Article

Association Between Arterial Hyperoxia Following Resuscitation From Cardiac Arrest and In-Hospital Mortality

Department of Emergency Medicine, Cooper University Hospital, One Cooper Plaza, Camden, NJ 08103, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 06/2010; 303(21):2165-71. DOI: 10.1001/jama.2010.707
Source: PubMed

ABSTRACT

Laboratory investigations suggest that exposure to hyperoxia after resuscitation from cardiac arrest may worsen anoxic brain injury; however, clinical data are lacking.
To test the hypothesis that postresuscitation hyperoxia is associated with increased mortality.
Multicenter cohort study using the Project IMPACT critical care database of intensive care units (ICUs) at 120 US hospitals between 2001 and 2005. Patient inclusion criteria were age older than 17 years, nontraumatic cardiac arrest, cardiopulmonary resuscitation within 24 hours prior to ICU arrival, and arterial blood gas analysis performed within 24 hours following ICU arrival. Patients were divided into 3 groups defined a priori based on PaO(2) on the first arterial blood gas values obtained in the ICU. Hyperoxia was defined as PaO(2) of 300 mm Hg or greater; hypoxia, PaO(2) of less than 60 mm Hg (or ratio of PaO(2) to fraction of inspired oxygen <300); and normoxia, not classified as hyperoxia or hypoxia.
In-hospital mortality.
Of 6326 patients, 1156 had hyperoxia (18%), 3999 had hypoxia (63%), and 1171 had normoxia (19%). The hyperoxia group had significantly higher in-hospital mortality (732/1156 [63%; 95% confidence interval {CI}, 60%-66%]) compared with the normoxia group (532/1171 [45%; 95% CI, 43%-48%]; proportion difference, 18% [95% CI, 14%-22%]) and the hypoxia group (2297/3999 [57%; 95% CI, 56%-59%]; proportion difference, 6% [95% CI, 3%-9%]). In a model controlling for potential confounders (eg, age, preadmission functional status, comorbid conditions, vital signs, and other physiological indices), hyperoxia exposure had an odds ratio for death of 1.8 (95% CI, 1.5-2.2).
Among patients admitted to the ICU following resuscitation from cardiac arrest, arterial hyperoxia was independently associated with increased in-hospital mortality compared with either hypoxia or normoxia.

Full-text

Available from: Nathan I Shapiro, Mar 06, 2014
CARING FOR THE
CRITICALLY ILL PATIENT
Association Between Arterial Hyperoxia
Following Resuscitation From Cardiac Arrest
and In-Hospital Mortality
J. Hope Kilgannon, MD
Alan E. Jones, MD
Nathan I. Shapiro, MD, MPH
Mark G. Angelos, MD
Barry Milcarek, PhD
Krystal Hunter, MBA
Joseph E. Parrillo, MD
Stephen Trzeciak, MD, MPH
for the Emergency Medicine Shock
Research Network (EMShockNet)
Investigators
S
UDDEN CARDIAC ARREST IS THE
most common lethal conse-
quence of cardiovascular dis-
ease. Even if return of sponta-
neous circulation (ROSC) from cardiac
arrest is achieved, approximately 60%
of patients will not survive to hospital
discharge.
1,2
The high mortality is at-
tributed to the postcardiac arrest syn-
drome, which involves global ischemia-
reperfusion injury, myocardial
stunning, and anoxic brain injury.
3
The
recent success of therapeutic hypother-
mia for post-ROSC neuroprotection
4,5
has increased momentum for investi-
gating post-ROSC factors that can im-
prove outcomes.
In the search for modifiable post-
ROSC factors, the role of supplemen-
tal oxygen, which is often adminis-
tered in high concentrations to patients
after cardiac arrest has come into con-
troversy.
6
There is a paradox with oxy-
gen when delivered to the injured brain.
Too little oxygen may potentiate an-
oxic injury. Too much oxygen may in-
crease oxygen free radical production,
possibly triggering cellular injury and
For editorial comment see p 2190.
Author Affiliations: Department of Emergency
Medicine (Drs Kilgannon and Trzeciak), Division of
Critical Care Medicine, Department of Medicine (Drs
Parrillo and Trzeciak), and Biostatistics Group (Dr
Milcarek and Ms Hunter), Cooper University Hospi-
tal, Camden, New Jersey; Department of Emergency
Medicine, Carolinas Medical Center, Charlotte,
North Carolina (Dr Jones); Department of Emer-
gency Medicine and Center for Vascular Biology
Research, Beth Israel Deaconess Medical Center,
Boston, Massachusetts (Dr Shapiro); and Depart-
ment of Emergency Medicine, Ohio State University,
Columbus (Dr Angelos).
Corresponding Author: Stephen Trzeciak, MD, MPH,
Cooper University Hospital, One Cooper Plaza, D363,
Camden, NJ 08103 (trzeciak-stephen@cooperhealth
.edu).
Caring for the Critically Ill Patient Section Editor:
Derek C. Angus, MD, MPH, Contributing Editor,
JAMA (angusdc@upmc.edu).
Context Laboratory investigations suggest that exposure to hyperoxia after resuscita-
tion from cardiac arrest may worsen anoxic brain injury; however, clinical data are lacking.
Objective To test the hypothesis that postresuscitation hyperoxia is associated with
increased mortality.
Design, Setting, and Patients Multicenter cohort study using the Project IMPACT
critical care database of intensive care units (ICUs) at 120 US hospitals between 2001
and 2005. Patient inclusion criteria were age older than 17 years, nontraumatic car-
diac arrest, cardiopulmonary resuscitation within 24 hours prior to ICU arrival, and ar-
terial blood gas analysis performed within 24 hours following ICU arrival. Patients were
divided into 3 groups defined a priori based on Pa
O
2
on the first arterial blood gas
values obtained in the ICU. Hyperoxia was defined as Pa
O
2
of 300 mm Hg or greater;
hypoxia, Pa
O
2
of less than 60 mm Hg (or ratio of PaO
2
to fraction of inspired oxygen
300); and normoxia, not classified as hyperoxia or hypoxia.
