a b s t r a c t

Background: Prognostication of survival after out-of-hospital cardiac arrest (OHCA) remains challenging with current guidelines recommending the prognostication no earlier than 72 h after return of spontaneous circula- tion (ROSC). Prognostic factors that could be used earlier after ROSC, like Lactate clearance, are still being studied. Objectives: This paper aims to investigate the prognostic strength of early lactate clearance for survival after OHCA.

Methods: This retrospective observational single-center study focuses on patients for whom ROSC was achieved after OHCA. Patients >=18 years admitted between September 2012 and January 2019, for which arterial serum lactate measurements were available immediately at and 3 h after hospital admission (T0 and T3), were included. Results: 192 patients were included. Lactate clearance at T3 (p < 0.001) was identified as an independent predic- tor for 24 h, 48 h and 72 h survival. witnessed arrest, bystander CPR and initial shockable rhythm were indepen- dent significant predictors for long term survival after ROSC (1 month, 3 months and 1 year; p < 0.05), but not for 24 h survival. Age (above or below 65 years) was not significant for predicting survival. Upon combination of witnessed arrest, bystander CPR and initial shockable rhythm in a multivariate logistic regression model for long term survival, the initial rhythm was the dominant factor in the combined model, making witnessed arrest and bystander CPR redundant.

Conclusion: Lactate clearance at T3 after ROSC is associated with 24 h, 48 h and 72 h survival. Further research is needed to determine how to incorporate lactate clearance as part of a clinically useful tool to predict long term survival.

(C) 2021 Published by Elsevier Inc.

1. Introduction

Despite continuous efforts to improve the Chain of survival, out-of- hospital cardiac arrest (OHCA) remains associated with high morbidity and mortality. [1] Even when return of spontaneous circulation (ROSC) has been achieved, in-hospital survival rate remains low. An accurate and early estimation of prognosis is essential to identify patients that would benefit most from further intensive care. [2] Early prognostica- tion is not only of importance for decision-making and discussions about goals of care, but it can also help to keep healthcare budgets in Europe sustainable.

Once resuscitated patients are admitted to the intensive care unit (ICU), the European Resuscitation Council (ERC) recommends using a multimodal prognostic approach to predict outcome. Unfortunately, this algorithm, consisting of clinical, biological and radiological observa- tions, can only be initiated 72 h after the targeted temperature

* Corresponding author at: Emergency Department, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium.

E-mail address: [email protected] (P. Dewolf).

management treatment is completed. It can therefore not be used for early prognosis in the emergency setting. [3]

Early prognosis after OHCA has been the subject of several studies. In 2010, a systematic review by Sasson et al. found 4 Prehospital factors as- sociated with survival after OHCA: witnessed arrest, bystander cardio- pulmonary resuscitation (CPR), shockable initial rhythm and ROSC achieved on scene. [4] The Quality of CPR and post-resuscitation care have an impact on survival as well. [5] Recent studies have shown an in- creasing interest in the use of serum biomarkers for early prognostica- tion, with a particular interest in serum lactate and lactate clearance as a surrogate marker for tissue perfusion. Although most of this research was conducted on septic patients and the results on OHCA pa- tients were often inconsistent, several studies have shown promising results. [6-11] In 2016, Williams et al. found that lower initial serum lac- tate and early lactate clearance were associated with an increased like- lihood of survival at hospital discharge after OHCA. [6] In addition, Vanwetswinkel et al. published an abstract reporting preliminary re- sults that suggest that serum lactate and lactate clearance are prognostic factors with a high sensitivity and specificity. [10] Finally, in 2017 Potpara et al. proposed a simple prognostication tool including lactate

https://doi.org/10.1016/j.ajem.2021.03.013 0735-6757/(C) 2021 Published by Elsevier Inc.

values for early in-hospital outcome after OHCA, but the results have not been repeated thus far. [11]

Based on preceding research, this paper aims to investigate the asso- ciation between early lactate clearance and survival for up to 1 year after OHCA, after adjusting for potential prehospital confounders. To this day, the prognostication strength of lactate clearance has not been studied as early as 3 h after ROSC. Ultimately this study aims to propose a clinically

Table 1

Definitions of the collected variables

Witnessed arrest^a A CA that is seen or heard by another person.

