reperfusion was applied in 36 patients (64.7 ± 15 years) with ALI of category IIA to III (33.7 ± 20.7 hr ischemic time). 52.8% had central (aortic and bifurcation) and 47.2% had peripheral (common iliac artery and distal) vascular occlusions. The common femoral artery and vein were cannulated, and a hypothermic (22 C), initially oxygen-free, potassium-free ringer’s solution was perfused using a heparincoated extracorporeal membrane oxygenation (ECMO) and hemofiltration system with lowdose heparinization. Thirty-day mortality, clinical recovery of neurological dysfunction, limb amputation, and fasciotomy rate were analyzed. Laboratory parameters associated with ischemia and IR injury were determined. Results: Average perfusion time was 94 ± 35 min. Thirty-day mortality was 27.8%. 55.5% of patients showed complete recovery of motor and sensory dysfunction. A total of 27.8% of patients developed a compartment syndrome and required fasciotomy. Lower leg amputation was necessary in 11.1% of patients. Lactate levels were reduced in ischemic limbs by 25.3% within 60 min (P < 0.05). Preoperative negative base excess of 1.96 ± 0.96 mmol/L was equalized after 12 hr (P < 0.05), while pH stayed balanced at 7.4. Serum potassium stayed within normal limits throughout 24 hr, and therefore systemic hyperkalemia was prevented and imminent metabolic acidosis was corrected. Conclusions: An initially oxygen-free, hypothermic, heparin-coated ECMO counteracts local and systemic effects of IR injury. Reduced mortality and morbidity might result from this new treatment, although this could not be conclusively proven in our study. A prospective, randomized controlled trial is needed to prove superiority of this new concept.
INTRODUCTION 1 Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland. 2
Vein Clinic Bellevue, Kreuzlingen, Switzerland.
3
The Cleveland Clinic, Cleveland, OH.
4
New York University Medical Center, New York, NY.
Correspondence to: Christian A.P. Schmidt, MD, PhD, Vein Clinic Bellevue, Br€ uckenstrasse 9, 8280 Kreuzlingen, Switzerland; E-mail: [email protected] Ann Vasc Surg 2015; 29: 560–572 http://dx.doi.org/10.1016/j.avsg.2014.09.033 Ó 2015 Elsevier Inc. All rights reserved. Manuscript received: May 29, 2014; manuscript accepted: September 14, 2014; published online: November 26, 2014.
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Acute limb ischemia (ALI) is defined as any sudden decrease in blood flow to a limb resulting in a potential threat to the viability of the extremity.1,2 As one of the most common vascular emergencies, its main causes are cardiac or arterial embolism, in situ arterial thrombosis of atherosclerotic vessels, acute graft occlusion, and aortic dissections.3,4 Depending on the severity of ischemia, 4 different categories of ALI are used today for clinical classification.5,6 Despite remarkable progress in pharmacological, interventional, and surgical therapies of ALI, the
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outcome has not considerably improved over decades.7e10 Depending on the category of ALI at presentation and on the time delay to treatment, patients still face a risk of 5e22% for amputation.10e12 Furthermore, mortality rates vary between 4% and over 40%.2,5,8,9,12,13 High morbidity and mortality rates are caused by preexisting comorbidities of mostly elderly patients, by the necessity of emergency interventions without adequate preoperative risk stratification, and especially by the ischemiaereperfusion (IR) injury which is caused by ALI and subsequent revascularization. In extensive IR injury, severe dysfunction of the affected limb or even amputation may result. In addition, multiple organ failure with lethal outcome may develop.14 In an attempt to reduce the extent of IR injury, the concept of ‘‘controlled reperfusion’’ for ALI has been introduced in 1989.15 It includes an alteration of the composition of the initial perfusate as well as a modification of the reperfusion conditions.16e21 So far, most clinical studies in humans utilized a blood perfusate enriched with oxygen. However, oxygen is thought to play a major role in the pathophysiology of IR injury.22,23 Furthermore, warm reperfusion is known to aggravate the damage to the ischemic limb, while hypothermia is supposed to reduce IR injury.22,24 Recently, an improved rodent model of ALI indicated positive effects of a flow-controlled hypothermic (15 C) limb perfusion with a crystalloid solution for 20 min.25 We have, therefore, established an initially oxygen-free, mildly hypothermic, heparin-coated extracorporeal membrane oxygenation (ECMO) and hemofiltration system. In this study, we report our experience with this perfusion technique.
