Anaesth Intensive Care 2011; 39: 449-455

The relationship between blood lactate and survival

following the use of adrenaline in the treatment of septic
shock
S. OMAR*, A. T. BURCHARD†, A. C. LUNDGREN‡, L. R. MATHIVHA§, J. M. DULHUNTY**
Intensive Care Unit, Chris Hani Baragwanath Hospital, University of Witwatersrand, Johannesburg, South Africa

SUMMARY
This prospective observational study evaluates the relationship between adrenaline, lactate and intensive care unit
survival in septic shock. Forty patients requiring adrenaline therapy for a first episode of septic shock acquired
>24 hours after admission to the intensive care unit had blood lactate levels measured two-hourly over a 24-hour
period. Adrenaline therapy was escalated until target mean arterial pressure was reached. The lactate index was
calculated as the ratio of maximum lactate increase to the adrenaline increase. Lactate increased from 2.3 to 2.9
mmol.l-1 (P=0.024) and the mean adrenaline increase was 0.14 μg.kg-1.minute-1. Peak lactate correlated with peak
adrenaline (rho=0.34, P=0.032). Lactate index was the only independent predictor of survival after controlling for
age and Acute Physiological and Chronic Health Evaluation II score (odds ratio 1.14, 95% confidence interval 1.03
to 1.26, P=0.009). A high lactate following adrenaline administration may be a beneficial and appropriate response.
Key Words: septic shock, survival, adrenaline, blood lactate

Severe sepsis is characterised by profound fluid resuscitation10. However, adrenaline is also