Main Outcome Measure In-hospital mortality.
Results Of 6326 patients, 1156 had hyperoxia (18%), 3999 had hypoxia (63%),
and 1171 had normoxia (19%). The hyperoxia group had significantly higher in-
hospital mortality (732/1156 [63%; 95% confidence interval {CI}, 60%-66%]) com-
pared with the normoxia group (532/1171 [45%; 95% CI, 43%-48%]; proportion
difference, 18% [95% CI, 14%-22%]) and the hypoxia group (2297/3999 [57%; 95%
CI, 56%-59%]; proportion difference, 6% [95% CI, 3%-9%]). In a model control-
ling for potential confounders (eg, age, preadmission functional status, comorbid con-
ditions, vital signs, and other physiological indices), hyperoxia exposure had an odds
ratio for death of 1.8 (95% CI, 1.5-2.2).
Conclusion Among patients admitted to the ICU following resuscitation from car-
diac arrest, arterial hyperoxia was independently associated with increased in-hospital
mortality compared with either hypoxia or normoxia.
JAMA. 2010;303(21):2165-2171 www.jama.com
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Page 1
apoptosis.
7
Although numerous labo-
ratory investigations support the po-
tentially detrimental effects of hyper-
oxia exposure after ROSC from cardiac
arrest, clinical data are lacking.
The incidence of post-ROSC hyper-
oxia and subsequent outcomes in pa-
tients who survived cardiac arrest to in-
tensive care unit (ICU) admission are
reported herein. The overall aim was to
determine whether exposure to hyper-
oxia after ROSC from cardiac arrest was
associated with poor clinical out-
come. Specifically, for patients who sur-
vived cardiac arrest to ICU admission,
the objectives were to determine (1)
whether the presence of post-ROSC hy-
peroxia (defined as Pa
O
2
300 mm Hg)
was a common occurrence; (2) whether
post-ROSC hyperoxia was associated
with lower survival to hospital dis-
charge; and (3) whether post-ROSC hy-
peroxia remained significantly associ-
ated with in-hospital death after
adjustment for a predefined set of con-
founding variables in a multivariable
analysis.
METHODS
Project IMPACT (Cerner Corpora-
tion, Kansas City, Missouri) is a large
administrative database (initially de-
veloped by the Society of Critical Care
Medicine) designed for critical care
units across all disciplines. Adult ICUs
from 131 US hospitals participate in
Project IMPACT and data from more
than 400 000 patients have been col-
lected. Participating institutions up-
load data quarterly to a central reposi-
tory. Data fields include hospital and
ICU organizational characteristics, ad-
mission source (eg, emergency depart-
ment vs inpatient), demographics,
physiological data (including hemody-
namic indices and laboratory values),
procedures, complications, hospital and
ICU length of stay, and outcomes. All
data are collected by dedicated onsite
personnel who must be trained and cer-
tified by Project IMPACT, which re-
quires passing a written certification ex-
amination to ensure uniformity in both
database definitions and entry. Onsite
data collectors receive additional cer-
tification from Project IMPACT as a
prerequisite to collating and upload-
ing data. The institutional review board
at Cooper University Hospital (Cam-
den, New Jersey) approved this study.
The ICUs in Project IMPACT repre-
sent a wide scope of practice environ-
ments, including medical, surgical, and
multidisciplinary ICUs. The institu-
tions are heterogeneous in terms of hos-
pital size, type (community vs aca-
demic; private vs public), and location
(urban, suburban, or rural). Participat-
ing hospitals are not restricted to any
particular geographic region.
Adult patients who sustained non-
traumatic cardiac arrest and were ad-
mitted to the ICU at a participating cen-
ter between 2001 and 2005 were
included. Specifically, inclusion crite-
ria were age older than 17 years, non-
traumatic cardiac arrest, cardiopulmo-
nary resuscitation within 24 hours prior
to ICU arrival, and arterial blood gas
analysis performed within 24 hours fol-
lowing ICU arrival.
The following variables were ab-
stracted: demographics, comorbidi-
ties, preadmission functional status, site
of origin prior to ICU arrival, hospital
characteristics, most abnormal physi-
ological parameters (including vital
signs, other hemodynamic indices, and
laboratory tests) over the first 24 hours
in the ICU, first arterial blood gas re-
sult over the first 24 hours in the ICU,
life-support interventions (eg, vaso-
pressor use), vital status at hospital dis-
charge (alive or dead), and functional
status at hospital discharge. The Project
IMPACT participation manual speci-
fies that race/ethnicity data be ab-
stracted from the registration informa-
tion at the time of hospital admission.
Race/ethnicity was included as a study
variable because prior data have sug-
gested an association between non-
white race and poor outcome. Statisti-
cal analyses were conducted using SPSS
software version 15.0.1 (SPSS Inc, Chi-
cago, Illinois).
Continuous data are presented as
means and standard deviations or me-
dians and interquartile ranges (IQRs)
as appropriate based on distribution of
the data; categorical data are reported
as proportions and 95% confidence in-
tervals (CIs). For the purposes of this
analysis, the cohort was divided into 3
exposure groups defined a priori based
on Pa
O
2
on the first arterial blood gas
values obtained in the ICU. Hyper-
oxia was defined as Pa
O
2
of 300 mm Hg
or greater
8
; hypoxia, PaO
2
of less than
60 mm Hg (or ratio of Pa
O
2
to fraction
of inspired oxygen [FIO
2
] 300)
9
; and
normoxia, cases not classified as hy-
peroxia or hypoxia. These classifica-
tions were defined in a written proto-
col by consensus of all authors prior to
querying the database or analyzing any
data.
