Parameters
Yes
No
Comment
Validity
Is the Randomization Procedure well described?
+1
1:1 to acetylcysteine or placebo generated by permuted blocks of variable size and stratified by site
Double blinded?
+2
Healthcare staff, data collectors, and outcome assessors were all blinded
Is the sample size calculation described/adequate?
+3
Estimated event rate of 15 % based on a prior meta-analysis. To detect 30 % relative risk reduction with 90 % power strived to include 2,300 patients
Does it have a hard primary end point?
+.5
25 % elevation of serum creatinine above baseline 48–96 h after angiography
Is the end point surrogate?
0
Is the follow-up appropriate?
+1
Followed to 30 days for mortality and need for RRT
Was there a Bias?
+2
Is the dropout >25 %?
+1
36 patients did not have primary end point follow-up; 29 patients did not return to collect serum creatinine
Is the analysis ITT?
+3
Utility/usefulness
Can the findings be generalized?
+1
Only 5 % had eGFR <30 so this may not be generalized to the highest risk population
Was the NNT <100?
N/a: negative study
Score
97 %
Well-designed and well-conducted study
Summary and Conclusions
Acetylcysteine is a vasodilator and antioxidant that has been extensively investigated for the prevention of contrast-induced acute kidney injury (CIAKI). This study builds on the data from previous studies that demonstrated benefits of the agent in CIAKI. In 2000, Tepel et al. randomized 83 patients undergoing contrast-enhanced CT scanning to either oral acetylcysteine 600 mg twice daily on the day before and the day of the CT scan or placebo. They found that acetylcysteine in combination with adequate hydration reduced the incidence of CIAKI from 21 to 2 %, with a relative risk reduction of 90.5 % [1]. Since this seminal paper, more than 40 RCTs have compared acetylcysteine to placebo on the impact of patient mortality, need for RRT, or prevention of CIAKI. Unfortunately, these clinical trials have resulted in conflicting results with some finding substantial benefit, while others reporting no effect [2, 3]. Many of these trials were small and underpowered, so meta-analyses were performed in an attempt to improve the estimate of treatment effect [4]. Seven out of 11 meta-analyses found a net benefit of acetylcysteine for prevention of CIAKI, with some reporting up to 50 % relative risk reduction. However, there was significant clinical heterogeneity among the pooled RCTs. Meta-analyses that reported benefits of acetylcysteine generally did not account for heterogeneity between included trials [5]. As a result, treatment recommendations were difficult to make. This called for larger, well-powered, multicenter studies in order to clarify the muddy literature and determine the true effect of acetylcysteine in contrast nephropathy.
The ACT is the largest multicenter, double-blinded RCT testing the effects of acetylcysteine for the prevention of CIAKI to date. The authors decided on oral acetylcysteine 1,200 mg twice daily because of previous trials that showed benefit at higher doses [6]. There was no difference in the development of CIAKI, defined as a ≥25% increase above baseline in serum creatinine within 48–96 h after angiography. Secondary end points, including death and the need for dialysis at 30 days, were also similar.
This trial has noteworthy strengths including a large sample size, adequately powered; 98 % of patients with complete follow-up; and a 95 % compliance with study drugs. In addition, the trial represented a population at risk for CIAKI with 60 % with history of diabetes, 85 % with hypertension, and 10 % with known heart failure. Thus, the target population at high risk of CIAKI is included in this study.
Nonetheless, there are some drawbacks that limit the generalizability of this trial. Although the trial included 823 patients who had CKD, a majority of patients had mild CKD with eGFR 30–60. In fact, only 5 % of the patients had an eGFR <30. Therefore, ACT was underpowered to exclude a benefit of acetylcysteine for patients at highest risk for AKI [7]. Furthermore, albuminuria (urine albumin to creatinine ration UACR) was not factored in, despite it being a known risk factor. In addition, the baseline creatinine was obtained several months prior to enrolment, so that baseline renal function as reported may not be accurate in a temporal sense.
