n engl j med 361;20 nejm.org november 12, 2009
1925
The new england
journal
of medicine
established in 1812
november 12, 2009
vol. 361 no. 20
The new england
journal
of medicine
established in 1812
Critical Care Services and 2009 H1N1 Influenza
in Australia and New Zealand
The ANZIC Influenza Investigators*
ABSTR ACT
The Australian and New Zealand Intensive
Care (ANZIC) study is a collaboration of
the ANZIC Society Clinical Trials Group
(CTG), the ANZIC Research Centre, the
Australasian Society of Infectious Diseas-
es CTG, the Paediatric Study Group of the
ANZIC Society, and the ANZIC Society
Centre for Outcome and Resource Evalua-
tion. The writing committee (Steven A.R.
Webb [chair], M.P.H., Ph.D., F.R.A.C.P.,
F.J.F.I.C.M., Ville Pettilä, M.D., Ph.D., Ian
Seppelt, F.A.N.Z.C.A., F.J.F.I.C.M., Rinal-
do Bellomo, M.D., F.R.A.C.P., F.J.F.I.C.M.,
Michael Bailey, Ph.D., David J. Cooper,
M.D., F.R.A.C.P., F.J.F.I.C.M., Michelle
Cretikos, M.P.H., Ph.D., Andrew R. Davies,
F.R.A.C.P., F.J.F.I.C.M., Simon Finfer,
F.R.C.P., F.J.F.I.C.M., Peter W.J. Harrigan,
F.J.F.I.C.M., Graeme K. Hart, F.A.N.Z.C.A.,
F.J.F.I.C.M., Belinda Howe, R.N., Jonathan
R. Iredell, Ph.D., F.R.A.C.P., F.R.C.P.A., Co-
lin Mc Arthur, F.J.F.I.C.M., Imogen Mitch-
ell, F.R.A.C.P., F.J.F.I.C.M., Siouxzy Morri-
son, R.N., M.P.H., Alistair D. Nichol,
Ph.D., F.C.A.R.C.S.I., David L. Paterson,
Ph.D., F.R.A.C.P., F.R.C.P.A., Sandra Peake,
F.J.F.I.C.M., Ph.D., Brent Richards,
F.R.A.C.P., F.J.F.I.C.M., Dianne Stephens,
F.A.N.Z.C.A., F.J.F.I.C.M., Andrew Turner,
F.R.A.C.P., F.J.I.C.M., and Michael Yung,
M.D.) takes responsibility for the content
and integrity of this article. Address re-
print requests to Dr. Webb at the Intensive
Care Unit, Royal Perth Hospital, Welling-
ton St., Perth, WA 6000, Australia, or at
sarwebb@cyllene.uwa.edu.au.
*Affiliations of the members of the writ-
ing committee, and the other study in-
vestigators, are listed in the Appendix.
This article (10.1056/NEJMoa0908481) was
published on October 8, 2009, at NEJM.
org.
N Engl J Med 2009;361:1925-34.
Copyright © 2009 Massachusetts Medical Society.
BACKGROUND
Planning for the treatment of infect ion w it h t he 2009 pandemic inf luenza A (H1N1)
virus through health care systems in developed countries during winter in the North-
ern Hemisphere is hampered by a lack of information from similar health care
systems.
METHODS
We conducted an inception-cohort study in all Australian and New Zealand inten-
sive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calcu-
lated, per million inhabitants, the numbers of ICU admissions, bed-days, and days
of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected
data on demographic and clinical characteristics of the patients and on treatments
and outcomes.
RESULT S
From June 1 through August 31, 2009, a total of 722 patients with conf irmed infec-
tion with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% conf idence
inter val [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of
the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were preg-
nant women; of the 601 adults for whom data were available, 172 (28.6%) had a
body-mass index (the weight in kilograms divided by the square of the height in
meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU
for a total of 8815 bed-days (350 per million inhabitants). The median duration of
treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 pa-
tients (64.6%) with available data underwent mechanical ventilation for a median
of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU
was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009,
a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114
(15.8%) remained in the hospital.
