Hydration for contrast induced nephropathy

Hydration for Contrast-Induced Acute Kidney Injury (CI-AKI) Prevention

Wisit Cheungpasitporn

August 8, 2014

Disclosure• None

Definition and frequency of CI-AKI

Lameire NH. Nephrol Dial Transplant. 2006 Jun;21(6):i11-23.

Definition in number of trials

Lameire NH. Nephrol Dial Transplant. 2006 Jun;21(6):i11-23.

CI-AKI: Definition

• An increase in SCr generally occurs within 3 days after contrast exposures (in a minority of cases, the peak increase of SCr may occur up until 5 days).

• Definition varies, increase in Cr of >25% from baseline and/or ≥0.5 mg/dL after 48 hrs is widely used in the literature.

• Individuals with increases of SCr compatible with the definition of AKI after administration of contrast media be also evaluated for other possible causes of AKI.

KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

CI-AKI: Incidence

• The reported incidence varies depending on risk factors, the amount and type of contrast, and the type of radiologic procedure.

• Among patients who have no risk factors, the risk of contrast nephropathy is negligible (ie, ≤1%).

• Among high risk patients (especially those with diabetes and CKD), the reported risk following percutaneous angiography with or without intervention is 10 to 20%.

Solomon RJ et. al. Clin J Am Soc Nephrol 2009; 4:1162.

Factors involved in CI-AKI pathogenesis

?Not well understood

Dangas G et al. Am J Cardiol. 2005;95:13-19.

Risk factors for CI-AKI• Patient-related

• Renal insufficiency • Diabetes mellitus• Intravascular volume depletion• Reduced cardiac output• Concomitant nephrotoxins

• Procedure-related• ↑ volume of radiocontrast• Multiple procedures w/i 72 hours• Intra-arterial administration• Type of radiocontrast

} additive risk

McCullough PA et al. Am J Med. 1997;103:368-375.

Risk models

McCullough et al. Am J Cardiol 2006

Mehran Risk Score for CIN post PCI

.

Mehran et al. JACC 2004

Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

• CCB

• Loop diuretics*

• Mannitol*

• Dopamine*

• Fenoldopam*

• ANP

• Hemodialysis*

• NAC

• Theophylline

• Aminophylline

• Ascorbic acid

• Statins

• Hemofiltration

• IVF• Choice of

contrast

Ineffective EffectiveUnclear benefit

* Possibly harmful

Preventive strategies for CI-AKIPreventive strategies for CI-AKI


Contrast AgentsNameName TypeType Iodine Iodine

ContentContentOsmolalityOsmolality

IonicIonic Diatrizoate (Hypaque 50)Diatrizoate (Hypaque 50) Ionic Ionic MonomerMonomer

300300 15501550 High High OsmolarOsmolar

Metrizoate (Isopaque Metrizoate (Isopaque Coronar 370)Coronar 370)

IonicIonic 370370 21002100

Ioxaglate (Hexabrix)Ioxaglate (Hexabrix) Ionic dimerIonic dimer 320320 580580 Low Low OsmolarOsmolar

Non-Non-IonicIonic

Iopamidol (Isovue 370)Iopamidol (Isovue 370) Non-ionic Non-ionic monomermonomer

370370 796796

Iohexal (Omnipaque 350)Iohexal (Omnipaque 350) Non-ionicNon-ionicmonomermonomer

350350 884884

IopromideIopromide Non-ionicNon-ionicmonomermonomer

Iodixanol (Visipaque 320)Iodixanol (Visipaque 320) Non-ionic Non-ionic dimerdimer

320320 290290 Iso Iso OsmolarOsmolar

Pannu N et. al. JAMA 2006; 295:2765.

Clinical trials of volume Clinical trials of volume expansionexpansion

• 1994 → present

• Provide clinical basis for:• Protective effect of IVF• Deleterious effect of furosemide• Superiority of isotonic IVF• Superiority of IVF to pt-directed oral

fluids• Potential benefit of oral NaCl

Rate of CIN: 11% 28% 40%

Solomon R et al. N Engl J Med. 1994;331:1416-1420.

