Edited by: Nicoleta Stoicea, Ohio State University Wexner Medical Center, USA
Reviewed by: Norma Beatriz Ojeda, University of Mississippi Medical Center, USA; Suren Soghomonyan, The Ohio State University Wexner Medical Center, USA; Nicoleta Stoicea, Ohio State University Wexner Medical Center, USA
*Correspondence: Katja R. Turner, Department of Anesthesiology, Wexner Medical Center at the Ohio State University, N411 Doan Hall, 410 W.10th Ave, Columbus, OH 43210, USA e-mail:
This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology.
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Cardiac surgery associated acute kidney injury (CSA-AKI) is associated with poor outcomes including increased mortality, length of hospital stay (LOS) and cost. The incidence of acute kidney injury (AKI) is reported to be between 3 and 30% depending on the definition of AKI. We designed a multicenter randomized controlled trial to test our hypothesis that a perioperative infusion of sodium bicarbonate (SB) during cardiac surgery will attenuate the post-operative rise in creatinine indicating renal injury when compared to a perioperative infusion with normal saline. An interim analysis was performed after data was available on the first 120 participants. A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received sodium chloride (SC) and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6–2.1, chi-square
Cardiac surgery associated acute kidney injury (CSA-AKI) is described as an acute worsening in kidney function observed after cardiac surgery that is associated with poor outcomes (Bellomo et al.,
Preventive techniques for perioperative AKI have traditionally focused on maintenance of hemodynamic stability, repletion of blood and electrolyte imbalances and avoidance of nephrotoxic drugs. Patients presenting for cardiovascular surgery were found to be at increased risk for AKI. Several scoring systems have been developed to stratify patients at increased risk (Higgins et al.,
The renal medulla receives a disproportionate share of renal blood flow (<10% medulla vs. ~90% cortex), making it an environment of relative hypoxia and acidosis, where the urine first becomes acidic. This region includes many of the active transport pumps which require ATP to achieve maintenance of the renal osmotic gradient. For these reasons it is the medulla which is often the initial site of renal injury in perioperative settings involving ischemic acute tubular necrosis (ATN) (Myers and Moran,
We hypothesized that a perioperative infusion of SB will attenuate the post-operative rise in creatinine indicating renal injury. The primary outcome, AKI, was determined based on post-operative changes in creatinine values measured in the bicarbonate group vs. normal saline group. The maximum change in glomerula filtration rate (GFR), LOS, incidence of dialysis, and mortality rate were assessed as secondary outcomes.
This was a multicenter, randomized, controlled trial of IV SB vs. IV normal saline in high risk adult patients requiring cardiovascular surgery to test the hypothesis that SB would be protective against AKI post-operatively. We developed our inclusion criteria based on studies describing patients at risk for developing severe renal dysfunction after requiring cardiovascular surgery (Higgins et al.,
• Calculated GFR ≤ 60 ml/min/m2 (MDRD) (OR) | |
• Any combination of two (2) of the following | |
• Age ≥ 70 | |
• Complex surgery (any of the following) | |
- CABG/Valve | - History of PVD surgery |
- Redo operation | - EF < 35% |
- Deep hypothermic arrest | - DM |
- Prior kidney transplant | - ≥ 2 valves |
- Proximal Aortic surgery (i.e., ascending aortic aneurysm) | |
• Age < 18 | |
• Pre-existing ESRD (dialysis patients) | |
• Pre-op GFR ≤ 15 ml/min/m2 | |
• Pre-op bicarbonate level ≥ 30 mEq/L | |
• Emergency surgery (unable to effectively consent) | |
• Pregnancy | |
• Heart transplant (OHT) | |
• Distal Aortic surgery (i.e., descending aortic aneurysm) | |
• Procedure does not require central venous access |
Patients undergoing cardiovascular surgery who met the inclusion and exclusion criteria were identified pre-operatively by study personnel who explained the study protocol and obtained written informed consent for the trial. Patients eligible for the study were identified more than 12 h prior to elective or urgent surgery to allow enough time to make an informed decision regarding the trial. Qualifying patients were randomized to receive either SB or normal saline (controls) as perioperative infusions. Subjects enrolled in the trial received a weight based pre-operative bolus of the designated fluid followed post-operatively by a weight based infusion of the designated fluid for 22 h. Serum creatinine levels were obtained pre-operatively and then on a daily basis for at least 72 h post-operatively. The serum creatinine level was measured daily using the Jaffe method. Other data collected during the trial period included length of stay in the hospital and need for dialytic therapy for treatment of AKI during hospitalization. The protocol for this prospective randomized controlled multicenter trial was approved by the Wake Forest and Ohio State School of Medicine's Institutional Review Boards and registered with Clinical trials.gov (NCT0048435).
