Acknowledgments
F.B. was supported by a grant from the University Hospital of Angers.
Septic shock is defined by a complex association of cardiovascular dysfunction: decreased systemic vascular resistance, hypovolemia, impaired microcirculation, and depressed myocardial function. This vascular impairment leads to an imbalance between oxygen delivery and demand. Thus, the aim of initial septic shock management is to rebalance this mismatch. Mean arterial pressure (MAP) is one of the hemodynamic targets used to try to ensure that organs are adequately perfused. During initial resuscitation, a MAP level of greater than 65 mm Hg is recommended in the Surviving Sepsis Campaign guidelines (grade 1C: high-grade recommendation based on low-level evidence). Although this goal may be acceptable in a global sense, a target MAP of 65 mm Hg is unlikely to be appropriate for many critically ill patients. However, intervention to achieve a higher MAP carries several risks. In septic shock, we must avoid three risks—underperfusion, tissue edema, and excessive vasoconstriction—that can lead to tissue hypoperfusion. The optimal MAP level (or the optimal vasopressor dose) corresponds to the optimal balance between these risks. The Surviving Sepsis Campaign guidelines suggest that the optimal MAP should be individualized because it may be higher in selected patients such as those with atherosclerosis or previous hypertension.
This review discusses the physiologic rationale and the different clinical studies addressing the question of the optimal MAP in patients with sepsis.
Physiologic Rationale
The ultimate goal of septic shock resuscitation is to adapt oxygen (O 2 ) delivery to each organ’s O 2 demand. MAP is commonly considered as a surrogate of global perfusion pressure. Thus, increasing MAP level in septic shock patients might lead to an increase in O 2 delivery to the tissue. However, a better understanding of autoregulatory mechanisms and microcirculation regulation during sepsis is needed to address this question. In addition, increasing MAP level implies increasing vasopressor load, and this raises the question of the side effects of these agents.
Autoregulation
Autoregulation refers to the ability of an organ to maintain a constant blood flow entering the organ irrespective of the perfusion pressure over a range of values called the “autoregulation zone.” Below this autoregulation threshold, blood flow is directly dependent on perfusion pressure. Autoregulation is of particular importance in the brain, heart, and kidney. Of note, autoregulation threshold values vary in different organs. The kidney has the highest autoregulation threshold; therefore it may be considered as the first resuscitation objective. Maintenance of a MAP within the renal autoregulatory range allows the organ to be perfused in times of stress. Autoregulation thresholds differ in accordance with patients’ age and associated comorbidities (e.g., chronic hypertension). It is unclear whether vascular reactivity impairment in septic patients is associated with changes in the autoregulatory range. In a study by Prowle et al., renal blood flow assessed by cine phase-contrast magnetic resonance imaging was lower in septic patients than in control healthy patients despite a MAP between 70 and 100 mm Hg. These findings suggest that renal autoregulation is disturbed during sepsis. However, in a rat model of sepsis, renal blood flow was altered over a large range of MAP. These findings support the conclusion that autoregulation may be conserved in sepsis. Thus, it is unknown whether autoregulation is maintained during sepsis and whether the autoregulation threshold is unchanged.
It is worth noting that perfusion pressure and MAP differ. Organ perfusion pressure is equal to the difference of the pressure in the artery entering the organ (usually approximated by the MAP) minus the organ venous pressure. The importance of the venous pressure has been shown in particular in the kidney.
Microcirculation
Sepsis is associated with microcirculatory alterations characterized by increased endothelial permeability, leukocyte adhesion, and blood flow heterogeneity that can lead to tissue hypoxia. Microcirculatory blood flow may be largely independent of systemic hemodynamics. Consequently, when systemic hemodynamic objectives (in particular MAP target) are achieved, microcirculation abnormalities may persist. Thus, increasing the MAP level above 65 mm Hg may not change microvascular perfusion. However, microcirculation alteration in the early phase of sepsis reflects a low perfusion pressure (i.e., a failure to achieve macrocirculation parameter targets at the beginning of the shock). Thus, although adjusting hemodynamic objectives at the second phase of the septic shock when patients are “hemodynamically stable” is unlikely to improve microcirculation impairment, an early intervention with high MAP levels may prevent microcirculation dysfunction.
