Question

Dient profylaxe met Vitamine C te worden aanbevolen naast hydratie om de kans om PC-AKI te verkleinen bij patiënten met chronische nierziekte die intravasculair CM krijgen toegediend?

Recommendation

Geef Vitamine C niet exclusief ter preventie van PC-AKI bij patiënten met een normale of verminderde (eGFR <60 ml/min/1,73m2) nierfunctie.

Introduction

The mechanism of PC-AKI is not completely understood. However, direct cell damage by the contrast medium with subsequent oxidative stress, endothelial dysfunction and decreased nitric oxide (NO) availability are supposed to play a major role. Intrarenal NO is crucial for maintaining perfusion and oxygen supply in the renal medulla. NO depletion causes vasoconstriction with hypoperfusion of the renal medulla and local hypoxia. In addition, NO depletion affects tubular fluid composition, tubuloglomerular feed-back signaling and decreases glomerular filtration rate (Liu, 2014).

 

Vitamin C (ascorbic acid) is the most effective circulating antioxidant (Frei, 1990). Ascorbate specifically protects the endothelium, NO and tetrahydrobiopterin (BH4), the co-factor of NO synthase, from oxidation. Thus, vitamin C may reduce renal oxidative damage and improve the renal microcirculation. For an optimal antioxidant effect, high vitamin C plasma concentrations seem to be needed, requiring pharmacological doses (Oudemans-van Straaten, 2014).

Conclusions

Low

GRADE

There is evidence of low quality that administration of vitamin C (oral or intravenous) in addition to hydration is more effective than no administration of vitamin C for the prevention of PC-AKI in patients with eGFR<60 ml/min/1.73m2 undergoing coronary angiography.

 

(Komiyama, 2017; Dvoršak, 2013; Sadat, 2013)

 

 

No studies were found evaluating the effects of vitamin C administration on PC-AKI in patients undergoing CT scans with intravascular contrast administration.

Literature summary

All studies were performed in patients undergoing CAG with or without PCI. The contrast medium was therefore administered via the arterial route before the kidneys in all patients.

 

The systematic review and meta-analysis of Sadat, 2013 included a total of 1536 patients in nine studies. We excluded four of the studies included in the Sadat meta-analysis. One of these because the control arm used N-acetylcysteine (Jo), one study because it did not restrict inclusion to patients with chronic kidney dysfunction (Hamdi, 2013) and two studies, because they only appeared in abstract form (Li, 2012; Komiyama, 2011). All randomized controlled trials are presented in table 1. Vitamin C was administered orally in four studies, intravenously in two and both orally and intravenously in two. All patients received hydration. Definition for inclusion kidney dysfunction differed between studies (sCr > 1.1 to 1.4mg/dl in 4 studies; CrCl ≤60 ml/min in 1 study). The two studies that were only available in abstract form did not report renal dysfunction inclusion criteria.

 

We additionally included 2 RCTs that appeared after the Sadat meta-analysis. These trials included a total of 510 patients undergoing coronary angiography with or without intervention comparing oral vitamin C to control and using saline hydration in both arms (Dvoršak, 2013; Komiyama, 2017).

 

No studies were found evaluating effects of ascorbic acid administration on post-contrast acute kidney injury in patients undergoing computer tomography (CT) scans with intravascular contrast administration.

 

Table 1 Description of the studies regarding dose and route of vitamin C, type of hydration and incidence of PC-AKI

 

Country

Abstract

Inclusion

Dose of

ascorbic acid

Route of

Vit C

Normal saline iv hydration

Incidence

Vit C (%)

Incidence

Control (%)

Spargias

2005

Greece

SCr >106 mmol/L

3 g at least 2-h before contrast,

2 g night before and morning after

oral

50-125 ml/h iv from randomization to 6-h after

9.3

20.4

Boscheri

2007

Germany

SCr >124 mmol/L

 

1 g 20 min before contrast

oral

500 ml before contrast

500 ml during/after for 6-h

6.8

4.3

Zhou

2012

China

SCr >97 mmol/L

 

3 g iv morning of procedure

0.5 g oral night before and morning after

iv and oral

1ml/kg/h for 4-h before and at least 12-h after

7.3

5.4

Komiyama a

2011

Japan

Abstract

Baseline renal insufficiency

3 g before procedure

2 g night and morning after

Iv

1.5 – 2L

8.6

52.2

Brueck

2013

Germany

Cr clearance <60 ml/min

Germany

0.5 g in 250 ml NS in 30 min 24-h and 1-h before

Iv

1 ml/kg/h 12-h before an 12-h after

24.5

32.1

Li a

2012 (A)

China

Abstract

Baseline renal insufficiency

3 g iv 2-4-h before procedure

Oral 1 g on d-1 and d-2 after

Iv and oral

hydration

6.4

5,6

Albabtain

2013

Saoudi Arabia

SCr >112 mmol/L

3 h 2-h before, 2 g after

2 g 24-h after

oral

50-125 ml/u from randomization until 6-h after

3.3

7.3

Dvorzak

2013

Slovenia

SCr >106 mmol/L

 

3 g before, 2 g night before and morning after

oral

50-100 ml/h for 2-h before and 6-h afer

5

7.3

Hamdi a.b

2013

Tunesia

Abstract

All,

Exclusion: cronic dialysis, AKI, heart failure, use of Vit C

Baseline SCr 98.6 ± 29 mmol/L

3 g 2-h before, 2 g after and next day

Not reported

Not reported

11.3

21.1

Komiyama 2017

Japan

Renal dysfunction (eGFR <60 mL/min/1.73 m2)

3g before the procedure, 2g after and the next day in combination with 20 mEq (in 20 ml) sodium bicarbonate befor the procedure in the ascorbic acid group.

