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Review

Fluids, Vasopressors, and Inotropes to Restore Heart–Vessel Coupling in Sepsis: Treatment Options and Perspectives

by
Francesca Innocenti
1,*,
Vittorio Palmieri
2 and
Riccardo Pini
1
1
High-Dependency Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliero Universitaria Careggi, Lg. Brambilla 3, 50134 Firenze, Italy
2
Cardiosurgery Unit, Cardiovascular Department, “Sant’Anna e San Sebastiano” National Hospital, 81100 Caserta, Italy
*
Author to whom correspondence should be addressed.
Anesth. Res. 2024, 1(2), 128-145; https://doi.org/10.3390/anesthres1020013
Submission received: 26 July 2024 / Revised: 21 August 2024 / Accepted: 6 September 2024 / Published: 14 September 2024
Browse Figure
Review Reports Versions Notes

Abstract

:
Sepsis is a complex syndrome with heterogeneous clinical presentation and outcome, characterized by an abnormal inflammatory response, potentially leading to multiorgan damage and hemodynamic instability. Early resuscitation with fluids and timely control of the source of sepsis are key treatment targets in septic patients. Recommendations on when to add vasopressors and inotropes are mostly empirical and anecdotal, therefore remaining a topic of debate. This narrative review was developed to present and discuss current options in the early management of hemodynamic derangement induced by sepsis. We discuss the strengths and drawbacks of the recommended treatment with fluids and how to optimize volume resuscitation in order to avoid fluid overload or under-resuscitation. The choice and timing of vasopressor use represent hot topics in the early management of septic patients. We describe the advantages and limitations of the early introduction of vasopressors and new catecholamine-sparing strategies. We conclude with a description of the inotropes, considering that the heart plays a key role in the pathophysiology of septic shock.

1. Introduction

Sepsis is caused by a dysregulated response of the host to the infection, with consequent multiorgan damage and increased mortality [1]. Despite different symptoms, signs, and even prognosis, two elements are common in all septic patients: the beginning of the disease, which always consists of the abnormal activation of an inflammatory response, and the modalities of early treatments. Unfortunately, we do not have typical symptoms or reliable biomarkers to assist for an early diagnosis of sepsis, such as “chest pain” or “troponin” for cardiac ischemia, and this condition frequently determines a relevant diagnostic delay.
Inflammation represents a stereotyped response of the human body to a variety of stimuli perceived as dangerous, such as the presence of pathogens or the alteration in homeostasis (for example, changes in temperature, oxygen level, acid–base balance, or levels of electrolytes) [2]. The recruitment of cellular lines normally absent in specific sites begins, in order to limit the damage and to prepare the process of healing [3,4]. When the complex interplay between the host and pathogen generates a disproportionate inflammatory reaction with a cytokine storm and the activation of multiple pathways, we are in the presence of sepsis (Figure 1).
The possibility to intervene directly on the inflammatory reaction has been repeatedly tested in past years through the use of inhibitors of the specific pathways activated during inflammation. Both several anti-cytokine molecules and treatments aimed at interfering with dysregulated coagulation failed to show any positive prognostic effect in septic patients [5,6,7]. In fact, the complexity of the involved pathways and their different timings of activation dampened the possibility to modify the course and the entity of the inflammatory response. In fact, the ways the infection process and the inflammatory activation affect the function of different target organs and systems depend on the presence of previous medical conditions, the involved pathogen, and the immune status of the patient [8].
At the moment of presentation, early antibiotic therapy and fluids aimed at controlling pathogens spread and restore the hemodynamic stability represent the cornerstones of treatment in all septic patients, albeit with several points that still represent a topic of debate. Existing guidelines suggest the management of early hemodynamic derangement, aimed at the restoration of adequate mean arterial pressure (MAP), as well as a reduction in lactate levels [9]. It is important to underline this double recommendation, as during septic shock, both macro- and microcirculation are affected. At the earliest stage, vasoplegia and relative hypovolemia, which result in reduced arterial pressure and tachycardia, are always coupled with microcirculatory abnormalities, consisting of heterogeneity in capillary perfusions, due to altered vascular permeability and fluid leakage, micro thrombosis, and capillary obstruction [10]. Early treatment based on fluids and vasopressors may resolve macrohemodynamic derangement but may leave unaffected or even worsen microcirculatory alterations. In fact, inappropriate fluid administration may damage the endothelium and increase capillary leak, while excessive vasoconstriction could further impair tissue perfusion [11]. The loss of so-called hemodynamic coherence may occur, upon which, despite being able to restore blood pressure to within normal limits, the microcirculation abnormalities persist and preclude normal organ perfusion [12].
In this narrative review, we briefly present the current recommendation for early hemodynamic stabilization and then present the most important, still-unanswered, questions on the early treatment of septic patients.

