vasopresina efectos adversos

7/27/2019 Vasopresina efectos adversos

1/9

1812 www.ccmjournal.org August 2014 Volume 42 Number 8

Objective:The frequency, risk factors, and mortality rates of seri-

ous adverse events associated with the use of vasopressin and

norepinephrine are not clear. The objectives of this study were to

determine frequency, risk factors (including candidate gene poly-

morphisms), and outcomes of serious adverse events in septicshock patients.

Design:Retrospective cohort study using multicenter discovery

and single-center validation cohorts.

Setting:ICUs at academic teaching centers.

Patients:Five hundred ninety-seven patients with septic shock in

discovery (Vasopressin and Septic Shock trial) and 533 patients

in validation (St. Pauls Hospital) cohorts.

Intervention:Vasopressin and norepinephrine for septic shock.

Measurements and Main Results: The primary outcome variable

was 90-day mortality rates of patients with and without serious

adverse events. Secondary outcome variables were the association

between vasopressor genotype pathway polymorphisms, plasma

vasopressin levels, and serious adverse events. Plasma vasopres-

sin concentrations were measured at baseline, 6 hours, 24 hours,

72 hours, and 7 days after vasopressor infusion. Patients with sep-

tic shock were genotyped for 268 vasopressor pathway tag sin-gle-nucleotide polymorphisms. Serious adverse events occurred

in 10.5% and 9.7% of patients in Vasopressin and Septic Shock

trial and St. Pauls Hospital cohorts, respectively. Patients who

had serious adverse events had higher mortality (p< 0.01) than

patients without serious adverse events (adjusted for age, serum

lactate, Acute Physiology and Chronic Health Evaluation II, and

maximum dose of norepinephrine day 1) (hazard ratio, 2.97;

95% CI, 2.204.00;p< 0.001 and hazard ratio, 1.89; 95% CI,

1.262.85;p= 0.002 in Vasopressin and Septic Shock trial and

St. Pauls Hospital, respectively). There was no difference in the

area under the plasma vasopressin concentration curve between

patients with and without serious adverse events (p= 0.1). TheAA genotype of rs28418396 single-nucleotide polymorphism

(near the arginine vasopressin receptor 1b gene) was signicantly

associated with serious adverse events in discovery and valida-

tion cohorts (p= 0.001 andp= 0.04, respectively).

Conclusion:Serious adverse events associated with vasopres-

sin and norepinephrine in patients who have septic shock are

associated with increased mortality and morbidity. AA genotype

of rs28418396 single-nucleotide polymorphism near the arginine

vasopressin receptor 1b gene is associated with serious adverse

events. The mechanism of this association requires investigation.

(Crit Care Med2014; 42:18121820)

Key Words: arginine vasopressin receptor 1b; norepinephrine;septic shock; serious adverse events; vasopressin

In the latest surviving sepsis guidelines, norepinephrine

(NE) is recommended as first vasopressor and vasopres-sin can be added to NE with intent of either raising mean

arterial pressure (MAP) or decreasing NE dosage (1). However,

these commonly used vasopressors are associated with serious

adverse events (SAEs) (2). Although the hemodynamic status

may be improved by vasopressors, several studies of vasopres-

sin and NE infusions found the prevalence of adverse drug

Copyright 2014 by the Society of Critical Care Medicine and LippincottWilliams & Wilkins

DOI: 10.1097/CCM.0000000000000333

*See also p. 1944.

1Centre for Heart Lung Innovation, St. Pauls Hospital, Vancouver, BC,Canada.

2Division of Critical Care Medicine, St. Pauls Hospital, University of BritishColumbia, Vancouver, BC, Canada.

Registration: ISRCTN94845869.

Supplemental digital content is available for this article. Direct URL cita-tions appear in the printed text and are provided in the HTML and PDFversions of this article on the journals website (http://journals.lww.com/ccmjournal).

Supported, in part, by VASST, Canadian Institutes of Health Research

(grant number: MCT 44152).Dr. Boyd is a recipient of a Providence Health Care Research Scholar -ship. Dr. Walley is employed by the University of British Columbia and hasstock options with Sirius Genomics. His institution received grant supportfrom the University of British Columbia and Canadian Institutes of HealthResearch. Dr. Russell served as board member for Sirius Genomics; con-sulted for Ferring Pharmaceutical, Grifols, Medimmune, and Astra Zeneca;lectured for Pzer; has a patent with the University of British Columbia andSirius Genomics; and has stock options with Sirius Genomics. His institu-tion received grant support from Ferring Pharmaceutical, Astra Zeneca,Sirius Genomics, and Eli Lilly. Dr. Anantasit has disclosed that he does nothave any potential conicts of interest.

For information regarding this article, E-mail:[email protected]

Serious Adverse Events Associated With Vasopressin

and Norepinephrine Infusion in Septic Shock*

Nattachai Anantasit, MD1; John H. Boyd, MD, FRCP(C)1,2; Keith R. Walley, MD, FRCP(C)1,2;

James A. Russell, MD, FRCP(C)1,2
http://journals.lww.com/ccmjournalhttp://journals.lww.com/ccmjournalmailto:[email protected]:[email protected]://journals.lww.com/ccmjournalhttp://journals.lww.com/ccmjournal


2/9

Clinical Investigations

Critical Care Medicine www.ccmjournal.org 1813

events ranged from 10% to 72% (36). SAEs of vasopressors

include arrhythmias, chest pain, myocardial infarction, cardiac

arrest, decreased cardiac output, stroke, limb ischemia, mesen-

teric ischemia, and water intoxication (711). SAEs occurred in

about 10% of patients in a randomized controlled trial of vaso-

pressin versus NE (Vasopressin and Septic Shock trial, VASST),

with no difference in frequency between treatment groups (5).