MATERIALS AND METHODS Patients Thirty-six consecutive patients (28 men and 8 women, mean age 64.3 ± 15 years; range 27e 91 years) presenting within an 8-year period with acute and persistent lower limb ischemia were included in the study (Tables I and II). Inclusion criteria in this prospectively planned, retrospectively analyzed study were a history of at least 6 hr of acute ischemia and ischemia-related neurological dysfunction (sensory, motor, or both). In cases of referrals from nearby hospitals, no treatment was started before which would have a major influence on our diagnostic work-up and treatment. According to the Rutherford classification of ALI, 13 patients (36.1%) presented with grade IIA, 10
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patients (27.8%) with grade IIB, and 13 patients (36.1%) with grade III. Nineteen patients (52.8%) had central (aortic and bifurcation) vascular occlusions (Table I), of whom 13 (36.1% of all) had acute distal aortic occlusion above the bifurcation (Leriche syndrome), 3 (8.3% of all) had aortic dissection Stanford type B, 2 (5.5% of all) had aortic dissection type A, and 1 (2.7%) had ALI because of a ruptured abdominal aortic aneurysm. Seventeen patients (47.2%) had peripheral (common iliac artery and distal) vascular occlusions (Table II), of whom 13 (36.1% of all) had iliaco-femoral and 4 (11.1% of all) had femoro-crural acute thrombotic or embolic occlusions. Study Protocol All patients underwent preoperative, 64-line angiocomputed tomography scan (Sensation 16; Siemens, Erlangen, Germany) and/or a selective angiography. To assess the severity of local ischemia and muscle necrosis as well as the systemic consequences and to evaluate the effectiveness of initially oxygenfree, mildly hypothermic limb perfusion (22 C), several laboratory parameters were obtained at different time points. Lactate was measured in the femoral venous drainage from the ischemic limb during reperfusion at 0, 30, and 60 min, as well as in systemic serum before and after reperfusion (2, 1, 6, 12, and 24 hr). Creatine kinase (CK), myoglobin, lactate dehydrogenase (LDH), potassium, creatinine, pH, and base excess were analyzed in systemic serum before start of reperfusion, 1 hr after end of reperfusion, and thereafter at 6, 12, 24, 48, 96, and up to 144 (CK) hr. The time course of the laboratory parameters was determined. The attending vascular surgeon or intensive care doctor assessed recovery of motor or sensory neurologic dysfunction clinically on a daily basis. After being discharged home, patients were seen on an outpatient basis at our institution 30 days after surgery. In case of a postoperative referral to another hospital, we received a discharge letter in all cases. Patient records were retrospectively analyzed with respect to all-cause hospital mortality, recovery of neurological dysfunction of the ischemic limb, limb amputation, and intraoperative or postoperative fasciotomy. All patients gave informed consent to the study, which was approved by the University of Zurich ethics committee. Controlled Reperfusion All surgical procedures were performed by 2 senior vascular surgeons under local or general anesthesia with invasive arterial blood pressure and central
DOI (hr) ALICat
Procedure
Outcome
48 IIa
Embolectomy, femoro-femoral bypass
Complete recovery
24 III
Bilateral iliaco-femoral embolectomy, left lower leg fasciotomy, left below-knee amputation on POD 4
Complete recovery of right leg
13 IIa
Replacement of ascending aorta and hemiarch, iliaco-femoral crossover bypass Bilateral iliaco-femoral thrombectomy, aorto-bifemoral 14- 7-mm graft, left profundaplasty, and left metatarsal IeV amputation Bilateral iliaco-femoral thrombectomy, right lower leg fasciotomy 8-mm right subclavio-external iliac bypass plus right external iliaco-femoral left common femoral bypass Open thoraco-abdominal aortic replacement with reimplantation of celiac trunk, SMA, and both renal arteries Open thoraco-abdominal aortic replacement with aorto-femoral/iliac Y graft plus reimplantation of celiac trunk, SMA, and right renal artery Thrombectomy Y graft and femoropoliteal bilaterally, neo-anastomosis of Y graft to bilateral common femoral artery Fenestration of dissection membrane, tube graft reconstruction of infrarenal aorta Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y graft, open fenestration of dissection membrane of perirenal aorta
Intraoperative stroke with right-sided hemiplegia sensory recovery impossible to assess because of psychotic syndrome Complete recovery of both legs
Gen-der
Age
Diagnosis
1
F
90
5
M
74
7
M
70
TEO of left leg after EVAR of ruptured AAA Leriche syndrome, bilateral ALI because of embolization from infrarenal aortic tube graft with subsequent left femorocrural bypass occlusion Acute type A aortic dissection with ALI of right leg
8
M
72
Leriche syndrome
48 IIa
10
M
68
Leriche syndrome
13 III
14
M
58
Acute type B aortic dissection
48 III
15
M
73
TEO because of TAAA Crawford III
48 IIa
16
M
55
TEO of both common iliac arteries plus occlusion of celiac trunk and IMA because of TAAA
48 IIa
17
M
58
Leriche syndrome because of TEO of an aorto-bifemoral Y graft implanted 2 years before
10 IIb
18
M
68
10 IIa
19
M
75
Acute type A aortic dissection with Leriche syndrome, paraplegia, and mesenterial infarction Subacute type B aortic dissection with Leriche syndrome and ruptured AAA
36 III
Died due to reperfusion MOF on POD 1 Recovery of lower extremity perfusion Complete recovery
Sensory deficit below L5, incomplete paraplegia below L2 (because of spinal ischemia) Recovery of leg perfusion Died because of malignant cerebral edema on POD 1
Bilateral lower leg fasciotomy on POD 1, complete bilateral motor recovery, remaining sensory deficit of right lower leg Died intraoperatively because of untreatable mesenteric ischemia before replacement of ascending aorta Complete recovery
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562 Schmidt et al.
