Hemodynamically unstable patients (with one of the following: mean capillary pressure lower than 90 mmHg, or MAP lower than 70 mmHg) and patients with lactate levels above 2 mmol/L should be treated with rapid crystalloid resuscitation at a volume of 30 mL/kg, which should be started within the first 1–3 hours. (17, 18) Balanced crystalloid solutions are preferable over normal saline, according to recommendations. (19, 20) This group of patients has a lower risk of developing acute renal injury and mortality. (18)

Surgical removal of infected tissue is as important as antibiotic therapy. The method of choice may be open surgery or percutaneous drainage.

Early antibiotic treatment reduces mortality in sepsis. Every hour of delay increases mortality by 7%. (20) However, one should be mindful of the side effects of premature and inappropriate use of antibiotics, as well as the increased risk of bacterial resistance. For this reason, each hospital should have its own recommendations and an antibiotic stewardship program. Empiric broad-spectrum antibiotics should be administered immediately upon diagnosis. Cultures and swabs should be sampled, and antibiotic therapy should be de-escalated based on the results. Patients with intra-abdominal infections should be considered for anaerobic coverage, and antifungal therapy should be considered for immunocompromised patients. (21)

The Surviving Sepsis Campaign (SSC) recommendations for sepsis management from 2017 are as follows:

If a patient remains hemodynamically unstable despite fluid resuscitation, vasopressor therapy should be initiated to achieve and maintain MAP values >65 mmHg. (18) The use of vasopressors carries serious adverse effects, such as tissue ischemia, increased cardiac load, and a risk of arrhythmias. According to all recommendations, the first-line therapy is norepinephrine (22) due to its greater potency and lower risk of arrhythmias compared to dopamine. (23) The use of norepinephrine and dopamine in septic patients has been compared in many randomized controlled trials and meta-analyses, several of which reported higher mortality rates associated with dopamine. (24, 25) Additionally, arrhythmogenic events were more frequently reported among patients treated with dopamine. (26)

According to the literature, vasopressin reduces the doses of catecholamines, but its effect on overall survival has not been confirmed. (27) Recently, two new drugs, selepressin and angiotensin II, have been introduced. (28) Inotropic agents can be considered in patients with myocardial dysfunction and low cardiac output. However, their routine use with vasopressors is not recommended. (29)

The Surviving Sepsis Campaign (SSC) recommends that vasopressor therapy should be initiated within 6 hours of hypotension onset. (18) Hypotension is defined as persistent MAP values <65 mmHg after administration of 30 mL/kg of crystalloids in bolus. (18, 22) Patients who receive vasopressor therapy within the first 2 hours of septic shock onset have a significantly lower 28-day mortality rate compared to those in whom vasopressors are started after 2 hours (30% vs. 43%). The same study (30) showed that mortality increased by 5.3% for each hour of delayed vasopressor therapy. Early norepinephrine infusion initiation results in fewer days of treatment and a lower total dose per patient. Additionally, target MAP values were achieved faster in the group that started norepinephrine infusion within the first 2 hours (6.1 hours vs. 4.6 hours, p < 0.001). There was no significant statistical difference between the groups in terms of fluid volume administered, the timing of antibiotic therapy, or corticosteroid use. (30)

Vasopressors should be administered through a central venous line, as complications like infections and phlebothrombosis are less common compared to peripheral lines. (31) Peripheral administration is considered safe if it lasts no longer than 2 hours, if a wide cannula is used, and if it is placed proximal to the cubital or popliteal fossa. (32)

Norepinephrine is recommended as the first-line therapy over other vasopressors in septic shock. (18) It is an endogenous catecholamine that primarily acts as an excitatory neurotransmitter. Its most important effect is vasoconstriction, mediated by stimulation of α and β adrenergic receptors, with a more prominent effect on α1 receptors. In sepsis, the adrenergic response to norepinephrine differs from the physiological response, resulting in increased renal vascular flow. A similar effect is observed in the splanchnic circulation, where norepinephrine normally causes decreased blood flow. (33) High doses, as well as long-term use of this catecholamine, may provoke intense vasoconstriction in renal and splanchnic circulation, leading to visceral hypoperfusion and additional organ damage. (34, 35) Norepinephrine also acts as a β1 agonist, producing a positive inotropic effect. Prolonged use may have direct toxic effects on myocytes, causing reflex bradycardia, cardiac arrhythmias, and myocardial ischemia. The usual dose range is 8–10 mcg/min (0.05–0.1 mcg/kg/min), and the dose may be increased according to MAP values. However, if a patient requires therapy with doses above 0.6 mcg/kg/min, it is preferable to add a second-line vasopressor, such as dopamine or vasopressin.

Adverse effects of norepinephrine are serious and include tissue necrosis due to drug extravasation, as well as intensive vasoconstriction that may lead to organ dysfunction when therapy involves extremely high doses.