Bystander CPR^a CPR performed by any person who is not part of an

organized EMS team responding to the emergency call. In case the arrest was witnessed by EMS and CPR was performed by them, this was also

useful Prognostic tool for survival after ROSC, using only a few variables which are immediately at the disposal of the emergency physician.

1. Methods
   1. Study design and setting

initial cardiac rhythm^a

considered bystander CPR.

First cardiac rhythm observed when a monitor or defibrillator is attached to the patient after a CA.

• Non-Shockable rhythms: asystole and pulseless electrical activity.
• Shockable rhythms: pulseless ventricular tachycardia and ventricular fibrillation.

This retrospective observational single-center cohort study was con- ducted between September 1, 2012 and January 1, 2019 at the emer- gency department of the University Hospital of Leuven, Belgium after approval by the ethics committee. The primary outcome was survival status up to 1 year after OHCA. In a secondary analysis, the prognostic strength of arterial lactate clearance was evaluated in addition to the prognostic strength of prehospital factors (age, witnessed arrest, by- stander CPR, initial cardiac rhythm).

• 1. Inclusion and exclusion criteria

EMS^o time The time interval from incoming call to the time the

first emergency response vehicle stops at a point closest to the patient’s location. The time of the incoming call is defined as the time the call is first registered at the center answering emergency calls, regardless of when the call is answered.

No flow time Time from CA to start of CPR (BLS or ACLS).

BLS⁺ time Duration of BLS, performed by any bystander, ambulance paramedic or general practitioner.

ACLS? time Duration of ACLS, performed by the EMS team responding to the emergency call. Ambulance paramedics arriving on the scene without assistance from other EMS are only considered to perform BLS.

CPR duration Duration of the total CPR attempt (BLS time + ACLS

time).

Adult patients (>= 18 years old) who had suffered any type of OHCA between September 1, 2012 and January 1, 2019, and for whom arterial serum lactate measurements were available immediately at and three hours after hospital admission (lactate (T0) and (T3)), were included. Lactate (T0) was defined as the lactate value on the first arterial blood sample taken at hospital admission. No time frame was set for this pa- rameter, as the largest factor influencing the time of hospital admission is the duration of CPR. Lactate (T3) was defined as the lactate value on an arterial blood sample taken 2 to 4 h post T0. If multiple blood samples were taken during this time period, the sample closest to 3 h post T0 was included. For all patients, survival status up to 1 year was recorded.

Serum lactate at T0 (lactate (T0))

Serum lactate at T3 (lactate (T3))

Lactate clearance at T3 (lactate clearance (T3))

Arterial serum lactate concentration measured in the first blood sample taken after hospital admission post ROSC.

Arterial serum lactate concentration measured in the blood sample taken 3 h after the first blood sample. Blood samples taken 2 h to 4 h post T0 were included. When multiple blood samples were taken during this time period, the sample closest to 3 h was included.

Percentage of initial lactate already cleared by the body at T3. Formula:

Lactate cl (T3) = Lactate (T0)-Lactate (T3) x 100

Lactate (T0)

Patients were excluded based on the following exclusion criteria: age < 18 years, in-hospital cardiac arrest, arterial serum lactate mea- surements not available at T0 and/or T3, incomplete medical record, ROSC prior to EMS arrival, no information on other predictors (witnessed arrest, bystander CPR, initial cardiac rhythm, Emergency Medical Services (EMS) time, no flow time, basic life support (BLS) time, Advanced cardiac life support time, CPR duration).

