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Premorbid beta blockade in sepsis 
is associated with a lower risk 
of a lactate concentration 
above the lactate threshold, 
a retrospective cohort study
Liam Schneider 1, Debra Chalmers 1, Sean O’Beirn 1, Miles Greenberg 2 & Grant Cave 1*
Sepsis and septic shock represent a significant worldwide mortality burden. A lactate greater than 
4 mmol/L is associated with increased mortality in septic patients. This is the concentration at the 
“lactate threshold” where serum lactate concentrations rise markedly with increased workload in 
exercise. Hyperlactatemia in both sepsis and exercise is contributed to by adrenergic agonism which 
stimulates aerobic glycolysis, increasing lactate production and decreasing lactate clearance. Our 
hypothesis is that in patients with sepsis, treatment with beta blockers in the community will be 
associated with a lower probability of initial lactate ≥ 4 mmol/L. This was single centre retrospective 
cohort study. We used an in-house SQL Database for all admissions to ICU/HDU for the 2017–2020 
calendar years. The dataset was filtered for an APACHE III Diagnosis of sepsis. T-tests were used for 
continuous data, Chi squared and Fisher’s exact test were used as appropriate to compare proportions. 
Logistic regression was used to investigate covariate effects. Of the 160 patient records analysed, 49 
were prescribed beta blockers. A greater proportion of patients not prescribed beta blockers in the 
community had a first lactate ≥ 4 mmol/L (p = 0.049). This was robust to regression analysis. There was 
no difference in the proportion of patients with lactate ≥ 2 mmol/L (p = 0.52). In our cohort patients 
previously prescribed beta blockers were less likely to have a lactate of ≥ 4 mmol/mL. This supports 
the proposed mechanism that treatment with beta blockers increases the lactate threshold in sepsis. 
Further study is warranted.
Sepsis is a major global health issue accounting for 20% of global mortality and 11 million deaths in  20171. Sepsis 
represents a significant proportion of intensive care unit (ICU)  caseload2. Hyperlactatemia in sepsis and septic 
shock correlates with the severity of sepsis and associated  mortality3. Reduction in serial lactate concentrations is 
associated with improved  outcomes4,5, while goal directed therapy targeting lactate clearance is part of the 2021 
surviving sepsis  guidelines6. Given the position serum lactate holds in the assessment and management of sepsis, 
any premorbid factors which impact on lactate concentrations are of potential interest to the treating clinician.
Lactate kinetics in health and the lactate threshold. 
Lactate is produced from pyruvate during gly-
colysis. This reaction regenerates NAD+ for the production of adenosine triphosphate (ATP)7. Lactate is metab-
olised via gluconeogenesis in liver and kidney and oxidation in skeletal  muscles8–10. At rest, lactate clearance is 
evenly distributed between these two mechanisms; during moderate to high exercise 60–80% of lactate clearance 
occurs in skeletal  muscle11. The lactate threshold refers to the level of exercise intensity at which serum lactate 
accumulation rapidly  increases12. This has been attributed to anaerobic metabolism and/or to an imbalance 
between lactate production and lactate clearance in the absence of tissue  hypoxia13,14. The lactate threshold can 
be taken as 4 mmol/L with reasonable  accuracy15. This threshold in health has a correlate in critical illness, with 
a marked increased mortality in sepsis when initial lactate is greater than 4 mmol/L16. In healthy subjects exercis-
ing at the lactate threshold, the amount of lactate metabolised is reduced compared to moderate  exercise17. This 
suggests that part of the marked increase in lactate with increased exercise intensity above the lactate threshold 
OPEN
1Hawkes Bay Hospital Intensive Care Unit, Hastings, New Zealand. 2University of Notre Dame, Freemantle, 
Australia. *email: grantcave@gmail.com
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is due to decreased metabolic clearance of lactate, an effect which may be mediated by beta agonism. Adrenergic 
stimulation of phosphofructokinase and Na/K ATPase result in increased conversion of glucose to pyruvate 
and cytosolic ATP to ADP, respectively. This increases production of lactate from pyruvate and ADP via lactate 
dehydrogenase in the cellular cytosol, resulting in decreased uptake of lactate by non-exercising tissues under 
adrenergic stimulation. This proposed mechanism is illustrated below in Fig. 1.
This physiology in health could also occur in sepsis—an adrenergically mediated decrease in cellular metabo-
lism of lactate could hypothetically account for part of the hyperlactataemia in sepsis. Any such effect (and the 
effect of its blockade) may be more marked near the lactate threshold of 4 mmol/L.