Iv

1.5 mL/kg/h 6–15 h before and during the procedure .2.5 mL/kg/h for 6 h after the procedure in both groups. The total amount 1,500–2,500 mL

2.8

8.7

a not included in the final meta-analysis because the study has appeared only in abstract form

b not included in the final meta-analysis because the study did not report restricting inclusion to patients with decreased kidney function

 

Results

Dvoršak, 2013 and Komiyama, 2017 reported that of the patients in the ascorbic acid group 2/40 (5%) and 6/211 (3%) developed PC-AKI, respectively (rise in serum creatinine >25%), compared to 3/41 (7%) and 19/218 (9%) patients in the placebo group. The difference in the study of Komiyama, 2017 was statistically significant (p=0.008), but not in the study of Dvoršak. None of patients required dialysis treatment.

 

Sadat, 2013 found 9 RCTs with a total of 1576 patients, 780 in the ascorbic acid group and 796 in the control group; and a total of 209 events, a total of 73 in the ascorbic acid group and 137 in the control group. Pooled results of Sadat, 2013 showed that ascorbic acid significantly decreased the risk of CI-Aki compared to no ascorbic acid administration: risk ratio of 0.67 (95% CI: 0.47 – 0.97, p=0.03, random effects model).

 

Meta-analyses

Three meta-analyses are reported

First, in the final meta-analysis (figure 1), we pooled the results of 5 RCTs from the meta-analysis of Sadat, 2013 (see above) and the studies of Dvoršak, 2013 and Komiyama, 2017. Ascorbic acid appears to significantly decrease the risk of CI-AKI: risk ratio 0.65 (95% CI: 0.453 – 0.92, p=0.02, random effects model) in patients undergoing coronary angiography. The meta-analysis is shown in figure 1.

 

Due to high heterogeneity of the included studies and the high imprecision noted in the meta-analysis of pooled data above, no separate meta-analyses were performed for oral and intravenous vitamin C administration.

 

Two other meta-analyses are presented as well in the Appendix. One that includes the studies that appeared in abstract form as well (figure 2) and one that includes all RCTs on vitamin C (figure 3). Both demonstrate a similar effect as the meta-analysis in figure 1.

 

Quality of evidence

The level of quality of evidence was decreased from level high to level moderate, due to imprecision (total number of events <300 per group) and inconsistency (inexplicable variation in incidence of events between studies).

 

Figure 1 Meta-analysis of Vitamin C in patients undergoing coronary angiography

F1

 

Figure 2 Meta-analysis also including the studies published in abstract form only

F2

 

Figure 3 Meta-analysis including all RCTs on vitamin C (both impaired kidney function and kidney function not reported)

F3

Search and select

To answer our clinical question a systematic literature analysis was performed for the following research question:

Can prophylactic intravenous Vitamin C/ascorbic acid in addition to hydration reduce the incidence of CI-AKI in patients with pre-existent reduced kidney function receiving intravascular contrast?

 

P (patient category) patients undergoing radiological examinations or interventions with reduced kidney function (eGFR < 60 ml/min/1.73m2) receiving intravascular iodine-containing contrast media;

I (intervention) vitamin C/ascorbic acid/ascorbate in combination with hydration, Vitamin C alone;

C (comparison) hydration alone, no preventive measures;

O (outcome) Post-Contrast AKI (PC-AKI), start renal replacement therapy, or chronic decrease in residual kidney function.

 

Relevant outcome measures

The working group considered PC-AKI, mortality, start renal replacement therapy, decrease in residual kidney function, critical outcome measures and the low risk, costs and general availability of the vitamin C intervention important factors for the decision-making process.

 

A difference of at least 10% in relative risk was defined as a clinically relevant difference; by expert opinion of the working group (no literature was available to substantiate the decision). To illustrate, if PC-AKI occurs with an incidence of 10% in the patient population, a difference of 10% of relative risk would mean a difference of 1% in absolute risk. Thus the number needed to treat would be 100, ergo: a doctor would need to treat 100 patients to prevent one case of PC-AKI. When the incidence of PC-AKI is 5%, a difference of 10% in relative risk would mean a difference of 0.5% in absolute risk, and a number needed to treat of 200.

 

Search and select (method)

The data bases Medline (OVID), Embase and the Cochrane Library were searched from January 1995 to 29th of June 2015 using relevant search terms for systematic reviews (SRs) and randomized controlled trials (RCTs). This search was updated on May 3rd 2017. A total of 127 studies were found. The initial literature search procured 113 hits and a total of 14 were added after the update.

 

The following search criteria were applied:

  • randomized controlled trial or meta-analysis;
  • adult patients who underwent radiological examination or intervention using intravascular contrast media;
  • patients with impaired kidney function (eGFR < 60 ml/min/1.73m2);
  • hydration types: hydration with intravenous (i.v.) NaCl or bicarbonate, oral hydration;
  • vitamin C that was administered in one of treatment arms i.v. or orally;
  • the control arm consisted of patients that received hydration only;
  • at least one of the outcome measures was described: PC-AKI, start dialysis, chronic decrease in kidney function, adverse effects of hydration (fluid overload, intensive care unit admission, and mortality), and cost-effectiveness.

 

Based on title and abstract 38 studies were initially selected. After examination of full text, 35 studies were excluded, leaving 3 studies to be included in the literature summary. Reasons for exclusion are described in the exclusion table.

