Objectives: Normal saline is the most common crystalloid solution that is used in renal transplant surgery. In this study, our aim was to determine the effects of a combination of half saline and bicarbonate versus normal saline as a routine solution.
Materials and Methods: For this double-blind random-ized clinical trial, we enrolled 100 adult patients undergoing kidney transplant. Patients were divided into 2 groups: those who received normal saline and those who received half saline and bicarbonate infusion as fluid replacement therapy during renal transplant. All patients received about 40 mL/kg of crystalloids during surgery. Serial creatinine con-centrations (primary outcomes) were compared between groups at 1, 2, 3, and 7 days after surgery. Urine output (secondary outcome) was compared between groups at recovery and at 6 and 24 hours after surgery. In addition, base excess, chloride, and sodium levels were measured before and 6 hours after surgery. Each liter of half saline-bircarbonate, which is relatively isoosmotic to human plasma, was composed of 70 mEq bicarbonate, 77 mEq chloride, and 147 mEq sodium.
Results: Patients who received half saline-bicarbonate had significantly lower postoperative creatinine levels at all time points than patients who received normal saline (P = .019). Serum chloride and sodium levels (P = .001) were significantly higher and base excess (P = .007) was significantly lower in the normal saline group at 6 hours after transplant. At all time points, urine output levels were significantly higher in the half saline-bicarbonate group (P = .001)
Conclusions: The use of half saline-bicarbonate was associated with better early graft function compared with normal saline in the first 7 days after transplant.
Key words : Graft function, Hyperchloremic acidosis, Kidney transplantation, Normal saline
Kidney transplant is the method of choice and the most cost-effective treatment modality for patients with end-stage kidney disease.1 The choice of crystalloid that is given during the transplant procedure may have a significant effect on both the early function of the transplanted kidney and the patient’s acid-base and electrolyte variables during the procedure.2 Three types of crystalloids have already been examined with regard to renal transplant through clinical trials; each one has its own merits and demerits.1-7
Delayed graft function, which is defined as the requirement for dialysis in the first week after transplant, is known to be dependent on multiple factors, including donor type, comorbidities, hemoglobin level, and ischemic time. In addition, the perioperative hydration status of the recipient and the type of crystalloid used are other possible considerations in cause of delayed graft function.3-8
Although it is well accepted that maintaining adequate intravascular volume facilitates early graft function, the type of crystalloid administered is still a matter of debate and varies between renal transplant centers.9-13 Tight control of metabolic acidosis using sodium bicarbonate has been shown to improve early renal function after kidney transplant.8
Given this above-mentioned fact, we decided to make a solution that is relatively isoosmotic and contained lower concentrations of chloride relative to plasma while including enough bicarbonate to neutralize background acidosis in patients with renal failure. To fulfill all 3 of these basic prerequisites, the only choice would be a balanced mixture of half saline and sodium bicarbonate. We hypothesized that infusion of half saline-bicarbonate (HSB) solution containing adjusted amounts of sodium, chloride, and bicarbonate may not only reduce the risk of ongoing metabolic acidosis but may also partially correct background acidosis and eventually improve early renal function after renal transplant.
Materials and Methods
This study was approved by the Ethics Committee of the Research Deputy of the University (ID: 242694). Informed consent was provided by 104 patients eligible for deceased-donor renal transplant, with a final group of 100 patients included in our study. Patients were divided into 2 groups using computer software in a prospective double-blind fashion: one group received normal saline (NS) and the other group received HSB as intraoperative fluid replacement therapy. Concealment of allocation was achieved using sealed envelopes.
Patients with serum potassium levels higher than 5.5 mEq/L at time of surgery, patients with diagnosis of chronic obstructive pulmonary disease, patients with diagnosis of chronic heart failure (ejection fraction < 30%), patients with certain arterial blood-gas variables (including preoperative base excess ≤ -15 mEq/L, preoperative bicarbonate ≤ 10 mEq/L, and preoperative pH ≤ 7.15), patients with chronic liver disease, and patients needing blood or colloid fluid during surgery (because of violation of study protocol) were excluded from this study.
General anesthesia was induced with a com-bination of intravenous midazolam (0.05 mg/kg), fentanyl (2-3 μg/kg), sodium thiopental (4 mg/kg), and atracurium (0.5 mg/kg). Anesthesia was maintained using isoflurane in an air-oxygen mixture and bolus injection of fentanyl (2 μg/kg) every hour; muscle relaxation was through intravenous injection of atracurium (0.15 mg/kg every 20 min). Every patient received 10 mg/kg of antithymocyte globulin at the rate of 100 mg/hour just after arrival to the hospital. All infusions concluded before induction of anesthesia.
