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Review article: Organ perfusion/permeability-related effects of norepinephrine and vasopressin in sepsis

[Exposé de synthèse : Les effets reliés à la perfusion et à la perméabilité organique de la norépinéphrine et de la vasopressine durant le "sepsis"]

Paul Farand, MD MSc^*, Mélanie Hamel, MD^,, François Lauzier, MD^,, Gérard E. Plante, MD PhD^*, and Olivier Lesur, MD PhD^,

^* From the Laboratoire de Physiologie Rénale et
Vasculaire, Institut de Pharmacologie, Groupe de Recherche en Physiopathologie Respiratoire,
Unité des Soins Intensifs Médicaux; and the
Service de Néphrologie, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Address correspondence to: Dr. Olivier Lesur, Centre de Recherche Clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada. Fax: 819-564 5377; E-mail: olivier.lesur{at}USherbrooke.ca

	Abstract

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Purpose: One invariable hallmark of severe sepsis is generalized tissue "malperfusion" and hyperpermeability secondary to microcirculatory/capillary leakage. This review focuses on direct and/or indirect influences of norepinephrine, as a standard of care, and vasopressin, as an alternative vasoactive drug, on organ and tissue perfusion/permeability in severe sepsis.

Source: English and French language articles and books published between 1966 and 2005 were identified through a computerized Medline search using the terms "sepsis, permeability, norepinephrine and vasopressin". Relevant publications were retrieved and scanned for additional sources.

Principal findings: There are few randomized clinical trials comparing different vasopressors in sepsis; most available literature consists of clinical reports, animal experiments and occasional reviews. Based on the best current evidence from these sources, we describe the status of major organ perfusion/permeability in sepsis (i.e., the lung, the kidney, the heart, the intestine/gut) in the context of sepsis-induced organ dysfunction/failure. Potential and differential therapeutic effects of the vasopressors norepinephrine and arginine-vasopressin, in the setting of sepsis, are identified.

Conclusions: In the treatment of sepsis, arginine-vasopressin exhibits organ-specific heterogeneity in vascular responsiveness, compared to norepinephrine. While norepinephrine is a current standard of care in sepsis, arginine-vasopressin shows promise for the treatment of septic shock.

	Fluid distribution to endothelial/epithelial cells in sepsis

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
One of the invariable hallmarks of severe sepsis is overall tissue hyperpermeability secondary to microcirculatory/capillary leakage. This condition is promoted by early, severe and acute alterations of several components of the Starling equation.¹ Consequently, there is frequently a drop in oncotic pressure initiated by dilution of circulatory volume, protein breakdown (hypercatabolism) and extravascular leakage. The first hours of resuscitation in severe sepsis and septic shock comprise large infusions of fluid, often leading to rapid soft tissue swelling and potentially to organ edema. Not surprisingly, organ damage and dysfunction are frequently accompanied by changes in fluid and protein extravasation, although no causal relationship has been established. For instance, acute respiratory distress syndrome (ARDS) patients exhibited a 78% mortality rate when gaining weight (mean 4 kg) vs a 50% mortality when losing weight (mean 6 kg)² at day 14. Thus, control of body fluids is an essential process that is altered in sepsis, with potential consequences on patient outcome.

Over 50% of total body weight represents fluid, the absolute and relative distribution of which varies according to species and age.³ In pathological situations such as sepsis, absolute and relative body fluid distribution between the various anatomical compartments varies considerably, and may ultimately contribute to a variety of reversible and/or irreversible target organ damage. Vascular and interstitial compartments of the extracellular fluid volume represent approximately 5 and 15% of total body weight, respectively, in normal adult humans. The vascular volume is divided into three major functional segments, the large delivery and resistance arteries (high pressure system), followed by numerous microcirculatory networks, and finally, by small and large collecting veins (low pressure system). Microcirculatory networks constitute the largest fraction, in which major and vital exchanges between vessels and adjacent interstitial compartments occur,⁴ and the one most affected during sepsis. Indeed, pre- and postcapillary resistances represent the physiological basis of fluid and solute movement across the vascular barrier. Thus the permeability properties of capillaries and postcapillary venules to macromolecules (tenfold variation) may explain the particular location of target organ damage in a variety of diseases⁵ including, most likely, sepsis.

