Hemodynamic support in the early phase of septic shock: a review of challenges and unanswered questions

Although the SSC 2016 recommends a MAP ≥ 65 mmHg during initial resuscitation (grade 1 B: strong recommendation, moderate level of evidence) [3], there is no precise evidence-based target determined to date. These guidelines suggest that the optimal MAP should be individualized and may be higher in selected patients such as those with atherosclerosis or previous hypertension [3]. In younger patients, a lower target may be acceptable.

The time spent below different threshold values of MAP during the first days has been analyzed and correlated with survival and organ dysfunction in two similarly designed retrospective studies using MAP recordings. The best MAP threshold was 65 mmHg, and the time spent under this value was positively correlated with mortality rate [6, 7].

A large prospective observational study (FINNAKI) [8] identified 423 patients with severe sepsis and showed that those with progression of acute kidney injury (AKI) within the first 5 days of ICU admission (36.2%) had a lower time-adjusted MAP than those without progression [9]. The best time-adjusted MAP value for predicting AKI progression was 73 mmHg. However, these data were not adjusted for disease severity. A retrospective analysis of health records of 8782 septic patients in the USA found increased mortality and AKI risks with time elapsed with average MAP below 85 mmHg [10].

In daily clinical practice, the actual objectified MAP level is often higher than the recommended target. This difference is also observed in all large prospective randomized controlled trials. Indeed, MAP was measured at 80 mmHg in three recent major clinical randomized trials aiming at comparing vasoactive drugs in patients with septic shock after 24 h of treatment (CATS, VASST, SOAP) [11‐13]. Another study (SEPSISPAM) suggests that a MAP target of 65 mmHg is usually sufficient in patients with septic shock. However, a higher MAP level (around 75–85 mmHg) may prevent the occurrence of AKI in patients with chronic arterial hypertension [14]. Of note, patients with a high MAP target received significantly more norepinephrine (NE) and for a longer duration, while experiencing more cardiovascular side effects, especially new more onset of atrial fibrillation.

Given the aforementioned results, the SSC 2016 and 2018 Guidelines [3, 4] as well as the ESICM recommendations suggest targeting MAP to or over 65 mmHg for the initial resuscitation and to individualize MAP according to the patient’s comorbidities.

In light of the above, MAP is commonly considered as a surrogate of global perfusion pressure, although several essential physiological particularities should be retained. Indeed, a better understanding of the autoregulatory mechanisms and microcirculatory regulation during sepsis is needed to rationally address this question. Furthermore, increasing MAP levels often (or always) imply increasing vasopressor load, raising the issue of vasopressor side effects, in addition to their action on MAP.

Autoregulation is the ability of an organ to maintain a constant blood flow entering the organ, irrespective of perfusion pressure, within a range of values called «autoregulation zone». Below this autoregulation threshold, the blood flow in the organ is directly dependent on perfusion pressure. Autoregulation is important in the brain [15], heart [16], and kidney [17], with varying autoregulation threshold values depending on the auto-regulated organ [16]. The kidney has the highest autoregulation threshold and may be considered as the first resuscitation objective, with regards to the potential impacts on the outcome [18]. Autoregulation thresholds differ with patient age and associated comorbidities (chronic hypertension). While autoregulation is a well-established key factor in acute stroke, it is still unknown whether it is maintained during sepsis and whether a traditional threshold remains unchanged [19].

Finally, perfusion pressure should not be regarded as being equivalent to MAP. Organ perfusion pressure is equal to the difference of the pressure in the artery entering the organ (usually approximated by MAP) minus the organ venous pressure. The importance of venous pressure has been shown, particularly in the kidney [20], and the relationship between a deficit of renal perfusion pressure and the risk of AKI has been reported in septic shock [21].

In addition, sepsis is associated with alterations in microcirculation characterized by increased endothelial permeability, leukocyte adhesion, and blood flow heterogeneity leading to tissue hypoxia [22, 23]. Microcirculatory blood flow may be independent from systemic hemodynamics [24]. Consequently, when systemic hemodynamic objectives (in particular MAP target) are achieved, microcirculation abnormalities may persist [23]. Hence, increasing MAP above 65 mmHg may not change microvascular perfusion. Thus, while adjusting hemodynamic objectives at the second phase of septic shock (when patients are “hemodynamically stable”) is unlikely to improve installed microcirculation impairment, an early intervention with high MAP levels may prevent the onset of microcirculatory dysfunction [25‐30] (Table 1). However, more knowledge and monitoring standardization are requested to secure microcirculation assessment and related support. Two trials are currently ongoing with a peripheral or targeted tissue perfusion-guided primary objective (NCT01397474, NCT02579525).

