Received: 8 October 2020 Revised: 3 April 2021 Accepted: 6 April 2021

DOI: 10.1002/mus.27248

CLINICAL RESEARCH ARTICLE

Hyperlactacidemia as a risk factor for intensive care

unit-acquired weakness in critically ill adult patients

Tao Yang MD1,2 | Zhiqiang Li MD3 | Li Jiang MD2 | Xiuming Xi MD2

1
Department of Critical Care Medicine, Beijing
Tiantan Hospital, Capital Medical University, Abstract
Beijing, China Introduction/Aims: Intensive care unit-acquired weakness (ICUAW) is a severe
2
Department of Critical Care Medicine, Fu
neuromuscular complication of critical illness. Serum lactate is a useful biomarker in
Xing Hospital, Capital Medical University,
Beijing, China critically ill patients. The relationship between serum lactate level and ICUAW
3
Department of Critical Care Medicine, North remains controversial. This study evaluated whether hyperlactacidemia (lactate level
China University of Science and Technology
Affiliated Hospital, Tangshan, China >2 mmol/L) was an independent risk factor for ICUAW in critically ill adult patients.
Methods: An observational cohort study was performed in a general multidisciplinary
Correspondence
Xiuming Xi, Department of Critical Care intensive care unit (ICU). Sixty-eight consecutive adult critically ill patients without
Medicine, Fu Xing Hospital, Capital Medical preexisting neuromuscular disease or a poor pre-ICU functional status whose length
University, No. 20 Fuxingmenwai Street,
Xicheng District, Beijing 100038, China. of ICU stay was 7 or more days were evaluated. Patients were screened daily for
Email: xixiumingfx@sina.com signs of awakening. Muscle strength assessment using the Medical Research Council
score was performed on the first day a patient was considered awake. Patients with
clinical muscle weakness were considered to have ICUAW.
Results: Among the 68 patients who achieved a satisfactory state of consciousness,
the diagnosis of ICUAW was made in 30 patients (44.1%). After multivariate analysis,
hyperlactacidemia (P = .02), Acute Physiology and Chronic Health Evaluation II score
(P = .04), duration of mechanical ventilation (P = .02), and the use of norepinephrine
(P = .04) were found to be significantly associated with the development of ICUAW
in critically ill patients.
Discussion: This study shows a number of risk factors to be significantly associated
with the development of ICUAW in critically ill adults. These factors should be con-
sidered when building early prediction models or designing prevention strategies for
ICUAW in future studies.

KEYWORDS
hyperlactacidemia, intensive care unit-acquired weakness, mechanical ventilation,
norepinephrine, risk factor

1 | INTRODUCTION

Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular

complication of critical illness and occurs frequently in septic patients.1,2

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence
ICUAW is associated with serious functional disability, prolonged mechan-
interval; ICU, intensive care unit; ICUAW, intensive care unit-acquired weakness; IQR, ical ventilation (MV), increased healthcare-related costs, longer hospital
interquartile range; MODS, multiple organ dysfunction syndrome; MRC, Medical Research
stays, and higher intensive care unit (ICU) -related and hospitalization-
Council; NMBAs, neuromuscular blocking agents; RR, relative risk; SIRS, systemic
inflammatory response syndrome; SOFA, sepsis-related organ failure assessment. related mortality.3-7 The etiology and mechanisms of ICUAW remain

Muscle & Nerve. 2021;1–6. wileyonlinelibrary.com/journal/mus © 2021 Wiley Periodicals LLC. 1

