Circulatory support in septic shock: looking beyond catecholamines

Why look for alternatives for the circulatory support of septic patients? 

Vasopressor therapy in patients with septic shock has centered around the use of noradrenaline titrated to a target mean arterial pressure. The surviving sepsis guidelines recommend noradrenaline as the first-line vasopressor in sepsis.¹ Noradrenaline increases venous return and the left ventricular end-diastolic volume by venoconstriction and mobilization of the “unstressed” volume from the splanchnic circulation. It increases myocardial contractility though beta-1 adrenergic receptor stimulation. The cardiac output and blood pressure increase, with no increase in the heart rate. In contrast to adrenaline, noradrenaline has no significant effect on the beta-2 adrenergic receptors, and hence, there is no rise in the lactate levels. Several clinical studies have been carried out comparing noradrenaline with dopamine, adrenaline, and vasopressin alone and in combination. These studies have clearly established that noradrenaline is equally efficacious or superior in the hemodynamic support of patients with septic shock.

Circulatory support using catecholamines is not entirely benign; several non-hemodynamic effects may adversely affect clinical outcomes. These include a hypermetabolic state characterized by hyperglycemia, hyperlactatemia, and an increase in the tissue oxygen demand. Catecholamines may cause mitochondrial uncoupling and lead to exacerbation of oxidative stress. Besides, they may exert a significant immunosuppressive effect, increasing the likelihood of secondary infections.² There is increasing concern that high doses of catecholamine support may adversely impact clinical outcomes. In a retrospective observational study, a noradrenaline dose of more than 1mcg/kg/min was the strongest independent predictor of mortality on multidimensional logistic regression analysis.³ Considering the possible deleterious effects of high-dose noradrenaline, there is an increased focus on “decatecholaminization” using non-catecholamine-based circulatory support.⁴ Let us consider the non-catecholamine pharmacological agents that have been evaluated in patients with septic shock. 

Vasopressin

A relative vasopressin deficiency may occur in septic shock. Exogenous vasopressin administration leads to vasoconstriction by its action on the non-adrenergic, V1 receptors located in the vascular endothelium. This leads to increased blood pressure, less requirement for noradrenaline, and possible inhibition of cytokine production. The VAAST study did not show any change in mortality in patients with septic shock with vasopressin use; however, it was associated with lower 28-d mortality among patients with less severe shock, who were on less than 15 mcg/min of noradrenaline infusion.⁵ Vasopressin use in vasoplegic shock following cardiac surgery may be associated with a lower incidence of atrial fibrillation compared to noradrenaline.⁶

In a factorial double-blind, randomized clinical trial with the use of noradrenaline, vasopressin, and hydrocortisone in septic shock, early vasopressin administration had no effect on the kidney failure-free days compared to noradrenaline.⁷Although frequently used in combination with noradrenaline and hydrocortisone, there is no firm evidence that vasopressin improves clinical outcomes in patients with septic shock. 

Selepressin

Besides its effect on the V1 receptors resulting in an increase in the vascular tone, vasopressin stimulates the V2 receptors located in the basolateral membrane of the collecting tubules of the kidneys. This may lead to fluid retention, release of procoagulant factors including Von Willebrand factor and factor VIII, leading to thrombosis. Furthermore, nitric oxide release may lead to vasodilatation. Selepressin is a novel, selective vasopressin V1a receptor agonist that may be devoid of many of the adverse effects related to vasopressin. In a phase IIa randomized controlled trial in patients with septic shock, selepressin in a dose of 2.5 ng/kg/minute resulted in rapid weaning down and cessation of noradrenaline. Furthermore, it reduced the duration of mechanical ventilation and the cumulative fluid balance over the study period.⁸ A recent phase 2b/3 randomized controlled trial compared three dosing regimens of selepressin with placebo. There was no difference noted in the primary endpoint of ventilator or vasopressor-free days at day 40 with the use of selepressin. The 90-d mortality, intensive care-free days, and the requirement for renal replacement therapy at 30 days were also not different compared to placebo. Future research is required to evaluate the appropriate dose of selepressin and assess patient-centred outcomes in adequately powered, controlled studies. 

Angiotensin II

Angiotensin II is the biologically active component of the renin-angiotensin system. It acts on two receptor subtypes, AT1 and AT2. The physiological effects leading to vasoconstriction, retention of water and sodium, and release of aldosterone and vasopressin are mediated through the AT1 receptors.  The ATHOS-3 trial evaluated the effect of angiotensin II in patients with vasodilatory shock in a placebo-controlled randomized controlled trial. The primary endpoint was an increase in the mean arterial pressure by at least 10 mm Hg or to a minimum level of 75 mm Hg, without any increase in the background vasopressor dose at 3 h after commencement of infusion. A significantly higher number of patients achieved the target MAP compared to placebo. The mean improvement in the cardiovascular SOFA score was also significantly higher with angiotensin II.⁹ The data from this study led to the approval of angiotensin II in septic shock by the Food and Drug Administration in the USA and the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP).