Next to microcirculatory networks, interstitial fluid compartments occupy a strategic position between blood vessels and all cellular volumes, the latter representing the largest fluid compartment, roughly 40% of total body weight overall. Moreover, the respective vascular, interstitial and cellular volumes between the various organs also vary considerably.⁶ The lymphatic system in the interstitial space is essential for returning excess fluid/proteins to the circulation, playing a key role in maintaining capillary/interstitial equilibrium. Lymphatic flow can significantly increase with increases in interstitial fluid pressure, but becomes quickly saturated.^7,8 In addition to distinctive fluid volume properties, the chemical composition of interstitial fluid differs markedly between organs, notably with regard to collagen, elastin, fibronectin and proteoglycan content^8,9 and has recently been proposed to explain unusual physical and chemical phenomena such as the albumin exclusion space. The latter appears to play a critical role in the transfer of vital substrates (including albumin-transported hormones and drugs) from blood vessels to the cell mass of all organs, as well as traffic of waste products in the opposite direction, a key process in target organ damage.⁵ This concept of target organ damage, summarized in Figure 1, is clearly related to the traditional parameters of the Starling equation.^1,6 Next to vascular and interstitial compartments, intracellular body fluid compartments are less heterogeneous, but have important clinical implications. Since movement of fluid and the highly selective passage of solutes across cellular compartments have a major impact on adjacent interstitial fluid volumes and henceforth on the entire vasculature, the active and/or passive modulation of these movements becomes critical in health, as well as in sepsis.

View larger version (72K): [in this window] [in a new window]   FIGURE 1 Vascular (3) pre- and postcapillary resistances (1, 2) and interstitial events (7) responsible for target organ damage/failure (8), following endothelial cell altera­tion/dysfunction. Alteration in endothelial (3) perme­ability to albumin (4, 5) is associated with extravasation of plasma into the interstital compartment. Changes in collagen (COL), albumin (ALB), fibronectin (FN) and gly­coaminoglycans (GAG) arise and can affect size and physi­cochemical properties of this strategic fluid compartment, depending on the limited capacity of the lymphatic flow to adapt (6). Reproduced with permission from Elsevier: Plante GE. Vascular response to stress in health and disease. Metabolism 2002; 51: 25–30 (reference 8).[Medline]

The following sections will focus on the status of major organ perfusion/permeability in sepsis in the context of sepsis-induced organ failure, which is an archetype of body fluid intercompartmental shift (at least at the vascular-interstitial level). In addition to discussing four of the main target organs involved in sepsis, potential and differential influences of the vasopressors norepinephrine (NE) and arginine vasopressin (AVP), two molecules that target different receptors as well as different signaling pathways (Table), will be also considered.

Currently, it is unknown whether the use of a particular catecholamine or another vasopressive drug is able to influence outcome in septic patients, and most current observations are predominantly physiological. Outcome differences between NE and AVP in management of septic shock are difficult to demonstrate, and investigations addressing this issue are ongoing. While exogenous AVP is first and foremost indicated for vasopressive activity in resistant redistributive shock, one must bear in mind that AVP serves a major role in the neuroendocrine control of body fluid metabolism.