2. Fluids in Sepsis: Are Septic Patients Really Empty?

During sepsis, a relative hypovolemia develops, due to increased vascular permeability, known as “vascular leak syndrome”, leading to low circulating blood volume and organ failure due to tissue edema. Multiple studies have shown a link between positive fluid balance and negative outcomes, including impaired organ function and an increased risk of death [13].
Recommendations for fluid administration in the early resuscitation of septic patients significantly changed in recent years. The first version of the Early Goal Directed Therapy recommended discontinuing fluid administration only after achieving an “adequate” filling pressure, regardless of the amount of infused fluids [14]. However, subsequent studies demonstrated a negative impact of an excessive fluid administration, with increased mortality in patients with elevated central venous pressure [15]. In fact, inappropriate fluid administration can lead to vasodilation, tissue oedema, and worsened perfusion and oxygenation.

2.1. The First Bolus: What Is the Supporting Evidence?

In 2012, the SSC recommended beginning early resuscitation in septic patients with a fluid bolus of 30 mL/kg within the first 3 h after diagnosis. This recommendation became the standard of care, even though the supporting evidence was reportedly low [16]. In the following years, several authors questioned this approach, due to the lack of supporting evidence [17,18]. However, no trial was conducted to evaluate the real advantages or risks of this practice, and all the trials that evaluated fluid administration in the early stages of sepsis assumed the use of the first bolus. On the other side, a recent retrospective analysis by Kuttab and colleagues [19] demonstrated that failure to complete the first bolus was associated with increased in-hospital mortality, regardless of comorbidities. Therefore, in actuality, there is insufficient evidence to support the administration of the first bolus, but it may represent a reasonable compromise to prevent fluid overload and avoid the risk of initiating vasopressors in fluid-depleted circulation, with a high risk of ischemia, especially in the splanchnic district.

2.2. Fluid Replacement after Early Resuscitation

The situation is different as regards the administration of fluids after the first bolus. We know that a consistent proportion of patients are not fluid responders after the first bolus and, in the event of persistent hypotension, further administration of fluids may not be beneficial. After the first fluid bolus, the SCC recommends using dynamic tests to determine the persistence of fluid responsiveness, because only in those cases, the administration of further fluids is useful for hemodynamic stabilization [9]. For patients who achieve hemodynamic stability, fluid replacement may be considered adequate in the absence of signs of hypoperfusion, such as elevated lactate levels or reduced urine output. In the presence of persistent hypotension, treating physicians must decide whether to administer further fluids or vasopressors [9].
In Table 1, we provide an overview of the main studies published after 2020 that discuss the possibility of standardizing the fluid regimen after the first fluid bolus. The FRESH study was the only one to include an evaluation of fluid responsiveness as a criterion for the randomization process [20]. The size of the FRESH population was limited, and it failed to demonstrate a positive effect of this strategy on patients’ prognosis. Further studies, which included larger populations, reached similar conclusions [21,22,23]. A recent meta-analysis confirmed these results [24].
In our opinion, disregarding the importance of a controlled fluid regimen, based on these results, could be dangerous for different reasons. There are several factors that may have hindered the real therapeutic and prognostic impact of a restrictive fluid regimen, compared to a liberal one. Firstly, all the studies prescribed a protocolized regimen in both arms, which could have improved the treatment for all included patients. On the other side, none of these studies included an assessment of fluid tolerance, and only the FRESH study considered the presence of fluid responsiveness. A simple tool like lung ultrasound allows clinicians to ascertain the presence of lung fluid overload at the bedside and could potentially enhance the stratification of patients when deciding the most appropriate fluid regimen [26]. Moreover, the sepsis source can significantly affect the need for fluids, but it was never considered in the allocation to different subgroups. We question whether a randomization, that takes all these factors into account, could lead to different results.
Finally, septic patients receive fluids in several ways, including nutrition and fluids for the administration of other treatments. Considering all these modalities is quite troublesome, but the overall fluid volume can significantly affect the true difference between different regimens of fluid administration.
In summary, we do not have robust results to support a change in ongoing clinical practice, without reliable criteria to assign patients to a tailored fluid regimen on their needs. The “one size fits all” strategy does not seem to work in this scenario. The current recommendation for a cautious administration of fluids based on the evaluation of fluid responsiveness should be complemented by a concurrent evaluation of fluid tolerance and consideration of the sepsis source and comorbidities, to avoid both overload and inadequate resuscitation. Further randomized prospective studies are needed to understand how to tailor fluid administration to individual patients.

3. From Sepsis to Septic Shock: Vasopressors for the Regulation of Peripheral Resistance

The SSC recommends considering vasopressors after the first fluid bolus, if adequate mean arterial pressure is not achieved by fluid resuscitation [9]. The goal is to reverse arterial dilation and to improve tissue perfusion, as both prolonged and severe hypotension is linked to an unfavorable prognosis for patients with septic shock [27,28]. NE is the first-choice vasopressor in septic shock. In fact, it combines a strong α-adrenergic activity that causes both arterial and venous vasoconstriction, alongside a mild inotropic and chronotropic effect. Increasing cardiac contractility may be beneficial, especially in the presence of sepsis-induced myocardial disfunction. Tachycardia could be detrimental, but this effect is less pronounced with NE compared to other vasoactive medications, especially epinephrine. NE can be increased up to doses ≥1 μg/kg/min, but there are still ongoing debates about the timing and dosage of NE in the earliest stages of resuscitation.