CONCLUSIONS
The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Austra-
lia and New Zealand. Our data can assist planning for the treatment of patients dur-
ing the winter in the Northern Hemisphere.
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The
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n engl j med 361;20 nejm.org november 12, 2009
1926
I
nfection with the 2009 pandemic in-
fluenza A (H1N1) virus emerged in Mexico
toward the end of the 2008–2009 influenza
season in the Northern Hemisphere. As of Septem-
ber 6, 2009, the World Health Organization had
reported over 277,607 laboratory-confirmed cas-
es of 2009 H1N1 influenza, with at least 3205
deaths.
1
From June through August 2009, Austra-
lia and New Zealand experienced the combined
effect of the pandemic and winter in the South-
ern Hemisphere. The reported incidence of infec-
tion with the 2009 H1N1 virus during winter in
Australia and New Zealand was 8 times that re-
por t ed for t he s a me period i n t he Un ited St at es.
1,2
This resulted in a substantial increase in demand
for hospital services, particularly critical care
services.
Reports of critical illness caused by 2009 H1N1
inf luenza during summer in the Northern Hemi-
sphere contain insufficient data to provide reli-
able estimates of the burden of critical illness to
be expected during winter in the Northern Hemi-
sphere.
3-9
Although the successful deployment of
a safe and effective vaccine may modify the bur-
den of disease,
10,11
population-based data from
Australia and New Zealand can currently provide
a reasonable estimate of the likely effect of 2009
H1N1 influenza during the Northern Hemisphere
winter. In addition, the data can be used to iden-
tify persons who are at high risk of developing
severe disease.
In this report, we describe the incidence of in-
tensive care unit (ICU) admission, demographic
characteristics, treatment, use of critical care re-
sources, and outcome for all patients with labo-
ratory-confirmed infection with the 2009 pan-
demic influenza A (H1N1) virus admitted to
ICUs in Australia and New Zealand during the
winter of 2009 in the Southern Hemisphere.
Methods
We performed a multicenter inception-cohort study
involving 187 ICUs in Australia and New Zealand
— all the ICUs (adult, pediatric, or adult and pe-
diatric) in the two countries.
12
The ICUs had a to-
tal of 1879 beds, of which 1449 were equipped
for mechanical ventilation. Each center obtained
approval from the institutional ethics committee.
The requirement for written informed consent
from individual patients was waived at all sites.
From June 1 through August 31, 2009, we
identified all patients admitted to the ICU with
confirmed infection with the 2009 pandemic in-
fluenza A (H1N1) virus. The 2009 H1N1 influenza
was confirmed by means of a polymerase-chain-
reaction (PCR) assay or serologic analysis. The
2009 pandemic influenza A (H1N1) virus and
seasonal subtypes (preexisting H1N1 and H3N2
strains) were confirmed by PCR assay. The PCR
assay was conducted initially at reference labora-
tories in each region and later, as the pandemic
evolved, at local laboratories. The performance of
these laboratories was accredited by the National
Association of Testing Authorities in Australia or
by International Accreditation New Zealand. In
addition, the 2009 H1N1 virus could be confirmed
in a single reference laboratory by means of a
hemagglutination-inhibition assay to detect anti-
bodies specific for the 2009 H1N1 virus. Popula-
tion data for Australia and New Zealand and their
constituent regions were obtained from Austra-
lian Bureau of Statistics
13
and Statistics New
Zealand.