All surgical procedures were performed through a median sternotomy. Equipment used during cardiopulmonary bypass included: a roller pump system (Terumo system I) with trillium coated tubing (Medtronic), a membrane oxygenator (Affinity trillium coated, Medtronic's), and an arterial filter (351 20 micron by Medtronic). The circuit was primed with Plasmalyte A, as well as 10,000 units of unfractionated heparin, 25 mg of Mannitol, and 50 mEq SB with a final pump volume of ~700 ml. The patients were resuscitated with crystalloids (lactated ringer's or normal saline solutions), blood products or colloids (albumin 5%). The patient's maximum blood glucose levels were maintained at <190 mg/dl using insulin infusions ± boluses as deemed necessary. Throughout the procedure, the patients' anesthetic was maintained using volatile anesthetics, benzodiazepines, and narcotics (fentanyl, morphine, and methadone) as per anesthesiologists' preference. Perioperative hemodynamic management targeted either the baseline cardiac output (CO) prior to induction or a CO >2.1 l/min/m2 and a mean arterial blood pressure >60 mmHg. The intraoperative fluid management was directed by the treating anesthesiologist and documented. All clinical data was collected prospectively and entered into a computerized database by the research team.
Those patients allocated to the normal saline arm (controls) underwent a protocol consisting of an initial bolus consisting of 0.154 M NaCl (NS) at 5.0 ml/kg (or a maximum bolus dose of 500 ml to avoid excessive fluid overload) given over 15 min prior to initiation of cardio-pulmonary bypass. Following the bolus, these patients were infused with NS (0.154 M) at a rate of 1.0 ml/kg/h (or a maximum rate of infusion of 125 mL/min to avoid excessive fluid overload) for a total of 10 h, and decreased to 0.4 ml/kg/h for a remaining 12 h; essentially until the following day. Those patients allocated to the SB (NaHCO3) arm received a 0.150 M NaHCO3 solution prepared in a sterile water base. Bicarbonate solution was prepared by a central pharmacy at each site. Blinding of clinical staff to treatment arm was not performed as the data collected in the study was objective data. This protocol consisted of an initial bolus of 0.150 M NaHCO3 at 5.0 ml/kg (or a maximum bolus dose of 500 ml) given prior to initiation of cardio-pulmonary bypass, followed by a 0.150 M NaHCO3 infusion at a rate of 1.0 ml/kg/h (or a maximum rate of infusion of 125 mL/min) for a total of 10 h followed by a NaHCO3 infusion of 0.4 ml/kg/h for another 12 h, as was done with the NS treated patients. The goal bicarbonate dose in this study was ~3.0 mEq/kg. This dose was based on what our group found to be efficacious in our previous studies (Fisher et al.,
This protocol consisted of ~22 h of IV study infusion. Any other IV fluid that the respective surgeons or anesthesiologists deemed necessary was allowed as part of routine patient management. For those patients felt to be volume overloaded, the randomized fluid was reduced to 10 mL per hour until the clinical conditions allow the higher rate to be resumed.
The primary outcome of the trial was to determine the rate of AKI in the study population. The study sample size was determined based on previous information in a high risk population. Historic data reported rates of ARF, defined arbitrarily as a change in SCr ≥ 1.0 mg/dL, to be ~11.7% in patients treated with sodium chloride (SC) and 2.7% in patients treated with the bicarbonate solution (Fisher et al.,
After the study was initiated, a consensus definition of AKI was introduced in 2004 (RIFLE) and subsequently modified based on the AKIN staging system (Mehta et al.,
Secondary endpoints of interest include the maximum change in estimated serum creatinine and the glomerular filtration rate (GFR) during the first 72 h post-operatively, LOS, incidence of dialysis (HD) and mortality.
At the interim time, we tested the hypothesis of a difference in the proportion of patients with any AKI between treatment groups, as described by the AKIN staging system (AKI as a 1.5 fold or ≥0.3 mg/dl increase in serum creatinine from baseline). Data from 120 patients was available for analysis (2 patients did not have post-surgery creatinine measurements recorded at OSU—one in each treatment arm). AKI was observed in 31 (26%) of patients, with nearly equal numbers in each randomized group [14 in the normal saline (24%), 17 in the SB group (27%)], resulting in an interim test
The primary analysis of AKI rates between treatment groups was evaluated by the chi-squared test and included estimates of the relative risk and associated 95% confidence intervals. Secondary outcomes included length of stay and maximum change in GFR which were compared by a two-sample
Patients were recruited to the study between August 2006 and February 2011. Patient characteristics of the study population are shown in Table
