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https://doi.org/10.26800/LV-146-11-12-9

Vazopresori i inotropi u sepsi

Radmilo Janković
Milena Stojanović *

* Dopisni autor.


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Sažetak

Sepsa se definira kao neadekvatan i poremećen odgovor organizma na infekciju, a septički šok je posljedica teške sepse praćene hipotenzijom koja ne reagira na nadoknadu tekućine. Ovo životno ugrožavajuće stanje, koje zahtijeva urgentno prepoznavanje i liječenje, i dalje predstavlja velik zdravstveni problem s visokom stopom smrtnosti. Hipovolemija i niska sistemska vaskularna rezistencija značajni su čimbenici rizika za smrtnost u sepsi i septičkom šoku. Jedan od glavnih ciljeva i preporuka jest dostizanje i održavanje srednjega arterijskog tlaka iznad 65 mmHg. Postizanje ovog cilja i zadovoljavanje adekvatne perfuzije tkiva zahtijeva nadoknadu velikih količina tekućine. Rasprava o najboljoj tekućini i dalje postoji, ali dosadašnje studije pokazale su prednosti slanih kristaloidnih otopina u odnosu na koloidne čija je primjena povezana s lošijom prognozom. Bolesnici kod kojih se prethodno
spomenute vrijednosti srednjega arterijskog tlaka ne mogu postići s tekućinama kandidati su za primjenu vazopresornih i inotropnih lijekova. Prvi lijek izbora među vazopresorima jest noradrenalin (potentni α-adrenergički agonist i manje potentni β-adrenergički agonist). Njegove se prednosti očituju u tome što ima sposobnost povećanja krvnog protoka kroz sustav splanhnične cirkulacije i manji rizik srčanih aritmija u usporedbi s drugim lijekovima. Lijek drugog izbora po preporukama jest adrenalin i treba ga koristiti kao dodatak noradrenalinu ili kao lijek prvog izbora ako adenalin pokaže neke značajnije neželjene učinke. Fenilefrin (čisti α-agonist) nije u preporukama, s obzirom na to da može smanjiti udarni i minutni volumen srca, osim kao spasonosna
terapija u kombinaciji s drugim vazopresorima ili inotropima. Vazopresin se preporučuje u kombinaciji s noradrenalinom, ali ne i kao samostalni lijek. Preporuke ne podržavaju primjenu dopamina kao renoprotektivnog lijeka koji treba koristiti samo u određenim indikacijama. Dobutamin ostaje zlatni standard kod bolesnika sa srčanom disfunkcijom i znacima neadekvatne tkivne
perfuzije i pored postignutih preporučenih vrijednosti srednjega arterijskog tlaka.

Ključne riječi

SEPSA – farmakoterapija; SEPTIČKI ŠOK – farmakoterapija; HIPOVOLEMIJA – liječenje; KRISTALOIDNE OTOPINE – terapijska uporaba; HIPOTENZIJA – farmakoterapija; VAZOKONSTRIKTORI – terapijska uporaba; NOREPINEFRIN – terapijska uporaba; EPINEFRIN – terapijska uporaba; KARDIOTONICI – terapijska uporaba; DOBUTAMIN – terapijska uporaba; INTENZIVNO LIJEČENJE

Hrčak ID:

327308

URI

https://hrcak.srce.hr/327308

Datum izdavanja:

22.1.2025.

Podaci na drugim jezicima: engleski

Posjeta: 49 *




Vasopressors and inotropes in sepsis

Vazopresori i inotropi u sepsi

Radmilo Janković1,2, Milena Stojanović1 (https://orcid.org/0000-0003-1343-1937)

1Clinic for Anesthesia and Intensive Therapy, University Clinical Center Niš, Serbia

2School of Medicine, University of Niš, Serbia

Descriptors SEPSIS – drug therapy; SHOCK, SEPTIC – drug therapy; HYPOVOLEMIA – therapy; CRYSTALLOID SOLUTIONS – therapeutic use; HYPOTENSION – drug therapy; VASOCONSTRICTOR AGENTS – therapeutic use; NOREPINEPHRINE – therapeutic use; EPINEPHRINE – therapeutic use; CARDIOTONIC AGENTS – therapeutic use; DOBUTAMINE – therapeutic use; CRITICAL CARE