 

Results

Three studies were included in the literature analysis, one meta-analysis and two randomized controlled studies. The most important study characteristics and results are included in the evidence tables. The evidence tables and assessment of individual study quality are included in the Appendix.  

References

  1. Albabtain MA, Almasood A, Alshurafah H, et al. Efficacy of ascorbic acid, N-acetylcysteine, or combination of both on top of saline hydration versus saline hydration alone on prevention of contrast-Induced nephropathy: a prospective randomized study. J Interv Cardiol. 2013 Feb;26(1):90-6.
  2. Boscheri A, Weinbrenner C, Botzek B, et al. Failure of ascorbic acid to prevent contrast-media induced nephropathy in patients with renal dysfunction. Clin Nephrol. 2007 Nov;68(5):279-86.
  3. Brueck M, Cengiz H, Hoeltgen R, et al. Usefulness of N-acetylcysteine or ascorbic acid versus placebo to prevent contrast-induced acute kidney injury in patients undergoing elective cardiac catheterization: a single-center, prospective, randomized, double-blind, placebo-controlled trial. J Invasive Cardiol. 2013 Jun;25(6):276-83.
  4. Dvoršak B, Kanic V, Ekart R, et al. Ascorbic Acid for the Prevention of Contrast-Induced Nephropathy After Coronary Angiography in Patients With Chronic Renal Impairment: A Randomized Controlled Trial. Ther Apher Dial. 2013;17(4):384-90.
  5. Frei B, Stocker R, England L, et al. Ascorbate: the most effective antioxidant in human blood plasma. Adv Exp Med Biol. 1990;264:155-63.
  6. Hamdi S, Selmi W, Hraiech A, et al. Prevention of contrast induced nephropathy in patients undergoing coronarography with ascorbic acid J Am Coll Cardiol. 2013S:6(2)
  7. Komiyama K, Tejima T, Tanab Y, et al. Is ascorbic acid effective in preventing contrast-induced acute kidney injury? Am J Cardiol, 105 (2011), p. 29A
  8. Komiyama K, Ashikaga T, Inagaki D, et al. Sodium Bicarbonate-Ascorbic Acid Combination for Prevention of Contrast-Induced Nephropathy in Chronic Kidney Disease Patients Undergoing Catheterization. Circ J. 2017;81(2):235-40.
  9. Li R, Chen H. Prevention of contrast-induced nephropathy with ascorbic acid. Heart. 2012-98:E211
  10. Liu ZZ, Schmerbach K, Lu Y, et al. Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedback. Am J Physiol Renal Physiol. 2014;306(8):F864-72.
  11. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014;18(4):460.
  12. Sadat U, Usman A, Gillard JH, et al. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials. J Am Coll Cardiol. 2013;62(23):2167-75.
  13. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004 Nov 2;110(18):2837-42. Epub 2004 Oct 18. Erratum in: Circulation. 2005 Jan 25;111(3):379. Iacovis, Panagiotis
  14. Zhou L, Chen H. Prevention of contrast-induced nephropathy with ascorbic acid. Intern Med. 2012;51(6):531-5. [corrected to Iokovis,Panagiotis].

Evidence tables

Table: Exclusion after revision of full text

Author and year

Reason for exclusion

Albabtain, 2013

Included in systematic review by Sadat, 2013

Alexopoulos, 2010

No vitamin C administration in one of the treatment groups

Au, 2014

review, not specifically focussed on vitamin C (review of Sadat, 2013 of better quality and includes same literature)

Boscheri, 2005

Included in systematic review by Sadat, 2013

Briguori, 2006

review, not systematic

Briguori, 2007_1

vitamin C group not being compared to hydration only or no hydration group (does not comply with PICO)

Briguori, 2007_2

vitamin C group not being compared to hydration only or no hydration group (does not comply with PICO)

Bruerck, 2013

Included in systematic review by Sadat, 2013

De Bie, 2011

review, not systematic

Generali, 2012

review, not systematic

Itoh, 2005

review, not systematic

Jo, 2009

Included in systematic review by Sadat, 2013

Joannidis, 2007

review, not systematic

Kayan, 2012

Not a clinical study

McCullough, 2008

Letter to editor

McCullough, 2013

Letter to editor

Naziroglu, 2013

review, not specifically focussed on vitamin C (review of Sadat, 2013 of better quality and includes same literature)

Oudemans – van Straaten, 2005

review, not systematic

Pattharanitima, 2014

review, not systematic

Reiner, 2009

review, not systematic

Sadat, 2015

review, not systematic

Shakeryan, 2013

oral administration of vitamin C in combination with pentoxyfilline in treatment group (does not comply with PICO)

Sinert, 2007

more recent review by Sadat, 2013 available

Sinert, 2013

review, not systematic

Spargias, 2005

Included in systematic review by Sadat, 2013

Stacul, 2006

more recent review by Sadat, 2013 available

Wang, 2014

Article not found

Zhou, 2012

Included in systematic review by Sadat, 2013

 

Table of quality assessment for systematic reviews of RCTs and observational studies

Based on AMSTAR checklist (Shea et al.; 2007, BMC Methodol 7: 10;doi:10.1186/1471-2288-7-10) and PRISMA checklist (Moher et al 2009, PLoS Med 6: e1000097; doi:10.1371/journal.pmed1000097)

Study

 

 

 

 

 

 

First author, year

Appropriate and clearly focused question?1

 

 

 

 

 