The risk of these SAEs in VASST has not yet been investigated.SAEs can lead to death, but it is not well understood whether

and to what extent patients who have SAEs associated with

vasopressin and NE have an increased risk of death.

In addition, SAEs associated with vasopressin or NE infu-

sion in patients with septic shock can be difficult to predict.

Clinical markers, vasopressin levels, and pharmacogenomic

markers could identify patients who have an increased risk

of SAEs and the clinician can then avoid or discontinue that

drug. Genetic single-nucleotide polymorphisms (SNPs)

are important identifiable risk factors in patients who may

develop SAEs (12).

Limited lists of candidate genes in the vasopressin and NEpathways modulate their actions and so could be candidates

for evaluation as SNPs predictive of SAEs associated with vaso-

pressin and NE. Vasopressin stimulates a family of receptors

including arginine vasopressin receptor (AVPR)1a (V1 recep-

tor), AVPR1b (V3 receptor), AVPR2 (V2 receptor), oxytocin

receptor, and purinergic receptors (13). Vasopressinase (leucyl/

cystinyl aminopeptidase, LNPEP) is associated with mortality

and increased vasopressin clearance in septic shock patients

(14). NE stimulates adrenergic receptors. The -adrenergic

receptor gene (ADR) plays an important role in cardiovascular

disease and SNPs of ADR have been associated with mortality

of septic shock (15). Furthermore, the angiotensin II signalingpathway gene polymorphisms are associated with outcomes in

cardiovascular disorders (16). An angiotensin II type 1 recep-

torassociated protein (AGTRAP) polymorphism is associated

with mortality in patients with septic shock (17).

Our overarching goal was to determine the mortality rate of

SAEs associated with vasopressin and NE infusion in patients

who have septic shock. We also sought to determine whether

commonly available clinical characteristics are associated with

an increased risk of developing SAEs. Finally, we hypothesized

that SNPs of candidate genes of the vasopressin and NE path-

ways and/or plasma arginine vasopressin (AVP) levels could

predict SAEs in patients who had septic shock who receivedvasopressin versus NE infusions.

MATERIALS AND METHODS

Patients

VASST Cohort. We used the VASST cohort as the discov-

ery cohort because VASST was a multicenter, randomized,

double-blind, controlled trial evaluating the safety and efficacy

of vasopressin 0.010.03 U/min versus NE 515 g/min in a

total of 778 patients with septic shock. Entry criteria required

that eligible patients were older than 16 years, had two of four

criteria for systemic inflammatory response syndrome (SIRS),

had a new proven or suspected infection, had new dysfunction

of at least one new organ dysfunction, and had hypotension

despite adequate fluid resuscitation on a minimum of 5 g/

min of NE at baseline (5). During the initiation and titration

of the study drug, the bedside nurse also titrated open-label

vasopressors to maintain a constant target MAP. An initial tar-

get MAP of 6575 mm Hg was recommended. Of these, 597

patients had complete patient data, DNA available, and wereincluded in the current study. The research ethics boards of

all participating institutions approved this trial, and writ-

ten informed consent was obtained from all patients or their

authorized representatives. The research ethics board at the

coordinating center (University of British Columbia) approved

the genetic analysis.

St. Pauls Hospital Cohort.We used the St. Pauls Hospi-

tal (SPH) cohort as a validation cohort because it included

patients in whom vasopressin and NE were used in prac-

tice. However, vasopressin and NE use were not randomized,

blinded, or protocolized. We did a retrospective chart review

of patients who admitted at SPHICU with septic shock. Septicshock was defined by infection, the presence of two or more

diagnostic criteria for the SIRS, and hypotension despite ade-

quate fluid resuscitation or requiring vasopressor (18). Vaso-

pressin was generally used after patients were already started

on NE infusions (as first vasopressor) usually, when patients

were not responsive and needed increased doses of vasopressin.

There was no difference in use of vasopressin over the 5 years.

Patients admitted to the ICU of SPH in Vancouver, Canada,

between July 2000 and January 2004 were screened (n= 1,626).

Of these, 533 patients had septic shock at admission, were

extensively phenotyped, and had DNA available. Phenotyping

and genotyping were not part of routine practice at SPH. Theinstitutional review board at SPH and the University of British

Columbia approved the study. This study used discarded blood

and anonymized databases, and so the ethics board ruled that

consent was not necessary.

