Why vasodilation occurs in sepsis

Since that time many hemodynamic studies in sepsis and septic shock have evaluated therapeutic strategies to increase cardiac output, blood pressure and organ blood flow. Their effect on the skin and other micro-circulatory areas has been neglected for the most part, probably because no monitoring techniques were available. Initial studies showed improved survival after the optimization of oxygen delivery DO 2 [2, 3]. However, controlled clinical trials establishing normal or even supra-normal DO 2 values failed to show any survival benefits [4, 5].

A therapeutic increase in blood pressure did not significantly affect surrogate markers of micro circulatory tissue perfusion and function [6]. In addition, the non-selective inhibition of the endothelial vasodilator nitric oxide NO , acting primarily in the microcirculation, by L-NG-methylarginine increased mortality in patients with septic shock [7].

One possible cause of this increased mortality is that unselective blockade of NO synthase NOS further harms the microcirculatory blood flow and aggravates the already existing impaired tissue oxygenation [8]. This extraction deficit could be causally related to a shut down of vulnerable microcirculatory units in organ beds promoting shunt flow of oxygen from the microcirculation to the venous system [10].

Unable to display preview. Download preview PDF. Skip to main content. This service is more advanced with JavaScript available. Advertisement Hide. The Rationale for Vasodilator Therapy in Sepsis.

Authors Authors and affiliations M. Siegemund I. Racovitza C. The small vessel perfusion was seen to improve rapidly in survivors as compared to non-survivors, with no difference in the global haemodynamic variables. Together with the evidence showing that organ function improves and mortality decreases when resuscitation boosts microcirculatory flow 36 , the microcirculation does appear to be a new target for resuscitation during sepsis 6.

Even though several experimental data are available regarding effect of various therapeutic interventions on microcirculation, human data is still limited The ideal modality to resuscitate the microcirculation and the endpoints to be achieved still remain to be defined. Against this background, the following section explores the suggested modalities for microcirculatory therapy. It has also however, been shown to improve the microcirculatory flow, organ function and ultimately the survival.

Intravascular resuscitation. Both crystalloid and colloid infusions recruit vessels, and improve barrier function and oxygen transport in the microcirculation 39 — Although prospective studies regarding the choice of fluid for resuscitation in patients with septic shock are lacking, a large prospective, controlled, randomized, double-blind study comparing 4 percent human albumin solution with 0. The results of this study show identical mortality rate in patients receiving albumin or 0.

However, subgroup analysis reveals that albumin might have some albeit not statistically significant benefit in patients with severe sepsis. Blood is a better oxygen carrier and hence improves oxygen delivery to microcirculation more than with either crystalloid or colloid.

Certain data however suggests that erythrocyte transfusion may not improve the microcirculatory perfusion due to the DPG depletion, poor erythrocyte deformability, and erythrocyte interaction with endothelium and other blood cells 6. Given the variable effects of erythrocyte transfusion it is emphasized that use of erythrocyte transfusion needs to be analyzed according to the baseline haematocrit, while also keeping in mind the storage time and presence or absence of residual leukocytes in transfused products.

The concept of NO inhibition therapy for sepsis is debatable at present 45 , with the role of NO itself being equivocal with respect to its effect on microcirculation Improvement in microvascular blood flow has been shown with both, NO donors 47 , and iNOS inhibitors 48 , In sepsis, overproduction of NO from endothelial cells through the upregulation of iNOS has been associated with impaired vascular reactivity, capillary leak, erythrocyte deformiability and refractory hypotension This is also known to inhibit mitochondrial respiration, reversibly or irreversibly, depending on the duration of NO exposure and the mitochondrial complex inhibited 51 — Early data in septic shock patients treated with NOS inhibitors showed increasing blood pressure and decreasing dose of vasopressors However, a subsequent randomized controlled multicenter phase III trial had to he stopped when interim analysis showed increased mortality with the NO synthase inhibitor C88 Other authors have also noted raised mortality despite an improvement in the general haemodynamic parameters with usage of NOS inhibitors 57 , Certain authors also suggest that completely inhibiting vasodilation is not the appropriate answer to sepsis.

A more specific approach by inhibiting the inducible form of NOS has been studied. In contrast to earlier trials, the therapy was initiated very early in sepsis and no attempt was made to normalize the mean arterial pressure, rather the aim was to maintain the NO level at baseline value. In recent animal studies it has been observed that combination of fluid therapy with iNOS inhibition was successful in recruiting vulnerable microcirculation in the intestine, while fluid therapy alone was unable to do so 41 , Use of steroids in sepsis represents a non-specific approach towards modulation of the systemic inflammatory response, and inhibition of iNOS.