	The lung in sepsis

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Sepsis-induced organ hyperpermeability can be a life-threatening and outcome-related condition. The lung as an oxygen-provider/discloser can be quickly affected and septic patients with ARDS share lower survival rates compared to other etiologies such as urosepsis.¹⁹ Indeed, increased extravascular lung water (EVLW) in critically-ill patients affects mortality rates, especially in septic ARDS patients.^2,20 Concomitantly, management of EVLW can reduce duration of mechanical ventilation,²¹ whereas increased lung edema and EVLW in extra-pulmonary sepsis can provoke alteration of gas exchange along with hypoxemia, as well as enhance work of breathing and oxygen consumption.²⁰ Such situations often compel attending intensive care unit teams to place the patient at rest on mechanical ventilation in order to slow down this sepsis-induced metabolic storm. Unfortunately, the tracheal intubation procedure per se is neither easy nor always safe to perform in context of septic shock instability, not to mention that mechanical ventilation can impact outcome by duration of mechanical support and potential side effects (e.g., superinfection, volutrauma, etc.). Thus, addressing sepsis-induced lung permeability is clearly a relevant and evidence-based process. Concomitant to increased lung permeability, pulmonary arterial hypertension is almost constantly associated with septic ARDS,²² further increasing hydrostatic pressure-directed fluid leakage. Some of these ARDS-associated high pulmonary arterial pressures are sensitive to inhaled nitric oxide (NO) therapy.²³ Strong arguments for sepsis-induced lung hyperpermeability to fluids and proteins not only stem from experimental endotoxic models which produce both functional and structural alterations of the alveolar-capillary barrier²⁴ but also from bedside clinical assessment.²⁰ Systemic response with recruitment of activated polymorphonuclear neutrophils releasing reactive oxygen species and proteases (including edemagenic serine protease and coagulation cascade-activator thrombin), together with multiple bloodstream inflammatory mediators (lipids, cytokines, etc.), are significant components of lung inflammation and hyperpermeability in sepsis, their blockage being ultimately effective in decreasing pulmonary vascular permeability.²⁵

Impact of NE and AVP on pulmonary function and vascular permeability in sepsis
High infusion rates of exogenous catecholamines (mainly NE as standard of care in septic shock) can induce lung edema by increasing filtration and microvascular pressure, as well as by other mechanisms.²⁶ It therefore seems logical that the combination of sepsis and related permeability disorders (i.e., protein breakdown/hypercatabolism and extravascular leakage) with aggressive supportive treatments such as large volume crystalloid infusion and high levels of NE infusion, are plausible cornerstone contributors to sepsis-induced lung edema, acute lung injury and ARDS. By comparison, AVP used either solely or as a catecholamine-sparing drug appears to be relatively safe for the alveolar-capillary barrier. In fact, hemodynamic effects of AVP on lung circulation are distinct from those observed with catecholamines. High doses of NE (1–2.5 µg·min^–1), often used in refractory shock, can induce (or contribute to) increased pulmonary arterial pressures/resistances, whereas AVP does not, unless given in unusually high doses (above 1.0 to 1.5 U·min^–1). In some cases, AVP may even decrease these circulatory parameters.²⁷ The use of AVP remains controversial however, especially for terlipressin, a synthetic analogue of AVP.²⁸ In an experimental setting, a rising pulmonary arterial pressure is an early initial event followed by right ventricular failure; hence control of associated pulmonary hypertension can protect against edema.^24,29 In the clinical setting, lowered pulmonary arterial pressure and improved right ventricular function is a distinctive pattern in septic shock survivors.³⁰ Thus, addition of pressure-supporting drugs sharing different pharmacological and physiological targets and pathways could influence the "physiological low-pressure pulmonary circulation". Remarkably, in a retrospective study of more than 600 patients, Hall et al.³¹ denoted an increased incidence of ARDS (34%) in patients treated for septic shock with exogenous catecholamines (dopamine, NE) compared to those treated with AVP (18%). There was, however, no tentative pathophysiological explanation proposed for this striking epidemiological observation. Subsequent analysis excluding most of the patients (over 70%), failed to reproduce this differential trend of ARDS association with vasopressor selection.³²

In contrast to the human experience, several experimentally-based studies relevant to this question have been reported. In a pig model of ventricular fibrillation, the use of epinephrine instead of AVP was associated with a deterioration in gas exchange (as assessed by ventilation/perfusion ratio and oxygen arterial partial pressures) in the first 30 min following cardiopulmonary resuscitation.³³ In an acute resuscitated model of rat endotoxemia, Evans Blue (sharing high affinity to albumin) was found to leak more heavily outside of the lung circulation when using NE instead of AVP after two hours of monitoring (Figure 2).³⁴ In a chronic ovine model of endotoxemia, there was pathological evidence of increased pulmonary edema and alveolar hemorrhaging in NE-treated animals compared to animals treated with AVP or a combination of AVP plus lower doses of NE.³⁵

View larger version (22K): [in this window] [in a new window]   FIGURE 2 End-experimentation Evans Blue lung content in rats challenged with LPS (E coli O127:B28, 10 mg·kg–1 iv) or saline (control) and pressure supported by saline, NE, AVP or L-canavanin (LC). Reproduced with permission from the American Physiological Society. Levy et al. Comparative effects of vasopressin, norepinephrine and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am J Physiol 2004; 287: H209–15 (reference 34). LPS = lipopolysaccharides; NE = norepinephrine; AVP = arginine-vasopressin.