Table I. Central vascular occlusions: characteristics, diagnosis, treatment, and outcome of 19 patients receiving ECMO therapy for acute limb ischemia because of central vascular occlusions
72
Leriche syndrome because of infrarenal TEO of AAA
48 III
21
M
72
Leriche syndrome
12 IIa
23
M
62
Leriche syndrome
48 III
25
M
56
Leriche syndrome
20 IIb
26
F
60
Subacute Leriche syndrome
48 IIa
28
M
59
TEO of left common iliac artery, partially thrombosed thoracic and abdominal aorta
72 IIa
30
M
53
Acute type B aortic dissection with Leriche syndrome, paraparesis
8 III
32
F
62
Leriche syndrome because of TEO of aorto-bifemoral Y graft implanted 23 years before
14 III
Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y graft, bypass revascularization of right internal iliac artery plus bilateral profundaplasty 10-mm axillo-bifemoral graft implantation Bilateral iliaco-femoral thrombectomy, aorto-bifemoral graft implantation Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y-graft implantation, right lower leg fasciotomy Bilateral iliaco-femoral thrombectomy, aorto-bifemoral Y-graft implantation Open thoraco-abdominal aortic replacement, reimplantation of celiac trunk, SMA, both renal arteries plus aorto-bifemoral graft implantation TEVAR, PTA, and stent implantation of right renal artery, right common iliac, and common femoral artery Replacement of aorto-bifemoral Y graft and right femoro-popliteal thrombectomy
Bilateral motor recovery, remaining sensory deficit, died on POD 30 because of sepsis Bi-iliacal thrombectomy on POD 1 because of graft occlusion, incomplete bilateral motor and sensory recovery Complete recovery Complete recovery, resuscitation on POD 2 because of MI, emergency CABG Incomplete bilateral motor and sensory recovery (preexisting since 2 weeks before operation) Complete recovery
Right lower leg fasciotomy on POD 1, died on POD 2 because of ventricular fibrillation and cardiomyopathy Recovery of leg perfusion Complete recovery, died on POD 4 because of massive small bowel infarction due to TEO of SMA
AAA, abdominal aortic aneurysm; ALICat, acute limb ischemia category; CABG, coronary artery bypass grafting; CMP, cardiomyopathy; DOI, duration of ischemia; DVT, deep vein thrombosis; EVAR, endovascular aortic repair; F, female; GSV, greater saphenous vein; HTX, heart transplantation; IABP, intra-aortic balloon pump; IMA, inferior mesenteric artery; M, male; MI, myocardial infarction; MOF, multiorgan failure; PE, pulmonary embolism; POD, postoperative day; PTA, percutaneous transluminal angioplasty; SMA, superior mesenteric artery; TAAA, thoraco-abdominal aortic aneurysm; TEO, thromboembolic occlusion; TEVAR, thoracic endovascular aortic repair; VAD, ventricular assist device.
Hypothermic, oxygen-free acute ischemic limb reperfusion
M
Vol. 29, No. 3, April 2015
20
563
DOI (h) ALICat
Gen-der
Age
Diagnosis
2
M
45
12 IIb
3
M
53
4
M
42
6
M
77
Acute cardioembolic occlusion of left common femoral artery Thrombotic occlusion of left common iliac artery Bilateral ALI because of suicidal neuroleptic intoxication Dissection of left common femoral artery after ECMO implantation post CABG
9
F
91
Embolic occlusion of left external iliac artery
22 III
Embolectomy of left external iliac, common femoral, and superficial femoral artery
11
M
73
48 IIb
12
M
88
13
F
54
TEO of left external iliac, common femoral and superficial femoral artery TEO of right common iliac artery 3 weeks after aorto-biiliac Y-graft implantation TEO of both common iliac arteries because of partially thrombosed suprarenal AAA
22
M
80
TEO of right leg of aorto-bifemoral Y graft implanted 8 years before
48 IIb
24
M
68
48 IIb
27
M
64
TEO of left axillo-femoral bypass, implanted in 1997 after aorto-bifemoral Y-graft occlusion (implanted in 1982) Thrombosed right popliteal aneurysm
29
M
80
Acute cardioembolic occlusion of left external iliac artery
8 III
31
M
49
7 III
33
F
46
TEO of right common femoral artery because of IABP insertion before CABG TEO of right common iliac artery because of paraneoplastic syndrome because of metastasizing lung cancer
Left profundaplasty, 8-mm femorofemoral crossover bypass Thromboembolectomy of right common iliac artery Bilateral iliac thrombectomy, aortobifemoral Y graft with reimplantation of SMA, celiac trunk, and both renal arteries Thromboembolectomy of right leg of Y graft and additional bypass grafting to right profunda femoris artery Axillo-femoral bypass graft thromboembolectomy, left lower leg fasciotomy GSV femoro-popliteal bypass, right lower leg fasciotomy Embolectomy of left external iliac and common femoral artery, left lower leg fasciotomy Thrombectomy of right common femoral artery, CABG Thromboembolectomy of right common iliac and superficial femoral artery
48 IIa 30 III 48 IIb
10 III 48 IIa
96 IIa
48 IIb
Procedure
Outcome
Embolectomy, lower leg fasciotomy on POD 1 Iliac thrombectomy, aorto-bifemoral 18- 9-mm graft Left through-knee amputation, right lower leg fasciotomy Embolectomy, left profundoplasty, and 6mm femoro-popliteal bypass
Complete recovery Complete recovery Incomplete sensory and motor recovery of right leg Died of cardiac tamponade on POD 6, motor recovery of left leg, sensory recovery impossible to assess Incomplete sensory and motor recovery, difficult to assess because of symptomatic transitory psychotic syndrome Complete recovery Incomplete sensory and motor recovery of right leg Complete recovery
Complete recovery, died on POD 11 because of DVT and subsequent PE Left below-knee amputation on POD 3
Complete recovery Complete recovery
Complete recovery Right below-knee amputation on POD 3, died on POD 10 because of cancer
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Table II. Peripheral vascular occlusions: characteristics, diagnosis, treatment, and outcome of 17 patients receiving ECMO therapy for acute limb ischemia because of peripheral vascular occlusions
30 IIb Thrombotic occlusion of right external iliac artery after resection of the sacroiliac joint for osteosarcoma F 36
36
21 IIa Acute cardioembolic occlusion of left common iliac artery F 35
85
24 IIb Occlusion of right common femoral artery because of ECMO implantation after resuscitation for restrictive CMP 27 M 34
AAA, abdominal aortic aneurysm; ALICat, acute limb ischemia category; CABG, coronary artery bypass grafting; CMP, cardiomyopathy; DOI, duration of ischemia; DVT, deep vein thrombosis; EVAR, endovascular aortic repair; F, female; GSV, greater saphenous vein; HTX, heart transplantation; IABP, intra-aortic balloon pump; IMA, inferior mesenteric artery; M, male; MI, myocardial infarction; MOF, multiorgan failure; PE, pulmonary embolism; POD, postoperative day; PTA, percutaneous transluminal angioplasty; SMA, superior mesenteric artery; TAAA, thoraco-abdominal aortic aneurysm; TEO, thromboembolic occlusion; TEVAR, thoracic endovascular aortic repair; VAD, ventricular assist device.