The primary outcome measure was
in-hospital mortality. The occurrence
of outcomes were compared between
the groups using the
2
test or the bi-
nomial test for the difference in pro-
portions with Bonferroni correction for
multiple pairwise comparisons (ie, for
3 groups, level of .05 divided by 3 or
.017). For days to primary outcome
analysis, Kaplan-Meier survival esti-
mates and log-rank tests were used to
compare the hyperoxia and normoxia
groups.
Odds ratios (ORs) were calculated to
determine independent predictors of
mortality. Given the dichotomous out-
come, multivariable logistic regres-
sion modeling was used. The analysis
proceeded in 2 stages. In the first stage,
significant risk factors were identified
from the candidate variables; in the sec-
ond stage, potential hospital effects were
assessed (ie, correlation among pa-
tients sampled within hospital clus-
ters). All patient-oriented data in
T
ABLE 1 were considered to be poten-
tial candidate variables for the model.
The regression model was run in 5 steps
with in-hospital mortality as the out-
come. At each step, a P value of less than
.05 was used as the criterion for reten-
tion in the model.
Step 1 considered demographics. For
entry into the model, age was coded by
deciles. Step 2 included patient char-
acteristics (other than demographics)
prior to cardiac arrest. Preadmission
functional status was coded as inde-
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Page 2
pendent or nonindependent. Site of ori-
gin prior to ICU admission was emer-
gency department or hospital inpatient.
Step 3 included preadmission comor-
bid conditions. Step 4 included pa-
tient physiological data after cardiac ar-
rest. Hypotension (systolic blood
pressure 90 mm Hg) on ICU admis-
sion and inotrope requirement were
coded as binary (yes or no) variables.
For the highest heart rate, each pa-
tient was coded as being above or be-
low the median for the entire cohort.
In the final step of the regression model,
the predictive effects on in-hospital
mortality were assessed for hyperoxia
and hypoxia. The hyperoxia and hy-
poxia groups were each coded as a con-
trast variable against normoxia. The
fifth step provides a significance test,
OR, and a 95% CI around the OR for
the primary covariate of interest, which
was exposure to hyperoxia. The re-
sults summarize the effect and are ad-
justed for all other variables included
in the earlier steps of the model.
Generalized estimating equations
were used to account for potential cor-
relation in mortality rates among patients
sampled within hospital clusters.
Three alternatives to the independence
assumption (no association) were exam-
ined for within-hospital correlation. The
quasi-likelihood independence crite-
rion was used to determine the best
working correlation structure assump-
tion. First, an exchangeable (or com-
pound symmetry) pattern was tested,
assuming identical (but unknown) cor-
relation between variables in the model
and mortality over patients clustered in
hospitals. Next, an unstructured pat-
tern was tested, assuming nonidentical
correlation between variables in the
model and mortality over patients clus-
tered in hospitals. Lastly, an autoregres-
sive pattern was tested, assuming
decreasing correlation between the vari-
ables in the model and mortality over
patients clustered in hospitals. Com-
pared with the independence assump-
tion, none of these alternative correla-
tion structures improved the model fit,
suggesting that a significant hospital
effect was not present in the model.
To test if hyperoxia exposure
remained a significant independent
predictor of in-hospital death when
the propensity of individuals to be
exposed to hyperoxia was adjusted
for, a sensitivity analysis was per-
formed using propensity scores (the
methods of the propensity score analy-
sis appear in eMethods at http://www
.jama.com). A preplanned secondary
analysis also was performed that was
identical to the univariable analysis but
used a higher Pa
O
2
cutoff to define hy-
peroxia (400 mm Hg rather than 300
mm Hg).
11-13
Assuming a ratio of approximately
3 patients in the hypoxia group for
every 1 patient in the normoxia and
hyperoxia groups, the sample size that
was analyzed allowed greater than
Table 1. Baseline Characteristics of the Study Patients
a
Patient Characteristics
No. (%) of Patients
b
All Patients
(N = 6326)
Hypoxia
(n = 3999)
Normoxia
(n = 1171)
Hyperoxia
(n = 1156)
Age, mean (SD), y 64 (17) 64 (16) 63 (17) 66 (16)
Female sex 2911 (46) 1766 (44) 573 (49) 572 (50)
Race/ethnicity
White 4757 (75) 3049 (76) 850 (73) 858 (74)
Black 1041 (17) 621 (16) 223 (19) 197 (17)
Latino/Hispanic 245 (4) 153 (4) 39 (3) 53 (5)
Asian/Pacific Islander 55 (1) 33 (1) 15 (1) 7 (1)
Other
c
228 (4) 143 (4) 44 (4) 41 (4)
Preadmission functional status
d
Independent 4146 (66) 2607 (65) 787 (67) 752 (65)
Partially dependent 1377 (22) 862 (22) 243 (21) 272 (24)
Fully dependent 803 (13) 530 (13) 141 (12) 132 (11)
Chronic comorbidities
Severe cardiovascular disease
e
732 (12) 463 (12) 124 (11) 145 (13)
Respiratory disease
f
693 (11) 459 (11) 113 (10) 121 (11)
End-stage renal disease 545 (9) 306 (8) 106 (9) 133 (12)
Hepatic cirrhosis with portal hypertension 154 (2) 104 (3) 25 (2) 25 (2)
Cancer with metastatic disease 271 (4) 180 (5) 40 (3) 51 (4)
Active chemotherapy 127 (2) 12 (1) 9 (1) 26 (2)
AIDS 37 (1) 19 (1) 9 (1) 9 (1)
Hematologic malignancy 29 (1) 24 (1) 4 (1) 1 (1)
ACC at ICU admission that may be associated
with oxygen status
Acute respiratory failure 599 (9) 415 (10) 111 (9) 73 (6)
Decompensated congestive heart failure 64 (1) 54 (1) 6 (1) 4 (1)
Pulmonary embolism 26 (1) 18 (1) 5 (1) 3 (1)
Exacerbation of asthma or COPD 91 (1) 63 (2) 19 (2) 9 (1)
Pneumonia 112 (2) 80 (2) 17 (1) 15 (1)
Noncardiogenic pulmonary edema 18 (1) 13 (1) 3 (1) 2 (1)
Location prior to ICU arrival
Emergency department 2747 (43) 1648 (41) 675 (58) 424 (37)
Hospital inpatient 3579 (57) 2351 (59) 496 (42) 732 (63)
Abbreviations: ACC, acute cardiopulmonary condition; COPD, chronic obstructive pulmonary disease; ICU, intensive
care unit.