Yes/no/unclear

Comprehensive and systematic literature search?2

 

 

 

 

Yes/no/unclear

Description of included and excluded studies?3

 

 

 

 

 

Yes/no/unclear

Description of relevant characteristics of included studies?4

 

 

 

 

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?5

 

 

 

 

 

 

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?6

 

 

 

 

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?7

 

Yes/no/unclear

Potential risk of publication bias taken into account?8

 

 

 

 

 

Yes/no/unclear

Potential conflicts of interest reported?9

 

 

 

 

 

Yes/no/unclear

Sadat, 2013

Yes

Yes

No

Yes

Not applicable

Yes

Yes

Yes

Yes

  1. Research question (PICO) and inclusion criteria should be appropriate and predefined
  2. Search period and strategy should be described; at least Medline searched; for pharmacological questions at least Medline + EMBASE searched
  3. Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons
  4. Characteristics of individual studies relevant to research question (PICO), including potential confounders, should be reported
  5. Results should be adequately controlled for potential confounders by multivariate analysis (not applicable for RCTs)
  6. Quality of individual studies should be assessed using a quality scoring tool or checklist (Jadad score, Newcastle-Ottawa scale, risk of bias table etc.)
  7. Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, intervention and definition of outcome measure to allow pooling? For pooled data: assessment of statistical heterogeneity using appropriate statistical tests (e.g. Chi-square, I2)?
  8. An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies.
  9. Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.

 

Risk of bias table for intervention studies (randomized controlled trials)


Research question:

Study reference

 

 

 

(first author, publication year)

Describe method of randomisation1

Bias due to inadequate concealment of allocation?2

 

 

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?3

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?3

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?3

 

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?4

 

 

 

(unlikely/likely/unclear)

Bias due to loss to follow-up?5

 

 

 

 

 

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?6

 

 

 

(unlikely/likely/unclear)

Komiyama 2017

Not reported

Unclear

Unclear

Unclear

Unclear

Unlikely

Unlikely

Unclear

Dvoršak, 2013

Not reported

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

  1. Randomisation: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
  2. Allocation concealment: refers to the protection (blinding) of the randomisation process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomisation (performed at a site remote from trial location) or sequentially numbered, sealed, opaque envelopes. Inadequate procedures are all procedures based on inadequate randomisation procedures or open allocation schedules..
  3. Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments. The outcome assessor records the study results. Blinding of those assessing outcomes prevents that the knowledge of patient assignement influences the proces of outcome assessment (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
  4. Results of all predefined outcome measures should be reported; if the protocol is available, then outcomes in the protocol and published report can be compared; if not, then outcomes listed in the methods section of an article can be compared with those whose results are reported.
  5. If the percentage of patients lost to follow-up is large, or differs between treatment groups, or the reasons for loss to follow-up differ between treatment groups, bias is likely. If the number of patients lost to follow-up, or the reasons why, are not reported, the risk of bias is unclear
  6. Participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the risk of bias is unclear; an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.

 

Evidence table for systematic review of RCTs and observational studies (intervention studies)

Research question:

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Sadat, 2013

 

[individual study characteristics deduced from [1st author,

year of publication

]]

 

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of [RCTs]

 

Literature search up to May 15th 2013

 

A: Sparglas, 2004

B: Boscheri, 2007

C: Jo, 2009

D: Zhou, 2011

E: Komiyama, 2011

F: Bruerck, 2011

G: Li, 2012

H: Albabtain, 2013

I:Hamdi, 2013

 

Study design: RCT [parallel]

 

Setting and Country:

Outpatients

England and Pakistan

 

Source of funding:

Not reported

 

Inclusion criteria SR:

1) RCTs assessing the use of ascorbic acid in reducing CI-AKI compared with placebo or other pharmacological treatments in patients undergoing coronary angiography

2) route of administration of ascorbic acid: oral or intravenous or both

3) Incidence of CI-AKI (absolute increase in serum creatinine of ≥0.5 mg/dl (44µmol/L) or a relative increase of ≥25% from the baseline value after administration of contrast media during angiography) was reported as outcome measure

 

Exclusion criteria SR:

-

 

9 studies included

 

 

Important patient characteristics at baseline:

Number of patients; characteristics important to the research question and/or for statistical adjustment (confounding in cohort studies); for example, age, sex, bmi, ...

 

N,

A: 238

B: 143

C: 212

D: 174

E: 70

F: 520

G: 149

H: 243

I:202

 

 

Groups comparable at baseline?

Unclear

Describe intervention:

 

 

A: Ascorbic acid, oral administration,

3g at least 2 hours after procedure, 2g night before and morning after procedure. Hydration with saline 50-125mg/hr IV from time of randomization to at least 6 hours after procedure

B: 1g ascorbic acid orally 20 minutes before exposure to contrast medium, 500mL saline, 2 hours before and 500ml during angiography and subsequent 6 hours

C: ascorbic acid, 3g (night before) and 2g morning of procedure; 2g night before and morning after procedure, oral administration, all doses 12 hours apart

D: ascorbic acid, IV administration, 3g morning of procedure, oral 0.5g on the night of procedure and next morning (all doses 12 hours apart). IV saline hydration1mg/kg/hr for 4 hours before and at least 12 hours after angiography

E: ascorbic acid, IV administration, 3g before procedure, 2g night and morning after procedure (12 hours apart). Saline hydration 1.5 – 2.5L

F: ascorbic acid, IV administration

G: ascorbic acid, IV 3g 2-4 hours before procedure and oral 1g on days 1 and 2 after procedure. IV saline hydration

