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CURITIBA TRIAL Custodiol VS Ringer

Qual è il miglior substrato per la protezione renale durante la chirurgia aperta per aneurisma

dell’aorta toracoaddominale?

Yamume TshombaUniversità Vita-Salute at Scientific Institute San Raffaele in Milano, Italy

Head of Department Professor Roberto Chiesa

Bologna, 24 Ottobre 2017

Disclosures

Yamume Tshomba

I have the following potential conflicts of interest to report:

Institutional research grant from Dr. Frantz Köhler Chemie GmbH (Bensheim - DE)Travel support from Dr. Frantz Köhler Chemie GmbH (Bensheim - DE)

NOReceipt of honorariaParticipation in a company sponsored speakers' bureauEmployment in industryShareholder in a healthcare companyOwner of a healthcare company

Disclosures

Yamume Tshomba

I have the following potential conflicts of interest to report:

Off-label discussion of the use of Custodiol for “in-vivo” renal perfusion

Background: Open Repair

TAAA Open Repair

Focusing On Renal Function

Acute Tubular NecrosisSuprarenal Clamping: increase of baseline Scr x 1.5 >70%

What Cells Are involved?

PROXIMAL TUBULE

67%

HENLE LOOP20%

COLLECTING DUCT3%

DISTAL TUBULE7%

Proximal Tubule: ↑ Na+ Reabsorption

Proximal Convoluted TubuleComplex Cytologic Architecture

TUBULAR LUMEN

BRUSH BORDER

BASAL PLASMA MEMBRANE

TUBULAR LUMEN

BRUSH BORDER

PERITUBULAR CAPILLARY

High Oxidative Metabolic ActivityProximal Convoluted Tubule

How Can We Protect Kidney in OR?

Crucial Step: Cold Crystalloid Perfusion

H. J. Bretschneider (1922-1993)S. Ringer (1835-1910)

OSR Crystalloyd PerfusionRINGER… until 2009 CUSTODIOL… since 2009

Total (n = 84)

Ringer group (n = 42)

Custodiol group (n = 42) p value

Total renal ischemic time, min, mean ± SD 47.9 ± 16.61 43.6 ± 15.99 51.5 ± 16.48 0,053

AKI 64 (76.2%) 38 (90.5%) 26 (61.9%) 0,002

AKI type 1 36 (42.9%) 21 (50.0%) 15 (35.7%) 0.27

AKI type 2 13 (15.5%) 9 (21.4%) 4 (9.5%) 0.13

AKI type 3 15 (17.9%) 8 (19.0%) 7 (16.7%) 0.77

Dialysis / CVVH 4 (4.8%) 1 (2.4%) 3 (7.1%) 0.15

Paraplegia/paraparesis 14 (16.8%) 10 (23.8%) 4 (9.5%) 0.07

30-day mortality 5 (5.9%) 4 (9.5%) 1 (2.4%) 0.16

Tshomba et al. J Vasc Surg

2014

Retrospective Study - Propensity Score MatchingCustodiol vs Ringer

Study Drawbacks

• Retrospective in nature • Temporal bias / Learning curve• Biomarkers of subclinical renal injuries?

ClinicalTrials.gov Identifier: NCT 02327611

CURITIBA TRIAL

Prospective, Randomized & Double-blinded Non-Inferiority Trial (Off-label Use)

CURITIBA TRIAL

CUstodiol versus RInger:whaT Is the Best Agent?