At present, there is no evidence that either oral or intravenous acetylcysteine can alter mortality or need for RRT after contrast-media administration to patients at risk for CIAKI [7]. Despite the lack of convincing evidence for benefit, the 2012 KDIGO guidelines suggest administration of acetylcysteine to patients at high risk as the agent is potentially beneficial, well-tolerated, and inexpensive [7]. This study suggests that despite these recommendations, it is not likely that the agent is of benefit. Given the quality and the totality of accumulating evidence, the use of N-acetylcysteine should not be recommended in guidelines, despite the acknowledgment that the medication is unlikely to be of harm.
Contrast Induced Acute Kidney Injury: Type of Contrast Media
Publication: Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial
Author: Rudnick M et al.
Reference: Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA, Winniford M, Cohen MB, VanFossen DB. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int. 1995;47(1):254–61.
Abstract
The incidence of nephrotoxicity occurring with the nonionic contrast agent, iohexol, and the ionic contrast agent, meglumine/sodium diatrizoate, was compared in 1,196 patients undergoing cardiac angiography in a prospective, randomized, double-blind multicenter trial. Patients were stratified into four groups: renal insufficiency (RI), diabetes mellitus (DM) both absent (N = 364); RI absent, DM present (N = 318); RI present, DM absent (N = 298); and RI and DM both present (N = 216). Serum creatinine levels were measured at −18–24, 0, and 24, 48, and 72 h following contrast administration. Prophylactic hydration was administered pre- and post-angiography. Acute nephrotoxicity (increase in serum creatinine of ≥1 mg/dl 48–72 h post-contrast) was observed in 42 (7 %) patients receiving diatrizoate compared to 19 (3 %) patients receiving iohexol, P < 0.002. Differences in nephrotoxicity between the two contrast groups were confined to patients with RI alone or combined with DM. In a multivariate analysis, baseline serum creatinine, male gender, DM, volume of contrast agent, and RI were independently related to the risk of nephrotoxicity. Patients with RI receiving diatrizoate were 3.3 times as likely to develop acute nephrotoxicity compared to those receiving iohexol. Clinically severe adverse renal events were uncommon (N = 15) and did not differ in incidence between contrast groups (iohexol N = 6; diatrizoate N = 9). In conclusion, in patients undergoing cardiac angiography, only those with preexisting RI alone or combined with DM are at higher risk for acute contrast nephrotoxicity
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | −1 | No description given of randomization or allocation concealment. However, groups were well balanced in characteristics | |
Double blinded? | +2 | Article claims it to be but not described | |
Is the sample size calculation described/adequate? | +3 | Overall, 90 % power to detect difference of 10 and 5 %. Sample size 290 per each 4 groups provides 80 % for incidence of 15 and 7.5 % | |
Does it have a hard primary end point? | +.5 | Increase in creatinine of 1 mg/dl or more within 48–72 h | |
Is the end point surrogate? | 0 | ||
Is the follow-up appropriate? | −1 | Follow up was from 48 to 72 h. 99 % had renal data at 48 h, but only 27 % had renal data at 72 h. No other clinical outcome data were recorded. This may have missed any CIAKI occurring after 48 h | |
Was there a Bias? | +2 | Well balanced characteristics | |
Is the dropout <25 %? | +1 | Paper did not specify how many were lost to follow-up explicitly, but out of 1,196 enrolled, 1,183 had outcome data in final analysis | |
Is the analysis ITT? | −3 | Not stated | |
Utility/usefulness | |||
Can the findings be generalized? | +1 | ||
Was the NNT <100? | +1 | NNT = 26 overall; NNT = 6 in those with CKD and DM2 | |
Score | 28 % | Study with serious limitations | |
Summary and Conclusions
The osmolality of a contrast medium (CM) has been implicated in the pathophysiology of CIAKI. Hyperosmolar CM can cause direct injury of renal tubular cells if tubular fluid osmolality is more than its surrounding medullary osmolality. High osmolality may increase the intrinsic cytotoxicity of CM [8]. In addition, increased osmotic work load increases renal oxygen consumption by enhanced tubular sodium reabsorption, contributing to medullary hypoxia [9]. Finally, higher osmolality contributes to medullary hypoperfusion by changing the shape and rigidity of erythrocytes, making its passage through small renal vessels more difficult.