However, this is a time dependent phenomenon since sepsis evokes NO induced inhibition of glucocorticoid receptor. Following the recent large, European multicenter trial 60 which failed to show any mortality benefit with steroids in septic shock, never recommendations 61 suggest that only adult septic shock patients in whom blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy should receive steroid therapy.

For improvement of autoregulation of microcirculation, relatively higher doses are required and thus not recommended for clinical use in sepsis. These recommendations have dampened the earlier enthusiasm created by the study of Annane et al 62 regarding the use of steroids in septic shock.

The role of statins in sepsis has been reviewed in great detail elsewhere Statins are widely used as cholesterol-lowering agents but appear to have an anti-inflammatory action during sepsis. The primary mechanism of their action in sepsis is by increasing expression of eNOS endothelial nitric oxide synthase — constitutive enzyme , along with a down-regulation of iNOS.

Together, this increases NO levels, restoring the endothelial functions. Other beneficial effects of statins in sepsis may also include its antioxidant activity and alterations in development of vascular atherosclerosis The future promise of statins in sepsis is a subject of great interest and current research 64 , As per the shunting theory of sepsis, correction of the condition should occur by recruitment of the shunted microcirculatory units.

In the very early stages of sepsis although eNOS decreases causing impaired endothelium-dependent vasodilation, the iNOS release contributing to hypotension may take several hours Thus, an early administration of a NO donor may be beneficial to preserve tissue perfusion. In a recent trial by Assadi et al 68 the use of sodium nitroprusside SNP , a NO donor, during early severe sepsis was observed to improve the hepatosplanchnic microcirculatoiy blood flow.

Recruitment of microcirculation by vasodilator therapy in the form of NO donors 41 , nitroglycerin 47 , prostacyclin 69 and even topical acetylcholine 33 has been found to be effective for microcirculatory recruitment. Pending However, is the usefulness of these approaches in clinical course While these are potent for correcting systemic haemodynamics, their use should be viewed with caution for intent of improving microcirculation.

Their detrimental effects on regional perfusion are well described 70 — Dobutamine can improve but not fully reverse microcirculatoiy alterations in patients with septic shock Vasopressin, a more recently investigated vasopressor in sepsis, has been shown to increase urine output while raising the blood pressure 74 , 75 , but it has also been seen to cause microcirculatory shutdown It appears that further studies are required to determine the best vasopressor for microcirculatory septic shock Combination therapy.

Combination of fluid therapy with vasoactive and inotropic support is effective in restoring the microcirculation Non-responders to this therapy have a poor prognosis. A seemingly contradictory combination of NO donor and iNOS inhibitor may also prove to be successful in recruitment of microcirculation Protein C, a component of the natural anticoagulation system, is an antithrombotic serine protease that is activated to APC in the body by thrombin thrombomodulin complex.

Deficiency of APC has been shown to increase morbidity and mortality in patients of sepsis and septic shock 78 , Therapy with APC aims directly at the pivot of sepsis, the endothelium, by a multimodal mechanism possessing anti-inflammatory properties independent of its anti-coagulation properties.

The only adverse effect to be considered was the risk of bleeding. Despite the encouraging report of successful use of APC 84 , the most recent guidelines however, limit its use only to very sick patients of sepsis Lehmann et al 85 have published a very elegant study regarding the effect of APC on the microcirculation and cytokine release, during experimental endotoxemia in rats.

These findings are consistent with those of earlier trials regarding, effect of APC on microcirculation 82 , 86 — APC also decreases the oxidative stress and glycocalyx destruction during endotoxemia Other pharmacologic interventions. Arachidonic acid metabolites are powerful lipid mediators playing a key role in microcirculatory failure. They increase interleukin-1 release by macrophages in sepsis. It has been demonstrated that pharmacologic inhibition of leukotrienes 88 , 89 and thromboxane A2 90 , and usage of thromboxane receptor antagonists is beneficial during sepsis.

On the other hand, prostaglandin El infusion for 7 days improved survival and decreased organ failure in patients of ARDS Preliminary animal data has shown benefits of cholinesterase inhibition with physostigmine or neostigmine in survival during sepsis The probable mechanism of action is the activation of the cholinergic anti-inflammatory pathway However, there is no data regarding its effect on the microcirculation as yet.

Till date, there is no single objective gold standard to assess the microcirculation. In clinical practice, microcirculatory perfusion has been traditionally judged by the color, capillary refill and temperature of the distal parts of the body i.