Died on POD 4 because of pulmonary and renal failure Complete recovery of leg Complete recovery
Hypothermic, oxygen-free acute ischemic limb reperfusion
8-mm graft interposition of bilateral common femoral artery, direct closure of venotomies, central ECMO implantation of right atrium/ascending aorta for bridging to VAD Embolectomy of left common and external iliac and superficial femoral artery Thrombectomy of right external iliac artery
Complete recovery, patient on VAD (Berlin Heart Excor), listed for HTX Successfully bridged to HTX
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venous pressure monitoring. In patients with central vascular occlusions, a pulmonary artery catheter was inserted and transesophageal echocardiography was performed. After induction of anesthesia and systemic low-dose heparinization (bolus of 80 IU/kg body weight), common, superficial, and deep femoral arteries and veins were exposed through a standard groin incision. The common femoral artery was clamped and a transverse arteriotomy was performed to insert a 10e18F FemFlex II cannula (Edwards Lifesciences, Irvine, CA) into the superficial femoral artery. In patients with peripheral occlusions, a standard embolectomy or thrombectomy using a Fogarty catheter, in some cases combined with local thrombolytic therapy with 4000 IU/min of Urokinase (Urokinase HS medac; Pharma Consulting Marion, Senn GmbH, Basel, Switzerland), preceded the cannulation. In patients without the need for evacuation of embolic/thrombotic material, a longitudinal common femoral artery incision was performed. In 1 patient with an additional lower limb embolic occlusion, an additional access through the popliteal artery was performed. For venous drainage, the common femoral vein was clamped and a 16e24F Fem-Flex II cannula was inserted into the superficial femoral vein. The venous cannula was then connected with the corresponding ECMO tubing passing the venous blood through the hemofilter on to the centrifugal pump and returning it through an oxygenator via the arterial cannula (Fig. 1). Controlled limb reperfusion was performed using a heparin-coated tip-to-tip perfusion and hemofiltration tubing system (Bioline; Jostra AG, Hirrlingen, Germany). For peripheral occlusions, a children’s minimal extracorporeal circulation (MECC) system consisting of an oxygenator (Minimax plus membrane oxygenator; Medtronic Cardiopulmonary, Anaheim, CA) and a centrifugal pump (BP-50 BioMedicus; Medtronic Bio-Medicus, Eden Prairie, MN) was used to limit priming volume. Standard 300 mL of priming volume (perfusate) consisted of 250 mL potassium-free Ringer’s solution, 20 mL of glucose 50%, 20 ml of Mannitol 20%, as well as 20 mmol of sodium bicarbonate 8.4% (all Braun Medical AG, Sempach, Switzerland), and 300 mg of allopurinol (Allopurinol; Teva Pharma AG, Basel, Switzerland) dissolved in 10 mL NaCl 0.9% (Table III). For central occlusions, a conventional cardiopulmonary bypass (St€ ockert S III; St€ ockert, Munich, Germany) including an oxygenator (Avant Physio; Dideco St€ ockert, Munich, Germany) with a priming volume of 1500 mL with the same relative amounts and concentrations of pharmaceuticals was used. A hemofilter (BC 60 Plus, Jostra AG) was installed in
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Table III. Reperfusate composition (300 mL priming volume) Potassium-free Ringer’s solution Glucose 50% Mannitol 20% Sodium bicarbonate 8.4% Allopurinol
250 mL 20 mL 20 mL 20 mmol 300 mg in 10 mL NaCl 0.9%
Additionally, heparin 80 IU/kg body weight was given intravenously.
