Macrocirculatory Disturbances

D. De Backer

Introduction

Severe sepsis and septic shock are associated with a state of inadequate supply or inappropriate use of oxygen and nutrients by the cells, which may result in tissue hypoxia and lactic acidosis. Unless transient, this will lead to irreversible tissue damage and death. As tissue necrosis is uncommon in patients with septic shock [1], adaptations of organ metabolism are likely to occur in order to shut down some less essential metabolic pathways and to preserve vital functions. This will lead to the development of multiple organ failure (MOF), which can be reversed if the underlying sepsis can be cured. MOF is frequent in patients with severe sepsis, despite the restoration of whole-body hemodynamics. Early interventions aiming at normalizing some specific hemodynamic end-points improve outcome of patients in septic shock [2]. Nevertheless, many patients will still develop MOF and will ultimately die, suggesting that other factors were not corrected. Global hemodynamic alterations, blood flow redistribution, microvascular blood flow alterations, and direct cellular toxicity may play a crucial role in the development of MOF in these patients.

Global Hemodynamic Alterations

Septic shock is a complex syndrome characterized by profound cardiovascular derangements, with alterations in cardiac function, blood flow redistribution be- tween organs, and microcirculatory alterations (Table 1).

Decreased Vascular Tone

Hypotension is a typical finding in sepsis. The endothelial dysfunction is respon-

sible for a marked resistance to vasopressors. The contractile response of arteries

and arterioles to norepinephrine or phenylephrine is decreased in sepsis [3], and

this effect is mediated by circulating factors. Several factors have been implicated

in this vasodilatory state. The role of nitric oxide (NO) has been clearly demon-

strated [4, 5] but NO inhibitors have failed to improve survival in patients with

septic shock even though these compounds increased arterial pressure. Vaso-

pressin deficiency has also been reported [6, 7], but it is unlikely that vasopressin

Table 1. Principal hemodynamic alterations in septic shock

Systemic hemodynamic alterations:

Decreased vascular tone Hypovolemia

Absolute (increased permeability)

Relative (blood pooling, especially in the splanchnic bed) Decreased venous compliance

Myocardial dysfunction Systolic

Diastolic

Regional blood flow alterations:

Hepatosplanchnic area Kidneys

Brain

Microvascular blood flow alterations

deficiency takes a prominent role in the early phases of sepsis as vasopressin levels are usually elevated at the onset of sepsis [7]. In addition to vasopressin deficiency, vasopressin resistance may also occur as there is desensitization of the vasopressin receptor, both in arteries and in venules [8, 9]. Inadequate cortisol levels or re- sistance to corticosteroids has also been suggested, especially in the late stages of sepsis, and hydrocortisone administration may help to restore the pressor re- sponse to norepinephrine in patients with septic shock [10]. Thus, it is likely that several mechanisms are implicated in the sepsis-induced vasodilatory state, but the contribution of each of these factors may vary over time.

Decreased Venous Return

A decrease in venous return is always present in sepsis. Pinsky et al. [11] reported that endotoxin administration caused a marked decrease in venous tone within 5 min. At this time, endotoxin did not yet alter arterial vasomotor tone. The venous congestion is not equally distributed, with the splanchnic area more prone to develop venous pooling. By studying portal pressure/flow relationships, Ayuse et al. [12] reported that endotoxin increased the closing pressure without changes in the slope of the relationship. This leads to portal hypertension and venous pooling, which is further exacerbated since the veno-arterial response in the mesenteric artery is abolished.

In addition, vascular permeability is increased in sepsis [13,14], and the combi-

nation of venous pooling and plasma losses results in severe hypovolemia. Finally,

Stephan et al. [15] observed that the venous vascular compliance is decreased in

septic patients, so that central venous pressure may underestimate the severity of

hypovolemia.

The consequences of hypovolemia include low or inadequate cardiac output and redistribution of regional blood flows, especially at the expense of splanchnic and renal blood flows.

Myocardial Depression

Septic shock is characterized by a high cardiac output and peripheral vasodilata- tion. However, various studies have demonstrated that myocardial contractility may be altered despite a normal or increased cardiac output. After administration of low doses of endotoxin to human healthy volunteers, Suffredini et al. [16] re- ported that the left ventricular ejection fraction was decreased although cardiac output increased. Myocardial depression is always observed in septic patients, whatever the method used to investigate cardiac function (e. g., echocardiogra- phy, isotopes), but its severity is variable and is related to outcome. Myocardial depression is related to the liberation of mediators of sepsis (e. g., cytokines, NO, etc), however the mechanisms responsible for myocardial depression are unclear.