2 YANG ET AL.

unclear, and thus, there are no specific treatment options for ICUAW. to perform the muscle testing. The assessments were performed on the
Efforts should be made to control risk factors and prevent the develop- awaking day and repeated the next day. The maximum total MRC score
ment of the disorder in the early disease course because the abnormalities from either day was defined as each subjectʼs strength for all analyses.
at this time may still be reversible.8,9 An early diagnosis is needed for early The muscle strength assessment for each patient was performed at
intervention. ICUAW is a clinically detectable weakness, and clinical least twice separated by 24 h.
examinations using manual muscle strength assessment are performed to Clinical risk factors for ICUAW based on the literature2 were cho-
diagnose the disorder but usually cannot be conducted in the early disease sen a priori, and these included potential risk factors at ICU admission,
course due to suboptimal levels of consciousness. The diagnosis of baseline characteristics, intervention measures, and metabolic variables.
ICUAW is always made late in the disease course; thus, early prediction of Variables thought to be associated with ICUAW were as follows: age,
the disorder is of high importance. Serum lactate levels are routinely mea- female sex, ICU stay before diagnosis, acute physiology and chronic
sured in critically ill patients, and may help clinicians predict and detect health evaluation II (APACHE II), sepsis-related organ failure assessment
severe disease in the early course. Increases in serum lactate levels are (SOFA), systemic inflammatory response syndrome (SIRS), sepsis, septic
associated with worse outcomes.10,11 Septic shock has been found to be shock, multiple organ dysfunction syndrome (MODS), MV, duration of
significantly associated with ICUAW,4,12 and hyperlactacidemia (lactate MV, aminoglycosides, neuromuscular blocking agents (NMBAs), corti-
13
level >2 mmol/L) is one of the clinical criteria for septic shock. However, costeroids, norepinephrine, parenteral nutrition, hypocalcemia, hyper-
the relationship between ICUAW and hyperlactacidemia remains unclear. glycemia, and electrolyte disturbances. APACHE II20 and SOFA21
Our aim was to examine this relationship. scores were recorded on ICU admission, and other risk factors were
prospectively recorded between ICU admission and the awaking day.
Sepsis or septic shock accompanied by organ dysfunction was classified
2 | METHODS according to consensus criteria.13,22 Hyperlactatemia was defined as a
blood lactate of >2 mmol/L.13 Serum lactate (mmol/L) and glucose
2.1 | Subjects levels, and serum Na+, Ca2+, and K+ concentrations included in the
routine laboratory set were acquired shortly after admission and regu-
The observational cohort study was performed in the ICU of a tertiary larly recorded every 6 h until the awakening day. They were recorded
care hospital between May 2017 and August 2018. All consecutive at least twice a day after normalization. These variables were analyzed
adult patients whose length of stay in the ICU was at least 7 days by means of a GEM Premier 3000 Blood Gas Analyzer (Instrumentation
were eligible for neuromuscular evaluation. Patients with pre-existing Laboratory, Bedford, MA, United States). Electrolyte disturbances were
neuromuscular disease, a poor pre-ICU functional status (modified thought to be significant only when they had lasted at least 36 h.
Rankin Scale14 >3) or fewer than four limbs in which muscle strength Normal values were considered as 134-149 mmoL/L for ionized Na+,
could be assessed were excluded. The study was approved by the 3.5-5.4 mmoL/L for ionized K+, and 1.16-1.30 mmoL/L for ionized
local ethical committee (2018FXHEC-KY032). Informed consent was Ca2+.23 Acute hyperglycemia was defined as serum glucose levels
obtained from legal proxies. above 180 mg/dL.24
After 7 days of ICU stay, patients were screened daily for signs of
awakening and cooperation based on adequate response to the follow-
ing five standard commands15-17: “Open your mouth and put out your 2.2 | Statistics
tongue,” “Open and close your eyes,” “Look at me,” “Nod your head,”
and “Raise your eyebrows while counting up to 5.” We considered the All statistical analyses were performed using SPSS 22 for Win-
first day that the patient was able to execute at least three commands dows (IBM Inc., Armonk, NY, USA). Continuous variables with a
on two consecutive evaluations at a 12-h interval as the awaking day. normal distribution are presented as the mean ± SD; nonnormally
Muscle strength assessment was performed according to the Medical distributed variables are reported as the median (interquartile
Research Council (MRC) scale18 after a satisfactory state of conscious- range [IQR]). The differences were tested using Fisherʼs exact test
ness was confirmed. It included bilateral assessment of muscle strength for comparison of categorical variables and the two-sample
of six muscle groups (wrist extension, elbow flexion, shoulder abduc- Wilcoxon test for comparison of continuous variables. The vari-
tion, knee extension, hip flexion, and ankle dorsiflexion). MRC scores of ables that were found to be significant on univariate analysis were
each muscle group (ranging from 0 to 5) were summed, and patients further studied by multivariate logistic analysis and identified by a
were diagnosed with ICUAW when the muscle strength sum score backward stepwise selection algorithm. P < .05 was considered
6,19
(ranging from 0 to 60) was less than 48, whereas patients with an statistically significant.
MRC score of 48 or higher were considered controls. Patients were
screened until discharge from the ICU or death. In an attempt to reduce
inter-examiner variability, muscle strength was assessed by a physical 3 | RE SU LT S
therapist who was blinded to all other parameters. Before the study,
the physical therapist received standardized instructions about the per- Sixty-eight patients (45.6% females) were included and evaluated by
formance of the MRC exam and was trained by a qualified neurologist muscle strength assessment. The flow diagram of the population
YANG ET AL. 3

