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(BQ) Part 1 book Evidence based practice of critical care has contents: Is persistent critical illness an iatrogenic disorder, what is the role of autonomic dysfunction in critical illness, how do i manage acute heart failure,.... and other contents. 40 What MAP Objectives Should Be Targeted in Septic Shock? Franỗois Beloncle, Peter Radermacher, Pierre Asfar Septic shock is defined by a complex association of cardiovascular dysfunction: decreased systemic vascular resistance, hypovolemia, impaired microcirculation, and depressed myocardial function.1 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.2 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 lowlevel evidence).3 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 (O2) delivery to each organ’s O2 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 O2 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 278 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.”4 Below this autoregulation threshold, blood flow is directly dependent on perfusion pressure Autoregulation is of particular importance in the brain,5 heart,6 and kidney.7 Of note, autoregulation threshold values vary in different organs.8 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.9 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.10 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.11 Microcirculation Sepsis is associated with microcirculatory alterations characterized by increased endothelial permeability, leukocyte adhesion, and blood flow heterogeneity that can lead to tissue hypoxia.12,13 Microcirculatory blood flow may be largely independent of systemic hemodynamics.14 Consequently, Chapter 40  What MAP Objectives Should Be Targeted in Septic Shock?     279 when systemic hemodynamic objectives (in particular MAP target) are achieved, microcirculation abnormalities may persist.13 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.15 The venous effect of norepinephrine might also affect the perfusion pressure.11 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.16 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.17 showed that the mean MAP for the first 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.18 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.19 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.20 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 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.21 showed that a low MAP averaged over 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 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,22 Poukkanen et al identified 423 patients with severe sepsis and showed that those with progression of AKI within the first days of ICU admission (36.2%) had lower time-adjusted MAP than those without progression.23 The best time-adjusted MAP value to predict progression of AKI was 73 mm Hg However, as in the study by Badin et al.,21 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.24 showed that increasing the MAP level from 65 to 85 mm Hg for hours with 280    Section VII SEPSIS 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.25 found that an increase in the MAP from 65 to 75 and 85 mm Hg using escalating vasopressor doses for less than 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 [Pco2]) 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 O2 delivery, consumption, or serum lactate, although the increase in norepinephrine infusion dose was associated with an increase in cardiac index.26 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.27 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 [Pto2] 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).28 However, as in the study conducted by Dubin et al.,26 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 hours after they achieved a MAP greater than 75 mm Hg.29 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.30 showed that increasing MAP from 65 to 75 mm Hg for 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.31 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.32 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 MAP IN LARGE, CONTROLLED RANDOMIZED TRIALS In clinical practice, safety limits may dictate that the actual MAP be higher than the originally prescribed target This difference is also observed in large, prospective, randomized controlled trials In the study by Rivers et al.33 comparing two strategies of resuscitation in patients with severe sepsis or septic shock (standard therapy vs early goal-directed therapy [EGDT]), the mean MAP reached in the EGDT group was 95 mm Hg The MAP was also in excess of the recommended target in the CATS trial from Annane et al.34 comparing epinephrine with norepinephrine plus dobutamine, in the large trial from De Backer et al.35 comparing dopamine with norepinephrine in patients with shock, and in the recent ProCESS (Protocolized Care for Early Septic Shock) multicenter study comparing EGDT with usual care.36 These studies reported any side effects that were suggestive of excessive vasoconstriction (e.g., digital or splanchnic ischemia).33-36 In the VASST (Vasopressin and Septic Shock Trial), comparing low-dose vasopressin and norepinephrine in addition with conventional catecholamine,37 the mean MAP level was approximately 80 mm Hg at days in the groups Although risk factors for ischemic injuries were an exclusion criterion, there was a relatively high rate of digital ischemia (2% in the vasopressin group and 0.5% in the norepinephrine group) In the study by Lopez et al.,19 a nitric oxide synthase inhibitor, LNMA, when added to conventional vasopressors, rapidly increased MAP (>90 mm Hg in 25% of the patients) This trial was stopped prematurely because of increased mortality in the LNMA group, primarily as a result of cardiovascular deaths The association between MAP level and mortality cannot be analyzed in this study because of the very likely direct effect of the LNMA, independent of the MAP effect Chapter 40  What MAP Objectives Should Be Targeted in Septic Shock?     281 Table 40-1  Clinical Interventional Studies Comparing Different MAP Targets MAP Titration (Time/Step) Reference Patients (n) Design Main Results of Increase in MAP Bourgoin et al.24 2 × 14 Open-label, randomized 65 vs 85 mm Hg controlled study (4 hours) CI ↑ Arterial lactate, Vo2, and renal function: NS LeDoux et al.25 10 Crossover 65, 75, 85 mm Hg (105 minutes) CI ↑ Arterial lactate, gastric intramucosal-arterial Pco2 difference, skin microcirculatory blood flow (skin capillary blood flow and red blood cell velocity), urine output: NS Dubin et al.26 20 Crossover 65, 75, 85 mm Hg (30 minutes) CI, systemic vascular resistance, left and right ventricular stroke work indexes ↑ Arterial lactate, DO2, Vo2, gastric intramucosal-arterial Pco2 difference, sublingual capillary MFI, and percentage of perfused capillaries (SDF imaging): NS Thoof et al.27 13 Crossover 65, 75, 85 mm Hg (30 minutes) CI, SvO2, StO2, sublingual perfused vessel density, and MFI (SDF imaging) ↑ Vo2: NS Arterial lactate ↓ Jhanji et al.28 16 Crossover 60, 70, 80, 90 mm Hg Do2, cutaneous Pto2, cutaneous microvascular red blood (45 minutes) cell flux (laser Doppler flowmetry) ↑ Sublingual capillary MFI (SDF): NS Deruddre et al.30 11 Crossover 65, 75, 85 mm Hg (120 minutes) 65 to 75 mm Hg: urine output ↑, RRI ↓ 75 to 85 mm Hg: urine output, RRI: NS Creatinine clearance: NS CI, cardiac index; Do2, oxygen delivery; MAP, mean arterial pressure; MFI, microvascular flow index; NS, not significant; Pco2, partial pressure of carbon dioxide; Pto2, tissue oxygen pressure; RRI; R-R interval; SDF, sidestream dark-field; StO2, thenar muscle oxygen saturation using near-infrared spectroscopy; SvO2, mixed venous oxygen saturation; Vo2, oxygen consumption ↑, increase; ↓, decrease The large clinical trials in septic patients suggest that a MAP of approximately 80 mm Hg is often reached without overt side effects SEPSISPAM To avoid the limitations described in the previous studies, the SEPSISPAM (Sepsis and Mean Arterial Pressure Trial) study, a randomized, open-label trial, was designed to enroll 800 patients as soon as possible after admission in the ICU (randomization within hours after the initiation of vasopressors) and to target one of two MAP strategies (65 to 70 vs 80 to 85 mm Hg) from day to day (or until the patient was weaned from vasopressor support).38 Patients also were stratified to account for chronic hypertension The highMAP target group received higher doses of catecholamines over a longer time period than the low-MAP target group No significant differences in 28-day mortality, in the overall rates of organ dysfunction, or in death at 90 days were identified However, in a prospectively defined group of patients with previous hypertension (>40% of the patients in the study), the incidence of AKI (defined by doubling of serum creatinine level) and the rate of renal replacement therapy were higher in the low-MAP target group The overall rate of serious adverse events was not different between the two groups, but there were more episodes of atrial fibrillation, known to be independently associated with an increased risk of stroke, in the high-MAP target group SEPSISPAM confirms that a MAP of more than 65 mm Hg may be needed to prevent AKI in patients with a history of arterial hypertension In addition, this study raises another question: How fluids and vasopressors have to be used to achieve a target MAP? In SEPSISPAM, the hemodynamic management consisted of the introduction of vasopressor (norepinephrine except in one center where epinephrine was used) after adequate fluid resuscitation (defined as the administration of 30 mL of normal saline per kilogram of body weight or of colloids or determined by clinician’s assessment with