Standard monitoring was used according to American Society of Anesthesiologists recom-mendations. After induction of anesthesia, a radial arterial cannula was inserted to monitor blood pressure and to obtain blood samples. A central vein catheter was used for fluid infusion, with central vein monitoring through the internal jugular vein. All patients received a total of 40 mL/kg of crystalloid, whether HSB or NS, during surgery.
Our primary outcome was serial creatinine concentrations at 1, 2, 3, and 7 days after transplant as an index of early renal function. As a secondary outcome, urine output was assessed at recovery and at 6 and 24 hours after transplant. In addition, base excess (as the metabolic index of acid-base status), chloride, and sodium levels were analyzed before operation and at 6 hours posttransplant. To keep patients safe during study, arterial blood-gas analyses were performed at the discretion of the clinician in all patients to correct probable severe acidosis with bicarbonate infusion. Severe acidosis was defined as base excess < -15 mEq/L, bicarbonate ≤ 10 mEq/L, or pH < 7.15. The clinician responsible for intraoperative management of patients was blinded to the type of intraoperative fluid. The outcome assessors were blinded to the study protocol.
The central pharmacy of the hospital was asked to prepare all solutions in the same shape containers and with similar labels. They were also asked to keep full sterility standards while mixing half saline with sodium bicarbonate: 70 mL of sodium bicarbonate (8.4%) was added to half saline after extracting 70 mL from a 1-liter bottle of half saline. Thus, 1 liter of sterile HSB contained about 77 mEq/L of chloride, 147 mEq/L of sodium, and 70 mEq/L of bicarbonate with a strong ion difference (Na+ - Cl-) equal to +70. Because the normal value for this strong ion difference is +40 to 44 in human blood, our HSB solution was more alkaline than human blood.
Data are presented as means and standard deviation for continuous variables and as percentages for categorical variables. A sample size of 50 in each group was calculated to have at least 80% power to detect the expected differences in mean serum creatinine levels (0.6 mg/dL was the effect size) between treatment protocols. All data were tested for normality with the Kolmogorov-Smirnov method. Sphericity assumption was checked by Mauchly test before comparisons. Different variants of multiple dimensions were independently analyzed using general linear model repeated-measurement analysis. Data were analyzed using SPSS 24 software (SPSS, Chicago, IL, USA). P values < .05 were considered statistically significant.
In this study, we analyzed 100 renal transplant recipients; age range was 19 to 57 years, and mean age was 48.8 ± 9.45 years. Demographic characteristics of the recipients and basic hemoglobin levels are shown in Table 1. The trend in postoperative reduction of serum creatinine concentration as an index of early graft function was significantly different between groups (P = .019) (Table 2 and Figure 1). Urine output on day 1 posttransplant was significantly higher in the HSB group (P = .001) (Figure 2).
Mean chloride, sodium, and base excess levels in both groups, including before transplant and at 6 hours posttransplant, are depicted in Table 3. Median cold ischemic time of all transplanted kidneys was 4 hours and 25 minutes (range, 2 h and 2 min to 6 h and 35 min). Average duration of the transplant procedure was 133 minutes (range, 125-160 min) from skin incision to skin closure. There were no incidences of need for sodium bicarbonate infusion to rescue patients from severe acidosis in our study.
Although kidney graft outcomes are influenced by many variables, including ischemia time, clinical outcomes of the grafted kidney are also likely to be affected by the choice of intraoperative and post-operative administration of fluids. In this clinical trial, we found that intraoperative infusion of HSB was associated with lower serial creatinine levels in the first week after transplant and better acid-base status and lower chloride concentration compared with infusion of NS. In addition, transplant recipients in the HSB group had higher urine output in the first 3 days after surgery.
Khajavi and associates found that lactated Ringer solution, because of its low chloride content, may lead to a lower rate of acidosis in the first week after renal transplant compared with NS. However, they were concerned that lactated Ringer infusion could lead to a hypercoagulable state in the patient.4 In the present study, we replaced lactate with bicarbonate to avoid such a concern. In a study from 2012, Etezadi and colleagues infused NS in both groups of patients while tightly controlling metabolic acidosis using sodium bicarbonate in one group of patients. They showed that tight control of metabolic acidosis culminates in a better early outcome after renal transplant.8 We found that adding sodium bicarbonate to half saline and making a solution containing less chloride and more bicarbonate and balanced sodium relative to normal physiologic serum composition led to the same beneficial effect on early renal outcomes as tight control of acidosis.
