What type of IV fluids are recommended in CKD patients (GFR 15-45 mL/min) prior to cardiac catheterization to prevent contrast-induced nephropathy? Is there any preference for normal saline over half normal saline?

Comment by InpharmD Researcher

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and other literature recommend isotonic sodium chloride (normal saline [NS]) over hypotonic solutions (e.g., half NS) as intravenous fluid for patients at risk of contrast-induced nephropathy. There is limited data studying normal saline over half normal saline, and the only randomized study is not in patients with renal insufficiency.

Background

Contrast-induced nephropathy (CIN) has become a clinically significant problem due to the increased use of radiographic contrast media in clinical practice as well as the increasing incidence of chronic kidney disease in an aging population overall. Pre-existing renal dysfunction is a major risk factor, especially in patients with a creatinine clearance > 60 mL/min. Strategies to mitigate CIN include intravenous hydration with normal saline or sodium bicarbonate, withholding of nephrotoxic medications, administration of low or iso-osmolar contrast media, and various intraprocedural methods for iodinated contrast dose reduction. The use of N-acetylcysteine is growing in popularity, however, it remains unproven. [1], [2], [3], [4], [5]

In non-dehydrated patients, some studies recommend 2,500 mL of normal saline given IV within 24 hours of contrast exposure to maintain urine generation rate >1 mL/kg//h. For high-risk patients, normal saline is recommended to be administered 6-12 hours before contrast at 1 mL/kg/h and continued for an additional 12-24 hours. Normal saline provides greater volume expansion than hypotonic solutions (e.g., ½NS [0.45% sodium chloride]) and has been shown to be superior to hypotonic solutions. While sodium bicarbonate has been studied, large randomized studies have failed to show any benefit of sodium bicarbonate over normal saline. [1], [2], [3], [4], [5]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What type of IV fluids are recommended in CKD patients with a GFR 15-45 mL/min prior to cardiac catheterization to prevent contrast-induced nephropathy?
Is there any preference for normal saline over half normal saline?

Please see Tables 1-3 for your response.

Prevention of Contrast Media-Associated Nephropathy: Randomized Comparison of 2 Hydration Regimens in 1620 Patients Undergoing Coronary Angioplasty
Design	Randomized, controlled, open-label study N=1,383
Objective	To compare the incidence of contrast-induced nephropathy with isotonic or half-isotonic hydration
Study Groups	0.9% saline (n=685) 0.45% saline (n=698)
Inclusion Criteria	Patients scheduled for elective or emergency coronary angioplasty
Exclusion Criteria	End-stage renal failure with regular hemodialysis, cardiogenic shock, mechanical ventilation
Methods	Patients scheduled for elective coronary angioplasty were randomized to hydration with 0.9% saline or 0.45% saline plus 5% glucose at a rate of 1 mL/kg of bodyweight/h starting the morning of angioplasty. Patients were also encouraged to drink plenty of fluids. In patients undergoing emergency intervention, no pre-hydration could be given. Patients with acute coronary syndromes were given a 500 mL crystalloidal infusion (Ringer's solution) as standard care. Their randomized infusions (0.9% or 0.45% saline) started on arrival to the catheter laboratory and continued until the next morning. All procedures were performed with low-osmolar nonionic contrast media (iopromide [Ultravist]). No medication changes were allowed in study participants.
Duration	Blood samples were collected in the morning before angioplasty, 24 hours and 48 hours after angioplasty
Outcome Measures	Contrast-associated nephropathy, defined as a rise in serum creatinine by 0.5 mg/dL within 48 hours
Baseline Characteristics		0.9% saline (n=685)	0.45% saline (n=698)	p-value
	Age, years (95% confidence interval [CI])	64 (63-65)	64 (63-65)	0.71
	Female	26%	25%	0.74
	Chronic renal insufficiency	20%	21%	0.92
	Baseline creatinine, mg/dL	0.92	0.93	0.81
	Baseline creatinine clearance, mL/min (95% CI)	84 (82-85)	84 (82-86)	0.79
Results		0.9% saline (n=685)	0.45% saline (n=698)	p-value
	Contrast-induced nephropathy (95% CI) Women Patients with diabetes Patients receiving >250 mL of contrast Elective procedures	0.7% (0.1%-1.4%) 0.6% (0%-1.7%) 0% 0% 0.7% (0.3%-1.6%)	2.0% (1.0%-3.1%) 5.1% (1.8%-8.4%) 5.5% (1.1%-9.8%) 3.0% (0.9%-5.0%) 2.7% (0.9%-4.6%)	0.04 0.01 0.01 0.01 0.06
	For patients undergoing emergency procedures, the overall incidence of contrast-induced nephropathy was 1.1% with no significant difference between the hydration group.
Adverse Events	Two patients required dialysis, one in each study group.
	Major adverse cardiovascular events were seen in 14 (5.3%) who received isotonic saline and 17 (6.4%) patients who received half-isotonic saline (p=0.59).
	Overall mortality was not significant between isotonic and half-isotonic saline groups (0.4% vs 1.1%; p=0.35).
Study Author Conclusions	Isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media-associated nephropathy.
InpharmD Researcher Critique	There were originally 1,620 patients randomized, but over 100 patients were excluded in each group due to repeat catheterization or incomplete data. Additionally, this patient population was of relatively low risk as only 286 patients had chronic renal insufficiency and any renal dysfunction was mild in these patients. Oral fluid intake was not measured between the groups, but it was not thought to be significantly different.