a
Percentages may not equal 100 due to rounding.
b
Unless otherwise indicated.
c
Defined as patients whose race is known, but do not fall into any of the included race categories.
d
Independent defined as able to live at home and requiring no assistance to complete activities of daily living (ADLs);
partially dependent, able to live at home, in a group home, or in a care facility and requiring some assistance to com-
plete ADLs; fully dependent, able to live at home or in a care facility but unable to perform ADLs so must be cared for
by others. The limitations requiring assistance may be physical or mental.
e
Defined as baseline symptoms such as angina or shortness of breath at rest or on minimal exertion (New York Heart
Association class IV) plus 1 or more of the following diagnoses: severe coronary artery disease, severe valvular heart
disease, or severe cardiomyopathy.
f
Defined as chronic obstructive, restrictive, or vascular pulmonary disease resulting in severe exercise restriction, such
as unable to climb stairs or perform household duties; or respirator dependency related to active respiratory disease;
or documented chronic hypoxia, hypercapnia, or pulmonary hypertension (40 mm Hg).
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80% power to detect a significant dif-
ference in proportions between the
groups (assuming an level of .017
when adjusted for multiple compari-
sons).
RESULTS
There were 8736 patients that met the
first 3 inclusion criteria of age older than
17 years, nontraumatic cardiac arrest,
and cardiopulmonary resuscitation
prior to ICU arrival. There were 2410
patients who did not have arterial blood
gas values obtained within the first 24
hours in the ICU and were thus ex-
cluded from the study. The remaining
6326 patients were from 120 hospi-
tals. The median number of cardiac ar-
rest cases per hospital was 41 (IQR, 17-
72). Baseline characteristics for all
groups appear in Table 1 and T
ABLE 2.
Patients were predominantly white and
from community, nonacademic hospi-
tals. Sixty-six percent (n=4146) of pa-
tients were living independently prior
to hospital admission and 43%
(n=2747) were admitted to the ICU
from an emergency department. The
most common comorbid condition was
severe cardiovascular disease (eg, New
York Heart Association class IV; n=732
patients). Of the 6326 patients, 1156
were in the hyperoxia group (18%),
3999 were in the hypoxia group (63%),
and 1171 were in the normoxia group
(19%).
Physiological data over the first 24
hours in the ICU for all groups are dis-
played in T
ABLE 3. Sixty percent of pa-
tients required a vasopressor agent (eg,
continuous infusion of dopamine, nor-
epinephrine, epinephrine, or phenyl-
ephrine); the overall mean (SD) for low-
est systolic blood pressure was 85 (22)
mm Hg. For all patients, the mean (SD)
high temperature was 38°C (3°C) and
for low temperature was 36°C (3°C).
The median ICU length of stay for sur-
vivors to hospital discharge was 4 days
(IQR, 2-8 days) and for nonsurvivors
was 2 days (IQR, 1-5 days). The me-
dian hospital length of stay for survi-
vors was 12 days (IQR, 7-22 days) and
for nonsurvivors was 4 days (IQR, 1-11
days).
Overall, 56% of patients (n=3561)
met the primary outcome of in-
hospital mortality (T
ABLE 4). Mortality
was highest in the hyperoxia group (732/
1156; 63% [95% CI, 60%-66%]) com-
pared with the hypoxia group (2297/
3999; 57% [95% CI, 56%-59%]) and the
normoxia group (532/1171; 45% [95%
CI 43%-48%]). The hyperoxia group
had significantly higher in-hospital mor-
tality compared with the normoxia
group (proportion difference, 18% [95%
CI, 14%-22%]; P .001). Mortality also
was significantly higher in the hyper-
oxia group compared with the hypoxia
group (proportion difference, 6% [95%
CI, 3%-9%]; P .001). On Kaplan-
Meier analysis, the survival fractions for
the hyperoxia and normoxia groups di-
verged significantly over time (log-
rank P .001; F
IGURE). In addition,
among hospital survivors, patients with
hyperoxia had a significantly lower pro-
portion of discharges from the hospi-
tal as functionally independent com-
pared with patients with normoxia
(29% vs 38%, respectively; proportion
difference, 9% [95% CI, 3%-15%];
P =.002; Table 4).
