A 52 year old female was admitted to the ICU with septic shock secondary to cholangitis. She had liver cirrhosis secondary to alcoholic liver disease, although she had been abstinent since an admission with acute alcoholic hepatitis  2 years previously. She had recently entered the assessment pathway for orthotopic liver transplantation.

She presented to the Emergency Department with a short history of fever and confusion and falls. She was pyrexial, tachycardic and hypotensive. Her inflammatory markers were elevated and her liver enzyme profile suggested cholestasis. There were no other localising features on examination or preliminary investigation.

She was commenced in the ED on broad-spectrum antibiotic therapy (piperacillin-tazobactam) and fluid resuscitation consisting of Hartmann’s solution and 4% human albumin solution. Her blood pressure remained labile throughout the early part of her admission. She fulfilled the criteria for septic shock with evidence of evolving multi-organ dysfunction.

 

The patient received early, aggressive multi-organ support. Tracheal intubation and pressure-controlled ventilation were instituted due to grade III/ IV encephalopathy and a high work of breathing in response to profound metabolic acidaemia. A thorough clinical assessment of intravascular volume status was conducted, suggesting that the patient was adequately filled. Vasopressor therapy was initiated using noradrenaline to achieve a target MAP of 65mmHg. CVVHDF was commenced to control the severe acidaemia and hyperlactataemia.

The patient was vasoplegic and remained profoundly hypotensive despite rapidly escalating doses of noradrenaline and the addition of hydrocortisone. Continued assessment of intravascular status confirmed adequate filling and cardiac output monitoring using a pulse-contour analysis system confirmed a low SVRI- high cardiac output state.  Her noradrenaline requirements soon exceeded 0.4mcg/kg/min^-1, at this point a vasopressin infusion was introduced at 0.03units/hr^-1. This was associated with an improvement in haemodynamic indices; the target MAP was achieved and thereafter remained stable with a slow reduction in noradrenaline requirement. On day 2 the continuous vasopressin infusion was converted to terlipressin by bolus dose regime (2mg QDS).

An urgent ultrasound scan of her biliary system revealed an obstructed common bile duct which was treated by percutaneous biliary drainage. An Enterococcus was isolated from drain fluid and blood cultures within 48 hours and antibiotic therapy tailored accordingly. The patient was weaned from organ support and discharged to the hepatology unit 9 days after admission.

What is the rationale for the use of vasopressin in septic shock? Are vasopressin analogues as effective?

Christopher Westall

 

Noradrenaline is recommended as the first line vasopressor for septic shock by the Surviving Sepsis Campaign collaborators; adjunctive therapy when haemodynamic targets are not achieved, in the absence of significant cardiac dysfunction, include adrenaline or vasopressin.¹

Conceptually the role for vasopressin in septic shock is attractive; stimulation of the AVPR1a (V1) receptor stimulates profound vasoconstriction (IP₃-mediated), although paradoxical vasodilatation of coronary and pulmonary blood vessels occurs (nitric oxide-mediated). The vasoconstrictor response is variable between vascular beds; increased renal blood flow is observed with vasopressin compared with noradrenaline, with decreased hepatic flow and a variable reduction in mesenteric flow. A state of relative vasopressin insufficiency is observed in septic patients, which may be sustained for several days.²

Classically cirrhotic patients have lower mean arterial pressures than non-cirrhotic individuals, characterised by a hyperdynamic cardiac output- low systemic vascular resistance state. This phenotype is exaggerated by sepsis and consequently cirrhotic patients tend to be hyporeactive to vasopressor therapy.³ It would appear intuitive therefore that vasopressin rather than adrenaline should be the adjunctive-vasopressor of choice for patients with underlying cirrhotic disease. Additionally there is persistent debate concerning potential harm associated with high-dose catecholamine infusions, with observed insulin resistance, muscle catabolism, myocardial injury, depressed response to bacterial infection and pro-coagulant states.⁴