Effects of ß-adrenergic agonists on pulmonary permeability in vascular barrier-enhancing conditions are also a matter of debate. On the one hand, catecholamines: 1) contribute to the maintenance of vascular integrity; 2) exhibit overall anti-inflammatory activity by supporting quiescent states of polymorphonuclear neutrophils and monocytes; and 3) improve (with cyclic adenosine monophosphate agonists) lung alveolar fluid clearance.^39–42 However, NE increases pulmonary microvascular pressure through greater constriction of postcapillary vessels,^26,42 while fever as well as acidosis, which are frequently observed in severe sepsis, can alter NE-induced barrier-improving functions.⁴³

In summarizing pulmonary responses, selection of NE, especially at high infusion rates, may have deleterious effects on lung function/permeability in sepsis, whereas AVP may potentially have catecholamine- and lung leakage-sparing capabilities.

	The kidney in sepsis

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Severe sepsis is commonly associated with kidney dysfunction and oliguria and accounts for more than 50% of intensive care unit admissions for acute renal failure (ARF).^44,45 Mortality rates in these patients remain very high.^44,45 Septic shock can lead to reduced renal blood flow and to afferent arteriolar vasoconstriction, resulting in ischemic kidneys, although this is still under debate. Recent data obtained from hyperdynamic septic shock animal models reveal increased renal blood flow with a reduction in vascular resistance, reflecting systemic vasodilatation.⁴⁶ Endotoxemia per se causes alteration in intrarenal blood flow distribution, inducing an imbalance between "dilator" (NO, prostaglandins) and "constrictor" (endothelin, angiotensin II, NE) circulatory molecules.⁴⁶ Overproduction of NO, via the triggering of inducible NO synthase, as well as sepsis-induced endothelial NO synthase attenuation have been singled out in the redistribution of renal flow.^46,47 In this respect, specific inhibitors of inducible NO synthase preserve renal function whereas the endothelial NO synthase knockout approach further induces renal dysfunction by altering glomerular filtration rate in endotoxemic rats and mice.⁴⁸ Indeed, glomerular filtration rate is disproportionally reduced comparatively to renal blood flow, highlighting the fact that hemodynamic factors are only some of the mechanisms responsible for renal function alteration in sepsis. Furthermore, systemic and local inflammatory mediators can provoke renal dysfunction even in the absence of any obvious hemodynamic perturbation, possibly through endothelial dysfunction. Hence, acute renal failure can at times be the first clinical manifestation of sepsis. While neutralization of platelet activating factor, endothelin and tumour necrosis factor alpha (TNF-) can prevent renal damage as well as adverse hemodynamic effects and glomerular filtration rate alteration in animal endotoxic models, it failed to show survival benefits in advanced phase trials.^49,50

Microalbuminuria is a sensitive marker of increased permeability of glomerular endothelium correlating with systemic permeability in several conditions which precede organ dysfunction. Postoperative patients exhibiting sepsis often have increased microalbuminuria associated with organ dysfunction (sequential organ failure assessment score).⁵¹ In addition, a rising microalbuminuria during the first 48 hr of intensive care unit stay is a good predictor of acute respiratory and multiple organ failures.⁵¹ Tubular function can also be affected in addition to glomerular function in sepsis. At the outset, acute renal failure is associated with low sodium excretion fraction, while later on, sepsis causes tubular damage/necrosis and a fall in sodium reabsorption. One proposed hypothesis is an increased leakiness of the proximal tubular epithelium resulting in sodium back-flow towards the tubular lumen as well as equal work for less sodium reabsorption.⁵²