Amongst the investigational modalities available to assess microcirculation, both indirect indicators as well as direct techniques exist 6 , even though any single objective reliable method is still not recognized. The direct imaging of microcirculatory perfusion seems a superior approach to assessment of microcirculation. Invention of microscope is perhaps the single most important advancement in technology linked to discovering the microcirculation, since experimental investigation of the microcirculation began soon after its advent.

Studies of human microcirculation began at the end of 19 th century, with Hueter using a microscope with reflected light to investigate vessels on inner border of lower lip. Lactate levels in the blood are thought to reflect anaerobic metabolism associated with tissue dysoxia and hence may predict the prognosis and response to therapy. However, the balance between lactate production due to global shock, hypoxia , local tissue ischemia , and cellular mitochondrial dysfunction factors on the one hand, and lactate clearance depending on metabolic liver function on the other hand, make the interpretation of lactate levels uncertain and difficult Even so, increased lactate levels do help to identify patients with tissue hypoperfusion, and if levels are markedly elevated, serve as a trigger for initiating early goal directed therapy Mixed venous oxygen saturation SvO2 can be measured using a pulmonary artery catheter and is thought to reflect the average oxygen saturation of all perlused microvascular beds.

But in sepsis, microcirculatory shunting can cause normal SvO2 despite existence of severe local tissue dysoxia 9. An appealing alternative to the evaluation of tissue dysoxia is the use tonometry of gastrointestinal tract. Tonometry is based on the principle that during hypoxia, anaerobic metabolism leads to production of acids which are buffered by bicarbonate ions leading to increased carbondioxide tension in tissues.

The optimal site for monitoring tissue pCO 2 is unclear Intestinal, gastric, oesophageal and rectal pCO 2 have all been investigated. Recently, sublingual mucosa and skin, which are not a part of splanchnic circulation have been investigated and appear promising. Sublingual capnometry has numerous advantages over gastric tonometry.

It is simple to perform, non-invasive, produces immediate result, and can be used at the bedside. It does not require premedication and acid suppression therapy, and patients do not have to be withheld from enteral feeding.

However, measurement of the difference between tissue intestinal pCO 2 and arterial pCO 2 has been found to be a better indicator since the arterial pCO 2 fluctuates in ventilated patients. Sublingual pCO 2 values have been found to correlate well with gastric intramucosal pCO 2 values The baseline difference between sublingual pCO 2 and arterial pCO 2 values is a better predictor of survival than the change in lactate or SvO2 Intravital microscopy IVM depends on transor epi-illumination and thus observations are limited to superficial layers of thin tissues only.

By using fluorescent dyes a higher contrast is possible as well as specific cells can be labeled for visualization and quantification. Its use has been primarily limited to animal studies because of the potentially toxic effects of dyes, and the limited access of tissues allowed with its usage. Its use in humans is usually restricted to the eye, skin and the nail fold.

Laser Doppler involves the principle of detection of frequency shift in laser light alter it encounters flowing erythrocytes. It measures the velocity of microcirculatory flow in a small area of microcirculation, being an average of the velocities in all the vessels present in the measured volume.

It can be used to measure the flow in skin, muscle, gastric mucosa, rectum and vagina. It has been validated in experimental models and gives an accurate assessment of changes in velocity induced by pharmacologic interventions.

The limitations of Laser Doppler include the estimation of an average flow in aboutonly about 1 mm 3 of tissue, disregard of the morphology of microvessels, the direction of flow, and heterogeneity of blood flow in the microcirculation, as well as failure to account for any changes in haematocrit.

The scanning Laser Doppler technique is an advancement over the conventional technique that allows two dimensional visualization of the microcirculation. It has been used to assess perfusion for oesophageal or colonic anastomosis, and cutaneous perfusion of the loot during arterial cannulation in critically ill patients.

Orthogonal Polarization Spectral OPS lmaging is a newer noninvasive method for direct visualization of microcirculation using green polarized light to illuminate the area of study The polarized light is scattered by the tissue and collected by an objective lens. A polarization filter or analyzer oriented orthogonal to the polarized light is placed in front of the imaging camera. This analyzer eliminates the reflected light which is scattered at or near the surface of the tissue, while depolarized light scattered deeper within the tissue passes through the analyzer.

When this depolarized light coming from deeper tissues passes through absorbing structures close to the surface, such as blood vessels, high contrast images of nlicrocirculation are formed.

It is especially useful for studying the tissues protected by a thin epithelial layer, such as mucosal surfaces. Incorporated in a hand held type of microscope, OPS imaging was introduced clinically to first identify pathologies during surgery. The sublingual area is the most frequently investigated mucosal surface. That the sublingual site indeed represents microcirculation of other areas finds favour with certain authors Limitations of OPS imaging in sublingual region include movement artifacts such as respiration, and presence of various secretions such as blood and saliva.