H: ascorbic acide, oral administration, 3g 2 hours before procedure, 2g after angiogram and 2g 24 hours after angiogram. IV saline 50-125 ml/hour from randomization until at least 6 hours after procedure

I: ascorbic acid 3g 2 hours before procedure, 2g day after procedure and next day, mode of administration not reported

Describe control:

 

A: placebo with IV hydration as in ascorbic acid arm

B: placebo with IV hydration as in ascorbic acid arm

C: 1200mG NAC orally 2x/daily on day of procedure and day before procedure

D: IV saline hydration 1mg/kg/hour for 4 hours before and at least 12 hours after angiography

E: IV saline hydration 1.5 – 2.5L

F: placebo (per ascorbic acid dose) and IV saline (1/mg/kg/hour) for 12 hours before to 12 hours after contrast medium exposure

G: IV saline hydration

H: IV saline hydration

I:IV saline hydration

 

End-point of follow-up:

Not reported

 

 

For how many participants were no complete outcome data available?

(intervention/control)

Not reported

 

 

 

Outcome measure-1

Defined as. Risk of CI-AKI (risk ratio)

 

Effect measure: relative risk [95% CI]:

A: 0.46 (0.23 – 0.90)

B: 1.55 (0.39 – 6.26)

C: 3.65 (0.42 – 31.99)

D: 1.35 (0.40 – 4.61)

E: 0.25 (0.08 – 0.81)

F: 0.76 (0.51 – 1.14)

G: 1.14 (0.32 – 4.07)

H: 0.46 (0.32 – 2.30)

I: 0.49 (0.09 – 2.30)

 

Pooled effect (random effects model): risk ratio:

0.672 [95% CI 0.466 to 0.969] favoring ascorbic acid

Heterogeneity (I2): 27%

 

Outcome measure-2

Risk of publication bias

Egger’s regression intercept:

1.086 (95% CI: -2.57 – 4.74)

df = 4

p=0.455

 

 

 

 

 

 

 

Facultative:

 

Brief description of author’s conclusion:

Ascorbic acid provides effective nephroprotection against CI-AKI and may form a part of effective prophylactic pharmacological regiments.

 

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question:

 

When studies on oral ascorbic acid administration and IV ascorbic acid administration were pooled separately, the ascorbic acid administration was as effective as control in prevention of CI-AKI.

 

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading:

For the outcome risk of CI-AKI the level of evidence was reduced to moderate, due to inconsistency of results.

 

 

Ascorbic acid = vitamin C;CI-AKI: contrast-induced acute kidney injury; CIN: contrast induced nephropathy; IV: intravenous; NAC: N-acetyl-cysteine; NR: not reported; RCT: randomised controlled trial

 

Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies [cohort studies, case-control studies, case series])1

This table is also suitable for diagnostic studies (screening studies) that compare the effectiveness of two or more tests. This only applies if the test is included as part of a test-and-treat strategy – otherwise the evidence table for studies of diagnostic test accuracy should be used.

 

Research question:

Study reference

Study characteristics

Patient characteristics 2

Intervention (I)

Comparison / control (C) 3

Follow-up

Outcome measures and effect size 4

Comments

Dvoršak, 2013

Type of study: randomized controlled trial

 

Setting: not clear

 

Country: Slovenia

 

Source of funding: no funding

Inclusion criteria:

1) patients with stable serum creatinine levels (>107µmol/L / 1.2 mg/dL)

2) undergoing elective coronary angiography or angioplasty

 

Exclusion criteria:

1) regular medication containing vitamin C

2) acute renal failure

3) end-stage renal disease

4) radiocontrast procedure in the last 3 months

5) cardiogenic shock

6) acute myocardial infarction

 

N total at baseline:

Intervention: 42

Control: 41

 

Important prognostic factors2:

For example

age ± SD:

I: 71 ± 9

C: 71 ± 9

 

Sex:

I: 78% M

C: 68% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

Ascorbic acid in 500mg capsules

3g orally before procedure

2g after the procedure in the evening and the next morning

 

Describe control (treatment/procedure/test):

 

 

Placebo

 

Length of follow-up:

4 days

 

Loss-to-follow-up:

Intervention:

2/42 (5%)

Reasons: lost to follow-up (?)

 

Control:

0/41 (0%)

Reasons: not applicable

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Contrast-induced nephropathy

(+an increase in serum creatinine level >25% from baseline or increase of serum cystatin C levels >25%, measured 3-4 days after procedure)

 

I: 2/40

C: 3/41

P=0.51

We found no statistically significant impact of ascorbic acid on the incidence of CIN in patients with chronic renal impairment undergoing coronary arteriography or angioplasty.

Komiyama 2017

Type of study: randomized controlled trial

 

Setting: hospital

 

Country: Japan

 

Source of funding: no funding

Inclusion criteria:

patients with renal dysfunction undergoing elective angiography

(including coronary angiography, aortography, and venography)

or intervention (including percutaneous coronary

intervention and endovascular treatment) with a catheter

 

Exclusion criteria:

1) aged <20 years

2) pregnant or undergoing maintenance dialysis. 3) acute conditions such as acute myocardial infarction and unstable angina

3) severe cardiac failure (New York Heart Association class III or

higher)

4) severe respiratory disease

5) undergone catheter procedures involving the use of a contrast agent within the previous 48 h

 

N total at baseline:

Intervention: 218

Control: 211

 

Important prognostic factors2:

For example

age ± SD:

I: 73 ± 10

C: 74 ± 10

 

Sex:

I: 79% M

C: 82% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

Sodium bicarbonate (20 mL=20 mEq; Meyron 84, Otsuka Pharmaceutical, Tokyo, Japan) and ascorbic acid (3 g) were given i.v. before the procedure. Ascorbic acid (2 g) was then administered after the procedure, followed by another 2 g of ascorbic

acid 12 h later after the procedure; this group also received the same saline hydration protocol as the control group.