Specific Effect of High Vasopressor Load
Increasing the MAP target to high levels may require high doses of vasopressor or inotropic drugs. Norepinephrine is the most commonly used agent in septic patients. It activates both α- and β-adrenergic receptors. Although its main hemodynamic effect is to increase systemic vascular resistance (and thus left ventricle afterload), norepinephrine usually slightly increases cardiac output because of its β-adrenergic stimulation and its effect on venous return. The venous effect of norepinephrine might also affect the perfusion pressure. In addition to the consequences of excessive vasoconstriction, other effects should be taken into account when addressing the question of optimal vasopressor load. Sympathetic overstimulation (or adrenergic stress) may be associated with harmful effects such as diastolic dysfunction; tachyarrythmia; skeletal muscle damage (apoptosis); altered coagulation; or endocrinologic, immunologic, and metabolic disturbances.
Observational Studies
Several observational clinical studies have examined optimal MAP targets in patients with sepsis. Two retrospective studies used MAP recordings and examined the time spent below different threshold values of MAP during early sepsis. Data were correlated with survival and organ dysfunction. In 111 patients with septic shock, Varpula et al. showed that the mean MAP for the first 6 and 48 hours predicted 30-day outcome. With the use of receiver operator characteristic (ROC) curves, the best predictive MAP threshold level for 30-day mortality was 65 mm Hg. In addition, the time spent under this value also correlated with mortality. However, because the MAP level is strongly associated with disease severity, these results may only reflect shock severity. Dünser et al. performed a similar analysis in 274 sepsis or septic shock patients, but they adjusted for disease severity (as assessed by the Simplified Acute Physiology Score [SAPS] II excluding systolic arterial pressure). The authors assessed the association between different arterial blood pressure levels during the first 24 hours after intensive care unit (ICU) admission and 28-day mortality or organ function. A 28-day mortality did not correlate with MAP drops below 60, 65, 70, and 75 mm Hg. However, an hourly time MAP integral that dropped below 55 mm Hg was associated with a significant decrease in the area under the 28-day mortality ROC curve. This suggests that a MAP level of 60 mm Hg was a sufficient target during the first 24 hours of sepsis. However, the need for renal replacement therapy was best predicted by the ROC curve for the hourly time integral of MAP drops below 75 mm Hg. Thus, a higher MAP level may be required to prevent acute kidney injury (AKI).
In a post hoc analysis of data from a study investigating the effects on mortality of L-NMMA ( N -methyl- l -arginine), a nitric oxide inhibitor, there was no association between MAP (or MAP quartiles) and mortality or occurrence of disease-related events in a control group that included 290 septic shock patients. This study used logistic regression models and adjusted for age, the presence of chronic arterial hypertension, disease severity at admission (SAPS II), and vasopressor load. Of note, in this study, age and chronic arterial hypertension did not modify the association between MAP and 28-day mortality or AKI. In addition, the mean vasopressor load correlated with mortality and the number of disease-related events. The authors concluded that “MAP levels of 70 mm Hg or higher do not appear to be associated with improved survival in septic shock” and that “elevating MAP >70 mm Hg by augmenting vasopressor dosages may increase mortality.”
In 217 patients with shock (127 or 59% of whom had septic shock), enrolled and followed prospectively, Badin et al. showed that a low MAP averaged over 6 hours or 12 to 24 hours was associated with a high incidence of AKI at 72 hours only in patients with septic shock and AKI at 6 hours. In these patients, the best MAP threshold to predict AKI at 72 hours ranged from 72 to 82 mm Hg. No link between MAP and AKI at 72 hours in the other patients was found. In line with the results of Dünser et al., the authors concluded that a MAP of approximately 72 to 82 mm Hg might be required to avoid AKI in patients with septic shock and initial renal function impairment.
Using the data from the large prospective observational FINNAKI study, Poukkanen et al. identified 423 patients with severe sepsis and showed that those with progression of AKI within the first 5 days of ICU admission (36.2%) had lower time-adjusted MAP than those without progression. The best time-adjusted MAP value to predict progression of AKI was 73 mm Hg. However, as in the study by Badin et al., the results were not adjusted for severity of disease.
These results are confounded by all of the limitations inherent to the observational studies, but they deserve to be analyzed at the MAP level from ICU admission (closer from the beginning of the disease process than in interventional studies). Although the results are not all consistent and the relationship of disease severity to MAP makes them difficult to interpret, these studies suggest that a MAP target higher than 65 mm Hg may prevent AKI in some septic patients.
