Article, Emergency Medicine

The value of lactate clearance in admission decisions of patients with acute exacerbation of COPD

a b s t r a c t

Background: Lactate and lactate clearance are being used as biomarkers in several critical conditions. The aim of this study was to examine the value of sixth hour lactate clearance in patients who were hospitalized with chron- ic obstructive pulmonary disease (COPD) exacerbations.

Methods: This single-center, cross-sectional study was conducted in a tertiary emergency department (ED) on patients who presented with acute exacerbation of COPD. Discharge or admission decisions were specified ac- cording to the Global Initiative for Chronic obstructive lung disease (GOLD) criteria and the clinician’s decision. In the study, lactate clearance was defined as the percent decrease in lactate from the time of presentation to the ED to the sixth hour.

Results: A total of 495 patients were evaluated and 397 patients were excluded. Among included patients, 53 (54.1%) were admitted to the hospital and 45 (45.9%) were discharged. The median lactate clearance was found to be -11.8% (95% CI: -50.0 to 34.5) in the admitted group and 14.7% (95% CI: -11.3 to 42.3) in the discharged group. Between the two groups, the median difference of lactate clearance was found to be 26.5% (95% CI: 0.6 to 52.4). Multivariate logistic regression analysis revealed that the delta lactate value can determine the hospitalization need of patients (OR: 0.91, 95% CI: 0.85 to 0.97).

Conclusion: Lactate clearance can be evaluated as a useful marker in patients with COPD exacerbations. This study suggests that lactate monitoring in the ED has clinical benefits in addition to GOLD guidelines when deciding whether to discharge or hospitalize a patient.

(C) 2017

  1. Introduction

Chronic obstructive pulmonary disease (COPD) is a major chronic disease that often requires emergency department (ED) care. Each year, Exacerbations of COPD account for N 1.5 million ED visits. COPD ex- acerbations are the fourth leading cause of death worldwide [1], the eighth cause of Disease burden as measured by disability-adjusted life years, and ranks globally among the top twenty conditions causing dis- ability [2].

Every year, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) publishes guidelines for the prevention, diagnosis and manage- ment of COPD. However, due to a relatively low number of studies con- ducted in the ED environment, the proper management of COPD exacerbations is still under debate [3]. The GOLD guidelines list several potential indicators of COPD that require hospital admission. These

? Source of funding and conflicts of interest: None declared.

* Corresponding author at: Kocaeli University, Faculty of Medicine, Kocaeli, Turkey.

E-mail address: [email protected] (N.O. Dogan).

include a marked increase in the intensity of symptoms, severe underly- ing disease, frequent COPD exacerbations, and the onset of new physical signs. Additional indicators that require hospitalization are older age, serious comorbidities, and the failure to respond to initial treatments. Although these clinical factors were previously determined as poor out- comes for Disease prognosis, multiple studies have dealt the role of bio- markers in COPD exacerbations [4,5]. Among various biomarkers, C- reactive protein (CRP) was previously investigated in COPD exacerba- tions; it is thought that CRP can predict the frequency and severity of ex- acerbations. However, its role in management and prognostication still remains unclear, as it was neither sufficiently sensitive, nor specifically alone [6,7].

Lactate levels have been used widely as a marker of altered tissue perfusion in critically ill patients [8]. Recently, the roles of lactate and lactate clearance were investigated in several critical conditions, which included sepsis, trauma, cardiac arrest, and respiratory insuffi- ciency. It was proposed to predict all-cause mortality in these patients [8-10], however its alteration in COPD exacerbations was not known. The present study investigated the role of lactate clearance in patients who presented to the ED with COPD exacerbations.

https://doi.org/10.1016/j.ajem.2017.11.002

0735-6757/(C) 2017

  1. Methods
    1. Study setting

This prospective, cross-sectional study was conducted from Novem- ber 2015 through February 2017 in a university hospital ED on patients who presented with COPD exacerbations. An institutional review board approval was obtained, before the study was started. The patients were asked to sign an informed consent form during the enrollment period.