14
We collected several types of data for the pa-
tients: the dates and times of admission to the
hospital and the ICU; age; race or ethnic group,
including indigenous group (reported by patients
or their next of kin or, for patients under 18 years
of age, by a parent or guardian); sex; pregnancy
or childbirth less than 28 days previously (for
women); coexisting conditions, which for patients
16 years of age or older were any condition that
is defined within the Chronic Health Evaluation
component of the Acute Physiology, Age, and
Chronic Health Evaluation (APACHE III, for which
scores can range from 0 to 299, with higher scores
indicating a greater severity of illness),
15
and for
patients under 16 years of age, defined as pre-
maturity, immunodeficiency, cystic fibrosis, con-
genital heart disease, neuromuscular disorder, or
chronic neurological impairment; history of asth-
ma or another chronic pulmonary disease, chronic
heart failure, or diabetes; measured or estimated
weight and height (for calculation of the body-
mass index [BMI]); date and time of first symp-
toms; presence and type of influenza syndrome,
including viral pneumonitis or the acute respira-
tory distress syndrome, secondary bacterial pneu-
monia, exacerbation of airflow limitation due to
either asthma or chronic obstructive pulmonary
disease, or intercurrent illness; and airway status
at the time of ICU admission (presence or absence
of endotracheal intubation, tracheotomy, sealed
face mask, and any artificial airway).
We categorized patients according to the age
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Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand
n engl j med 361;20 nejm.org november 12, 2009
1927
groups used in a previous report: 0 to 1 year of
age, 1 to 4 years, 5 to 24 years, 25 to 49 years, 50
to 64 years, and 65 years of age or older.
16
Data
were collected daily on the use of mechanical ven-
tilation and extracorporeal membrane oxygen-
ation. We calculated the duration of treatment in
the ICU and the hospital, as well as the rates of
occupancy of the ICU, for Australia and New Zea-
land and their constituent regions. We recorded
outcomes of patients in the ICU and whether the
patients had been discharged or were still in the
hospital or the ICU as of September 7, 2009. To
compare data from the current year with those
from previous years, we obtained the number of
patients who had been admitted to Australian or
New Zealand ICUs with viral pneumonitis during
the winters of 2004 through 2008, from the Aus-
tralian and New Zealand Intensive Care (ANZIC)
Society’s Adult Patient Database.
17
This source of
data does not categorize the cause of viral pneu-
monitis and may include some patients who had
viral pneumonitis due to causes other than inf lu-
enza A. To determine which groups were at in-
creased risk of admission to an ICU with 2009
H1N1 influenza, we compared the proportions of
patients with such an admission in each group of
interest with the proportions of the general popu-
lation of Australia
13
and New Zealand
14
that those
admitted patients represented.
Data Management
We collected data by means of electronic case re-
port forms. The study coordinating center was the
ANZIC Research Centre, Monash Universit y, Mel-
bourne, Australia.
18
Infect ion with t he 2009 H1N1
virus is subject to mandatory reporting in both
Australia and New Zealand, and all diagnoses were
conf irmed with the relevant st ate or territor y’s De-
partment of Health. In addition, to confirm the
completeness of case ascertainment, we contact-
ed the 83 ICUs that had no reported cases at the
end of the study period (August 31, 2009). Pat ients
transferred bet ween ICUs were counted as a single
ICU admission. We made no assumptions regard-
ing missing data; all proportions were calculated
as percentages of the patients with available data.
Statistical Analysis
We performed statistical analysis using SAS soft-
ware, version 9.1 (SAS Institute). We calculated de-
scriptive statistics for all study variables. We report
data for continuous variables as medians (with
interquar t ile ranges) and for categorical variables
as percentages (with 95% confidence intervals,
where appropriate). We estimated the age-based
population-admission rates.
