VASST

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Russel JA, et al. "Vasopressin versus norepinephrine infusion in patients with septic shock". The New England Journal of Medicine. 2008. 358(9):877-887.
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Clinical Question

Among patients with septic shock on a catecholamine vasopressor, does addition of low-dose vasopressin reduce all-cause mortality at 28 days when compared to addition of norepinephrine?

Bottom Line

Among patients with septic shock on a catecholamine vasopressor, addition of low-dose vasopressin did not reduce all-cause mortality at 28 days when compared to addition of norepinephrine.

Major Points

Septic shock is a major cause of morbidity and mortality in critically ill patients. Treatment focuses on early administration of antibiotics and maintaining blood pressure above a MAP of 65 mmHg with 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.[1] However, this vasoconstriction may result in decreased organ perfusion, which can be particularly detrimental in the setting of cardiac ischemia. Despite its popularity as a medication, the safety and efficacy of vasopressin had not been demonstrated in a large clinical trial.

The 2008 Vasopressin and Septic Shock Trial (VASST) randomized 779 patients with septic shock resistant to fluids being treated with low-dose norepinephrine to norepinephrine or low-dose vasopressin to maintain a MAP of 65-75 mmHg. Open label vasopressors were added as needed. Patients with unstable coronary syndrome or NYHA class III or IV HF were excluded. Groups were similar at baseline except for an older age of the norepinephrine group and higher rate of hematologic abnormalities and cumulative organ dysfunction in the vasopressin group. At 28 days there was no difference in the primary outcome of all-cause mortality. Groups did not differ significantly for multiple secondary outcomes including organ dysfunction and length of stay in the ICU and hospital. There were no differences in adverse events. A subgroup analysis suggested a survival benefit for vasopressin in less severe sepsis at 28 days (35.7% vs. 26.5%; NNT 11) and 90 days (46.1% vs. 35.8%; NNT 10) but not for more severe sepsis. The authors suggest that this outcome be used for hypothesis-generation rather than to guide clinical therapy.

VASST has several limitations. Its power calculation was based on an expected mortality of 60%. The lower mortality rate observed in the trial resulted in it being underpowered. As interventions early in the course of sepsis dramatically change mortality outcomes (as seen in the 2001 Rivers Trial), the 12 hour randomization delay limited ability to detect a survival benefit with the intervention. As the baseline MAPs averaged above 65 mmHg, this trial examined the use of vasopressin as a catecholamine-sparing agent rather as an adjunctive therapy in refractory sepsis.

The use of catecholamines in septic shock was further explored in the 2010 SOAP II trial, which compared dopamine and norepinephrine.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[2]

  • During the initial resuscitation, target MAP of 65 mm Hg in patients with septic shock needing vasopressors
  • Recommend norepinephrine as first-line vasopressor (strong recommendation, moderate quality of evidence)
    • Can add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to norepinephrine to achieve MAP targets
    • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, low quality of evidence)
  • Recommend against using low-dose dopamine for renal protection (strong recommendation, high quality of evidence)
  • Suggest using dobutamine in patients with persistent hypoperfusion despite adequate fluid loading and vasopressor agent use (weak recommendation, low quality of evidence)

Design

  • Multicenter, randomized, double-blind, controlled trial
  • N=779
    • Norepinephrine 5-15 mcg/min (n=382)
    • Vasopressin 0.01-0.03 U/min (n=397)
  • Setting: 27 centers in Canada, Australia, and the US
  • Enrollment: 2001-2006
  • Mean follow-up: 90 days
  • Analysis: Per-Protocol
  • Primary outcome: All-cause mortality 28 days after infusion initiation

Population

Inclusion Criteria

  • Age >16 years
  • Septic shock resistant to fluids
    • Septic shock defined by:
      • ≥2 SIRS criteria
      • Suspected or proven infection
      • New organ dysfunction
      • Hypotension despite fluids requiring vasopressors of norepinephine ≥5/min or an equivalent vasopressor
    • Resistance to fluids defined by one of the following:
      • Lack of response to NS 500 mL
      • Requirement for vasopressors
  • Low-dose norepinephrine