CURITIBA TRIAL

- Spontaneous Study- Independent Design Process- PI’s Data Property- External Provider

- Randomization- Data collection and cleaning- Statistical analysis

- Obtained funding: YT

Primary End-PointPostoperative Acute Kidney Injury

Acute Kidney Injury: Kidney Disease Improving Global Outcomes (KDIGO)

clinical practice guidelines. Ostermann et al. Crit Care 2008*

AKI stage Serum creatinine criteria Urine output criteria

11.5 to 1.9 times or ≥ 0.3 mg/dl

(≥ 26.5 µmol/l) increase within 48 hours

<0.5 ml/kg/hr for 6 to 12 hours

2 2.0 to 2.9 times baseline <0.5 ml/kg/hr for ≥12 hours

3

3.0 times baseline or increase in serum creatinine ≥ 4.0 mg/dl

(≥ 353.6 µmol/l) or initiation of renal replacement therapy or in patients <18 years

a decrease in estimated GFR to <35 ml/minute per 1.73 m2

<0.3 ml/kg/hr for ≥24 hours or

anuria for ≥12 hours

Submarkers

Urinary Retinol Binding Protein

Flow Of Study Patients

Excluded in OR (n=1)- Change in extent (n=1)

Did not receive allocated perfusion for distal suprarenal clamping

Assessed for eligibility (n=113)

Enrolled (n=96)

Randomized (n=90)

Allocated to Custodiol renal perfusion (n=45) Allocated to Ringer renal perfusion (n=45)

Received allocated perfusion (n=44) Received allocated perfusion (n=44)

Excluded (n=6)- Medical decision (n=5)- Consent withdrawn (n=1)



- Lost to follow up (n=2)[Intraoperative death]

Analysed (n=42) Analysed (n=44)

Randomized (ITT population)

Prescreening

Screening

Efficacy Analysis(PP population)

Allocation

Follow up

Excluded (n=17)- Refused to partecipate (n=12)- Not meeting inclusion criteria (n=5)

- Emergency procedures (n=4) - Age > 18 yrs (n=1)

Baseline Renal FunctionTotal (n = 90) Ringer group

(n = 45)Custodiol group

(n = 45)p

value

CKD stages

Stage I 31 (34.4%) 14 (31.1%) 17 (73.3%) 0.82

Stage II 32 (35.6%) 15 (33.3%) 17 (37.8%) 0.66

Stage III 27 (30.0%) 16 (35.6%) 11(24.4%) 0.49

Stage IV 0 (0%) 0 (0%) 0 (0%)

Stage V 0 (0%) 0 (0%) 0 (0%)

Intraoperative DetailsTotal

(n = 90)Ringer group

(n = 45)Custodiol group

(n = 45) p value

Overall Operative Time, min, mean ± SD 288.3 ± 66.3 265.6 ± 68.1 298.6 ± 72.7 0.21

Overall Clamping Time, min, mean ± SD 49.0 ± 19.2 50.3 ± 19.1 48.5 ± 20.2 0.15

Visceral Selective Perfusion Time, min, mean ± SD 26.6 ± 10.42 25.7 ± 17.01 27.9 ± 7.6 0.12

Total renal ischemic time, min, mean ± SD 49.7 ± 12.8 46.6 ± 16.7 51.7 ± 19.8 0.08

Isothermic renal distal perfusional time, min 22.2 ± 11.1 24.4 ± 10.2 20.9 ± 14.4 0.07

Cold renal perfusional time, min 23.1 ± 12.4 24.7 ± 13.3 22.5 ± 8.2 0.31

Total renal perfusional volume, ml, mean ± SD 401.4±77.3 388.7±77.3 413.9±77.1 0.57

Urine output during operation, ml, mean ± SD 3834.7 ± 2245.3 3873.6 ± 2245.3 3791.1± 2220.0 0.62

Results

Total (n = 90)

Ringer group (n = 45)

Custodiol group (n = 45) p value

Peak serum creatinine, mg/dL, mean ± SD 1.9 ± 1.1 1.9 ± 1.0 1.9 ± 1.2 0,21

Minimum peak of eGFR, mean ± SD 46.4 ± 25.0 46.5 ± 24.3 46.0 ± 26.2 0,18

AKI 56 (62.2%) 34 (75.6%) 22 (48.9%) 0,008

AKI type 1 29 (32.2%) 18 (40.0%) 11 (24.4%) 0,08

AKI type 2 13 (14.4%) 6 (13.3%) 7 (15.5%) 0,38

AKI type 3 14 (15.5%) 10 (22.2%) 4 (8.8%) 0,07

Dialysis / CVVH 7 (7.7%) 6 (13.3%) 1 (2.2%) 0,06Paraplegia/Paraparesis 6 (6.6%) 4 (8.8%) 2 (4.4%) 0,24

30-day mortality 7 (7.8%) 5 (11.1%) 2 (4.4%) 0,16

Short-Term OutcomesIntention To Treat Analysis

Submarkers

POSTOPERATIVE VALUES

CUSTODIOL GROUP

RINGER GROUP P

U-Albumin (mg/L) Range 0-15

12.6 (6.5-50.1)

14.9 (4.5-43.4) 0.94

U-RBP (mg/L) Range 20-50

5720 (228-13700)

2510 (321-15000) 0.86

U-NGAL (𝜇g/L) Range < 133

33.5 (11-94.2)

26 (9-82) 0.54

S-Cystatin C (mg/L)Range 0.53-0.95

1.305 (1.1-1.64)

1.42 (1.1-1.63) 0.64

Blood / Urine Collection (PO d 3-6)



Randomized (n=90)


Received allocated perfusion (n=44) Received allocated perfusion (n=44)




Allocation

Per Protocol Analysis

Chi-square without Yates correction: P= .0128

Extent AKI NO AKI Total

Custodiol 23 (52.3%) 21 (47.7%) 44

Ringer 34 (77.3%) 10 (22.7%) 44

Total 57 (64.7%) 31 (35.2%) 88

Received Custodiol perfusion (n=44) Received Ringer perfusion (n=44)

- Lost to follow up (n=2)[Intraoperative death]

Analysed (n=42) Analysed (n=44)Efficacy Analysis(PP population)

Follow up

“Post-Hoc” Analysis



Custodiol 23 (54.7%) 19 (45.2%) 42

Ringer 34 (77.3%) 10 (22.7%) 44

Total 57 (66.3%) 29 (33.7%) 86

0

8,75

17,5

26,25

35

All AKIs AKI I AKI II AKI III

RINGER CUSTODIOL

AKI Distribution

0.008

0.08

0.380.076

2218

11

34

710

4

Multivariate AnalysisMultivariate cut-off 0.05

(Significant variables at Univariate: ASA 2 & Custodiol)

OR IC 95% P value

Renal perfusion with Custodiol solution 4.12 1.90-8.93 0,0001

Multivariate cut-off 0.1: (Significant variables at Univariate: Hb, HCT, ASA 2 & Custodiol)

OR IC 95% P value


Multivariate cut-off 0.2 (Significant variables at Univariate: CABG, Aortic Surgery, Prostatic K, Hb, HCT, ASA 2 & Custodiol)

OR IC 95% P value


Renal Custodiol Perfusion In TAAA

- Safe, simple use, effective in renal cooling

- Not increased submarkers of filtration impairment

- Not increased submarkers of tubular injury

- Significantly reduced AKI compared to Ringer

READY FOR ON LABEL USE?

Enrolled (n=96)

Randomized (n=90)


Excluded (n=6)- Medical decision (n=5)- Consent withdrawn (n=1)


Allocation



Custodiol 23 (51%) 22 (49%) 45

Ringer 34 (75.6%) 11 (24.4%) 45

Total 57 (63.3%) 33 (36.7%) 90

Intention To Treat Analysis

LAST 511 TAAA n

1.5 to 1.9 times

baseline

2.0 to 2.9 times

baseline

3.0 times

baselineTot

Type I 103 33 (32%) 18 (17%) 15 (14%) 66 (64%)

Type II 148 56 (38%) 19 (13%) 16 (11%) 91 (61%)

Type III 136 42 (31%) 20 (15%) 22 (16%) 84 (61%)

Type IV 124 65 (52%) 32 (26%) 26 (21%) 123 (99%)

Total 511 196 (38%) 89 (17%) 79 (15%) 364 (71%)

Serum Creatinine Criteria Postoperative ChangesChiesa’s series 1993-2017: 1024 TAAAs

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