• 1. Data collection and management

The following data were manually extracted from the hospital infor- mation system for each patient: demographic data (age, gender), CPR data based on the Utstein definitions of cardiac arrest (witnessed arrest, bystander CPR, initial cardiac rhythm, EMS time, no flow time, BLS time, ACLS time, CPR duration), arterial Serum lactate levels and patient survival. [12] Definitions of the variables are presented in Table 1, Appendix, online material. For each patient, the percentage of initial lac- tate already cleared by the body at T3 was calculated using the following formula:

Lactate clearance (T3) = Lactate (T0)-Lactate (T3) x 100

Lactate (T0)

• 1. Statistical analyses

Statistics were performed using SPSS for Windows, version 10.0 (Chicago, IL, USA) and SAS software for Windows, version 9.4 (Copy- right (C) 2002, Cary, NC, USA). Descriptive statistics were used to summa- rize the study population using mean and standard deviation, or median

EMS: Emergency Medical Services. This includes the ambulance, the Paramedical Inter- vention Team (PIT, a medical unit in Belgium consisting of one ambulance paramedic and one registered emergency nurse) and the mobile emergency team (Mobiele UrgentieGroep, MUG, a medical unit in Belgium consisting of one registered emergency nurse and one emergency physician). BLS: Basic Life Support: Airway, breathing and circu- lation support without the use of equipment other than a protective device. ACLS: Ad- vanced Cardiovascular Life Support, ROSC: return of spontaneous circulation.

^a Witnessed arrest, bystander CPR, initial cardiac rhythm and EMS time are defined based on the Utstein criteria. (11) CA: cardiac arrest, CPR: cardiopulmonary resuscitation.

and interquartile range in case of large deviations from the normal distribution. Categorical data are presented as frequencies with percent- ages. To evaluate the effect of lactate clearance on survival, a Cox regres- sion analysis and two-tailed two-sampled Student’s t-test were performed. To analyze the ability of lactate clearance to predict 24 h sur- vival, a Receiver Operating Characteristic (ROC) curve was generated. Fisher’s exact tests were used to evaluate the effect of the nominal var- iables age < 65 years, witnessed arrest, bystander CPR and initial cardiac rhythm on survival. These four established predictors were combined in a ‘Basic model’ [4]. Cox regression analyses were used to assess the asso- ciation between all-cause mortality and the ‘Basic model’, and the ‘Basic model’ including lactate clearance after 3 h. Hazard ratios and 2-sided 95% confidence intervals were calculated. To assess the fit of the model, time-dependent AUC(t) values were calculated and plotted which determine the discrimination of the model over time. In addition, the integrated AUC was calculated to assess the overall discriminatory ability of the Cox regression model. All statistical tests were 2-sided and assessed at a significance level of 5%.

For one patient, an unusually large increase in lactate clearance was observed at 3 h. In all regression analyses, this observation was found to

be influential to the results of the analyses. Therefore, this patient was excluded from all regression analyses.

1. Results
   1. Study population

From September 2012 to January 2019, the University Hospital Leuven EMS treated 760 patients suffering from an OHCA of which 286 patients (37.6%) achieved ROSC. For 192 patients arterial serum lac- tate levels at T0 and T3 were present.

• 1. Patient characteristics

Table 2 summarizes the patient characteristics of the total study population and compares the 24 h, 48 h and 72 h survivors and non-survivors. The non-survivor groups contained more CA victims with initially a Non-shockable rhythm. The survivors had lower initial serum lactate concentrations and higher lactate clear- ance at T3.

• 1. Association between lactate clearance and survival

The association between lactate clearance at T3 and all-cause mor- tality, was investigated using Cox regression analysis. A statistically sig- nificant linear association was found (p = 0.0091).

Using a two-tailed two-sampled Student’s t-test, the relationship be-

tween lactate clearance at T3 and survival at specific time points (24 h,

48 h, 72 h, 1 month, 3 months and 1 year) was investigated.

Survivors at 24 h showed significantly higher lactate clearance than non-survivors (p < 0.001) (Fig. 1). At 48 h and 72 h, lactate clearance remains significantly higher in the survivor group than the non-survivor group (48 h: p = 0.001; 72 h: p = 0.030). (Table 2) However, when looking at long term survival, lactate clearance was not significantly different between survivors and non-survivors (1 month: p = 0.396; 3 months: p = 0.712; 1 year: p = 0.586) (Fig. 1). The area under the curve (AUC) calculated from the ROC

curve for predicting 24 h survival and 1 month survival are 0.752 and 0.628, respectively (Fig. 2).