Hyperlactatemia in sepsis. 
Hypoperfusion and the resultant tissue hypoxia is traditionally held to explain 
the hyperlactatemia seen in  sepsis7,18,19. Studies measuring partial pressures of oxygen in septic patients have 
however not demonstrated tissue  hypoxia20–24, which has led to the consideration of other  mechanisms7.
Activation of beta-2 adrenergic receptors, stimulated as part of a stress response is one such  explanation7,25. 
This pathway has been experimentally blocked at various points, with a resultant reduction in  lactate22,26,27. Esmo-
lol infusion in septic patients was found to reduce lactate, and in beta blocker overdose a lower than expected 
lactate concentration is seen for the degree of haemodynamic  compromise28,29.
Other mechanisms have been proposed. Impaired oxygen utilisation rather than inadequate oxygen delivery 
 (DO2–VO2 mismatch) has been suggested, though there is little research correlating  DO2–VO2 mismatch to lac-
tate  levels30–33. Gattinoni et al. hypothesised a combination of tissue hypoxia and inadequate oxygen utilisation 
as an explanation, finding that high lactate correlated in septic patients with either the highest or lowest central 
venous oxygen saturation  (ScVO2)34. Other proposed mechanisms are the Warburg effect in immune activation 
and microcirculatory  dysfunction35–37. It has been suggested that many or all of these suggested mechanisms 
play a role in hyperlactatemia in  sepsis38.
Premorbid beta blockade and lactate levels in sepsis. 
Five observational studies have assessed the 
effect of pre-morbid beta-blockade on lactate levels in patients presenting with  sepsis39–43. Three trials found a 
significant reduction in lactate levels with beta-blockade39,41,43, while two showed no  difference40,42. A recent 
meta-analysis of these studeis found lactate levels to be lower in patients on beta-blockers44.
If the effect of beta blockade is mediated by an alteration of the lactate threshold, the effects on serum lactate 
would be expected to be greater in patient cohorts with higher lactates. Figure 2 represents data from these five 
studies.
Figure 1.  The proposed effect of beta adrenergic stimulation on lactate metabolism.
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All these trials have limitations—the majority of studies are retrospective observational in design; only one 
study was multicenter; two trials looked at lactate concentrations as a secondary outcome; inclusion criteria and 
sepsis definitions were variable between studies as was the timing of lactate  measurement39–43. However, the pat-
tern of data from the studies supports the theory that the effect of beta blockers on lactate is more pronounced 
in populations with higher lactate levels.
Effect of premorbid beta-blockers on mortality. 
Pre morbid beta blockers may confer a mortality 
benefit in patients presenting with  sepsis40,43–47, however the evidence is not  homogenous48,49. The use of ultra-
short acting beta blockers infusions in patient admitted with sepsis has shown a mortality  benefit28,50–56. A meta-
analysis including ten studies found premorbid beta blockade was associated with lower short term mortality 
in patients admitted with  sepsis44. The proposed mechanisms of a mortality benefit include direct and indirect 
cardio protective effects; enhanced microvascular circulation due to reduction in coagulopathy and indirect 
immune modulatory  effects42,43,47,48. In this regard evidence of a potentially beneficial effect on lactate metabo-
lism of beta blockade would be of interest.
Aim. 
To assess whether previous beta blocker prescription affected the probability that the first lactate in 
patients admitted from the Emergency Department to our intensive care unit with sepsis was above the lactate 
threshold.
Hypothesis. 
The hypothesis was that in patients admitted with sepsis, treatment with beta blockers in the 
community will be associated with a lower probability of a lactate ≥ 4 mmol/L.
Methods
Setting. 
This was a retrospective cohort study conducted in the intensive care unit (ICU) of the Hawkes 
Bay Fallen Soldiers Memorial Hospital in Hastings, New Zealand. The hospital has 364 beds and approximately 
1000 ICU and High Dependency Unit (HDU) admissions a year. The unit can provide mechanical ventilation 
and continuous renal replacement therapy, and cares for both adult and paediatric patients with medical and 
surgical conditions. Approval for the audit was granted by the Hawkes Bay DHB audit registration committee 
and the Northern B Health and Disability Ethics Committee of New Zealand. As only de-identified date was 
used a consent waiver was given by both committees. All research was performed in accordance with relevant 
guidelines/regulations. We used an In-house SQL Database that tracked all admissions to ICU/HDU for the 
2017–2020 calendar years, which also allows collection of the ANZICS CORE Dataset. This was then filtered 
by a diagnosis of sepsis. A keyword search of free-text fields that supplemented the APACHE III Diagnosis that 
contained terms such as “Sepsis”, or “Septic Shock”, was carried out to identify those patients admitted with a 
co-diagnosis of sepsis. The data was then reviewed, and all duplicate or non-sepsis admissions were removed.