Contrast media are tri-iodinated benzene derivatives that use iodine for their radiopacity. Since a minimum concentration of iodine (250–400 mg I/mL) is required to achieve adequate opacification, the ratio of iodine atoms to dissolved particles and the iconicity of any contrast medium determine its osmolality [10]. High osmolality CM are ionic monomers with very high osmolalities ranging from 1,500 to 2,000 mOsm/kg. Second-generation low osmolar CM were developed using ionic dimers or nonionic monomers. Low osmolar CM achieved an osmolality of 500–850 mosmol/kg, which is still higher than that of plasma.
The best data comparing ionic, high osmolality contrast to nonionic low osmolality contrast iohexol in CI-AKI comes from Rudnick et al. Patients undergoing non-emergent diagnostic cardiac angiography stratified into four groups based on whether they had diabetes or CKD (defined as Scr >1.5 mg/dl for more than 6 weeks): Group 1: Non-diabetic and no CKD; Group 2 Diabetic and no CKD; Group 3: Nondiabetic and CKD; Group 4 Diabetic and CKD. Each of the four groups randomly received either high or low osmolar CM. The authors found that the nonionic, low osmolar CM was associated with significantly less nephrotoxicity than ionic, high osmolar CM in high-risk patients (CKD and diabetes) undergoing elective cardiac angiography.
The results of this landmark study revealed several important facts that have now become widely accepted in clinical practice. The realization that high osmolar contrast agents are associated with an increased risk of CIAKI has led to the use of low or iso-osmolar CM in the Western world [11]. However, studies comparing the nephrotoxicity of low osmolar versus iso-osmolar CM have been conflicting and unresolved.
Secondly, this study identified the fact that baseline renal impairment is the principal risk factor for CIAKI. This potentially heightens our awareness of the need to identify patients with decreased kidney function prior to the administration of contrast. This premise is key to many of the current guideline recommendations from national and international radiology groups. The identification of high-risk groups is essential in order to target preventive care. Diabetes is also a risk multiplier for CIAKI in a patient with CKD. Finally, the study found that higher volumes of contrast increased the risk of CIAKI. Subsequent studies also confirmed this finding.
Thus, KDIGO recommendations are that it is important to minimize contrast exposure in high-risk patients. Despite this, there is an important caveat: studies have suggested that concern over contrast-induced AKI leads to underutilization of imaging techniques, particularly coronary angiography, in high-risk patients with CKD [12] and that this ultimately may adversely impact patient care. The final decision to undergo diagnostic or therapeutic interventions with contrast exposure should be individualized, after considering risks and benefits and recognizing that the CIAKI can be mitigated with a number of strategies. The totality of evidence would suggest that performing contrast studies in CKD patients with appropriate proactive interventions would be prudent, where the information would be used to guide care.
Contrast Induced Acute Kidney Injury: Effects of Intravenous Hydration
Publication: Effects of hydration in contrast-induced acute kidney injury after primary angioplasty: a randomized, controlled trial.
Author: Maioli M, Toso A, Leoncini M, Gallopin M, Tedeschi D, Micheletti C, Bellandi F
Reference: Maioli M, Toso A, Leoncini M, Micheletti C, Bellandi F. Effects of hydration in contrast-induced acute kidney injury after primary angioplasty: a randomized, controlled trial. Circ Cardiovasc Interv. 2011;4(5):456–62.
Abstract
Background: Intravascular volume expansion represents a beneficial measure against contrast-induced acute kidney injury (CI-AKI) in patients undergoing elective angiographic procedures. However, the efficacy of this preventive strategy has not yet been established for patients with ST-elevation myocardial infarction (STEMI), who are at higher risk of this complication after primary percutaneous coronary intervention (PCI). In this randomized study we investigated the possible beneficial role of periprocedural intravenous volume expansion and we compared the efficacy of two different hydration strategies in patients with STEMI undergoing primary PCI. Methods and Results: We randomly assigned 450 STEMI patients to receive (1) preprocedure and postprocedure hydration of sodium bicarbonate (early hydration group), (2) postprocedure hydration of isotonic saline (late hydration group), or (3) no hydration (control group). The primary end point was the development of CI-AKI, defined as an increase in serum creatinine of ≥25 % or 0.5 mg/dL over the baseline value within 3 days after administration of the contrast medium. Moreover, we evaluated a possible relationship between the occurrence of CI-AKI and total hydration volume administered. There were no significant differences in baseline clinical, biochemical, and procedural characteristics in the three groups. Overall, CI-AKI occurred in 93 patients (20.6 %): the incidence was significantly lower in the early hydration group (12 %) with respect to both the late hydration group (22.7 %) and the control group (27.3 %) (P for trend = 0.001). In hydrated patients (early and late hydration groups), lower infused volumes were associated with a significant increase in CI-AKI incidence, and the optimal cutoff point of hydration volume that best discriminates patients at higher risk was ≤960 mL.
