Title

Author(s)

Management of severe sepsis in patients admitted to intensive

care units in Hong Kong, focus on early blood culture taking and
starting of antibiotics
Lam, Koon-ngai;

Citation

Issued Date

URL

Rights

2012

http://hdl.handle.net/10722/173740

Creative Commons: Attribution 3.0 Hong Kong License

Management of severe sepsis in patients admitted to

Intensive Care Units in Hong Kong,
Focus on early blood culture taking and starting of antibiotics
By
Lam Koon Ngai
This work is submitted to
Faculty of Medicine of The University of Hong Kong
In partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Disease,
PDipID(HK)
Supervisor: Dr. SSY Wong

Management of severe sepsis in patients admitted to intensive care units in Hong

Kong, focus on early blood culture taking and starting of antibiotics

ABSTRACT
Objectives

To assess the compliance of HK intensive care units to early taking of

blood culture and early administration of board-spectrum antibiotics and to discuss the
reasons behind the observed phenomenon.
Design

Retrospective review of the data from a prospective cohort study.

Setting

Six intensive care unit across Hong Kong.

Participants

102 adult patients with severe sepsis who were admitted to these

intensive care units in July 2009. The organizational characteristics of participating

centres, the patients baseline characteristics, the achievement of targets within the
resuscitation and management bundles, and outcome data were recorded.
Results

Compliance with early taking of the blood cultures is 64.7% and compliance

with early administration of antibiotics was 55.9%. There is no significant difference in

time to antibiotics administration across different source of sepsis, different hospital/ICU
and present or absent of persistent hypotension.
Conclusions

Compliance of early blood culture and early antibiotic administration in

Hong Kong cohort were comparable to international cohorts

INTRODUCTION
The Management Of Severe sepsis in Asias Intensive Care unitS (MOSAICS)
study was a multicentre prospective cohort study involving 150 intensive care units in 16
Asian countries1. In the study, there are a few major findings: Firstly, compliance rates
for the entire resuscitation and management bundles were much lower than the
compliance rate observed in the other cohorts in European countries2-6

Secondly,

High-income countries, university hospitals, intensive care units with an accredited

fellowship programme, and surgical intensive care units were more likely to be
compliant to the bundle. Thirdly, compliance to early taking of blood cultures, early
administration of broad-spectrum antibiotics and central venous pressure target
independently predicted decreased mortality. It was also suggested that more should be
done to improve compliance to the sepsis bundles in Asia.
As a high-income countries with well-structured intensive care/critical care
fellowship accreditation programme, we would wishfully believe that our performance
should be up to international standard and closely adhere to those performance
indicators. The findings in MOSAICS had shaken our belief, thus it is important to know
the compliance rate of our locality and analysis them separately and to look into varies
factors that lead to that low compliance to the protocol.
Since compliance to the individual component of the bundle may be as
efficacious as compliance to all, and early antibiotics therapy is the only target, which is
consistently linked with survival in bundle studies6-8, attentions and improvement effort
should be focus mainly on those three important components of the bundles. Data on

compliance on blood culture and early antibiotic administration in Hong Kong will be
closely inspected and discussed in this paper.

METHODS
Study design
Retrospective review of the data collected from MOSAICS.
The detail methodology of MOSAICS study was published in the original paper.
A steering committee of coordinators from various Asian countries, formed in February
2009, invited physicians representing intensive care units in their countries to participate
through direct contact, circulated e-mails, and local meetings.
All patients admitted to participating intensive care units in July 2009 were
screened for eligibility; there was no formal sample size calculation. All adult patients
with severe sepsis, excluding those younger than 21 years old, transfers from another
intensive care unit or hospital, and readmissions to the intensive care unit during the
current hospital stay, were enrolled. Patients developed severe sepsis or septic shock
before admission to the intensive care unit or during the stay in the intensive care unit
were included. The definition of severe sepsis was adapted from the 2001 International
Sepsis Definitions Conference and the Surviving Sepsis Campaign,9 10 ie sepsis with the
following organ dysfunctions: hypotension (systolic blood pressure<90 mmHg or
decrease>40 mm Hg or mean arterial pressure<65 mm Hg), hyperlactatemia (2
mmol/L), renal (acute increase in serum creatinine to>176.8 mmol/L or urine output<0.5
mL/kg/hour for>2 hours), lung (acute lung injury with the ratio of the partial pressure of
arterial oxygen to the fractional inspired oxygen being300 mmHg), liver (acute increase

in bilirubin to>34.2 umol/L), thrombocytopenia (acute decrease to<100,000/L), and/or

coagulopathy (international normalised ratio>1.5 or a partial thromboplastin time>60
secs).