Epinephrine is a potent non-selective α and β adrenergic agonist. The Surviving Sepsis Campaign (SSC) recommends epinephrine as an alternative to norepinephrine in septic shock management, (18) with usual doses ranging from 0.01 to 0.20 mcg/kg/min. Doses below 0.1 mcg/kg/min predominantly exert a β effect on cardiac contractility and heart rate. (36) Higher doses show a dominant α1 vasoconstrictor effect. A multicenter, randomized, controlled, double-blind study by Annane et al., which compared two groups of patients receiving epinephrine versus norepinephrine and dobutamine, showed no significant difference in the duration of vasopressor therapy, hospital stay, or 28-day and 90-day mortality rates. (37) However, patients treated with epinephrine exhibited lower pH in blood gas analyses during the first four days, as well as higher lactate levels on the first day of treatment. These metabolic disturbances following epinephrine infusion are well-known and are considered to be the result of strong α-1 vasoconstriction. Additionally, β-2 mediated anaerobic glycolysis may contribute to the acid-base imbalance. (38)

Vasopressin is an endogenous peptide hormone that stimulates the V1 receptor in the smooth muscles of blood vessels, causing vasoconstriction. (39) In healthy subjects, vasopressin-mediated vasoconstriction is observed in the lungs and kidneys. However, very low doses of vasopressin in lung circulation stimulate nitric oxide (NO) liberation and consequent vasodilation. (40) This effect may be beneficial in acute right heart failure. (41) Vasoconstrictive effects become more pronounced in severe hypotension, when vasopressin release from the hypothalamus may increase by more than tenfold compared to basal levels. (42) Since the endogenous reserve of vasopressin depletes rapidly, the administration of exogenous vasopressin becomes crucial to achieving and maintaining adequate MAP values. (43)

The half-life of vasopressin is 5–20 minutes, so it should be administered as a continuous infusion. Recommended doses in septic shock are 0.01–0.04 U/h.

The SSC does not recommend vasopressin as a single therapy. It is recommended to add vasopressin in patients with inadequate MAP levels, instead of escalating the dose of norepinephrine. (18) The VASST study, which included 778 septic patients, compared norepinephrine alone versus a combination of norepinephrine and vasopressin. It showed that therapy with low-dose vasopressin (0.03 U/min) reduced the need for norepinephrine during the first four days. However, there was no difference in adverse events. (44) Some evidence also suggests that adding vasopressin infusion to norepinephrine therapy (with doses below 15 mcg/min) in moderate to severe sepsis may improve survival rates. (45)

Vasopressin also affects water retention and reabsorption in the distal renal tubule through V2 receptors, and it stimulates ACTH secretion from the anterior pituitary via V3 receptors. These effects are negligible when vasopressin is administered in therapeutic doses.

Dopamine is an endogenous catecholamine and a precursor to norepinephrine. It is not recommended as the first-line therapy for hypotension in septic shock. (18) However, it may be administered to patients at risk of tachyarrhythmia or bradycardia. (44) Since 2013, it has also been excluded as a first-line treatment for cardiogenic shock. (46)

At lower doses, dopamine acts via presynaptic and postsynaptic DA1 and DA2 receptors which are present in the coronary, renal, cerebral, and splanchnic endothelia. In healthy individuals dopamine increases renal blood flow and promotes natriuresis in a dose-dependent manner. (47, 48) For this reason, low “renal doses” of dopamine were once thought to protect and preserve kidney function in septic patients. However, none of the randomized studies have shown a benefit in terms of preventing acute renal failure. (49) It is now believed that the renal afferent arteriole is already maximally dilated in sepsis, which limits the renoprotective effect of dopamine. (50)

At doses of 2–10 mcg/kg/min dopamine primarily exerts a β-1 effect. (51) In patients receiving β-blocker therapy dopamine’s effects via DA1 and DA2 receptors can still occur at these doses, potentially causing vasodilation in the renal and splanchnic vasculature, which may exacerbate existing hypotension. (52)

At doses of 10–20 mcg/kg/min the dominant effect is on α-1 receptors, resulting in an increase in systemic vascular resistance and MAP. Higher doses can lead to serious vasoconstriction, limb ischemia, and additional organ hypoperfusion. A study comparing the effects of dopamine and norepinephrine across various types of shock in critically ill patients found that dopamine use was associated with reduced survival, especially in cardiogenic shock. This may be due to dopamine-induced increases in heart rate and cardiac arrhythmias. (26)

Phenylephrine is a pure α-1 agonist with purely vasoconstrictive properties and no direct effect on the heart. This isolated increase in afterload can lead to a drastic drop in stroke volume and cardiac output. For these reasons, there is limited evidence supporting the use of phenylephrine in septic patients. (53)

In sepsis, phenylephrine is recommended under certain conditions, such as in cases of serious cardiac arrhythmias caused by norepinephrine, when cardiac output is high despite persistent hypotension, or as an adjunct to other vasopressors in cases of refractory hypotension. (18)

A study in 18 non-septic patients with cardiomyopathy showed that a dose of 50–200 mcg led to a rapid increase in MAP (within 20–40 seconds), but also a deterioration in cardiac output. (54) The negative effects on stroke volume and cardiac output are more pronounced if cardiac function is already impaired. Given that sepsis is often accompanied by impaired cardiac function and potential sepsis-induced cardiomyopathy, the use of phenylephrine is rare and should be done with extreme caution.