Describe control (treatment/procedure/test):

 

 

The control group received 0.9% physiological saline 6–15 h before, and during, the procedure at a rate of 1.5 mL/kg/h. This rate was then increased to 2.5 mL/kg/h for 6 h after the procedure. The total amount of saline administered was 1,500–2,500 mL

Length of follow-up:

3 days

 

Loss-to-follow-up:

Intervention:

None reported

Reasons: not applicable

 

Control:

None reported

Reasons: not applicable

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Contrast-induced nephropathy

(+an increase in serum creatinine level >25% from baseline or increase of serum cystatin C levels >25%, measured 3 days after procedure)

 

I: 6/211

C: 19/218

P=0.008

Use of i.v. sodium bicarbonate and ascorbic acid and a saline hydration protocol in patients with CKD undergoing elective procedures can prevent CIN more effectively than saline hydration alone.

Notes:

  1. Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
  2. Provide data per treatment group on the most important prognostic factors [(potential) confounders]
  3. For case-control studies, provide sufficient detail on the procedure used to match cases and controls
  4. For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders

Considerations

The present search shows that that vitamin C offers some protection against PC-AKI in patients with CKD undergoing coronary angiography with or without intervention. However, the risk reduction was less than of 10% and therefore not considered to be clinically relevant. Furthermore, the evidence is weak due to the quality of the trials and the heterogeneity of the results. Finally, the dose and route of administration of vitamin C differed between studies, and the incidence of PC-AKI in the control arm greatly differed among studies, ranging from 4% to 32%.

 

Because of this marginal protection, the Working Group does not recommend adding vitamin C to hydration routinely in patients with an increased risk of PC-AKI. Reasons are that the level of evidence is weak and the potential benefit is small and clinically likely not relevant. In addition, none of the studies showed significant differences in clinical meaningful endpoints such as need of renal replacement therapy. Since the risk of renal replacement therapy after intravascular contrast media administration is low, none of the studies was powered to show such result.

 

Intervention with vitamin C is without risk, cheap, and generally available, and some protection seems likely. The addition of vitamin C to hydration may therefore be considered in patients with a very high risk of PC-AKI such as those with eGFR <30 ml/min/1.73 m2. Although several doses of vitamin C were used, most positive studies used a dose of 3 g orally 2 hours before the contrast, and 2 g the night before and day after the contrast administration. Since oral vitamin C is generally available and the oral route is cheapest, we suggest using this dose if the risk of AKI is considered extremely high and maximal renal protection is wanted. However, the evidence for this recommendation is very low.

Authorization date and validity

Last review : 01-11-2017

Last authorization : 01-11-2017

The board of the Radiological Society of the Netherlands will determine at the latest in 2023 if this guideline (per module) is still valid and applicable. If necessary, a new working group will be formed to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be seen as a reason to commence revisions. The Radiological Society of the Netherlands is considered the keeper of this guideline and thus primarily responsible for the actuality of the guideline. The other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.

 

Authotization

The guideline is submitted for authorization to

  • Radiological Society of the Netherlands
  • Netherlands Association of Internal Medicine
  • Dutch Federation of Nephrology
  • Dutch Society of Intensive Care
  • Association of Surgeons of the Netherlands
  • Netherlands Society of Cardiology
  • Netherlands Society for Clinical Chemistry and Laboratory Medicine
  • Netherlands Society of Emergency Physicians
  • Dutch Association of Urology
  • Dutch Society Medical Imaging and Radiotherapy

Initiative and authorization

Initiative : Nederlandse Vereniging voor Radiologie

General details

The guideline development was assisted by the Knowledge Institute of Medical Specialists and was financed by the Quality Funds for Medical Specialists (Kwaliteitsgelden Medisch Specialisten: SKMS).

Scope and target group

Goal of the current guideline

The aim of the Part 1 of Safe Use of Iodine-containing Contrast Media guidelines is to critically review the present recent evidence with the above trend in mind, and try to formulate new practical guidelines for all hospital physicians to provide the safe use of contrast media in diagnostic and interventional studies. The ultimate goal of this guideline is to increase the quality of care, by providing efficient and expedient healthcare to the specific patient populations that may benefit from this healthcare and simultaneously guard patients from ineffective care. Furthermore, such a guideline should ideally be able to save money and reduce day-hospital waiting lists.

 

Users of this guideline

This guideline is intended for all hospital physicians that request or perform diagnostic or interventional radiologic or cardiologic studies for their patients in which CM are involved.

Members of the guideline panel

A multidisciplinary working group was formed for the development of the guideline in 2014. The working group consisted of representatives from all relevant medical specialization fields that are involved with intravascular contrast administration.

 

All working group members have been officially delegated for participation in the working group by their scientific societies. The working group has developed a guideline in the period from October 2014 until July 2017.

 

The working group is responsible for the complete text of this guideline.