• 1. Prognostic tool for survival

Since previous studies demonstrated a relationship between ROSC and witnessed arrest, bystander CPR, an initial shockable rhythm and age < 65 years, a multivariate analysis was performed to determine whether a combined model including both these established predictors as well as lactate clearance can be cast in a clinically useful prognostic tool for survival after ROSC. [2,4,13-22]

In a first step, the prognostic strength of the individual parameters was investigated using the Fisher’s exact test. Although previous re- search has demonstrated that age < 65 years increases the patient’s chance of ROSC, we could not confirm a significant association between age and survival after ROSC in our study population (Table 3). A signif- icant association between survival after ROSC and witnessed arrest, by- stander CPR or initial shockable rhythm was found, but only for long term survival (72 h, 1 month, 3 months and 1 year).

Upon combination of these 4 parameters in a so called ‘Basic model’ to predict survival, only the initial rhythm of a CA victim was found to be a significant parameter for Survival prediction after ROSC (Table 4). The integrated AUC for this ‘Basic model’ was 0.66.

In a combined model (including the ‘Basic model’ and lactate clear- ance), 3 parameters were found to be statistically significant: initial rhythm, age and lactate clearance (Table 4). Addition of lactate clear- ance to the ‘Basic model’ improved survival prediction, demonstrated by an increased integrated AUC (‘Basic model’: 0.66; ‘Basic + lactate model’: 0.73) (Fig. 3). Zooming in on the plots of the AUC(t) values, one can see good improvement of the ‘Basic model’ when lactate clear- ance is added up to approximately 36 h (0.05 months) after CA.

1. Discussion

This study shows that lactate clearance at T3 is significantly higher in patients surviving the first 24, 48 and 72 h. This might be explained by the fact that patients with lower lactate clearance, thus persistent

Table 2 Baseline characteristics of the total study population and by 24 h survival status. All continuous variables are expressed as medians with their interquartile ranges. Categorical variables are expressed as frequencies with percentages

Variables	All patients	Survivors 24 h	Non-survivors	Survivors 48 h	Non-survivors	Survivors 72 h	Non-survivors
	(n = 192)	(n = 168)	24 h	(n = 152)	48 h	(n = 131)	72 h
			(n = 24)		(n = 24)		(n = 61)
Demographics
Age (years)	68 (18-96)	68 (18-96)	66 (35-89)	68 (18-96)	66 (35-96)	68 (18-90)	66 (25-96)
Gender (% male)	65.5	68.5	54.2	68.4	62.5	68.7	63.9
Cardiac arrest details
Witnessed (%)	79.6	80.4	79.2	80.3	80.0	84.7	70.5
Bystander CPR (%)	54.6	55.4	54.2	57.9	45.0	61.2	42.6
Initial shockable rhythm	30.9	33.3	16.7	34.9	17.5	38.2	16.4
(%) EMS time (min)	10.0 (0-42.0)	10.0 (0-42.0)	11.5 (3.0-31.0)	10.0 (0-42.0)	11 (0.0-31.0)	10.0 (0-22.0)	11 (5.0-42.0)
No flow time (min)	1.0 (0-60.0)	0.5 (0-60.0)	1.5 (0-30.0)	0.0 (0-60.0)	5 (0-30.0)	0.0 (0-60.0)	6.0 (0-30.0)
BLS time (min)	7.5 (0-24.0)	7.0 (0-20.0)	8.0 (0-24.0)	7.0 (0-20.0)	8.0 (0-24.0)	7.0 (0-20.0)	8.0 (0-20.0)
ACLS time (min)	10 (0-80)	10 (0-80)	13 (0-80)	10 (0-80)	13 (0-80)	10 (0-80)	8 (0-53)
CPR duration (min)	20 (0-95)	20 (0-94)	21 (6-80)	20 (0-94)	20.5 (6-95)	20 (0-94)	20 (7-63)
Lactate clearance
Serum lactate T0 (mmol/L)	8.5 (0.9-29.0)	8.2 (0.9-25.0)	11.7 (3.7-29.0)	8.2 (0.9-22.0)	11.3 (3.7-29.0)	7.5 (0.9-22.0)	10.1 (5.0-18.0)
Serum lactate T3 (mmol/L)	3.90 (0.60-26.00)	3.55 (0.60-20.00)	8.75 (1.40-26.00)	3.25 (0.60-16.00)	7.05 (0.90-26.00)	3.1 (0.60-16.00)	5.90 (0.90-12.80)
Lactate clearance T3 (%)	49.3 (-177.8-90.4)	53.6 (-177.8-90.4)	28.1 (-56.3-74.1)	55.0 (-177.8-90.4)	32.6 (-56.3-83.3)	53.9 (-177.8-90.4)	39.5 (1.60-83.3)

CPR: cardiopulmonary resuscitation. EMS: emergency medical services. BLS: basic life support.

