RECOVER 2.0 Worksheet

QUESTION ID: MON-02

PICO Question:
In cats and dogs that have experienced ROSC after CPA (P), does serial plasma lactate measurement (lactate clearance) (I) as opposed to single time-point plasma lactate measurement (C), improve ... (O)?

Outcomes:
Duration of post-arrest hospitalization,Favorable neurologic outcome,Prediction of recurrent CPA,Survival to Discharge

Prioritized Outcomes (1= most critical; final number = least important):

1.Favorable neurologic outcome

2.Survival to Discharge

3.Prediction of recurrent CPA

4.Duration of post-arrest hospitalization

5.

Domain chairs: Selena Lane, Ben Brainard, final edits Dan Fletcher

Evidence evaluators: Berit Fischer, Shana O'Marra

Conflicts of interest:

Search strategy: See attached document

Evidence Review:

Study Design		Reduced Quality Factors 0 = no serious, - = serious, - - = very serious				Positive Quality Factors 0 = none, + = one, ++ = multiple			Dichotomous Outcome Summary			Non-Dichotomous Outcome Summary Brief description	Overall Quality High, moderate, low, very low, none
No of studies	Study Type	RoB	Indirectness	Imprecision	Inconsistency	Large Effect	Dose-Response	Confounder	# Intervention with Outcome	# Control with Outcome	RR (95% CI)
Outcome: Favorable neuro outcome
17	Obs	0	- -	0	-	0	0	0					Very low
Outcome: Survival to discharge
19	Obs	0	--	0	-								Very low
1	Exp	-	- -	-	0								Very low

Outcome: Prediction of recurrent CPA

0

Outcome: Duration of post-arrest hospitalization

0

PICO Question Summary

Introduction

Inadequate tissue perfusion likely results in hyperlactatemia commonly in the post-cardiac arrest (PCA) period. Persistently increased lactate concentrations in the PCA period may indicate ongoing tissue hypoperfusion that may be associated with worse outcomes. The aim of this question was to evaluate whether monitoring lactate clearance in the PCA period is more helpful for guiding therapy than a single point lactate measurement.

Consensus on science

Outcome 1: Favorable neurologic outcome (FNO) For the most critical outcome of favorable neurologic outcome, 17 observational studies in people were identified that were relevant to the PICO question (very low quality of evidence, downgraded for very serious indirectness and inconsistency). Ten of the studies evaluated both single time-point lactate concentrations and either lactate clearance or lactate at multiple additional standardized time points.1–10 Although there is some inconsistency among the studies, in 8 of the 10, multivariate analyses including both admission lactate and either lactate clearance or lactate concentrations at later time points post-ROSC showed that lactate clearance, lactate at 48 hours post-ROSC or last measured lactate post-ROSC were independently associated with FNO while admission lactate or lactate measurements at other time points were not.1,3–8,10 One of the remaining studies documented a negative association between FNO and persistently increased lactate concentrations 12 and 24 hours post-ROSC, but did not include a statistical analysis to compare serial lactate measurements to a single measurement.2 In only 1 of the 10 studies, admission lactate but not lactate concentrations at 6, 12, 24 or 48 hours post-ROSC was an independent predictor of FNO.9 Taken together, 9 of these 10 observational studies provide evidence that serial lactate measurements documenting decreasing lactate concentrations in the initial 48 hours post-ROSC likely provide better prognostic information regarding FNO than admission lactate alone. The remaining 7 observational studies only evaluated a single lactate concentration shortly after ROSC.3,11–16 Four of the 7 studies used multivariate analyses including lactate concentrations in addition to other potentially prognostic factors and showed an independent association between lactate concentration and FNO.3,12,15,16 One of the 7 studies was a retrospective evaluation of 55 elderly people who achieved OOH ROSC and used receiver operating characteristic curve analysis to identify a cut-off admission lactate concentration of 70 mg/dl (7.8 mmol/L), which had a sensitivity of 90.5% and a specificity of 55.9% to predict FNO.13 The other 2 studies found no association between admission lactate and FNO in adult people with OHCA.11,14 Outcomes 2-4: Survival to discharge, Prediction of recurrent CPA, Duration of post-arrest hospitalization Because of the large amount of evidence available to inform a recommendation for the most critical outcome, the remaining outcomes were not exhaustively evaluated. There were no studies identified that addressed outcomes 3 and 4, and most studies identified that addressed outcome 2 were the same as those used to evaluate outcome 1. It should be noted that no studies were identified in people or veterinary species that specifically evaluated the impact on outcome of using lactate in the PCA period to guide treatment. Most of the studies were retrospective in nature, and those that were prospective were observational and hence did not compare patients treated based on lactate concentrations to those in which lactate was not used to guide therapy.

Treatment recommendation

We recommend serial measurement of lactate in the PCA period. (strong recommendation, very low quality of evidence) We recommend that serial lactate measurements be used to guide and evaluate response to treatment in dogs and cats in the PCA period. (strong recommendation, expert opinion)

Justification of treatment recommendation

Although there is some variability in the primary findings of the observational studies evaluated for this PICO question, the majority showed that lactate concentration measurement in the PCA period offers prognostic information about FNO and that serial measurements or evaluation of lactate clearance are likely superior to a single lactate measurement for this purpose. Given that lactate is a well-established marker of decreased oxygen delivery to tissues, the committee believe that a strong recommendation to use lactate and lactate clearance to guide resuscitation of patients in the PCA period is warranted.

Knowledge gaps

There are no studies comparing the use of single lactate measurements to lactate clearance following ROSC in dogs and cats for prognostication. In addition, there are no studies in any species evaluating the impact of using lactate or lactate clearance data to guide therapy in the PCA period or evaluating the optimal interval between lactate measurements.

References:

1. Kim JC, Lee BK, Lee DH, et al. Association between lactate clearance during post-resuscitation care and neurologic outcome in cardiac arrest survivors treated with targeted temperature management. Clin Exp Emerg Med. 2017;4(1):10-18.

2. Orban JC, Novain M, Cattet F, et al. Association of serum lactate with outcome after out-of-hospital cardiac arrest treated with therapeutic hypothermia. PLoS One. 2017;12(3):e0173239.

3. Lee TR, Kang MJ, Cha WC, et al. Better lactate clearance associated with good neurologic outcome in survivors who treated with therapeutic hypothermia after out-of-hospital cardiac arrest. Crit Care. 2013;17(5):R260-R260.

4. Hayashida K, Suzuki M, Yonemoto N, et al. Early Lactate Clearance Is Associated With Improved Outcomes in Patients With Postcardiac Arrest Syndrome: A Prospective, Multicenter Observational Study (SOS-KANTO 2012 Study). Crit Care Med. 2017;45(6):e559-e566.

5. Laurikkala J, Skrifvars MB, Bäcklund M, et al. Early Lactate Values After Out-of-Hospital Cardiac Arrest: Associations With One-Year Outcome. Shock. 2019;51(2):168-173.

6. Donnino MW, Andersen LW, Giberson T, et al. Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. Crit Care Med. 2014;42(8):1804-1811.

7. Jung C, Bueter S, Wernly B, et al. Lactate Clearance Predicts Good Neurological Outcomes in Cardiac Arrest Patients Treated with Extracorporeal Cardiopulmonary Resuscitation. J Clin Med. 2019;8(3).

8. Cassina T, Clivio S, Putzu A, et al. Neurological outcome and modifiable events after out-of-hospital cardiac arrest in patients managed in a tertiary cardiac centre: A ten years register. Med Intensiva. Published online 2019.

9. Dell’Anna AM, Sandroni C, Lamanna I, et al. Prognostic implications of blood lactate concentrations after cardiac arrest: a retrospective study. Ann Intensive Care. 2017;7(1):101.

10. Kliegel A, Losert H, Sterz F, et al. Serial lactate determinations for prediction of outcome after cardiac arrest. Medicine (Baltimore). 2004;83(5):274-279.

11. Cho YM, Lim YS, Yang HJ, et al. Blood ammonia is a predictive biomarker of neurologic outcome in cardiac arrest patients treated with therapeutic hypothermia. Am J Emerg Med. 2012;30(8):1395-1401.

12. Pérez-Castellanos A, Martínez-Sellés M, Uribarri A, et al. Development and External Validation of an Early Prognostic Model for Survivors of Out-of-hospital Cardiac Arrest. Rev Esp Cardiol (Engl Ed). 2019;72(7):535-542.

13. Nagata K, Tsurukiri J, Ueno K, Mishima S. Predictors of neurological outcome in the emergency department for elderly patients following out-ofhospital restoration of spontaneous circulation. Signa Vitae. 2015;10(1):53-63.

14. Momiyama Y, Yamada W, Miyata K, et al. Prognostic values of blood pH and lactate levels in patients resuscitated from out-of-hospital cardiac arrest. Acute Med Surg. 2017;4(1):25-30.

15. Isenschmid C, Kalt J, Gamp M, et al. Routine blood markers from different biological pathways improve early risk stratification in cardiac arrest patients: Results from the prospective, observational COMMUNICATE study. Resuscitation. 2018;130:138-145.

16. Müllner M, Sterz F, Domanovits H, et al. The association between blood lactate concentration on admission, duration of cardiac arrest, and functional neurological recovery in patients resuscitated from ventricular fibrillation. Intensive Care Med. 1997;23(11):1138-1143.

Supplemental:

FNO

Kim 2017: 282 patients, 184 (65.2%) poor FNO, 62 (22%) died. All had TTM – Lactate but not clearance

Poor FNO

Lactate at 12 hrs: odds ratio [OR], 1.157; 95% confidence interval [CI], 1.006 to 1.331

Lactate at 24 hours: OR, 1.320; 95% CI, 1.084 to 1.607

Lactate at 48 hrs: OR, 2.474; 95% CI, 1.459 to 4.195

Lactate clearance not associated

S2D

Lactate at 48 hrs: OR, 1.459; 95% CI, 1.181 to 1.803

Lactate clearance not associated

***Orban 2017: 272 patients, 89 good outcome, 183 poor outcome All had TTM – Lactate at time points, did not look at clearance

Poor FNO

Admission: (5.4 (3.3–9.4) vs. 2.2 (1.5–3.6) mmol/L; p<0.01)

12 hrs: 2.5 (1.6–4.7) vs. 1.4 (1.0–2.2) mmol/L; p<0.01

24 hrs: 1.8 (1.1–2.8) vs. 1.3 (0.9–2.1) mmol/L; p<0.01

Patients that died due to organ failure vs. neurologic failure:

Admission: 7.9 (3.9–12.0) vs. 5.2 (3.3–8.8) mmol/L; p<0.01

12 hrs: 4.9 (2.1–8.9) vs. 2.2 (1.4–3.4) mmol/L; p<0.01

24 hrs: 3.3 (1.8–5.5) vs. 1.4 (1.1–2.5) mmol/L; p<0.01

Lee 2013: 76 patients, 34 had good FNO All had TTM – Multivariate, clearance only

Poor FNO

Admission: (6.07 ±4 .09 mmol/L vs 7.13 ± 3.99 mmol/L, P = 0.42)

6 hrs: (3.81 ± 2.81 vs 6.00 ± 3.22 P <0.01

12 hrs: 2.95 ± 2.07 vs 5.00 ± 3.49 P <0.01

24 hrs: 2.17 ± 1.24 vs 3.86 ± 3.92 P <0.01

48 hrs: 1.57 ± 1.02 vs 2.21 ± 1.35 P = 0.03,

Lactate Clearance: 6hr : 35.3 ± 34.6% vs 6.89 ± 47.4% P = 0.01, 12hr:54.5 ± 23.7% vs 25.6 ± 43.7% P <0.01

Multivariate analysis adjusting for confounders: 6 (1.02 (1.03 to 1.05) P=0.03) and 12 hr (1.03 (1.00 to 1.07) P= 0.02) lactate clearance associated with outcome:

XX Lee 2014: Lactate within 1hr after ROSC, all had TTM. Multivariate model: Lactate at time points, did not look at clearance

FNO: 1.072 (95% confidence interval (CI) 1.026–1.121)

S2D: 1.087 (95% CI = 1.031–1.147)

XX Perez-Castellanos 2018: Lactate at time points, did not look at clearance

244 patients, 107 survived with good FNO. Developed a model to predict good neuro outcome using 5 parameters including lactate ((Shockable rhythm, Age, Lactate at admission, Time Elapsed to return of spontaneous circulation, and Diabetes. sensitivity of 73.5%, specificity of 78.6%, and area under the curve of 0.82 (95%CI, 0.73-0.91).

Hayashida 2017: Multivariate, clearance only

543 patients, 30-day survival and good neurologic outcome were 47.1% and 27.4% respectively.