3.1. What Is the Correct Moment to Begin Vasopressors?

The issue of NE timing is closely related to the debate about the benefits of a restricted fluid regimen. In the resuscitation phase, the decision whether to prioritize fluids or NE depends on the prevailing mechanism causing hypotension, relative hypovolemia or vasoplegia [29]. It has already been demonstrated that persistent hypotension is prognostically detrimental, both in terms of the mortality rate and severity of organ dysfunction [30]. In a large group of patients with distributive shock, Vincent and colleagues reported that the longer the duration of hypotension, the higher the ICU mortality, independent to the SOFA score, lactate level, and several other parameters of disease severity [28].
Several studies have explored the advantages of the early administration of NE (Table 2), and a recent meta-analysis was published [31]. It included five studies, with only two randomized controlled trials and three observational retrospective or prospective studies. The quality was reported as high, but there were significant differences between the studies, beginning from the definition of “early” vasopressors, which varied from <1 to <6 h, to the variable combination with fluid administration, which could anticipate or begin simultaneously with NE. The meta-analysis concluded for a prognostic advantage with an early administration of vasopressors, in agreement with a recent paper by Joufrroy and colleagues Ref. [32], who anticipated the treatment with NE to the pre-hospital setting. Opposite results were reported by Yeo and colleagues, with an observational study [33]. The heterogeneity of the protocols, in terms of timing of vasopressors and modalities of fluid administration, makes it necessary to interpret these results cautiously, even though the data in favor of the early administration seem to prevail. One more time, we argue that a better selection of patients than the simple randomization could improve the results by allowing for the correct identification of patients requiring additional fluids or vasopressors. The selection criteria mimic those already cited when speaking about fluids: (1) the previous medical conditions, especially those which can reduce fluid tolerance, like heart or kidney failure; (2) the sepsis source: sepsis with an abdominal source is often associated with high fluid loses, which need to be replaced before giving vasopressors, to prevent the negative effects of the vasoconstriction of hypovolemic circulation, while in the presence of a pulmonary source, the careful administration of fluids is often the best option; (3) the conditions of fluid responsiveness and fluid tolerance, as in their absence the administration of further fluids may be detrimental; (4) the evaluation of left and right ventricular systolic function, as new-onset sepsis-related dysfunction occurs in a high proportion of patients.
Finally, an emerging criterion for selection based on the pathophysiology of septic shock could be the diastolic shock index (DSI), as defined by the ratio between heart rate (HR) and diastolic blood pressure (DAP). Ospina-Tascon and colleagues reported that the DSI before starting vasopressors or at the starting point was significantly higher in non-survivors than in survivors. This suggests that DSI could serve as a very early indicator of severe vasoplegia, signaling the need for early treatment with NE [38]. On the other side, isolated DAP or HR values did not show a clear association with adverse prognosis. In a following study, patients were grouped based on DSI quintiles with those in the highest quintile showing a significant survival benefit from early NE administration, an advantage not clearly evident in other subgroups.
Recently, Russell and colleagues explored the relationship between the dosing intensity of NE in the first 24 h and in-hospital mortality [39]. They demonstrated that increasing dosages of vasopressors during the first 24 hours after the diagnosis were associated with increased mortality risk. However, increasing fluid volumes in the first 6 hours mitigated this association. Notably, early and intense exposure to vasopressors was associated with lower mortality compared to later and sustained exposure. This suggests that aggressive early vasopressor titration may be safer than gradual titration to high doses, but it is crucial to ensure early and adequate fluid resuscitation to prevent the potential deleterious effects of high-dose vasopressors. In other words, the early administration of NE must be paired with an adequate fluid resuscitation to mitigate the risk of ischemic damage.

3.2. Will Vasopressors Worsen the Sepsis-Induced Myocardial Dysfunction?

The treatment with NE may impact the management and prognosis also in the presence of sepsis-induced myocardial dysfunction due to its ability to increase cardiac output through different mechanisms [36,40]. NE achieves this by reducing venous capacitance through its α-adrenergic effect, thereby increasing cardiac preload and subsequently the cardiac index [41]. Additionally, it may reduce preload dependency by directly affecting cardiac β-adrenoceptors and improving contractility. Monnet and colleagues showed that in patients with a positive passive leg raising test, the adjunct of NE reduced the response of the cardiac index after a second test, conducted a few minutes after the beginning of vasopressors [42]. The authors interpreted these data as a demonstration that in the presence of improved contractility, myocardial function was less preload-dependent. Hamzaoui and colleagues evidenced that early NE administration increased LV EF and other indices of left and right systolic function [40], improving coronary perfusion pressure by an increase in the DAP and stimulating β1-adrenoceptors. In a small series of patients with septic shock, we demonstrated that NE infusion improved LV systolic function, evaluated by means of LV Global Longitudinal Strain, a load-independent parameter of contractility. This effect was confirmed both in patients with baseline normal and reduced systolic function, confirming that it was mainly mediated by direct action on contractility alongside a more marked increase in preload than in afterload [43].