Also, patients have to be cooperative or adequately sedated such that they do not bite the device. The technique can investigate only those tissues that are covered with a thin epithelial layer, and of course internal organs are not available except during intraoperative conditions. It does not give the exact measurement of red blood cell flow velocity in individual vessels. What it does allow, is prediction of a semiquantitative flow score based on average score over a maximum of 12 quadrants three regions X four quadrants per region , derived from the overall flow impression of all vessels with a particular range of diameter in a given quadrant.

The flow score is a semi-quantitative one, and whether the flow score from 0 to 3 is actually a linear relationship with the actual flow is also not established.

With repeated measures, selecting the exact site as before is also a difficult task. It consists of a light guide surrounded by nm light-emitting diodes, a wavelength of light that is absorbed by haemoglobin of erythrocytes, allowing their observation as dark cells flowing in the microcirculation. As compared to OPS it offers the advantage of improved image quality, relative technical simplicity, and lack of need of a high-powered light source With several clinical and laboratory indicators of identifying hypoperf ision due to the microcirculation dysfunction being available, it is perhaps time to recognize shock in sepsis keeping tissue hypoperfusion as distinct from hypotension.

A perfusion based scoring system has been proposed by Spronk et al It emphasizes the need of extending recognition of shock severity to include microcirculatory parameters, besides global haemodynamic and oxygen-derived parameters. Therapy in shock should be aimed at optimizing cardiac function, arterial hemoglobin saturation, and tissue perfusion.

This not only includes correction of hypovolemia, but the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport as well. The role of vasodilators in recruiting the microcirculation will need to be looked into further. Direct monitoring of sublingual microcirculation monitoring appears to be a promising endpoint for resuscitating the microcirculation.

An integrative approach incorporating both macrocirculatory and microcirculatory haemodynamic data may indeed hold the answer to resuscitation in sepsis.

National Center for Biotechnology Information , U. D represents isovolumetric relaxation. Point 1 represents opening of the mitral valve. Point 2 represents closure of the mitral valve. Point 3 represents opening of the aortic valve. Stroke volume SV is demonstrated. The slope of this line represents the contractility of the heart.

Pressure—volume curve for the LV during sepsis. Stroke volume SV is maintained. The end-systolic pressure—volume relationship demonstrates decreased contractility. Pressure—volume curve for the LV during severe sepsis. There is hypotension. In these circumstances, cardiac force is compromised by the resulting abnormalities of fibre length. Finally, NO decreases the sensitivity of the myocardium to endogenous adrenergic ligands by altering the response of second messenger systems.

The protein kinase and cyclic GMP messenger systems are affected in this manner. Vasodilatation is the principal physiological abnormality in the cardiovascular response to sepsis.

This leads to a low SVR and hypotension. One of the physiological functions of NO is to provide an intrinsic response to alterations in peripheral blood flow myogenic control. When NO is formed in the endothelium, it diffuses into the vascular smooth muscle cells where it activates the enzyme guanylyl cyclase.

This increases concentrations of cyclic GMP levels which lead to a reduction in intracellular calcium levels and activation of potassium channels.

This leads to vascular smooth muscle relaxation. Peripheral vascular dysfunction during sepsis is mediated by excessive production of NO by the enzyme iNOS. Increased NO concentration leads to hyperpolarization of potassium channels and persistent relaxation of smooth muscle. In addition to vasodilatation, there is a failure of the cardiovascular reflexes, which normally control arterial pressure. The sympathetic and neuroendocrine responses to shock cause vasoconstriction, which is mediated by G-proteins and second messenger systems, in turn activating intracellular pathways.

These responses to sympathetic activity and angiotensin II are decreased due to the increased production of NO, which decreases the cellular activity of signal transduction mechanisms. The right ventricle RV differs embryologically, structurally, and functionally from the LV. The principle function of the RV is to facilitate efficient gas exchange.

It has a thin wall with a low muscle mass, ejecting into the pulmonary circulation, which has a low resistance and a high compliance. The pressures generated on the right side are low; mean pulmonary artery pressure is 15 mm Hg.

The RV depolarizes and then contracts in a longitudinal manner from the inflow tract to the outflow tract and produces a wave which is peristaltic in manner. This contrasts with the circumferential pressure generating contraction of the left side of the heart. Like the LV, the cardiac output of the RV is determined by changes in preload, afterload, and contractility.

The changes in ventricular function in sepsis are similar to those on the left side. The function is compromised by changes in contractility and afterload. The free wall of the RV has a low muscle mass and can respond to increases in preload by dilating, but it responds poorly to afterload because of its relative inefficiency as a muscle pump.

