Septic ShockPhase 2NCT05141071
Effect of Ivabradine on Microcirculation and Cardiac Output in Septic Shock Patients
A Phase 2 study testing Ivabradine 5mg Tab in people with Septic Shock, run by Cairo University at 1 site in Egypt.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Septic Shock
- What is being tested?
- Ivabradine 5mg Tab
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 44 participants
- Where
- 1 siteEgypt
- Study dates
- 25 Nov 2021to 5 Jun 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 18 years.
- Patients admitted to ICU with septic shock.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effect of Ivabradine on Microcirculation and Cardiac Output in Patients Diagnosed With Septic Shock (Open-label Randomized Controlled Study)
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.
Read more
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®.
Read the 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).
- Conditions
- Septic Shock
- Being tested
- Ivabradine 5mg Tab, Placebo
- Keywords
- Micro-circulation, Septic shock, Cardiac output, Ivabradine
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ivabradine 5mg TabDrug
Also called procoralan, ATC code: C01EB17
Ivabradine will be administrated enterally
PlaceboDrug
Also called 0.9% saline solution
50 ml of saline will be administrated enterally
| Study group | Role | What they receive |
|---|---|---|
| Ivabradine | Experimental | In the study group, Ivabradine(I) group; patients will receive an enteral Ivabradine (dissolved in distilled water) 5mg twice daily (every 12 hours) via a naso-gastric tube. Receives: Drug: Ivabradine 5mg Tab |
| Placebo | Placebo comparator | the control group, Placebo (P) group; patients will receive 50 ml of saline twice daily also via a naso-gastric tube. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Microvascular flow index
absent (0), intermittent (1), sluggish (2), or normal (3)
Measured: 6 hours after administration of Ivabradine or Placebo.
Secondary outcomes (10)
Microvascular flow index
absent (0), intermittent (1), sluggish (2), or normal (3)
Measured: Before drug administration and at 1, 12, and 24 hours thereafter.
Total vessel density
mm/mm2
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Percentage of perfused vessels
Percentage
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Cardiac output
litres per minute
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Heart rate
beats per minute
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Central venous saturation
Percentage
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Central venous-arterial blood carbon dioxide partial pressure difference
mmHg
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Mean arterial blood pressure
mmHg
Measured: Before drug administration and at 1, 6,12, and 24 hours thereafter.
ICU length of stay
Days
Measured: from the date of patient recruitment till the date of discharge from the ICU or the date of death, assessed up to 28 days
28 days ICU mortality
Percentage
Measured: 28 days after ICU admission
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2021
- Study start25 Nov 2021
- Primary completion25 May 2022
- Study completion5 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- More trials run by Cairo UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 44 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cairo University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Amr Kamal Zahran, Cairo University
- Investigators
- Amr K Abdelhakim, MD, Principal investigator, Cairo University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05141071
- Sponsor's protocol ID
- MD-214 -2019
- Status last verified
- Aug 2022
- First submitted
- 12 Aug 2021
- Last updated
- 1 Sep 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Ivabradine on Microcirculation and Cardiac Output in Patients Diagnosed With Septic Shock (Open-label Randomized Controlled Study)
- ClinicalTrials.gov ID
- NCT05141071
- Acronym / sponsor ID
- MD-214 -2019
- Conditions
- Septic Shock
- Keywords
- Micro-circulation, Septic shock, Cardiac output, Ivabradine
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 44 participants (actual)
- Lead sponsor
- Cairo UniversityUniversity, hospital or other
- Study start
- 25 Nov 2021 (actual)
- Primary completion
- 25 May 2022 (actual)
- Study completion
- 5 Jun 2022 (actual)
- First posted
- 2 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ivabradine | Experimental | Drug: Ivabradine 5mg TabIn the study group, Ivabradine(I) group; patients will receive an enteral Ivabradine (dissolved in distilled water) 5mg twice daily (every 12 hours) via a naso-gastric tube. |
| Placebo | Placebo comparator | Drug: Placebothe control group, Placebo (P) group; patients will receive 50 ml of saline twice daily also via a naso-gastric tube. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age > 18 years.
- Patients admitted to ICU with septic shock.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ivabradine 5mg TabAlso: procoralan, ATC code: C01EB17Ivabradine will be administrated enterally | Drug | Ivabradine |
| PlaceboAlso: 0.9% saline solution50 ml of saline will be administrated enterally | Drug | Placebo |
Primary outcome
Microvascular flow index
Time frame: 6 hours after administration of Ivabradine or Placebo.
absent (0), intermittent (1), sluggish (2), or normal (3)
10 secondary outcomes
Microvascular flow index
Time frame: Before drug administration and at 1, 12, and 24 hours thereafter.
Total vessel density
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Percentage of perfused vessels
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Cardiac output
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Heart rate
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Central venous saturation
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Central venous-arterial blood carbon dioxide partial pressure difference
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
Mean arterial blood pressure
Time frame: Before drug administration and at 1, 6,12, and 24 hours thereafter.
ICU length of stay
Time frame: from the date of patient recruitment till the date of discharge from the ICU or the date of death, assessed up to 28 days
28 days ICU mortality
Time frame: 28 days after ICU admission
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2022.
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Septic Shock
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amr K Abdelhakim, MD principal investigator
Cairo University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ivabradine 5mg Tab in people with Septic Shock, run by Cairo University at 1 site in Egypt.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Egypt. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microvascular flow index (time frame: 6 hours after administration of Ivabradine or Placebo.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2022; AzTrials last refreshed its copy on 7 Nov 2026.