Intestinal microcirculation dysfunction in sepsis:pathophysiology,clinical monitoring,and therapeutic interventions

A-ling Tang ,Mei-jia Shen ,Guo-qiang Zhang

1 Graduate School,Beijing University of Chinese Medicine,Beijing 100029,China

2 Graduate School,Peking Union Medical College,Beijing 100730,China

3 Department of Emergency,China-Japan Friendship Hospital,Beijing 100029,China

BACKGROUND: Intestinal microcirculation dysfunction is an important factor that causes poor prognosis in sepsis patients and is an important pathophysiological basis for the occurrence and development of sepsis.DATA RESOURCES: PubMed,Web of Science,and China National Knowledge Infrastructure(CNKI) were searched from inception to August 1,2021.The search was limited to the English language only.Two reviewers independently identified studies related to intestinal microcirculation dysfunction in sepsis.Exclusion criteria were duplicate articles according to multiple search criteria.RESULTS: Fifty articles were included,and most of them were animal studies.These studies reported pathogenesis,including endothelial dysfunction,leukocyte recruitment and adhesion,microthrombus formation,microcirculation hypoperfusion,and redistribution of intestinal wall blood flow.The monitoring methods of intestinal microcirculation were also diverse,including handheld microscopes,intravital microscopy (IVM),laser Doppler blood flow instruments,laser speckle contrast imaging,tissue reflectance spectrophotometry,biochemical markers of intestinal ischemia,and histopathological examination.In view of the related pathogenesis of intestinal microcirculation disorder in sepsis,existing studies also have different opinions on its treatment.CONCLUSIONS: Limited by monitoring,there are few clinical studies on intestinal microcirculation dysfunction in sepsis.Related research mainly focuses on basic research,but some progress has also been made.Therefore,this review may provide a reference for future research on intestinal microcirculation dysfunction in sepsis.

KEYWORDS: Sepsis;Microcirculation;Intestinal barrier;Intestinal ischemia;Review

INTRODUCTION

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection.Tissue hypoperfusion is an important pathophysiological process in the occurrence and development of sepsis.Long-lasting microcirculation dysfunction can drive the pathological process of sepsis.The intestinal mucosa is particularly sensitive to microcirculation dysfunction,which can easily lead to the impaired intestinal barrier function and the migration of intestinal bacteria to other organs.The related research on intestinal microcirculation dysfunction in sepsis is an important direction in the medical field,and some research progress has been made.This study aims to provide a summary of the current research.

METHODS

Search strategy

We systematically performed an electronic search of PubMed,Web of Science,and China National Knowledge Infrastructure (CNKI) from inception to August 1,2021.The search was limited to the English language only.We combined MeSH and title/abstract keywords,such as“sepsis”,“septic shock”,“intestinal”,“gastrointestinal”,“dysfunction”,and “microcirculation” to identify all studies related to intestinal microcirculation dysfunction in sepsis.

Study selection

Two authors independently identified the articles for inclusion based on their titles and abstracts,evaluated the full texts of the papers,and reviewed the bibliographies of each article to identify additional studies.

Exclusion criteria

Studies that were published before 2010 and duplicate articles were excluded.

RESULTS

A total of 108 articles were identified.After reviewing the titles and abstracts,which was followed by assessing the full text,50 articleswere included (Figure 1),and most of them were animal studies.These studies reported pathogenesis,including endothelial dysfunction,leukocyte recruitment and adhesion,microthrombus formation,microcirculation hypoperfusion,and redistribution of intestinal wall blood flow.The monitoring methods of intestinal microcirculation were also diverse.In view of the related pathogenesis of intestinal microcirculation disorder in sepsis,existing studies also have different opinions on its treatment.

Figure 1. The flowchart of the study.

DISCUSSION

Pathogenesis

In patients with sepsis,endothelial dysfunction is one of the key pathophysiological mechanisms of microcirculation dysfunction,which is also an essential link in leukocyte-endothelial interactions.Studies have shown that nitric oxide (NO) plays an important role in vascular endothelial function.In the vascular endothelium,an imbalance between inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase(eNOS) may play a certain role in sepsis microcirculation dysfunction.The integrity of the vascular endothelial glycocalyx plays a key role in the intestinal microcirculation,which can inhibit intercellular adhesion.Glycocalyx degradation can occur in certain pathologic conditions,such as septic shock.The excessive release of histones may cause changes in the structure and function of the endothelium,which will further lead to microcirculation dysfunction.When the cell is severely damaged,histones can be passively released outside the cell or formed through neutrophil extracellular traps (NETs),which is a special type of programmed cell death (PCD).The increase in leukocyte-endothelial interactions may be related to the increase in E-selectin expression in endothelial cells.

Various proinflammatory signals appear in sepsis,including the expression of adhesion molecules.Selectin and integrin are important adhesion molecules in the initial steps of leukocyte recruitment,which can trigger the rolling and adhesion process of leukocytes.When leukocytes adhere to the vascular endothelium,they release a series of inflammatory mediators,cytotoxic substances,elastase,myeloperoxidase,and reactive oxygen species (ROS).These substances can not only damage the function of the vascular endothelium,but also indirectly activate the coagulation process.