Initial serum lactate level at our centre was measured on an ABL 800 Flex blood gas analyser (Radiometer 
Medical ApS, Bronshoj, Denmark). Serum lactate was defined as the first lactate measured during an Emergency 
Department (ED) presentation. Only patients admitted directly from the ED were included. Serum lactate, 
current medications, presenting vital signs, illness severity scores, laboratory data and mortality outcome were 
extracted from patients’ electronic medical record and the unit’s clinical database.
Inclusion. 
A single investigator (GC) blinded to beta blocker treatment status evaluated the electronic medi-
cal record to assess whether the clinical or microbiologic picture was consistent with infection.
Exclusion. 
A single investigator (LS) reviewed the Emergency Department electronic medical record was 
reviewed and a qSOFA score calculated for each patient prior to evaluation of beta blocker status. Patients with 
0
0.5
1
1.5
2
2.5
3
0
1
2
3
4
5
6
Difference in latate between BB and non BB
Average lactate in trial
Average lactate in trial vs Mean difference 
BB/non BB (95% CI) 
Figure 2.  Average lactate in individual trials vs. difference in mean lactate for those prescribed and not 
previously prescribed beta blockers.
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qSOFA < 2 were excluded from analysis as patients with a qSOFA score < 2 are identified as low risk of  sepsis57. 
Patients who did not have lactate measured were also excluded from analysis.
Calculation of sample size. 
We used unpublished data from previous work where 25% fewer patients 
who were prescribed beta blockers in the community had an initial lactate > 4 mmol/L when compared with 
those not prescribed beta blockers (20% vs 45%). The study was powered under the assumptions that there 
would be the same proportion of beta blocked patients in the population and the proportions of patients with 
lactate > 4 mmol/L would be the same as in our previous  work41. Under these assumptions, our study was > 80% 
powered at and alpha of 0.05 with 180 patient records included in the analysis. We anticipated that abstraction 
of four calendar years of data would provide these patient numbers.
Statistical analysis. 
Our data were analysed using the Graphpad Prism version 9. Continuous data are 
presented as means with 95% confidence intervals. Proportions are presented as percentages with 95% confi-
dence intervals. Students T-test was used for continuous data, Chi squared and Fisher’s exact test as appropriate 
to compare proportions. Logistic regression was used to investigate for significance and magnitude of covariate 
effects. Criterion for covariate entry into multiple regression modelling were a statistically significant difference 
in distribution of the variable between groups, an effect demonstrated in previously published work or a plausi-
ble covariate effect and a p value < 0.1 on univariate regression.
Ethics approval and consent to participate. 
Approval for the use of de-identified data from this study 
was given by the Hawkes Bay hospital clinical audit committee and the Northern B Health and Disability Ethics 
Committee of New Zealand.
Results
293 patient records were identified for audit. Of these, 129 were excluded for a qSOFA < 2 and a further 3 were 
excluded as the clinical situation and/or microbiology did not fit with the diagnosis of sepsis. One patient record 
of the remaining 161 did not have their lactate measured and was excluded from analysis.
Baseline characteristics. 
The baseline characteristics for the 160 patients included in the analysis are pre-
sented in Table 1. At baseline the beta blocker group was older and had lower lactate than those not exposed to 
beta blockers. The site of sepsis by group is shown in Table 2. Fewer beta blocker patients had a respiratory source 
of sepsis. There was no statistically significant difference in mean lactate between those with a respiratory source 
of sepsis and those with other sites (mean difference 0.48, 95% CI − 1.04 to 2.0 mmol/L) nor between those with 
APACHE classified chronic cardiovascular disease (mean difference 0.08, 95% CI − 1.75 to 1.91 mmol/L).
Primary endpoint. 
A greater proportion of patients not prescribed beta blockers in the community had a 
first lactate ≥ 4 mmol/L (48% of patients no beta blockers vs 29% prescribed beta blockers, p = 0.049). There was 
no significant difference in the proportion of patients with lactate ≥ 2 mmol/L (79% of non-beta blocker patients 
versus 83% of beta blocker patients, p = 0.52). These results are displayed graphically in Fig. 3.
