Summary
Background
Remote ischaemic preconditioning (RIPC) protects tissues against ischaemia-reperfusion (I/R) injury, a common occurrence in several clinical settings.
Aims
To evaluate whether RIPC has a beneficial impact on walking disability in arterial intermittent claudication.
Methods
A total of 20 patients with proven intermittent claudication underwent two treadmill walking tests with a 7-day interval in between; they were randomized according to the order in which they received either RIPC or a control procedure before the first treadmill test, with a crossover at the second test. Patients received three cycles of alternating 5-minute inflation and 5-minute deflation of blood-pressure cuffs on both arms, with inflation to a pressure of 200 mmHg in the RIPC procedure or 10 mmHg in the control procedure. Walking distances and limb oxygenation data, assessed with transcutaneous oximetry and near infrared spectroscopy measurements, were obtained during both RIPC and control procedures in all patients.
Results
Similar exercise intensities were achieved after the control and RIPC procedures. Walking distances did not significantly differ after the control and RIPC procedures (204 [141–259] m vs 215 [162–442] m, respectively; P = 0.22). Similarly, no difference was observed in terms of transcutaneous oxygen pressure change and near infrared spectroscopy measurements during exercise between the two procedures.
Conclusion
RIPC did not improve walking distance or limb ischaemia variables in patients with peripheral artery disease and intermittent claudication.
Résumé
Contexte
La capacité d’un préconditionnement ischémique à distance (RIPC) à protéger les tissus exposés à une ischémie-reperfusion a été démontrée dans plusieurs situations cliniques.
Objectif
Évaluer l’effet du RIPC dans l’artériopathie oblitérante des membres inférieurs avec claudication.
Méthodes
Vingt patients souffrant d’une claudication des membres inférieurs avérée ont réalisé 2 tests de marche sur tapis à 7 jours d’intervalle. Ils ont été randomisés pour recevoir, soit le RIPC, soit la procédure contrôle lors du premier test puis les procédures ont été inversées pour le second test. Un brassard à tension a été gonflé aux deux bras en alternance selon une séquence de 3 inflations de 5 minutes espacées de 5 minutes. Le brassard était gonglé à 200 mmHg pour le RIPC et à 10 mmHg pour la procédure contrôle. La distance de marche et les paramètres d’oxygénation des membres inférieurs mesurés par oxymétrie transcutanée et par spectroscopie infra-rouge ont été relevés chez tous les patients.
Résultats
L’intensité des efforts et les distances de marche (204 [141–259] m dans le groupe contrôle vs 215 [162–442] m dans le groupe RIPC ; p = 0,22) n’ont pas été significativement différentes entre les deux groupes. De même, il n’a pas été observé de différence entre les deux procédures concernant les paramètres d’oxygénation tissulaire.
Conclusion
Le RIPC n’a pas significativement modifié les distances de marche et les paramètres d’oxygénation tissulaire chez des patients atteints d’artériopathie oblitérante des membres inférieurs avec claudication.
Background
Prolonged ischaemia induces cell dysfunction and death in several cardiovascular diseases. The damage can be amplified by restoring appropriate blood flow. The whole phenomenon is named ischaemia-reperfusion (I/R) injury. In 1986, Murry et al. first reported the concept of ischaemic preconditioning: a series of short, non-lethal periods of ischaemia interspersed with reperfusion periods that rendered a target organ more resistant to a subsequent ischaemic event . First assessed within one organ by Przyklenk et al. in 1993 , remote ischaemic preconditioning (RIPC) is a conditioning strategy in which an organ or tissue other than the target is exposed to brief periods of I/R for conditioning . Given its advantage of avoiding invasive procedures, the RIPC technique using transient limb ischaemia as a stimulus has emerged as an attractive strategy in various clinical settings . RIPC was proven to be able to attenuate I/R injury in patients undergoing cardiac surgery , elective surgery for abdominal aortic aneurysm , elective percutaneous coronary intervention and reperfusion in acute myocardial infarction . RIPC was also found to improve maximal performance in highly trained swimmers and cyclists . While intensive exercise may represent a physiological form of ischaemic insult in healthy humans, even moderate exercise (i.e. walking) exposes patients with peripheral artery disease and intermittent claudication to the risk of I/R injury. For this reason, the Protection de l’artéritique par conditionnement à distance ([PARADIS]: arterial protection via remote conditioning) study was designed to determine whether RIPC induced by transient arm ischaemia had a beneficial impact on the maximal walking distance in patients with intermittent claudication.
Methods
Study design
The PARADIS study was a prospective, double-blind, crossover, randomized controlled trial, conducted at the University Hospital in Angers, France. All participants provided written informed consent. The study protocol was approved by the regional ethics committee and conducted in accordance with the Declaration of Helsinki. The study was registered at ClinicalTrials.gov (Identifier: NCT01971879 ).
Study criteria
We screened patients aged ≥ 18 years who were consecutively referred to our laboratory for typical intermittent lower-limb claudication. To be eligible, patients had to exhibit an ankle-to-brachial index < 0.90 either in the symptomatic leg or in both, as well as scoring positive on a treadmill test performed in our laboratory. A positive test was defined as the combination of claudication experienced during the treadmill test, a walking distance < 750 m, and a positive exercise oximetry test that was ipsilateral to symptoms. A positive oximetry test was defined as a DROP index (changes in transcutaneous pressure in oxygen from rest at the leg minus changes at the chest level) less than –15 mmHg .
Patients displaying the following criteria were excluded from the study: exercise hypoxaemia, defined as the loss of ≥ 4 points of saturation during the treadmill test; metformin intake within the previous seven days; and humeral systolic blood pressure at rest > 200 mmHg.