ACLS: advanced cardiac life support.

Fig. 1. Boxplot representation of lactate clearance at T3 between survivors and non-survivors. a) survival at 24 h; b) survival at 1 month.

a. b.

1.00

0.75

0.50

Sensitivity

0.25

0.00

0.00 0.25 0.50 0.75 1.00

1 - Specificity

Fig. 2. Receiver Operating Curve: prediction accuracy of lactate clearance at T3 for survival. a) at 24 h. Area under the curve: 0.752. b) at 1 month. Area under the curve: 0.628.

Table 3 The effect of witnessed arrest, bystander CPR, age and initial shockable rhythm on survival after ROSC for OHCA. In every box the odds ratio and 95% confidence interval (between brackets) are depicted for the independent variable at the specific time points. Odds ratios and confidence intervals were not depicted if no statistically significant effect was found

	24 h	48 h	72 h	1 m	3 m	1y
Age > 65 years	-	-	-	-	-	-
Witnessed arrest	-	-	2.3 (1.1-4.8)	2.6 (0.9-5.5)	2.8 (1.0-7.7)	3.3 (1.1-9.8)
Bystander CPR	-	-	2.1 (1.1-3.9)	2.7 (1.4-5.1)	2.8 (1.4-5.5)	2.7 (1.3-5.4)
Initial shockable rhythm	-	2.5 (1.0-6.1)	3.2 (1.5-6.8)	6.3 (3.2-12.4)	6.0 (3.0-12.0)	5.9 (2.9-12.0)

CPR: cardiopulmonary resuscitation.

Table 4

Proportional Hazards regression (Cox regression) using Basic Model versus Basic Model including lactate clearance at 3 h

Basic model Basic model + lactate clearance

	Comp.	Est.	CI	P-value	Overall		Est.	CI	P-value	Overall
Witnessed arrest	Yes vs No	0.863	(0.56; 1,34)	0.510			0.947	(0.60; 1.48)	0.812
Bystander CPR	Yes vs No	0.774	(0.53; 1,13)	0.182			0.820	(0.56; 1.20)	0.307
Initial shockable rhythm	Yes vs No	0.409	(0.27; 0.63)	< 0.001			0.416	(0.27; 0.64)	<0.001
Age < 65 yearsa	Spline Term 1	1.034	(0.99; 1.07)	0.092	0.152		1.044	(1.00; 1.09)	0.034	0.046
	Spline Term 2	0.999	(1.00; 1.00)	0.083			0.999	(1.00; 1.00)	0.027
	Spline Term 3	1.004	(1.00; 1.01)	0.057			1.004	(1.00; 1.01)	0.015
Lactate clearance at 3 ha	Spline Term 1						1.005	(0.99; 1.02)	0.538	0.028
	Spline Term 2						0.999	(1.00; 1.00)	0.115
	Spline Term 3						1.00	(1.00; 1.00)	0.262

CPR: cardiopulmonary resuscitation. Est.: hazard ratio.

CI: confidentiality interval. Comp.: comparison.

Overall: statistical significance of the overall effect of the covariate.

^a: Restricted cubic spline with knots at 5%, 35%, 65% and 95%.

higher levels of lactate and lactic acidosis due to a low-flow state, will have a decrease in cardiac output. This decrease itself will maintain this low-flow state. [23] It is our understanding that these patients are more likely to pass away within the first 72 h. These results are in line with previously published research. Multiple studies have shown an association between lower initial serum lactate concentrations and an increased likelihood of survival after OHCA. [2,13,24,25] Several other studies found a link between higher lactate clearance and survival. Donino et al. linked higher lactate clearance 12 h after OHCA to higher survival rates at 24 h and at hospital discharge. [14,26] Williams et al. described more survival to hospital discharge with higher lactate clear- ance 4 h after OHCA. [6] Like Williams et al., this study explored early lactate clearance in a similar study population. In contrast to

the research above, this publication looked at short- and long-term survival with specific time intervals in the attempt to develop a prognostic tool.

