Background

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Background
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Vasopressin

• endogenously released peptide hormone
• commonly adjunct to catecholamines in refractory
  septic shock
• effect on mortality ?
• Rationale relative vasopressin deficiency in
  patients with septic shock

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Hypothesis

• exogenously administered vasopressin can restore
  vascular tone and BP
• ?? the need for use of catecholamines

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Vasopressin

• Observational studies
• infusion lt 0.1 U/min in vasodilatory shock
• ? improved short-term BP
• ? may ? blood flow in the heart, kidneys, and
  intestine
• Only 2 small randomized trials
• ?BP
• ?catecholamine requirements
• improved renal function

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Our study

• Multicenter, randomized, stratified, double-blind
  trial
• Primary outcome 28-day mortality
• 2nd hypothesis
• beneficial effects of vasopressin would be
  more pronounced than those of norepinephrine in
  the subgroup more severe septic shock

15 µg or more of norepinephrine or the equivalent
per minute
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Methods
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• July 2001 April 2006
• 27 centers in Canada, Australia, and the United
  States
• approved by the research ethics boards of all
  participating institutions
• Written informed consent

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• data collected by the investigators
• analyzed by the data management committee
• The executive committee vouches for the accuracy
  and completeness of the data and analysis
• article was written by the writing committee
• decision to publish by the executive committee

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Study Patients
lack of response to 500 ml of N/S or a
requirement for vasopressors

• older than 16 y/o
• septic shock that was resistant to fluids and
  low-dose norepinephrine

Vasopressor requirement 1). 5 µg/min of
norepinephrine or equivalent for at least six
consecutive hours in the preceeding 24 hours, and
to have received at least 5 µg/min within the
last hour prior to randomization 2). high
vasopressor doses (norepinephrine equivalent gt 15
µg/hr for three consecutive hours), could be
randomized at three hours rather than at six hours
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Septic shock
Respiratory (ventilated and PaO2/FiO2 lt 300
mmHg) Renal (U.O. lt 30 mL/hour or lt 0.5 mL/kg BW,
at least one hour) Coagulation (platelet lt
80K/mm3) Neurologic (GCS lt 12, prior to receiving
sedation)
requiring vasopressor support consisting of at
least 5 µg/min of norepinephrine or the
equivalent for 6 hours

• ? 2 diagnostic criteria for SIRS
• proven or suspected infection
• new dysfunction of at least one organ
• hypotension despite adequate fluid resuscitation

Norepinephrine equivalent dose was calculated as
norepinephrine (µg/min) dopamine (µg/kg/min)
2 epinephrine (µg/min) phenylephrine
(µg/min) 10 , study of Patel et al
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Exclusion criteria

• (1) unstable coronary syndrome (AMI during this
  episode of shock)
• (2) gt 24 hours had elapsed since the patient met
  entry criteria
• (3) use of open-label vasopressin
• (4) malignancy or other irreversible disease or
  condition for which six-month mortality was
  estimated to be 50

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Exclusion criteria

• (5) acute mesenteric ischemia either proven or
  suspected
• (6) death anticipated within 12 hours
• (7) underlying chronic heart disease (NYHA class
  III or IV) and shock
• (8) physician and team were not committed to
  aggressive care

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Exclusion criteria

• (9) severe hyponatremia (lt 130 mmol/L)
• (10) traumatic brain injury (GCS lt 8 prior to
  onset of sepsis)
• (11) Raynauds phenomenon, systemic sclerosis or
  vasospastic diathesis
• (12) pregnancy (positive serum ß-HCG).

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Treatment Assignments

• central telephone randomization system
• A computer-generated randomization list
• stratified by center and by severity of shock in
  the hour before randomization
• Infusions of both study drugs ? locally by study
  pharmacists who were aware
• All others ? unaware

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Drug Infusion

• Vasopressin (30 U) and norepinephrine (15 mg)
  were mixed in identical 250-ml D5W
• Final concentrations
• vasopressin 0.12 U/ml
• norepinephrine 60 µg /ml
• started at 5 ml/hr
• increased by 2.5 ml/hr every 10 minutes during
  the first hour to achieve a constant target rate
  of 15 ml/hr

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• MAP 65 to 75 mm Hg recommended
• could modify by attending ICU physician
• Open-label vasopressors increased
• ?only if on maximal study-drug infusion
• Tapering of open-label vasopressors
• ?permitted only when MAP had been reached
• Tapering of the study drug
• ?only when MAP maintained for 8 hours without any
  open-label vasopressors

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• Infusion continued at 15 ml/hr until
• died
• a serious adverse event
• patients condition improved to the extent that
  open-label vasopressors were no longer required