Recent analyses have shown that, due to a shortage of norepinephrine, phenylephrine was often used, but this was associated with increased mortality. (55)

There is still insufficient evidence regarding the benefit of this drug in refractory shock. “Decatecholaminization” is a well-known phenomenon that occurs as a result of either down-regulation of α-1 receptors or inadequate interaction between receptors and intracellular second messengers. (56) Additionally, in sepsis, the levels of endogenous vasopressin and the expression of V1 receptors decrease. This can generally be overcome by the administration of exogenous vasopressors, most commonly catecholamines.

The ATHOS study examined the effect of angiotensin II as an adjunct to norepinephrine, epinephrine, or vasopressin. The study concluded that angiotensin II is a safe drug and that its use reduces the need for norepinephrine, thus minimizing its associated side effects. (57) However, there is still considerable controversy regarding its use in septic shock. Some studies have shown that the metabolites of angiotensin II may have pro-inflammatory and pro-coagulant properties, as well as harmful microcirculatory effects.

A number of studies have examined the effects of ACE inhibitors in sepsis and concluded that while ACE inhibitors may improve microcirculation, they do not provide a survival benefit. Moreover, these studies found that ACE inhibitors could contribute to the impairment of kidney function and disrupt gas exchange in the lungs. (58) The only promising study to date is the ATHOS study, but since it is a pilot study with a small sample size, larger randomized clinical trials are needed to determine the drug’s effectiveness, optimal dosage, and the appropriate timing for its use.

When to Start Using Inotropes in Sepsis?

Septic shock is a hyperdynamic state characterized by an increase in stroke volume and cardiac output with low systemic vascular resistance. Prolonged peripheral vasodilation and increased cardiac index can sometimes mask existing myocardial depression. (59) Cardiac dysfunction is very common in sepsis (60%). (60) and is thought to result from non-ischemic cardiac depression or self-protective myocardial hibernation. (61) Although coronary flow increases in sepsis, the difference in oxygenation between the coronary arteries and the coronary sinus is smaller than expected. (62) This suggests that impaired cellular metabolism and changes in microvascular autoregulation contribute to reduced cardiac contractility in sepsis.

Inotropes should be administered when signs of myocardial dysfunction, such as reduced stroke volume, low cardiac output, increased cardiac filling pressures, or persistent hypoperfusion despite fluid replacement and vasopressor support, are present. An ideal inotrope should increase cardiac contractility without significantly increasing myocardial oxygen demand.

Dobutamine is a derivative of isoproterenol, with predominant β-1 and less pronounced β-2 agonistic effects. (63) It increases heart rate and stroke volume through β-1 receptor stimulation and causes vasodilation via β-2 receptor activation. It is also a mild α-1 agonist, which becomes noticeable at doses above 15 mcg/kg/min. The more common effect, however, is vasodilation caused by β-2 agonist activity at doses of 5–15 mcg/kg/min.

According to the SSC, dobutamine is the drug of choice for inotropic support in septic patients with high cardiac filling pressures and cardiac output dysfunction. (18, 22) Its inotropic effect is more pronounced than its chronotropic effect. Even at lower doses, dobutamine can increase myocardial oxygen demand, potentially leading to malignant arrhythmias. A multicenter, randomized study from 2007 involving 330 septic patients showed that the combination of dobutamine and norepinephrine was associated with similar outcomes compared to epinephrine monotherapy. (37) The most common side effects in both groups were supraventricular arrhythmias (13% vs 12%) and ventricular arrhythmias (5% vs 7%).

The Surviving Sepsis Campaign and the European Society of Intensive Medicine recommend dobutamine use in septic patients with cardiac dysfunction, inadequate cardiac output, and signs of tissue hypoperfusion after optimization of preload and MAP with fluids and vasopressors. (18, 22, 29)

Milrinone is a non-adrenergic inodilator that works by inhibiting phosphodiesterase-3 (PDE3) and increasing cAMP levels. This leads to the release of calcium from the sarcoplasmic reticulum, raising intracellular calcium concentration and improving contractility. Milrinone also exerts vasodilatory effects on peripheral vessels, which may be beneficial in cardiogenic shock, especially when accompanied by right ventricular weakness, as it reduces pulmonary vascular resistance. (64)

However, the vasodilatory effect of milrinone often necessitates the addition of a vasopressor. Since it is metabolized by the kidneys, its half-life is prolonged in patients with renal impairment, requiring dose adjustments. (53)

Because milrinone does not affect catecholamines it is particularly useful in patients on chronic β-blocker therapy. (64)

Levosimendan is an inotropic and vasodilatory agent. Its vasodilatory effects are observed in the pulmonary, coronary, and peripheral vasculature and are mediated via potassium channels in smooth muscle. Its inotropic effect is achieved by stabilizing intracellular calcium concentrations and prolonging its binding to troponin C. (64)

Although levosimendan is not approved in the U.S., it is approved for use throughout Europe. The Surviving Sepsis Campaign recommends against the use of levosimendan in adults with septic shock and cardiac dysfunction accompanied by persistent hypoperfusion, despite adequate volume status and arterial blood pressure. (18)