conservative vs conventional oxygen therapy on mortality...

Conservative vs Conventional oxygen therapy on mortality among patients

in an intensive care unit: The Oxygen-ICU trial

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Disclosures

MILD HYPOXIA

PaO2 50-60 mmHg

Mild Hypoxia for reducing

the harmful effects of

reactive oxygen species

HYPEROXIA

PaO2 >100 mmHg

High level of PaO2 for

avoiding tissue hypoxia

Which is the appropriate level of Arterial PO2 in critically ill patients ?

STRICT NORMOXIA

PaO2 60-100 mmHg

O2 therapy in critically ill patients:Which evidence ?

→ Oxygen is a ‘drug’ essential for human life; tissue hypoxia(uncertain the level) cause organ dysfunction

→ Oxygen is the most widely prescribed therapy in critically illpatients to prevent and/or correct hypoxemia

→ The use of supplemental oxygen therapy is recommended innumerous clinical practice guidelines but specific limits forthe PaO2 (or SaO2) maximum levels are not provided

→ ICU patients spend substantial periods in hyperoxemia thatis rarely corrected (de Graff et al, Intensive Care Med 2011; Suzuki et al,

J Crit Care 2013)

→ Mild hyperoxemia is considered safe and useful since it mayprovide a safety buffer

Hyperoxemia: Possible Effects in Critically ill Patients

BENEFICIAL- Prevention of tissue hypoxia- Vasoconstriction- Reduction of inflammation

Depend on- duration and dose of O2 exposure (lung and blood) ,- concomitant conditions (ARDS, endothelial dysfunction, bacteremia),

other

DETRIMENTAL- Pulmonary effects (hyperoxia)- Impairment of microcirculation- Immune-paralysis

HYPEROXEMIA: IS IT SAFE ?

→ Observational or interventional studies: hyperoxemia (defined as supranormal arterial O2 tension) and mortality in adult ICU patients

→ 17 studies (2008-2014)• mechanically ventilated ICU (k=4 studies, n=189,143 ), • post-cardiac arrest (k=6, n=19,144), • stroke (k=2, n=5,537), • traumatic brain injury (k=5, n=7,488).

O2 therapy in critically ill patients:Which evidence ?

HYPEROXEMIA: IS IT SAFE ?

Heterogeneity: 91.85, p<0.001; I2 = 96.73

O2 therapy mechanically ventilatedcritically ill patients: Which evidence ?

Patients with PaO2/FiO2 < 300

Adult with MV >24 hours1. Conservative Group (n= 52) SpO2 88-92%2. Liberal Group (n=51) SpO2 >96%


CONSERVATIVE

n = 35LIBERAL

N= 32P

ICU mortality

6 (17%) 9 (28%) 0,28

90-day mortality

10 (29%) 12 (38%) 0,44

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Girardis and coauthors

Effect of Conservative vs

Conventional Oxygen Therapy on

Mortality Among Patients in an

Intensive Care Unit: The Oxygen-

ICU Randomized Clinical Trial

Published online October 5, 2016

Oxygen-ICU trial ClinicalTrials.gov: NCT01319643

DESIGN: Single-centre, prospective, open-label, randomized controlled trialperformed in the 12 beds medical-surgical ICU of the Modena University Hospital(800 beds) from March 2010 to October 2012

PATIENTS: aged 18 years of age or older admitted to our ICU with an expected lengthof stay ≥72 hours.Exclusion criteria: pregnancy, ICU re-admission, acute decompensation of chronic pulmonarydisease, acute respiratory distress syndrome with an PaO2/FiO2 ratio <150, a decision towithhold life-sustaining treatment, immunosuppression and/or neutropenia, and enrolment inanother study.

OBJECTIVE: To evaluate whether the application of aconservative protocol for O2 supplementation, in order tomaintain PaO2 within physiological limits, could improveoutcomes in critically ill ICU patients.

CONVENTIONAL: O2 therapy was administered according to standardICU practice: FiO2 at least 0,4, allowing PaO2 values up to 150 mmHgand SpO2 values ranging between 97-100%. During endotrachealintubation, airway suction or hospital transfer FiO2 was 1.0.