Table IV. Conditions of reperfusion Temperature Oxygen
Flow rate Perfusion pressure Total perfusion time Hemofiltration
Fig. 1. Schematic diagram of the cannulation technique and ECMO therapy for peripheral occlusions. A 10e18F Fem-Flex II cannula was inserted into the superficial femoral artery. For venous drainage, a 16e24F FemFlex II cannula was inserted into the superficial femoral vein. A heparin-coated tip-to-tip perfusion system was used (Bioline; Jostra AG). An MECC system consisting of an oxygenator (Minimax plus membrane oxygenator) and a centrifugal pump (BP-50 Bio-Medicus) was used. A hemofilter (Jostra BC 60 plus) was installed in the venous ECMO line.
the venous ECMO line to prevent fluid overload and to filtrate potassium, hydrogen ions, and creatinine from the venous effluent. Ischemic limbs were perfused pressure controlled (not exceeding 70 mm Hg) under initially oxygen-free (FiO2 of ECMO set to 0.21, which provides no external oxygenation) and mild hypothermic conditions (perfusate at room temperature 22 C) for 20 min. Thereafter, the oxygen content in the perfusate was increased to an FiO2 of 0.44 ± 0.13 (Table IV). Because only the pressure was controlled by the MECC or the cardiopulmonary bypass, the flow followed passively dependent on the local vascular resistance of the ischemic limb. After termination of reperfusion, the cannulae were removed and venotomies and arteriotomies were closed with
Hypothermic (reperfusate at room temperature 22 C) Initially oxygen free (FiO2 set to 0.21) for 20 min After 20 min, normoxic (FiO2 set to 0.44 ± 0.13) 504 ± 222 mL/min (range 200e1000 mL/min) 68.5 ± 9.9 mm Hg 94 ± 35.3 min (range 45e170 min) 678.9 ± 724.6 mL (range 270 to 3000 mL)
5-0 prolene running sutures and single stitches, respectively. In 13 patients, bilateral perfusion was necessary because of acute ischemia in both legs; and in 23 patients a unilateral perfusion was performed. In total, 49 ischemic lower limbs were perfused.
Concomitant Surgical Procedures Associated preceding procedures were as follows: open replacement of the abdominal aorta in 10 patients (27.8%); thoraco-abdominal aorta in 3 patients (8.3%); ascending aorta and hemiarch in 1 patient (2.7%); endovascular aortic repair in 1 patient (2.7%); iliaco-femoral, femoro-femoral, or femoro-popliteal bypasses in 8 patients (22.2%); thrombo embolectomy of iliac or femoral arteries, bypass grafts, or bypass limbs in 24 patients (66.7%); axillo-bifemoral bypass in 1 patient (2.7%); subclavio-iliac bypass in 1 patient (2.7%); profundaplasty in 4 patients (11.1%); percutaneous transluminal angioplasty and stent implantation in peripheral arteries in 1 patient (2.7%); coronary artery bypass grafting in 1 patient (patient 31, 2.7%); and implantation of a central ECMO in 1 patient (patient 34, 2.7%) (Table II).
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Hypothermic, oxygen-free acute ischemic limb reperfusion
Statistical Analysis
first 2 postoperative days (PODs) (4/36). Ten patients developed a lower leg compartment syndrome (27.8%), of whom 5 (13.9%) required intraoperative and 5 (13.9%) postoperative fasciotomy. Fasciotomy was performed during reconstructive surgery when a lower leg compartment syndrome was present or expected to develop, as well as postoperatively in case of clinical evidence of a compartment syndrome at a later stage. According to our standard, all 4 compartments were released using an anterolateral and a posteromedial double incision technique. Six of these 10 patients showed complete (4) or partial (2) recovery of preoperative motor and sensory dysfunction. Two of the fasciotomized patients required lower leg amputation on POD 3 and 4, respectively, because of massive myonecrosis and 2 patients died on POD 1 and 2 because of cardiac failure. Four patients (11.1%) had severe limb ischemia which made a ‘‘through-knee’’ (n ¼ 1) or a ‘‘below-knee’’ (n ¼ 3) lower limb amputation necessary. A detailed description of each patient’s functional and overall outcome is shown in Tables I and II.
All data are given as mean ± standard error of the mean or as median and range in case of nonparametric distribution of variables. We used Student’s 2-sided t-test to evaluate significant changes in serum lactate, myoglobin, CK, LDH, potassium, creatinine, pH, and base excess within the same group. A P value of <0.05 was considered statistically significant.
RESULTS Perfusion Data Ischemic limbs were perfused at a mean arterial perfusion pressure of 68 ± 9.9 mm Hg. This resulted in a flow rate of 504 ± 222 mL/min (range 200e 1000 mL/min) (Table IV). Average total perfusion time was 94 ± 35.3 min (range 45e170 min). Mean hemofiltration was 678.9 ± 724.6 mL (median 500 mL, range 270 to 3000 mL). Mean duration of lower limb ischemia from onset of symptoms to start of perfusion was 33.7 ± 20.7 hr (range 7e96 hr).