Data collection
All data were extracted from the original MOSAICS study. In the original study
data collection, no attempts were made to educate the participating centres on the
sepsis bundles. Collected data included organizational characteristics of intensive care
unit and the Demographics of the patients, patient location at diagnosis of severe sepsis
(emergency department, ward, intensive care unit), source of infection, organ
dysfunction, number of organ failures, the Acute Physiology and Chronic Health
Evaluation (APACHE) II score, intensive care unit and hospital mortality, intensive care
unit and hospital length of stay, and duration of invasive mechanical ventilation. Lastly,
the achievement of targets in both the resuscitation bundle (lactate measurement, blood
cultures, broad-spectrum antibiotics, fluids vasopressors, central venous pressure,
and central or mixed venous oxygen saturation within 6 hours of presentation) and the
management bundle (steroids, drotrecogin alfa, glucose control, lung-protective
ventilation within 24 hours) (table 1). The time of presentation, determined via chart
review, was defined as the time of presentation to the emergency department with
severe sepsis, or the time of diagnosis of severe sepsis for patients who developed
severe sepsis in the ward (and other non-emergency department units) or intensive
care unit.
Statistical analyses

Categorical variables are given as number (percentage, as well as 95%

confidence interval for compliance to bundle targets), normally distributed numerical
variables as mean (standard deviation), and other numerical variables as median
(interquartile range). Categorical variables were analysed using the 2 test or Fisher
exact test. When normality and homogeneity assumptions were satisfied, quantitative
variables were compared using the t-test, otherwise, the Mann-Whitney U-test was
used. P value of <0.050 was considered significant.
RESULTS
Six intensive care units from Hong Kong participated in the study, enrolling 102
adult patients, which accounted for 17.5 % of all intensive care unit admissions during
the study period. The mean APACHE II score was 24.4. The average length of stay was
9 days. There were 64 survivors. The overall hospital mortality was 37.3 %. The median
intensive care unit and hospital lengths of stay were 6 days and 19.5 days respectively.
Table 2 shows the patients baseline characteristics. Figure 1 show the source of
infection of the patient. Pneumonia, Intra-abdominal infection and Urinary tract infection
complies majority of the source of sepsis.
Overall Compliance with the entire resuscitation bundle and management bundle
were 1% (1/102) and 13.7 %(14/102) respectively. There is 64.7% of the time when
blood cultures were taken within 6 hours (figure 2), and 55.9% of the time when
antibiotics were given within 3 hours from AED admission or 1 hour within ward or ICU
admission (figure 3). If cultures taken before time-zero were excluded, the median time
for a blood culture to be taken after sepsis being diagnosed was 135 minute (IQR 44257). If antibiotics given before time-zero were excluded, antibiotic was given within

time in 19.6% only and the median time to received antibiotics was 128 minute (IQR 60300)(figure 4). Time to receive antibiotic is independent to individual hospital/unit, the
location of making the diagnosis of sepsis and the presence of persistent shock.
(Figures 5-7)

DISCUSSION
To improve outcomes in severe sepsis, the Surviving Sepsis Campaign
recommends a 6-hour resuscitation bundle,10 including early blood cultures and
antibiotics,11 and various aspects of early goal-directed therapy for haemodynamic
derangements.12 A 24-hour management bundle is also recommended, which includes
low-dose steroids,13 drotrecogin alfa (activated),14 glucose control,15 and guidelines on
ventilatory support.14 16 Several single and multicentre studies and a meta-analysis have
suggested that compliance with these recommendations may lead to a survival
benefit.2-7

