Discussion
This meta-analysis of the RCTs demonstrates that hydration with PO fluids is as effective as hydration with IV fluids in prevention of CIN. This is important since administration of IV fluids requires hospitalisation that is economically burdensome, whereas taking PO fluids can be done at home. PO hydration is currently more relevant since most of the procedures using radiocontrast, such as CT, cardiac catheterisations, percutaneous coronary interventions and other vascular procedures by interventional radiology, are conducted on an outpatient basis.17 CKD is an important risk factor for CIN;18 nevertheless, this analysis shows that PO hydration is at least as effective as IV hydration in patients with both CKD and normal kidney function.
There were three trials, one with patients with CKD8 and two with normal kidney function,5 ,11 which reported change in serum creatinine and were conducted exclusively on patients undergoing a coronary angiogram. These trials have shown that there was a significantly lower rise in serum creatinine in the PO hydration group compared with the IV hydration group. However, there was a significant heterogeneity among the trials and the results need to be interpreted with caution. There were insufficient data to perform a meta-regression analysis to explore the heterogeneity on the level of the reported rise in serum creatinine results in regard to baseline gender and the use of renin–angiotensin–aldosterone system (RAAS) blockade and diuretics. However, a meta-regression of these three studies including the baseline characteristics of age, history of type 2 diabetes mellitus, baseline serum creatinine and contrast volume showed no heterogeneity (p>0.05). None of the patients required dialysis in either arm among the four trials reporting data on this outcome.5 ,6 ,8 ,11 However, some studies presented data on the length of hospitalisation. Cho et al7 reported no significant difference in length of hospitalisation (4.1 days in the IV arm vs 5.6 days in the PO arm). Trivedi et al5 did not report the length of hospitalisation but reported that one patient in the IV arm and three patients in the PO arm had extended hospital stay due to CIN.
The incidence of CIN in our study population is 8%, which is higher than the reported incidence of <2% in the general population but in high-risk populations with congestive heart failure, CKD, diabetes mellitus and anaemia, its incidence has been reported up to 20–30%.3 Our study population was at a relatively increased risk compared with the general population with 42.3% with diabetes and 63.7% with CKD who are at a higher risk than the population without diabetes and normal kidney function.18 The incidence of CIN among the patients with normal renal function was 9.8% and was especially high in the PO hydration arm (13.2%) which is probably skewed by the results from Trivedi et al. The reported incidence of CIN in the study was 18.9% with 34.6% in the PO hydration arm and 3.7% in the IV hydration arm. Incidentally, this is the only study included in the analysis to suggest that IV hydration is more effective than PO hydration.5 Trivedi et al acknowledge that the incidence of CIN in their study is higher than the reported incidence and the authors attribute it to sicker study population with 39–48% of patients had acute myocardial infarction and 42–52% were admitted to intensive care unit. The PO hydration arm had unrestricted fluid access; however, the amount consumed was not recorded, so it is plausible that this group was not adequately hydrated, contributing to a higher incidence of CIN in this group. Even though there was no statistical significant difference in baseline serum creatinine between both arms, the PO arm had a higher baseline serum creatinine and wider range of distribution (1.27±0. 37) compared with the IV arm (1.14±0.24) which could have contributed towards the higher incidence of CIN. Furthermore, the initial results could have occurred by chance in the interim analysis which may not have persisted if the trial was not terminated prematurely only after the enrolment of one-third of the expected study population.
Isotonic normal saline is known to be more protective in the prevention of CIN than an equivalent amount of hypotonic saline,19 and all the trials in our analysis used normal saline for IV hydration but different regimens. Cho et al7 administered a bolus of IV normal saline solution over 1 h prior to contrast administration, while others used a continuous regimen of IV fluids beginning 6 h6 ,8 or 12 h5 ,11 prior to the procedure. The PO hydration protocol varied greatly, with no two trials having a similar PO regimen. Except for Trivedi et al,5 who recommended unrestricted PO fluids, all other trials had prespecified outpatient PO regimens. Dussol et al6 used salt tablets (1 g/10 kg of body weight/day) for 48 h before procedure; Wrobel et al8 administered mineral water (1 mL/kg/h) starting 6–12 h before, during and 12 h after procedure while Cho et al7 recommended at least 1100 mL of regular water with 500 mL 4 h prior to and 600 mL after the procedure; and Kong et al11 recommended 2000 or 2500 mL of water with at least 2000 mL of hydration postprocedure (table 1).
Comparison with other meta-analysis
There were two meta-analyses published so far which included six trials.9 ,10 Our study is more representative of a comparison of PO and IV hydration regimens since we excluded two trials as they did not meet our inclusion criteria, as the patients received additional treatments along with hydration but were included in the prior analyses. PREPARED trial20 was excluded as the PO hydration arm received additional IV hydration with half normal saline and RCT by Lawlor et al21 was excluded since they administered N-acetyl cysteine in addition to the hydration regimen. One additional randomised trial has been published since the prior meta-analysis.11 We have also performed the subgroup analysis of patients with normal kidney function and CKD at enrolment and calculated the SMD for change in creatinine along with a meta-regression to study the heterogeneity across the studies.
Hydration in general has been accepted as the cornerstone to prevent CIN; however, there is no consensus regarding the mode of administration. As illustrated in ours and prior meta-analyses, PO fluids are as effective as IV fluids. However, the data is based on only a few small studies with some inherent bias which is limiting their ability to change the practice. Hence, larger multicentre and higher quality randomised clinical trials are necessary to change the practice. In modern medicine, with an evolving number of diagnostic studies that depend on iodinated contrast along with an increasing number of complex high-risk patients, CIN is becoming a common cause of iatrogenic harm, so much so that even small improvements would lead to large reductions in CIN and thus better patient care. Similarly, costs of hospitalisations, nursing care and IV medication are increasing and since PO hydration has similar efficacy to IV fluids in preventing CIN, its wide-spread acceptance will have a greater impact on procedural costs.
Limitations
As with any meta-analysis, conclusions drawn are subject to the limitations of the original studies. Patient-level data were not available precluding subgroup analysis and the use of metaregression to evaluate the heterogeneity in baseline characteristics across the studies is not perfect and only tells us that the trend seen in outcome was irrespective statistically from the variance noted in the baseline characteristics. The evidence is based on a small number of clinical trials and patients with stages 4 and 5 CKD and left ventricular systolic dysfunction were not represented, making it less applicable to these groups. PO and IV hydration regimens were too diverse to make specific recommendations. There was significant heterogeneity among the trial, especially in calculating the SMD for change in creatinine, which was hard to explore due to the limited number of studies and reported baseline characteristics. The trials included in the analysis are of low-to-moderate quality.
