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This study aims to investigate the effect of angiotensin II on microcirculation and peripheral perfusion in patients with septic shock.
Shock is a syndrome characterized by acute circulatory failure resulting in impaired peripheral tissue perfusion. Distributive shock is the most common type of shock and is usually caused by severe sepsis. Distributive shock is characterized by profound vasodilatation leading to decreased arterial blood pressure and impaired organ perfusion despite high cardiac output.
The use of vasopressors is an essential management line for distributive sock. Two groups of vasopressors are usually used for management of shock: catecholamines and vasopressin-like peptides. There is a continuous need for other vasopressors because:
1- Available vasopressors have narrow therapeutic window. 2- Patients with severe hypotension refractory to the currently available classes usually die.
A third system is usually engaged in the physiology of shock which is Renin-Angiotensin-aldosterone system. Angiotensin II is a natural hormone which is a potent vasopressor; moreover, angiotensin II stimulates the production of both antidiuretic hormone and adrenocorticotropin hormone.
In a pilot study, angiotensin II was reported as an effective rescue vasopressor in septic shock patients on multiple vasopressors. Angiotensin II improved mean arterial pressure and helped in reduction of the doses of catecholamines. In a recent large randomized controlled trial, angiotensin II improved blood pressure in catecholamine-resistant distributive shock patients.
Microcirculation is the primary site of oxygen and nutrient exchange. Maintenance of microcirculatory perfusion is a prerequisite for preservation of organ function. Multiple organ failure is common in patients with distributive shock despite maintenance of parameters of global perfusion due to disrupted microcirculatory perfusion. Furthermore, restoration of microcirculatory perfusion was correlated with improvement in survival. This study aims to investigate the effect of angiotensin II on peripheral microcirculation in patients with septic shock.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Angiotensin group | Experimental | Patients will receive Angiotensin II at a starting dose of 20 ng/Kg/min. During the first 30 minutes after randomization, the angiotensin II infusion will be titrated to achieve a mean arterial pressure of 65-75 mmHg while the norepinephrine infusion will be withdrawn and stopped. Following a stabilization of 60 minutes, the angiotensin II infusion is titrated to achieve a mean arterial pressure of 85-95 mmHg. Following a 30 minutes wash-in period and a 60 minutes stabilization period, a third set of measurements will be taken. Then, the angiotensin II infusion will be withdrawn in small steps and replaced by a norepinephrine infusion which will then be titrated to achieve a mean arterial pressure of 65-75 mmHg. Then, the final set of measurements will be taken. |
|
| Normal saline group | Placebo Comparator | Patients will receive normal saline infusion in addition to norepinephrine infusion. The same mean arterial pressure levels (65-75 mmHg > 85-95 mmHg > 65-75 mmHg) will be achieved by titration of the norepinephrine infusion. Identical wash-in and stabilization periods will be kept as in the study group. Measurements will be taken at the same time points as in the study group. The maximum dose of norepinephrine applied will be 0.7 mcg/kg/min. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Angiotensin II | Drug | Patients will receive angiotensin-II at a starting dose of 20 ng/Kg/min. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean flow index | Mean flow index measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands). The microvascular flow index (MFI) will be used to quantify microvascular blood flow. In this score, flow is characterized as absent (0), intermittent (1), sluggish (2), or normal (3), for each patient the values from 5 videos will be averaged. Since our investigation will be focused on small vessels, calculations will be separately performed for vessels with a diameter less than 20 ųm. | 6 Hours |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of perfused vessels | Proportion of perfused vessels measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ahmed Mukhtar, Professor | Head of research committee section in anesthesia department | Study Director |
| Martin W Dünser, Professor | Department of critical care, University of London college hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cairo University | Cairo | Egypt |
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| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
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| ID | Term |
|---|---|
| D000804 | Angiotensin II |
| D000077330 | Saline Solution |
| D009638 | Norepinephrine |
| ID | Term |
|---|---|
| D000809 | Angiotensins |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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| Normal saline | Drug | Patients will receive normal saline. |
|
| Norepinephrine | Drug | patients will receive norepinephrine infusion adjusted according to blood pressure |
|
|
| 6 Hours |
| Perfused vessel density | Perfused vessel density measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands) | 6 Hours |
| systolic blood pressure | systolic blood pressure measured in mmHg | 6 hours |
| Diastolic blood pressure | diastolic blood pressure measured in mmHg | 6 hours |
| Heart rate | heart rate in beats per minute | 6 hours |
| Serum lactate | Serum lactate measured in milligrams per deciliter | 6 hours |
| Urine output | quantity of urine in milliliters | 6 hours |
| Serum Creatinine | serum creatinine measured in milligrams per deciliter | 24 hours |
| Serum Sodium | Serum sodium measured in milligrams per deciliter | 24 hours |
| Serum potassium | Serum potassium measured in milligrams per deciliter | 24 hours |
| Cardiac output | quantity of blood pumper by the heart measured by electrical cardiometry in liters per minute | 6 hours |
| systemic vascular resistance | systemic vascular resistance measured by electrical cardiometry | 6 hours |
| Norepinephrine requirements | total requirement of norepinephrine needed to maintain mean arterial blood pressure above 65 mmHg | 6 hours |
| perfusion index | proportion of pulsatile to non-pulsatile portions in peripheral circulation | 6 hours |
| total fluid intake | amount of fluids received by the patient in milliliters | 24 hours |
| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D000588 | Amines |
| D015306 | Biogenic Monoamines |
| D001679 | Biogenic Amines |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |