End-of-Surgery Serum Lactate concentration as a major predictor of postoperative

outcome. A multicentre prospective study.

Eric Vibert, Emmanuel Boleslawski, Cyril Cosse, Rene Adam, Denis Castaing, Daniel Cherqui, Salima Naili, Jean-Marc

Régimbeau, Antonio Sa Cunha, Stéphanie Truant, Maher Fleyfel, François René Pruvot, Catherine Paugam, Olivier Farges

ACHBT Hepatectomy Registry

PST-AST = 450 UI/LPST-ALT = 420 UI/L

AUROC = 0.61 AUROC = 0.57

French Multicentric Study : 651 pts in 9 HPB Centers

Postoperative Peak of Transaminase is not a relevant endpoint to predict outcome

2014

Objectives of the study

After an elective liver resection:

1. Is Arterial Lactate Concentration at the end

of surgery (LCT-EOS) predictive of outcome ?

2. If yes, is there pre- or intraoperative

predictors of an increase in LCT-EOS ?

Study endpoints

• End of surgery arterial Lactate Concentration

– Between 1 and 4 hours after end of liver transection

• Postoperative outcome (90-day outcome)

– High Clinical Comprehensive Index (> 3rd quartile)

– Mortality

– Severe morbidity (Clavien’s grade III-V)

ACHBT Web Prospective Registry

1342 Consecutive Hepatectomies in 4 Hospitals

Training CohortJune 2012 – December 2014

In Paul Brousse Hosp.

Validation CohortJune 2012 – December 2014

In Beaujon, Lille, Amiens Hosp.

565 Patients 777 Patients

519 Patients 466 Patients

Dosage of Art. LCT routinely at the end of sugery (92%)

Dosage of Art. LCT according to surgical complexity (60%)

519 Patients in the Training CohortPatients

Age (yr), median (IQR) 62 (18-87)Gender, male 298 (57%)BMI (kg/m²), mean ± DS 25.1 ± 4.8Diabetes 100 (19%)Cirrhosis 62 (12%)Preoperative Portal Vein Occlusion 67 (13%)Major Hepatectomy 236 (45.5%)Laparoscopy 59 (12%)Synchronous Major Procedure 81 (16%)Inflow Occlusion 348 (67%)Blood Loss > 500 cc 176 (34%)

DiagnosisMetastatic disease 259 (50%)Primary malignancy 199 (38%)Benign and Living Donor 51 (10%)Parasitosis 10 (2%)

Postoperative Outcome in the 2 cohorts

Training cohortn = 519

Validation cohortn = 466

P value

Grade of Clavien N(%) N(%)

0.0001

Grade 0 212 (40.8) 121 (30.0)Grade I 36 (6.9) 41 (8.8)Grade II 164 (31.6) 164 (35.2)Grade III 88 (16.9) 69 (14.8)Grade IV 9 (1.7) 41 (8.8)Grade V 10 (1.9) 30 (6.4)

CCI , median (95%CI) 20.92 (18.91-22.93) 24.24 (22.42-26.06) <0.0001

CCI > 3rd Quartile 124 (23.9) 192 (41.2) 0.0001

3 steps to evaluate LCT-EOS prognostic impact

1. Building models of outcome in the training cohort

- LCT-EOS cut-off was determined by ROC-curves for the 3 endpoints (High CCI, Mortality, Severe Morb)

- Uni- and Multivariate analyses of pre- and intraoperative factors, including LCT-EOS, were performed for the 3 endpoints.

- AUROC of each model (which included or not LCT-EOS) were compared to evaluate the additive value of LCT-EOS

2. Testing the models in the validation cohort (Real Life)

– AUROC of each model with / without LCT-OES

– Calibration : Prediction vs Observation ?

3. Calculate Se, Sp, Accuracy of models in the entire cohort

Firt Step : Building Models

Training Cohort : LCT-EOS cut-offs

End Point LCT-EOS cut-off AUROC

High CCI (>3rd quartile) 3.0 mmol/L 0.86 (95%CI 0.82 – 0.89)

90-day Mortality 3.0 mmol/L 0.87 (95%CI 0.83 – 0.91)

90-day Severe Morbidity 2.8 mmol/L 0.76 (95%CI 0.72 – 0.80)

High CCI > 3rd Q.

Mortality.

Severe Morbidity

2012-2014 : 519 Patients with systematic dosage of Lactate

at the end of surgery

Variables Hazard ratio 95% CIFor high CCI (> 3rd quartile)

Major hepatectomy 2.0 1.1 - 4.6Associated procedure 3.6 1.3 – 10Transection > 90 min 1.8 1.0 - 3.4Blood Loss > 500 cc 2.3 1.2 - 4.4LCT-EOS > 3 mmol/L 2.2 1.1 - 4.2

For 90-day MortalityDiabetes 7.34 2.1 – 25Cirrhosis 4.34 1.9 – 28Associated procedure 4.31 1.5 – 28Length of Surgery > 300 min 2.6 1.1 - 5.4LCT-EOS > 3 mmol/L 3.4 2.5 - 5.2

For 90-day Severe MorbidityBMI > 28 2.5 1.2 – 5.2Associated procedure 2.9 1.4 – 6.2Ischemia duration > 30 min 2.2 1.2 – 4.2Transection > 90 min 1.9 1.0 – 3.4Blodd Loss > 500 cc 2.7 1.4 – 5.1LCT – EOS > 2.8 mmol/L 2.0 1.1-3.9

Predictive Models for the 3 endpoints

0.75 (0.68-0.82)

0.77 (0.71-0.83)

0.69 (0.64-0.73)

0.74 (0.70-0.78)

0.68 (0.65-0.71)

0.72 (0.65-0.71)

Second Step : Validate Models in the « real-life » Cohort…

Impact of LCT-EOS in validation cohort

The role of LCT-EOS was more important for predicting High-CCIand Mortality than severe morbidity

0.73 (0.70-0.76)

0.85 (0.78-0.92)

0.69 (0.65-0.73)

0.72 (0.69-0.75)

0.71 (0.68-0.74)

0.76 (0.68-0.74)

High CCI Mortality Severe Morb.

Model Calibration in the Validation cohort

predicted (%) real (%) predicted (%) real (%) predicted (%) real (%)

0 17 17,1 1,08 1,25 20,6 20,8

1 17,95 18,1 2,5 2,09 21,5 21,5

2 18,74 19,5 3,7 3,05 22,3 22,9

3 19,53 20,3 5,16 4,22 23,15 24,5

4 20,32 20,8 6,36 5,06 24,75 25,8

5 21,26 22,4 7,78 6,4 26,5 28,3

High CCI score 90-day mortality Severe morbidityN. of risk factors

Result of model (Prediction) VS Real Outcome in Validation cohort according to the N. of risk factors

High CCI Mortality Severe Morb.

Third Step : Use all patients to calculated Se, Sp and Accuracy

End pointModels

without LCTModelswith LCT

IncreasedAccuracy with

LCT

High CCI Score

DOR 4.69 5.46

Sensitivity 71% 74% 16%

Specificity 66% 66%

Mortality

DOR 2.35 3.16

Sensitivity 69% 74% 34%

Specificity 51% 52%

SevereMorbidity

DOR 2.55 2.99

Sensitivity 71% 74% 17%

Specificity 65% 65%

“Diagnostic accuracy is defined as the proportion of all tests that give a correct

result (Scott et al. 2008)”

Objectives of the study

After an elective liver resection:

1. Is Arterial Lactate Concentration at the end

of surgery (LCT-EOS) predictive of outcome ?

2. If yes, is there pre- or intraoperative

predictors of an increase in LCT-EOS ?

Variables Hazard ratio 95% CI

Diabetes 2.2 1.1 - 4.6Major Hepatectomy 3.7 2.1 – 6.5Repeat Hepatectomy 2.7 1.2 – 6.0Synchronous Major Procedure 2.4 1.1 - 5.0Inflow occlusion 2.0 1.0 – 3.8Transfusion 2.3 1.1 - 4.5

Pre- and Intraoperative factors predictive of LCT-EOS > 3 mmol/L

Results of Multivariate analyis in the Training Cohort

Conclusions

• This multicentric study including a training cohort of 519patients and validation cohort of 466 patients over a 24months with a prospective outcome evaluation perioddemonstrated that

Arterial Lactate concentration at the End of Surgery is anearly, convenient and reliable endpoint for postop. outcomesLCT-EOS must be used to explore the impact of pre- and/orintraoperatives factors on the outcome of liver resection

• LCT-EOS > 3 mmol/L is a surrogate endpoint thatdetermine the need for critical care after hepatectomy