RCT 78 patients

http://content.nejm.org/content/vol331/issue21/images/large/04f1.jpeg

Isotonic v. hypotonic saline Isotonic v. hypotonic saline

Mueller C, et al. Arch Int Med. 2002; 162:329-336

RCT 1,620 patients

Elective+emergency PCILow osmolar non-ionic contrast

Saline vs. Bicarbonate IV fluidSaline vs. Bicarbonate IV fluid

13.6%

1.7%

0%

2%

4%

6%

8%

10%

12%

14%

NaCl (n=59) NaHCO3(n=60)

rate of CIN

(8/59)

(1/60)

Merten et al. JAMA 2004;291:2328-2334

P = 0.02

RCT 119 patients

All procedures with contrast exposureLow osmolar non-ionic contrastPatients with Creatinine > 1.1 mg/dL



KDIGO 2012: CI-AKI


KDIGO 2012: CI-AKI


Brar SS et. al. Lancet. 2014 May 24;383(9931):1814-23.

LEFT VENTRICULAREND DIASTOLIC PRESSURE

( LVEDP )

What does LVEDP mean anyway?

• LVEDP is the left ventricular end-diastolic pressure, and serves as a measure of the pre-load and thus that of circulating blood volume.

• Direct measurement of LVEDP is routinely performed during cardiac catheterization.

Kern MJ. The Cardiac Catheterization Handbook, 5th ed2011

Clinical Measurement of Preload

• LVEDP is measured just before the start of the systole ( i.e : End of the diastole )

• LVEDP; normal = 4 - 12 mmHg• Cardiogenic pulmonary edema: LVEDP ≥ 18 mmHg

Kern MJ. The Cardiac Catheterization Handbook, 5th ed2011

Brar SS et. al. Lancet. 2014 May 24;383(9931):1814-23.

Objective

• To investigative different rates of fluid administration guided by the LVEDP to prevent CI-AKI in patients undergoing cardiac catheterization.

ParticipantsInclusion criteria

• ≤ GFR* 60 ml/min/1.73 m2

• ≥ 18 years

And at least one of the following

• DM

• CHF

• HTN

• Age ≥ 75 years

Exclusion criteria

• No consent

• Emergency cardiac catheterization

• RRT

• Exposure to contrast within 2 days

• Contrast allergy

• Acute decompensated HF

• Severe valvular disease

• Mechanical aortic prosthesis

• LV thrombus

• Hx of kidney or heart Tx

• Change in eGFR ≥ 7.5%/d or a cumulative change ≥ 15% during the preceding 2 days

* GFR was calculated using MDRD formula

Intervention – Fluid therapy

Standard hydration

3 ml/kg in 1 hour before procedure

Measure LVEDP

Randomization(1:1 ratio)

LVEDP-guided hydration

LVEDP •< 13 5ml/kg/h•13-18 3ml/kg/h•> 18 1.5 ml/kg/h

Fluid - NSS

1.5 ml/kg/h

Fluid started right before procedure and continued until 4 hours after procedure

Intra-arterial ioxilan (350 mg iodine/ml)

Non-ionic, low – osmolar

Randomization and masking• Stratified by DM status and NAC use

• NAC use • 600 mg twice daily for 2 days• Starting the day before index procedure • Use was at the discretion of the physician.

• Permuted block sized of 4

• Partly blinded• Patient masked• Lab personnel masked• Physician not masked

Outcomes

• Primary endpoint• ≥ 25% or 0.5 mg/dl increase in the SCr• Only patients with ≥ 2 SCr values between day 1-4 were included• Calculated with a baseline value obtained before procedure

and the highest post-procedure value on days 1-4

• Secondary endpoint• Components of primary endpoint• Occurrence of major adverse events

• A composite of all-cause mortality, MI, and RRT at 30 days and 6 months

• Safety endpoint• Clinical sequelae of fluid administration and LVEDP measurement• All adverse events were confirmed by personnel who were

masked to treatment assignment

Post-hoc analysis

• Rate of contrast-induced AKI• Increase in SCr ≥ 0.3 mg/dl

• The frequency of persistent renal impairment• ≥ 15% increase in SCr above baseline• SCr samples were obtained 2-8 weeks after the index procedure

and the 1st SCr value during this period was used in analysis

Statistical analysis

• Primary outcome• Relative risk, absolute risk reduction, number needed to treat

• Power calculation• Superiority trial• 18% in control group and 8% in LVEDP• 390 patients needed for 80% power and a two-sided alpha of 0.05

Outpatient/ambulatory procedure-58% overall-61% in LVDP-guided group -56% in control group P = 0.29

1727 (583) 812 (142)