Impact of NE and AVP on renal function in the septic patient
Norepinephrine, as a standard of care in septic shock resistant to fluid resuscitation, was originally thought to deteriorate renal function by extreme renal vascular constriction, combining both afferent and efferent effects. It is still debated as to whether "relevant dosing" of NE, by restoring blood pressure and vascular tone, can help maintain renal blood perfusion, glomerular filtration rate and urine output.^53,54 Like other ß-adrenergic agonists, NE is antinatriuretic;⁵⁵ however, whether this can influence kidney permeability/leakiness has not been extensively studied until just recently in an acute model of endotoxemia (Figure 3).³⁴

View larger version (23K): [in this window] [in a new window]   FIGURE 3 Effect of endotoxin (E coli O127:B5) on urine output and whole kidney EB permeability in anesthetized, mechanically ventilated animals: (A) adult rats, LPS 10 mg·kg–1 iv, two hours of experiments (reproduced with permission from the American Physiological Society. Levy et al. Comparative effects of vasopressin, norepinephrine and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am J Physiol 2004; 287: H209–15 (reference 34); and (B) ewes LPS: ~ 80–100 nanog·kg–1·min–1 iv, three hours of experiments (unpublished). Support of blood pressure by saline; NE or AVP is aimed at maintaining MAP 65 mmHg. * P < 0.05 vs saline group. EB = Evans Blue; LPS = lipopolysaccharides; NE = norepinephrine; AVP = arginine-vasopressin; MAP = mean arterial pressure.

Finally, AVP exhibits a well known physiological antidiuretic property through activation of vasopressin-2 receptor and subsequently of the AQP-2 shuttle system, leading to increased water permeability in collecting ducts. In this respect, AQP-2 expression in animal kidney medulla was shown to be modulated after endotoxin challenge, downregulated in a subacute model⁶² but upregulated in a short-term acute model.⁶³ In the latter instance, exogenous AVP further enhanced AQP-2 epithelial membrane translocation, but suppressed pump release in urine.⁶³ Finally, AVP also stimulates sodium reabsorption by activating sodium channels in collecting ducts.³⁷

In summarizing effects on the kidney, sepsis-affected renal function does not appear to be adversely affected, but rather, is potentially improved by AVP as well as by NE therapy. The influence of AVP infusion on sepsis-induced altered AQP-2 expression and kidney permeability remains to be determined.

	The heart in sepsis

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Endotoxic experimental models have demonstrated evidence of acute and subacute remodelling alterations in the heart (e.g., increased collagen content, myocardial edema, etc.),⁶⁴ observations also confirmed by postmortem studies of deceased septic shock patients. However, these alterations are not necessarily specific to septic conditions, and can be observed in other states of shock requiring catecholamine support.⁶⁵ Hence, it is not clear whether myocardial edema, although possibly responsible for alterations in heart compliance by pressure/volume curve displacement, can actually affect organ function. On the other hand, indirect impact of myocardial permeability/edema can be readily observed by a permissive effect on polymorphonuclear neutrophil migration into the myocardium.⁶⁶ More specifically, the increase in myocardial permeability observed in sepsis could be explained by several mechanisms including: 1) alteration of the endocardial surface layer; 2) myocardial cellular apoptosis; 3) myocardial dysfunction induced by inflammatory mediators [platelet activating factor, TNF–, NO, IL-6, macrophage migration inhibitory factor]^67,68 and; 4) sepsis-induced microcirculatory malperfusion/redistribution.

The endothelial surface layer which contains mostly proteoglycans, TNF-⁶⁹ as well as platelet activating factor,⁷⁰ alters its composition and function in sepsis. It is also known that destroying the endothelial surface layer by hyaluronidase treatment can lead to irreversible myocardial tissue edema.⁷¹ Consequently, endothelial surface layer alterations may partly explain the presence of cardiac tissue edema observed in sepsis.

Apoptosis associated with intramural hemorrhagic areas has also been observed in autopsies of septic patients.⁷² This apoptotic process may be partly responsible for decreased heart function in sepsis. Inflammatory cytokines such as TNF- and IL-1ß⁷³ are some of the many factors suspected of inducing cardiomyocyte apoptosis in sepsis as well.