17 18

. Nonetheless, not all components within the bundles were considered

equally important. The efficacy of some components of the bundles has been
questioned with large randomized controlled trial19.
The MOSIACS study point out that compliance to the resuscitation and
management bundles is generally poor in much of Asia ICU. Form the Hong Kong data
subset; sepsis accounted for 17.5 % of all intensive care unit admissions a rate, which
is slightly higher than the 11% seen in the United States,20 Australia and New
Zealand.21 The overall compliance rate to the resuscitation bundles was concernedly
low at 1%(1/102) only. This is partly because no centre in Hong Kong do SvO2 or ScvO2
measurement routinely However, the hospital mortality was only 37.3 % in our cohort,

which is comparable to the 38% mortality reported in a study from Australia and New
Zealand, despite our slightly higher APACHE II score (24.4 vs 21).22 These, once again,
support queries about the importance of every single component of the bundles.
While only blood cultures, early broad-spectrum antibiotics and central venous
pressure target were the components within the bundle that independently associated
with patients outcomes, our compliance rate to the first two component were
comparable to other cohorts23 24. That might be one of the explanations why we could
still achieve a comparably satisfactory patient outcome.
In fact, the association between early board-spectrum and good clinical outcome
was supported by human and animal data25-28. One retrospective cohort had
demonstrated that when antibiotics is progressively delayed beyond 6 hours, there will
be an average decrease in survival of 7.6% per hour in the subsequent hours27.
Therefore, we should attempt every effort to avoid delay in antibiotics administration
once diagnosis of severe sepsis is made.
Antibiotics administration delay can be related to patients, clinicians and
systematic factors.

The most obvious patients factor will be delay presentation to

healthcare service, which will not be reflected in our data. Patients presentations, like
atypical symptoms in community acquired pneumonia, may delay antibiotics29. Certain
type of infection like meningitis, pneumonia and septic shock, might lead to prompt
antibiotic administration26

28 30 31

. However, such disease-specific factors were not

demonstrated in our cohort. It is quite surprising that even persistent hypotension is not
associated with earlier antibiotic treatment. Barriers to adherence to clinical practice
guidelines have been categorized into three areas: knowledge, attitudes, and

behaviour32. Clinicians delay in administrating antibiotics might be due to failure to

consider the diagnosis, a lack of knowledge. In ICU setting, diagnosis of infection is
sometime not easy, as there are a lot of background noise signal. Fever complicates up
to 70 percent of all ICU admissions 33, and could be due to non-infectious causes. Even
high WBC and lung infiltrate might not be specific enough to diagnosis sepsis in ICU.
Clinician attitudes are difficult to test and local data concerning this aspect is lacking. In
addition clinicians behaviors are affected by the availability of resources. Protocols
alone cannot ensure compliance. For example, if blood culture bottle were not available
in some emergency departments, clinician cannot perform blood cultures. Systematic
delay might also happen with rigid sequential workflow. One of the examples is insisted
on getting a CT brain scan and then lumbar puncture before starting antibiotics for
meningitis. Recently, some of the hospital in Hospital Authority had restricted the ward
stock of antibiotics, so that all prescription must go through centre pharmacy and check
with their database. This measure aims at crosschecking patients allergic history but
the possible impact on delaying antibiotic administration has not been studied. This type
of systematic factors will be reflected in performance in the hospital-level. Hospital B
and Hospital D are within the same cluster and they have the longest median time to
administered antibiotics compare to the other centres. This raises a concern about
some systematic problems on sepsis management within the cluster. If early
administration of antibiotics is consider a kind of performance indicator, and antibiotics
may sometime initiated before we are not certain about their necessity, we will inevitably
subject more patients to unnecessary antibiotics and its side effect. We do not know

whether the risk of delaying antibiotic treatment outweigh the slight risk of anaphylactic
reaction or antibiotic overuse.