The evidence base for vasopressin use is dominated by a single, large multicentre randomised control trial (VASST). Patients receiving noradrenaline for septic shock were randomized to either noradrenaline with vasopressin or noradrenaline alone using a methodology that allowed for blinding. There was no difference observed in 28 or 90-day mortality or rates of organ dysfunction between the two groups, though lower total doses of noradrenaline were required to achieve target MAP in the vasopressin group. There was some suggestion that mortality might be improved for patients with “less severe septic shock” (defined as those that required <15mcg/min^-1 of noradrenaline, equivalent to <0.2mcg/kg/min^-1 for a 70kg patient) if they received adjuvant vasopressin infusions.⁵ Subsequent meta-analyses have variously supported or refuted this finding depending on the methodology employed.^6,7

Based on renewed interest in vasopressin, the use of synthetic vasopressin analogues in septic shock is increasingly being investigated. Analogues offer some theoretical advantage to vasopressin; namely greater selectivity for the AVPR1a (V1) receptor and longer half-life allowing for bolus dosing. The evidence for analogues is evolving, but at present is limited to case-series and small single-centre randomised control trials. The present literature suggests that continuous infusion of terlipressin (the most widely used analogue) in septic shock is non-inferior to vasopressin in reducing catecholamine requirement and is associated with lower rates of rebound hypotension on withdrawal compared with vasopressin.^8,9

With respect to bolus administration of terlipressin, while the haemodynamic response achieved appears equivalent to continuous infusion, concerns persist regarding the negative impact of high peak plasma concentrations (with the experimental evidence best summarised in a review by Singer, 2008). These include larger decreases in cardiac output, increased pulmonary vascular resistance, reduced splanchnic perfusion and localised skin necrosis.¹⁰

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Lessons learnt

Adjunctive vasopressin infusion is useful in septic shock where target MAP is difficult to achieve without high noradrenaline requirements. There is no clear mortality benefit associated with this, though it may attenuate some potentially harmful consequences seen with high-dose catecholamine use. Conceptually it appears ideally suited to cirrhotic patients with septic shock. Although synthetic vasopressin analogues have theoretical advantages to vasopressin itself, there is not enough evidence to justify their use routinely. Bolus use of vasopressin analogues for septic shock, outside of cirrhotic patients with associated gastrointestinal haemorrhage or hepatorenal syndrome, cannot be recommended at this time.

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References

 

1. Dellinger R, Levy M, Carlet J, Bion J, Jaeschke R, Reinhart K, Angus D, Brun-Buisson C, Beale R, Calandra T, Dhainaut J, et al. Surviving Sepsis Campaign: International Guidelines for management of severe sepsis and septic shock: 2012. Intensive Care Med, 2013;41:580–637.
2. Russell J. Bench-to-bedside review: Vasopressin in the management of septic shock. Critical Care, 2011;15:226.
3. Gines P, Fernandez J, Durand F, Saliba F. Management of critically-ill cirrhotic patients. J Hepatol, 2012;56 Suppl 1:S13-24.
4. Singer M. Catecholamine treatment for shock- equally good or equally bad? Lancet, 2007;370:636-7.
5. The VASST Investigators. Russell J, Walley K, Singer J, Gordon A, Hébert P, Cooper J, Holmes C, Mehta S, Granton T, Storms M, Cook D, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med, 2008;358:877-88.
6. Serpa Neto A, Nassar A, Cardoso S, Manetta J, Pereira V, Espósito D, Damasceno M, Russell J. Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials. Critical Care, 2012;166:R154.
7. Polito A, Parisini E, Ricci Z, Picardo S, Annane D. Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis. Intensive Care Med, 2012;38:9-19.
8. Albanese J, Leone M, Delmas A, Martin C. Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Crit Care Med, 2005;33:1897-1902.
9. Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Cecchini V, Bechetoni A, D”Alessandro M, Van Aken H, Pietropaoli P, Westphal M. Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study. Crit Care, 2009;13:R130.
10. Singer M. Arginine vasopressin vs. terlipressin in the treatment of shock states. Best Pract Res Clin Anaesthesiol, 2008;22:359-68.