ICU Management & Practice, Volume 16 - Issue 3, 2016

Vasoactive Drugs in Sepsis

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In this update review on vasoactive drugs in sepsis, we focus on the ‏most recent data regarding the type of vasopressors that should be ‏used, the timing of infusion, the mean arterial pressure target and ‏the alternative approaches.

 

Sepsis and especially septic shock is associated ‏with arterial vasodilation refractory to ‏fluid challenge. The use of vasoactive drugs ‏is strongly recommended by the Surviving Sepsis ‏Campaign (Dellinger et al. 2013) and the European ‏consensus on circulatory shock management ‏and monitoring (Cecconi et al. 2014).

 

Which Vasopressor Should be Used?

 

Arterial vasoconstrictive response is mediated ‏by three physiological pathways involving ‏α1-adrenergic receptors, V1a agonist receptors ‏and angiotensin receptors. To date most studies ‏have examined the use of catecholamines (i.e. ‏dopamine, norepinephrine and epinephrine). ‏De Backer et al. (2012) compared survival in ‏patients with septic shock treated with dopamine ‏or norepinephrine in a meta-analysis that ‏included 2,768 patients. In randomised trials ‏dopamine was associated with an increased risk ‏of death (relative risk (RR) 1.12; 95% confidence ‏interval (CI) 1.01–1.20; p=0.035) and ‏cardiac arrhythmias (RR 2.34; 95% CI 1.46 ‏–3.77; p=0.001). The most recent meta-analysis ‏focusing on vasopressors in patients with septic ‏shock analysed data from 32 trials including 3544 ‏patients and compared six vasopressors, alone or ‏in combination (Avni et al. 2015). Compared to ‏dopamine (866 patients, 450 events), norepinephrine ‏(832 patients, 376 events) was associated ‏with a decrease in all-cause mortality (RR ‏0.89; 95% CI 0.81-0.98), corresponding to an ‏absolute risk reduction of 11% and a number of ‏patients needed to be treated of 9 to avoid one ‏death. Compared to dopamine, norepinephrine ‏was associated with a lower risk of major adverse ‏events and cardiac arrhythmias.

 

Epinephrine was compared with norepinephrine ‏in two double-blind randomised controlled ‏trials, and did not demonstrate a better survival ‏in patients with septic shock (Annane et al. 2007; ‏Myburgh et al. 2008). Of note, both trials were ‏underpowered, which led the Surviving Sepsis ‏Campaign experts to recommend that epinephrine ‏“may be added to, or substituted, for norepinephrine ‏when an additional agent is needed ‏to maintain adequate blood pressure (grade 2B, ‏weak recommendation based on moderate level ‏of evidence)” (Dellinger et al. 2013).

 

Catecholamines are associated with an ‏increased risk of cardiac arrhythmias (Asfar et ‏al. 2014) and pro-inflammatory side effects ‏(Andreis and Singer, 2016). A high catecholamine ‏load is associated with a high mortality ‏rate (Dünser et al. 2009a). These data prompted ‏some authors to assess an alternative approach ‏using V1a agonists. The largest trial, published by ‏Russell et al. (2008), compared the administration ‏of norepinephrine versus a combination of ‏low dose of vasopressin plus norepinephrine in ‏778 patients with septic shock. Overall, there ‏was no difference in survival rate. However, in ‏the a priori defined strata of less severe patients, ‏the vasopressin-treated patients experienced a ‏lower mortality rate and lower renal replacement ‏therapy requirements. The reasons for this beneficial ‏effect in this subgroup of patients with septic ‏shock is unclear, but could be attributed to the ‏so-called “decatecholaminisation effect” (Asfar ‏et al. 2016), as norepinephrine weaning was ‏faster in this subgroup and may have improved ‏patients’ outcome by reducing norepinephrine ‏side effects. A recent meta-analysis in patients with ‏septic shock by Oba et al. (2014) showed that ‏norepinephrine and norepinephrine plus lowdose ‏vasopressin was associated with a decreased ‏mortality rate in patients treated with the combination, ‏compared with dopamine (Odds ratio ‏(OR) 0.80 [95% CI 0.65-0.99], 0.69 [0.48- ‏0.98], respectively). In the VANISH trial vasopressin ‏was compared to norepinephrine in terms ‏of renal outcome in patients with septic shock ‏(Gordon et al. 2016). Unfortunately, early administration ‏of vasopressin was not associated with ‏a better renal outcome. However, the confidence ‏interval included a potential clinically important ‏benefit for vasopressin. Efficacy of selepressin, ‏a new V1a agonist, is currently being assessed ‏in patients with septic shock in the Selepressin ‏Evaluation Programme for Sepsis-Induced Shock ‏- Adaptive Clinical Trial (SEPSIS-ACT) that aims ‏to recruit 1800 patients, NCT02508649 (clinicaltrials. ‏gov/ct2/show/NCT02508649). ‏


According to the latest published data, norepinephrine ‏is still the first line vasopressor in ‏patients with septic shock

 

When to Start?