Randomization and masking
The randomization list was computer generated by an independent methodologist. The randomization results were sealed in envelopes and assigned to the patients after their enrolment into the study. Each patient underwent two treadmill tests, separated by a 7-day interval; each test was performed at the same time of day. Patients were randomized according to the order in which they underwent either RIPC or a control procedure before the first treadmill test, with a crossover at the second test.
All study investigators and participants were blinded to treatment assignment for the duration of the study. Only the nurse was informed of the procedure (RIPC or control) that had to be performed before the treadmill test. The physician supervising the treadmill test was not told which procedure was performed prior the treadmill test, and the patients were not told which procedure offered a potential beneficial impact. Lastly, patients were requested not to pass on any information to the physician supervising the treadmill test.
Procedures
In both the RIPC and control procedures, patients received three cycles of alternating 5-minute inflation and 5-minute deflation of standard upper-arm blood-pressure cuffs on both arms. The blood-pressure cuffs were inflated to a pressure of 200 mmHg and 10 mmHg in the RIPC and control procedures, respectively. The walking treadmill test began 5 minutes after the release of the last series of cuff inflation.
Treadmill test
The standard treadmill test was performed at a 10° slope and speed of 3.2 km/h (transition phase from 0 to 3.2 km/h lasting 1 minute). In the absence of symptoms or in cases of non-limiting symptoms after 15 minutes (approximately 750 m), the speed and slope of the treadmill were progressively increased every minute. The exercise was discontinued at the patient’s request. The maximal walking distance was then recorded. Oxygen consumption during the treadmill test (VO 2 , in mL O 2 /kg/min standard temperature and pressure, dry [STPD]), carbon dioxide production (VCO 2 , in mL CO 2 /kg/min STPD) and heart rate (HR, in beats per minute [bpm]) were all measured and recorded continuously. VO 2 and VCO 2 at the end of exercise (VO 2 end in mL O 2 /kg/min STPD and VCO 2 end in mL CO 2 /kg/min STPD) were used for the analysis. Maximum HR during exercise (HRmax) and HR at both 1 and 2 minutes post exercise were used for the analysis. The maximal walking distance was the major endpoint of the study.
Tissue oxygenation
Two different tools were used to detect limb exercise-induced regional blood flow impairment: transcutaneous oxygen pressure (TcPO 2 ) and near infrared spectroscopy (NIRS).
TcPO 2 exercise profile
The TcPO 2 exercise profile is a measurement of oxygen partial pressure (PO 2 ) taken from the skin that also offers the advantage of detecting and accounting for exercise-induced changes in the chest by means of a reference-point chest electrode. The standard technique consists of attaching a minimum of five TcPO 2 probes, one to each calf, one to each buttock and one to the chest, to measure potential systemic changes (TCM400; Radiometer, Copenhagen, Denmark). The calibrations and procedures to be used for the TcPO 2 recordings have been extensively described elsewhere . The DROP index has been proven to provide better accuracy in detecting proximal and distal ischaemia than TcPO 2 absolute values . To measure the DROP index, we corrected the TcPO 2 change from rest on each limb probe to align with the corresponding absolute change from rest of the chest electrode TcPO 2 at each 2-second interval, subtracting or adding the chest TcPO 2 changes from the results of the TcPO 2 changes at limb if the chest TcPO 2 increased or decreased, respectively. Because of the potential differences in test duration, we used the value of the DROP index observed at the end of exercise (DROPend) for our analysis.
NIRS-measured saturation
Tissue oxygenation in both lower limbs was also measured by NIRS (NIRO-200NX system; Hamamatsu Photonics, Hamamatsu City, Shizuoka, Japan). NIRS is a surface technique used for measuring skin and muscle oxygen saturation, which has the advantage of being instantaneous . NIRS is a promising tool for detecting ischaemia in peripheral artery disease . The principles of NIRS measurement have been described elsewhere . Briefly, two NIRS probes were placed on the gastrocnemius to project near-infrared light through the biological tissue. The levels of oxyhaemoglobin, deoxyhaemoglobin and haemoglobin oxygen saturation were then recorded every second during rest, exercise and recovery. The absolute haemoglobin oxygen saturation value at the end of exercise (StO 2 end) was used for the analysis.
Blood lactates
Two venous blood samples of 3 mL were collected in vacuum containers in a sodium fluoride solution. These samples were taken just before the start of the treadmill test and 2 minutes after the end. The samples were placed on ice and transported to the laboratory within 15 minutes of collection. Serum lactate concentrations were measured by means of a routine automated assay (ARCHITECT c16000; Abbott Diagnostics, Lake Forest, IL, USA).
Statistical analysis
At the time of designing the PARADIS study, no data existed concerning RIPC use in peripheral artery disease. Conducting RIPC before an incremental bicycle exercise test was found to improve maximal oxygen consumption and power output in 15 healthy, well-trained cyclists . Similarly, RIPC has been shown to improve maximal performance in 18 highly trained swimmers . We therefore decided arbitrarily to include 20 patients.
All statistical tests were conducted by means of a commercially available statistical programme (SPSS15; SPSS, Inc., Chicago, IL, USA). The data are expressed as means ± standard deviations or medians (25th–75th percentiles), unless stated otherwise. Shapiro-Wilk and Kolmogorov-Smirnov tests indicated a normal (Gaussian) distribution of the data, except for the walking distance during the treadmill test. We therefore proceeded with a paired two-tailed Student’s t test to assess differences in oxygen consumption, carbon dioxide production, DROPend, StO 2 end, heart rate and lactate concentration between the two groups, along with a Wilcoxon test for the walking distance. A two-tailed P < 0.05 was set to indicate statistical significance.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