Definitions

SAEs were defined as any severe, life-threatening event tem-

porally associated with the use of vasopressin or NE. Acute

myocardial ischemia was defined by serum cardiac troponin

T above normal plus electrocardiogram (ECG) findings sug-

gesting myocardial ischemia as interpreted by clinical cardi-

ologists interpreting ECGs. Tachyarrhythmia was defined as anew onset of atrial fibrillation. Bradyarrhythmia was defined

as a new heart rate below 50 beats/ min which require rapid

intervention. Cardiac arrest defined as asystole, ventricular

fibrillation, or pulseless electrical activity. Digital ischemia was

defined as the occurrence of new areas of mottled or livido

skin in one or more extremities (4). Mesenteric ischemia was

defined by evidence of radiographic signs of ischemic bowel

on abdominal radiograph as interpreted by clinical radiolo-

gists. Cerebrovascular accident was defined as new neurologic

deficit and acute cerebral infarct or hemorrhage on CT brain.

Hyponatremia was defined as a serum sodium level of less than

130 mmol/L.


3/9

Anantasit et al


We evaluated organ dysfunction by calculating days aliveand free (DAF) of organ dysfunction (19). Organ dysfunction

for each organ system was considered to be present duringeach 24-hour period if there was evidence of moderate, severe,

or extreme organ dysfunction according to the Brussels cri-teria (20). Each day a patient was given 1 if alive and free of

organ dysfunction and zero if dead or had organ dysfunction.

We also similarly assessed DAF ventilation, vasopressors, andrenal support over 28 days. The lowest score possible for eachvariable was zero and the highest score possible was 28. A low

score indicates more organ dysfunction, whereas a high scoreindicates less organ dysfunction.

Plasma Vasopressin Levels

Blood for measurement of plasma vasopressin levels was col-lected at baseline, 6 hours, 24 hours, 72 hours, and 7 days in

VASST. Plasma vasopressin concentration was measuredafter extraction on reversed phase column by double anti-

body immunoassay (5). This subgroup of 88 patients who

had plasma vasopressin concentrations measured (n= 45 invasopressin group and n= 43 in NE group) had similar clini-cal characteristics to the original VASST cohort (subgroup vs

original VASST cohort, median age [yr]: 62 vs 63; male [%]:60.2 vs 60.9; Acute Physiology and Chronic Health Evalua-

tion II [APACHE II]: 26 vs 27; serum lactate [mmol/L]: 2.1vs 2.2). We calculated the area under the plasma vasopressin

concentration-time curve (AUC of the vasopressin levels) ofeach patient for later group comparisons.

Selection of SNPs of Vasopressin and NE Pathway

and Genotyping

DNA was extracted from the buffy coat of discarded bloodsamples using a QIAamp DNA maxi kit (Qiagen, Mississauga,

ON, Canada) and genotyped using the Illumina Golden Gateassay (Illumina, San Diego, CA). We used genotyping data

from Seattle SNPs (http://pga.gs.washington.edu/) and Hap-Map (http://www.hapmap.org/ ) with an r2 threshold of 0.65

for SNPs with a minor allele frequency more than 5% to iden-tify tag SNPs. We identified four tag SNPs (AGTRAP) and 16

tag SNPs (ADR) in NE pathway and three tag SNPs (AVPR1a),

five tag SNPs (AVPR1b), 237 tag SNPs (LNPEP), and three tagSNPs (OXTR) in the vasopressin pathway.

Primary and Secondary Outcomes

The primary outcome was 90-day mortality, and we compared

the mortality rates of patients who did or did not have a SAE.We also evaluated whether baseline clinical characteristics dif-

fered between patients with or without SAEs. Finally, we alsodetermine whether plasma vasopressin levels and SNPs related

to vasopressin and NE were associated with SAEs.

Statistical Analysis

Statistical analysis was performed using R, version 2.8.1 (http://www.R-project.org), and SPSS, version 16 (SPSS, Chicago, IL)statistical software packages. We compared patients who had

developed SAEs with no SAEs and tested for differences inbaseline characteristics and hospital outcomes including DAF

of organ dysfunction by using the Mann-Whitney Ustatistictest for continuous data or a chi-square test for categorical data.

Normally distributed continuous variables were described bymean and SD, whereas nonnormally distributed continuous

variables were expressed by median and interquartile ranges.Categorical variables were expressed as number of patients and

percentage. We tested for Hardy-Weinberg equilibrium using a

chi-square test primarily as a data quality check. The Armitagetrend test was used for evaluation of the association of SNPs

TABLE 1.Serious Adverse Events in Discovery (Vasopressin and Septic Shock Trial) andValidation (St. Pauls Hospital) Cohorts

VariableVasopressin and Septic Shock

Trial Cohort (n= 597) (%)St. Pauls Hospital Cohortc

(n= 533) (%) p

Myocardial ischemia 12 (2) 14 (2.6) 0.49

Tachyarrhythmias 6 (1) 14 (2.6) 0.039a

Bradyarrhythmias 7 (1.2) 10 (1.9) 0.332

Cerebrovascular accident 2 (0.3) 7 (1.3) 0.093

Unexpected cardiac arrest 7 (1.2) 3 (0.6) 0.349

Digital ischemia 8 (1.3) 3 (0.6) 0.184

Mesenteric ischemia 14 (2.3) 2 (0.4) 0.005a

Hyponatremia 2 (0.3) 0 0.501

Othersb 6 (1) 0 0.032a

Total 63 (10.6) 52 (9.7) 0.658

ap


4/9



with presence or absence of SAEs. Kaplan-Meier curves wereconstructed for comparison of the estimated probability of

survival in the two outcome groups and were tested for differ-ence using the log-rank test. We also did an analysis comparing

SAE versus no SAE adjusting for important baseline variablesusing Cox regression analysis. The occurrence of SAE dur-

ing hospital stay was considered a time-dependent covariate

in the analysis. We tested the above hypotheses in the discov-ery cohort and then took forward only those baseline clinicalcharacteristics and SNPs that were significant in the discovery

cohort for further evaluation in the validation cohort. In allcomparisons,pvalue of less than 0.05 was considered statisti-

cally significant.