the method of his or her choice) according to the recommendations of the French Society of Intensive Care Medicine.39 This strategy led to different “profiles” between fluid and vasopressor loads to obtain the same MAP level in comparison with other large clinical randomized studies.40 For example, patients received less fluids and more norepinephrine in SEPSISPAM than in some other trials33,37 but less norepinephrine and more fluids than in the large randomized controlled trial conducted by De Backer et al.35 CONCLUSION Recent studies, especially SEPSISPAM, suggest that a MAP target of 65 mm Hg is usually sufficient in patients with septic shock However, a higher MAP level (∼75 to 85 mm Hg) may prevent the occurrence of AKI in patients with chronic arterial hypertension This point is of major clinical importance in view of the high prevalence of AKI and the subsequent morbidity of this condition in patients admitted in the ICU for septic shock In addition, a delay in 282    Section VII SEPSIS achieving the target MAP may be as important as the target itself Finally, the manner in which a MAP target is achieved (amount of fluids, association of vasopressors) requires further investigations, especially in patients with chronic arterial hypertension who may benefit from a high MAP level AUTHORS' RECOMMENDATIONS •Increasing MAP in shocked patients improves perfusion in autoregulated organs and microcirculatory blood flow but implies higher vasopressor load •Recent studies suggest that a MAP target of 65 mm Hg is usually sufficient in the patients with septic shock •A higher MAP level (around 75 to 85 mm Hg) may prevent the occurrence of AKI in patients with chronic arterial hypertension •The microvascular response to MAP changes varies from patient to patient, suggesting that the optimal MAP may need to be individualized •A delay in achieving the target MAP may be as important as the target itself •The manner in a MAP target is achieved (amount of fluids, association of vasopressors) requires further investigations, especially in patients with chronic arterial hypertension who may benefit from a high MAP level •It is unknown whether higher than required MAP targets have   either beneficial or detrimental effects ACKNOWLEDGMENTS F.B was supported by a grant from the University Hospital of Angers REFERENCES Angus DC, van der Poll T Severe sepsis and septic shock N Engl J Med 2013;369:2063 Augusto J-F, Teboul J-L, Radermacher P, Asfar P Interpretation of blood pressure signal: physiological bases, clinical relevance, and objectives during shock states Intensive Care Med 2011;37:411–419 Dellinger RP, Levy MM, Rhodes A, et al Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock Intensive Care Med 2012;2013(39):165–228 Johnson PC Autoregulation of blood flow Circ Res 1986;59:483–495 Strandgaard S, Olesen J, Skinhoj E, Lassen NA Autoregulation of brain circulation in severe arterial hypertension Br Med J 1973;1:507–510 Berne RM Regulation of coronary blood flow Physiol Rev 1964;44:1–29 Cupples WA, Braam B Assessment of renal autoregulation Am J Physiol Renal Physiol 2007;292:F1105–F1123 Bellomo R, Wan L, May C Vasoactive drugs and acute kidney injury Crit Care Med 2008;36(suppl 4):S179–S186 Prowle JR, Molan MP, Hornsey E, Bellomo R Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation Crit Care Med 2012;40:1768–1776 10 Burban M, Hamel JF, Tabka M, et al Renal macro- and microcirculation autoregulatory capacity during early sepsis and norepinephrine infusion in rats Crit Care Lond Engl 2013;17:R139 11 Legrand M, Dupuis C, Simon C, et al Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study Crit Care Lond Engl 2013;17:R278 12 De Backer D, Donadello K, Taccone FS, Ospina-Tascon G, Salgado D, Vincent J-L Microcirculatory alterations: potential mechanisms and implications for therapy Ann Intensive Care 2011;1:27 13 De Backer D, Creteur J, Preiser J-C, Dubois M-J, Vincent J-L Microvascular blood flow is altered in patients with sepsis Am J Respir Crit Care Med 2002;166:98–104 14 De Backer D, Ortiz JA, Salgado D Coupling microcirculation to systemic hemodynamics Curr Opin Crit Care 2010;16:250–254 15 Hamzaoui O, Georger J-F, Monnet X, et al Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension Crit Care Lond Engl 2010;14:R142 16 Dünser MW, Hasibeder WR Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress J Intensive Care Med 2009;24:293–316 17 Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki L-M, Pettilä V Hemodynamic variables related to outcome in septic shock Intensive Care Med 2005;31:1066–1071 18 Dünser MW, Takala J, Ulmer H, et al Arterial blood pressure during early sepsis and outcome Intensive Care Med 2009;35: 1225–1233 19 López A, Lorente JA, Steingrub J, et al Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock Crit Care Med 2004;32:21–30 20 Dünser MW, Ruokonen E, Pettilä V, et al Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial Crit Care Lond Engl 2009;13:R181 21 Badin J, Boulain T, Ehrmann S, et al Relation between mean arterial pressure and renal function in the early phase of shock: a prospective, explorative cohort study Crit Care Lond Engl 2011;15:R135 22 Nisula S, Kaukonen K-M, Vaara ST, et al Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study Intensive Care Med 2013;39:420–428 23 Poukkanen M, Wilkman E, Vaara ST, et al Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study Crit Care Lond Engl 2013;17:R295 24 Bourgoin A, Leone M, Delmas A, Garnier F, Albanèse J, Martin C Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function Crit Care Med 2005;33:780–786 25 LeDoux D, Astiz ME, Carpati CM, Rackow EC Effects of perfusion pressure on tissue perfusion in septic shock Crit Care Med 2000;28:2729–2732 26 Dubin A, Pozo MO, Casabella CA, et al Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study Crit Care Lond Engl 2009;13:R92 27 Thooft A, Favory R, Salgado DR, et al Effects of changes in arterial pressure on organ perfusion during septic shock Crit Care Lond Engl 2011;15:R222 28 Jhanji S, Stirling S, Patel N, Hinds CJ, Pearse RM The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock Crit Care Med 2009;37:1961–1966 29 Marik PE, Mohedin M The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis JAMA 1994;272:1354–1357 30 Deruddre S, Cheisson G, Mazoit J-X, Vicaut E, Benhamou D, Duranteau J Renal arterial resistance in septic shock: effects of increasing mean arterial pressure with norepinephrine on the renal resistive index assessed with Doppler ultrasonography Intensive Care Med 2007;33:1557–1562 31 Lerolle N Please don’t call me RI anymore; I may not be the one you think I am! Crit Care Lond Engl 2012;16:174 32 Redfors B, Bragadottir G, Sellgren J, Swärd K, Ricksten S-E Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury Intensive Care Med 2011;37:60–67 33 Rivers E, Nguyen B, Havstad S, et al Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 2001;345:1368–1377 Chapter 40  What MAP Objectives Should Be Targeted in Septic Shock?     283 34 Annane D, Vignon P, Renault A, et al CATS Study Group: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial Lancet 2007;370:676–684 35 De Backer D, Biston P, Devriendt J, et al SOAP II Investigators: Comparison of dopamine and norepinephrine in the treatment of shock N Engl J Med 2010;362:779–789 36 ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al A randomized trial of protocol-based care for early septic shock N Engl J Med 2014;370:1683–1693 37 Russell JA, Walley KR, Singer J, et al Vasopressin versus norepinephrine infusion in patients with septic shock N Engl J Med 2008;358:877–887 38 Asfar P, Meziani F, Hamel J-F, et al High versus low bloodpressure target in patients with septic shock N Engl J Med 2014;370:1583–1593 39 Pottecher T, Calvat S, Dupont H, Durand-Gasselin J, Gerbeaux P, SFAR/SRLF Workgroup Haemodynamic management of severe sepsis: recommendations of the French Intensive Care Societies (SFAR/SRLF) Consensus Conference, 13 October 2005, Paris, France Crit Care Lond Engl 2006;10:311 40 Russell JA Is there a good MAP for septic shock? N Engl J Med 2014;370:1649–1651 41 What Vasopressor Agent Should Be Used in the Septic Patient? Colm Keane, Gráinne McDermott, Patrick J Neligan This chapter briefly summarizes the hemodynamic derangement associated with sepsis and then sequentially evaluates the various vasopressor agents that have been investigated and are in current use for the treatment of septic shock HEMODYNAMIC DERANGEMENT IN SEPSIS Early sepsis is characterized by hypoperfusion, manifest as cold extremities, oliguria, confusion, lactic acidosis, and increased oxygen extraction, measured by reduced mixed venous oxygen saturation (SvO2) Current conventional therapy involves early administration of (best-guess) antibiotics and empirical fluid resuscitation of 30 mL/kg.1 The goal of fluid therapy is to reestablish global blood flow and generate a mean arterial pressure (MAP) of more than 65 mm Hg Failure to respond to fluid therapy is an indication for vasopressor therapy Most patients respond to antibiotics and fluids, and vasopressor therapy is usually relatively short.2,3 A minority of patients become acutely critically ill, consequent of septic shock, because of delayed therapy, failure of source control, or genetic reasons, and require critical care for multiorgan support.4 Established (late-stage) septic shock is a complex disease characterized by various cardiovascular and neurohormonal anomalies Although the hemodynamic consequences are easily described, the underlying mechanisms are incompletely understood The major features of established septic shock are as follows: Vasoplegia arises from loss of normal sympathetic tone associated with local vasodilator metabolites, which cause activation of adenosine triphosphate–sensitive potassium channels, leading to