Exclusion Criteria

  • Unstable coronary syndrome
  • >24 hours since meeting entry criteria
  • Use of vasopressin for BP support during the current admission
  • Malignancy or other medical condition with six-month mortality ≥50%
  • Proven or suspected acute mesenteric ischemia
  • Likely death in next 12 hours
  • Underlying NYHA class III or IV and shock
  • Medical team not committed to aggressive care
  • Sodum <130 mmol/L
  • Traumatic brain injury with GCS <8 before sepsis onset
  • Raynaud's phenomenon, systemic sclerosis, or vasospasm
  • Pregnancy

Baseline Characteristics

Norepinephrine group shown. Groups were similar. Comparisons are norepinephrine vs. vasopressin.

  • Demographics: Age 62 vs. 60 years (P=0.03), male 60%, White race 84%
  • PMH: Ischemic heart disease 17%, HF 8%, COPD 19%, CKD 13%, DM 23%, liver disease 9%, alcoholism 14%, IVDU 4%, cancer 27%, immunocompromised 19%, recent trauma 4%
  • PSH: Solid organ transplant 4%
    • Recent surgery: 35% (elective 2%, emergent 33%)
  • Acute illness specifics: APACHE II score 27
    • Organ failure: CV 100%, respiratory 89%, renal 67%, hematologic/coagulation 22% vs. 30% (P=0.02), neurologic 23%
      • Number of organ systems failed: 3.4 vs. 3.5 (P=0.04)
    • Infection source: 43%, abdomen 26%, other 31%
    • Cultured pathogen: Gram positive only 15%, gram negative only 11%, mixed organism 36%, other 13%, no pathogen 23%
  • Baseline medications: Corticosteroids 23% (77% received sepsis-directed corticosteroids), activated protein C 15%
  • Vasoactive drug at randomization:
    • Norepinephrine: 0.28 ug/kg/min
    • Epinephrine: 0.12 ug/kg/min
    • Dopamine: 7.3 ug/kg/min
    • Dobutamine: 5.1 ug/kg/min
    • Milrinone: 0.4 ug/kg/min
    • Phenylephrine: 2.03 ug/kg/min
    • Norepinephrine alone: 58% (no norepinephrine 14%)
    • ≥2 vasopressors 29%
  • Baseline health data: BP 110/73 (MAP 85), ABG pH 7.31, lactate 3.5
  • Tidal volume 7% mL/kg
  • Time from meeting inclusion criteria to receipt of study medication: 11.5 hours

Interventions

  • Randomized to a group:
    • Norepinephrine - Titration of 5-15 micrograms norepinephrine to maintain MAP 65-75 mmHg
    • Vasopressin - Titrated doses of 0.03-0.05 U vasopressin to maintain MAP 65-75 mmHg
  • Open label vasopressors were titrated to achieve target MAP if maximum dose of study-drug reached.
  • Study drug was weaned only when target MAP was achieved for 8 hours without open label vasopressors.
  • Study drug was continued until patient died, a serious adverse event occurred or patient's clinical condition improved to the point vasopressors were not required.

Outcomes

Presented as norepinephrine vs. vasopressin. RR is relative risk.

Primary Outcome

All-cause mortality 28 days after infusion initiation
39.3% vs. 35.4% (RR 0.90; 95% CI 0.75-1.08; P=0.26)

Secondary Outcomes

All-cause mortality 90 days after infusion initiation
49.6% vs. 43.9% (RR 0.88; 95% CI 0.76-1.03; P=0.11)
Days alive
Free of organ dysfunction
CV: 17 vs. 19 days (P=0.58)
Vasopressor use: 17 vs. 19 days (P=0.61)
Respiratory: 2 vs. 3.5 days (P=0.15)
Ventilation (intubation with PPV): 6 vs. 8.5 days (P=0.24)
Renal: 18.5 vs. 21.5 days (P=0.54)
RRT: 23 vs. 25 days (P=0.64)
Hepatic: 24.5 vs. 25 days (P=0.80)
Neurologic: 15 vs. 15 days (P=0.57)
Free of any organ failure: 0 vs. 0 days (P=0.14)
Free of SIRS: 6 vs. 6 days (P=0.21)
Free of corticosteroid use: 13.5 vs. 16 days (P=0.33)
Length of stay
ICU: 16 vs. 15 days (P=0.14)
Hospital: 26 vs. 27 days (P=0.23)