RESULTSThe frequency of SAEs was similar in the discovery and vali-

dation cohorts (Table 1). There were 64 SAEs in 63 patients(10.7% of the VASST cohort) and 53 events in 52 patients

(9.9% of the SPH cohort). Mesenteric ischemia (2.3%) was the

most common SAE in VASST, whereas myocardial ischemia

and tachyarrhythmias (2.6%) were the most common SAEs in

SPH (Table 1).

We found that similar proportions of patients on vaso-

pressin versus NE in the discovery and validation cohorts had

SAEs. In VASST, 33 of 304 patients who received vasopressin

(AVP group) (10.8%) had SAEs and 30 of 293 patients whoreceived NE (NE group) (10.2%) had SAEs. Similarly, in SPH,

14 of 111 patients in AVP group (12.6%) and 38 of 422 patients

in NE group (9%) had SAEs.

In VASST, patients who had developed SAEs were sig-

nificantly older (69 vs 63 yr, p= 0.045) and had a higher ini-

tial arterial lactate level (2.8 vs 2.2 mmol/L, p= 0.035) than

patients who did not develop SAEs. In addition, patients who

had SAEs received significantly higher (median) NE dose on

day 1 than patients without SAEs (20 g/min vs 15 g/min,

p= 0.016) (Table 2). In the SPH cohort, patients who had SAEs

TABLE 2.Baseline Characteristics of Patients With or Without Serious Adverse EventsWith Septic Shock in the Discovery (Vasopressin and Septic Shock Trial) and Validation(St. Pauls Hospital) Cohorts

Variable

Vasopressin and Septic ShockTrial Cohort

St. Pauls HospitalCohort

No SAE(n= 534)

Any SAE(n= 63) p

No SAE(n= 481)

Any SAE(n= 52) p

Age, yr 63 (5072) 69 (5475) 0.045a 62 (4772) 64 (4873) 0.341

Gender: male, n(%) 320 (59.9) 33 (52.4) 0.249 307 (63.8) 31 (59.6) 0.549

Race: Caucasian, n(%) 449 (84.1) 51 (81.0) 0.524 374 (77.8) 42 (80.8) 0.618Acute Physiology and Chronic Health Evaluation II 26 (2232) 28 (2334) 0.100 26 (2132) 29 (2434) 0.035a

Use vasopressor: NE 263 (49.3%) 30 (47.6%) 0.806 384 (79.8%) 38 (73.1%) 0.254

Maximum dose of NE on day 1 (g/min) 15 (926) 20 (1134) 0.016a 12 (525) 15 (625) 0.593

Preexisting condition, n(%)

Congestive heart failure 44 (8.2) 2 (3.2) 0.154 27 (5.6) 5 (9.6) 0.226

Chronic obstructive lung disease 97 (18.2) 8 (12.7) 0.281 78 (16.2) 10 (19.2) 0.578

Chronic renal failure 62 (11.6) 3 (4.8) 0.099 33 (6.9) 2 (3.8) 0.562

Liver disease 57 (10.7) 11 (17.5) 0.109 50 (10.4) 6 (11.5) 0.798

Chronic corticosteroid use 114 (21.3) 8 (12.7) 0.107 28 (5.8) 3 (5.8) 1Initial hemodynamic

Mean arterial pressure (mm Hg) 55 (5061) 56 (4863) 0.876 54 (5059) 54 (5060) 0.659

Heart rate (beats/min) 126 (110140) 130 (112142) 0.146 115 (95130) 105 (90130) 0.024a

Serum lactate (mmol/L) 2.2 (1.44.3) 2.8 (1.95.5) 0.035a 2.3 (1.44.7) 2.9 (2.05.6) 0.054

rs28418396_AVPR1B

TT/TA 150 (28.1%) 8 (12.7%) 0.009a 134 (27.9%) 6 (11.5%) 0.011a

AA 384 (71.9%) 55 (87.3%) 347 (72.1%) 46 (88.5%)

SAE = serious adverse event, NE = norepinephrine.ap< 0.05.

Data are median (interquartile range) for continuous variables.pvalues were calculated with the use of Pearson chi-square test and Mann-Whitney Utest.


5/9

Anantasit et al


had higher APACHE II than patients who did not have SAEs

(29 vs 26, p= 0.035) and had lower heart rates (105 vs 115,

p= 0.024) (Table 2). There were no other significant differ-

ences between groups.