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Mortality In-hospital mortality was 27.8% (10 of 36 patients) (Tables I and II). One patient presenting with acute aortic dissection Stanford type A (patient18) died intraoperatively, and 2 other patients presenting with central occlusions because of distal aortic occlusion (patient 10) and a thoraco-abdominal aortic aneurysm (patient 16) died from procedure-related causes within the first 48 hr. The other 7 patients died within 30 days postoperatively because of cardiac failure (2), mesenteric ischemia (1), pulmonary embolism (1), metastatic lung cancer (1), sepsis (1), or multiorgan failure (1). About 22.2% of patients (8 of 36 patients) developed postoperative renal failure and required temporary continuous venovenous hemofiltration. Functional Outcome Twenty patients (55.6%) showed complete recovery of motor and sensory dysfunction, and 2 patients (5.6%) had complete recovery of the motor dysfunction with remaining sensory deficits. Five patients (13.9%) showed incomplete recovery of motor and sensory dysfunction with resulting paresis or paralysis and hypesthesia of the affected legs. In the remaining 9 patients (25%), recovery could not be determined because of poor general condition in the intensive care unit (3/36), because of early amputation of the reperfused limb (2/36), or because patients died intraoperatively or within the
Laboratory Parameters Laboratory parameters reflected the severity of ischemia as well as the efficiency of counteracting IR injury by controlled limb reperfusion. The severity of ischemia leading to cellular damage and myonecrosis was reflected by massive elevations of cellular enzymes such as serum CK up to 22,989 U/L (norm 0e80 U/L), serum myoglobin up to 20,078 U/L (norm 20e100 U/L), and serum LDH up to 1514 U/L (norm 50e150 U/L), which all culminated at 12e24 hr after start of perfusion. Using controlled limb perfusion, the massively elevated end product of anaerobic glycolysis, namely lactate of the leg measured from the venous effluent, was reduced within 60 min from 8.65 to 5.45 mmol/L (norm 0.7e2.1 mmol/L). The elimination of the metabolic waste products lactate and potassium from the ischemic leg by controlled perfusion resulted in only temporary elevation of systemic serum lactate to 3.54 mmol/L 1 hr after end of perfusion returning to the almost normal value of 2.86 mmol/L after 12 hr. Serum potassium stayed within normal range in serum all the time. Imminent metabolic acidosis reflected by the negative base excess of 1.96 mmol/L was corrected and pH remained within the normal range. Serum creatinine levels stayed at a slightly elevated level without a significant increase. A detailed illustration of laboratory parameters is shown in Figure 2.
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DISCUSSION Acute lower limb ischemia because of arterial embolism, thrombosis, or dissection remains a limb and life-threatening condition despite recent advances in operative and interventional management.8,9 In bilateral limb ischemia, mortality rates increase up to 50%26 and can reach even over 80% in case of extensive rhabdomyolysis because of acute distal aortic occlusion (Leriche syndrome).27 Among several factors which contribute to the poor outcome, such as the comorbidities of the mostly elderly patients and the necessity for emergency interventions, the IR injury has the most important impact. Ischemia alone creates a depletion of intracellular energy-rich phosphates because mitochondrial oxidative phosphorylation ceases.28 However, in acute ischemia, capillary permeability and increased filtration does not occur immediately28 and even after 4 hr of warm ischemia, cellular viability is preserved and ultrastructural changes are reversible.29 Nevertheless, with sudden restoration of blood flow at systemic arterial pressure, as seen in traditional revascularization, IR injury is likely to occur. Ischemic tissues transform xanthine, which has been accumulated through the depletion of adenosine triphosphate, to uric acid and the superoxide radical which is subsequently converted to the hydroxyl radical.30e32 These oxygen-derived free radicals are extremely short lived, but trigger peroxidation of membrane lipids (including endothelial cells) which results in increased capillary permeability and filtration. Furthermore, leucocytes are activated which leads to increased leucocyteeendothelial cell interaction, leucocyteeplatelet aggregation, and activation of the complement system.22,33 This leads
=Fig. 2.
Laboratory parameters. (A) Blood lactate levels in the ischemic limbs as determined in the venous effluent were significantly reduced by 37% from 8.65 ± 0.93 mmol/L (range 1.7e21 mmol/L) to 5.45 ± 0.48 mmol/L (range 1.9e13.2 mmol/L) within 60 min (*P ¼ 0.003, as indicated by *). (B) Systemic serum lactate levels peaked 1 hr after beginning of perfusion at 3.54 ± 0.52 mmol/L (range 0.8e13.6 mmol/L), which was not significantly different from preoperative values (P > 0.05), and almost returned to preoperative levels within 12 hr (2.86 ± 0.56 mmol/L, P > 0.05 as compared with preoperative levels). (C) Serum CK levels peaked at 12e24 hr at values of 22,340 ± 6506 U/L (P ¼ 0.008 compared with preoperative levels, as indicated by *) and 22,998 ± 7493 U/L (P ¼ 0.02 compared with preoperative levels, as indicated by *), respectively, and declined later. (D) Serum myoglobin levels peaked at
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to calcium influx into cells and ultimately cell death. Morphological changes include endothelial cell swelling, increased vascular permeability, and microthrombi formation which clinically causes the ‘‘no-reflow phenomenon’’ with local thrombosis, edema development, tissue acidosis, and muscle necrosis.34 The washout of lactate, potassium, and myoglobin into the systemic circulation following reperfusion, also known as ‘‘postreperfusion syndrome’’, can lead to renal, cardiac, pulmonary, and multiorgan failure and eventually death.14 The concept of ‘‘controlled reperfusion,’’ first described for myocardial ischemia in 1986 and adopted for ALI in 1989,15 is characterized by an altered composition of the perfusate and modified conditions of the initial blood flow and perfusion pressure.16 Studies on animals as well as in humans have indicated that limitation of the initial reperfusion pressure and modification of the perfusate composition can prevent edema development, preserve muscle contractility and structural integrity, and thus reduce the incidence of death and complications such as fasciotomies and amputations. Perfusion pressure was kept below 60e70 mm Hg, and the perfusate consisted of a potassium-free 4:1 to 6:1 blood:crystalloid oxygenated solution with addition of glucose, buffer, amino acids, and free radical scavengers.15,17e21,35 However, a bloodbased oxygenated perfusion solution induces the production of oxygen-derived free radicals following reestablishment of oxidative metabolism during reperfusion, and thus promotes the development of IR injury.22,23,31 Therefore, in this study including 36 patients presenting with ALI, our group used a crystalloid, initially oxygen-free perfusate at room temperature (22 C). Positive
6e12 hr with a maximum of 20,078 ± 7598 U/L (at 12 hr, P ¼ 0.04 compared with preoperative levels, as indicated by *) followed by a decline to 1559 ± 849 U/L after 4 days. (E) Serum LDH levels peaked at 12 hr at values of 1514 ± 275 U/L (P > 0.05 compared with preoperative levels), declining to nearly preoperative levels within 48 hr. (F) Serum potassium did not change significantly and stayed within normal range throughout 24 hr (P > 0.05). (G) Preoperative negative base excess of 1.96 ± 0.96 mmol/L was equalized after 12 and 24 hr (P ¼ 0.02, as indicated by *), while pH stayed balanced at 7.4. (H) Serum creatinine remained at slightly elevated levels (normal: <106 mmol/L) throughout the study period without a significant increase (P > 0.05). However, 8 of the 36 patients (22.2%) developed postoperative renal failure and required continuous venovenous hemofiltration.