Subgroup Analysis

Mortality
More severe sepsis
Requiring norepinephrine ≥ 15 ug/minute or equivalent dosing at randomization.'
At day 28: 42.5% vs. 44.0% (RR 1.04; 95% CI 0.83-1.30; P=0.76)
At day 90: 52.8% vs. 51.8% (RR 0.98; 95% CI 0.81-1.18; P=0.84)
Less severe sepsis
Requiring norepinephrine 5-14 ug/minute or equivalent dosing at randomization.
At day 28: 35.7% vs. 26.5% (RR 0.74; 95% CI 0.55-1.01; P=0.05; NNT 11)
At day 90: 46.1% vs. 35.8% (RR 0.78; 95% CI 0.61-0.99; P=0.04; NNT 10)
Test for heterogeneity P=0.10
Plasma vasopressin levels
Of the 179 participants (53 norepinephrine, 126 vasopressin) with these data collected.
Baseline, both group: 3.2 pmol/L
6 hours: No change vs. 73.6 pmol/L
24 hours: No change vs. 98.0 pmol/L

Adverse Events

Norepinephrine group/Vasopressin group
≥1 serious event: 10.5% vs. 10.3%(P=1.00)
Acute MI: 1.8% vs. 2.0% (P=1.00)
Cardiac arrest: 2.1% vs. 0.8% (P=0.14)
Life-threatening arrhythmia: 1.6% vs. 2.0% (P=0.79)
Mesenteric ischemia: 3.4% vs. 2.3% (P=0.39)
Hyponatremia: 0.3% vs. 0.3% (P=1.00)
Digital ischemia 0.5% vs. 2.0% (P=0.11)
CVA 0.3% vs. 0.3% (P=1.00)
Other 0.5% vs. 1.3% (P=0.45)

Criticisms

  • Lower mortality rate than expected suggests a selection bias[1]
  • Underpowered given lower-than-expected mortality[3][4][5]
  • Exclusion of patients with HF or ischemic heart disease (groups that may experience increased mortality from vasopressin) so unclear safety in patients with these conditions[1][5]
  • Average MAPs at baseline were >65 mmHg so vasopressin was used as a catecholamine-sparing agent rather than as an adjunct treatment for individuals with catecholamine-resistant shock[1]
  • Prolonged time from meeting inclusion criteria to randomization[1][4]
  • Unclear effect of higher doses of vasopressin[3]
  • As the detrimental effects of catecholamine agents occur at higher infusion rates than were studied in this trial, it's unclear if vasopressin may have had a mortality benefit in those with higher vasopressor requirements[3]
  • The population had acceptable responses to norepinephrine so unlikely that they would derive benefit from vasopressin[4]
  • Did not address vasopressin monotherapy versus norepinephrine monotherapy as initial treatment[4]
  • Only 12.5% of screened patients were included[5]
  • No reporting of fluid and antibiotic administration before randomization[5]

Funding

  • Canadian Institutes of Health Research
  • Multiple disclosures, including several patents related to vasopressin and its use in septic shock

Further Reading

  1. 1.0 1.1 1.2 1.3 1.4 Parrillo JE. "Editorial: Septic shock -- Vasopressin, norepinephrine, and urgency." The New England Journal of Medicine. 2008;358:954-956.
  2. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  3. 3.0 3.1 3.2 Multiple authors. "Correspondence: Vasopressin in septic shock." The New England Journal of Medicine. 2008;358:2736-2738.
  4. 4.0 4.1 4.2 4.3 Maki DG. "Low-dose vasopressin did not reduce mortality more than norepinephrine in septic shock." ACP Journal Club. 2008;149(3):14
  5. 5.0 5.1 5.2 5.3 Keyes R and Brindley PG. "Vasopressin in septic chock: Pressing questions remain." Canadian Journal of Anesthesiology. 2009;56:80-82.