The onset of sepsis leads to a change in contractility due to effects of circulating inflammatory mediators which are the same as those outlined above. There is a decrease in RVEF similar to that in the systemic circulation. The stresses imposed by sepsis on the RV muscle mass and the changes in afterload can ultimately lead to right ventricular failure.

The pulmonary circulation is a low-pressure system, which can respond to an increased cardiac output during exercise or after a physiological stress.

The ability of the pulmonary circulation to respond to a large cardiac output without a major change in pressure ensures that effective gas exchange can take place. It is important to consider the concept of blood flow in addition to generated pressure when considering the physiology of the pulmonary circulation. The right-sided circulation responds to changes in cardiac output by recruitment of pulmonary vessels which have low perfusion during stable conditions. In addition to recruitment, distension of these vessels allows an increase in blood flow which will support the need for improved gas exchange.

These processes occur without vasomotor control. The major stress imposed on the RV during sepsis is an increase in the afterload due to pulmonary hypertension. Hypoxic pulmonary vasoconstriction HPV is a response of the small arterioles of the pulmonary circulation to a decrease in alveolar or mixed venous oxygen content.

The greater influence is from alveolar hypoxia. The function of this response is to divert blood from the hypoxic areas of the lungs to those which are ventilated, thus attempting to maintain optimum ventilation and perfusion ratios and ensure efficient gas exchange. It is a rapid response and occurs within seconds of induced hypoxia. The reflex occurs in the isolated lung and is independent of neural connections.

The precise mechanism has not been proven, but NO is implicated. During sepsis, unregulated NO production in the systemic circulation leads to vasodilatation. In the presence of hypoxia, NO production decreases in the pulmonary circulation and local vasoconstriction occurs. It is also thought that local release of the potent vasoconstrictor endothelin occurs due to hypoxia. There is evidence that the active control of the pulmonary circulation is influenced by ligands of systemic origin which lead to receptor activation.

There are both cholinergic and adrenergic receptors in the pulmonary vascular tree, which allow changes in pulmonary vascular tone and resistance. The predominant response is vasoconstriction. Cholinergic parasympathetic nerves cause vasodilatation by stimulation of muscarinic M3 receptors, with NO acting as a mediator for cholinergic transmission.

Other circulating humoral factors can induce a local vasoconstrictor response, including endothelin, angiotensin, and histamine. Pulmonary hypertension is thus a multifactorial consequence of sepsis and is probably due to inhibition of NO production due to hypoxia and also an enhanced vasoconstriction due to acidosis, increased adrenergic stimulation, and local mediators such as endothelin Table 2.

The mediators involved in the active control of the pulmonary circulation 6. Ventricular interdependence is defined as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral, or circulatory effects.

Ventricular interdependence is a result of the close anatomical correlation of the ventricular cavities within the pericardium. The ventricles can be considered in series. Stroke volume of systolic contraction of one cavity creates the preload of the next Fig. This is an oblique transverse section of the heart taken through the mid-cavity. It demonstrates the thick walled LV and the thinner wall of the RV. It demonstrates the crescentic shape of the RV in comparison with the round ventricular cavity on the left.

The septum is noted. The failing RV can impede left-sided performance by decreasing LV preload. This severe RV diastolic dysfunction can be seen in sepsis Fig. This is a four-chamber view of the heart observed with transoesophageal echocardiography. It is taken during end-diastole. The atrioventricular TV and MV valves are open.

There is volume overload of the RV which has moved the septum towards the left side of the heart. The pericardium normally allows free movement of the ventricular cavities even in the presence of a dilated heart; however, this may itself be compromised by pericardial disease during sepsis or high intrathoracic pressures caused by mechanical ventilation.

Supraventricular tachyarrhythmias are commonly found in patients with sepsis, especially atrial fibrillation. The voltage-dependent L-channels which are responsible for calcium flux in phase 2 of the cardiac action potential have a specific heteromeric structure.

It is a known site of channel regulation by second messenger systems. Animal studies have demonstrated that during sepsis, NO decreases the influx of calcium by alteration of the activity of this channel during phase 2 of repolarization.

The potassium channel is also affected during sepsis and an increased influx of potassium occurs in myocytes during repolarization. These two mechanisms are responsible for the timing of repolarization. Action potential duration APD is decreased during sepsis in atrial myocytes. There is no change in resting membrane potential. A decrease in influx of calcium during phase 2 of repolarization is one of the electrophysiological changes associated with the genesis of tachyarrhythmias in sepsis Fig.