In sepsis,inflammation and clotting interact with each other.This pathological condition leads to the formation of microthrombi.Pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs) in the early stages of sepsis are thought to be involved in the formation of immune thrombosis.At the same time,the von Willebrand factor (vWF) is released to the outside of the cell in large quantities.It can be used as a carrier protein for factor VIII and mediate platelet aggregation and adhesion at the site of endothelial cell injury.With the activation of the coagulation cascade,thrombin activates endothelial cells and platelets,which will lead to excessive release of P-selectin.This process promotes the granulocyte-platelet interaction,which in turn leads to platelet-neutrophil aggregation.

Small blood vessels need sufficient arterial pressure to maintain perfusion.The increased permeability of blood vessels leads to continuous leakage of fluid and protein to the outside of the vessels,and the effective blood volume is reduced.These pathologic conditions lead to hypoperfusion of the microcirculation.Microcirculation changes are not related to systemic hemodynamics and the microcirculation response is not synchronized with systemic hemodynamics during treatment.

Physiologically,the blood flow distribution in the intestinal wall is uneven,and the mucosal layer receives 70%-80% of the blood supply.In sepsis,the reduction in mucosal blood flow is greater than that in serosal/muscular blood flow.Intestinal villous vessels have physiological defects,and their unique “hairpin capillary structure” causes the blood supply to the villous tip to be uneven.As a result,intestinal villous microcirculation is more prone to disturbance than other parts of the intestinal wall.In addition,similarities between intestinal and sublingual microcirculation also exist.

During sepsis,excess oxygen free radicals are produced,which results in depletion of endogenous antioxidants and loss of protection against potential oxygen free radical damage.Some studies have also confirmed mitochondrial dysfunction.Dysfunction of the mitochondrial electron transport system (ETS) makes aerobic metabolism disorders more serious.A study found that in septic rats,the increase in GPR55 expression mediates the interaction between leukocytes and endothelium in the microcirculation.Intestinal microcirculation disorders can be reversed by Tolllike receptor 4 (TLR4) antagonists.

Monitoring methods

Currently,there are three different handheld microscopes that can be used to directly observe the intestinal microcirculation,including the orthogonal polarization spectral (OPS)imaging technique,sidestream dark-field(SDF)imaging,and incident dark field (IDF)imaging.The microvascular flow index (MFI),total vascular density(TVD),perfusion vascular density (PVD),and perfusion vascular vessels (PPV) were commonly used for observation.

Intravital microscopy (IVM) is often used to observe the intestinal microcirculation in sepsis.Functional capillary density (FCD) was used to represent the microcirculatory perfusion of the tissue.The number of adherent leukocytes (cells/mm) and the number of rolling leukocytes (cells/min) were recorded.This technology can be used not only to observe the perfusion of the microcirculation but also to observe the adhesion and rolling of the microcirculation leukocytes,which reflects the leucocyte-endothelial interaction and the inflammation of the microcirculation.

The principle is based on the emitted laser beam being scattered by the tissue and part of the light being absorbed.In applications involving intestinal microcirculation,the main observation index is the blood flow of the microcirculation,which is expressed as the percentage of the blood flow to the baseline after intervention and reflects the blood flow velocity and blood flow of the microcirculation.

This technique is currently commonly used to monitor blood flow in brain tissue,and it is also used in septic intestinal microcirculation monitoring.The main observation index is the blood flow intensity of the microcirculation,which is expressed in perfusion units(PU) of flow and is related to the product of the moving speed and the concentration of the moving red blood cells in the tissue sample.

In applications involving intestinal microcirculation,through tissue reflectance spectrophotometry,the monitoring of intestinal microcirculation will not be limited to the perfusion of microcirculation but can also provide a timely understanding of the utilization of oxygen.

The intestinal fatty acid-binding protein (I-FABP) is a very sensitive indicator of intestinal ischemic disease,which can increase in the early stage of ischemia.D-lactic acid(D-Lac) is the fermentation product of intestinal bacteria.When intestinal barrier function is impaired,a large amount of D-Lac in the intestinal tract enters the blood,which will result in the elevation of plasma D-Lac.Günel et albelieve that this marker also has a certain role in the diagnosis of intestinal ischemic diseases.Sessa et alfound that intestinal serum diamine oxidase (DAO) activity decreased during intestinal ischemia,while serum DAO levels significantly increased.

Through transmission electron microscopy,the glycocalyx of the intestinal capillary endothelium and the concentration of vWF and soluble thrombomodulin (sTM)can be observed.HE-stained pathological sections of small intestine tissue are scored to understand the destruction of intestinal tissue in sepsis microcirculation disorder.