  • A.J. van der Molen, radiologist, Leiden University Medical Centre, Leiden (chairman)
  • R.W.F. Geenen, radiologist, Noordwest Ziekenhuisgroep (NWZ), Alkmaar/Den Helder
  • T.H. Pels Rijcken, interventional radiologist, Tergooi, Hilversum
  • H.M. Dekker, radiologist, Radboud University Medical Centre, Nijmegen
  • A.H. van den Meiracker, internist-vascular medicine, Erasmus Medical Centre, Rotterdam
  • E.K. Hoogeveen, nephrologist, Jeroen Bosch Hospital, ‘s-Hertogenbosch
  • H.M. Oudemans - van Straaten, internist-intensive care specialist, Free University Medical Centre, Amsterdam
  • Y.W.J. Sijpkens, nephrologist, Haaglanden Medical Centre, The Hague
  • J. Kooiman, research physician, Leiden University Medical Centre, Leiden
  • C. Cobbaert, clinical chemist, Leiden University Medical Centre (member of advisory board from September 2015)
  • T. Vainas, vascular surgeon, University Medical Centre Groningen (until September 2015)
  • O.R.M. Wikkeling, vascular surgeon, Heelkunde Friesland Groep, location: Nij Smellinghe Hospital, Drachten (from September 2015)
  • P. Danse, interventional cardiologist, Rijnstate Hospital, Arnhem

 

Advisory board

  • K. Prantl, Coordinator Quality & Research, Dutch Kidney Patient Association
  • R. Hubbers, patient representative, Dutch Kidney Patient Association
  • J. Mazel, urologist, Spaarne Gasthuis, Haarlem
  • J. van den Wijngaard, resident in Clinical Chemistry, Leiden University Medical Center
  • A.Y. Demir, clinical chemist, Meander Medical Center, Amersfoort, (member of working group until September 2015)
  • S. Moos, resident in Radiology, HAGA Hospital, The Hague

 

Methodological support

  • I.M. Mostovaya, advisor, Knowledge Institute of Medical Specialists
  • S. Persoon, advisor, Knowledge Institute of Medical Specialists (March 2016 – September 2016)
  • K. Burger, senior advisor, Knowledge Institute of Medical Specialists (until March 2015)
  • A. van Enst, senior advisor, Knowledge Institute of Medical Specialists (from January 2017)
  • J. Boschman, advisor, Knowledge Institute of Medical Specialists (from May 2017)
  • W. Harmsen, advisor, Knowledge Institute of Medical Specialists (from May 2017)

Declaration of interest

The working group members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that are related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested at the administrative office of the Knowledge Institute of Medical Specialists and are summarised below.

 

Member

Function

Other offices

Personal financial interests

Personal relationships

Reputation management

Externally financed research

Knowledge-valorisation

Other potential conflicts of interest

Signed

Workgroup

Van der Molen

Chairman, radiologist

Member Contrast Media Safety Committee of the European Society of Urogenital Radiology (unpaid,CMSC meetings are partially funded by CM industry))

None

None

Secretary section of Abdominal Radiology; Radiological Society of the Netherlands (until spring of 2015)

None

None

Receives Royalties for books: Contrast Media Safety, ESUR guidelines, 3rd ed. Springer, 2015

Received speaker fees for lectures on CM safety by GE Healthcare, Guerbet, Bayer Healthcare and Bracco Imaging (2015-2016)

Yes

Geenen

Member, radiologist

Member Contrast Media Safety Committee of the European Society of Urogenital Radiology (unpaid, meetings are partially funded by CM industry)))

None

None

None

None

None

Has been a public speaker during symposia organised by GE Healthcare about contrast agents (most recently in June 2014)

Yes

Dekker

Member, radiologist

None

None

None

None

None

None

None

Yes

Pels Rijcken

Member, interventional radiologist

None

None

None

None

None

None

None

Yes

Danse

Member, cardiologist

Board member committee of Quality, Dutch society for Cardiology (unpaid)

Board member Conference committee DRES (unpaid)

None

None

None

None

None

None

Yes

Oudemans – van Straaten

Member, intensive care medical specialist

Professor Intensive Care

none

None

None

None

None

None

None

Yes

Hoogeveen

Member, nephrologist

Member of Guideline Committee of Dutch Federation of Nephrology

None

None

Member of Guideline Committee of Dutch Society for Nephrology

Grant from the Dutch Kidney Foundation to study effect of fish oil on kidney function in post-MI patients

None

None

Yes

Sijpkens

Member, nephrologist

None

None

None

None

None

None

None

Yes

Van den Meiracker

Member, internist vascular medicine

None

None

None

None

None

None

None

Yes

Cobbaert

Member, physician clinical chemistry

Head of clinical chemistry department in Leiden LUMC.

Tutor for post-academic training of clinical chemists, coordinator/host for the Leiden region

Member of several working groups within the Dutch Society for Clinical Chemistry and member of several international working groups for clinical chemistry

None

None

Member of several working groups within the Dutch Society for Clinical Chemistry and member of several international working groups for clinical chemistry

None

None

None

Yes

Wikkeling

Member, vascular surgeon

None

None

None

None

None

None

None

Yes

Vainas

Member, vascular surgeon

None

None

None

None

None

None

None

Yes

Kooiman

Member, research physician

Resident in department of gynaecology & obstetrics

None

None

None

None

None

None

Yes

Burger

Advisor, Knowledge Institute of Medical Specialists

None

None

None

None

None

None

None

Yes

Mostovaya

Advisor, Knowledge Institute of Medical Specialists

None

None

None

None

None

None

None

Yes

Advisory Board

Prantl

Member, policy maker, Dutch Society of Kidney Patients

None

None

None

None

None

None

None

Yes

Hubbers

Member, patient’s representative, Dutch Society of Kidney Patients

None

None

None

None

None

None

None

Yes

Mazel

Member, urologist

None

None

None

None

None

None

None

Yes

Van den Wijngaard

Member, resident clinical chemistry

Reviewer for several journals (such as American Journal of Physiology)