Survival to 30 days increased with increasing clearance quartile 1, 29.4%; quartile 2, 42.6%; quartile 3, 51.5%; quartile 4, 65.2%; p < 0.001

lactate clearance quartile was an independent predictor of the 30-day survival and good neurologic outcome.

multivariate logistic regression analysis revealed that lactate clearance was a significant predictor of good neurologic outcome at 30 days

Laurikkala 2019: 458 OHCA patients Multivariate, clearance and last measured lactate

Admission lactate: median [IQR] 3.06 [2.68–3.44] mmol/L vs 4.76 [4.29–5.23] mmol/L, survivors vs non-surv, P<0.001

Lowest and highest: (0.73 [0.67–0.79] mmol/L vs 1.83 [1.52– 2.14] mmol/L) ;(3.44 [3.05–3.83] mmol/L vs 5.25 [4.76–5.74] mmol/L), P<0.001

multivariate backward regression models, time-weighted mean lactate for the entire ICU stay (OR 1.41 per mmol/L, CI 95% 1.08–1.86, P ¼ 0.013) and the last measured lactate in the ICU (OR 2.16 per mmol/L, CI 95% 1.47–3.18, P< 0.001) were independent predictors of poor 1-year outcome

higher lactate values at admission, higher time-weighted mean lactate for the first 24, 48, and 72 h were not independent predictors of poor long-term outcome

Donnino 2014: Multivariate, clearance only

4 center prospective observational, 100 patients, 97% TTM

patients with good neurological outcome had lower lactate levels at 0, 12 and 24 hours (p < 0.01).

In adjusted models percent lactate decrease at 12 hours was greater in survivors (OR 2.2 [95% CI

1.1 – 6.2]) and in those with good neurological outcome (OR 2.2 [95% CI 1.1 – 4.4]) but not admission lactate

Jung 2019: 93 patients with ECPR Multivariate, clearance only

In a multivariable model, only lactate clearance (after 6 h; OR 0.97; 95% CI 0.94–0.997; p = 0.03) was associated with a good GOS score. The optimal cut-off of lactate clearance at 6 h for the prediction of a bad GOS score was at ≤13%. Patients with a lactate clearance at 6 h ≤13% evidenced higher rates of bad GOS scores (97% vs. 73%; p = 0.01).

Cassina 2019: Multivariate, clearance only

Retrospective study of v 245 patients admitted to ICU after OHCA, 131 survived with good NO

Immediate admission to the cardiac centre (OR 0.5; 95%CI 0.3---0.9) and lactate clearance reaching plasma levels <2.5 mmol/l at 12 h (OR 0.4; 95%CI

0.2---0.8) were associated with better outcomes.

***Dell’Anna 2017: Lacate but not clearance

High lactate concentration at admission was predictive of FNO ((OR 1.18, 95% CI 1.08–1.30; p < 0.001). but lactate clearance was not

XX Isenschmida 2018: Prospective observational, 321 patients with OHCA multivariate admission lactate, did not look at clearance

Multivariate model – lactate was independent predictor of FNO 12.44, 5.23 – 29.56, P < 0.001

Did not look at clearance

Kliegel 2004: 394 patients that survived at least 48 hours after CPA, FNO 186 multivariate lactate at 48 hours independent predictor but not admission or 12

In multivariate analysis, lactate levels at 48 hours were an independent predictor for unfavorable neurologic outcome (OR: 1.28

increase per mmol/L, 95% CI: 1.08–1.51).

Lactate levels higher than 2 mmol/L after 48 hours predicted poor neurologic outcome with a specificity of 87% and sensitivity 31%

XX Mullner 1997: multivariate admission lacate, did not look at clearance

Multivariate analysis showed that with increasing admission concentrations of arterial lactate functional neurological recovery was more likely to be unfavorable (OR 1.15 per mmol/L increase, 95 % CI 1.04-1.27). Did not look at serial

Momiyama 2017: Admission Lactate only, no association

372 OHCA patients, 31 had a favorable neurological outcome.

No difference in lactate between good and bad FNO

Nagata 2015: Retrospective, 55 patients, 21 with FNO Lactate at time points, did not look at clearance

The areas under the ROC curve (AUC) for a favorable neurological outcome were 0.82 (95% CI = 0.70–0.94, p < 0.01) for lactate level and 0.74 (95% CI

lactate levels above 70 mg/dL (7.8 mmol/L) predictor of unfavorable neurological outcome sens 90.5%, spec 55.9%

Did not look at lactate clearance

Cho 2012: Lactate at admission All had TTM, no association between admission lactate and FNO – Admission Lactate only, no association