3.3. What Is the Role and Timing of Vasopressin?

Another hot topic is the role and timing of vasopressin, where high-dose NE is required. In the presence of septic shock, patients initially have elevated plasma vasopressin concentrations, induced by the development of hypotension. However, within hours, the concentration drops to levels lower than other forms of shock, both due to depletion and reduced synthesis and release [44]. Only the administration of exogenous vasopressin may restore concentrations to physiologic and, more often, supraphysiologic levels, but there is no clear evidence that this treatment leads to improved outcomes. In Table 3, we report the most recent studies, which evaluated the impact of early adjuncts of vasopressin when high-dose adrenergic vasopressors are needed to restore hemodynamic stability. We also mentioned the VASST study, which is not so recent but represents the cornerstone in the evaluation of the role of vasopressin in the treatment of septic shock. Although it failed to demonstrate a survival benefit with the association of vasopressin plus NE compared to the use of NE alone, post hoc analyses identified subgroups of patients who could benefit from the use of vasopressin, especially those with low lactate levels at the beginning of the treatment with vasopressin. Further studies confirmed the association between low lactate levels at the time of vasopressin initiation and a positive outcome [45,46], as well as an improved prognosis when vasopressin was begun at a low NE dose [46,47]. Therefore, vasopressin couples a catecholamine-sparing effect with the correction of a hormonal deficiency induced by the shock itself, alongside a positive effect on the renal circulation and the absence of the immunosuppressive action shown by NE. In fact, at the glomerular level, vasopressin increases resistance only in the efferent arterioles and possibly causes vasodilation of the afferent glomerular arterioles by V2 receptors, leading to an increase in the glomerular pressure and flow. Several studies (Table 3) reported a reduced need for renal replacement therapies in patients treated with vasopressin, although without a consequent reduction in the mortality rate. Therefore, these results need to be confirmed. On the other side, vasopressin exerts its vasoconstrictive effects only at the arterial level, without any venoconstriction and increased cardiac preload. The absence of any positive inotropic effect makes treatment with vasopressin disadvantageous, especially in cases of sepsis-induced myocardial dysfunction. This is one of the reasons why vasopressin does not appear to be a suitable first-line vasopressor but remains a viable option when the NE dosage needs to be increased over 0.5 γ/kg/min, with a high risk of β-agonist-related adverse events. The exact dosage and timing of the treatment with NE to begin vasopressin varied widely between different studies and remain topics of debate.
The future of the treatment of hemodynamic derangement induced by septic shock is represented by a tailored approach, based on the aforementioned criteria alongside the analysis of genetic polymorphisms and circulating peptides. Taken together, they could allow physicians to address the treatment to correct impaired pathways [52,53], in a stepwise approach based on early multimodal vasopressors.

3.4. Is a Role for Other Vasopressors Foreseeable?

In refractory shock, several other molecules have been tested as an adjunct or substitute for NE. Epinephrine has been considered in patients with advanced myocardial dysfunction and reduced cardiac output, as its beta-receptor agonist activity could address the cardiogenic component of the refractory shock [54]. It should be initiated at a NE dosage lower than 133 mcg/min to optimize the possibility of restoring hemodynamic stability [55]. Its side effects, including tachyarrhythmias, hyperglycemia, hypokalemia, and hyperlactatemia, need to be carefully monitored [56].
Angiotensin II is a naturally occurring hormone, produced by the cleavage of angiotensin I, with a high affinity for angiotensin II type 1 receptors, whose stimulation induces aldosterone secretion, endogenous vasopressin release, and a direct arterial and venous vasoconstriction [57]. The rationale beyond its use is a possible derangement in the endogenous renin–angiotensin system functioning during septic shock. A deficient activity of the angiotensin-converting enzyme determines a lack of Angiotensin II, alongside an accumulation of renin, Angiotensin I, and vasodilatory angiotensin byproducts, namely angiotensin 1–9 and angiotensin 1–7 [56].
In the Angiotensin II for Treatment of High-Output Shock (ATHOS-3) study, which included about 90% septic patients, the authors demonstrated that Angiotensin II effectively increased blood pressure in patients with vasodilatory shock, refractory to high doses of conventional vasopressors [58]. Post hoc analysis showed a narrow window of low conventional vasopressor dosage, at which adding AT II determined a significant hemodynamic response and increased survival [59]. In a further analysis of patients included in the ATHOS-3 trial, Bellomo and colleagues found that in patients with renin concentrations above the study population median, the administration of Angiotensin II significantly improved 28-day mortality, while in those with low renin activity, this treatment did not determine any survival advantage [60]. Once again, the need to identify subgroups of patients who may benefit from specific treatments for hemodynamic stabilization appears to be of the utmost relevance.