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• Infusion discontinued or interrupted
• acute ST elevation (12-lead EKG)
• cardiac arrhythmias serious or life-threatening
• acute mesenteric ischemia
• digital ischemia
• hyponatremia ( lt130 mmol/L)

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• discontinued for at least 8 hours reported
• ?If an adverse event considered to be related to
  the study drug
• could be restarted if
• ?the adverse event had been treated
• ?the condition had been reversed
• ?the event was not thought to have been a result
  of the study drug or study protocol

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• If had been weaned from the study drug
• ?preferentially reinfused, as long as no
  exclusion criteria were met

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End Points

• primary outcome ? 28 days mortality
• Secondary outcomes includ
• 90-day mortality
• days alive and free of organ dysfunction during
  the first 28 days according to the Brussels
  criteria
• days alive and free of vasopressor use,
  mechanical ventilation, or renal replacement
  therapy
• days alive and free of SIRS
• days alive and free of corticosteroid use
• length of stay in the ICU and hospital

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Brussels organ dysfunction definitions
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Statistical Analysis

• 776 pts enrollment, randomization, and receipt of
  the study drug
• detect an absolute 10 difference in mortality
• assuming a mortality rate of 60 in the
  norepinephrine group
• a two-sided alpha error of 0.05 and a power of
  80
• An OBrienFleming approach
• ? sequential stopping rules for safety and
  efficacy according to the LanDeMets method

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• The primary analysis-- 28-day mortality
• ?unadjusted chisquare test
• Results
• ?absolute relative risks 95 confidence
  intervals
• KaplanMeier curves
• ?estimated probability of survival
• ?the log-rank test

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• Age, APACHE II score at baseline, serious
  coexisting conditions, and other baseline
  covariates
• Results ? as odds ratios and 95 confidence
  intervals
• compare all secondary outcomes
• ?parametric procedures (independent t-test)
• ?nonparametric procedures (Wilcoxon rank-sum
  test)
• ?or Fishers exact test

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• treatment effect assessed according to more
  severe or less severe septic shock
• ? chi-square test
• SAS software (version 9.1.3)
• two-sided P values

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Results
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Vasopressin
Norepinephrine
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norepinephrine group
vasopressin group
similar
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norepinephrine group
vasopressin group
During the first 4 days of treatment (Plt0.001)
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norepinephrine group
vasopressin group
During the first 4 days of treatment (Plt0.001)
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multivariate logistic-regression analysis (odds
ratio)
No significant difference
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No significant difference
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No significant difference
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lt 130 mmol/L
acute hepatitis, agranulocytosis, pulmonary
embolism, seizures, drug error , and two cases of
drug extravasation from the central venous
catheter
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vasopressin infusion, n 54
98.0
73.6
? vasopressin infusions had stopped
? norepinephrine group, n 53
extremely low at baseline (median, 3.2 pmol/L
interquartile range, 1.7 to 4.9)
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norepinephrine gt15µg/min
norepinephrine 5 14µg/min
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different indicators of illness severity
Moderately significant P values (P 0.04) ?a
possible advantage of vasopressin in patients
with less severe shock
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Discussion
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Our study

• NOT able to demonstrate
• ?any significant difference in the 28-day
  mortality rate
• ?any significant difference in 90-day mortality
• ?or the rate of organ dysfunction
• No difference in the rates of serious adverse
  events

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• Low-dose vasopressin (0.03 U/min)
• ?allowed a rapid decrease in the total
  norepinephrine dose while maintaining MAP

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• Observed mortality rates
• ?considerably lower than previous studies
• ?perhaps overall improvements in the care
• ?Data exclude with 95 confidence, associated
  with the use of vasopressin
• a harm gt 2.9 or
• a benefit gt 10.7

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2nd hypothesis

• beneficial effects of vasopressin as compared
  with norepinephrine would be more pronounced in
  the subgroup of patients with more severe septic
  shock
• ?No significant interaction

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• Vasopressin may be more beneficial in less severe
  septic shock
• ?significance is uncertain
• ?should be considered only as a
  hypothesis-generating concept to be tested in
  future trials

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Several limitations

• Vasopressin
• ?infused over a set range of doses
• ?did not measure its levels as a guide to the
  dose or the duration of infusion
• Baseline MAP 72 73 mm Hg
• ?effects of low-dose vasopressin as a
  catecholamine-sparing drug
• ?NOT an evaluation of vasopressin in pts with
  catecholamine-unresponsive refractory shock

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• Mean time from meeting inclusion criteria to
  study drug infusion
• ?12 hours
• ?greater than 6 hours (early goal-directed
  therapy)
• ?may be one reason that we did not find a benefit
  of vasopressin as compared with norepinephrine

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Summary

• Low-dose vasopressin did NOT reduce mortality
  rates as compared with norepinephrine among
  patients with septic shock who were treated with
  catecholamine vasopressors