Effect of Ivabradine on Microcirculation and Cardiac Output in Septic Shock Patients
Condition: Septic Shock
MeSH terms: Shock, Septic; Shock
Study type: Interventional
Phase: Phase 2

Summary: 
      Persistent tachycardia in sepsis or multi-organ dysfunction syndrome (MODS) is an ominous
      sign. This usually comes under control with judicious use of antibiotics, fluid
      resuscitation, sedation. Uncontrolled tachycardia in systemic inflammatory response syndrome
      and sepsis deprives the heart muscle of oxygen. As it progresses, insufficient heart muscle
      nutrition eventually leads to myocardial dysfunction. It can also present as heart failure.
      In acute coronary syndromes, beta blockers are used to control heart rate. However in MODS,
      it cannot be used due to hemodynamic instability and worsened myocardial function.

      Sinoatrial (SA) myocytes are the pacemaker cells in the heart. Pacemaker activity involves
      several ionic currents that influences spontaneous depolarization of SA node including I(f)
      current. The word I(f) means funny, because this current has unusual properties as compared
      with other currents known at the time of its discovery. It is one of the most important ionic
      current for regulating pacemaker activity in SA node.

      Ivabradine is an I(f) current inhibitor in SA node. Currently, it is the only agent shown to
      clinically lower heart rate with no negative inotropism or effects on conduction and
      contractility.so usage of Ivabradine to control tachycardia in patients with septic shock may
      help to improve myocardial filling and cardiac output.

      Marcos L.Miranda et al. found that Ivabradine was effective in reducing microvascular
      derangements evoked by experimental sepsis, which was accompanied by less organ dysfunction.
      These results suggest that ivabradine yields beneficial effects on the microcirculation of
      septic animals.

      No data found on effect of Ivabradine on the microcirculation of human. In this study the
      investigators will investigate the effect of Ivabradine on perfusion in capillary circulation
      using Cytocam video microscope, Braedius®.
    

Detailed description: 
      All patients will be monitored with non-invasive arterial blood pressure, five-lead
      electrocardiography (ECG), pulse oximetry, and invasive arterial pressure (AP) obtained from
      a radial arterial catheter.

      Upon ICU admission, according to the investigators' institutional protocol, fluid
      responsiveness will be done for all enrolled patients to determine the need for fluid therapy
      (fluid responsiveness is defined as an increase in the stroke volume (SV) by 15% after
      infusing 500 ml crystalloids). Fluid boluses will be repeated till the patients become fluid
      unresponsiveness. If mean arterial pressure (MAP) remained < 65 mm Hg after administration of
      the initial fluid bolus, norepinephrine infusion will be titrated to maintain MAP ≥ 65 mmHg.

      After establishment of blood pressure and normovolemia, the patient will receive either
      placebo or Ivabradine according to the group randomization.

      Assessment of microcirculation:

      Sublingual microcirculatory measurements will be performed with an incident dark-field
      illumination device Cytocam- incident dark-field illumination (IDF), Braedius Medical,
      Huizen, Netherlands). The new technology Cytocam-IDF imaging device consists of a pen-like
      probe incorporating IDF illumination with a set of high-resolution lenses projecting images
      on to a computer-controlled image sensor synchronized with a short-pulsed illumination light.
      Flow characteristics of the microvasculature will be quantified using the microvascular ﬂow
      index (MFI), a semiquantitative technique consistent with recommendations from a consensus
      conference on microcirculatory image analysis in human subjects.The image is divided into
      four quadrants and the vessels <20 μ m diameter are assigned a score based on the predominant
      flow characteristics of the vessels in that quadrant (0 = absent flow; 1 = intermittent; 2 =
      sluggish; 3 = normal). The values in each quadrant will be averaged to give an MFI for each
      sublingual site at each time point. To determine heterogeneity of perfusion, the flow
      heterogeneity index will be calculated as the highest MFI minus the lowest MFI divided by the
      mean MFI. A quantitative measurement of the total vessel density (TVD), perfused vessel
      density (PVD), and proportion of perfused vessels (PPV), will also be taken automatically
      with dedicated software (Cytocam video microscope, Braedius®, Netherlands). The observer will
      be well-trained and experienced with offline analysis. On all videos, post-process contrast
      enhancement will be applied. Thereafter videos will be blinded and anonymized so that the
      observer will not be aware of the used drug.

      Assessment of cardiac output using LiDCOrapid Examination:

      A 20-G arterial catheter will be placed in the radial artery and connected to the standard
      monitor. LiDCOrapid (LiDCO Ltd, Cambridge, UK) will be connected to the monitor and data will
      be extracted from the AP line. Values for AP and heart rate extracted by LiDCOrapid will be
      in all patients within 5% of the standard monitor's displayed values (datex monitor). The
      LiDCO system is based on a PulseCO algorithm for calculating nominal cardiac output (CO), SV
      and heart rate from AP waveform characteristics.

      Assessment of metabolic parameters:

      Metabolic parameters including central venous saturation (ScvO2), central venous-arterial
      blood carbon dioxide partial pressure difference (Pv-aCO2), and arterial lactate will be
      recorded. Simultaneous blood gas measurements will be obtained from arterial and central
      venous catheters. Blood gas analysis will be performed and arterial lactate concentration
      will be determined using the GEM Premier 3000 (Instrumentation Laboratory, Bedford, MA, USA).
      ScvO2 will be calculated from a sample taken from the central venous catheter, the tip of
      which will be confirmed to be in the superior vena cava near or at the right atrium by
      radiography. The (Pv-aCO2) will be calculated as the difference between the partial pressures
      of central venous carbon dioxide (PcvCO2) and arterial carbon dioxide (PaCO2).
    

Intervention name(s): Ivabradine 5mg Tab; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ivabradine will be administrated enterally; 50 ml of saline will be administrated enterally
Other intervention name(s): procoralan, ATC code: C01EB17; 0.9% saline solution
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Micro-circulation; Septic shock; Cardiac output; Ivabradine