Nine risk factors proved to be sig-
nificantly associated with in-hospital
death on multivariable logistic regres-
sion analysis. Significant demographic
and other factors prior to cardiac
arrest included age, nonindependent
preadmission functional status, emer-
Table 3. Abnormal Vital Signs in the First 24 Hours in the Intensive Care Unit and
Interventions
All Patients
(N = 6326)
Hypoxia
(n = 3999)
Normoxia
(n = 1171)
Hyperoxia
(n = 1156)
Mean (SD)
High temperature, °C 38 (3) 38 (3) 38 (1) 38 (3)
Low temperature, °C 36 (3) 36 (1) 36 (1) 36 (3)
High heart rate, beats/min 117 (25) 119 (25) 114 (24) 117 (26)
High respiratory rate, breaths/min 26 (9) 24 (8) 24 (8) 25 (6)
Low systolic blood pressure, mm Hg 85 (22) 83 (22) 91 (21) 83 (23)
Low mean arterial pressure, mm Hg 60 (16) 58 (16) 65 (15) 58 (16)
No. (%)
Hemodynamic support
Vasopressor agent
a
3789 (60) 2574 (64) 513 (44) 702 (61)
Dobutamine 591 (9) 412 (10) 83 (7) 96 (8)
Ventilator support
b
6123 (97) 3842 (96) 1150 (98) 1131 (98)
a
Defined as initiation of a continuous infusion of dopamine, norepinephrine, epinephrine, or phenylephrine.
b
Indicates presence of mechanical ventilation when index arterial blood gas in the intensive care unit was obtained.
Table 2. Baseline Characteristics of the Study Hospitals
a
Hospital Characteristics
No. (%) of Patients
All Patients
(N = 6326)
Hypoxia
(n = 3999)
Normoxia
(n = 1171)
Hyperoxia
(n = 1156)
Hospital size
b
Small to medium (300 beds) 979 (16) 594 (15) 198 (17) 187 (16)
Large (301-500 beds) 2685 (42) 1737 (43) 490 (42) 458 (40)
Extra large (500 beds) 2661 (42) 1668 (42) 483 (41) 510 (44)
Hospital type
Community (nonacademic) 5023 (79) 3130 (78) 939 (80) 954 (83)
Academic (university-based) 1116 (18) 740 (19) 206 (18) 170 (15)
Public 144 (2) 97 (2) 20 (2) 27 (2)
Military 43 (1) 32 (1) 6 (1) 5 (1)
Hospital location
Urban 3300 (52) 2091 (52) 583 (50) 626 (54)
Suburban 1976 (31) 1194 (30) 392 (34) 390 (34)
Rural 1050 (17) 714 (18) 196 (17) 140 (12)
a
Percentages may not equal 100 due to rounding.
b
Defined according to the criteria from Halpern et al.
10
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Page 4
gency department origin, active che-
motherapy, and chronic renal failure.
Significant physiological factors
included hypotension on ICU arrival,
tachycardia, and hypoxia. Exposure to
hyperoxia was found to be a signifi-
cant predictor of in-hospital death
(OR, 1.8 [95% CI, 1.5-2.2]; T
ABLE 5).
This is an independent effect that per-
sists after adjusting for all other sig-
nificant risk factors. In the sensitivity
analysis adjusting the model for pro-
pensity scores, the OR and 95% CIs
for hyperoxia exposure did not
change (see eResults and eTable 1 at
http://www.jama.com).
In the secondary analysis using a Pa
O
2
of 400 mm Hg or greater to define the
hyperoxia group, mortality was even
greater in the hyperoxia group (377/
549; 69% [95% CI, 65%-72%]) com-
pared with the hypoxia group (2297/
3999; 57% [95% CI, 56%-59%]) and the
normoxia group (887/1778; 50% [95%
CI, 48%-52%]). The hyperoxia group
had significantly higher in-hospital
mortality compared with the nor-
moxia group (proportion difference,
19% [95% CI, 14%-24%]; P .001).
Mortality also was significantly higher
in the hyperoxia group compared with
the hypoxia group (proportion differ-
ence, 12% [95% CI, 8%-16%];
P .001).
COMMENT
In this large multicenter cohort study
of patients admitted to an ICU after re-
suscitation from cardiac arrest, we
found that post-ROSC exposure to hy-
peroxia was a common occurrence, as
evidenced by the first arterial blood gas
values obtained after ICU arrival. In this
cohort, post-ROSC hyperoxia was as-
sociated with the lowest survival rate
to hospital discharge among all pa-
tients, including those who had hy-
poxia. After controlling for a pre-
defined set of confounding variables in
a multivariable analysis, we found that
exposure to hyperoxia was an indepen-
dent predictor of in-hospital death. This
effect remained robust in sensitivity
analyses that adjusted for hospital fac-
tors and propensity of hyperoxia ex-
posure. Additionally, we found that
among hospital survivors, hyperoxia
was associated with a lower likelihood
of independent functional status at hos-
pital discharge compared with nor-
moxia. To our knowledge, this is the
first large multicenter study document-
ing the association between post-
ROSC hyperoxia and poor clinical out-
come. While we acknowledge that
association does not necessarily imply
causation, these data support the hy-
pothesis that high oxygen delivery in
the postcardiac arrest setting may have
adverse effects.
Reperfusion after an ischemic in-
sult is associated with a surge of reac-
tive oxygen species, which may over-
whelm host natural antioxidant
defenses.
15-17
The oxidative stress from
the reactive oxygen species formed af-
ter reperfusion may lead to increased
cellular death by diminishing mito-
chondrial oxidative metabolism, dis-
rupting normal enzymatic activities, and
damaging membrane lipids through
peroxidation.
7
In clinically relevant ex-
perimental models of cardiac arrest, hy-
peroxia has been shown to worsen the
severity of oxidative stress, causing a
greater loss of pyruvate dehydroge-
nase complex,
18
impairment of oxida-
tive energy metabolism,
11
and higher
oxidation of brain lipids,
19
culminat-
ing in more severe brain histopatho-
logic changes and worse neurological
deficits.
12,19,20
In addition, recent pre-
clinical data suggest that early posti-
schemic hyperoxic reperfusion may
worsen brain injury via cellular inflam-
matory reactions in the neurons or their
microenvironment (eg, activation of mi-
croglia and astrocytes).