hyperpolarization of smooth muscle cells There is increased production of inducible nitric oxide synthetase/nitric oxide synthase-2, resulting in excessive production of nitric oxide Finally, there is acute depletion of vasopressin Vasoplegia is associated with relative hypovolemia Vascular tone is characteristically resistant to catecholamine therapy, but it is very sensitive to vasopressin Reduced stroke volume is widely thought to be due to the presence of circulating myocardial depressant 284 factors, although it may result from mitochondrial dysfunction There is reversible biventricular failure, a decreased ejection fraction, myocardial edema, and ischemia Cardiac output is maintained by a dramatic increase in heart rate Microcirculatory failure manifests as dysregulation and maldistribution of blood flow, arteriovenous shunting, oxygen utilization defects, and widespread capillary leak This results in increased sequestration of proteinrich fluid in the extravascular space These abnormalities are incompletely understood In addition, there is initial activation of the coagulation system and deposition of intravascular clot, causing ischemia In mitochondrial dysfunction, the capacity of mitochondria to extract oxygen is impaired This results in elevated SvO2 and elevated serum lactate despite adequate oxygen delivery to tissues Septic shock should be seen as part of a complex paradigm of multiorgan dysfunction that characterizes acute critical illness These include kidney injury, hepatic dysfunction, delirium, coagulopathy, and acute hypoxic respiratory failure The goal of the Surviving Sepsis Campaign1 is to treat early-phase septic shock and prevent multiorgan failure and chronic critical illness (CCI) This has been remarkably effective,2,3 despite ongoing controversies regarding components of the bundles CCI is manifest by failure to liberate from mechanical ventilation, kwashiorkor-like malnutrition, extensive edema, neuromuscular weakness, prolonged dependence on vasopressors/inotropes, and neuroendocrine exhaustion No interventions currently exist to modulate CCI VASOPRESSOR THERAPY Hypotension and tissue hypoperfusion, unresponsive to intravenous fluid in sepsis, are indications for vasopressor therapy.4,5 It is generally agreed that fluid resuscitation should precede vasopressor use, although the quantity and type of fluid remain controversial.6 The question of which vasopressor(s) to use in sepsis has long been debated Vasopressors are used to target MAP, and inotropes are used to increase cardiac output, stroke volume, and SvO2 The exact MAP target in patients with septic shock is uncertain Chapter 41  What Vasopressor Agent Should Be Used in the Septic Patient?     285 because each patient autoregulates within individualized limits Autoregulation in various vascular beds can be lost below a specific MAP, leading to perfusion becoming linearly dependent on pressure Often, the patient-specific autoregulation range is unknown The titration of norepinephrine to a MAP of 65 mm Hg has been shown to preserve tissue perfusion.6 However, the patient with preexisting hypertension may well require a higher MAP to maintain perfusion The ideal pressor agent would restore blood pressure while maintaining cardiac output and preferentially perfuse the midline structures of the body (brain, heart, splanchnic organs, and kidneys) Currently, norepinephrine is considered the agent of choice in the fluid-resuscitated patient Norepinephrine Norepinephrine has pharmacologic effects on both α1- and β1-adrenergic receptors In low dosage ranges, the β effect is noticeable, and there is a mild increase in cardiac output In most dosage ranges, vasoconstriction and increased MAP are evident Norepinephrine does not increase heart rate The main beneficial effect of norepinephrine is to increase organ perfusion by increasing vascular tone Studies that have compared norepinephrine to dopamine head to head have favored the former in terms of overall improvements in oxygen delivery, organ perfusion, and oxygen consumption.7 Marik and Mohedin8 randomized 20 patients with vasoplegic septic shock to dopamine or norepinephrine, titrated to increase the MAP to greater than 75 mm Hg and measured oxygen delivery, oxygen consumption, and gastric mucosal pH (pHi, determined by gastric tonometry) at baseline and after hours of achieving the target MAP Dopamine increased the MAP largely by increasing the cardiac output, principally by driving up heart rate, whereas norepinephrine increased the MAP by increasing the peripheral vascular resistance while maintaining the cardiac output Although oxygen delivery and oxygen consumption increased in both groups of patients, the pHi increased significantly in those patients treated with norepinephrine, whereas the pHi decreased significantly in those patients receiving dopamine (P 
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