metabolic and inflammatory derangement which
can lead to multi-organ failure and death1. During
septic shock, oxygen delivery may fail to meet tissue
demand resulting in increased oxygen extraction.
Once tissue needs are no longer met, an oxygen
debt with global tissue hypoxia and associated
hyperlactataemia ensues. Several studies have
shown that blood lactate may be used as a marker of
global tissue hypoxia and prognosis in shock states1-7.
A common physician’s view of lactate is that it is a
marker of poor prognosis, while for the scientist
lactate may be considered a dead-end metabolite8.
Vasoactive agents, including adrenaline and
noradrenaline, are often required to restore
adequate cardiovascular function in addition to
* M.B., Ch.B., F.C., Path. (SA) Chem., D.A. (SA), Critical Care (SA),
Critical Care Specialist.
† M.B., Ch.B., F.C.A. (SA), Specialist Anaesthetist, Department of
Anaesthesia.
‡ M.B., Ch.B. (Cape Town), D.A. (SA), F.F.A. (SA), Professor of
Anaesthesiology, University of Witwatersrand, Chris Hani Baragwanath
Hospital.
§ M.B., Ch.B., F.C.Paed. (SA), Crit. Care. (SA), Professor of Critical Care,
University of Witwatersrand and Chris Hani Baragwanath Hospital.
** M.B., B.S., M.T.H., Ph.D., Research Fellow, Department of Intensive
Care Medicine, Royal Brisbane and Women’s Hospital and Burns, Trauma
and Critical Care Research Centre, The University of Queensland,
Brisbane, Queensland, Australia.
Address for correspondence: Dr S. Omar, email: shahed@analyzit.co.za
Accepted for publication on November 25, 2010.
Anaesthesia and Intensive Care, Vol. 39, No. 3, May 2011
linked to lactate production due to the metabolic
effects of this drug10,11.
Adrenaline is a strong agonist for the α1, β1
and β2 receptors with metabolic effects related
to β2 stimulation11. Its use has been associated
with a significant but transient increase in blood
lactate concentration, but no attributable mortality
difference when compared with noradrenaline12,13.
Modern theory suggests that the lactate rise may be
due the effect of adrenaline on Na+/K+-ATPase
activity14. Experimental data supports the role of
adrenaline in inducing hyperlactataemia by binding
to muscle β2 receptors and raising AMP production.
This leads to the co-ordinated stimulation of
both Na+/K+-ATPase and glycogenolysis. ADP is
generated, accelerating aerobic glycolysis via
phosphofructokinase activation. The glucose
substrate required for this is provided by the
induced glycogenolysis. In a human septic model,
over-production of skeletal muscle lactate is
correspondingly blocked by ouabain inhibition of
Na+/K+-ATPase7.
Given our hypothesis that a ‘lactate stress test’
may reflect underlying metabolic reserve, we
conducted a prospective observational study to
evaluate the relationship between adrenaline,
blood lactate and survival among critically ill adult
patients suffering from vasopressor-dependent septic
shock.
450 S. Omar, A. T. Burchard et al
MATERIALS AND METHODS
Approval for the study was granted by the Human
Research Ethics Committee of the University of
Witwatersrand, South Africa. Informed consent was
obtained from the patient or legal surrogate. The
setting was a university affiliated mixed medical-
surgical intensive care unit (ICU) in Johannesburg,
South Africa.
Inclusion and exclusion criteria
All patients admitted to the ICU over a total
period of six months were considered for enrolment.
Patients were eligible for the study if they were 18
years and older and had adrenaline therapy initiated
or escalated for the management of new onset septic
shock more than 24 hours after ICU admission.
The diagnostic criteria for sepsis and septic shock
used definitions by the American College of Chest
Physicians/Society of Critical Care Medicine
Consensus Conference15. Patients with known
adrenal disease or secondary hypertension were
excluded. No participants were known to be taking
monoamine oxidase inhibitors prior to enrolment.
Patients in whom dobutamine was used were
excluded.
Baseline data collection and fluid therapy
Acute Physiology and Chronic Health Evaluation
(APACHE) II scores were recorded for the 24
hours prior to study enrolment16. Baseline APACHE
II scores at ICU admission were used to predict
hospital mortality. Fluid therapy received during
the observation period was recorded for all but the
first 16 participants. The standard crystalloid used
in our ICU is Balsol® (Fresenius Kabi, Bad
Homburg, Germany) which contains no lactate. The
standard colloids used are Gelofusine® (B. Braun,
Melsungen, Germany) and Voluven® (Fresenius
Kabi, Bad Homburg, Germany). Both contain no
lactate.
Inotrope initiation
Adrenaline was the inotrope of choice for septic
shock in our ICU. Noradrenaline is not registered
with the Medicines Control Council in South Africa.
A mean arterial pressure (MAP) target was set by
the intensivist with a default target of above
65 mmHg17. Indications for initiating adrenaline were
a MAP below the target that was unresponsive to a
500 ml colloid challenge. If the patient was on
adrenaline and the MAP was below the target,
the adrenaline dose was escalated, with or without
further colloid infusion depending on assessment
of fluid responsiveness in that patient. Crystalloid
infusion, enteral nutrition and/or parenteral nutrition
were continued as usual.
Procedure at adrenaline initiation
A baseline blood sample was collected for
initial lactate measurement (LAC1) at initiation of
adrenaline as defined above. The adrenaline dose at
this point (ADR1) was 0, except for patients already
receiving adrenaline. An adrenaline infusion was
then commenced or escalated. The dose of adrenaline
that achieved the target MAP (ADR2) was then
recorded in μg.kg-1.minute-1. Blood lactate was then
measured two-hourly over the next 24 hours with
peak lactate occurring within eight hours in all
participants. The peak lactate during this period
was recorded as LAC2.
Calculation of lactate index
Lactate index (LI) is an index termed by the
authors in an attempt to quantify the increase
in lactate over eight hours per dose increase in
adrenaline. It is the ratio of the change in whole blood
lactate concentration (in mmol.l-1) to the increase in
adrenaline dosage (in μg.kg-1.minute-1), represented
mathematically as follows:
LI=(LAC2–LAC1)/(ADR2–ADR1)=ΔLAC/ΔADR
Ultimately, we postulate that LI is a measure of
the ability of the cells enzyme (Na+/K+-ATPase) and
metabolic (glycogenolysis) systems to respond to an
exogenous stimulus (adrenaline).
Follow-up of patients
Patient survival was followed up to discharge from
the ICU. Survival status at this point was recorded.
Statistical analysis
Values are reported as mean ± SD for normally
distributed data (APACHE II score and LI) with
median (IQR [range]) reported for the predominantly
non-normal dataset. Non parametric statistical
methods were used in bivariate analysis. A Mann-
Whitney U test was used to determine differences
between survivors and non-survivors (P values from
a Student’s t-test are also reported for normally
distributed variables). Wilcoxon signed rank sum test
was used to test the change in lactate and adrenaline
dose between time periods. Spearman’s rank
correlation coefficient (rho) was used to determine
the association between lactate and adrenaline
dose. A two-tailed P value <0.05 was considered
statistically significant. A multivariate model
was used to test the association of LAC1, LAC2,
ΔLAC, ADR1, ADR2, ΔADR and LI with hospital
mortality. Logistic regression analysis with backward
Anaesthesia and Intensive Care, Vol. 39, No. 3, May 2011
 Blood lactate & survival following adrenaline use in septic shock 451