Covariates and regression analysis. 
Of the covariates in table 3 only APACHE 3 score was significantly 
correlated with lactate. Logistic regression was undertaken to evaluate the effect of covariates as per the analysis 
Table 1.  Baseline characteristics.
Beta blocker
Non-beta blocker
p value for difference
Number (n)
49
111
Male (%)
32 (65)
64 (58)
0.36
Age (years)
71
63
< 0.01
First lactate (mmol/L)
3.54
4.46
0.04
Lowest systolic blood pressure in ED (mmHg)
90
91
0.64
Lowest HR first 24 h in ICU
75.6
78
0.42
SaO2 (%)
92
90
0.74
Highest Creatinine first 24 h (mmol/L)
173
187
0.55
Lowest Haematocrit first 24 h
0.32
0.33
0.34
APACHE III score
75
70
0.31
Number qSOFA score 3 n(%)
7 (14)
16 (14)
0.98
Vasopressors used in ED, n (%)
24 (49)
63 (57)
0.36
Prescribed metformin, n (%)
14 (29)
22 (19)
0.22
Chronic cardiovascular disease (APACHE) n (%)
6 (12)
5 (5)
0.07
Chronic respiratory disease (APACHE) n (%)
1(2)
7(6)
0.67
Mortality, n (%)
8 (16)
17 (15)
0.87
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plan in the methods. The odds ratio for beta blocker prescription for first lactate being ≥ 4 mmol/L regressed for 
the covariates age, APACHE 3, metformin prescription, site of sepsis being respiratory and lowest haemotocrit 
(Hct Lo) in the first 24 h of ICU admission was 0.31 (0.13–0.71). Of note the upper bound of the 95% CI for the 
odds ratio was < 1. This finding was robust to regression with covariates individually, the removal from the model 
of age (which exhibited a linear correlation with Apache 3), and addition of lowest systolic blood pressure in the 
Emergency Department to the model.
Table 2.  Site of sepsis by group.
Site of sepsis
Beta blocker, n (%)
Non-beta blocker, n (%)
p value
Respiratory
7(14)
32 (29)
0.05
Skin/soft tissue/joint
16 (33)
26 (23)
0.22
Genitourinary
12 (25)
18 (16)
0.22
Unknown
5 (10)
24 (22)
0.08
Biliary
5 (10)
3 (3)
n/s
Intra-abdominal
3 (6)
3 (3)
n/s
Cardiac
0 (0)
2 (2)
n/s
Vascular catheter
1 (2)
0 (0)
n/s
CNS
0 (0)
1 (1)
n/s
Figure 3.  Percentages of those prescribed and not prescribed beta blockers with lactate greater than 2 and 
4 mmol/L at presentation.
Table 3.  Covariate analysis.
Covariate
95% CI odds ratio, p value
Male sex
0.8–1.75 to 0.21, p 0.82
Age (years)
0.98–1.01, p 0.99
Lowest recorded  SpO2 in ED (%)
0.96–1.07, p 0.36
Lowest haematocrit first 24 h
0.99 to 1.1, p 0.053
APACHE III score
1.013 to1.04, p < 0.001
Vasopressors used in ED
0.39 to 1.4, p 0.44
SBP in ED
0.96–1, p 0.11
Prescribed metformin
0.8–3.8, p 0.31
Site of sepsis respiratory
0.31–1.4, p = 0.6
Cardiovascular disease (APACHE)
0.35–4.4, p = 0.89
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Discussion
In this patient cohort pre-morbid beta blocker treatment was associated with a lower initial lactate, driven by a 
reduction in the proportion of patients with a lactate of ≥ 4 mmol/L. This effect was robust to regression analysis. 
There was no significant difference in the proportion of beta blocker/non beta blocker exposed patients with 
lactate ≥ 2 mmol/L. Extension from our findings holds obvious caveats in that our methodology permits identi-
fication of association only, and lactate threshold is a concept from exercise physiology that has not been proven 
to have an effect in the clinical context. Nonetheless, these findings provide inferential support for premorbid 
beta blockade reducing serum lactate in sepsis by increasing the proportion of patients below the concentration 
where lactate production and metabolism uncouple in response to metabolic stress. Restated, our findings offer 
support for the view that beta blockers increase the lactate threshold in sepsis.