SAŽETAK

Sepsa se definira kao neadekvatan i poremećen odgovor organizma na infekciju, a septički šok je posljedica teške sepse praćene hipotenzijom koja ne reagira na nadoknadu tekućine. Ovo životno ugrožavajuće stanje, koje zahtijeva urgentno prepoznavanje i liječenje, i dalje predstavlja velik zdravstveni problem s visokom stopom smrtnosti. Hipovolemija i niska sistemska vaskularna rezistencija značajni su čimbenici rizika za smrtnost u sepsi i septičkom šoku. Jedan od glavnih ciljeva i preporuka jest dostizanje i održavanje srednjega arterijskog tlaka iznad 65 mmHg. Postizanje ovog cilja i zadovoljavanje adekvatne perfuzije tkiva zahtijeva nadoknadu velikih količina tekućine. Rasprava o najboljoj tekućini i dalje postoji, ali dosadašnje studije pokazale su prednosti slanih kristaloidnih otopina u odnosu na koloidne čija je primjena povezana s lošijom prognozom. Bolesnici kod kojih se prethodno spomenute vrijednosti srednjega arterijskog tlaka ne mogu postići s tekućinama kandidati su za primjenu vazopresornih i inotropnih lijekova. Prvi lijek izbora među vazopresorima jest noradrenalin (potentni α-adrenergički agonist i manje potentni β-adrenergički agonist). Njegove se prednosti očituju u tome što ima sposobnost povećanja krvnog protoka kroz sustav splanhnične cirkulacije i manji rizik srčanih aritmija u usporedbi s drugim lijekovima. Lijek drugog izbora po preporukama jest adrenalin i treba ga koristiti kao dodatak noradrenalinu ili kao lijek prvog izbora ako adenalin pokaže neke značajnije neželjene učinke. Fenilefrin (čisti α-agonist) nije u preporukama, s obzirom na to da može smanjiti udarni i minutni volumen srca, osim kao spasonosna terapija u kombinaciji s drugim vazopresorima ili inotropima. Vazopresin se preporučuje u kombinaciji s noradrenalinom, ali ne i kao samostalni lijek. Preporuke ne podržavaju primjenu dopamina kao renoprotektivnog lijeka koji treba koristiti samo u određenim indikacijama. Dobutamin ostaje zlatni standard kod bolesnika sa srčanom disfunkcijom i znacima neadekvatne tkivne perfuzije i pored postignutih preporučenih vrijednosti srednjega arterijskog tlaka.

Corresponding author / Adresa za dopisivanje:

Milena Stojanović, https://orcid.org/0000-0003-1343-1937, University Clinical Center Niš, Serbia, e-mail: milenastojanoviclaci@gmail.com

Received / primljeno 28. kolovoza 2024., accepted / prihvaćeno 2. prosinca 2024.

Sepsis is a complex disorder that occurs as a result of the host’s inadequate response to infection and is associated with acute organ failure and a high mortality rate. (1) It is a critical health issue that requires urgent recognition and treatment because any delay reduces survival rates. Over the past 30 years numerous studies and research have been conducted, resulting in faster recognition of septic patients through the use of adequate scoring systems. (2, 3) In 2017, the World Health Organization declared sepsis a health priority and adopted measures concerning the improvement of prevention, diagnosis, and treatment. (4)

Definition

The definition of sepsis has undergone many revisions since it was first defined in 1992 as an inflammatory response to infection, based on two or more criteria (hypo/hyperthermia, leukocytosis/leukopenia, heart rate >90/min, respiratory rate >20/min) from the systemic inflammatory response syndrome (SIRS) with a suspected or confirmed source of infection. (5) In 2001, a criterion for evaluating organ dysfunction, the SOFA score, was introduced, indicating severe sepsis. (6) In 2016, the Third International Consensus on Sepsis and Septic Shock defined sepsis as life-threatening organ dysfunction due to an inadequate host response to infection, and septic shock as sepsis with circulatory, metabolic, and cellular abnormalities. (79) Organ dysfunction is defined as a SOFA score >2 and is accompanied by persistent hypotension (MAP <65 mmHg) and increased serum lactates >2 mmol/L after fluid resuscitation. Septic shock carries a mortality rate of approximately 40%, while sepsis alone carries a mortality rate of about 10%. (1)