elimination was used with forced entry of age and prior to entry into the model; ΔLAC and ADR1 were
APACHE II score into the model; variables with not log-transformed due to zero/negative values.
P >0.05 were eliminated. To confirm model choice, The Hosmer-Lemeshow test was used to evaluate
individual LAC/ADR parameters were entered into goodness of fit; a model with P >0.05 was considered
a logistic regression model with age and APACHE II to fit the data well; Nagelkerke’s R2 is also reported.
score and the likelihood ratio was used to evaluate Data analysis was conducted using SPSS 15.0 (SPSS
the overall model fit compared with an intercept-only Inc., Chicago, IL, USA).
model. Non-normal variables were log-transformed
RESULTS
Table 1 Forty-three patients with new onset ICU-acquired
Admission category and infection site for survivors and non-survivors septic shock were included in the study with three
of ICU admission patients excluded from the analysis due to missing
Characteristic Survivors, Non-survivors,
ADR2 data. Patients were initially admitted from
n=19 n=21 trauma (17), general surgery (11), obstetrics and
N (%) N (%) gynaecology (7), internal medicine (3), oncology (1)
Admission source and vascular surgery (1) services. Admission source
Trauma 7 (41) 10 (59) and site of infection by ICU survival status are
displayed in Table 1. All patients had a minimum of
General surgery 4 (36) 7 (64)
two organ systems requiring support, i.e. respiratory
Obstetrics and gynaecology 6 (86) 1 (14)
support in the form of positive pressure ventilation
Internal medicine 2 (67) 1 (33) and cardiac support in the form of vasopressors. The
Oncology 0 1 (100) median age was 32 (21 to 52 [19 to 80]) years and
Vascular surgery 0 1 (100) the mean APACHE II score was 24±7.5. Gender
Infection site was approximately equivalent; 22 (55%) were male.
The mortality at ICU discharge in this study was
Lung/pleural 7 (54) 6 (46)
52.5% (21/40). Predicted hospital mortality at ICU
Abdominal 4 (31) 9 (69)
admission was 44%.
Gynaecologic 5 (83) 1 (17)
Lactate and adrenaline
Central nervous system 0 2 (100)
The median lactate level before shock treatment
Cardiac 1 (50) 1 (50)
with adrenaline (LAC1) was 2.3 (1.5 to 3.9 [0.6 to
Skin 1 (100) 0
10.7]) mmol.l-1. The median dose of adrenaline at
Unknown 1 (33) 2 (67) this initial point (ADR1) was 0 (0 to 0.10 [0 to 0.63])
ICU=intensive care unit. μg.kg-1.minute-1.

Table 2
Study characteristics for survivors and non-survivors of ICU admission using the first episode of septic shock after the first day of ICU admission

Characteristic Survivors, n=19 Non-survivors, n=21 P value

Median (IQR [range]) Median, (IQR [range])
Age (26 [19-80]) (45 [19-75]) 0.019
APACHE II score (20 [11-36]) (25 [9-40]) 0.010
LAC1 (1.8 [0.6-5.7]) (3.0 [1.3-10.7]) 0.072
LAC2 (2.9 [0.8-10.1]) (2.9 [1.0-8.5]) 0.95
ΔLAC (0.9 [-1.4-8.6]) (-0.1 [-2.2-3.1]) 0.007
ADR1 (0 [0-0.55]) (0.051 [0-0.63]) 0.11
ADR2 (0.10 [0.050-0.69]) (0.20 [0.050-0.71]) 0.27
ΔADR (0.10 [0.022-0.67]) (0.080 [0.013-0.50]) 0.54
LI (10 [-4.7-40]) (-1.0 [-2.3-22]) 0.001
Significance tested by Mann-Whitney U test. ICU=intensive care unit, IQR=interquartile rage, APACHE=Acute Physiological and
Chronic Health Evaluation. LAC1=initial lactate (mmol.l-1), LAC2=peak lactate (mmol.l-1), ΔLAC=difference between initial and peak
lactate (mmol.l-1), ADR1=initial adrenaline dose (μg.kg-1.min-1), ADR2=peak adrenaline dose (μg.kg-1.min-1), ΔADR=difference between
initial and peak adrenaline dose (μg.kg-1.min-1), LI=lactate index.
Anaesthesia and Intensive Care, Vol. 39, No. 3, May 2011
 452 S. Omar, A. T. Burchard et al