Age, years |
69.7 (13.5) | 70.2 (12.6) |
Sex | ||
Female | 16 (27%) | 30 (47%) |
Male | 43 (73%) | 34 (53%) |
Race | ||
White | 47 (80%) | 57 (89%) |
Black | 9 (15%) | 5 (8%) |
Unknown | 3 (5%) | 2 (3%) |
Weight, kg |
90.2 (19.5) | 85.4 (18.4) |
Site | ||
OSU | 36 (61%) | 35 (55%) |
Wake Forest | 23 (39%) | 29 (45%) |
Previous CV surgery | 13 (22%) | 22 (34%) |
Previous PVD surgery | 5 (8%) | 7 (11%) |
History of kidney disease | 2 (3%) | 0 (0%) |
History of HTN | 51 (86%) | 51 (80%) |
History of DM | 26 (44%) | 30 (47%) |
History of COPD | 6 (10%) | 12 (19%) |
History of MI | 13 (22%) | 10 (16%) |
Aprotinin | 14 (24%) | 16 (25%) |
Amicar | 18 (31%) | 13 (20%) |
Contrast | 30 (51%) | 34 (53%) |
Plasma creatinine mg/dl |
1.2 (0.5) | 1.0 (0.4) |
Plasma HCO3 |
25.8 (3.1) | 26.1 (3.0) |
Plasma CA |
8.2 (1.8) | 8.2 (1.8) |
Plasma K |
4.3 (0.4) | 4.2 (0.4) |
Due to slow enrollment, the study team and independent clinical ethicist agreed to perform an interim analysis once 120 subjects were enrolled to determine if treatment efficacy had been met. A total of 123 patients were enrolled between the two centers to either receive intravenous SB (
A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received SC and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6–2.1, chi-square
No | 36 (62%) | 42 (68%) | 1.0 |
Yes | 22 (38%) | 20 (32%) | 0.9 (0.5–1.4) |
No | 55 (95%) | 55 (89%) | 1.0 |
Yes | 3 (5%) | 7 (11%) | 2.2 (0.6–8.0) |
No | 44 (76%) | 45 (73%) | 1.0 |
Yes | 14 (24%) | 17 (27%) | 1.1 (0.6–2.1) |
No | 47 (81%) | 44 (71%) | 1.0 |
Yes | 11 (19%) | 18 (29%) | 1.5 (0.8–3.0) |
No | 38 (66%) | 41 (66%) | 1.0 |
Yes | 20 (34%) | 21 (34%) | 0.9 (0.6–1.6) |
No | 50 (91%) | 58 (94%) | 1.0 |
Yes | 5 (9%) | 4 (6%) | 0.7 (0.2–2.5) |
No | 48 (83%) | 54 (86%) | 1.0 |
Yes | 10 (17%) | 9 (14%) | 0.8 (0.4–1.9) |
Mean (std) | 14.6 (14.4) | 14.2 (15.4) | 0.43 (–5.1–5.9) |
No | 21 (75.0) | 22 (66.7) | 1.0 |
Yes | 7 (25.0) | 11 (33.3) | 1.3 (0.6–3.0) |
No | 19 (67.9) | 22 (66.7) | 1.0 |
Yes | 9 (32.1) | 11 (33.3) | 1.0 (0.5–2.1) |
No | 23 (82.1) | 21 (63.6) | 1.0 |
Yes | 5 (17.9) | 12 (36.4) | 2.0 (0.8–5.1) |
No | 20 (71.4) | 21 (63.6) | 1.0 |
Yes | 8 (28.6) | 12 (36.4) | 1.3 (0.6–2.7) |
No | 27 (96.4) | 29 (87.9) | 1.0 |
Yes | 1 (3.6) | 4 (12.1) | 3.4 (0.4–28.7) |
We observed a similar number of deaths (10 in the SC group and 9 in the SB group) and patients in need for post-operative dialysis (5 in the SC group and 4 in the SB group) in both groups. Further, the number of days spend in the hospital did not differ substantially between the treatment groups with an average of 14.2 days [standard deviation (sd) = 15.4] in SB patients and 14.6 days (
In this trial, we did not find a benefit of IV SB administration in decreasing the rate of AKI compared to placebo. The incidence of AKI defined as an increase of creatinine by 0.3 mg/dl in our study was not different between study groups (24% in the SC group, and 24% in the SB group). Moreover, ARF, as defined in the original study design, was rare and not improved by the use of SB. The incidence of ARF observed in our study was lower than historical data indicated; only 3 patients (5%) in the SC group and 7 (11%) patents in the SB group had ARF compared to 11.7% reported. Based on our data and the definition of ARF stated above, we observed no beneficial effect of a perioperative SB infusion, but rather a suggestion of increased incidence of ARF. During the enrollment of our patients, a pilot study was published by Haase et al., indicating a beneficial effect of a perioperative infusion of SB to prevent an increase of serum creatinine after cardiac surgery (Haase et al.,
Nevertheless, our results are more in line with the results of studies recently published, that were conducted in a larger patient population (Heringlake et al.,
A clear limitation of our study is the number of patients that we eventually enrolled. Our initial sample size, based on an incidence of renal failure of 11.7%, was 360 patients. With any lack of benefit demonstrated in the interim analysis, we terminated our study early. While even larger studies could not demonstrate a beneficial effect of perioperative treatment with SB, Haase's most recent work observed a trend of increased mortality in patients receiving SB (Haase et al.,
In conclusion, patients undergoing cardio-vascular surgery exposed to cardiopulmonary bypass represent the second most common group of patients treated in intensive care unit settings to develop AKI (Uchino et al.,
This study was funded, in part, by a grant for the Southeastern Kidney Council.
This study was funded, in part, by a grant for the Southeastern Kidney Council. We are appreciative of the staff of the cardiothoracic units at Ohio State University and Wake Forest University for their support of this trial.