Selection of participants

All adult patients who presented to ED with COPD exacerbation were evaluated for inclusion in the study. COPD exacerbation was de- fined based on GOLD guidelines, which state: “an acute event character- ized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medica- tion” [3]. Exclusion criteria include: Pregnancy, inability to perform the first or subsequent arterial blood gas analysis, identification of type B lactic acidosis (according to Cohen and Woods classification) [11], and patient refusal. Type B lactic acidosis was defined as occur- rence of lactic acidosis when no clinical evidence of poor tissue perfu- sion or oxygenation exists.

Study protocol

After a patient presented to the ED with symptoms of COPD exacer- bation, a senior emergency medicine resident (two years or more in res- idency) evaluated the patient. The patient’s main symptoms, vital signs, exacerbation features, comorbid conditions, previous admissions due to COPD, and other laboratory data were recorded using standardized charts. After the appropriate treatment was started, the first arterial

blood gas analysis was performed. In accordance with the GOLD guide- lines, all patients were treated with supplemental oxygen, short-acting bronchodilators, and corticosteroids [3]. According to patients’ status, other co-treatments were implemented, which included antibiotics and invasive or non-invasive mechanical ventilation. After the sixth hour of presentation to the ED, a following arterial blood gas analysis was performed. The caring physician, who was blind to the lactate levels of the patient, was asked to make a decision about whether to discharge or hospitalize the patient. The hospitalization decision was based on GOLD criteria for acute COPD exacerbations and physicians own exper- tise. GOLD criteria for potential indications for hospital admission in- clude marked increase in intensity of symptoms, severe underlying COPD, onset of new physical signs, failure to respond initial medical treatment, presence of serious comorbidities, frequent exacerbations, older age, and insufficient home support [3].

The first and second lactate values were recorded on study charts

and lactate clearance was calculated. Lactate clearance (percent) was defined using the following formula suggested by Nguyen et al. [8]: (LactateED Presentation – Lactate6th hour) x 100 / LactateED Presentation.

Outcomes

The primary outcome measure was defined as the change in lactate clearance between the discharged and hospitalized groups. The second- ary outcome measure was the role of other clinical and laboratory pa- rameters, which can be predictors of hospitalization in COPD exacerbations.

Statistical analysis

All statistical analyses were performed with SPSS (version 15.0; SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov test was used to

Fig. 1. Patient flow chart.

Table 1

Main characteristics of the study population and the features of exacerbation

All patients

Admitted

Discharged

p value

n = 98

n = 53

n = 45

Age (yr)

69 (60-73)

69 (61-73)

68 (60-76)

0.861

Male gender

79 (80.6%)

44 (83.0%)

35 (77.8%)

0.513

Medical history

Diabetes mellitus

20 (20.4%)

10 (18.9%)

10 (22.2%)

0.681

Hypertension

45 (45.9%)

25 (47.2%)

20 (44.4%)

0.787

Hyperlipidemia

12 (12.2%)

8 (15.1%)

4 (8.9%)

0.350

Chronic kidney disease

4 (4.1%)

3 (5.7%)

1 (2.2%)

0.622

Clinical characteristics

Temperature (?C)

36.5 (36.0-36.8)

36.5 (36.2-37.0)

36.4 (36.0-36.8)

0.211

Heart rate (beats/min)

104 (94-115)

107 (96-115)

101 (89-115)

0.052

Systolic blood pressure (mm Hg)

142 (125-160)

144 (128-159)

140 (123-161)

0.660

SpO2 (%)

90 (83-94)

88 (81-93)

92 (87-95)

0.057

Respiratory rate (beats/min)

30 (27-34)

30 (28-36)

28 (26-32)

0.076

Disease characteristics

Active Tobacco use

11 (11.2%)

3 (5.8%)

8 (17.8%)

0.063

Cigarette (package/yr)

60 (45-100)

50 (30-74)

43 (35-60)

0.350

Admission due to COPD exacerbation last one year

10 (3-20)

10 (3-20)

6 (3-18)

0.373

Number of IMV for last one year

0 (0-0)

0 (0-0)