 

By definition, septic shock is defined as circulatory ‏impairment associated with hypotension ‏refractory to fluid resuscitation. This definition ‏immediately raises two questions related to the ‏amount of fluid resuscitation and the timing of ‏vasoactive drug initiation. The Surviving Sepsis ‏Campaign recommends in its bundle of resuscitation ‏an amount of 30 mL/Kg (Dellinger et ‏al. 2013). However, this strong recommendation ‏is based on a low level of evidence (grade ‏1C). The timing of vasoactive drug initiation ‏and amount of fluid resuscitation were recently ‏shown to be strongly associated with mortality ‏in a retrospective study in patients with ‏septic shock (Waechter et al. 2014). The lowest ‏mortality rate was observed for a minimum ‏one litre of fluids administered within the first ‏hour after shock onset and when the vasoactive ‏drug was started within 1-6 hours after the ‏fluid resuscitation. A very early administration ‏of vasoactive drugs within the first hours after ‏hypotension recognition was associated with ‏a higher mortality rate.

 

Similarly, Bai et al. (2014) reported in a ‏retrospective cohort the effects of early versus ‏late norepinephrine administration. Every one ‏hour of administration delay during the first 6 ‏hours was associated with a 5.3% increase in ‏mortality. The 28-day mortality rate was significantly ‏higher when norepinephrine administration ‏was started ≥ 2 hours after septic shock ‏onset. Finally, Lee et al. (2014) reported in a ‏retrospective study including 594 patients with ‏septic shock that a high proportion of fluid ‏received within the first 3 hours was associated ‏with a high survival rate.

 

See Also: Study: Vasopressin vs. Norepinephrine in Septic Shock - VANISH trial


According to the latest published data, we ‏suggest starting norepinephrine after one ‏hour of aggressive fluid resuscitation with ‏at least 1-2 litres of fluids.

 
Which Mean Arterial Pressure Level ‏Should We Target?

 

Organ perfusion pressure in shock states is driven ‏by mean arterial pressure both in pressureregulated ‏organs (i.e. brain, kidney and heart) ‏as well as in non-pressure-regulated organs. ‏The optimal mean arterial pressure target for ‏every patient is unknown and an individualised ‏approach is necessary. As suggested by the ‏Surviving Sepsis Campaign recommendations, ‏the mean arterial pressure target may be set to ‏higher threshold in patients with cardiovascular ‏comorbidities such as chronic hypertension ‏(Dellinger et al. 2013).

 

Mean Arterial Pressure Target and Mortality

 

Based on observational studies (Dünser et al. ‏2009b; Varpula et al. 2005), a threshold of 60 ‏to 65mmHg of mean arterial pressure appears ‏suitable in patients with septic shock. Below these ‏values the mortality rate increases proportionally ‏to the time spent under the threshold. Interestingly, ‏above the threshold of 70 mm Hg, in a ‏retrospective study, Dünser et al.(2009a) did not ‏report any relationship between mean arterial ‏pressure level and mortality in patients with ‏septic shock, but showed a significant relation ‏between catecholamine load and mortality rate. ‏Finally, the Sepsispam trial assessed two levels of ‏mean arterial pressure (65 to 70 mm Hg versus ‏80 to 85 mm Hg) in patients with septic shock ‏and did not demonstrate beneficial effect on ‏survival (Asfar et al. 2014). However, patients ‏treated with the higher mean arterial pressure ‏target experienced more cardiac arrhythmias ‏probably due to the higher load of catecholamines.

 

Mean Arterial Pressure and Kidney Function

 

The kidney circulation is highly autoregulated. ‏Dünser et al. (2009a) reported that, in patients ‏with septic shock, higher target pressures were ‏associated with better renal outcome. In an ‏observational study, Badin et al. (2011) reported ‏that, in patients with septic shock and initial ‏renal function impairment, those who maintained ‏their mean arterial pressure between 72 ‏to 82 mm Hg within the first day of septic shock, ‏had a better renal outcome at day 3. Similarly, ‏Poukkanen et al. (2013) reported in a multicentre ‏study, including 423 patients with severe ‏sepsis, that hypotensive episodes below 73 mm ‏Hg were associated with worse renal outcome. ‏The Sepsispam trial did not report any beneficial ‏effect on kidney function in the overall studied ‏population (Asfar et al. 2014). However, in the ‏a priori defined strata of patients with chronic ‏hypertension, patients who were treated with ‏the higher mean arterial pressure target had less ‏occurrence of renal failure.

