Effect of Ivabradine on Microcirculation and Cardiac Output in Septic Shock Patients

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).

Inclusion criteria

• Age > 18 years.
• Patients admitted to ICU with septic shock.

Exclusion criteria

• Patients contraindicated to begin oral feeding (NPO patients).
• Patients diagnosed with arrhythmia.
• Patients taking drugs with known or suspected interactions with ivabradine (strong CYP3A4 inhibitors and QT-prolonging agents) within five half-lives prior to inclusion and during the first 24 h of the study.