Increasing the MAP target to high levels often requires high vasopressor doses. Norepinephrine (NE) is the most commonly used vasopressor in septic patients. It activates both alpha- and beta-adrenergic receptors and increases systemic vascular resistance (and thus left ventricle afterload); NE usually slightly increases cardiac output due to beta-adrenergic stimulation and its effect on venous return [31]. This venous effect of NE can also impact perfusion pressure, as outlined above [20]. In addition to the consequences of excessive vasoconstriction, other effects should also be taken into account when addressing the question of optimal vasopressor load. Sympathetic overstimulation (or adrenergic stress) can be associated with numerous harmful effects such as diastolic dysfunction, tachyarrhythmia, skeletal muscle damage (e.g., apoptosis), altered coagulation or endocrinological, immunological and metabolic disturbances [32].

‘According to the most recent SSC 2016–2018 Guidelines [3] “norepinephrine (NE) is recommended as the first-choice vasopressor (strong recommendation, moderate quality of evidence)” because of its vasopressor and positive inotropic properties as well as its effect on venous return [61]. These guidelines also “suggest epinephrine (E) to NE with the intent of raising MAP to target (weak recommendation, low quality of evidence).” E titrated to comparable systemic hemodynamic targets clearly results in more pronounced metabolic stress than NE [62], although to date, large RCTs have failed to show the superiority of NE alone [12] or in combination with dobutamine [11] in septic shock when compared to E. Dobutamine is frequently used as an inotropic drug, and accordingly, the SSC 2016–2018 Guidelines [3] suggest its use “…in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents.” However, in contrast to the use of NE this rational only represents a “weak recommendation with low quality of evidence.” In fact, the data supporting the use of dobutamine are “…primarily physiologic, with improved hemodynamics and some improvement in indices of perfusion….” There are no RCT on the use of dobutamine alone, and, as mentioned above, NE in combination with dobutamine was similar to E with respect to overall outcome. Moreover, from a pharmacological point of view, the efficacy of dobutamine per se might be limited when used in combination with NE: in vitro, dobutamine is a weak β-adrenergic agonist when compared to NE [63], and a comparably lower activity of dobutamine than NE was demonstrated in healthy volunteers with respect to catecholamine-induced glucose and lactate metabolism [64]. This issue may assume particular importance in the context of the sepsis-related adrenoceptor desensitization, which is exacerbated by ongoing catecholamine treatment [65]. Furthermore, catecholamines exhibit marked immune-modulatory properties [66] and are known to profoundly affect energy, in particular glucose metabolism [67], and inhibit gastrointestinal peristalsis (for review: see [68, 69]). In addition, “vasopressor load” from high-dose catecholamine infusion rates has been found to be directly related to mortality regardless of the specific MAP achieved [70] due to catecholamine-induced cardiac toxicity [71]. Therefore, the concept of “decatecholaminization” has been put forward in the last decade [72, 73]. Several approaches have been tested, including arginine vasopressin (AVP) or its synthetic analogs, levosimendan, angiotensin II, as well as β-blockade (Table 3). The most abundant data available is on arginine vasopressin (AVP). Albeit “not recommended as a first line vasopressor,” the SSC 2016–2018 Guidelines [3] in fact “suggest adding…vasopressin (up to 0.03 U/min)…to decrease NE dosage (weak recommendation, moderate quality of evidence).” This addition has “catecholamine-sparing” capacity [12] and was recently proven to lower risk of new onset atrial fibrillation in patients with distributive shock [74], which is per se a significant worsening factor of in-hospital stroke and mortality in sepsis [75]. Nevertheless, so far there has been no clear evidence from RCT that the “decatecholaminization” concept is really more efficient than the standard approach using NE. However, data from the VASST, ATHOS, and esmolol trials demonstrated its feasibility, safety and, moreover, suggested improved morbidity and mortality (see below).

Overall, the VASST trial more than 10 years ago did not find any outcome benefit for low-dose (0.01–0.03 U/min) AVP compared to NE [12]. However, in contrast to the underlying hypothesis that the more severe patients might benefit from this approach, the subgroup of patients with only moderate NE requirements (pre-defined as < 15 μg/min), i.e., those in whom weaning from NE was more frequent [76], presented significantly improved survival. Moreover, more patients died while still on NE in the NE group than in the AVP group. Interestingly, a post hoc analysis of the VASST database according to the Septic Shock 3.0 definition [5] showed that AVP lowered the mortality rate compared to NE in patients with lactate levels ≤ 2 mmol/L [77]. The VANISH trial, a 2 × 2 comparison of either AVP (up 0.06 U/min) or NE as initial vasopressor to maintain target MAP followed by hydrocortisone (HCT) or placebo, did not improve the number of kidney failure-free days, although the confidence interval did suggest a potential benefit for AVP [41]. Finally, the single-center VANCS trial showed that AVP (0.01–0.06 U/min) used as first-choice vasopressor reduced morbidity (in particular the incidence of acute renal failure and de novo atrial fibrillation) in vasoplegic patients post-cardiac surgery [78].