P < 0.001

Incidence of contrast-induced AKI 11.4%NNT = 11 for LVEDP-guided treatment

No significant interaction between treatment assignment by subgroup

Result: contrast-induced AKI

Outcomes LVEDP –guided hydration

Control RR (95% CI) P-value

Contrast-induced AKI

5/60 (8%) 14/61 (23%) 0.36 (0.14-0.95)

0.03

In patients GFR ≤ 45 ml/min/1.73 m2

NNT = 7


LVEDP level LVEDP- guided Control RR (95% CI) P-value

< 18 mmHg 8/152 (5.3%) 21/146 (14.4%) 0.37 (0.17-0.80)

0.008

≥ 18 mmHg 4/26 (15.4%) 7/26 (26.9%) 0.57 (0.19-1.72)

0.31


Volume of NSS received Rate of contrast-induced AKI

Tertile 1 (448-874 ml) 20/117 (17%)

Tertile 2 (874-1512 ml) 13/117 (11%)

Tertile 3 (1512-3055 ml) 7/116 (6%)

OR = 0.91 (95% CI 0.89 – 0.94); P = 0.01 for every additional 100 ml of NSS administered

P = 0.03

Increasing volume of NSS administered were associated with reduced rates of contrast-induced AKI

Result: persistent renal impairment

Outcome LVEDP- guided Control RR (95% CI) P-value

Persistent renal impairment

6/178 (3.4%) 12/172 (7.0%) 0.48 (0.19-1.26)

0.13

Outcome LVEDP- guided Control RR (95% CI) P-value

Persistent renal impairment

6/12 (50%) 12/27 (44%) 1.13 (0.56-2.28)

0.75

patients who developed contrast-induced AKI – persistent renal impairment occurred in 46%

NNT for LVEDP for prevention of one major adverse event at 6 mo = 16

Result

At 6 month Contrast-induced AKI

No contrast-induced AKI

RR (95% CI)

P-value

All-cause mortality

higher 0.002

Myocardial infarction

higher 0.02

Need for RRT higher <0.001

Cumulative major adverse event

10/40 (25%) 11/310 (3.5%) 7.1 (3.2-15.5) <0.001

Result- Safety

• 6 patients terminated the IV fluid early due to SOB• 3 in LVEDP-guided LVEDP 3, 7 and 26 mmHg• 3 in control LVEDP 3, 23 and 31 Hg

• No ventricular arrhythmias or other complication associated with LVEDP measurements reported

Result

Outcome Risk ratio (95% CI)

Contrast-induced AKI OR = 0.37 (0.18-0.74)Adjusted OR = 0.40 (0.19-0.81)

Major adverse events at 6 months

HR = 0.31 (0.13-0.78)Adjusted HR = 0.35 (0.14-0.89)

*adjusted for history of CHF and PCI status

Discussion

• Pts with stable renal insufficiency undergoing cardiac catheterization and followed up for 6 months:

• LVEDP-guided fluid administration as compared with standard treatment resulted in 68% relative reduction in CI-AKI, and 59% relative reduction in major adverse clinical events.

Discussion

• LVEDP group was able to receive roughly twice the volume of NSS with a similar rate of fluid termination than the control group.

• Despite more IV fluid with LVEDP-guided therapy than with standard hydration, IV fluids were terminated at a similarly low rate in both study groups, which suggests that higher rates can be tolerated.

Discussion

• Pts with CI-AKI had a 7-fold increase in the rate of the composite major adverse events endpoint, and a significant increase in each of the components including death, MI, and RRT.

• These findings emphasize the importance of longer term follow-up in patients with CI-AKI.

• The study population was at a moderate to high risk of CI-AKI • all patients had eGFR ≤ 60 mL/min/ 1.73 m2 and one additional CI-

AKI risk factor

Limitations

• The study was single-blinded (patients, and not investigators) which is understandable as the rate of fluid infusion would be difficult to mask.

• Patients with acute decompensated heart failure or severe valvular heart disease were excluded from the study.

• LVEDP assessment of intravascular volume status, it is only available in patients undergoing cardiac catheterization.

Conclusion

• IV NSS guided by LVEDP is well tolerated and could substantially reduce the incidence of CI-AKI and major adverse clinical events in patients undergoing cardiac catheterization.

My ConclusionMore IV fluid is better!!!

PRESERVE


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Hydration for contrast induced nephropathy