Regarding timing of SAEs (Supplemental Table 1,

Supplemental Digital Content 1, http://links.lww.com/CCM/

A913), the mean time of SAEs after onset of vasopressor

infusion was similar in the vasopressin and NE groups andranged from 0 to 26 days. Time to SAE in the VASST and SPH

cohorts is shown in Supplemental Figure 1(Supplemental

Digital Content 2, http://links.lww.com/CCM/A914). Nearly

all SAEs occurred within 10 days of onset of shock treat-

ment. There was no difference in time to SAE according

to treatment group (vasopressin vs NE) in the VASST or

SPH cohorts (Supplemental Fig. 2, Supplemental Digital

Content 3, http://links.lww.com/CCM/A915; Supplemental

Fig. 3, Supplemental Digital Content 4, http://links.lww.

com/CCM/A916).

Overall, 90-day mortality rates were 44.5% and 54.4% in

VASST and SPH cohorts, respectively. Patients who had SAEs

had higher 90-day (and 28-day) mortality rates (Fig. 1) and

had greater organ dysfunction (cardiovascular, vasopressor use,

ventilation, renal replacement, neurologic, hematologic, and

hepatic) (Table 3). Cox regression analysis to adjust for clinicalvariables significantly associated with SAEs (age, serum lactate,

APACHE II, and maximum dose of NE on day 1) confirmed that

patients who had serious events had higher mortality at 90 days

(hazard ration [HR], 2.97; 95% CI, 2.204.00;p< 0.001 and HR,

1.89; 95% CI, 1.262.85;p= 0.002 in the whole VASST cohort

[n = 779] and SPH, respectively) than patients without SAEs

even after adjusting for these prognostic factors. Cox regression

analysis to adjust for clinical variables significantly associated

with SAEs (age, serum lactate,

APACHE II, maximum dose of

NE on day 1, and AA genotype

of rs 28418396) confirmed thatpatients who had serious events

had higher mortality at 90 days

(HR, 1.654; 95% CI, 1.152.39;

p = 0.007 and HR, 2.08; 95%

CI, 1.373.14; p < 0.001 in

VASST and SPH, respectively)

than patient without SAEs.

Furthermore, Cox regression

analysis to adjust for clinical

variables significantly associated

with SAEs (age, serum lactate,

APACHE II, maximum doseof NE on day 1, and any SAE)

confirmed that patients who

had AA genotype of rs28418396

had higher mortality at 90 days

(HR, 1.41; 95% CI, 1.061.88;

p= 0.018 and HR, 1.53; 95% CI,

1.132.07; p = 0.006 in VASST

and SPH, respectively) than

patient who had TA/TT geno-

type of rs28418396.

Comparing the vasopres-

sin with NE groups in VASSTand then in SPH, patients with

SAEs had higher mortality and

fewer DAF of organ dysfunc-

tion in most comparisons except

for the vasopressin group in

SPH (Supplemental Table 2,

Supplemental Digital Content

5, http://links.lww.com/CCM/

A917).

The area under the curve of

plasma vasopressin concentra-

tion was not different between

Figure 1.Kaplan-Meier survival curves of septic shock patients who had developed any serious adverse events(SAEs) compared with septic shock patients who had not developed SAEs in both discovery (Vasopressin and

Septic Shock trial, VASST) and validation (St. Pauls Hospital, SPH) cohorts.
http://links.lww.com/CCM/A913http://links.lww.com/CCM/A913http://links.lww.com/CCM/A914http://links.lww.com/CCM/A915http://links.lww.com/CCM/A916http://links.lww.com/CCM/A916http://links.lww.com/CCM/A917http://links.lww.com/CCM/A917http://links.lww.com/CCM/A917http://links.lww.com/CCM/A917http://links.lww.com/CCM/A916http://links.lww.com/CCM/A916http://links.lww.com/CCM/A915http://links.lww.com/CCM/A914http://links.lww.com/CCM/A913http://links.lww.com/CCM/A913


6/9



patients with and without SAEs (Fig. 2). As expected, the AUC

of AVP level showed that patients in NE group had much lower

AUC than those in the vasopressin group (Fig. 2).

We successfully genotyped 268 tag SNPs in vasopressor path-

way genes in VASST cohort. All SNPs were in Hardy-Weinberg

equilibrium. In VASST, nine SNPs were significantly associated

with SAEs (Table 4). Of these, only rs28418396 was also signifi-

cant in the validation (SPH) cohort. We found that patients who

had AA genotype of rs28418396 in NE group were statistically

significant increased risk of SAEs in both cohorts (p= 0.001 in

VASST discovery cohort, which is significant after Bonferroni

correction; p= 0.04 in SPH validation cohort, single SNP vali-dation so not corrected in validation cohort) (Fig. 3).

An adjusted analysis (multiple logistic regression) in the

discovery cohort (VASST) using age, APACHE II, arterial lac-

tate, and maximum dose of NE on day 1 as covariates showed

that patients who had the AA genotype of rs28418396 SNP had

significantly more SAEs than patients who had TA/TT geno-

types (AA vs TA/TT, VASST: adjusted odds ratio [OR], 2.27;

95% CI, 1.034.98; p= 0.041). Logistic regression analysis for

SAEs in SPH validated that patients who had AA genotype of

rs28418396 had greater risk of SAEs than patients who had TT/

TA genotypes of rs28418396 (AA vs TT/TA, adjusted OR, 2.99;

95% CI, 1.247.21; p = 0.014 after adjusting for age, serum

lactate, and APACHE II). Patients who had AA genotype of

rs28418396 in vasopressin group had significant lower AUC ofAVP level over the first 7 days than patient who had TA/TT

genotype (p= 0.022).