Reid and associates found that hyperchloremic acidosis caused by infusion of moderate-to-large quantities of NS can last for several hours after the end of the infusion in healthy volunteers; sluggish urinary response, slower time to first urination, and smaller urine volumes and sodium excretion were shown compared with that shown with Hartmann solution.11
In 2012, Chowdhury and associates performed a similar trial in which 2 liters of NS versus a low-chloride balanced crystalloid were administered to healthy volunteers. That study showed that admin-istration of NS resulted in a decline in velocity of renal blood and renal cortical tissue perfusion.12 Our study results are in concordance with their findings.
In a meta-analysis from 2015, Krajewski and colleagues assessed the relationship between chloride content of intravenous resuscitation fluids and patient outcomes in a perioperative or intensive care unit setting. They concluded that high-chloride fluids did not affect mortality but were associated with a significantly higher risk of acute kidney injury and hyperchloremic metabolic acidosis.14 It is noteworthy that what they found as a higher risk of renal injury was more important in recently grafted kidneys, which are already under serious ischemic insult during transport. The results of our present study support their findings. Because the kidney in transplant recipients lacks the capacity to rapidly compensate for electrolyte and acid-base derang-ements to a variable degree, we suggest that it is acceptable to help the transplanted kidney through administration of a less problematic fluid.
In a systematic review from 2016 by Wan and colleagues, infusion of balanced electrolyte solutions during renal transplant was shown to be associated with less hyperchloremic metabolic acidosis com-pared with NS infusion; however, it remained uncertain whether lower-chloride solutions led to improved graft outcomes versus NS.15 In our study, we found that administration of a solution of less hyperchloremic acidosis was associated with better early renal function. We can explain that differences shown between our results and the results of the above study were due to use of different types of solutions. All balanced solutions currently available on the market (Plasma-Lyte [Baxter Healthcare, Deerfield, IL, USA], Normosol [Hospira, Lake Forest, IL, USA], and Ringer lactate) lack bicarbonate but contain bicarbonate precursors, which are converted to bicarbonate in the liver. In addition, balanced salt solutions are also relatively hypotonic to human plasma. Nevertheless, HSB lacks this negative aspect because it is relatively isotonic and is full of ready bicarbonate anion, which is the most easy-handling and physiologic buffer in the body.
Weinberg and associates evaluated administration of intraoperative and early postoperative NS or Plasma-Lyte in 148 deceased-donor renal transplant recipients.5 The results showed that transplant recipients who received NS were more acidic (pH 7.32 vs 7.39; P = .001) and had higher serum chloride concentrations (107 vs 101 mmol/L; P < .001) at the end of surgery. No differences in rate of delayed graft function were observed. However, they found that patients who received Plasma-Lyte had a greater reduction in creatinine on day 2 posttransplant and that surprisingly those patients required less dialysis than the other group on subsequent days.5 Given the aforementioned finding and our promising results, it can be speculated that a low-chloride solution such as HSB, which contains bicarbonate instead of chloride, can lead to better early outcomes while avoiding the probable deleterious effects of lactate in renal transplant patients.
The most prominent shortcoming of our study is that only short-term outcomes were evaluated. It seems plausible to design a study to investigate whether there are any significant differences in long-term outcomes between groups. Another limitation was our use of only serial creatinine as an index of early renal function because of limited logistics. In the future, we suggest the use of new specific biomarkers of renal injury like interleukin 18 and neutrophil gelatinase-associated lipocalin to assess the extent of renal graft inflammation and injury, although it is still acceptable among clinicians to use serial creatinine as a marker of renal function.16 It is important to mention that Hall and associates, in a recent multicenter study, showed the importance of creatinine concentration on day 7 after renal transplant as the only biomarker, which has the strongest association with 12-month estimated glomerular filtration rate.17
Intraoperative administration of HSB compared with NS is associated with less hyperchloremic metabolic acidosis and improved early graft function after deceased-donor renal transplant.
DOI : 10.6002/ect.2018.0328
From the Department of Anesthesiology, Sina Hospital, Tehran University of
Medical Sciences, Tehran, Iran
Acknowledgements: We are indebted to the surgical team, statisticians, and research development center of Sina Hospital for their kind support. The authors received no financial support and have no conflicts of interest regarding this work. This work was conducted under clinical trial number IRCT2017080535510N1.
Corresponding author: Farhad Etezadi, Sina Hospital, Department of Anesthesiology, Tehran University of Medical Sciences, Tehran, Iran
Phone: +98 9102121843
Table 1. Demographic and Preoperative Measurements in Study Patients
Table 2. Comparison of Creatinine Concentration and Urine Volume Between Groups
Table 3. Comparison of Sodium, Chloride, and Base Excess Levels Between Groups
Figure 1. Creatinine Levels During the Postoperative Period
Figure 2. Urine Output During the Postoperative Period