Conclusions: Adequate intravenous volume expansion may prevent CI-AKI in patients undergoing primary PCI. A regimen of preprocedure and postprocedure hydration therapy with sodium bicarbonate appears to be more efficacious than postprocedure hydration only with isotonic saline.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | +1 | ||
Double blinded? | −2 | ||
Is the sample size calculation described/adequate? | +3 | Powered to detect reduction of the primary end point of CIAKI from 25 % in the control group to 12.5 % in the hydration groups. The inclusion of 130 patients in each group allowed for a statistical power of 80 % | |
Does it have a hard primary end point? | +.5 | Primary end point of the study was the development of CI-AKI, defined as an increase in serum creatinine of >25 % or 0.5 mg/dL over the baseline value within 3 days after administration of contrast medium | |
Is the end point surrogate? | 0 | CIAKI incidence was only outcome. No mortality/morbidity or long-term outcome | |
Is the follow-up appropriate? | +1 | ||
Was there a Bias? | +2 | Despite using sodium bicarbonate for early hydration group and NS for late hydration group | |
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | −3 | Not explicitly stated | |
Utility/usefulness | |||
Can the findings be generalized? | +1 | Generalizable to PCI population, but single-center study | |
Was the NNT <100? | +1 | NNT = 7 | |
Score | 40 % | Study with limitations | |
Summary and Conclusions
The protective effect of volume expansion in patients at risk for CIAKI come from the cumulative evidence of animal studies, observational analyses, and randomized clinical trials [13]. However, the exact mechanism by which volume expansion protects against CIAKI is speculative and remains unknown. Volume expansion may ameliorate the vasoconstrictive and cytotoxic effects of contrast through dilution. Maioli et al. conducted a three-arm open-label, single-center RCT to investigate the effect of intravenous hydration in patients at risk for CIAKI.
Patients presenting with STEMI undergoing urgent primary PCI, a particularly high-risk group, were randomly assigned in a 1:1:1 ratio to early hydration, late hydration, or no hydration. The early hydration group received a bolus of 3 cc/kg of sodium bicarbonate for a total of 1 h before PCI, followed by 1 cc/kg infusion for 12 h after PCI. The late hydration group received 0.9 % normal saline at 1 cc/kg for 12 after PCI. The decision to use sodium bicarbonate as a rapid bolus and normal saline as a slow infusion was based on the study done by Merten et al. Hydration rate was reduced to 0.5 mL/kg/h in patients with ejection fraction <40 % or NYHA class III–IV.
The early hydration had significantly less CIAKI compared to both late hydration and no hydration groups (12 % vs. 22 % and 27 %, respectively). The total volume of fluid administered had the greatest impact on the incidence of CIAKI. For instance, when patients were divided into tertiles of total volume of fluids received, the authors observed that those who received more volume had a lower incidence of CIAKI. Importantly, CIAKI rates were similar between early and late hydration groups when separated into tertiles of volume administered, suggesting the timing of fluid administration may be of less importance. A hydration volume of <960 cc was identified as the optimal cutoff point to predict risk for CIAKI incidence. Major adverse outcomes including mortality, need for hemofiltration, cardiogenic shock, and repeat vascularization did not differ between the three groups. Furthermore, patients with CIAKI had significantly higher mortality, cardiogenic shock, and longer hospitalization.
The significant benefit derived from volume expansion may have been partially due to the rehydration of those patients whose intravascular volume was depleted due to nausea, diaphoresis, or decreased oral intake. Volume resuscitation may have also benefitted those who were in preload-dependent cardiogenic shock.