References:

Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002;162(3):329-336. doi:10.1001/archinte.162.3.329

Randomized Trial of Bicarbonate or Saline Study for the Prevention of Contrast-Induced Nephropathy in Patients with CKD
Design	Prospective, double-blind, multicenter randomized clinical trial N=391
Objective	To evaluate high dose sodium bicarbonate and its effect on rates of adverse outcomes
Study Groups	Sodium Bicarbonate (n=195) 0.9% Sodium chloride (n=196)
Inclusion Criteria	Eighteen years or older, elective coronary or peripheral angiography, eGFR <45 mL/min per 1.73 m²
Exclusion Criteria	Subjective hemodynamic instability, renal replacement therapy (RRT), hypocalcemia
Methods	Bicarbonate solutions used were prepared in each individual pharmacy. Solutions were prepared via a kit containing three 50 mL ampules of sodium bicarbonate along side a partially filled bag with 830 mL of sterile water. Sodium chloride (0.9%) was used in the opposing cohort. Patients in both cohorts received 5 mL/kg over 60 minutes before angiography and then 1.5 mL/kg/hr during and after angiography. Electrolytes and serum creatinine was collected 12 hours before administration of contrast and then collected on days 1, 3, 7, 30, 90, and 180. Creatinine levels used in the primary outcome were precontrast level and level on days 7, 30, 90, and 180. If the patient presented with cardiovascular complications (reduced ejection fraction <40%, congestive heart failure and/or edema) either bicarbonate or sodium chloride was infused over 5 hours after angiography was complete. Blinding of the treatment arms was done by enclosing a nontransparent bag. Non-steroidal anti-inflammatory (NSAID) and diuretics were recommended to be discontinued before day of procedure.
Duration	Follow-up period was 6 months. Readings were confirmed by at least two separate measurements between day 30 and day 180 creatinine compared with the baseline value before contrast administration.
Outcome Measures	Primary outcome: composite of mortality, dialysis, or a sustained 20% reduction in eGFR at 6 months
Baseline Characteristics		Bicarbonate (n=195)	Sodium Chloride (n=196)	p-value
	Age, years	72 ± 10	72 ± 9	0.73
	Male	57%	58%	1.00
	Weight, kg	89.1 ± 19.7	88.3 ± 22.3	0.71
	Creatinine, mg/dL	1.98 ± 0.62	1.85 ± 0.49	0.02
	eGFR, mL/min/1.73 m²	31.7 ± 7.7	33.8 ± 7.3	0.01
Results		Bicarbonate (n=195)	Sodium Chloride (n=196)	p-Value
	Primary composite endpoint	39 (20%)	41 (20.9%)	0.90
	Sustained >20% loss of eGFR	21 (10.7%)	16 (8.1%)	0.39
	Dialysis	8 (4.1%)	6 (3.1%)	0.60
	Death	10 (5.1%)	19 (9.7%)	0.12
	Contrast Induced Acute Kidney Injury (CIAKI)	26 (13.3)	18 (9.1%)	0.20
	Individual components of the composite primary endpoint were analyzed in the per-protocol analysis, it determined that patients treated with bicarbonate had statically less mortality.
Adverse Events	High dose bicarbonate did not lead to safety issues. New onset congestive heart failure at day 7, 30, 90, and 180 was 7.4% (bicarbonate) versus 7.5% (sodium chloride) between both cohorts (p=0.99). Contrast-induced AKI occurred in 44/368 (12%) of patients in per-protocol analysis, 13.3% in bicarbonate cohort and 9.2% in sodium chloride cohort (unadjusted RR=1.45; 95% CI, 0.86 to 2.69; p=0.20) Contrast-induced AKI occurred was associated with prolonged loss of kidney function at 6 months (unadjusted RR=2.85; 95% CI, 1.58 to 5.12; p=0.002)
Study Author Conclusions	High-dose sodium bicarbonate infusion in patients with eGFR,45 ml/min per 1.73 m2 undergoing angiography did not demonstrate a difference in incidence of the composite of death, dialysis, or sustained 6-month reduction in eGFR or CIAKI compared with sodium chloride.
InpharmD Researcher Critique	The study findings are specific to a patient population with eGFR <45 mL/min/1.73 m² and cannot be made generalizable to other patient populations. The study was prematurely terminated due to insufficient power to detect a difference between cohorts. This may have introduced false-positives and/or false-negatives results.