Etiology

Sepsis can be caused by any microorganism (bacteria, viruses, fungi, parasites). Approximately 80% of sepsis cases occur as a result of infections in outpatient settings. The most common sites of infection are the lungs (64%), abdomen (29%), blood (15%), and kidneys/genitourinary tract (15%). (1012) The most common causative agents among Gram-positive bacteria are Staphylococcus aureus, while in Gram-negative sepsis, Pseudomonas sp. and Escherichia coli are frequently involved. (1015)

Sepsis triggers an immune response via Toll-like receptors on immune cells, leading to the release of pro-inflammatory and anti-inflammatory mediators. Cytokines such as TNF-α, IL-1, IL-6, and IL-8 promote neutrophil adhesion to endothelial cells, activation of the complement system, and the coagulation cascade, resulting in microthrombi formation. (16) Recent research indicates that sepsis is characterized by both pro-inflammatory and immunosuppressive responses occurring simultaneously, with the intensity of each depending on the host (age, genetics, comorbidities) and the pathogen (virulence, strain). (16)

Sepsis Treatment

Sepsis and septic shock must be treated as urgent conditions in critically ill patients. Early recognition and antibiotic therapy are the foundation of successful treatment.

Initial Fluid Resuscitation

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 Control of the Infection

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

Antibiotic Therapy

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:

1) Intravenous antibiotic therapy should start within the first hour of admission;

2) Broad-spectrum antibiotics, either single or in combination, should be administered;

3) The spectrum of antibiotics should be narrowed once the biogram and antibiogram are available or when the clinical picture allows;

4) The dosing strategy should be optimized based on pharmacokinetic and pharmacodynamic principles;

5) De-escalation of antibiotics should be considered on a daily basis and at the earliest stage based on the clinical picture. (22)

When is the Right Time to Start Vasopressor Therapy and How to Choose the Right One?

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)

Vasopressor Timing

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

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

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

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

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

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)

Angiotensin II

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

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

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

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)

Conclusion

Sepsis and septic shock remain leading causes of long-term morbidity and mortality in the modern era. Early diagnosis and appropriate management, including the use of vasopressors, reduce complications, healthcare costs, and mortality. Norepinephrine is the first-line vasopressor according to all available recommendations, as it is associated with a lower risk of cardiac arrhythmias and mortality. Second-line agents are epinephrine, vasopressin, and, in rare and clearly defined indications, phenylephrine may be used. Vasopressin has catecholamine sparing effects. According to the newest guidelines, it should be added early as a second-line vasopressor, rather than escalating doses of norepinephrine. In patients with cardiac dysfunction, inotropes can be useful.

Ongoing research based on an individualized approach will likely provide insights into earlier detection of sepsis and prevention of multiorgan failure. Additionally, further studies are needed to determine the best second-line agents and the optimal timing for their use.

INFORMATION ON CONFLICT OF INTEREST

The authors declare that there are no conflicts of interest relevant to this work

FINANCING INFORMATION

No financial resources were used for this article

AUTHOR’S CONTRIBUTION

Conception or design of the manuscript: RJ

Data acquisition, analysis or interpretation: MS

Drafting of manuscript: RJ, MS

Critically revising for important intellectual content: RJ

References

 

Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet. 2018;392:75–87. PubMed https://doi.org/10.1016/S0140-6736(18)30696-2</jrn>

 

Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsagonos T. Schlattmann P i sur. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193:259–272. PubMed https://doi.org/10.1164/rccm.201504-0781OC</jrn>

 

Tiru B, DiNino EK, Orenstein A, Mailloux PT, Pesaturo A, Gupta A, et al. The economic and humanistic burden of severe sepsis. PharmacoEconomics. 2015;33:925–937. PubMed https://doi.org/10.1007/s40273-015-0282-y</jrn>

 