DISCUSSIONIn this study, we found that 10% of patients with septic shock

who received vasopressin or NE had SAEs in discovery and val-

idation cohorts. Second, we found that patients who had SAEs

had about double the mortality rates of patients who did nothave SAEs. Third, we found that the area under the vasopres-

sin concentration curve was not different between patients onvasopressin infusion with or without SAEs. Finally, we found

that patients who had the AA genotype of rs28418396 SNP had

significantly higher rates of SAEs in both discovery and valida-tion cohorts.

The SAE rates we found are somewhat lower when com-

pared with other studies (6, 9). One reason could be use of dif-

ferent definitions of SAEs in different studies. Different dosing

of vasopressin and NE is not likely the explanation as the doses

of vasopressin and NE of our study were similar (vasopressindose was 0.010.03 U/min; mean maximum doses of NE were

26.7 and 24.6 g/min in VASST and SPH cohort, respectively)

to other studies.

TABLE 3.Mortality Rates and Morbidities of Patients With or Without Serious AdverseEvents in the Discovery (Vasopressin and Septic Shock Trial) and Validation (St. PaulsHospital) Cohorts

Variable

Vasopressin and Septic Shock Trial Cohort St. Pauls Hospital Cohort

No SAE (n= 534) Any SAE (n= 63) p No SAE (n= 481) Any SAE (n= 52) p

Outcome, n(%)

28-day mortality 168 (31.5%) 35 (55.6%) < 0.001a 215 (44.7%) 34 (65.4%) 0.005a

90-day mortality 228 (42.7%) 38 (60.3%) 0.008a 251 (52.2%) 39 (75%) 0.002a

Length of ICU stay (d) 10 (516) 9 (319) 0.62 8 (415) 10 (421) 0.611

Days alive and free of organ dysfunction

Cardiovascular 20 (024) 3 (021) < 0.001a 11 (023) 4 (016) 0.006a

Vasopressor useb 20 (024) 3 (022) 0.001a 18 (125) 7 (020) 0.004a

Ventilationc 10.5 (021) 0 (08) < 0.001a 3 (020) 1 (09) 0.039a

Renal replacement 26 (628) 16 (128) 0.006a 15 (228) 7 (123) 0.042a

Neurologicd 18 (025) 2 (018) < 0.001a 22 (427) 9 (225) 0.007a

Hematologice 25 (728) 19 (128) 0.005a 21 (428) 10 (225) 0.031a

Hepatic 27 (728) 11 (128) 0.001a 20 (328) 8 (127) 0.013a

Any organ failure 0 (010) 0 (02) 0.012a 0 (00) 0 (00) 0.216a

SAE = serious adverse events.ap< 0.05.bVasopressor use was dened as 5 g or more of dopamine/kg/min or any dose of norepinephrine, epinephrine, or phenylephrine.cVentilation was dened as intubation and positive-pressure ventilation.dNeurologic was dened as Glasgow Coma Score < 12, prior to receiving sedation.eHematologic was dened as new onset of coagulation defect or platelet count < 80,000/mm3.

Data are median (interquartile range) for continuous data.pvalues were calculated with Pearson chi-square test and Mann-Whitney Utest.


7/9

Anantasit et al


This study showed that patients with SAEs had higher (about

double) mortality rate than patients without SAEs. Because

this was an association study, it is not clear whether the SAEs

were in some part causal of the increased mortality rates or

whether the presence of SAEs simply identified sicker patients

at increased risk of death. Some clinical markers were associated

with increased risk of SAEs in one or both cohorts. For example,

patients who had developed SAEs had a trend to higher serum

lactate than patients without SAEs. Prior studies found that high

serum lactate is a risk predictor of nonocclusive mesenteric isch-

emia (21). Patients with SAEs also were older and had higher

APACHE II than patients without SAEs. These simple clinical

markers could be used to iden-

tify patients at increased risk of

SAEs while on vasopressin or NE

infusions for septic shock.

We found that the AA geno-

type of rs28418396 SNP was sig-

nificantly associated with SAEs

in discovery (VASST) and vali-dation (SPH) cohorts. To our

knowledge, this is the first study

to demonstrate that AA geno-

type of rs28418396 SNP is a risk

factor for SAEs in patients with

septic shock. The rs28418396 is

near the 5untranslated region

of the AVPR1b gene. AVPR1b

gene sized is 7,200 bases in

chromosome 1q32. AVP is pro-

duced in the hypothalamus,

stored in posterior pituitary,and released into the circula-

tion (2). There is an impor-

tant interaction between AVP

and the adrenal axis in stress

situations that is linked by the

AVPR1b receptor (22). When

vasopressin binds to the V1b

receptor on corticotrophs in the

anterior pituitary (coded for by

the AVPR1b gene), adrenocor-

ticotropin hormone (ACTH) is

released (23). Septic shock acti-vates vasopressin release to sup-

raphysiologic levels and then

vasopressin levels decrease rap-

idly (24). Furthermore, animal

studies show that the activation

of central vasopressin may be

mediated by NE through 1-

adrenergic receptors (25). NE

also triggers the pituitary gland

to release ACTH.