According to the results, lactate clearance cannot be used as a predic- tor for long term survival. We believe that while short term CA survival depends on the recuperation of the patient’s heart, long term survival of CA victims is more determined by whether or not a patient has suffered from hypoxia induced brain injury. The focus of survival thus shifts from the patient’s heart on the short term, to the patient’s brain on the long term.

As in preceding research, witnessed arrest, bystander CPR and initial shockable rhythm were found to be statistically significant independent predictors for long term survival, with initial shockable rhythm being

Fig. 3. Cox Regression Analyses: Improvement of Basic Model by Lactate Clearance. Plot of the area under the curve in function of time to death. The integrated area under the curve (AUC) for the Basic model increases when adding lactate clearance at 3 h to the model. This increase is due to an improvement of the model especially for early survival prognostication (zoom in of the curve).

Declaration of interests”>the most discriminating factor. [2,13-22] In contrast to some of these papers, this study did not find age to be an independent predictor for mortality. It is important to note that our analyses only used patients for whom ROSC was achieved. Although lactate clearance on its own is not statistically significant associated with long term survival, com- bined with witnessed arrest, bystander CPR, age and initial shockable rhythm it does allow for a more accurate prediction of the long term survival of CA victims.

Unfortunately, since lactate clearance becomes less significant as more time elapses after ROSC while the other variables become more significant the longer after ROSC, based on these results it is not possible to create a single tool to reliably predict outcome in the early stages after CA. Nevertheless, the fact that lactate clearance at T3 is associated with 24, 48 and 72 h survival can be used as a stepping stone for future re- search to create a prognostication tool for short term survival. However, one should be very careful when developing such a tool, since the deci- sion of cessation of post resuscitation care can only be based on a prog- nostication tool whose sensitivity and specificity tends to 100%.

1. Limitations

This is a retrospective single center trial with a rather small study population. Due to incomplete data, only 192 of the 286 patients with OHCA in the studied time span were included in the database. This may contribute to a form of selection bias. Due to the retrospective char- acter of the study, errors in estimations of time frames are possible as well.

Secondly, the time from CA to the collection of the first blood sample is not equal in all patients. This is reasonable, as an emergency setting does not allow for such standardized methods. But the later the first blood sample was taken, the more lactate could already have been cleared. This could have had an impact on our results. In 88% of patients the first blood sample was taken less than two hours after the CA. This is probably due to the wide range of total CPR time (0 to 90 min) and added transportation time. For the second blood sample taken at T3, we allowed for a one hour margin to limit the disturbing effect on our results. Blood samples taken 2 to 4 h after the initial sample were allowed.

Lastly, the implementation of the Utstein guidelines for reporting of OHCA may vary between communities and even physicians. It is possi- ble that reporting errors were made.

An important note is that we did not include the amount of adrena- line (epinephrine) used during CPR in our analyses, even though adren- aline is known for elevating serum lactate levels. [27] Neither did we investigate whether induced hypothermia or the use of an Automatic External Defibrillator by bystanders had an effect on lactate clearance.

1. Conclusion

Prognostication of survival after OHCA remains challenging. An ac- curate and early estimation of prognosis is essential to identify patients that would most benefit from further intensive care and would there- fore help drive appropriate resource allocation. This retrospective ob- servational single centre study found an association between lactate clearance at T3 after ROSC and 24, 48 and 72 h survival. Further research is needed to determine how lactate clearance can be incorporated in a clinically useful tool to predict long term survival.

Conflicts of interest

There were no conflicts of interest to declare.

Funding

There was no financial disclosure of funding. Ethics

This study was performed in accordance to the Belgian legislation and the guidelines of the medical ethics committee of University Hospi- tals Leuven (approval reference number MP012433).

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influ- ence the work reported in this paper.

Author contributions

Both Willemina Sofie Lonsain and Loranne De Lausnay contributed equally to this article.

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