Coronary arterial flow is usually considered to be increased in human septic shock⁷³ (although several animal models have reported a decreased arterial flow) together with a general occurrence of microcirculatory dysfunction.⁷³ Increased but dysregulated coronary blood flow with secondary hyperemia may be induced by local NO production.⁷⁴ On the other hand, myocardial ischemia in susceptible areas is induced by NO inhibition, hence reducing coronary blood flow.⁷⁵ Overall, any mismatch of perfusion to oxygen consumption ratio occurring in septic patients is liable to induce patchy microareas of myocardial damage with troponin I release,⁷⁶ because of the limited available myocardial oxygen extraction reserve.

Impact of NE and AVP on myocardial function and ischemia in sepsis
Vasopressors in general can have a potentially deleterious role on the endotoxic/septic heart. In experimental settings, ß-agonist isoproterenol infusion is associated with cardiac edema and tissue injury.⁷⁷ High doses of catecholamines increase cardiac output and rate, oxygen consumption, cardiomyocyte apoptosis, as well as inducing coronary vasoconstriction.^77,78 In contrast, high infusion rates of AVP as well as terlipressin (an analogue of AVP) have been shown to reduce cardiac output and rate, both of which are secondary to increased vagal and decreased sympathetic tones, associated with a decrease in coronary blood flow. Such observations have been confirmed in a model of isolated rabbit hearts without vasodilatory shock.⁷⁹ On the other hand, it is unlikely that AVP moderates excess edema in cardiac tissue, since V1R are the only subtype receptors expressed in the heart (along with oxytocin receptors), with no evidence of vasopressin-2 receptor or AQP-2 expression.

In summarizing the cardiac response of these pharmacological strategies, although the effects of AVP and NE on the heart are distinctive, both drugs have the potential to be harmful by enhancing ischemia in susceptible myocardium. Their impact on sepsis-induced cardiac permeability is still unknown, although AVP may prove to be an interesting substitute to NE by preserving catecholamine-induced myocardial dysfunction. However, the functional relevance of this myocardial permeability observed during sepsis remains equivocal.

	The intestine in sepsis

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Splanchnic hypoperfusion is generally associated with poor outcome in sepsis.⁸⁰ In addition, by enhancing intestinal mucosal and microcirculatory permeability, sepsis can lead to bacterial translocation, which in turn is related to the onset of multiple organ failure.⁸¹ Hypoperfusion per se contributes, but is not indepedently sufficient to account for all mesenteric permeability mechanisms.⁸² However, hypoperfusion as well as pro-inflammatory cytokines are triggers for epithelial cellular apoptosis, all of which are putative incriminating agents/events in sepsis-induced gut hyperpermeability. Intestinal epithelial apoptosis in human sepsis⁸³ can in fact compromise mucosal integrity whereas Bcl-2 intestinal overexpression is partially protective in mice challenged with Pseudomonas aeruginosa pneumonia.⁸⁴ In addition, apoptosis mediated by Fas (a cell-surface protein) causes an increased flux of small molecules in human intestinal cells while the caspase inhibitor z-VAD prevents gut apoptosis with improved barrier dysfunction.⁸⁵ Mechanisms leading to intestinal apoptosis involve several inflammatory molecules, including IL-1ß and IL-6.⁸⁶ Interleukin-6, by inducing intracellular actin rearrangement, as well as vascular endothelial growth factor, released by inflammatory and structural cells in response to endotoxin stress; both increase vascular permeability.^87,88 In this respect, IL-6 knockout mice are hence protected from sepsis-induced gut hyperpermeability.⁸⁹

Impact of NE and AVP on intestinal function in the septic patient
Norepinephrine leads to local endothelium-derived IL-6 production⁹⁰ which can ultimately contribute to bacterial translocation, while AVP is a recognized vascular endothelial growth factor secretagogue⁹¹ and therefore may be implicated in sepsis-induced gut hyperpermeability. In a rodent endotoxin model, both NE- and AVP-treated rats demonstrated better preservation of gut permeability in comparison to control animals, as measured by Evans Blue tissue concentration.³⁵ Sun et al.³⁶ also reported that sheep undergoing cecal perforation exhibit less small intestinal edema and congestion when exposed to combined AVP and NE in lieu of NE alone.