The exact mechanism by which

rs28418396 SNP of AVPR1bgeneinfluences any SAEs, particularly patients who received NE infu-

sion, is unknown and requires further investigation.

Plasma vasopressin levels were not associated with SAEs in

septic shock patients. In particular for patients on vasopressin

infusion, vasopressin levels were not different between patients

with or without SAEs suggesting that simple pharmacokinetics

and higher vasopressin levels were not associated with SAEs.

Vasopressin secretion is complex and depends on blood pres-

sure, plasma osmolarity, and blood volume (26), as well as

hypercapnia, hypoxia, hyperthermia, pain, nausea, and mor-

phine. Furthermore, many hormones are direct stimulators

of vasopressin, such as acetylcholine, histamine, angiotensin

Figure 2.The area under the plasma vasopressin concentration-time curve (AUC) in septic shock patients inthe discovery (Vasopressin and Septic Shock trial) cohort at 24 hr and 7 days in the norepinephrine (NE) andarginine vasopressin (AVP) groups without (top) or with regard to the genotype of rs28418396 of AVPR1b.SAE = serious adverse events.


8/9



II, prostaglandins, dopamine, and, particularly, the adrenergicsystem. At low concentrations, NE increases vasopressin activ-

ity; conversely, at high concentrations, NE inhibits vasopressinsecretion (27). The half-life of vasopressin is approximately 10

minutes. Therefore, vasopressin levels are not good estimatesof its production and release. This study showed that the area

under the plasma concentration-time curve of vasopressin wasnot different between patients with or without SAEs in both

vasopressin and NE groups.

The clinical implications of our study are important. Wesuggest that the original VASST randomized controlled trial

provides guidance on efficacy of vasopressin versus NE in thatin the stratum of patients who had less severe shock (defined

as NE infusion < 15 g/min), patients in the vasopressin grouphad lower mortality than patients in the NE group. Regarding

safety, the original publication and the current study sug-gest that the risk of SAEs is similar for vasopressin versus NE.

Furthermore, patients must be proactively monitored for SAEsbecause they are frequent and

are associated with increasedmortality. Second, we sug-

gest that vasopressor infusionsshould be altered (decrease

dose, switch to an alternativevasopressor, re-evaluate volume

status, and consider administer-

ing volume to allow vasopressorweaning). Third, if the genomic

marker rs28418396 is validatedfurther, then in future, patients

could be assessed by measur-

ing their genotype and alteringvasopressor choice according togenotype.

There are several limitationsin this study. First, the valida-

tion (SPH) cohort was a retro-spective chart review (which

may underestimate SAEs seenin practice) and there were no

plasma vasopressin level mea-surements. Second, this is an

association study so we can-

not conclude to what extent

TABLE 4.Allele Frequency and Associations With Serious Adverse Events of SignificantTag Single-Nucleotide Polymorphisms in Vasopressor Pathway Genes in the Discovery(Vasopressin and Septic Shock Trial) Cohort

Single-Nucleotide Polymorphism_GeneMajor/Minor

AlleleMinor Allele Frequency

(n= 597)Hardy-Weinberg

Equilibrium pSerious Adverse

Event p

rs28418396_AVPR1bA/T 0.14 0.538 0.034

rs11121816_AGTRAP G/T 0.40 0.156 0.031

rs11953730_LNPEPregion C/T 0.001 0.984 0.004

rs11958177_LNPEPregion A/G 0.001 0.984 0.004



rs17531248_LNPEPregion C/G 0.18 0.474 0.031



AVPR1b= arginine vasopressin receptor 1b, AGTRAP= angiotensin II type 1 receptorassociated protein, LNPEP= leucyl/cystinyl aminopeptidase.pvalue were calculated with the use of chi-square test for Hardy-Weinberg equilibrium and Breslow generalized Wilcoxon test for serious adverse events.

Figure 3.Percentage of AA genotypes of rs28418396 single-nucleotide polymorphism in septicshock patients with or without serious adverse events (SAE) according to arginine vasopressin (AVP) ornorepinephrine groups in discovery (Vasopressin and Septic Shock trial, VASST) and validation (St. Pauls

Hospital, SPH) cohorts. *p= 0.001 in VASST andp= 0.04 in SPH.


9/9

Anantasit et al


the development of SAEs while on vasopressin or NE infu-

sion contributed to increased mortality. Third, we could not

directly address vasopressin production and release. We did,

however, assess the relationship between plasma vasopressin

levels and occurrence of SAEs because higher doses and levelsof vasopressin could have caused greater vasoconstriction and

so could have caused more ischemic SAEs. The lack of differ-

ence in plasma vasopressin levels between those who did ordid not have an SAE could dissociate the biological plausibility

between SAE and use of vasopressor.

CONCLUSIONSAbout 10% of patients with septic shock on vasopressin or

NE infusion had SAEs. The development of SAEs identified

patients with greatly increased (about double) mortality rates

compared with patients who did not have SAEs. In patients

on vasopressin infusion, vasopressin levels were not different

between patients with or without SAEs suggesting that simple

pharmacokinetics and higher vasopressin levels did not causeSAEs. Patients who had the AA genotype of rs28418396 SNP

had significantly higher rates of SAEs in both discovery and

validation cohorts; the mechanism of this association requires

further investigation.