CONSERVATIVE: O2 therapy was given at the lowest possible FiO2 tomaintain PaO2 values between 70-100 mmHg and/or SpO2 valuesbetween 94-98%. O2 therapy was regulated according to a nurse orderset. During endotracheal intubation, airway suction or hospitaltransfer O2 was given only if SpO2 decreased <94%.

ProtocolOxygen-ICU trial ClinicalTrials.gov: NCT01319643

OUTCOMEPRIMARY OUTCOME: ICU mortalitySECONDARY OUTCOMES:– Hospital mortality– New respiratory, cardiovascular, liver and renal failure (SOFA score ≥3) (≥48 hours

after admission)– re-operation in surgical patients ( ≥48 hours after admission)– bloodstream, respiratory and surgical site infections ( ≥48 hours after admission)

POWER SIZE and ANALYSIS– Data from our institution showed an ICU mortality of 23% in patients staying >72 hours. – 660 patients over a 24 months in order to have the capacity to detect an absolute difference

in mortality of 6% (RRR 25%) between the 2 different groups (two-sided alpha level 0.05, power 80%).

– Due to low inclusion rate, we stopped the study after 32 months (480 patients randomized) as indicated by our EC/statistical review after an interim analysis (not defined at priori).

– A modified intent-to-treat (MITT) population, consisting of all randomized patients with an ICU length of stay ≥72 hours and with at least 1 ABG per day, was the primary population for analysis.


From 1st March 2010 to 30th October 2012

Results

Consort diagram


Conservative

O2 therapy

N = 216

Conventional

O2 therapy

N = 218

Female, no. (%) 95 (44,0) 93 (42,7)

Age, median (IQR) 63 (51-74) 65 (52-76)

Type of ICU admission, no.(%)

Medical 77 (35,7) 86 (39,5)

Surgical 139 (64,3) 132 (60,7)

SAPS II, median (IQR) 37 (26-49) 39 (28-55)

Respiratory Failure, no.(%) 121 (56,0) 129 (59,2)

Mechanical Ventilation, no.(%) 143 (66,2) 148 (67,9)

Shock , no.(%) 68 (31,4) 72 (33,0)

Liver Failure , no.(%) 40 (18,5) 45 (20,6)

Renal Failure, no.(%) 32 (14,8) 35 (16,1)

Documented Infections, no.(%) 81 (37,5) 88 (40,4)

Characteristics of the patients at study inclusion

ResultsOxygen-ICU trial ClinicalTrials.gov: NCT01319643

O2 control

Results

P<0.001

Time-weighted PaO2 average during ICU stay

Median PaO2

102 mmHg [IQR 88-116]

P<0.001

Time-weighted FiO2 average during ICU stay

Median FiO2

0,39 [IQR 0,35-0,42]

Median PaO2

87 mmHg [IQR 79-97]

Median FiO2

0.36 [IQR 0,30-0,40]


Probability of survival from study inclusion through day 60

Results

PRIMARY

OUTCOME

Conservative

O2therapy

N = 216

Conventional

O2 therapy

N = 218

P

value

ARR

(95% CI)

ICU mortality, no. (%)25/216 (11,6) 44/218 (20,2)

0,01 8,6

(1,7-15,0)


Results

New organ dysfunctionduring ICU stay * *

* p< 0,01

New documented infectionduring ICU stay

*

* p< 0,05



Results

Hypothesis Effects of the high O2 concentration (in the lung and in the blood) on the innate immune system and host inflammatory response

→ High blood level of reactive oxygen species and IL 6, IL 10 duringperitoneal infection (Rodriguez-Gonzalez R et al Shock 2014).

→ Structural and functional changes of the alevolar macrophageswith impairment of antimicrobial activity and dissemination ofinfection (Baleeiro et al, Journal of immunology 2003; Morrow et al, Free radical

biology & medicine 2007)

→ Liver dysfunction due to the high immune-mediate oxidativeburst after Ischemia/reperfusion model (Zangl Q et al, Anesthesiology

2014)


Limitations of the study → Design: single-center, open-label. sample-size limited for subgroup

analysis (Stroke, TBI, AMI ?)

