A 70 year old man with known prostatic malignancy and stage III chronic kidney disease developed fevers, left flank pain, urinary frequency and confusion. He deteriorated rapidly in ED becoming hypotensive and drowsy. He had a lactic acidosis. CT abdomen was showed left hydronephrosis and hydroureter and was suggestive of an infected obstructed kidney. During the scan he became peri-arrest and was intubated. There was a logistical delay in achieving nephrostomy, and he was requiring escalating levels of noradrenaline. Vasopressin was commenced in order to maintain his mean arterial pressure and reduce the noradrenaline requirement from 0.8mcg/kg/min. Nephrostomy was achieved around 12 hours later and he subsequently made a full recovery.
What is the role of Vasopressin for Adults in Septic Shock
Arginine vasopressin (AVP) is an endogenous peptide hormone also known as anti-diuretic hormone. A relative deficiency of endogenous AVP in septic shock was shown by Landry et al in 1997 (1), who determined that secretion of AVP is significantly suppressed in patients with septic shock compared to those with cardiogenic shock. Administration of exogenous vasopressin to the septic shock group resulted in a significant pressor response with a mild reduction in cardiac output.
This finding led to further study into the role of vasopressin in vasodilatory shock, and it was recently recommended as an adjunctive pressor agent in the 2008 update to the Surviving Sepsis Guidelines (2). This recommendation is informed largely by the findings of the VASST study, an international multi-centre, randomised double-blind trial comparing low-dose vasopressin infusion (up to 0.03U/min) to noradrenaline infusion in patients with septic shock (3). The trial found no overall difference in mortality between the groups treated with vasopressin or noradrenaline at 28- or at 90-days. Vasopressin administration had a significant noradrenaline-sparing effect. There was no significant overall difference in adverse events between the groups, but there was a trend towards a higher rate of cardiac arrest in the noradrenaline group and a trend suggesting increased incidence of digital ischaemia in the vasopressin group.
A pre-defined secondary hypothesis attempted to identify a mortality benefit from vasopressin treatment in patients with more severe septic shock. Therefore, patients receiving 15mcg/min noradrenaline or more at randomisation were stratified to the more severe sepsis group, compared to those receiving less than 15mcg/min noradrenaline. No difference in mortality was found between vasopressin and noradrenaline therapy in the group with more severe septic shock. However there were significant trends in favour of vasopressin in the less severe septic shock group suggesting improved 28- and 90-day mortality.
Prior to the publication of the VASST study (3), there were only a limited number of prospective randomised controlled trials evaluating use of low-dose vasopressin in septic shock; however none of those trials were sufficiently powered to detect mortality differences between treatment groups (4-6). These trials showed concordance with the findings of Landry et al.(1) in confirming an improvement in haemodynamic indices when using vasopressin in septic shock, and a noradrenaline-sparing effect. However, there is some disparity in the dose ranges targeted in these trials. Malay et al. (4) targeted a vasopressin dose of 0.04U/min, the protocol used by Patel et al. (5) titrated dose up to 0.08U/min, while Dunser et al. (6) used a constant infusion rate of 0.66U/min. The Surviving Sepsis Guidelines (2) recommends a vasopressin infusion titrated to a rate of 0.03U/min according to the protocol used by the VASST investigators.
This variation of infusion rates may stem from a lack of phase II studies evaluating dosing ranges, suggesting that the optimal dose is unknown and most trial protocols set dosing based on expert opinion (7). Torgersen et al. attempted to address this by prospectively comparing haemodynamic response, organ function and adverse outcomes in patients with vasodilatory shock receiving 0.033U/min or 0.067U/min of vasopressin (8). They found a dose-dependent reduction in noradrenaline requirement, base deficit and troponin levels. However, both groups had similar increases in arterial pressure and arterial pH, with reduced heart rate and lactate levels. Interestingly, increased plasma vasopressin levels were found in patients receiving concomitant glucocorticoids. Adverse events were similar in both groups, but the trial lacked sufficient power to detect differences in patient mortality between groups.
The investigators concluded that the higher dose infusion of vasopressin of 0.66U/min restored cardiovascular function more effectively than the lower dose of 0.33U/min. It is worth noting that all the patients in this trial would have been considered to fall into the more severe septic shock group according to VASST criteria, and the findings of this trial may suggest that the doses of vasopressin used in the VASST study were too low.
The VASST investigators also investigated the interaction between vasopressin treatment and corticosteroid treatment in a post-hoc analysis of their trial data (9) They found a significant mortality benefit in patients treated with vasopressin and corticosteroids, compared to noradrenaline. Conversely, patients treated with vasopressin without corticosteroids were associated with increased mortality compared with noradrenaline. Patients who received corticosteroids and vasopressin had significantly higher plasma concentration of vasopressin compared to patients receiving vasopressin only, a finding in concordance with Torgersen et al (8).
Another post-hoc analysis of the VASST patient data investigated the effects of vasopressin versus noradrenaline on outcome of acute kidney injury in septic shock (10). Using RIFLE criteria for AKI (11); for patients in the ‘Risk’ category, vasopressin was associated with a trend to a lower rate of progression to renal ‘Failure’ or ‘Loss’ and a lower rate of renal replacement therapy compared to those in the noradrenaline group. In addition there was a trend towards reduced mortality in the vasopressin group compared to patients treated with noradrenaline without vasopressin. These results are concordant with the findings of Patel et al. (5) where the vasopressin treatment group had significantly increased urine output and creatinine clearance compared to the noradrenaline treatment group.
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