21
After the burst
of reactive oxygen species that occurs
in the initial minutes after reperfu-
sion, oxidant stress can be perpetu-
ated in a persistently hyperoxic envi-
ronment. Analogous to the concept that
hyperoxia exposure may be associ-
ated with harm in the resuscitation of
Figure. In-Hospital Death Between
Hyperoxia and Normoxia
1.0
0.8
0.6
0.4
0.2
0
No. at risk
Normoxia
Normoxia
Hyperoxia
Hyperoxia
Log-rank P<.001
1171
1156
7
514
406
14
236
211
21
129
115
28
83
70
Days
Survival Proportion
Table 4. Outcomes of Study Patients
All Patients
(N = 6326)
Hypoxia
(n = 3999)
Normoxia
(n = 1171)
Hyperoxia
(n = 1156)
In-hospital mortality, No.
(%) [95% CI]
a
3561 (56)
[55-58]
2297 (57)
[56-59]
532 (45)
[43-48]
732 (63)
[60-66]
Survivors, No. (%) 2765 (44) 1702 (43) 639 (55) 424 (37)
Independent functional
status at hospital
discharge, No.
(%) [95% CI]
b
939 (34)
[32-36]
570 (33)
[31-36]
245 (38)
[35-42]
124 (29)
[25-34]
Discharge destination,
No. (%)
Home 1203 (44) 746 (44) 294 (46) 163 (38)
Rehabilitation
facility
405 (15) 248 (15) 87 (14) 70 (17)
Nursing home 759 (27) 462 (27) 162 (25) 135 (32)
Transfer to another
acute care
hospital
91 (3) 64 (4) 13 (2) 14 (3)
Other or unknown 307 (11) 182 (11) 83 (13) 42 (10)
a
P.001 for both comparison of hyperoxia with normoxia and for hyperoxia with hypoxia.
b
Defined as able to live at home and requiring no assistance to complete activities of daily living. P=.002 for compari-
son of hyperoxia with normoxia and P=.10 for comparison of hyperoxia with hypoxia.
ARTERIAL HYPEROXIA AFTER CARDIAC ARREST
©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2010—Vol 303, No. 21 2169
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Page 5
neonates,
22
the ongoing oxidant stress
associated with hyperoxic reperfusion
may be capable of worsening anoxic
brain injury in adult patients with post-
cardiac arrest syndrome.
Current American Heart Associa-
tion guidelines for adult cardiopulmo-
nary resuscitation advocate 100% in-
spired oxygen during resuscitative
efforts because this may maximize the
likelihood of achieving ROSC.
23
How-
ever, after circulation is successfully re-
stored, clinicians frequently maintain
high F
IO
2
for variable periods.
24
Our
study quantifies the incidence of post-
cardiac arrest hyperoxia. Nearly 1 in 5
patients had exposure to hyperoxia
(Pa
O
2
300 mm Hg) postcardiac ar-
rest and almost half of these patients
had Pa
O
2
of 400 mm Hg or greater.
Therefore, arterial hyperoxia appears to
be a common occurrence in patients re-
suscitated from cardiac arrest. These
data provide insight into a potential
large-scale problem in postcardiac ar-
rest care.
A recent consensus statement on the
treatment of postcardiac arrest syn-
drome by the International Liaison
Committee on Resuscitation advo-
cated the avoidance of unnecessary ar-
terial hyperoxia and a controlled reoxy-
genation strategy targeting an arterial
oxygen saturation not to exceed 94%
to 96%.
24
However, the consensus state-
ment acknowledged that this recom-
mendation was based solely on pre-
clinical data and identified the role of
post-ROSC oxygenation as a critical
knowledge gap for resuscitation sci-
ence.
24
The present study provides im-
portant data to help fill this knowl-
edge gap. Although it may be intuitive
that adequate oxygenation is vital (and
persistent hypoxia should be avoided)
after resuscitation from cardiac arrest,
the present study questions whether a
more is better strategy for post-ROSC
oxygenation is actually harmful as op-
posed to beneficial. In fact, these data
support the hypothesis that both hy-
peroxia and hypoxia are harmful and
underscore the need for clinical trials
of controlled reoxygenation in adults
resuscitated from cardiac arrest.
We acknowledge important limita-
tions in this study. First, this was a
purely observational study; therefore,
we can only identify association rather
than causation. Next, we defined hy-
peroxia as Pa
O
2
of 300 mm Hg or greater
based on PaO
2
levels from a previously
published experimental study,
8
but the
precise PaO
2
level associated with maxi-
mal risk is unknown. In addition, our
definition for the hypoxia group was not
based on Pa
O
2
alone but rather in-
cluded the ratio of Pa
O
2
to FIO
2
as a
component of the definition. This was
necessary because a patient with nor-
mal Pa
O
2
may have required a high FIO
2
to achieve the observed PaO
2
value (ie,
PaO
2
of 65 mm Hg on a FIO
2
of 1.0), and
such a patient would be at high risk of
death, similar to patients with a Pa
O
2
of less than 60 mm Hg. Although our
exposure variable is based on the first
Pa
O
2
value measured over the first 24
hours after arrival in the ICU, the ar-
terial blood gas data in Project IMPACT
are not precisely time stamped. Thus,
it is possible that some of the Pa
O
2
mea-
surements were not obtained early dur-
ing the postresuscitation period; spe-
cifically, we did not capture intraarrest
arterial blood gas data. Laboratory data
indicate that early exposure to hyper-
oxia after reperfusion worsens ischemia-
reperfusion injury; however, hyper-
oxia exposure at later time points may
not.
25
In this context, the limitation of
this study that later PaO
2
measure-
ments may be included in our sample
would be expected to bias the results
toward the null (ie, no association be-
tween hyperoxia exposure and in-
creased mortality).