13
We performed a uni-
variate analysis for in-hospital mortalit y, using the
chi-square test, Fisher’s exact test, or Wilcoxon
rank-sum test, as appropriate. We performed mul-
tivariate logistic-regression analysis to identify fac-
tors independently associated with in-hospital
mor t alit y, w it h the mult iva ri at e model const ructed
by using both stepwise-selection and backward-
elimination techniques. We first included age, as
a continuous variable. We then included in the
model, as categorical variables,
16
the presence or
absence of pregnancy, asthma or anot her chronic
pulmonar y disease, and chronic heart failure; BMI
6 col
33p9
856 Patients were admitted to ICU
with confirmed influenza A
722 Patients (84.3%) had
confirmed infection with
2009 H1N1 virus
505 Were discharged
103 (14.3%) Died
114 Were still in hospital
37 Patients (4.3%) had infection
with seasonal H1N1 or
H3N2 virus
27 Were discharged
6 (16.2%) Died
4 Were still in hospital
97 Patients (11.3%) had infection
with influenza A that was not
subtyped
72 Were discharged
13 (13.4%) Died
12 Were still in hospital
AUTHOR:
FIGURE:
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Revised
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Please check carefully.
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Figure 1. Enrollment and Follow-up of Patients with Influenza A Admitted to Intensive Care Units (ICUs) in Australia
and New Zealand.
Follow-up data are as of September 7, 2009.
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n engl j med 361;20 nejm.org november 12, 2009
1928
(the weight in kilograms divided by the square of
the height in meters) greater than 35 versus 35 or
less; race or ethnic group; and the presence or ab-
sence of any coexisting condition; and the type of
influenza syndrome. Goodness of fit was deter-
mined with the use of the Hosmer–Lemeshow sta-
tistic. A two-sided P value of less than 0.05 was
considered to indicate statistical significance, ex-
cept in the multivariate model, where a P value of
less than 0.01 was considered to indicate statisti-
cal significance.
Results
We identified 856 patients with influenza A infec-
tion who were admitted to an ICU between June 1
and August 31, 2009. Of these, 722 (84.3%) had a
confirmed infection with 2009 pandemic influ-
enza A (H1N1) virus (Fig. 1). The 2009 H1N1 vir us
was diagnosed by means of PCR assay in 717 pa-
t ient s and serolog ic a nalysis i n 5 p at ient s. A mong
the 722 patients with 2009 H1N1 influenza, 626
were admitted to an ICU in Australia and 96 to an
ICU in New Zealand. The numbers of patients with
viral pneumonitis admitted to Australian or New
Zealand ICUs from June 1 through August 31 were
57 in the year 2005, 33 in 2006, 69 in 2007, and
69 in 2008 (mean, 57 patients). During the winter
of 2009, 37 patients were admitted to an ICU with
conf i rmed s e ason a l subt y pe s of in f luen z a A (H1N1)
virus. The combined population of Australia and
New Zealand was estimated at 25,180,770, giving
an incidence of ICU admission for 2009 H1N1 in-
fluenza during winter 2009 of 28.7 (95% confi-
dence interval [CI], 26.5 to 30.8) per million in-
habitants.
13,14
The number of admissions and the age-specific
incidences varied substantially according to the
age group (
Fig. 2
). The highest age-specific inci-
dence of ICU admission was among infants (0 to
1 year of age) (
Fig. 2A
), whereas the highest num-
ber of ICU admissions was among patients 25 to
49 years of age (
Fig. 2B
). Additional demographic
data and data on risk factors and type of critical
illness among patients with 2009 H1N1 inf luenza
are presented in Table 1.
Pregnant women represent approximately 1%
of the general population of Australia and New
Zealand.
13,14
A total of 66 of the 722 patients
(9.1%) admitted to the ICU with 2009 H1N1 in-
f luenza were pregnant women. Of the 601 adults
for whom BMI data were available, 172 (28.6%)
had a BMI greater than 35. The proportion of a
representative adult Australian population with a
BMI greater than 35 was 5.3% in 2003.
19
We esti-
mate the proportion of patients with asthma or
other chronic pulmonary disease in the general
population to be around 13%.
