Limb RIPC in Patients Undergoing Lung Lobectomy. Study of Oxidative Lung Damage
Condition: Acute Lung Injury
MeSH terms: Lung Injury; Acute Lung Injury
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): remote ischemic preconditioning (RIPC)
Intervention type(s): Procedure
Intervention description(s): Remote ischemic preconditioning: The limb RIPC was applied after the induction of anaesthesia and consisted of 3 cycles: 5 min of ischemia by a cuff-inflator on a thigh and inflated to 200 mmHg, followed by 5 min deflated. The control group had during the same time a deflated cuff on a thigh.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: oxidative stress; lung lobectomy