None

None

None

None

None

None

Yes

Demir

Member, physician clinical chemistry

None

None

None

None

None

None

None

Yes

Patient involvement

Patients’ perspective was represented, firstly by membership and involvement in the advisory board of a policy maker and a patients’ representative from the Dutch Kidney Patient Association. Furthermore, an online survey was organized by the Dutch Kidney Patient Association about the subject matter of the guideline. A summary of the results of this survey has been discussed during a working group meeting at the beginning of the guideline development process. Subjects that were deemed relevant by patients were included in the outline of the guideline. The concept guideline has also been submitted for feedback during the comment process to the Dutch Patient and Consumer Federation, who have reported their feedback through the Dutch Kidney Patient Association.

Method of development

Evidence based

Implementation

In the different phases of guideline development, the implementation of the guideline and the practical enforceability of the guideline were taken into account. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found with the Related Products. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found with the Related Products.

Methods and proces

AGREE

This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0; the advisory committee of the Quality Counsel. This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreetrust.org), a broadly accepted instrument in the international community and on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).

 

Identification of subject matter

During the initial phase of the guideline development, the chairman, working group and the advisor inventory the relevant subject matter for the guideline. Furthermore, an Invitational Conference was organized, where additional relevant subjects were suggested by the Dutch Kidney Patient Association, Dutch Society for Emergency Physicians, and Dutch Society for Urology. A report of this meeting can be found in Related Products.

 

Clinical questions and outcomes

During the initial phase of guideline development, the chairman, working group and advisor identified relevant subject matter for the guideline. Furthermore, input was acquired for the outline of the guideline during an Invitational Conference. The working group then formulated definitive clinical questions and defined relevant outcome measures (both beneficial land harmful effects). The working group rated the outcome measures as critical, important and not important. Furthermore, where applicable, the working group defined relevant clinical differences.

 

Strategy for search and selection of literature

For the separate clinical questions, specific search terms were formulated and published scientific articles were sought after in (several) electronic databases. Furthermore, studies were looked for by cross-referencing other included studies. The studies with potentially the highest quality of research were looked for first. The working group members selected literature in pairs (independently of each other) based on title and abstract. A second selection was performed based on full text. The databases search terms and selection criteria are described in the modules containing the clinical questions.

 

Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search, so that risk of bias could be estimated. This is described in the “risk of bias” tables.

 

Summary of literature

The relevant research findings of all selected articles are shown in evidence tables. The most important findings in literature are described in literature summaries. When there were enough similarities between studies, the study data were pooled.

 

Grading the strength of scientific evidence

A) For intervention questions

The strength of the conclusions of the scientific publications was determined using the GRADE-method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org/) (Atkins, 2004).

 

GRADE defines four gradations for the quality of scientific evidence: high, moderate, low or very low. These gradations provide information about the amount of certainty about the literature conclusions. (http://www.guidelinedevelopment.org/handbook/).

 

F1

 

B) For diagnostic, etiological, prognostic or adverse effect questions, the GRADE-methodology cannot (yet) be applied. The quality of evidence of the conclusion is determined by the EBRO method (van Everdingen, 2004)

 

Formulating conclusion

For diagnostic, etiological, prognostic or adverse effect questions, the evidence was summarized in one or more conclusions, and the level of the most relevant evidence was reported. For intervention questions, the conclusion was drawn based on the body of evidence (not one or several articles). The working groups weighed the beneficial and harmful effects of the intervention.

 

Considerations

Aspects such as expertise of working group members, patient preferences, costs, availability of facilities, and organization of healthcare aspects are important to consider when formulating a recommendation. These aspects were discussed in the paragraph Considerations.

 

Formulating recommendations

The recommendations answer the clinical question and were based on the available scientific evidence and the most relevant considerations.

 

Constraints (organization of healthcare)

During the development of the outline of the guideline and the rest of the guideline development process, the organization of healthcare was explicitly taken into account. Constraints that were relevant for certain clinical questions were discussed in the Consideration paragraphs of those clinical questions. The comprehensive and additional aspects of the organization of healthcare were discussed in a separate chapter.

 

Development of quality indicators

Internal (meant for use by scientific society or its members) quality indicators are developed simultaneously with the guideline. Furthermore, existing indicators on this subject were critically appraised; and the working group produces an advice about such indicators. Additional information on the development of quality indicators is available by contacting the Knowledge Institute for Medical Specialists. (secretariaat@kennisinstituut.nl).

 

Knowledge Gaps

During the development of the guideline, a systematic literature search was performed the results of which help to answer the clinical questions. For each clinical question the working group determined if additional scientific research on this subject was desirable. An overview of recommendations for further research is available in the appendix Knowledge Gaps.

 

Comment- and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The commentaries were collected and discussed with the working group. The feedback was used to improve the guideline; afterwards the working group made the guideline definitive. The final version of the guideline was offered for authorization to the involved scientific societies, and was authorized.

 

References

Atkins D, Eccles M, Flottorp S, et al. GRADE Working Group. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv Res. 2004 Dec 22;4(1):38.

Van Everdingen JJE, Burgers JS, Assendelft WJJ, et al. Evidence-based richtlijnontwikkeling. Bohn Stafleu van Loghum. Houten, 2004

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.