4. Inotropes in Septic Shock: Recruiting the Heart in the Fight!

4.1. The Use of Inotropes: What Is the Role of Dobutamine?

The SSC recommends using dobutamine in the presence of myocardial dysfunction, as indicated by elevated cardiac filling pressures and low cardiac output or persistent signs of hypoperfusion, despite achieving adequate intravascular volume and mean arterial pressure [9].
Dobutamine used in clinical practice is a racemic mixture of (+) and (–) enantiomers. The (–) enantiomer has a prevalent α-1 agonist activity, with strong effects on arterial pressure, while the (+) enantiomer is a potent β-1 and β-2 agonist, with minimal agonist activity on the alpha counterpart. The final effect is an increased cardiac output due to the positive inotropic stimulus, with variable and usually mild effects on peripheral vascular resistances and mean arterial pressure due to the mutual compensation of the vascular effects of each isomer [61]. Low doses of dobutamine seem to have favorable effects on microcirculatory blood flow, independent of macro hemodynamics [62,63]. Dobutamine may exert a favorable effect on microvascular blood flow distribution and, consequently, on cellular oxygen consumption capabilities. Several studies have investigated dobutamine’s role in resuscitation protocols, but no randomized controlled trials have compared its effects to placebo on clinical outcomes. The studies, which included the administration of dobutamine for the early resuscitation of septic patients (EGDT, ProCESS, ProMISe, and ARISE trial), did not perform any specific analysis on the impact of dobutamine on prognosis [14,64,65,66]. In a cohort of patients with septic shock, Wilkman and colleagues reported higher 90-day mortality (43% vs. 24%, p < 0.001) and in-hospital mortality (19% vs. 34%, p < 0.001) in patients who received inotropes than those who did not [67], alongside a higher age and APACHE II score. However, those who received inotropes were more ill than the rest of the group, as shown by their higher CVP, lactate levels, and dosage of vasoactive medications. The authors themselves recognized the need for further prospective studies to assess the real prognostic weight of the treatment with inotrope medications. A recent meta-analysis, which investigated the prognostic effect of several vasoactive medications, demonstrated that a combination of NE and dobutamine was associated with a reduction in 28-day mortality in patients with septic shock, especially in those with low cardiac output [68].
Most of the studies regarding the use of dobutamine in septic shock were conducted more than ten years ago, when awareness about the specific features of sepsis-induced cardiomyopathy was low. We demonstrated that the classical echocardiographic indices of myocardial function failed to diagnose myocardial dysfunction in a relevant proportion of septic patients [69,70]. In the presence of reduced peripheral resistances, the heart can show a normal chamber function, mirrored by a normal ejection fraction, despite reduced myocardial contractility. The employment of new indices of contractility, like Global Longitudinal Strain, showed that sepsis-induced myocardial dysfunction is present in most septic patients, up to 60–80% of them, and its presence exerts a relevant prognostic effect [71,72]. Whether the use of dobutamine could improve the myocardial performance and the prognosis of septic patients remains undefined [73]. The need for an appropriate selection of patients to treat with inotropes has emerged, in terms of hemodynamic profile and entity of myocardial dysfunction, alongside a better definition of the timing and dosing of the inotropes. Several trials are ongoing, in order to clarify these relevant and intriguing issues [74,75].