Reinhart K, Daniels R, Kissoon N, Kissoon N, Mahando FR. SchachterRD i sur. Recognizing sepsis as a global health priority— a WHO resolution. N Engl J Med. 2017;377(5):414–417. PubMed https://doi.org/10.1056/NEJMp1707170</jrn>

 

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM. Knaus A i sur. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101(6):1644–1655. PubMed https://doi.org/10.1378/chest.101.6.1644</jrn>

 

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D. Cook D i sur. 2001SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003April;31(4):1250–6.PubMed. https://doi.org/10.1097/01.CCM.0000050454.01978.3B</jrn>

 

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D. Bauer M i sur. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–810. PubMed https://doi.org/10.1001/jama.2016.0287</jrn>

 

Shankar-Hari M, Phillips GS, Levy ML, Seymor CV, Liu WX. Deutschman SC i sur. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:775–787. PubMed https://doi.org/10.1001/jama.2016.0289</jrn>

 

Seymour CW, Liu VX, Iwashyna TJ, Brunkhort FM, Rea TD. Scherag A i sur. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:762–774. PubMed https://doi.org/10.1001/jama.2016.0288</jrn>

 

Vincent JL, Rello J, Marshall J, Silva E, Anzueto A. Martin CD i sur. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–2329. PubMed https://doi.org/10.1001/jama.2009.1754</jrn>

 

Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhard K. Gerlach H i sur. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34:344–353. PubMed https://doi.org/10.1097/01.CCM.0000194725.48928.3A</jrn>

 

Karlsson S, Varpula M, Ruokonen E, Pettila V, Parviainen I. Ala-Kokko TI i sur. Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finn sepsis study. Intensive Care Med. 2007;33:435–443. PubMed https://doi.org/10.1007/s00134-006-0504-z</jrn>

 

Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I. Lipman J i sur. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med. 2014;2:380–386. PubMed https://doi.org/10.1016/S2213-2600(14)70061-X</jrn>

 

Vincent JL, Lefrant JY, Kotfis K, Rahul Nanchal R, Martin-Loeches I. Wittebole X i sur.Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP). Intensive Care Med. 2018. 44(3):p. 337–344. PubMed https://doi.org/10.1007/s00134-017-5043-2</jrn>

 

Boyd JH, Russell JA, Fjell CD. The meta-genome of sepsis: host genetics, pathogens and the acute immune response. J Innate Immun. 2014;6:272–283. https://doi.org/10.1159/000358835 PubMed</jrn>

 

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–150. PubMed https://doi.org/10.1056/NEJMra021333</jrn>

 

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A. B Knoblich i sur. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–1377. PubMed https://doi.org/10.1056/NEJMoa010307</jrn>

 

Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM. French C i sur. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–1247. PubMed https://doi.org/10.1007/s00134-021-06506-y</jrn>

 

Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566–1572. PubMed https://doi.org/10.1001/jama.2012.13356</jrn>

 

Kumar A, Roberts D, Wood KE, Light B, Parrillo JE. Sharma S i sur. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–1596. PubMed https://doi.org/10.1097/01.CCM.0000217961.75225.E9</jrn>

 

Font MD, Thyagaraja B, Khanna A. Sepsis and Septic Shock – Basics of diagnosis, pathophysiology and clinical decision making. Med Clin North Am. 2020;104(4):573–585. PubMed https://doi.org/10.1016/j.mcna.2020.02.011</jrn>

 

Rodes A, Evans L, Alhazzani W, Levy M, Antonelli M. Ferrer R i sur. Survivin Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock:2016. Intensive Care Med. 2017;45(3):486–552

 

Avni T, Lador A, Lev S, Leibovici L. Paul M, Grossman A. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One. 2015;10(8):e0129305. PubMed https://doi.org/10.1371/journal.pone.0129305</jrn>

 

Sakr Y, Reinhart K, Vincent JL, Sprung CL, Moreno R. Ranieri VM i sur. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006;34:589–597. PubMed https://doi.org/10.1097/01.CCM.0000201896.45809.E3</jrn>

 

Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000;28(8):2758–2765. PubMed https://doi.org/10.1097/00003246-200008000-00012</jrn>