0 (0-0)

0.139

Number of NIMV for last one year

0 (0-1)

0 (0-2)

0 (0-1)

0.043

Dyspnea

94 (95.9%)

50 (94.3%)

44 (97.8%)

0.622

Increase in sputum production

51 (52.0%)

24 (45.3%)

27 (60.0%)

0.146

Increase in sputum purulency

62 (63.3%)

34 (64.2%)

28 (62.2%)

0.844

Cough

79 (80.6%)

44 (83.0%)

35 (77.8%)

0.513

Chest pain

22 (22.4%)

13 (24.5%)

9 (20.0%)

0.592

Altered mental status

2 (2.0%)

1 (1.9%)

1 (2.2%)

1.000

Severe bronchospasm

22 (22.4%)

16 (30.2%)

6 (13.3%)

0.046

Lobar infiltration in X-ray

55 (56.7%)

33 (62.3%)

22 (50.0%)

0.225

Pleural effusion in X-ray

22 (22.7%)

15 (28.3%)

7 (15.9%)

0.147

Values are presented as n (%) or median (interquartile range).

IMV: invasive mechanical ventilation, NIMV: non-invasive mechanical ventilation.

analyze the normal distribution of the variables. The continuous inde- pendent variables were analyzed using the Mann-Whitney U test and expressed with median and interquartile range. The categorical vari- ables were analyzed using the Pearson ?2 test and were expressed with numbers and percentages.

The primary outcome was defined as the median between group change in lactate clearance and was assessed with the Mann-Whitney U test. The median differences were expressed with 95% confidence in- tervals (CIs) using the method proposed by Bonett and Price [12]. All statistical analyses were two-sided.

Additionally, a binary logistic regression model was constructed to assess the factors predicting hospitalization decision in who patients presented to the ED with COPD exacerbation. The univariate model con- sidered the main characteristics of exacerbations, which are easily ob- tained after presentation to the ED. The model included major symptoms, clinical characteristics, co-morbid conditions, vital parame- ters, radiographic findings, and laboratory variables. Each variable was tested with the univariate model, and those that were significant at an alpha level of 0.05 were then tested with the multivariate model. Multicollinearity analysis was performed using the Spearman correla- tion test. The fitness of the multivariable regression model was

evaluated with the Hosmer-Lemeshow test. Odds ratios (ORs) were presented with 95% CIs. An alpha value of 0.05 was accepted as the nom- inal level of significance.

The sample size estimation was performed using the G-Power pro-

gram for Mac OS X (version 3.1.9.2; Universitat Dusseldorf, Germany). Previously, Jansen et al. used a 20% lactate clearance to guide treatment in their study [13]. It was hypothesized that discharged patients would be able to eliminate lactate easier than those who have been hospital- ized. Thus, this study aimed to achieve a 20% difference in lactate clear- ance between groups. To detect this difference, assuming an alpha value of 0.05, a sample size of 90 patients to achieve 90% power (n = 45 for both groups) was anticipated.

  1. Results

After a total of 495 patients were assessed for eligibility, 377 patients (whose clinical deterioration was not primarily related to COPD exacer- bation) and 20 patients (with several reasons) were excluded from the study (Fig. 1). Eventually, 98 patients were included in the analysis. Of the 98 patients, 45 were discharged from the ED and 53 were admitted to the hospital.

Table 2

First (at presentation) and follow-up (at 6th hour) results of arterial blood gas analyses.

All patients

Admitted

Discharged

p value

(median, IQR)

(median, IQR)

(median, IQR)

(n = 98)

(n = 53)

(n = 45)

First measurement

pH

7.41 (7.36-7.44)

7.41 (7.36-7.45)

7.41 (7.37-7.44)

0.875

pO2 (mm Hg)

65.3 (53.5-77.2)

60.3 (50.1-81.9)

68.5 (59.2-76.3)

0.053

pCO2 (mm Hg)

41.0 (36.1-49.9)

43.3 (36.4-50.1)

40.5 (35.6-49.6)

0.439

HCO3 (mEq/L)

