DOVSS

In Review

Jeon K et al. "Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial". Critical Care. 2018. 22(131):1-12.
PubMed • Full text • PDF

Clinical Question

In adult patients admitted to critical care with septic shock, does tapering vasopressin before norepinephrine lead to less hypotentive events during convalescence.

Bottom Line

Tapering vasopressin first may be associated with less hypotension than if norepinephrine is tapered first during the weaning process.

Major Points

Septic, or distributive shock, is a major cause of morbidity and mortality in the critically ill. Treatment focuses on early administration of antibiotics and maintaining blood pressure above a MAP of 65 mmHg with rapid infusion of fluids and vasopressors like catecholamines (eg, norpepinephrine) or the hormone vasopressin (also called antidiuretic hormone or arginine vasopressin). Vasopressin is thought to elevate blood pressure through smooth muscle V1 receptor-mediated peripheral vasoconstriction. It is often added to therapy when norepinepherine is insufficient. As a patient convalescences and stablization occurs following shock, taper and withdrawal of vasopressors must occur. Hypotention may be a common occurrence during the process however, this may lead to end-organ hypoperfusion and damage. When more than one vasopressor is employed, equipoise exists on which vasopressor should be tapered first.

The incidence of hypotension according to the Discontinuation Order of Vasopressors in the management of Septic Shock (DOVSS) is a single centre, prospective, double-blind, control trial including 78 patients designed to address which vasopressor should be tapered first, following septic shock. They randomized adult patients that presented with septic shock and received both norepinepherine and vasopressin to manage their shock and hypotention, to taper one of the two vaospressors. The primary outcome was the incidence of hypotention within 1 hour of tapering the first vasopressor. They found that in patients that tapered vasopressin first, 23% developed hypotension as compared to 68% that tapered norepinepherine (ARR 45%, p < 0.001, NNT 2). The majority of their secondary outcomes did not reach statistical significance, however, hospital mortality was higher in the vasopressin group (57% vs. 34%, AAR 23.3%, p = 0.039) but ICU and 28 day mortality did not reach statistical significance. It should be noted that this trial was terminated early due to benefit.

There are currently no guidelines recommending the taper of vasopressors following shock. This trial suggests that removing vasopressin may have a lower risk of hypotention but the signal of higher hospital mortality is troubling but may be by chance. THis was a single centre trial and thus generalizability is limited. There may have been a randomization failure as there were some significant differences between the two groups. A larger, multicentre trial should be conducted to confirm these findings.

Guidelines

As of November 2018, no guidelines have been published that reflect the results of this trial.

Design

• single-centre, prospective, randomized, double-blind, controlled trial
• N=78
  • Norepinephrine tapered first (n=38)
  • Vasopressin tapered first (n=40)
• Setting: University-affiliated, tertiary referral hospital in Seoul, South Korea
• Enrollment: January 2012 to February 2014
• Analysis: Modified intention-to-treat
• Primary Outcome: Incidence of hypotension within 1 hour of tapering first vasopressor

Population

Inclusion Criteria

• ≥20 years old
• admitted to medical ICU
• septic shock
• receiving concomitant norepinephrine (NE) and vasopressin (AVP)
• Mean Arterial Pressure (MAP) ≥65 mmHg for at least 2 h after reducing NE to 0.3 mcg/kg/min while maintaining AVP of 0.03 U/min

Exclusion Criteria

• terminally ill patients classified as “do not resuscitate”
• patients who were suspected to have AVP deficiency (e.g. hypothalamic–pituitary–adrenal axis dysfunction, empty sella syndrome)
• acute myocardial infarction
• congestive heart failure
• acute mesenteric ischemia
• treated with vasopressors other than NE and AVP

Baseline Characteristics

• Demographics: age 66 years, 63% male,
• Cause of septic shock: pneumonia 50%, intraabdominal infection 28%, urogenital infection 21%, catheter related infection 6%, endocarditis 3%, other 4%
• Physiologic parameters: initial MAP 52 mmHg, initial CVP 7 mmHg, SAPS3 74, SOFA 10
• Labs: total bilirubin 18 mmol/L [1.05 mg/dL], serum creatinine 118.5 mmol/L [1.34 mg/dL], lactic acid 3.6 mmol/L, procalcitonin 12.7 ng/mL, CRP 13.96 mg/mL

Interventions

• taper vasopressin first
• taper norepinephrine first

Outcomes

Comparisons are vasopressin tapered first vs. norepinephrine tapered first.

Primary Outcomes

Hypotension (MAP <65 mmHg) within one hour after tapering of vasopressor

23% vs. 68% (ARR 45%); P<0.001 NNT 2

Secondary Outcomes

Time to hypotension after tapering vasopressors, hours

4.3(2.5-5.1) vs. 2.0(1.2-2.5) p < 0.001

Total vasopressor duration, h

58.4(33.0-100) vs. 43.8(28.9-81.9) p = 0.169

ICU Mortality

37.5% vs. 28.9% (ARR 8.6%) p = 0.42

ICU Length of stay, days

9(6-13) vs. 7(2-12) p = 0.107

28 day mortality

42.5% vs. 32.4% (ARR 10.1%) p = 0.362

Hospital mortality

57.5% vs. 34.2% (ARR 23.3%) p = 0.039

Hospital length of stay, days

25(15-38) vs. 21(13-37) p = 0.542

Subgroup Analysis

Univariate Analysis, only significant variables displayed

Copeptin concentration, pg/mL

77(67 – 90) vs. 168(131 – 207) p < 0.001

Criticisms

• Single centre, limiting generalizability
• some baseline characteristics may have introduced bias in the findings
  • Vasopressin group required greater ventilation, leading to a higher mortality rate
• trial under powered to detect clinical secondary outcomes

Funding

• A grant from Samsung Medical Center (SMR112132)