This trial, focused on a high-risk patient group, has elegantly demonstrated that periprocedural volume expansion appears to mitigate the risk for CIAKI. Another randomized controlled trial of 1,620 patients undergoing elective and emergent cardiac angiography also found that volume expansion with NS was more beneficial than half NS [14]. Furthermore, the hydration protocol used in this trial did not result in more adverse events such as heart failure. The optimal volume administered probably needs to be individualized, but the results of this study estimate that 1 L of isotonic crystalloid is reasonable and safe in hydration protocols in high-risk patients undergoing contrast administration.
Contrast Induced Acute Kidney Injury: Comparison of Sodium Bicarbonate Versus Normal Saline in Prevention of Contrast Nephropathy
Publication: Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial
Authors: Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N, Ree M, Shah AI, Burchette RJ
Reference: : Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N, Ree M, Shah AI, Burchette RJ (2008) Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial. JAMA 2008;300(9):1038–46.
Abstract
Context: Sodium bicarbonate has been suggested as a possible strategy for prevention of contrast medium-induced nephropathy, a common cause of renal failure associated with prolonged hospitalization, increased health care costs, and substantial morbidity and mortality.
Objectives: To determine if sodium bicarbonate is superior to sodium chloride for preventing contrast medium-induced nephropathy in patients with moderate to severe chronic kidney dysfunction who are undergoing coronary angiography.Design, Setting, and Patients: Randomized, controlled, single-blind study conducted between January 2, 2006, and January 31, 2007, and enrolling 353 patients with stable renal disease who were undergoing coronary angiography at a single US center. Included patients were 18 years or older and had an estimated glomerular filtration rate of 60 mL/min per 1.73 m(2) or less and 1 or more of diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years.
Interventions: Patients were randomized to receive either sodium chloride (n=178) or sodium bicarbonate (n=175) administered at the same rate (3 mL/kg for 1 hour before coronary angiography, decreased to 1.5 mL/kg per hour during the procedure and for 4 hours after the completion of the procedure).
Main outcome measure: The primary end point was a 25 % or greater decrease in the estimated glomerular filtration rate on days 1 through 4 after contrast exposure.
Results: Median patient age was 71 (interquartile range, 65–76) years, and 45 % had diabetes mellitus. The groups were well matched for baseline characteristics. The primary end point was met in 13.3 % of the sodium bicarbonate group and 14.6 % of the sodium chloride group (relative risk, 0.94; 95 % confidence interval, 0.55–1.60; P = .82). In patients randomized to receive sodium bicarbonate vs. sodium chloride, the rates of death, dialysis, myocardial infarction, and cerebrovascular events did not differ significantly at 30 days (1.7 % vs. 1.7 %, 0.6 % vs. 1.1 %, 0.6 % vs. 0 %, and 0 % vs. 2.2 %, respectively) or at 30 days to 6 months (0.6 % vs. 2.3 %, 0.6 % vs. 1.1 %, 0.6 % vs. 2.3 %, and 0.6 % vs. 1.7 %, respectively) (P > .10 for all).
Conclusions: The results of this study do not suggest that hydration with sodium bicarbonate is superior to hydration with sodium chloride for the prevention of contrast medium-induced nephropathy in patients with moderate to severe chronic kidney disease who are undergoing coronary angiography.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | +1 | Yes | |
Double blinded? | −2 | Patient not blinded. Physician and lab personnel blinded | |
Is the sample size calculation described/adequate? | +3 | ||
Does it have a hard primary end point? | +1 | Outcome of 25 % reduction in eGFR, 25 % increase in serum creatinine, 30 day mortality and need for RRT | |
Is the end point surrogate? | 0 | ||
Is the follow-up appropriate? | +1 | Clinical outcomes followed for up to 6 months post study | |
Was there a Bias? | +2 | ||
Is the dropout <25 %? | +1 | No loss to follow up. But 12 % of patients had no baseline eGFR and excluded | |
Is the analysis ITT? | +3 | Yes | |
Utility/usefulness | |||
Can the findings be generalized? | +1 | Patients for elective PCI, single-center study | |
Was the NNT <100? | N/a: negative study | ||
Score | 73 % | Well-designed and well-conducted study | |
Summary and Conclusions
The alkalizing property of sodium bicarbonate solutions has been thought to give protection against free radicals. There has been considerable interest regarding the use of sodium bicarbonate in the prevention of CIAKI.