AVP non-selectively activates all vasopressin receptor subtypes and the oxytocin receptor, thus potentially resulting in undesirable side effects (e.g., water retention, platelet aggregation) other than the hemodynamic targets [79]. Therefore, more selective V₁ agonists have been tested. While the use of terlipressin does not “offer advantages over AVP” [80] due to its long duration of action over several hours, the pilot SEPSIS-ACT trial of the new, short-acting selective V_1A receptor agonist selepressin reduced cumulative NE doses and net fluid balance, and it increased the number of ventilator-free days [81].

Many patients with sepsis develop cardiac dysfunction (“septic cardiomyopathy” [82]), which prompted the investigation of the “calcium sensitizer” levosimendan. The LeoPARDS trial comparing levosimendan (0.05–0.2 µg/kg/min, depending on rate-limiting side effects) and placebo in addition to standard treatment neither reduced sepsis-induced organ failure nor affected mortality or any other secondary outcome. Levosimendan was associated, however, with a higher incidence of supraventricular tachyarrhythmia [83].

It has been known for decades that septic shock causes activation of the renin–angiotensin–aldosterone system [84], which leads to angiotensin II release [85]. The ATHOS-3 trial compared angiotensin II (1.25–40 ng/kg/min) or placebo to achieve a target MAP ≥ 75 mmHg in patients with vasodilatory shock receiving NE > 0.2 µg/kg/min [86]. This primary endpoint was reached in a significantly higher proportion of patients in the treatment versus the placebo arm (69.9 vs. 23.4%). While the number of serious adverse events and mortality at day 28 did not differ between the two groups, angiotensin II-treated patients exhibited a greater improvement in organ failure score(s) at 48 h.

At first glance, β-blockade appears to be counterintuitive in patients with vasodilatory shock depending on vasopressor therapy, i.e., catecholamine treatment to achieve target MAP. However, based on the similarity in hyperadrenergic response between patients with septic shock and those with cardiac disease [87], an open-label trial in patients with septic shock requiring continuous i.v. NE and presenting with a heart rate > 95/min after 24 h of ICU care investigated the infusion of the short-acting β-blocker esmolol titrated to maintain heart rate at 80–94/min for 96 h in addition to conventional treatment [88]. Esmolol treatment coincided with a lower area under curve for lactatemia and need of fluid resuscitation, and it was ultimately associated with a significantly lower mortality than in the conventional treatment group (49.4 vs. 80.5%).

Given the side effects of high-dose catecholamine treatment and the consequences of sympathetic overstimulation, new approaches based on the concept of “decatecholaminization” are being considered by the latest SSC Guidelines to treat sepsis-induced vasoplegia. On the other hand, angiotensin II and β-blockers—if used—should be handled with considerable caution and only in selected patients. New drug prospects for an optimized ventriculo-arterial coupling are currently under investigation [89].

Albeit HCT is not a hemodynamic drug in the sense of direct vasopressor and/or inotropic activity, since its first use in small-sized trials in the late 1990s [90, 91], the existing RCT data unanimously showed that HCT allowed accelerated resolution of shock as defined by complete weaning from vasopressor support to achieve MAP targets [92, 93]. The hastened resolution of circulatory shock was referred to attenuation of the sepsis-induced hyper-inflammatory response, inhibition of the inducible isoform of the nitric oxide (NO) synthase, thereby attenuating excess NO release, and improved adrenergic receptor responsiveness [95]. Nevertheless, since overall outcome results were equivocal, inasmuch both improved survival [94] and unchanged survival [92, 93] were reported, the use of HCT remains a matter of debate. Accordingly, the SSC 2016–2018 Guidelines [3]—which could not take into the account the more recent ADRENAL [93] and APROCCHSS [94] trials—in fact suggest “…i.v. hydrocortisone at a dose of 200 mg per day” only if adequate fluid resuscitation and vasopressor support do not allow restoring hemodynamic stability, however, as a weak recommendation with low quality of evidence. Clearly, HCT seems not to have any beneficial effect in the prevention of septic shock [96] and should be tapered down once resolution of shock is achieved [3]. Of note, in the context of “decatecholaminization,” HCT may assume particular importance: a post hoc analysis of the VASST data base demonstrated a significant interaction between AVP and HCT, inasmuch the un-protocolized use HCT was associated with attenuated mortality and morbidity in the AVP arm, whereas the opposite result was found in patients who did not receive HCT [97].