Interventional Studies
Some prospective interventional studies have attempted to delineate an optimal MAP target in septic patients by modifying the MAP level over a short period of time. In a small randomized controlled trial of 28 patients with septic shock, Bourgoin et al. showed that increasing the MAP level from 65 to 85 mm Hg for 4 hours with norepinephrine increased cardiac index in the experimental arm. However, no change in arterial lactate, oxygen consumption, or renal function variables (urine output, serum creatinine, and creatinine clearance) was detected in either of the groups.
In 10 patients with septic shock, LeDoux et al. found that an increase in the MAP from 65 to 75 and 85 mm Hg using escalating vasopressor doses for less than 2 hours did not significantly alter systemic oxygen metabolism, skin microcirculatory blood flow (assessed by skin capillary blood flow and red blood cell velocity), urine output, or splanchnic perfusion (assessed by gastric mucosal partial pressure of carbon dioxide [P co 2 ]). Of note, many of the patients received dopamine and not norepinephrine. In addition, in 20 patients with septic shock, targeting a MAP of 65, 75, or 85 mm Hg did not alter O 2 delivery, consumption, or serum lactate, although the increase in norepinephrine infusion dose was associated with an increase in cardiac index. Furthermore, no change was observed in sublingual capillary microvascular flow index or the percentage of perfused capillaries.
Conversely, in a study including 13 patients with septic shock, Thooft et al. showed that, in comparison with 65 mm Hg, targeting MAP to 85 mm Hg for 30 minutes by increasing norepinephrine increased cardiac output, improved microcirculatory function (assessed by thenar muscle oxygen saturation using near-infrared spectroscopy with serial vaso-occlusive tests on the upper arm and sublingual microcirculation using sidestream dark-field imaging in six patients), and decreased arterial lactate. Interestingly, the microvascular response to MAP changes varied largely from patient to patient, suggesting that the optimal MAP may need to be individualized.
In another study of similar design investigating 16 septic shock patients, raising MAP from 60 to 70, 80, and 90 mm Hg for 45 minutes increased oxygen delivery, cutaneous microvascular flow, and tissue oxygenation (using cutaneous tissue oxygen pressure [Pt o 2 ] measured by a Clark electrode, cutaneous red blood cell flux assessed by laser Doppler flowmetry, and sublingual microvascular flow evaluated by sidestream dark-field imaging). However, as in the study conducted by Dubin et al., no change in the sublingual microvascular flow abnormalities or lactate or urine output observed at 60 mm Hg were detected when MAP was increased to 90 mm Hg.
In a randomized short-term study comparing the effects of dopamine and norepinephrine in 20 patients, patients were evaluated at baseline (MAP = 65 and 63 mm Hg in the norepinephrine and dopamine group, respectively) and 3 hours after they achieved a MAP greater than 75 mm Hg. Oxygen delivery and consumption (determined by indirect calorimetry) increased in both groups. However, the gastric intramucosal pH (determined by gastric tonometry) increased in the norepinephrine group but decreased in the dopamine group.
Finally, in 11 septic patients, Derrudre et al. showed that increasing MAP from 65 to 75 mm Hg for 2 hours increased urinary output and decreased the renal resistive index measured by echography. However, no changes were detected when MAP was increased from 75 to 85 mm Hg. Importantly, the interpretation of renal resistive index changes is complex because of its numerous determinants. Nevertheless, this study suggests that for some patients, the optimal balance between the positive effects (i.e., increase in perfusion pressure) and the negative effects of norepinephrine (i.e., excessive vasoconstriction) could correspond to a MAP target of approximately 75 mm Hg. This premise is supported by data from a study on 12 nonseptic, postcardiac surgery patients with vasodilatory shock and AKI. In these individuals, increasing MAP from 60 to 75 mm Hg improved renal oxygen delivery, the renal oxygen delivery/consumption relationship, and glomerular filtration rate, but increasing from 75 to 90 mm Hg did not alter these parameters.
Thus, the data regarding the effects of a MAP of more than 65 mm Hg on organ function and microcirculation are divergent. In addition to the small number of patients and the short observation periods, these differences may be related to differences in cardiac preload and to the point in time at which data were collected. It is of critical importance to note that the inclusion time in all of these studies was very wide and that most of the enrolled patients were already hemodynamically controlled. These human interventional studies are summarized in Table 40-1 .
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