25.8 (24.3-28.0)

26.2 (24.4-29.7)

25.4 (24.0-27.0)

0.066

Second measurement

pH

7.40 (7.37-7.43)

7.39 (7.36-7.43)

7.41 (7.38-7.44)

0.152

pO2 (mm Hg)

75.6 (56.7-102)

71.1 (51.7-94.2)

83.1 (60.3-107.0)

0.065

pCO2 (mm Hg)

42.3 (37.2-49.8)

44.9 (37.7-52.4)

41.0 (36.5-45.7)

0.040

HCO3 (mEq/L)

25.5 (24.0-28.0)

26.6 (24.0-29.1)

25.2 (24.1-26.7)

0.049

IQR: interquartile range.

Table 3

First and follow-up measurements of lactate levels and lactate clearance.

Admitted patients

Discharged patients

Median difference

p value

(median, IQR)

(median, IQR)

(95% CI)

(n = 53)

(n = 45)

First lactate level (mg/dL)

13 (9-18)

16 (11-22)

3.0 (-1.1-7.1)

0.088

Follow-up lactate level (mg/dL)

13 (9-19)

13 (9-16)

0.0 (-3.5-3.5)

0.610

Delta lactate (mg/dL)

-1 (-6-5)

3.0 (-1-9)

4.0 (0.2-7.8)

0.015

Lactate clearance, %

-11.8% (-50.0-34.5)

14.7% (-11.3-42.3)

26.5% (0.6-52.4)

0.023

IQR: interquartile range.

Bold values indicate significance at P b 0.05.

The main characteristics of the study population are presented in Table 1. Previous medical history, exacerbation characteristics, and clin- ical findings were similar between the discharged and admitted groups. However, more severe bronchospasms (silent chest) presented in ad- mitted patients than in discharged patients (p = 0.046). Regarding pa- tients’ arterial blood gas analyses, both admitted and discharged patients had similar characteristics (Table 2). However, the sixth hour arterial blood gas analysis revealed that admitted patients were more hypercapnic (p = 0.040) and their bicarbonate levels were higher than discharged patients (p = 0.049).

The results of lactate levels and lactate clearance in the sixth hour re- garding a patient’s admission status are shown in Table 3. Whereas the lactate levels were similar at presentation for both groups, discharged patients had a lactate clearance of 14.7% (95% CI: -11.3 to 42.3) while admitted patients had a lactate clearance of -11.8% (95% CI: -50.0 to 34.5). The median difference between the admitted and discharged groups was 26.5% (95% CI: 0.6 to 52.4) (p = 0.023).

Additionally, a multivariate model was created that contained signif- icant predictors from the univariate analysis (Table 4). As potential pre- dictors of hospitalization need, the number of non-invasive mechanical ventilations (NIMVs) needed in the last year, severe bronchospasms at ED presentation, follow-up pCO2 and bicarbonate levels, delta lactate, and lactate clearance were evaluated for inclusion in the multivariate analysis. Before including the variables into the multivariate model, a multicollinearity analysis was performed. Significant correlations were observed between follow-up pCO2 and bicarbonate levels (r = 0.679, p b 0.001) and between delta lactate levels and lactate clearance (r = 0.976, p b 0.001). Therefore, the multivariate model was constructed only using the NIMVs needed in the last year, delta lactate, severe bron- chospasms, and follow-up pCO2 levels. The results show that delta lac- tate levels are an independent predictor of hospitalization need in COPD exacerbations (OR: 0.91, 95% CI: 0.85 to 0.97). The Hosmer- Lemeshow test confirmed that the created logistic regression model was fit (p = 0.624).

A receiver operating characteristic curve was constructed to deter-

mine the accuracy of delta lactate levels when predicting admission sta- tus. The area under the curve was 0.642 (95% CI: 0.533 to 0.752) (Fig. 2). When the delta lactate level was taken as 0.5 mg/dL, a sensitivity of 64.4% and a specificity of 59.5% were found.

  1. Discussion

The results of the study reveal that lactate clearance did not occur in admitted patients as hypothesized. Discharged patients were found to

Table 4

multivariate logistic regression model to predict hospitalization need in patients with COPD exacerbation.

