Limb RIPC in Patients Undergoing Lung Lobectomy. Study of Oxidative Lung Damage

Background: In patients undergoing lung lobectomy, lung collapse and re-expansion after resection is associated to severe oxidative lung injury. The researchers hypothesized that remote ischemic preconditioning (RIPC) could reduce oxidative lung injury and improve the oxygenation parameters.

Methods: We designed a single-centre, randomized, prospective and double-blind study, conducted in fifty-three patients with non-small cell lung cancer undergoing elective lung lobectomy.

Fifty-three patients were randomly assigned to 2 groups: 26 patients received limb RIPC (3 cycles: 5 min ischemia/5 min reperfusion induced by an ischemia cuff applied on the thigh) and 27 controls.

Time course of oxidative stress marker levels was simultaneously studied in exhaled breath condensate (EBC) and blood at four specific time points: T0, pre-operatively; T1, during operated lung collapse and one-lung ventilation (OLV); T2, immediately after resuming two-lung ventilation (TLV); T3, 120 min after resuming TLV.

EBC 8-isoprostane was the primary outcome. Secondary outcomes included PaO2/FiO2, other pulmonary oxygenation variables, other oxidative markers (NO2-+NO3-, H2O2) and pH.

In patients with non-small-cell lung carcinoma (NSCLC), the surgical resection remains the primary and preferred approach to the treatment of stage I-II NSCLC. Despite advances in surgical techniques, these patients have a risk of development a severe lung injury, because during lobectomy the operated lung is completely collapsed and hypoperfused. This hypoperfusion is due in part to a reactive hypoxic pulmonary vasoconstriction in response to alveolar hypoxia, which optimizes gas exchange. Hypoxic or ischemic tissues increase the reactive oxygen species (ROS) production in mitochondria respiratory chain, because the respiratory cytochromes become redox-reduced allowing them to directly transfer electrons to O2 producing large amount of superoxide anions, which contributes to more vasoconstriction. The primary site of ROS production during hypoxia appears to be complex III, and paradoxical increase of ROS production during hypoxia may be explained by an effect of O2 within mitochondria inner membrane on the ubisemiquinone radical in complex III. Thus, patients undergoing lobar resection suffer a relative lung ischemia-hypoxia during the collapse, followed by expansion-reperfusion injury attributed to the production of ROS. Acute lung injury (ALI) and postoperative adult respiratory distress syndrome (ARDS) after major thoracic surgery remains the leading cause of death from pulmonary surgery. Because to date few studies have assessed this subject in detail, we have showed recently also an increase of oxidative stress damage during lung lobectomy, associated to a direct correlation of lung collapse time with oxidative stress marker levels in exhaled breath condensate and blood.

Remote ischemic preconditioning (RIPC) has emerged as a procedure for different organs protection against acute ischemia/reperfusion injury as is shown by different clinical trials. Although most studies have been conducted in patients undergoing coronary artery by-pass grafting and valvular heart surgery, also were observed protective effect in other organs as kidneys, intestine and others. RIPC is an innate and powerful mechanism where a tissue or organ is exposed to a transient episode of ischemia-reperfusion and then confer a global resistance to subsequent episodes of ischemia in remote organs. However the potential mechanism through which RIPC works is unclear. The signal transfer to organs is through humoral, neuronal and systemic communications, which activate specific receptors, intracellular kinases and mitochondrial function. Recently has been reported that limb RIPC attenuates intestinal and pulmonary injury after abdominal aortic aneurysm repair and also after pulmonary resection, where they found significant decreases in serum malondialdehyde in treated group with RIPC.

EBC collection is non-invasive method for obtain samples from the lower respiratory tract, which contains large number of biomarkers including isoprostanes, nitrogen oxides and hydrogen peroxide. The isoprostanes are a family of products from arachidonic acid produced by the non-enzymatic action of ROS. Increased blood level of 8-isoprostane is considered a reliable index of lipid peroxidation in vivo due to its chemical stability. NO. and superoxide anion (O2.-) react to form ONOO-, which is a powerful oxidant. Nitrites (NO2-) and nitrates (NO3-) are end products of nitric oxide (NO.) and peroxynitrite anion (ONOO-) metabolism and present in the epithelial lining fluid of the respiratory tract. Hydrogen peroxide (H2O2) is a ROS and volatile molecule produced from conversion of superoxide anion (O2.-) to H2O2 by superoxide dismutase and released from inflammatory and epithelial cells of respiratory system.

The aim of this study is to investigate whether RIPC would reduce the oxidative lung injury in cancer patients undergoing lung lobectomy. The primary outcome of this study was compare 8-isoprostene and others oxidative marker levels in EBC and blood between patients receiving RIPC and control patients. Also to evaluate whether there is a correlation between OLV duration and oxidative stress marker levels in EBC and blood.

Eligibility Criteria:
Inclusion Criteria:

* lung cancer patients (clinical stage I-II NSCLC)
* elective lung lobectomy
* patients were randomized and prospectively studied in a single centre
* all patients were ASA physical status I-II category
* pregnants

Exclusion Criteria:

* previous radiotherapy-chemotherapy
* previous thorax surgery
* PaO2 \<60 mmHg
* FEV1 \<50%
* cardiac disease (NYHA II-IV)
* active infections and temperature \>37.5 ºC