 

De Backer D, Biston P, Devriendt J, Madl C, Chochrad D. Aldecoa C i sur. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779–789. PubMed https://doi.org/10.1056/NEJMoa0907118</jrn>

 

Dünser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G. Pajk W i sur. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003;107(18):2313–2319. PubMed https://doi.org/10.1161/01.CIR.0000066692.71008.BB</jrn>

 

Khanna A, English SW, Wang XS, Ham K, Busse LW. Altaweel L i sur. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430. PubMed https://doi.org/10.1056/NEJMoa1704154</jrn>

 

Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J. Hofer C i sur. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40(12):1795–1815. PubMed https://doi.org/10.1007/s00134-014-3525-z</jrn>

 

Bai X, Yu W, Ji W, Lin Z, Tan S. Duan K i sur. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18:532PubMed https://doi.org/10.1186/s13054-014-0532-y</jrn>

 

Ricard JD, Salomon L, Boyer A, Thiery G, Meybeck A. Roy C i sur. Central or peripheral catheters for initial venous access of ICU patients: a randomized controlled trial. Crit Care Med. 2013;41(9):2108–2115. PubMed https://doi.org/10.1097/CCM.0b013e31828a42c5</jrn>

 

Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):6539–65317. PubMed https://doi.org/10.1016/j.jcrc.2015.01.014</jrn>

 

Nasa JIL, Pawlik W, Shepherd AP, Jacobson ED. Effect of vasoactive agents on intestinal oxygen consumption and blood flow in dogs. J Clin Invest. 1975;56(2):484–490. PubMed https://doi.org/10.1172/JCI108115</jrn>

 

Richer M, Robert S, Lebel M. Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man. Crit Care Med. 1996;24(7):1150–1156. https://doi.org/10.1097/00003246-199607000-00014 PubMed</jrn>

 

Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther. 2015;20(3):249–260. PubMed https://doi.org/10.1177/1074248414559838</jrn>

 

Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C. Martin C i sur. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial. Lancet. 2007;370(9588):676–684. PubMed https://doi.org/10.1016/S0140-6736(07)61344-0</jrn>

 

Levy B. Lactate and shock: the metabolic view. Curr Opin Crit Care. 2006;12(4):315–321. PubMed https://doi.org/10.1097/01.ccx.0000235208.77450.15</jrn>

 

Barr JW, Lakin RC, Rosch J. Similarity of arterial and intravenous vasopressin on portal and systemic hemodynamics. Gastroenterology. 1975;69(1):13–19. PubMed https://doi.org/10.1016/S0016-5085(19)32630-7</jrn>

 

Holmes CL, Landry DW, Granton JT. Science review: vasopressin and the cardiovascular system part 1–receptor physiology. Crit Care. 2003;7(6):427–434. PubMed https://doi.org/10.1186/cc2337</jrn>

 

Ventetuolo CE, Klinger JR. Management of acute right ventricular failure in the intensive care unit. Ann Am Thorac Soc. 2014;11(5):811–822. PubMed https://doi.org/10.1513/AnnalsATS.201312-446FR</jrn>

 

Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345(8):588–595. PubMed https://doi.org/10.1056/NEJMra002709</jrn>

 

Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S. D’Alessandro D i sur. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95(5):1122–1125. PubMed https://doi.org/10.1161/01.CIR.95.5.1122</jrn>

 

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC. Cooper DJ i sur. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887. PubMed https://doi.org/10.1056/NEJMoa067373</jrn>

 

Dellinger RP, Levy MM, Rhodes A, Annane DJ, Gerach H. Opal SM i sur. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. PubMed https://doi.org/10.1097/CCM.0b013e31827e83af</jrn>

 

O’Gara PT, Kushner FG, Ascheim DD, Casey CE Jr, Mina K. Chung MK, de Lemos JA i sur. 2013ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [Internet]. Circulation. 127:e362–425. Dostupno na:. https://pubmed.ncbi.nlm.nih.gov/23247304/[Pristupljeno 18. travnja 2024.].</eref>.