4.2. The Use of Inotropes: Do Medications Independent of the Adrenergic System Positively Impact Prognosis?

Cardiac myocyte Ca++ homeostasis is often disrupted during sepsis and exposure to lipopolysaccharides, leading to significant changes in cardiac muscle contractility. Nevertheless, it is unclear whether this is due to abnormal rapid calcium cycling [76], decreased myofilament sensitivity to calcium [77], or inadequate intracellular calcium handling.
Levosimendan is a calcium (Ca2+) sensitizer that increases myocardial contractility by enhancing the sensitivity of troponin-C (TnC) to Ca++ through conformational changes [78]. This enhances actin–myosin interaction, independent of the concentration of intracellular Ca++, without a relevant increase in myocardial oxygen consumption [79]. However, the increased Ca++ sensitivity can exert a negative effect on the relaxation phase (“negative lusitropic effect”), potentially worsening diastolic dysfunction already present in several septic patients. On the other hand, levosimendan also has a strong inhibitory effect on phosphodiesterase-3, resulting in a positive lusitropic effect and counteracting the consequences of Ca++ sensitization. In the peripheral circulation, levosimendan activates ATP-sensitive K+ channels, leading to systemic vasodilation [80].
A recent meta-analysis by Feng and colleagues explored the effectiveness of levosimendan in septic patients and found that it improved cardiac function and reduced lactate levels, without significant effects on the mortality rate. However, one study accounted for half of the population of the meta-analysis, with most other papers including small populations. The main study was prospective and randomized, but the randomization protocol did not consider any parameter of cardiac function [81]. Once again, the selection criteria likely played a crucial role, as the inclusion of an unknown proportion of patients with normal systolic function could have affected the results and precluded the possibility of appreciating a prognostic advantage with the administration of levosimendan [82].
Milrinone, a phosphodiesterase inhibitor, acts as an inotropic agent and vasodilator by inhibiting the intracellular degradation of cyclic AMP. It can increase myocardial contractility without increasing myocardial oxygen consumption [83,84]. Its hemodynamic effects include increasing the cardiac index and reducing pulmonary artery and wedge pressure [85]. Data on the efficacy and safety of its use in sepsis are scarce and mainly derived from experimental studies. A recent subgroup analysis of a big-data, real-world study showed that, compared to dobutamine, milrinone did not decrease in-hospital mortality, but it increased the use of renal replacement therapy and the length of hospital stay [86].
Cardiovascular failure during sepsis results from a complex interplay of cardiac and vascular factors, affecting both macro- and microcirculation, ultimately causing reduced organ perfusion and multisystem failure. Medications that act on both the heart and vessels are used to manage this complex pathophysiology, but their effects can sometimes be detrimental. For example, dobutamine is used for the positive inotropic effect, but its positive chronotropic effect or vasodilation may be deleterious in septic patients. This is probably the reason why the data on the effectiveness of these treatments are disappointing. Moreover, most studies use 28-day mortality rate as the primary end-point, but during this extended period, several complications and new infections may occur. The time course and possible recovery of multiorgan failure vary and are influenced by the baseline situation, which is often not considered in current research, especially in randomized protocols. The adoption of different end-points, for example, 7-day mortality, could provide a better understanding of the relationship between vasoactive medications and the outcome. Moreover, a careful selection of patients based on hemodynamic monitoring and echocardiographic assessment or left and right systolic and diastolic performance will likely be crucial for offering the right medication to the right patient at the most appropriate stage of their disease.