Brar et al. conducted the best randomized controlled trial to date addressing this question. The trial was a single-center, single-blind study that randomized 353 patients undergoing elective coronary angiography to either saline or sodium bicarbonate before and after iso-osmolar contrast medium administration. Importantly, the infusion protocol was identical for both fluid types.
The overall rate of CIAKI, defined by a >25 % reduction of eGFR or >25 % increase of serum creatinine, was similar in both groups. The overall mortality at 6 months was 3.1 % among all randomized patients vs. 9.8 % among the patients developing contrast-induced nephropathy. At 6 months follow-up, the mortality rate was similar between sodium chloride and sodium bicarbonate (3.9 % and 2.3). Only six patients needed dialysis at 6 months with similar rates between the two groups. Notably, all four patients who needed dialysis due to CIAKI died at 6 months, illustrating that the need for dialysis after CIAKI portends a poor prognosis after PCI.
A major strength of this study is that it reported clinical adverse events at 30 days and 6 months after contrast exposure among all randomized patients. Most previous trials have had limited follow-up post contrast administration. The trial was adequately powered and met its enrolment goals.
The population represented in this trial was at moderate risk for CIAKI. The trial excluded very high-risk patient populations, such as those with cardiogenic shock and acute myocardial infarction. Also, only ~6 % of patients had severe renal impairment eGFR <30 at baseline. Other limitations included the fact the physicians performing the procedure were not blinded and its single-center design.
The cumulative evidence from several meta-analyses and randomized controlled trials examining the benefit of sodium bicarbonate in CIKAI yields conflicting results. A systematic review recently concluded a lack of evidence for sodium bicarbonate. It commented that the earlier, smaller trials tended to show more benefit, whereas more recent, larger trials showed neutral effect [15, 16]. Since no trial has demonstrated that sodium bicarbonate is inferior to normal saline, the most recent KDIGO recommendations are that either normal saline or sodium bicarbonate can be used in high-risk patients [17]. However, since isotonic bicarbonate solutions are not as readily available, there is a potential for mixing errors with using sodium bicarbonate.
Thus, pragmatically, any isotonic hydration strategy may be of benefit. Difficulties with access and mixing issues are not seen with the use of premixed normal saline. In addition, depending on the facility, preparation of isotonic sodium bicarbonate solutions takes time and resources. Given the totality of evidence, it may be that isotonic saline solution may be preferable in emergent situations prior to contrast administration. Nonetheless, any hydration protocol is better than no hydration protocol in vulnerable populations.
Prevention of Acute Kidney Injury: Role of Loop Diuretics
Publication: High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial
Authors: Cantarovich F, Rangoonwala B (High-Dose Furosemide in Acute Renal Failure Study Group)
Reference: Cantarovich F, Rangoonwala B, Lorenz H, Verho M, Esnault VLM, High-Dose Furosemide in Acute Renal Failure Study G. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis. 2004;44(3):402–9.
Abstract
Background: The effect of furosemide on the survival and renal recovery of patients presenting with acute renal failure (ARF) is still debated.
Methods: Three hundred thirty-eight patients with ARF requiring dialysis therapy were randomly assigned to the administration of either furosemide (25 mg/kg/day intravenously or 35 mg/kg/day orally) or matched placebo, with stratification according to severity at presentation. The primary end point was survival. The secondary end point was number of dialysis sessions. Tertiary end points included time on dialysis therapy, time to achieve a serum creatinine level less than 2.26 mg/dL (<200 μmol/l), and time to reach a 2 L/day diuresis.
Results: There were no differences in survival and renal recovery rates between the two groups. Time to achieve a 2-L/day diuresis was shorter with furosemide (5.7 ± 5.8 days) than placebo (7.8 ± 6.8 days; P = 0.004). Overall, 148 patients achieved a urine output of at least 2 L/day during the study period (94 of 166 patients; 57 %) with furosemide versus 54 of 164 patients (33 %) with placebo (P < 0.001). However, there were no significant differences in number of dialysis sessions and time on dialysis therapy between the furosemide and placebo groups, even in the subgroup of patients reaching a 2-L/day diuresis.