Myocardial contractility and relaxation are both affected. Histological changes are common and troponin can be released although coronary blood flow is increased and lactate is usually consumed by the heart. Nevertheless, myocardial depression resolves completely after resolution of sepsis.

Altered Oxygen Extraction and VO

/DO

Dependency

A large number of experimental studies have shown that oxygen extraction ca- pabilities are impaired in sepsis and that this may lead to the development of dependence of oxygen consumption (VO

) on oxygen delivery (DO

), or VO

/DO

dependency, even at normal values of DO

[17, 18]. Several factors may account for the altered extraction capabilities, including blood flow redistribution between the organs (due to the altered vascular tone), redistribution of blood flow within each organ (due to microvascular alterations), and altered use of oxygen by the cells (also called cytopathic hypoxia). The contribution of each of these factors is difficult to separate. As oxygen extraction is preserved in a perfused capillary [19], the role of decreased vascular tone and microcirculatory alterations seems to be prominent, at least in the early phases of sepsis. Due to methodological limitations, the reality of this phenomenon in humans has been difficult to demonstrate [20].

Consequences of Global Hemodynamic Alterations

To what extent doe the hypotension induced by the decrease in vascular tone

contribute to organ hypoperfusion and dysfunction in sepsis? In experimental

studies, correction of hypotension by adrenergic agents has been shown to im-

prove survival [21]. In patients, several studies have reported that the severity of

hypotension is related to outcome [22]. In addition, the more severe the resis-

tance to catecholamines, the greater the likelihood of developing organ failure and

death [23, 24]. In a recent study, Varpula et al. [25] showed that a mean arterial pressure (MAP) level below 65 mmHg on arrival, during the first 6 hours, and the first 48 hours were independently associated with 30 day-mortality. Raising blood pressure above this level may not be associated with improved tissue perfu- sion [26, 27]. Accordingly, it may be considered that maintaining blood pressure above 65 mmHg is sufficient.

The combination of hypovolemia and myocardial dysfunction may be severe enough to impair cardiac output, leading to an inadequate DO

(whether VO

/DO

dependency occurs or not). Many experimental studies have shown that cardiac output is initially low and that the hyperdynamic state can only be observed after fluid resuscitation [28,29]. To what extent does impaired DO

play a role in the de- velopment of organ dysfunction? Several studies have reported that cardiac output and DO

are higher in survivors than in non-survivors [30–32]. In addition, it has been shown that early hemodynamic optimization is associated with a decreased risk of new onset organ failure and death [2]. What component of the decreased DO

is the most relevant? Early fluid administration prolongs survival time in ani- mals [33], but its role in patients with septic shock, especially in prolonged shock, remains unclear. The role of inotropic agents is also controversial. Combining the findings of the studies by Rivers et al. [2] and Gattinoni et al. [34], it may be proposed that hemodynamic optimization using fluids, inotropic agents, and red blood cell transfusions may be beneficial in the early phases of sepsis. In the late stages of sepsis, maintaining DO

at high levels seems not to be beneficial, even though it seems reasonable to avoid tissue hypoperfusion. The lowest tolerable level of DO

has to be defined on an individual basis.

Regional Blood Flow Alterations

In addition to systemic hemodynamic alterations, sepsis can induce profound alterations in blood flow distribution. These can lead to cerebral blood flow alter- ations, with possible loss of cerebral autoregulation, and alterations in renal and hepatosplanchnic blood flow.

Hepatosplanchnic Hemodynamics

Important histological alterations can be observed in the gut [35] and the liver [36]

during sepsis. Although a direct cytotoxic effect of NO or cytokines can be en- visaged, an imbalance between oxygen supply and demand in the splanchnic area may participate in the development of organ failure [37].

Anatomic and Physiologic Considerations

The liver is supplied by a dual circulation. Hepatic artery and portal blood flow

mix at the entry of the hepatic acinus, the functional liver unit, which is 2 mm

wide. Before being drained by the hepatic vein, blood will provide oxygen and

nutrients to the hepatocytes located in the sinusoids, but a wide PO

gradient can be observed between the periportal and the centrilobular zones, so that the latter is much more sensitive to decreases in oxygen supply. In normal circumstances, the hepatic vein saturation (ShO

) is close to mixed venous oxygen saturation (SvO

) so that the gradient between ShO

and SvO

is usually less than 10% [38].