5. Conclusions

In summary, cautious fluid administration and early employment of NE in septic shock unresponsive to fluids are gaining more precise support in the literature and should be considered in the next guidelines, alongside the “dark sides” of most inotropes. Finding the correct balance between the application of current guidelines and future ones is essential. In actuality, we do not have clear answers, but it is important to be aware of areas of uncertainty, to apply novelties cautiously and, why not, test new selection criteria and treatment options in rigorous studies.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Anesthres 01 00013 g001
Figure 1. Main mechanisms of organ damage during sepsis.
Figure 1. Main mechanisms of organ damage during sepsis.
Anesthres 01 00013 g001
Table 1. Recent papers comparing different fluid regimens in septic patients: an overview.
Table 1. Recent papers comparing different fluid regimens in septic patients: an overview.
YearStudy PopulationDesignProtocolEnd-PointsMain Results
FRESH study
Fluid Response Evaluation in Sepsis Hypotension and Shock [20]		2020Patients admitted to the ED for sepsis, already treated with the first fluid bolus, with anticipated ICU admission: 83 patients in the intervention arm and 41 with usual careProspective, multicenter, randomized clinical
trial		Intervention arm: assessment for fluid responsiveness before clinically driven fluid bolus or increase
in vasopressors.
Control arm: usual care.		Primary endpoint: the difference between the two treatment groups
mean fluid balance at 72 h or ICU discharge		Lower fluid balance at 72 h or ICU discharge (−1.37 L)
Reduced need of renal replacement therapy (5% vs. 18%) or
mechanical ventilation (18% vs. 34%);
CLOVERS study: Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension [23] 20231563 patients: 782 assigned to the restrictive fluid group and 781 to the liberal fluid groupMulticenter, randomized, unblinded superiority trialRestrictive fluid strategy: prioritizing vasopressors and lower intravenous fluid volumes.
Liberal fluid strategy: prioritizing higher volumes of intravenous fluids before vasopressor use. 		Primary outcome: all-cause mortality before discharge home by day 90.Less fluids administered in the Group assigned to the restrictive strategy.
No difference in the mortality rate and occurrence of serious adverse events.
REFACED study: Restrictive fluids versus standard care in adults with sepsis in the emergency department [22]2022Sepsis patients without shock: 123 patients, with 61 in the Fluid restriction group and 62 assigned to standard care. Multicenter, randomized feasibility trialFluid restriction: fluid boluses only permitted if predefined criteria for hypoperfusion occurred.
Standard care: at the discretion of the treating team.		Primary outcome: total IV crystalloid fluid volumes at 24 h after randomizationAt 24 h, significantly less fluids administered in the Fluid restriction group (mean difference—801 mL).
No differences between groups in adverse events, use of mechanical ventilation or vasopressors, acute kidney failure, length of stay, or mortality
CLASSIC trial: Restriction of Intravenous Fluid in ICU Patients with Septic Shock [25]2022Patients with septic shock in the ICU: 1554 patients; 770 in the restrictive-fluid group and 784
in the standard-fluid group		International, randomized trialRestrictive-fluid group: intravenous fluid (1 L) could only be given under pre-specified-conditions.
Standard fluid group: no upper limit for the amount of intravenous fluids		Primary outcome: all-cause mortality by day 90.Restrictive fluid group: median of 1798 mL of intravenous fluids vs. 3811 mL the standard-fluid group
No difference in the mortality rate or incidence of serious adverse events.
Table 2. Timing of the use of noradrenaline in sepsis: an overview of most recent papers.
Table 2. Timing of the use of noradrenaline in sepsis: an overview of most recent papers.
YearStudy PopulationDesignProtocolEnd-PointsMain Results
Early Use of Norepinephrine Improves Survival in Septic Shock: Earlier than Early [34]2019101 patients admitted to the emergency department with septic shock, 57 in the Early group and 44 in the Late group Randomized multicenter studyEarly group: early NEP simultaneously with IV fluids
Late group: after failed fluids trial		Primary outcome: in-hospital survivalThe Early group showed:
  • Shorter time to achieve MAP > 65 mmHg
  • Reduced mortality rate (46% vs. 72%)
Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER study) [35]2019310 adults diagnosed with sepsis
with hypotension, 155 in each subgroup. 		Single-center, randomized, double-blind, placebo-controlled clinical trialEarly norepinephrine: low-dose NE together with fluid resuscitation
Standard treatment 		Primary outcome: shock control rate by 6 h after diagnosisIn the Early group,
  • shock control rate by 6 h achieved in 76% vs. 48%;
  • 28-day mortality rate not different,
  • lower incidences of cardiogenic pulmonary edema and new-onset arrhythmia
Delayed vasopressor initiation is associated with increased mortality in patients with septic shock [36]2019Patients with septic shock, 76 with early vasopressors and 43 with delayed vasopressors Retrospective, single-centered, cohort studyEarly vasopressors: within 6 h from initial hypotension
Delayed vasopressors: after 6 h from initial hypotension		Primary outcome: all-cause 30-day mortality In patients with Early vasopressors,
  • shorter time to MAP of 65 mmHg (1.5 h vs. 3.0, p < 0.01).
  • more vasopressor-free hours at 72 h (34.5 h vs. 13.1, p = 0.03)
  • lower 30-d mortality rate (25% vs. 51%, p < 0.01).
Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis [37]2020Patients with sepsis requiring VP support for at least 6 h selected from a prospectively collected database and classified into Very Early NE (VE-VPs, n = 93) or Delayed (D-VPs, n = 93)Propensity score-based analysis Very early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or
not within/before the next hour of the first resuscitative fluid load. 		Primary outcome: all-cause 30-day mortality In the VE-VPs group:
  • Significant lower net fluid balances 8 and 24 h after VPs
  • Significant reduction in the risk of death compared to D-VPs
Vasopressor Initiation Within 1 Hour of Fluid
Loading Is Associated With Increased Mortality
in Septic Shock Patients: Analysis of National
Registry Data [33]		2022Patients with septic shock, classified into Early (n = 149), propensity
matched to Late (n = 149) patients. 		Prospective, multicenter, observational studyEarly patients: VP initiated within 1 h of the first resuscitative fluid load.