→ Unplanned early stop may have exaggerated the effect size

→ Time weighted median PaO2 is a rough approximation of true O2exposure in patients with only 1 or 2 ABG for day. EC did not allowto perform more arterial blood gas analysis to avoid influences onthe study results introduced by changes in in the standard of careand for patient safety reasons

→ Underestimation of the infection rate due to the use of onlydocumented infections

→ The high percentage of patients with respiratory failure at studyinclusion (58%) hinders a proper analysis on the possible protectiveeffects of the conservative O2 strategy on the respiratory function.


In critically ill patients with ICU length of stay > 72 Hours, aconservative oxygen strategy aimed to maintain SpO2/PaO2 levelswithin the physiological range→ Is safe

→ Resulted in lower ICU mortality as compared to a liberal oxygentherapy.

→ Due to limitations of the study (e.g. early termination)the results should be considered preliminary


Confirmatory trial is urgently needed

Conclusions

MILD HYPOXIA

PaO2 50-60 mmHg




HYPEROXIA

PaO2 >100 mmHg




STRICT NORMOXIA

PaO2 60-100 mmHg

RESEARCH STAFF

Massimo Girardis, MD

Stefano Busani, MD

Rinaldi Laura, MD

Andrea Marudi, MD

Marta Buoncristiano, MS

Oxygen-ICU trial

RESEARCH AND CLINICAL STAFF

REST MODE

IN ACTION

TAKE HOME PICTURE


Patients with PaO2/FiO2 < 300


O2 in critically ill patients

ICU mechanical Ventilation

Oxygen-ICU, ClinicalTrials.gov: NCT01319643

Conservative O2

therapy

N= 216

Conventional O2

therapy

N = 218

P value

ICU mortality, no. (%) 25/216 (11.6) 44/218 (20.2) 0.014

Hospital mortality, no. (%) 52/216 (24.2) 74/218 (33.9) 0.025

New organ failure during ICU stay, no. (%) 41/216 56/218 0.094

Respiratory failure 14/216 (6.5) 14/218 (6.4) 0.98

Shock 8/216 (3.7) 23/218 (10.6) 0.006

Liver failure 4/216 (1.9) 14/218 (6.4) 0.017

Renal failure26/216 (12.0) 21/218 (9.6)

0.42

New infections during ICU stay, no. (%)39/216 (18.1) 50/218 (22.9)

0.21

Respiratory 30/216 (13.9) 37/218 (17.0) 0.37

Bacteremia 11/216 (5.1) 22/218 (10.1) 0.049

Surgical Site* 10 /139 (4.6) 12/132 (5.5) 0.68

Mechanical ventilation free-hours, median (IQR) 72 (35-110) 48 (24-96) 0.016

ICU length of stay, days- median (IQR)6 (4-10) 6(4-11)

0.33

Hospital length of stay , days- median (IQR)21 (13-38) 21 (12-34)

0.21


ICU mechanical Ventilation

Oxygen-ICU, ClinicalTrials.gov: NCT01319643


ACC

Hyperoxia. Heterogeneity = 12.4, p = 0.015; I2 = 67.73

O2 in critically ill patientsICU

mechanical Ventilation

HyperoxiaHeterogeneity: 91.85, p<0.001; I2 = 96.73

Study Design Country Comparator Outcome

de Jonge 2008 retrospective cohort, multi-center Netherlands PaO2 between 66-80 mmHgIn-hospital

mortality

Eastwood 2012 retrospective cohort, multi-centerAustralia, New

Zealand

PaO2 <120 mmHg for unadjusted

analysis; PaO2 75-85 mmHg for

adjusted analysis

In-hospital

mortality

Suzuki 2013 prospective observational cohort, single-

centerAustralia Non-exposed to hyperoxia

In-hospital

mortality

Suzuki 2014 prospective before-after, single-center AustraliaConservative period: SpO2 between

90-92%28-day mortality

POTENTIAL CONFLICT OF INTEREST

Unrestricted grants, lectures, advisory

boards, etc.

Astra Zeneca

Baxter

Biotest

Eli-Lilly

CSL-Behring

Kedrion

MSD

Novartis

NovoNordisk

Orion Pharma

Pfizer

Thermofisher

I trust in Physiology & EBM,

but the latter is more ‘voluble’

Disclosures

MILD HYPOXIA

PaO2 50-60 mmHg




HYPEROXIA

PaO2 >100 mmHg




STRICT NORMOXIA

PaO2 60-100 mmHg

conservative vs conventional oxygen therapy on mortality...

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