selection process is shown in Figure 1. Of the included patients, the 4 | DI SCU SSION
mean (SD) age was 79.9 (10.1) years, and the mean (SD) APACHE II
score was 21.3 (8.1). Thirty-four patients were transferred from the In agreement with previous studies,25-27 the APACHE II score was
general inpatient units: 28 patients were from the emergency depart- regarded as a significant predisposing factor for ICUAW in our study.
ment, and the remaining 6 patients were transferred after surgery. APACHE II scores ≥15 (relative risk [RR], 11.6; 95% confidence inter-
Based on the results of manual muscle testing, the study population val [CI], 4.9-27.2)28 were found to be associated with a significant risk
was divided into two groups: 30 patients with ICUAW and 38 patients of developing ICUAW. Hyperlactacidemia is also a common laboratory
without ICUAW. The incidence of the ICUAW was 44.1%. Nineteen abnormality among critically ill patients. A raised blood lactate concen-
patients with ICUAW died, and 8 patients without ICUAW died. The tration is considered to be a marker of the severity of illness and can
mortality rate was 63.3% in patients with ICUAW versus 21.1% in predict short-term prognosis in critically ill patients.29,30 An increased
patients without ICUAW (P < .01). blood lactate concentration is a significant predictor of mortality.31,32
Univariate analysis of potential risk factors for ICUAW is shown Together with the APACHE II score, hyperlactacidemia was found to
in Table 1. Patients with clinical weakness had significantly higher be significantly associated with ICUAW, which may help to support
admission APACHE II scores and SOFA scores than patients without the hypothesis that more severely ill patients were more susceptible
clinical weakness. Patients with clinical weakness had significantly to the development of ICUAW. In our study, elevated lactic acid levels
more days with MV than patients without clinical weakness. The use were present mostly within the first 3 days after ICU admission, and
of norepinephrine was an important risk factor based on univariate using such early variables may be a way to predict the incidence of
analysis. Hyperlactacidemia, hypocalcemia, and electrolyte distur- ICUAW after ICU admission.
bance were found to be significantly associated with ICUAW. The var- Lactate is a standard laboratory test in ICUs, and it has been used
iables above were entered in the multivariate regression analysis. as a more objective surrogate for tissue perfusion than physical exam-
After the backward selection of regression analysis, hyper- ination.22 Lactate is the main metabolite of anaerobic glycolysis
lactacidemia, APACHE II, duration of MV, and use of norepinephrine induced by tissue hypoperfusion and hypoxia. Lactate can be released
were regarded as independent risk factors for the development of by different cells,33 among which skeletal muscle34 plays an important
ICUAW (Table 2). role. The highest lactate level has been explored as a predictor for

F I G U R E 1 Flow diagram of
the population selection process
4 YANG ET AL.