 

According to the latest published data, regarding ‏the effects of mean arterial pressure on ‏mortality, a target of 65 mm Hg is reasonable ‏as suggested by the Surviving Sepsis Campaign ‏recommendations. ‏

 

Regarding the prevention of kidney failure ‏occurrence, a higher mean arterial pressure ‏target may be recommended in patients with ‏chronic hypertension. However, this should be ‏weighted with the cardiovascular side effects ‏due to the increase in catecholamine load.


‏Which Inotropic Agent Should We Add?

 

Haemodynamics targets may not be achieved ‏despite aggressive fluid resuscitation and early ‏vasopressor initiation. Myocardial failure, due ‏to a complex combination of haemodynamic, ‏genetic, molecular, metabolic, and structural ‏alterations is frequent and may often explain ‏this situation. It occurs early in septic shock, ‏but is often silent, as 15 to 50% of patients have ‏overt cardiac failure (Antonucci et al. 2014). ‏Cardiac failure may worsen oxygen delivery ‏to peripheral organs. To maintain the balance ‏between oxygen delivery and oxygen uptake, ‏it is recommended to monitor central venous ‏oxygen or mixed venous oxygen saturations ‏with a target of 70% and 65% respectively ‏(Dellinger et al. 2013 ; Cecconi et al. 2014). ‏Adequate oxygen administration, red blood cells ‏transfusions, fluid challenge to increase cardiac ‏preload and finally inotropic drugs could be ‏used. The Surviving Sepsis Campaign recommends ‏the use of a dobutamine test, up to 20 ‏μg/Kg/min, when cardiac filling pressures are ‏high, associated with myocardial failure, and/or ‏when there are persistent signs of low peripheral ‏perfusion despite adequate fluids and pressure ‏resuscitation (Dellinger et al. 2013).

 

To date only few data from small randomised ‏control trials with limited outcome are available, ‏making it difficult to come to a conclusion ‏about the role of dobutamine in the treatment ‏of patients with septic shock (Levy et al. 1997; ‏Seguin et al. 2002). ‏

 

Other inotrope agents have been used to ‏support cardiac function, including phosphodiesterase ‏inhibitors, such as milrinone or ‏enoximone, and calcium sensitisers, such as ‏levosimendan. In addition to their inotropic ‏effects, these drugs also have arterial vasodilatation ‏properties and may worsen hypotension ‏in patients with septic shock. However, these ‏drugs may reduce the catecholamine load and ‏participate in the so-called “decatecholaminisation ‏effect” of patients with septic shock. In ‏addition, extra haemodynamic properties, such ‏as immunomodulator and anti-oxidative effects ‏of levosimendan (Asfar et al. 2016; Hasslacher ‏et al. 2011), are of potential interest and may ‏also improve survival in patients with septic ‏shock. In a recent meta-analysis, Zangrillo et al. ‏(2015) showed a significant decreased mortality ‏in patients with severe sepsis or septic shock ‏treated by levosimendan (59/125 [47%]) as ‏compared with standard inotropic treatment, ‏dobutamine (74/121 [61%]) (risk difference = ‏− 0.14, risk ratio = 0.79 [0.63-0.98], p = 0.03, numbers needed to treat = 7). The Levosimendan for the Prevention of ‏Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial is a multicentre ‏randomised control trial, performed in the United Kingdom, aimed ‏at comparing levosimendan for 24 hours versus placebo within 24 ‏hours of septic shock onset (Orme et al. 2014). The recruitment of ‏patients is now completed. The results will probably help us to better ‏delineate levosimendan indications.

 

Dobutamine remains the first line inotropic drug according to the ‏Surviving Sepsis Campaign recommendations. However, this statement ‏may be challenged by the results of the LeoPARDS trial assessing ‏levosimendan efficacy.

 

Conclusion

 

We have focused on the recent literature related to the use of vasoactive ‏drugs in patients with septic shock. Recent publications have ‏improved our knowledge regarding norepinephrine, which is still ‏the first line vasoactive drug. To date, the Surviving Sepsis Campaign ‏guidelines (Dellinger et al. 2013) are still relevant. The ongoing trials ‏related to the use of vasoactive drugs in patients with septic shock ‏may alter these recommendations.

 

Conflict of Interest

 

Simon Bocher declares that he has no conflict of interest. François ‏Beloncle declares that he has no conflict of interest. Pierre Asfar declares ‏that he has no conflict of interest.


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