Conclusion: High-dose furosemide helps maintain urinary output, but does not have an impact on the survival and renal recovery rate of patients with established ARF.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | −1 | Assigned by “random plan” and stratified based on severity of illness. Allocation concealment not fully described | |
Double blinded? | +2 | A pharmaceutical company provided blinded medications | |
Is the sample size calculation described/adequate? | +3 | 80 % power, 45 % of event rate, 15 % difference | |
Does it have a hard primary end point? | +1 | The primary end point was survival at the end of the 1-month for patients not showing a recovery in renal function or 7 days after RRT discontinuation for patients showing a recovery in renal function | |
Is the end point surrogate? | 0 | ||
Is the follow-up appropriate? | +1 | ||
Was there a Bias? | −2 | Imbalanced baseline characteristics: Lasix group had more diabetics, more severe renal failure, and more septic shock patients | |
Is the dropout <25 %? | +1 | None lost to follow-up | |
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | −1 | AKI due to mostly shock and sepsis. Few diabetics enrolled | |
Was the NNT <100? | N/a: negative study | ||
Score | 33 % | Study with serious limitations | |
Summary and Conclusions
Loop diuretics have been postulated to protect against AKI via several mechanisms. Loop diuretics have been shown in animal models to reduce metabolic demands of injured tubular cells, prevent tubular obstruction by flushing tubular debris, improve renal blood flow, and even attenuate apoptosis in renal tubular cells [18–20]. Also, oliguria is a known poor prognostic indicator in patients with AKI and further increases the risk of death compared to nonoliguric AKI [21, 22]. Oliguric AKI makes fluid management difficult and there is mounting evidence that fluid overload in AKI is independently associated with increased mortality [23]. Therefore, many clinicians wondered whether diuretics converting an oliguric AKI to a nonoliguric one impacts clinical outcomes [24–27].
Catarovich et al. conducted the largest prospective, double-blinded, placebo-controlled trial examining whether furosemide improves the survival rate in patients with established AKI to date. There was no difference in survival or renal recovery at 1 month despite the time to reach 2 L per day of diuresis was shorter in the furosemide arm.
Some key elements of the trial design need to be highlighted. First, this is a study of patients with established ATN since the authors carefully excluded patients with dehydration and prerenal failure using urinary-plasma osmolarity ratio, urinary sodium, and volume filling measurements. Secondly, the trial excluded any patients showing renal recovery, so that all the patients included in the final analysis eventually needed renal replacement therapy. Finally, a high dose of 25 mg/kg furosemide IV to a maximum of 2 g/day was used in the study to ensure effective delivery of the drug to its site of action in the tubular lumen. Interestingly, although this dose was in the upper range when compared prior controlled trials, there were no increased ototoxicity in the furosemide arm.
The results of this trial need to be considered within its limitations. Only a minority of patients, approximately 14 % had diabetes. Baseline renal functions of the patients were not available. Other comorbidities were not mentioned nor controlled for. More importantly, the furosemide and placebo groups were not balanced at randomization: more patients with diabetes and septic shock were in the furosemide arm. Renal impairment was also worse in the furosemide group at randomization, despite being similar before the first dialysis session. These factors may have masked a possible beneficial effect of furosemide.
Despite these limitations, this study in conjunction with other studies reveals that there is no convincing evidence to support the use of loop diuretics in order to attenuate the severity of AKI or improve outcomes. A systematic review and meta-analysis by Ho and Power included six studies that used furosemide to treat AKI, with doses ranging from 600 to 3,400 mg/day [27]. No significant reduction was found for in-hospital mortality or for RRT requirement. Thus, loop diuretics in early or established AKI may help with fluid management, but the strategy does not have proven benefit to attenuate the course of AKI or patient outcomes.
Prevention of Acute Kidney Injury: Synthetic Colloids
Publication: Hydroxyethyl starch or saline for fluid resuscitation in intensive care (CHEST)
Authors: Myburgh et al.