Late patients: VP initiated more than 1 h of the first resuscitative fluid load.		Primary outcome: all-cause 28-day mortality In the Early group, compared to the late group:
  • SOFA score and lactate level higher at day-3 of ICU stay
  • Significantly higher mortality rate
Prehospital norepinephrine administration reduces 30-day mortality among septic shock patients [32]2022Patients with SS requiring prehospital Mobile Intensive Care Unit interventionRetrospective, single center478 patients, 143 received prehospital norepinephrineMAP > 65 mmHg at the end of the prehospital stage and 30-day mortality.Cox regression analysis, after the propensity score, showed a significant association between prehospital norepinephrine administration and 30-day mortality (adjusted hazard ratio 0.42, 0.25–0.70)
Table 3. Role of vasopressin in sepsis resuscitation.
Table 3. Role of vasopressin in sepsis resuscitation.
YearStudy PopulationDesignProtocolEnd-PointsMain Results
Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock [44]2008Patients with septic shock (n = 778, 396 receiving vasopressin and 382 NA)Multicenter, randomized, double-blind trial, Patients receiving a minimum of NA 5 μg/min randomized to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or NA (5 to
15 μg per minute) in addition to open-label vasopressors		28-day mortality rateNo significant difference between the subgroups in the 28-day mortality rate (35% vs. 39%), in 90-day mortality (44% and 50%) and in the overall rates of serious adverse events (10% in both subgropus, all p > 0.05).
Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients With Septic Shock
The VANISH Randomized Clinical Trial [48]		2016Pts with septic shockProspective, open label trialRandom allocation to:
  • vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101),
  • vasopressin and placebo (n = 104)
  • NA and hydrocortisone (n = 101),
  • NA and placebo (n = 103)
Primary: kidney failure-free days
Secondary: rates of renal replacement therapy, mortality, and serious adverse events.		Less use of renal replacement therapy in the vasopressin group (25% vs. 35%); no difference for the other end-points.
Vasopressin Versus Norepinephrine for the Management of Septic Shock in Cancer Patients: The VANCS II Randomized Clinical Trial [49]2019Pts with septic shock and cancerSingle-center, randomized, double-blind clinical trialPatients randomized to either vasopressin or norepinephrine as first-line vasopressor therapy (n = 125 in each subgroup)Primary outcome: 28-day all-cause mortality; secondary outcomes: 90-day all-cause mortality rate; number of days alive and free of advanced organ support at day 28; 24-h and 96-h SOFA; prevalence
of adverse effects in 28 days.		No significant difference in any of the prespecified outcome
Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock [50]2019Pts with septic shock (48 pts in each subgroup)Retrospective cohort studyTo compare early addition of vasopressin within 4 h of septic shock onset to norepinephrine versus initial norepinephrine monotherapy Primary outcome: time to achieving and maintaining MAP > 65 mm Hg for at least 4 h
  • Secondary outcomes: duration of AVP and NE infusions,
  • change in SOFA scores from 6 h to 48 and 72 h since septic shock onset,
  • new-onset arrhythmia development
Patients started on early
vasopressin achieved and maintained goal MAP sooner (6.2 vs. 9.9 h, P ¼ 0.023), experienced greater reductions in SOFA scores at 72 h (_4 vs. _1, P ¼ 0.012), and had shorter hospital durations (343 vs. 604 h, P ¼ 0.014).
Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock [46]2022Pts with septic shock (n = 1610)Retrospective, observational studyTo evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality.In-hospital mortalityFor every 10 μg/min increase in norepinephrine-equivalent dose up to 60 μg/min at the time of vasopressin initiation, there was an increased odd of in-hospital mortality of 21%
Linear association between increasing lactate concentration at the time of vasopressin initiation and increasing in-hospital mortality.
No association with mortality rate for time elapsed from shock onset.
Early initiation of vasopressin reduces organ failure and mortality in septic shock [51]2022Patients with septic shock (n = 385)Multicenter, retrospective, cohort studyTo determine whether initiating vasopressin earlier in septic shock reduces organ dysfunction and in-hospital all-cause mortality. Primary composite outcome: proportion of patients with a change in the SOFA score greater than 3 from baseline to 72 h after initiation of vasopressin and/or in-hospital all-cause mortality.
Secondary outcomes: time to hemodynamic stability, acute kidney injury, and intensive care unit length of stay.		Primary composite outcome significantly reduced in patients who had vasopressin initiated earlier in septic shock (odds ratio = 1.08, 95% confidence interval = 1.03–1.13), even after multivariate analysis.
Timing of vasopressin initiation and mortality in patients with septic shock: analysis of the MIMIC-III and MIMIC-IV databases [47]2023Patients with septic shock.Retrospective observational cohort study, To compare low doses of NA group (NA < 0.25 μg/kg/min) and the high doses of NE group (NE ≥ 0.25 μg/kg/min, n = 535 for each subgroups)28-day mortalityCompared to those in the high dose of NA, patients in the low doses of NE group showed:
  • shorter duration of NE,
  • less intravenous fluid volume on the first day after initiation of vasopressin,
  • more urine on the second day,
  • longer mechanical ventilation- and CRRT-free days
  • lower 28-day mortality.
NA: noradrenaline; SOFA: Sequential Organ Failure Assessment.
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Innocenti, F.; Palmieri, V.; Pini, R. Fluids, Vasopressors, and Inotropes to Restore Heart–Vessel Coupling in Sepsis: Treatment Options and Perspectives. Anesth. Res. 2024, 1, 128-145. https://doi.org/10.3390/anesthres1020013

AMA Style

Innocenti F, Palmieri V, Pini R. Fluids, Vasopressors, and Inotropes to Restore Heart–Vessel Coupling in Sepsis: Treatment Options and Perspectives. Anesthesia Research. 2024; 1(2):128-145. https://doi.org/10.3390/anesthres1020013

Chicago/Turabian Style

Innocenti, Francesca, Vittorio Palmieri, and Riccardo Pini. 2024. "Fluids, Vasopressors, and Inotropes to Restore Heart–Vessel Coupling in Sepsis: Treatment Options and Perspectives" Anesthesia Research 1, no. 2: 128-145. https://doi.org/10.3390/anesthres1020013

APA Style

Innocenti, F., Palmieri, V., & Pini, R. (2024). Fluids, Vasopressors, and Inotropes to Restore Heart–Vessel Coupling in Sepsis: Treatment Options and Perspectives. Anesthesia Research, 1(2), 128-145. https://doi.org/10.3390/anesthres1020013

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