Treatment

Infection is the initiating factor of sepsis,and antibiotics have become the central link in the treatment of sepsis.Polymyxin B can reduce the damage from endotoxin to the intestinal microcirculation by reducing the level of endotoxin.Daptomycin,tigecycline,erythromycin,and linezolid can improve intestinal microcirculation perfusion or reduce leukocyte adhesion.Vancomycin and tobramycin may increase the adhesion of leukocytes in the intestinal microcirculation.But another studyshowed that vancomycin and tobramycin had microcirculation vasodilator effects and increased FCD,which may be related to the promotion of histamine release from mast cells.

The use of anticoagulants is a direction that can be explored.Excessive release of histones is a cause of intestinal microcirculation disorder in sepsis,which can be ameliorated by unfractioned heparin.The mechanism may be to reduce the inflammation induced by histones,enhance the affinity between antithrombin III and thrombin,and accelerate the inactivation of thrombin.Heparin itself is also thought to have anti-inflammatory effects.Argatroban can reduce not only the formation of microthrombi but also the activation of leukocytes.

Currently,the Surviving Sepsis Campaign (SSC)recommends that patients with sepsis hypoperfusion should receive an intravenous infusion of 30 mL/kg crystalloid solution within 3 h after diagnosis.Which type of fluid resuscitation can best alleviate sepsis intestinal microcirculation dysfunction? Langanke et alfound that compared with balanced crystalloids,the third-generation hydroxyethyl starch (HES)solution was more effective in improving the intestinal microcirculation.However,Schick et albelieved that compared with colloidal liquid,balanced crystalloids had a more positive effect on intestinal microcirculation.

As sepsis can lead to hypotension,vasoactive drugs are needed to maintain blood pressure and ensure the perfusion of vital organs.Current guidelines recommend the use of norepinephrine (NE) as a first-line vasoactive agent,but its effect on intestinal microcirculation remains controversial.Nantais et alreported that NE could improve intestinal microcirculation dysfunction;while Nacul et alfound that NE could aggravate or have no significant effect on intestinal microcirculation dysfunction.Dopexamine,dopamine,and dobutamine are used alone,and the combination of dobutamine and NE is thought to improve intestinal microcirculation dysfunction.

In a studyof brain dysfunction in sepsis,statins were believed to inhibit leukocyte-endothelial interactions and improve microcirculation dysfunction.It has also been reported that bezafibrate can improve intestinal microcirculation dysfunction in sepsis by inhibiting the expression of iNOS;however,the adhesion and rolling of leukocytes in the microcirculation increases when highdensity lipoprotein (HDL) is given.

Based on “Expert consensus on diagnosis and treatment of septic shock with integrated traditional Chinese and Western medicine”,intestinal microcirculation disorders in sepsis are classified as syndromes of intestinal dysfunction and obstruction of “Fu-qi” and are often treated by purgation.Therefore,it is recommended that the heat-clearing and purgation prescriptions Dachengqi decoction be used,to promote blood circulation.

In view of the microcirculation dysfunction caused by the vasoconstrictor effect of endothelin (ET) in sepsis,selective endothelin type B receptor (ETB-R) agonists combined with endothelin type A receptors (ETA-R) antagonists could maintain systemic circulation blood pressure and improve microcirculation dysfunction.Dexmedetomidine is an α2 adrenergic receptor agonist.A studyreported that this drug could improve intestinal microcirculation dysfunction in sepsis and reduce vascular endothelial damage.Insulin administration improves intestinal microcirculation and reduces leukocyte activation in septic rats through immune regulation,vascular regulation and regulation of the prostaglandin A2 (PGA2)/thromboxane A2 (TxA2)balance of insulin.The new iron chelator DIBI can inhibit iron-catalyzed ROS production,thereby improving microcirculation.Deletion of cIAP2 showed potential therapeutic benefit in endotoxemia.Selective inhibition of adenosine triphosphate (ATP)-sensitive potassium (K)channels in vasodilatory shock by continuous infusion of glipizide could partially restore vasomotor tone in endotoxemic rats and improve systemic hemodynamics in septic rats.Tetrahydrobiopterinl,toll-like receptor 4 (TLR4) antagonist,and desmopressinhave an effect on improving the intestinal microcirculation.There are individual reports of vasopressin V1A receptors,physostigmine,and dehydroepiandrosterone combined with orthovanadate,showing that they could improve microcirculation.Activation of cannabinoid 2 receptorsand estradiol receptors,inhibition of cannabinoid receptor,endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH),and lectin-like oxidized lowdensity lipoprotein receptor-1 (LOX-1)are possible therapeutic targets to consider.

CONCLUSIONS

Intestinal microcirculation dysfunction in sepsis needs more attention,and its pathogenesis is complex,which is an important factor affecting the prognosis of patients with sepsis.However,due to the limitation of detection methods,most of the studies on its pathogenesis and treatment are animal studies,without the support of clinical research data.It is expected that future studies will find more convenient indicators to monitor the changes in intestinal microcirculation and supplement the lack of clinical data.

None.

Not needed.

The authors declare that they have no competing interests.

ALT proposed the study and wrote the paper.All authors contributed to the design and interpretation of the study and to further drafts.