The vascularization of the gut is also complex. In normal conditions, the distribution of blood flow to the different components is related to metabolic requirements. The amount of blood flow (by unit of weight) directed to the small intestine is twice the amount directed to the stomach or the colon, the mucosal and submucosal regions receiving 70% of total gut blood flow. Metabolism is also very high in this area since the gut mucosa accounts for 10–15% of total body protein production. In addition, the gut mucosa is particularly sensitive to alterations in blood flow due to the typical vascularization of the microvilli. The artery to the villus forms a right angle with the mesenteric artery so that plasma skewing occurs and hematocrit is lower in the mucosa than in the submucosa and serosa. Also, the artery is located in the center of the villus, surrounded by laces of veins in which the flows are in the opposite direction. This particular anatomical vascular network allows better absorption of the nutrients but also leads to countercurrent exchange of oxygen from the artery to the vein along their parallel course. Consequently, PO

decreases from the base of the villus to its tip, reaching values as low as 30 mmHg. In healthy humans, Temmesfeld-Wollbrück et al. [39] reported that oxygen saturation ranged from 50 to 100%.

Effects of Sepsis on Hepatosplanchnic Blood Flow and Metabolism

The normal splanchnic VO

represents 20–35% of total VO

while splanchnic blood flow is equal to 25% of cardiac output. In sepsis, various studies [40,41] have reported a disproportionate increase in metabolic requirements in the splanchnic area (and especially in the liver with an increase in glucose output, lactate uptake, and protein synthesis). This increase in hepatosplanchnic metabolism exceeded the increase in splanchnic blood flow so that the gradient between SvO

and ShO

was increased, ranging between 20 and 40% [38,42]. We [43] reported that an increased gradient (higher than 10%) was associated with covariance of hepatosplanchnic VO

and DO

during dobutamine administration or application of positive end- expiratory pressure (PEEP) in septic patients.

The effects of sepsis on the gut are more difficult to investigate. In experi-

mental studies on septic shock, mesenteric blood flow has been reported to be

reduced, unchanged, or increased. Such differences may depend on the animal

species, the technique used to investigate regional blood flow, and the amount

of fluid administered. Even in experimental models in which mesenteric blood

flow was increased, alterations in gut mucosal permeability, gut mucosal acidosis,

and histological lesions can be observed [35]. Tugtekin et al. [44] reported that

perfusion of the villi was markedly decreased and heterogeneous, and the authors

ascribed the increase in gut mucosal PCO

to these alterations in mucosal blood

flow. In addition, oxygen extraction capabilities are impaired by endotoxin, both

in the liver and in the gut, and this could possibly be related to increased blood flow heterogeneity [45]. In septic patients, Temmesfeld-Wollbrück et al. [39] reported that gut oxygen saturation heterogeneity was increased and ranged from 0 to 70%.

In humans, liver dysfunction [46] and gut mucosal acidosis [47] are associated with a poor outcome.Even though therapeutic strategies using gastric mucosal pH as a goal yielded controversial results [48, 49], it seems reasonable to avoid interventions that could further impair hepatosplanchnic blood flow.

Renal Perfusion

Renal failure frequently occurs in sepsis and several mechanisms have been im- plicated, including renal hypoperfusion [50]. The involvement of renal blood flow impairment in sepsis has been reviewed recently by Langenberg et al. [51]. These authors reported that renal blood flow was impaired in 62% of the 159 animal stud- ies identified; in most of these studies renal blood flow impairment was associated with signs of under-resuscitation (hypodynamic shock). As the measurement of renal blood flow is difficult in critically ill patients, it remains uncertain whether renal blood flow alterations have a role in the development of acute renal failure in hyperdynamic sepsis. Indirect evidence suggests that afferent and efferent arterial tone in sepsis may be affected differently. Increasing MAP from 65 to 85 mmHg with norepinephrine, which acts primarily on the afferent arteriole, is not accom- panied by any change in urine output or creatinine clearance [27], while partially replacing norepinephrine by vasopressin administration, which acts mostly on the efferent arteriole, increased both urine output and creatinine clearance [52].

Cerebral Perfusion

The role of cerebral hypoperfusion in the development of septic encephalopathy is also controversial [53–55]. Although cerebral autoregulation theoretically protects the brain from whole body hemodynamic alterations [53], some authors have found that this regulatory mechanism may be lost in sepsis [56, 57]

Conclusion

Sepsis induces profound metabolic and cardiovascular derangements. Although

some indices indicate that cytopathic hypoxia may coexist, early correction of

global hemodynamic alterations is essential. Regional blood flow alterations may

persist after correction of systemic hemodynamics. Although a systematic increase

in splanchnic blood flow may not be warranted, several arguments suggest that

the maintenance of an adequate balance between oxygen supply and demand in

the splanchnic area may be useful.

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