Reference: Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901–11.
Abstract
Background: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.
Methods: We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6 % HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9 % sodium chloride or 0.9 % sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy.
Results: A total of 597 of 3,315 patients (18.0 %) in the HES group and 566 of 3,336 (17.0 %) in the saline group died (relative risk in the HES group, 1.06; 95 % confidence interval [CI], 0.96–1.18; P = 0.26). There was no significant difference in mortality in six predefined subgroups. Renal replacement therapy was used in 235 of 3,352 patients (7.0 %) in the HES group and 196 of 3,375 (5.8 %) in the saline group (relative risk, 1.21; 95 % CI, 1.00–1.45; P = 0.04). In the HES and saline groups, renal injury occurred in 34.6 and 38.0 % of patients, respectively (P = 0.005), and renal failure occurred in 10.4 and 9.2 % of patients, respectively (P = 0.12). HES was associated with significantly more adverse events (5.3 % vs. 2.8 %, P < 0.001).
Conclusions: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6 % HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal replacement therapy.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | +1 | ||
Double blinded? | +2 | ||
Is the sample size calculation described/adequate? | +3 | Power of 90 % to detect an absolute difference of 3.5 percentage points in 90-day mortality on the basis of an estimated baseline mortality of 26 % | |
Does it have a hard primary end point? | +1 | Primary: 90 days mortality. Secondary: incidence of AKI by RIFLE and use of RRT | |
Is the end point surrogate? | 0 | ||
Is the follow-up appropriate? | +1 | ||
Was there a Bias? | +2 | ||
Is the dropout <25 %? | +1 | Approximately 2.5 % were lost to follow-up | |
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | −1 | Almost half of all screened patient excluded in trial, limiting its generalizability | |
Was the NNT <100? | N/a: negative study | ||
Score | 87 % | Well-designed and well-conducted study | |
Summary and Conclusions
Colloids are used in for patients with hypovolemia secondary to sepsis because they are thought to remain in the intravascular space longer and require less amount of fluid for resuscitation compared with crystalloids. Hydroxyethyl starches (HES) are synthetic colloids that vary in concentration, molecular weight, and hydroxyethyl moieties. The concentration of colloid in solution determines its osmotic pressure effect. A 10 % HES is hyper-oncotic to plasma and is a better blood volume expander than 6 % iso-oncotic HES [28]. Recently, concerns about hyper-oncotic HES emerged after RCTs and meta-analyses reported increasing rates of AKI associated with its use [29]. HES may cause AKI by increased uptake of the starch into the proximal renal epithelial cells inducing “osmotic nephrosis-like lesions,” tubular obstruction caused by the production of hyperviscous urine, and renal interstitial inflammation [30]. In addition, high molecular substitution starch may impair coagulation by decreasing factor VIII and vWF. These concerns have led to a widespread usage of iso-oncotic starches with lower molecular and substitution ratios for fluid resuscitation over the last decade in critically ill patients.
However, the large multicenter, double-blinded randomized controlled trial by Myburg et al. demonstrated that iso-oncotic 6 % HES is still associated with an increased risk of AKI compared to crystalloid. The study randomized 7,000 patients admitted to the ICU to receive either 6 % HES (130/0.4) in 0.9 % saline (Voluven) or normal saline for 90 days. The HES group and normal saline group had similar mortality at 90 days (18 % vs. 17 %). Significantly more renal replacement therapy was required in the HES compared to the saline group (7 % vs. 5.8 %), with a number needed to harm of 83. Subgroup analysis showed a trend towards greater mortality in the HES group. Furthermore, HES had higher rates of pruritus and rash. Interestingly the study did not find a large volume sparing effect of HES, in agreement with prior blinded studies.
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Related posts:
Lipids and Chronic Kidney Disease Clinical Trials: A Critical Appraisal
Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical Trials: A Critical Appraisal
Anemia in Chronic Kidney Disease Clinical Trials: A Critical Appraisal
Peritoneal Dialysis Clinical Trials: A Critical Appraisal
Primary Glomerular Disease Clinical Trials: A Critical Appraisal
Lupus Nephritis Clinical Trials: A Critical Appraisal
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