The median adrenaline dose increased significantly
after treatment of shock from 0 (ADR1) to 0.14 (0.08
to 0.36 [0.05 to 0.71]) μg.kg-1.minute-1 (ADR2) after
the target MAP was achieved (P <0.001). A similar
increase in lactate occurred after adrenaline treatment
of shock. The median blood lactate concentration
increased 26% from 2.3 mmol.l-1 (LAC1) to 2.9
mmol.l-1 (2.2 to 4.5 [0.8 to10.1]) (LAC2) (P=0.024).
The peak lactate (LAC2) correlated with peak
adrenaline (ADR2) (rho=0.34, P=0.032). Total fluid
received during the data collection period in a sub-
group analysis was not statistically different between
patients whose lactate increased compared with
patients whose lactate decreased or stayed the same
(1300 ml vs 1500 ml, respectively, in 24/40 patients,
P=0.58).
Survival
Age, APACHE II score, ΔLAC and LI were
associated with ICU mortality in bivariate analysis
(Table 2). Neither initial lactate (LAC1) nor peak
lactate (LAC2) was significantly associated with
survival. The mean APACHE II values for survivors
and non survivors were 21±6.4 and 27±7.5,
respectively (Student’s t-test: P=0.015). Figure 1
shows LI by survival status. The mean LI of survivors
was 11.8±12.4 compared to -2.11±11.4 for non
survivors (Student’s t-test: P=0.001). LI was not
associated with age (P=0.94) or APACHE II score
(P=0.30).
In multivariate analysis, LI was the only study
parameter to remain significantly associated with
ICU survival after controlling for age and APACHE
II score (Table 3). The Hosmer-Lemeshow statistic
for the model is 7.98 (P=0.44) suggesting that the
model fitted the data well. When compared with
other models containing individual LAC/ADR
parameters, the model which included lactate index
had the best fit with a likelihood ratio chi-square of
23.63 (P <0.001).

DISCUSSION
12
We conducted this study to evaluate the
relationship between adrenaline and blood lactate
10 concentration in ICU-associated septic shock. We
found a significant positive relationship between
Lactate (mmol.l -1)

peak adrenaline dose and maximum blood lactate

8
concentration. Increases in lactate followed increases
in adrenaline with a peak observed within eight
6
hours of therapy initiation or escalation. The variable
increase in lactate in comparison to adrenaline dose
escalation, as determined by the LI, was significantly
4 associated with survival.
The mortality rate in our study was 52.5%, which
is close to the expected mortality of 50% in a group
2
characterised by septic shock18. Unlike the relationship
of APACHE II score with mortality, we could not
0 convincingly show a similar mortality relationship
with peak lactate. There was a trend towards a
Alive Dead higher initial lactate (LAC1) in nonsurvivors
LAC1 compared to survivors (P=0.072).
LAC2
The most interesting finding, however, was
Figure 1: Lactate index for survivors and non-survivors of ICU the relationship between LI and survival. Taking
admission.
advantage of a potential strong mechanistic link
Table 3 between adrenaline and lactate led us to coin the
Logistic regression model predictive of ICU survival term ‘lactate index’ for the ratio of the increase in
lactate to the increase in adrenaline. We found that
Characteristic OR (95% CI) P value survivors had a significantly higher LI than non-
Age 0.94 (0.88-1.00) 0.049 survivors. This may suggest that lactate response to
APACHE II score 0.91 (0.79-1.04) 0.17 β2 stimulation, as opposed to an elevated lactate
LI 1.14 (1.04-1.26) 0.007 from cellular hypoxia, is predictive of survival in a
critically ill population.
Nagelkerke’s R =0.60. ICU=intensive care unit, OR=odds ratio,
2

CI=confidence interval, APACHE=Acute Physiology and Chronic An experimental study using an animal model
Health Evaluation, LI=lactate index. has shown that adrenaline, but not noradrenaline,
Anaesthesia and Intensive Care, Vol. 39, No. 3, May 2011