570 Schmidt et al.
effects of an oxygen-free perfusate were recently published in a rodent model of ALI.25 In addition, we added allopurinol to the perfusate because it is known to inhibit the enzyme xanthin oxidase which is predominantly involved in the production of oxygen-free radicals.23,30,32 Because hypothermia has been described to reduce postreperfusion skeletal muscle edema and to diminish IR injury,22,24,36 we perfused at 22 C. The perfusion pressure was adjusted to values below 70 mm Hg, as suggested by others.15,19,21 Despite the application of several measures to reduce the extent of IR injury, as outlined above, the overall mortality of our patients was not markedly reduced as compared with that in other studies. This might be because of the large number of complex vascular lesions in our patients with 52.8% central vascular occlusions including 36.1% Leriche syndrome, 13.9% aortic dissections, and 2.7% ruptured abdominal aortic aneurysms. Less than half of the patients (47.2%) had peripheral vascular occlusions. With the exception of the study published by Vogt et al. (19.5% mortality, 86% neurological recovery),19 who reported on 56% distal aortic occlusions (23 of 41 patients), all other studies describe mainly unilateral peripheral vascular occlusions. Beyersdorf et al.37 reported on 14 patients, only one of whom had distal aortic occlusion (14.3% mortality, 78% complete limb recovery). Bayersdorf et al. published 1996 on controlled limb reperfusion in 19 patients after cardiac operations, 3 of whom (15.8%) exhibited distal aortic occlusions.17 They found an 84% complete limb recovery rate, a 16% mortality rate (33% mortality in patients with distal aortic occlusions), and a 63% fasciotomy rate. Defraigne reported on 2 cases.18 One patient had a unilateral and one a bilateral occlusion. There were no amputations and no death, and in both patients prophylactic fasciotomy was performed. The results appear to be better in patients with only peripheral occlusions. The only randomized controlled study, so far, reported on 14 patients in the treatment arm with unilateral, peripheral occlusions, of whom 8 patients presented with chronic limb ischemia (no mortality, 2/14 ¼ 14.3% amputations).20 Using a simplified perfusion system, Wilhelm et al. reported on 7 patients presenting with unilateral ALI (iliac and femoral occlusions). In 6 patients, full neurologic recovery (85.7%) was achieved and no patient underwent amputation or died.21 Taking into account the severity of vascular disease in our patients, the rate of complete neurologic recovery in 20 of the 36 patients (55.6%) and the
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rate of predominant motor recovery in 2 of the 36 patients (5.6%) compare well in accordance with those reported in the literature. Blaisdell and Thompson reported on 17.6% and 16% rate of nonfunctional limbs after embolectomy for peripheral occlusions.27,38 In our patient cohort with over 50% central occlusions, 5 of the 36 patients (13.9%) had incomplete motor and sensory recovery. Similarly, the rate of fasciotomy performed in 10 of the 36 patients (27.8%), as well as the need for amputation in 4 of the 36 patients (11.1%) matches well with the results of other groups.17,20 In addition, the exceptionally long duration of acute ischemia of 33.7 hr (range 7e96 hr) may have had a major impact on outcome. Apart from the importance of a remaining collateral circulation, time delay from onset of acute ischemia to treatment has been shown to affect clinical outcome directly. If treatment was initiated within 12 hr after onset of acute ischemia, limb salvage rate was reported to be 93% and mortality amounted to 19%.11 If treatment started after 12 hr, however, limb salvage decreased to 78% and mortality increased to 31%.11 There seems to be a linear relationship between time delay and increased risk for limb loss and death.39 The question of venous drainage remains controversial. In only 2 human studies it was reported that the venous efflux was eliminated from the ischemic limb, which was associated with reduced mortality rates and improved functional results as compared with controls.19,20 Walker et al.20 used a specially designed drainage/occlusion catheter, which was inserted into the common femoral vein. A mean drainage volume of 775 mL was achieved passively by gravity in 6 patients. Because a total volume of 1835 mL reperfusion solution was administered, a volume challenge of more than 1 L remained in the patients. In other studies, volume challenges of between 500 and 1500 mL were reported with resulting increase in central venous pressure.18,21 In ALI patients who mostly have a considerable preoperative cardiac morbidity, strict intravascular volume control seems to be of great importance. Therefore, we used a circuit including venous drainage and in-line serial hemofiltration. Hereby, not only was a volume overload prevented, but a negative balance could be achieved by a mean filtration rate of more than half a liter (687 mL, median 500 mL). As an additional effect and maybe the most important benefit of ischemic limb isolated perfusion, the washout of large amounts of muscular waste products including potassium and hydrogen ions into the systemic circulation was prevented by hemofiltration. Systemic washout of muscle
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waste products has been shown to be responsible for the systemic reperfusion syndrome leading to multiorgan failure and death.33 Systemic lactate did not rise significantly, potassium remained stable, kidney function was preserved in most patients, and metabolic acidosis did not develop. Lethal cardiac arrhythmias, which are known to occur following reperfusion because of changes in serum potassium, were seen in only 1 patient. Systemic complications, however, could not be prevented completely in this high risk group of patients. The idea of using a heparin-coated perfusion system is to allow administration of lower dosages of heparin. This reduces the extent of bleeding during surgery and the potential need for blood products. However, this effect could not be demonstrated in our study because the respective data were not documented quantitatively. As a study limitation, we do not have a control group without controlled reperfusion of the ischemic limb. Therefore, we can only report observational, retrospective data with all their limitations. Another limitation of our study is the heterogeneity of pathologies in our patients resulting in very different surgical treatment regimes. However, our report on 36 patients presenting with ALI and treated by controlled limb reperfusion is the largest case series published so far. Certainly, a prospective, randomized study would be necessary to prove the advantage of the perfusion system described in this study.