Corticosteroids

The use of corticosteroids as adjunctive therapy in septic shock has captivated intensive care physicians for over five decades. The concept of corticosteroid insufficiency related to critical illness (CIRCI) has arisen more recently. CIRCI is based on the hypothesis that even maximal stimulation of the hypothalamic-pituitary-adrenal axis in disease states such as sepsis results in insufficient corticosteroid levels. Besides, there may be tissue resistance to corticosteroids in the presence of sepsis. The ADRENAL trial is the largest randomized controlled trial that compared hydrocortisone infusion at 200 mg/day to placebo in patients with septic shock. No difference was observed in the 90-d mortality, the primary outcome, for which the study was powered. However, hydrocortisone reduced the median time to shock resolution, the median time to initial discontinuation of mechanical ventilation, the median time to ICU discharge, and the requirement for blood transfusion.¹⁰ The APROCCHSS trial evaluated the efficacy of a combination of hydrocortisone and fludrocortisone in patients with septic shock. In contrast to ADRENAL, a statistically significant difference was observed in the 90-d mortality, which was the primary endpoint. The all-cause mortality at ICU and hospital discharge, and at 180 days, were also significantly lower among corticosteroid-treated patients. Earlier shock reversal was also observed; there were more patients alive and off vasopressor support at 28 days with corticosteroids.¹¹ In light of the available evidence, it may be appropriate to consider the administration of corticosteroids in patients with refractory septic shock.

Methylene blue 

Vasodilatory shock is mediated by excessive production of nitric oxide (NO) and cyclic GMP. Methylene blue inhibits the effects of endothelial NO and may act as a NO scavenger, thereby offsetting its vasodilator effect. Thus, it may be useful in clinical states characterized by extreme vasodilation, including post-cardiopulmonary bypass, septic shock, drug toxicity, and anaphylactic reactions. In a systematic review of mostly observational studies, Kwok et al. observed that methylene blue resulted in an increase in the systemic vascular resistance and the mean arterial pressure with a decrease in the requirement for vasopressors.¹² However, there is no robust evidence from controlled studies that support its clinical efficacy in septic shock. 

Vitamins for circulatory support

Vitamin C (ascorbic acid) is a cofactor for the enzymes required for the synthesis of endogenous vasopressin and noradrenaline. A relative or absolute deficiency of Vitamin C may exist in septic patients, resulting in depletion of endogenous noradrenaline and vasopressin. Besides, vitamin C is a powerful antioxidant end effectively scavenges oxygen free radicals and replenishes cellular antioxidants. Thiamine (vitamin B1) is a cofactor for the enzyme pyruvate dehydrogenase that converts pyruvate to acetyl-coA and entry in to the Kreb’s cycle. If thiamine levels are deficient, conversion of pyruvate to acetyl-coA does not occur, with shift to anerobic metabolism and an increase in the lactate levels. Thiamine deficiency is common in septic patients and may lead to increased mortality.¹³ Marik et al. conducted a retrospective, before-after study to evaluate the effect of a combination of vitamin 1.5 g 6 hourly, hydrocortisone 50 mg 6 hourly, and thiamine 200 mg twice daily among patients with severe sepsis or septic shock. The hospital mortality was significantly lower with this combination compared to a historical control group. The mean duration of vasopressor therapy and the requirement for renal replacement therapy was also significantly lower in the treatment group. A multicentre, randomized controlled trial is currently recruiting patients to evaluate the efficacy of this cocktail in patients with septic shock.¹⁴

The bottom line 

• Noradrenaline is the time-tested and the most widely recommended vasopressor agent in septic shock.
• However, considering the adverse effects of catecholamine-based circulatory support, it may be appropriate to pursue alternative therapies, especially as a rescue intervention in septic shock.
• Vasopressin has been evaluated in randomized controlled trials and found to be effective in maintaining blood pressure; however, improved clinical outcomes have not been demonstrated. 
• Selepressin, V1A-selective vasopressin analog has undergone preliminary clinical studies and found to result in more rapid weaning down of noradrenaline support and reduced cumulative fluid balance. 
• Angiotensin II has been shown to be effective in attaining the target mean arterial pressure with improvement in cardiovascular SOFA scores. 
• Based on the findings of two recent randomized controlled trials, corticosteroids administration appears to improve outcomes in refractory septic shock.
• The combination of thiamine, vitamin C, and hydrocortisone has been shown to improve outcomes in septic shock in an observational study; the results of a randomized controlled study are awaited. 

References

1.         Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6

2.         Hartmann C, Radermacher P, Wepler M, Nußbaum B. Non-Hemodynamic Effects of Catecholamines. Shock Augusta Ga. 2017;48(4):390-400. doi:10.1097/SHK.0000000000000879

3.         Martin C, Medam S, Antonini F, et al. NOREPINEPHRINE: NOT TOO MUCH, TOO LONG. Shock. 2015;44(4):305-309. doi:10.1097/SHK.0000000000000426

4.         Singer M, Matthay MA. Clinical review: Thinking outside the box–an iconoclastic view of current practice. Crit Care Lond Engl. 2011;15(4):225. doi:10.1186/cc10245

5.         Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. doi:10.1056/NEJMoa067373

6.         Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology. 2017;126(1):85-93. doi:10.1097/ALN.0000000000001434

7.         Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485

8.         Russell JA, Vincent J-L, Kjølbye AL, et al. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017;21(1):213. doi:10.1186/s13054-017-1798-7

9.         Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154

10.       Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835

11.       Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716

12.       Kwok ESH, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med. 2006;21(6):359-363. doi:10.1177/0885066606290671

13.       Donnino MW, Andersen LW, Chase M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016;44(2):360-367. doi:10.1097/CCM.0000000000001572

14.       Fujii T, Udy AA, Deane AM, et al. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc J Australas Acad Crit Care Med. 2019;21(2):119-125.