REFERENCES 1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign

Guidelines Committee including the Pediatric Subgroup: SurvivingSepsis Campaign: International guidelines for management ofsevere sepsis and septic shock, 2012. Intensive Care Med 2013;39:165228

2. Obritsch MD, Bestul DJ, Jung R, et al: The role of vasopressin in vaso-dilatory septic shock. Pharmacotherapy2004; 24:10501063

3. Obritsch MD, Jung R, Fish DN, et al: Effects of continuous vasopres-sin infusion in patients with septic shock. Ann Pharmacother2004;38:11171122

4. Dnser MW, Mayr AJ, Tr A, et al: Ischemic skin lesions as a compli-cation of continuous vasopressin infusion in catecholamine-resistantvasodilatory shock: Incidence and risk factors. Crit Care Med2003;31:13941398

5. Russell JA, Walley KR, Singer J, et al; VASST Investigators:Vasopressin versus norepinephrine infusion in patients with septicshock. N Engl J Med2008; 358:877887

6. Hall LG, Oyen LJ, Taner CB, et al: Fixed-dose vasopressin comparedwith titrated dopamine and norepinephrine as initial vasopressor ther-apy for septic shock. Pharmacotherapy2004; 24:10021012

7. Ferguson-Myrthil N: Vasopressor use in adult patients. Cardiol Rev2012; 20:153158

8. Annane D, Vignon P, Renault A, et al; CATS Study Group:Norepinephrine plus dobutamine versus epinephrine alone for

management of septic shock: A randomised trial. Lancet 2007;370:676684

9. Torgersen C, Dnser MW, Wenzel V, et al: Comparing two differ-ent arginine vasopressin doses in advanced vasodilatory shock: Arandomized, controlled, open-label trial. Intensive Care Med2010;36:5765

10. van Haren FM, Rozendaal FW, van der Hoeven JG: The effect of vaso-pressin on gastric perfusion in catecholamine-dependent patients inseptic shock. Chest2003; 124:22562260

11. Holmes CL, Walley KR, Chittock DR, et al: The effects of vasopressinon hemodynamics and renal function in severe septic shock: A caseseries. Intensive Care Med2001; 27:14161421

12. Phillips KA, Veenstra DL, Oren E, et al: Potential role of pharmacoge-nomics in reducing adverse drug reactions: A systematic review.JAMA2001; 286:22702279

13. Russell JA: Bench-to-bedside review: Vasopressin in the manage-ment of septic shock. Crit Care2011; 15:226

14. Nakada TA, Russell JA, Wellman H, et al: Leucyl/cystinyl aminopepti-dase gene variants in septic shock. Chest2011; 139:10421049

15. Nakada TA, Russell JA, Boyd JH, et al: Beta2-Adrenergic receptorgene polymorphism is associated with mortality in septic shock. Am JRespir Crit Care Med2010; 181:143149

16. Wu CK, Tsai CT, Chang YC, et al: Genetic polymorphisms ofthe angiotensin II type 1 receptor gene and diastolic heart failure.J Hypertens2009; 27:502507

17. Nakada TA, Russell JA, Boyd JH, et al: Association of angiotensin IItype 1 receptor-associated protein gene polymorphism with increasedmortality in septic shock. Crit Care Med2011; 39:16411648

18. Bone RC, Balk RA, Cerra FB, et al: Denitions for sepsis and organfailure and guidelines for the use of innovative therapies in sepsis.Chest1992; 101:16441655

19. Sutherland AM, Walley KR, Manocha S, et al: The association of inter-leukin 6 haplotype clades with mortality in critically ill adults. ArchIntern Med2005; 165:7582

20. Sibbald WJ, Vincent JL: Round table conference on clinical trials forthe treatment of sepsis. Intensive Care Med1995; 21:184189

21. Groesdonk HV, Klingele M, Schlempp S, et al: Risk factors for nonoc-clusive mesenteric ischemia after elective cardiac surgery. J ThoracCardiovasc Surg2013; 145:16031610

22. Hernando F, Schoots O, Lolait SJ, et al: Immunohistochemical local-ization of the vasopressin V1b receptor in the rat brain and pituitarygland: Anatomical support for its involvement in the central effects ofvasopressin. Endocrinology2001; 142:16591668

23. Lolait SJ, Stewart LQ, Jessop DS, et al: The hypothalamic-pituitary-adrenalaxis response to stress in mice lacking functional vasopressin V1breceptors. Endocrinology2007; 148:849856

24. Sharshar T, Blanchard A, Paillard M, et al: Circulating vasopressinlevels in septic shock. Crit Care Med2003; 31:17521758

25. Xu S, Guo S, Jiang X, et al: The role of norepinephrine and nitric oxidein activities of rat arginine vasopressin neurons in response to immunechallenge. Neurosci Lett2005; 383:231235

26. Delmas A, Leone M, Rousseau S, et al: Clinical review: Vasopressinand terlipressin in septic shock patients. Crit Care2005; 9:212222

27. Leng G, Brown CH, Russell JA: Physiological pathways regulatingthe activity of magnocellular neurosecretory cells. Prog Neurobiol1999; 57:625655

vasopresina efectos adversos

Documents