CONCLUSIONS The application of an initially oxygen-free, mildly hypothermic, heparin-coated perfusion and hemofiltration system might potentially limit mortality and complication rate in ALI patients despite the severe underlying vascular lesions and the long ischemia time. Prospective, randomized studies comparing this perfusion technique with the conventional blood-based reperfusion system are necessary to prove the concept. Because of the relatively small number of patients over time, a multicenter trial would be desirable to increase the validity of the study. REFERENCES 1. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31(1 Pt 2):S1e296. 2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5e67.
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18. Defraigne JO, Pincemail J, Laroche C, et al. Successful controlled limb reperfusion after severe prolonged ischemia. J Vasc Surg 1997;26:346e50. 19. Vogt PR, Lutz HJ, Akint€ urk HI, et al. Prevention of postischemic tissue injury by controlled reperfusion: a preliminary study. Int J Angiol 2003;12:172e7. 20. Walker PM, Romaschin AD, Davis S, et al. Lower limb ischemia: phase 1 results of salvage perfusion. J Surg Res 1999;84:193e8. 21. Wilhelm MP, Schlensak C, Hoh A, et al. Controlled reperfusion using a simplified perfusion system preserves function after acute and persistent limb ischemia: a preliminary study. J Vasc Surg 2005;42:690e4. 22. Khalil AA, Aziz FA, Hall JC. Reperfusion injury. Plast Reconstr Surg 2006;117:1024e33. 23. Walker PM, Lindsay TF, Labbe R, et al. Salvage of skeletal muscle with free radical scavengers. J Vasc Surg 1987;5: 68e75. 24. Wright JG, Araki CT, Belkin M, et al. Postischemic hypothermia diminishes skeletal muscle reperfusion edema. J Surg Res 1989;47:389e96. 25. Dick F, Li J, Giraud MN, et al. Basic control of reperfusion effectively protects against reperfusion injury in a realistic rodent model of acute limb ischemia. Circulation 2008;118:1920e8. 26. Panetta T, Thompson JE, Talkington CM, et al. Arterial embolectomy: a 34-year experience with 400 cases. Surg Clin North Am 1986;66:339e53. 27. Thompson JE, Sigler L, Raut PS, et al. Arterial embolectomy: a 20 year experience with 163 cases. Surgery 1970;67: 212e20. 28. Paaske WP, Sejrsen P. Microvascular function in the peripheral vascular bed during ischaemia and oxygen-free perfusion. Eur J Vasc Endovasc Surg 1995;9:29e37.
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29. Beyersdorf F, Unger A, Wildhirt A, et al. Studies of reperfusion injury in skeletal muscle: preserved cellular viability after extended periods of warm ischemia. J Cardiovasc Surg (Torino) 1991;32:664e76. 30. Korthuis RJ, Granger DN, Townsley MI, et al. The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability. Circ Res 1985;57:599e609. 31. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159e63. 32. Parks DA, Granger DN. Ischemia-induced vascular changes: role of xanthine oxidase and hydroxyl radicals. Am J Physiol 1983;245:G285e9. 33. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002;10:620e30. 34. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation 2002;105:656e62. 35. Mitrev Z, Beyersdorf F, Hallmann R, et al. Reperfusion injury in skeletal muscle: controlled limb reperfusion reduces local and systemic complications after prolonged ischaemia. Cardiovasc Surg 1994;2:737e48. 36. Mowlavi A, Neumeister MW, Wilhelmi BJ, et al. Local hypothermia during early reperfusion protects skeletal muscle from ischemia-reperfusion injury. Plast Reconstr Surg 2003;111:242e50. 37. Beyersdorf F, Sarai K, Mitrev Z, et al. New surgical treatment for severe limb ischemia. J Invest Surg 1994;7:61e71. 38. Blaisdell FW, Steele M, Allen RE. Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery 1978;84:822e34. 39. Elliott JP Jr, Hageman JH, Szilagyi E, et al. Arterial embolization: problems of source, multiplicity, recurrence, and delayed treatment. Surgery 1980;88:833e45.