We also recognize that the Project
IMPACT database was designed from
an ICU perspective, and thus it does not
capture variables in the Utstein style
26
(eg, initial cardiac rhythm, no-flow
time, cardiopulmonary resuscitation
quality) specific to the cardiac arrest
event that preceded the admission to the
ICU. However, the ICU perspective
makes Project IMPACT a valuable
source of information on this topic be-
cause cardiopulmonary resuscitation
registries may not collect Pa
O
2
data af-
ter ROSC. Another limitation worthy
of note is that our study did not cap-
ture whether or not therapeutic hypo-
thermia was attempted. However, only
6% of patients had a lowest body tem-
perature under 34°C in the first 24
hours after arrival in the ICU, indicat-
ing that therapeutic hypothermia was
not widely applied in this cohort. Al-
though the postulated scientific basis
for the association between hyperoxia
exposure and outcome is related to the
degree of anoxic brain injury, we also
acknowledge that hyperoxia could po-
tentially be associated with extracere-
bral deleterious consequences that were
not ascertained in our study. In addi-
tion, Project IMPACT does not cap-
ture airway pressure measurements
Table 5. Multiple Logistic Regression Model With In-Hospital Mortality as the Dependent
Variable
a
Variable OR (95% CI) P Value
Age decile 1.1 (1.1-1.2) .001
Emergency department origin 1.5 (1.3-1.7) .001
Nonindependent functional status at admission 1.3 (1.1-1.4) .001
Chronic renal failure 1.6 (1.3-1.9) .001
Active chemotherapy 2.8 (1.8-4.6) .001
High heart rate in ICU
b
1.9 (1.7-2.1) .001
Hypotension at ICU arrival
c
2.1 (1.9-2.3) .001
Hypoxia exposure 1.3 (1.1-1.5) .009
Hyperoxia exposure 1.8 (1.5-2.2) .001
Abbreviations: CI, confidence interval; ICU, intensive care unit; OR, odds ratio.
a
Event rates (mortality) for each variable and for the relevant reference group appear in eTable 2 at http://www.jama
.com. The following variables were removed from the model because of nonsignificance: female sex, OR, 1.1 (95%
CI, 1.0-1.2; P = .29); chronic respiratory disease, OR, 1.3 (95% CI, 1.0-1.6; P = .05); human immunodeficiency virus,
OR, 1.9 (95% CI, 1.0-3.7; P = .06); and requiring inotropic therapy, OR, 1.1 (95% CI, 0.9-1.3; P = .19).
b
Indicates the highest value for first 24 hours in the ICU (1 =exceeds median; 0 =median or lower).
c
Defined as any systolic blood pressure of less than 90 mm Hg within 1 hour of ICU arrival.
14
ARTERIAL HYPEROXIA AFTER CARDIAC ARREST
2170 JAMA, June 2, 2010—Vol 303, No. 21 (Reprinted) ©2010 American Medical Association. All rights reserved.
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Page 6
from the ventilators that could be a sur-
rogate for barotrauma (such as peak or
plateau airway pressure or positive end-
expiratory pressure). Finally, there may
have been unmeasured confounders
that may have influenced the associa-
tion between oxygenation status and
mortality.
CONCLUSIONS
In this large multicenter cohort of adult
patients admitted to the ICU after re-
suscitation from cardiac arrest, we
found that exposure to hyperoxia is a
common occurrence and an indepen-
dent predictor of in-hospital mortal-
ity. These data support the hypothesis
that postresuscitation hyperoxia could
be harmful and provide scientific ra-
tionale for clinical trials of controlled
reoxygenation during the postresusci-
tation period.
Author Contributions: Drs Kilgannon and Trzeciak had
full access to all of the data in the study and take re-
sponsibility for the integrity of the data and the ac-
curacy of the data analysis.
Study concept and design: Kilgannon, Jones, Shapiro,
Angelos, Parrillo, Trzeciak.
Acquisition of data: Trzeciak.
Analysis and interpretation of data: Kilgannon, Jones,
Shapiro, Milcarek, Hunter, Parrillo, Trzeciak.
Drafting of the manuscript: Kilgannon, Trzeciak.
Critical revision of the manuscript for important in-
tellectual content: Kilgannon, Jones, Shapiro, Angelos,
Milcarek, Hunter, Parrillo, Trzeciak.
Statistical analysis: Kilgannon, Jones, Shapiro, Milcarek,
Hunter, Trzeciak.
Obtained funding: Parrillo.
Administrative, technical, or material support: Parrillo.
Study supervision: Parrillo, Trzeciak.
Financial Disclosures: Dr Trzeciak reported that he re-
ceives material support for research from Ikaria and
serves as a consultant to Spectral Diagnostics, but he
receives no personal remuneration from any commer-
cial interest. None of the other authors reported fi-
nancial disclosures.
Funding/Support: Dr Kilgannon was supported by a
career development grant from the Emergency Medi-
cine Foundation. Dr Jones was supported by grant
GM76652 from the National Institutes of Health and
the National Institute of General Medical Sciences. Dr
Shapiro was supported in part by grant HL091757 from
the National Institutes of Health and the National Heart,
Lung, and Blood Institute and grant GM076659 from
the National Institute of General Medical Sciences. Dr
Trzeciak was supported by grant GM83211 from the
National Institutes of Health and the National Insti-
tute of General Medical Sciences.
Role of the Sponsor: The sponsors had no role in the
design and conduct of the study; collection, manage-
ment, analysis, and interpretation of the data; and
preparation, review, or approval of the manuscript.
Online-Only Material: The eMethods, eResults, eTable
1, and eTable 2 are available at http://www.jama
.com.