References:

Solomon R, Gordon P, Manoukian SV, et al. Randomized Trial of Bicarbonate or Saline Study for the Prevention of Contrast-Induced Nephropathy in Patients with CKD. Clin J Am Soc Nephrol. 2015;10(9):1519-1524. doi:10.2215/CJN.05370514

Short-Term High-Dose Vitamin E to Prevent Contrast Medium–Induced Acute Kidney Injury in Patients With Chronic Kidney Disease Undergoing Elective Coronary Angiography: A Randomized Placebo-Controlled Trial
Design	Double-blind, placebo-controlled, 2-center, randomized clinical trial N=298
Objective	To evaluate vitamin E for possible renal protective effects against contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography
Study Groups	Vitamin E (n=149) Placebo (n=149)
Inclusion Criteria	Eighteen years or older, baseline eGFR <60 mL/min/1.73 m², stable angina with ischemia requiring coronary angiography, non-ST elevation (NSTE) acute coronary syndrome (ACS) requiring early invasive strategy
Exclusion Criteria	Acute ST-segment elevation myocardial infarction; high-risk NSTE-ACS emergency coronary angiography (<2 hours); cardiogenic shock; ejection fraction <30%; bleeding and/or coagulopathy diseases; AKI; history of dialysis; consumption of vitamin E, C, or N-actylcysteine at least 48 hours before intervention
Methods	Patients were randomized 1:1 into two cohorts. Patient and care-providers were blinded to the study groups. Baseline blood samples were retrieved before intervention and within 72 hours postoperatively via venipuncture. CIAKI was defined in this study as an absolute increase of ≥0.5 mg/dL or relative increase ≥25% over baseline serum creatinine in a 72-hour period. All patients received prophylaxis administration, 0.9% saline infusions were given 1 mL/kg for 12 hours before and after coronary angiography. This was combined with 600 mg oral vitamin E 12 hours before coronary angiography plus 400 mg 2 hours before intervention or placebo, administered in the same fashion. Maximum dose of 1000 mg vitamin E was used. All coronary interventions used Judkins technique. Iodixanol (Visipaque, GE Healthcare; 320 mg iodine/mL) contrast medium was used for all patients.
Duration	72 hours post-administration of contrast media
Outcome Measures	Primary endpoint: development to CIAKI within 72 hours after coronary angiography
Baseline Characteristics		Placebo (n=149)	Vitamin E (n=149)	p-value
	Age, years	67 ± 10	66 ± 11	0.4
	Male	69 (46.3%	68 (45.6%)	0.9
	Height, m (IQR)	1.62 (1.53-1.7)	1.63 (1.54-1.7)	0.4
	Weight, kg (IQR)	78 (67-84)	75 (67-86)	0.8
	Hypertension	120 (80.5%)	119 (79.9%)	0.8
	Diabetes Mellitus	53 (35.6%)	53 (35.6%)	1
	Hypercholesterolemia	25 (16.8%)	26 (17.4%)	0.8
	Current smoker	34 (22.8%)	29 (19.5%)	0.4
	Congestive Heart Failure	15 (10.1%)	7 (4.7%)	0.076
	Procedural Features Presentation Stable Ischemic Heart Disease (IHD) NSTE-ACS Multivessel disease	62 (41.6%) 87 (58.4%) 45 (30.2%)	48 (32.2%) 101 (67.8%) 48 (32.2%)	0.093 0.7
Results	Endpoint: CIAKI incidence	A	B	p-Value
Results	CIAKI Definitions Serum creatinine ↑ by ≥25% Serum creatinine ↑ by ≥0.5 mg/dL Serum creatinine ↑ by ≥25% or serum creatinine ↑ by ≥0.5 mg/dL eGFR ↓ by ≥25%	21 (14.1%) 20 (13.4%) 21 (14.1%) 20 (13.4%)	10 (6.7%) 8 (5.4%) 10 (6.7%) 10 (6.7%)	0.037 0.017 0.037 0.054
Adverse Events	Side effects relating to interventions were not observed. Two (0.7%) cases of NSTE-ACS were seen in the vitamin E cohort (p=0.5). One (0.35%) patient in the vitamin E cohort experienced ST-segment elevation myocardial infarction, resulting in death.
Study Author Conclusions	Prophylactic short-term high-dose vitamin E combined with 0.9% saline infusion is superior to placebo for prevention of CIAKI in patients undergoing elective coronary angiography.
InpharmD Researcher Critique	The study excluded high-risk patients (such as those requiring dialysis), and therefore should not be extrapolated to patients who requiring renal replacement therapy (RRT). Also, study researchers did not collect patients' vitamin E serum levels.

References:

Rezaei Y, Khademvatani K, Rahimi B, Khoshfetrat M, Arjmand N, Seyyed-Mohammadzad MH. Short-Term High-Dose Vitamin E to Prevent Contrast Medium-Induced Acute Kidney Injury in Patients With Chronic Kidney Disease Undergoing Elective Coronary Angiography: A Randomized Placebo-Controlled Trial. J Am Heart Assoc. 2016;5(3):e002919. Published 2016 Mar 15. doi:10.1161/JAHA.115.002919