Page 1
 Blood lactate & survival following adrenaline use in septic shock 453

increases lactate without a change in lactate to
pyruvate ratio. ATP concentrations in the heart,
muscle, liver and gut were unchanged, suggesting a
non-hypoxic mechanism19. Sair et al found increased
muscle PO2 in human septic shock compared to
controls, also negating a hypoxic mechanism20.
Similarly, Myburgh et al suggested that the
adrenaline-induced hyperlactatemia in human
subjects was probably not due to hypoxia, but rather
to β2 stimulation12. More recently, Mikkelsen et
al showed that initial serum lactate is associated
with mortality independent of shock and organ
dysfunction21.
Probably the most daring hypothesis to support
our findings is the cell-to-cell lactate shuttle22. This
hypothesis highlights the role of lactate as a fuel.
Highly oxidative muscle like the heart may be net
consumers of lactate. Although hotly disputed, there
is evidence that mitochondria may directly take up
and oxidise lactate, without cytosolic conversion to
pyruvate. Lactate may therefore compete with glucose
as a fuel, and its increase may have physiological
benefit. In another animal model, Levy et al have
shown how systemic lactate deprivation by selective
β2-antagonism and pyruvate dehydrogenase
stimulation with dichloracetate resulted in
cardiovascular collapse23. This myocardial energy
failure was blunted by lactate infusion.
Several authors have postulated that the human
response to sepsis is nonlinear, i.e. the ‘whole’ is
more than the sum of its parts24-26. Nonlinear systems
are composed of many interconnected (mutually
dependent) variables. The quantity of these
variables may be constantly changing. This results
in a complex and dynamic web of interactions. A
change in one variable will result in changes in other
components and in the interaction between variables.
An important property of this system is its ability,
through these complex interactions, to generate less
disorder. Therefore a small perturbation can cause a
large change (the ‘butterfly effect’). The properties
are called emergent as they materialise at increasing
levels of connectivity.
Consider lactate as a case in point. Over a thousand
mmol are produced in an average adult daily, yet
the mean blood concentration is less than 2 mmol/l.
Lactate depends on numerous factors relating to its
production and also its clearance (Figure 2). To look
at the lactate concentration and relate it to clinical
outcome is simplistic and does not consider lactate
in relation to its environment. If we consider that
lactate is continuously produced and metabolised
depending on a myriad of biological processes
including metabolic control mechanisms, oxygen
carrier capacity, acid base status, autonomic balance,
adequate cardiac output and normal enzyme systems,
we see lactate as part of a complex interdependent
system.
Lactate index is an attempt to evaluate lactate in
terms of some of these inter-relationships. Could
LI be one such emergent property? Our study
suggests that the ability of lactate production to
increase in response to an appropriate stimulus
may represent the variability and responsiveness
indicative of health reserve. On the other hand, failure
to do so may herald disease. As a further hypothesis,
could the early lactate clearance associated with
survival shown by Nguyen et al27 represent the ability
to utilise lactate as a fuel? Whether a physiological
role of lactate can explain the association of

Adrenaline
B2

↑ H+
- Increased glycolysis + SNS

Lactate

Pyruvate Krebs
cycle
Figure 2: Lactate production and metabolism in relation to β2 receptor stimulation, hydrogen ion (H+)
concentration and sympathetic nervous system (SNS) stimulation.
Anaesthesia and Intensive Care, Vol. 39, No. 3, May 2011
454 S. Omar, A. T. Burchard et al
endogenous production with survival in our study,
or is merely a marker of survival, requires further
investigation.
Our study has three important limitations which
need to be taken into consideration. First, our survival
endpoint was at ICU discharge and whether LI is
predictive of 28-day mortality was not determined.
Second, this was a small study and further testing of
the prognostic ability of the LI in a larger sample is
warranted. Utility of the index in all cases of septic
shock, not just ICU-associated sepsis, requires
further evaluation. Third, this study was observational
and all potential confounders were unable to be
controlled or adjusted for. In particular, only 24
patients had fluid therapy recorded during the
observation period and fluid resuscitation prior to
study enrolment was not accounted for. Whether
depleted glycogen stores or circulatory insufficiency
amongst poor responders could contribute to our
findings was unable to be determined.
We have shown that the relationship of lactate to
adrenaline is more important than the peak lactate
concentration in terms of prognosis for patients
with ICU-associated septic shock. We have provided
evidence that lactate responsiveness to adrenaline
administration is associated with survival, and may
be a beneficial and appropriate response in human
septic shock. We have also defined an emergent
property, the LI, which may serve as a prognostic
marker in a critically ill population.
ACKNOWLEDGEMENTS
Dr Dulhunty was supported by a Queensland
Health clinical research registrar position (2008)
and a grant from the Royal Brisbane and Women’s
Hospital Private Practice Trust Fund (2009) during
preparation of this manuscript.
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