 

Olsen NV. Effects of dopamine on renal haemodynamics, tubular function and sodium excretion in normal humans. Dan Med Bull. 1998;45(3):282–297. (PubMed</jrn>).

 

McDonald RH, Goldberg LI, McNay J, Tuttle EP Jr. Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J Clin Invest. 1964;43(6):1116–1124. PubMed https://doi.org/10.1172/JCI104996</jrn>

 

Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J ANZICS Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Lancet. 2000;356(9248):2139–2143. PubMed https://doi.org/10.1016/S0140-6736(00)03495-4</jrn>

 

Bersten AD, Rutten AJ. Renovascular interaction of epinephrine, dopamine and intraperitoneal sepsis. Crit Care Med. 1995;23(3):537–544. PubMed https://doi.org/10.1097/00003246-199503000-00020</jrn>

 

Strehlow MC. Vasopressors and inotropes. In: Arbo JE, editor. , editor. Decision making in emergency critical care: an evidence-based handbook [Internet]. Philadelphia: Wolters Kluwer; 2015Dostupno na:. https://emergency.lwwhealthlibrary.com/book.aspx?bookid=1235[Pristupljeno 12. travnja 2024].</eref>.

 

Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A. Laderchi i sur. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial [Internet]. Crit Care. 2008;12(6):R143. Dostupno na:. https://pubmed.ncbi.nlm.nih.gov/19017409/[Pristupljeno 18. svibnja 2024.].</eref>.

 

Colling KP, Banton KL, Beilman GJ. Vasopressors in Sepsis. Surg Infect (Larchmt). 2018;19(2):202–207. PubMed https://doi.org/10.1089/sur.2017.255</jrn>

 

Schwinn DA, Reevs JG. Time course and hemodynamic effects of alpha-1- adrenergic bolus administration in anesthetized patients with myocardial disease. Anesth Analg. 1989;68(5):571–578. PubMed https://doi.org/10.1213/00000539-198905000-00005</jrn>

 

Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA. 2017;317(14):1433–1442. PubMed https://doi.org/10.1001/jama.2017.2841</jrn>

 

Ramracheya RD, Muller DS, Wu Y, Whitehouse BJ, Huang GC. Amiel SA i sur. Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans. Diabetologia. 2006;49:321–331. PubMed https://doi.org/10.1007/s00125-005-0101-7</jrn>

 

Khanna A, English SW, Wang XS, Ham K, Tumlin J. Szerlip H i sur. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377:419–430. PubMed https://doi.org/10.1056/NEJMoa1704154</jrn>

 

Newby DE, Lee MR, Gray AJ, Boon NA. Enalapril overdose and the corrective effect of intravenous angiotensin II. Br J Clin Pharmacol. 1995;40:103–104. PubMed https://doi.org/10.1111/j.1365-2125.1995.tb04546.x</jrn>

 

Merx MW, Weber C. Cardiovascular involvement in general medicine conditions:sepsis and the heart. Circulation. 2007;116(7):793–802. PubMed https://doi.org/10.1161/CIRCULATIONAHA.106.678359</jrn>

 

Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B, Jardin F. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med. 2008;36(6):1701–1706. PubMed https://doi.org/10.1097/CCM.0b013e318174db05</jrn>

 

Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA. Karp JS i sur. Evidence of myocardial hibernation in the septi heart. Crit Care Med. 2005;33(12):2752–2756. PubMed https://doi.org/10.1097/01.CCM.0000189943.60945.77</jrn>

 

Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth. 2010;104(1):3–11. PubMed https://doi.org/10.1093/bja/aep339</jrn>

 

Overgaard CB, Dzavık V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008;118:1047–1056. PubMed https://doi.org/10.1161/CIRCULATIONAHA.107.728840</jrn>

 

Stratton L, Berslin DA, Erbo JE. Vasopressors and Inotropes in Sepsis. Emerg Med Clin North Am. 2017;35:75–91. PubMed https://doi.org/10.1016/j.emc.2016.09.005</jrn>

 

Papp Z. E´ des I, Fruhwald S, De Hert GS, Salmenpera M, Leppikangas H i sur. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159(2):82–87. PubMed https://doi.org/10.1016/j.ijcard.2011.07.022</jrn>


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