T A B L E 1 Univariate comparison of
Variable Control (38) ICUAW (30) P-Value
risk factors between ICUAW and control
Age (y) 80.5 (72.8, 86) 82.5 (79, 87.3) .17 patients
Female, n (%) 17 (44.7%) 14 (46.7%) .87
ICU stay before diagnosis, (d) 10 (8.8, 15) 11 (9.8, 18.5) .32
MRC score 52.5 (51, 54) 38.5 (33, 42) <.01
APACHE II 18.8 ± 7.8 24.4 ± 7.4 .04
SOFA 6 (5, 10) 10 (7.8, 11.3) <.01
SIRS, n (%) 35 (92.1%) 30 (100%) .33
Sepsis, n (%) 31 (81.6%) 28 (93.3%) .29
Septic shock, n (%) 20 (52.6%) 27 (90%) <.01
MODS, n (%) 28 (73.7%) 29 (96.7%) .03
MV, n (%) 32 (84.2%) 30 (100%) .06
Duration of MV, (d) 6.8 ± 4.7 10.9 ± 5.4 <.01
Aminoglycoside, n (%) 0 (0) 2 (6.7%) .19
NMBAs, n (%) 3 (7.9%) 7 (23.3%) .15
Corticosteroids, n (%) 23 (60.5%) 22 (73.3%) .27
Norepinephrine, n (%) 19 (50%) 28 (93.3%) <.01
Parenteral nutrition, n (%) 11 (28.9%) 9 (30%) .93
Hyperlactatemia, n (%) 25 (65.8%) 28 (93.3%) <.01
Hypocalcemia, n (%) 25 (65.8%) 28 (93.3%) <.01
Hyperglycemia, n (%) 24 (63.2%) 25 (83.3%) .07
Electrolyte disturbances, n (%) 31 (81.6%) 30 (100%) .04

Note: Mean values are presented ±SD, median values with IQR and proportions with percentages and
total numbers.

TABLE 2 Multivariate analysis of risk factors for ICUAW

MV was another risk factor. The association between the dura-
Independent risk factor OR (95% CI) P-Value tion of MV and ICUAW is complex. ICUAW was recognized as a risk
Hyperlactatemia 8.54 (1.40-52.12) .02 factor independently associated with weaning failure.37 Since weaning
APACHE II 1.10 (1.00-1.20) .04 failure was correlated with an increased risk of death, it may partly
Duration of MV 1.01 (1.00-1.01) .02 explain the poor outcome of ICUAW patients. In addition, ICUAW
Norepinephrine 6.29 (1.14-34.79) .04 was also found to prolong the duration of MV.15,37 In turn, the dura-
tion of MV was found to increase the occurrence of ICUAW.38 Con-
Abbreviations: OR, odds ratio.
sistent with previous studies, we also observed that the duration of
MV before diagnosis was an independent risk factor for the develop-
ICUAW and incorporated into its prediction model.35,36 Previous ment of ICUAW in ICU patients. A MV duration of more than 1 wk
studies focused on the highest lactate level and demonstrated that it can lead to alterations in both respiratory and limb muscle strength,39
was significantly higher in ICUAW patients than in those without which partly reflects the negative effect of immobilization on neuro-
ICUAW. Our study, based on a mixed medical-surgical ICU, explored muscular weakness. Clinicians need to optimize ventilatory manage-
the relationship between ICUAW and hyperlactacidemia and revealed ment and facilitate the development of care management for patients
that hyperlactacidemia was independently associated with the devel- on MV. Early mobilization26,40,41 for patients with MV has been found
opment of ICUAW. Hyperlactacidemia has been used as one of the to be effective for preventing the development of the disorder.
clinical criteria for septic shock.13 Lactate-guided resuscitation and Our study was not without limitations. This was a single-center,
decreasing the concentrations of lactic acid may help to reduce the observational study, and the number of patients was relatively small.
incidence of ICUAW. In addition, norepinephrine is widely used in The clinical significance may be addressed in further studies. The
patients with shock. The use of norepinephrine was also found to be timing of the lactate measurements was not uniform. We performed
significantly associated with increased odds of developing ICUAW. the first measure shortly after admission and completed the majority
Thus, exposure to norepinephrine should be limited or administration of the second lactate measurements 6 h after admission. Another limi-
time shortened in clinical practice to decrease the incidence of tation was the lack of electrophysiological tests or muscle biopsies;
ICUAW. Early resuscitation and rapid treatment of shock are essential thus, no distinctions were made to determine whether the patients
to reducing the incidence of ICUAW. had myopathy, neuropathy, or both. In addition, sensation and
YANG ET AL. 5

reflexes were not regularly or quantitatively tested for all the patients. 6. Fan E, Cheek F, Chlan L, et al. An official American Thoracic Society
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