Study limitations
This is the first cohort data to study sepsis management across intensive care
units of Hong Kong. However, selection bias is expected as only six centres participate
in the study. Two university centres were enrolled which therefore over represent in the
cohort. Physician might change their usual practice when they are aware of being
observed (Hawthorne effect). The sample size was small and the surveillance only carry
out for one month. The net effect of the selection bias may be an overestimate of
compliance. Due to the method of data collection (time zero set at the time when
diagnosis of sepsis was made), information about time delay for attending the patients
and time delay on making the diagnosis of sepsis were not revealed. Other study
limitations include lack of data collection for antibiotic dosage and the sensitivity of the
organism to the antibiotic used. Appropriate antibiotic dosage and spectrum is another
important factor that may impact outcome in sepsis25 34.
Conclusions
Although the compliance to the Surviving Sepsis Campaigns resuscitation and
management bundles for severe sepsis in adult patients is quite low in Hong Kong, the
compliance to blood culture taking and early administration of antibiotics were
comparable to international cohorts. Healthcare policymakers should look into various
factors that can further improve these important performance indicators, especially
systematic factors that related to individual hospital structure and practice.

10

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13

Target*
Resuscitation bundle (first 6h)
Measure lactate
Blood cultures before antibiotics
Broad-spectrum antibiotics within 3h for ED admissions and 1h for others
Fluids (20 mL/kg of crystalloids or equivalent)vasopressors
CVP8 mm Hg
ScvO2 70% or SvO2 65%
Management bundle (first 24h)
Low-dose steroids administered or considered
Glucose4.5 and 10.0 mmol/L at 6-24h
Tidal volume6 mL/kg predicted body weight
Table 1: Bundle targets used (after exclusion of rhAPC)

Applicable to relevant clinical scenarios

All patients
All patients
Hypotension or lactate4 mmol/L (fluids
required)septic shock (hypotension despite
initial fluids: vasopressors required)
Septic shock or lactate 4 mmol/L
Septic shock or lactate 4 mmol/L

Septic shock
All patients
ALI/ARDS

ALI= acute lung injury; APACHE=Acute Physiology and Chronic Health Evaluation; ARDS=acute respiratory distress syndrome;
CVP=central venous pressure; ED=emergency department; PBW=predicted body weight; ScvO2=central venous oxygen saturation;
SvO2=mixed venous oxygen saturation.

14

Table 2:Baseline characteristics of patients

Characteristic*
Demographics
Age (years)
Male
Diagnosis on ICU admission
Medical/non-operative
Scheduled/elective post-operative
Unscheduled/emergent post-operative
Location at diagnosis of severe sepsis
ED
Ward
ICU
Organ dysfunction on arrival at ICU
Hypotension or on vasopressors
Hyperlactatemia
Acute kidney injury
Acute lung injury
Hyperbilirubinemia
Thrombocytopenia
Coagulopathy
No. of organ failures
APACHE II score

All
(n=102)

Survivors
(n=64)

Nonsurvivors
(n=38)

P value

66.9 (15.6)
69

65.0(16.2)
43

67.9(14.7)
26

0.37

63 (61.7)
3 (3.0)
36(35.3)

42 (65.6)
1(1.6)
21 (32.8)

21 (55.2)
2(5.3)
15 (39.5)

10(9.8)
72(70.6)
20(19.6)

5(7.8)
49(76.6)
10(15.6)

5(13.2)
23(60.5)
10(26.3)

86
12
40
33
17
12
22
2.2(1.4)
24.4 (9.1)

52
7
22
18
8
3
11
1.9(1.2)
22.2 (7.9)

34
5
18
15
9
9
11
2.7(1.5)
28.2 (9.9)

0.207
0.484
0.138
0.167
0.118
0.006
0.126
0.021
0.085

APACHE II=Acute Physiology and Chronic Health Evaluation II Score during the first 24 hours of ICU
admission; ED=emergency department; ICU=intensive care unit.
*Data are number of patients (percentage) or mean (standard deviation).

15

Figure 1: Source of Infections

Figure 2: Proportion of patients have their blood culture taken at different time

16

Figure 3: Proportion of patients received antibiotics at different time

Figure 4: Distribution curve of the number of Patient's received antibiotics

at different time (excluding those received before time zero)

17

Figure 5: Boxplot median time to antibiotics administration Vs persistent hypotension

18

P=0.17

Figure 6: Median time to antibiotic administration Vs location at diagnosis

Figure 7: Median time to antibiotics Vs different hospital

19

20