20
Data on premor-
bid pulmonary disease were missing for 15 of the
722 patients with 2009 H1N1 influenza in our
study; of the remaining 707 patients, 231 (32.7%)
had asthma or another chronic pulmonary dis-
ease. Indigenous groups were relatively overrep-
resented in our study: aboriginal and Torres Strait
3 col
16p6
ICU Admissions (no. per million
inhabitants)
120
100
60
80
40
20
0
0 to <1
1 to 4
5 to 24
25 to 49
50 to 64
≥65
Years of Age
A
No. of ICU Admissions
350
200
250
150
200
100
50
0
0 to <1
1 to 4
5 to 24
25 to 49
50 to 64
≥65
Years of Age
B
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Figure 2. Incidence and Number of Admissions to the
Intensive Care Unit (ICU), According to Age Group.
The incidence of ICU admission, expressed as the
number per million residents, is shown in Panel A, and
the number of ICU admissions is shown in Panel B.
The age-specific incidence was calculated by dividing
the number of admissions in each age group by the es-
timated number of persons in that age group in the
population of Australia and New Zealand (which was
350,346 for 0 to 1 years, 1,324,185 for 1 to 4 years,
6,938,498 for 5 to 24 years, 9,111,600 for 25 to 49
years, 4,563,709 for 50 to 64 years, and 3,377,580 for
65 years or older). I bars indicate the 95% confidence
intervals.
The New England Journal of Medicine
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Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand
n engl j med 361;20 nejm.org november 12, 2009
1929
Islanders account for 2.5% of the Australian popu-
lation
13
but made up 9.7% of our patients with
2009 H1N1 influenza who were admitted to Aus-
tralian ICUs. Maori represent 13.6% of the New
Zealand population
14
but accounted for 25.0% of
the patients with 2009 H1N1 inf luenza who were
admitted to New Zealand ICUs. Overall, 229 pa-
tients (31.7%) had no known predisposing factor.
Almost half of all patients (48.8%) had the acute
respiratory distress syndrome or viral pneumonitis,
Table 1. Baseline Characteristics of Patients with Confirmed Critical Illness Related to 2009 H1N1 Influenza.*
Characteristic Value
Age — yr
Median 40
IQR 26–54
Female sex — no./total no. (%) 376/722 (52.1)
Pregnant — no./total no. (%) 66/722 (9.1)
Race or ethnic group — no./total no. (%)†
White 483/683 (70.7)
Aboriginal or Torres Strait Islander
All patients 61/683 (8.9)
Admitted to ICU in Australia 61/683 (8.9)
Maori
All patients 31/683 (4.5)
Admitted to ICU in New Zealand 24/683 (3.5)
Pacific Islander 37/683 (5.4)
Asian 29/683 (4.2)
Other 42/683 (6.1)
Adults with BMI >35 — no./total no. (%)‡ 172/601 (28.6)
Diabetes — no./total no. (%) 112/700 (16.0)
Asthma or chronic pulmonary disease — no./total no. (%) 231/707 (32.7)
Chronic heart failure — no./total no. (%) 74/703 (10.5)
Coexisting condition — no./total no. (%)§ 192/687 (27.9)
No known predisposing factors — no./total no. (%) 229/722 (31.7)
Time from first symptoms to hospital admission — days¶
Median 4
IQR 2–7
Influenza syndrome — no./total no. (%)
Viral pneumonitis or ARDS 336/689 (48.8)
Secondary bacterial pneumonia 140/689 (20.3)
Exacerbation of airflow limitation 95/689 (13.9)
Intercurrent illness or other illness 118/689 (17.1)
* ARDS denotes the acute respiratory distress syndrome, ICU intensive care unit, and IQR interquartile range.
† Race or ethnic group was reported by patients or their next of kin or, for patients under 18 years of age, by a parent or
guardian.
‡ The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
§ Coexisting conditions for patients 16 years of age or older were any condition that is defined within the Chronic Health
Evaluation component of the Acute Physiology, Age, and Chronic Health Evaluation (APACHE III),
15
and for patients
under 16 years of age, defined as prematurity, immunodeficiency, cystic fibrosis, congenital heart disease, neuromuscu-
lar disorder, or chronic neurologic impairment.
¶ Time from first symptoms to hospital admission was known for 712 of the 722 patients.
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