Furthermore, AVP and NE exhibit distinctive hemodynamic properties on splanchnic circulation. Arginine vasopressin induces vasoconstriction of endotoxin-stressed human gastroepiploic arteries⁹² while potentiating vasoreactivity of catecholamine-exposed vessels in vitro.⁹³ Arginine-vasopressin also upregulates V1R messenger ribonucleic acids in mesenteric arteries, in contrast to kidney and brain arteries of animals with septic shock, and should contribute to direct flow away from the gut to other organs.⁹⁴ However, AVP-induced splanchnic hypoperfusion, as measured by either continuous dye dilution technique, ultrasonic microcirculatory flow probes or gut-arterial carbon dioxide partial pressures gradient modulations, has not been clearly demonstrated in septic shock. Two small short-term studies (two to four hours observation time and less than 25 patients overall) found that AVP infusion was associated with an increase in gut-arterial carbon dioxide partial pressures gradient. However, in the first study, NE was not titrated in order to maintain a threshold mean arterial pressure⁹⁵ while in the second study, AVP was infused up to very high concentrations but still increased absolute and fractional splanchnic blood flow.⁹⁶ In contrast, two other studies did not observe AVP-associated splanchnic hypoperfusion.^75,97 Furthermore, perfusion of terlipressin or AVP showed no detrimental effect on hepatosplanchnic perfusion in a porcine model of endotoxemia, as well as no impact on mesenteric flow with a further tendency of attenuating lactate content in endotoxin-challenged gut tissues.^35,98 Mechanisms potentially related to the beneficial effects of low-dose terlipressin and AVP have been linked to inducible NO synthase inhibition.³⁵ As in the case of AVP and analogs, there is no evidence that NE is deleterious to the gut during septic shock. Norepinephrine appears to be safe when used alone in septic shock.⁹⁹

In summarizing effects on the intestine, sepsis-induced splanchnic hypoperfusion and gut epithelial apoptosis lead to bidirectional intestinal permeability, and therefore could be affected by vasopressor use. However, there are no known human studies which have clearly demonstrated any superiority or, alternatively, any distinctive deleterious effect of NE over AVP on gut perfusion/permeability in sepsis. Fears regarding the use of high dosages of AVP and splanchnic perfusion remain to be evaluated in large scale human studies.

	Conclusions

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
Sepsis-induced tissue and organ hyperpermeability is a clinical evidence-based phenomenon observed daily by critical care physicians at the bedside, although its contribution to patient outcome is still not clear. From a bench perspective, tissue hyperpermeability is both multifactorial and complex. In addition, a majority of studies presented herein stem from animal models of endotoxemia, and caution must be exercised not only in context of species model variability, but also in translating data obtained from animal settings to humans. At a time when knowledge on sepsis pathophysiology is still growing, together with the advent of novel and efficient therapies, critical care physicians must remain vigilant of both "old" and emerging issues such as the unrecognized impact of a standard treatment (NE) and a novel indication for AVP in sepsis on vital organ perfusion/permeability. In this respect, AVP exhibits organ-specific heterogeneity in vascular responsiveness, compared to NE.

Last but not least, one should bear in mind that NE is currently the standard of care in the treatment of septic shock, whereas AVP is still under evaluation.¹⁰⁰ Although infusion rates of AVP as high as ~ 2 to 6 U·hr^–1 (0.03–0.1 U·mL^–1 for a 70 kg-adult) were suggested in vasodilatory shock,¹⁰¹ it has been recently recommended to select a range of 0.01–0.04 U·min^–1 as a "physiological replacement dose" in patients with septic shock.¹⁰⁰ Other potential clinical uses of AVP still under evaluation, and not the focus of this review, include weaning from extracorporeal circulation, out of hospital cardiac arrest, and pulseless ventricular arrhythmia.^102–104

	Footnotes

Accepted for publication December 6, 2005. Revision accepted February 15, 2006.

	References

TOP Abstract Fluid distribution to... The lung in sepsis The kidney in sepsis The heart in sepsis The intestine in sepsis Conclusions References

 
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