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ARTERIAL HYPEROXIA AFTER CARDIAC ARREST
©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2010—Vol 303, No. 21 2171
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  • Source
    • "Hypothermia induces a right shift of the oxygen dissociation curve, decreases oxygen amounts released and increases carbon dioxide solubility [31]. Precisions on temperature are lacking in some studies [30, 32], whereas various proportions of patients are treated with therapeutic hypothermia in others (even if the induced or spontaneous nature of this hypothermia is not clearly indicated) ranging from 6 % [23] to 80 % [33] . Moreover , methodological details regarding temperature corrections of arterial blood gas are missing in most of the studies. "
    [Show abstract] [Hide abstract] ABSTRACT: This review gives an overview of current knowledge on hyperoxia pathophysiology and examines experimental and human evidence of hyperoxia effects after cardiac arrest. Oxygen plays a pivotal role in critical care management as a lifesaving therapy through the compensation of the imbalance between oxygen requirements and supply. However, growing evidence sustains the hypothesis of reactive oxygen species overproduction-mediated toxicity during hyperoxia, thus exacerbating organ failure by various oxidative cellular injuries. In the cardiac arrest context, evidence of hyperoxia effects on outcome is fairly conflicting. Although prospective data are lacking, retrospective studies and meta-analysis suggest that hyperoxia could be associated with an increased mortality. However, data originate from retrospective, heterogeneous and inconsistent studies presenting various biases that are detailed in this review. Therefore, after an original and detailed analysis of all experimental and clinical studies, we herein provide new ideas and concepts that could participate to improve knowledge on oxygen toxicity and help in developing further prospective controlled randomized trials on this topic. Up to now, the strategy recommended by international guidelines on cardiac arrest (i.e., targeting an oxyhemoglobin saturation of 94-98 %) should be applied in order to avoid deleterious hypoxia and potent hyperoxia.
    Preview · Article · Dec 2016 · Annals of Intensive Care
  • Source
    • "Taken together, these data suggest that pulmonary oxygen toxicity is not a clinically important mediator of the association between hyperoxia and patient outcomes after CA. A study of the Project IMPACT database found an association between arterial hyperoxia and worsened survival after CA [8]. The same authors reported increasing odds of mortality in a linear fashion for PaO 2 values in excess of 100 mmHg, suggestive of dose-dependent toxicity [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: Post-cardiac arrest patients often exposed to 100% oxygen during cardiopulmonary resuscitation and the early post-arrest period. It is unclear whether this contributes to development of pulmonary dysfunction or other patient outcomes. We performed a retrospective cohort study including post-arrest patients who survived and were mechanically ventilated at least 24 hours after return of spontaneous circulation. Our primary exposure of interest was inspired oxygen, which we operationalized by calculating the area under the curve of the fraction of inspired oxygen (FiO2AUC) for each patient over 24 hours. We collected baseline demographic, cardiovascular, pulmonary and cardiac arrest-specific covariates. Our main outcomes were change in the respiratory subscale of the Sequential Organ Failure Assessment score (SOFA-R) and change in dynamic pulmonary compliance from baseline to 48 hours. Secondary outcomes were survival to hospital discharge and Cerebral Performance Category at discharge. We included 170 patients. The first partial pressure of arterial oxygen (PaO2):FiO2 ratio was 241 ± 137, and 85% of patients had pulmonary failure and 55% had cardiovascular failure at presentation. Higher FiO2AUC was not associated with change in SOFA-R score or dynamic pulmonary compliance from baseline to 48 hours. However, higher FiO2AUC was associated with decreased survival to hospital discharge and worse neurological outcomes. This was driven by a 50% decrease in survival in the highest quartile of FiO2AUC compared to other quartiles (odds ratio for survival in the highest quartile compared to the lowest three quartiles 0.32 (95% confidence interval 0.13 to 0.79), P = 0.003). Higher exposure to inhaled oxygen in the first 24 hours after cardiac arrest was not associated with deterioration in gas exchange or pulmonary compliance after cardiac arrest, but was associated with decreased survival and worse neurological outcomes.
    Full-text · Article · Dec 2015 · Critical care (London, England)
  • Source
    • "It shows that unfavorable effects cannot be consistently captured when the results are stratified by groups based on arbitrary thresholds. Indeed, studies assessing arterial hyperoxia with lower thresholds usually failed to show significant effects on outcome, whereas higher risks were observed with substantially higher upper limits56789. The current findings validate the recent calls for caution with hyperoxia in cardiac arrest patients only to a limited extent. "
    [Show abstract] [Hide abstract] ABSTRACT: Arterial concentrations of carbon dioxide (PaCO 2 ) and oxygen (PaO 2 ) during admission to the intensive care unit (ICU) may substantially affect organ perfusion and outcome after cardiac arrest. Our aim was to investigate the independent and synergistic effects of both parameters on hospital mortality. This was a cohort study using data from mechanically ventilated cardiac arrest patients in the Dutch National Intensive Care Evaluation (NICE) registry between 2007 and 2012. PaCO 2 and PaO 2 levels from arterial blood gas analyses corresponding to the worst oxygenation in the first 24 h of ICU stay were retrieved for analyses. Logistic regression analyses were performed to assess the relationship between hospital mortality and both categorized groups and a spline-based transformation of the continuous values of PaCO 2 and PaO 2 . In total, 5,258 cardiac arrest patients admitted to 82 ICUs in the Netherlands were included. In the first 24 h of ICU admission, hypocapnia was encountered in 22 %, and hypercapnia in 35 % of included cases. Hypoxia and hyperoxia were observed in 8 % and 3 % of the patients, respectively. Both PaCO 2 and PaO 2 had an independent U-shaped relationship with hospital mortality and after adjustment for confounders, hypocapnia and hypoxia were significant predictors of hospital mortality: OR 1.37 (95 % CI 1.17–1.61) and OR 1.34 (95 % CI 1.08–1.66). A synergistic effect of concurrent derangements of PaCO 2 and PaO 2 was not observed (P = 0.75). The effects of aberrant arterial carbon dioxide and arterial oxygen concentrations were independently but not synergistically associated with hospital mortality after cardiac arrest.
    Full-text · Article · Sep 2015 · Critical Care
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