Wald

p value

Multivariate OR (95% CI)

Number of NIMV in last year

2.581

0.108

1.14 (0.97-1.34)

Severe bronchospasm

3.184

0.074

2.86 (0.90-9.06)

pCO2 (follow-up)

2.285

0.131

1.04 (0.99-1.09)

Delta lactate

8.016

0.005

0.91 (0.85-0.97)

NIMV: non-invasive mechanical ventilation, OR: odds ratio.

have a 14.7% lactate clearance. However, this finding is not statistically significant. The difference in lactate clearance between the two groups was 26.5% and delta lactate value was found to be an independent pre- dictor of hospitalization need in COPD exacerbations. Although several studies handled lactate clearance as a mortality indicator, this study used lactate clearance as a biomarker, which suggested more severe dis- ease. Thus, even normal lactate values were used to point out the prog- nosis of COPD exacerbations.

When evaluating critical patients in an emergency setting, a single measurement of lactate, or any other biomarker, may play a limited role. However, it is well known that persistent elevation of lactate levels are related to mortality or Negative outcomes in several clinical condi- tions [8-10,14-18]. Although the initial trigger event differs in each clin- ical scenario, vasodilation, the release of Inflammatory mediators, and global tissue hypoxia (which contributes to the endothelial activation) all result in Multiple organ dysfunction syndrome and death [10]. Since lactate is mainly metabolised by the liver, even minor increases in lactate concentrations to N 1.5 mEq/l are associated with higher mor- tality rates [19].

Recently, two systematic reviews were published regarding the value of lactate clearance in critically ill patients [8,9]. Zhang et al. eval- uated 15 articles in a meta-analytic model in different populations [9]. Although the primary outcome was established as lactate clearance in these studies, the lactate reduction target (10%-50%) and target time in- terval (6 h-24 h) significantly differed between them. On the other

Fig. 2. Receiver operating curve analysis to determine the accuracy of delta lactate levels when predicting admission status.

hand, all included studies consistently demonstrated that a higher lac- tate clearance was associated with a lower risk of death, with the rela- tive risk ranging from 0.04-0.57. More recently, Vincent et al. performed a systematic review and 96 studies were included [8]. Al- though this review also consists of different patient groups, three stud- ies involving Respiratory insufficiency were also included in the review. These studies were carried out on patients with acute respiratory failure to determine the association between improved survival and lactate clearance [20-22]. This review suggests that changes in blood lactate ki- netics were clearly significant after the sixth hour, and that it is current- ly not possible to define the best time interval between lactate measurements [8].

COPD exacerbation is an emergent respiratory condition, with bio- markers playing a very limited role in the decision-making process [3]. A study that involved plasma biomarkers, to conclude exacerbation di- agnosis, established that the most selective biomarker was CRP. Howev- er, CRP has a very limited sensitivity and specificity, the area under the curve for exacerbation diagnosis was 0.73 (95% CI: 0.66 to 0.80). This study also argued that there were no significant relationships between biomarker concentrations and clinical indices of COPD exacerbation se- verity [6]. By measuring serial lactate, useful information may be added in this setting, therefore optimizing Resuscitative efforts and oxygen de- livery to tissues in patients with COPD exacerbations.

Limitations

The study had several limitations. First, the study was conducted in a single center ED, which limits the generalizability of the results. Second, the sample size contained relatively well COPD patients. If critically ill or septic COPD patients were studied, lactate changes within this popula- tion may become more apparent. Third, only the formal definition of COPD exacerbation was considered in this study. Inevitably, COPD pa- tients may have several comorbidities that may affect lactate metabo- lism and clearance.

  1. Conclusion

The results of the present study suggest that, lactate clearance may play a role in the decision-making process in patients who present to the ED with COPD exacerbations. Delta lactate was found to be an inde- pendent predictor of hospitalization need in this clinical condition. New studies may emphasize the role of lactate metabolism in patients who present to the ED with more severe COPD exacerbations.

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