This data fits with the pattern observed the previous five studies as demonstrated in Fig. 2, that the effect 
of premorbid beta-blockers on initial lactate was most significant in patient populations with higher mean 
lactate concentrations. The papers which found no effect analysed cohorts with an average initial lactate 
of ≤ 2 mmol/L40,42; we did not identify any association for premorbid beta blockade with the probability of lac-
tate being ≥ 2 mmol/L. The three other studies which demonstrated an effect of beta blockade when looking at 
cohorts with higher average  lactates39,41,43. Our proposed mechanism to explain the findings seen in our study, 
while hypothetical, offers a unifying explanation for the current heterogeneity of evidence in this area.
Our study has several limitations. The most significant is that seeking an association based on a hypothesized 
mechanism can establish the association while the mechanism remains hypothetical. While there is a mark-
edly increased mortality with lactate ≥ 4 mmol/L in sepsis the lactate threshold is a concept proven in exercise 
physiology rather than established in clinical medicine. Our study design is a retrospective observational and as 
such can only demonstrate an association rather than prove causation for the effects of premorbid beta blockade 
on serum lactate concentrations. Additionally, our study is single centre creating limits on external validity. 
The mean initial lactate was 3.54 mmol/L for the beta blocked patients compared to 4.46 mmol/L in those not 
premorbidly prescribed beta blockade. Both concentrations are above a threshold which would trigger clini-
cal action—viewed from this perspective the clinical significance of the concentration difference is uncertain. 
This study is not powered to assess whether statistically significant difference in lactates concentration affected 
clinical outcomes. A qSOFA score of ≥ 2 was used as part of the inclusion criteria. The qSOFA score has been 
found to have a decreased predictive value in ICU compared to SOFA score but a better predictive value outside 
 ICU57. A flaw with the qSOFA is the potential for inter-user variability in the recording of scores particularly in 
the altered mental status variable. In addition, some of the cohort was excluded due to incomplete data from the 
Emergency Department admission. As with other studies, it is only possible to ascertain whether patients were 
prescribed beta blockers at the time of to their admission, the actual compliance in the cohort is unknown. The 
reason for beta blocker prescription is not available for this patient cohort and as such the role of any underlying 
cardiac dysfunction is difficult to quantify. There may also be an effect of other unmeasured variables such as 
amount of fluid resuscitation prior to initial lactate measurement. We abstracted patient data in blocks of calendar 
years and anticipated 4 years would provide 180 records for study. The 5% reduction in power from analysis of 
160 subjects from this period did not result in a type I error—our results were positive. Underpowered studies 
which return positive results additionally tend to overestimate the magnitude of effect—a lower proportion of 
underpowered studies are expected to be positive with the tendency to exhibit more extreme results. This was 
again not the case in our work as the overall difference in proportion of patients with lactate ≥ 4 in was lower 
than that powered for (19% vs 25%).
Further research is recommended into the effect of beta blockade on the lactate threshold and its significance. 
Our group has commenced bench top mechanistic work in a prospective study of the effect esmolol infusions 
on lactate in animal models of sepsis aiming to further examine the proposed mechanism of the effect of beta 
blockade on lactate.
Conclusion
In our cohort patients previously prescribed beta blockers presenting with sepsis were less likely to have a lactate 
of ≥ 4 mmol/ml. This is in keeping with the pattern of results seen in the current literature and supports the pro-
posed mechanism that treatment with beta blockers increases the lactate threshold. Further study is warranted 
as such a mechanism could have clinical significance.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on 
reasonable request.
Received: 13 June 2022; Accepted: 28 November 2022
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Acknowledgements
The authors would like to acknowledge Penny Park, ICU research nurse at the Hawkes Bay hospital for her 
assistance with data extraction.
Author contributions
G.C. and M.G. were responsible for study conception. G.C. was responsible for analysis. L.S. and S.O. were 
responsible for data extraction. L.S. authored the first draft of the manuscript. All authors subsequently con-
tributed to revisions. No individual identifying patient data is included in this manuscript. The requirement for 
informed consent was waived by the Hawkes Bay hospital clinical audit committee and the Northen B Health 
and Disability Ethics Committee of New Zealand.
Funding
No funding was received to undertake this study.
Competing interests 
The authors declare no competing interests.
Additional information
Correspondence and requests for materials should be addressed to G.C.
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© The Author(s) 2022

Premorbid beta blockade in sepsis is associated with a lower risk of a lactate concentration above the lactate threshold, a retrospective cohort study.
Schneider, Liam,Chalmers, Debra,O'Beirn, Sean,Greenberg, Miles,Cave, Grant