The efficacy of sodium bicarbonated Ringer’s solution versus lactated Ringer's solution for goal-directed fluid therapy in elderly patients undergoing gastrointestinal surgery: a prospective randomized controlled trial

Abstract

Background

Sodium bicarbonated Ringer’s solution (BRS) has been gradually applied to clinic in recent years, while few clinical studies focused on the efficacy of BRS among elderly patients undergoing major surgery until now. This randomized controlled trial investigated the lactate metabolism and clinical outcomes of sodium bicarbonate Ringer's solution vs. sodium lactated Ringer’s solution (LRS) in elderly patients undergoing gastrointestinal surgery.

Methods

Sixty-two elderly patients undergoing gastrointestinal surgery were enrolled in this prospective, randomized controlled study. The enrolled participants were assigned into the sodium bicarbonated Ringer’s solution group (BRS group) or lactated Ringer's solution group (LRS group) randomly, which received goal-directed fluid therapy with sodium bicarbonated Ringer’s solution or sodium lactated Ringer’s solution, respectively. The primary outcome was the lactate level at the end of the surgery. Secondary outcomes included pH, bicarbonate, BE, hemodynamics, plasma biochemistry, recovery of gastrointestinal function and postoperative complications within 30 days after surgery.

Results

Sixty patients completed the trial and were analyzed finally. At the end of surgery, the level of lactate was significantly lower in BRS group than that in the LRS group (1.00 vs. 1.89, p < 0.001), and the probability of hyperlactacemia was lower (3.3% vs. 40.0%, p = 0.002). PH, bicarbonate, BE, hemodynamics, plasma biochemical alterations and postoperative gastrointestinal function recovery were not significant different between the two groups (p > 0.05). However, compared to the LRS group, the BRS group had a lower risk of wound bleeding (10.0% vs. 36.7%, p = 0.033) and newly impaired liver function (16.7% vs. 50.0%, p = 0.006), lower red blood cells infusion (0 vs. 0, p = 0.021), lower albumin infusion (10 vs. 35, p = 0.040), and shorter length of postoperative hospital stay (9 vs. 11.5, p = 0.012).

Conclusions

Sodium bicarbonated Ringer’s solution is more effective for elderly patients undergoing gastrointestinal surgery compared with sodium lactated Ringer’s solution through reducing the lactate levels, reducing the risk of wound bleeding and impaired liver function, red blood cells and albumin infusion, and decreasing the length of hospital stay.

Trial registration: This randomized trial was approved by the Clinical Medical Research Ethics Committee of the First Affiliated Hospital of Anhui Medical University, China (PJ2020-15-21) and registered at the Chinese Clinical Trial Center (http://www.chictr.org.cn/index.aspx, identifier: ChiCTR2000039406,date: 26/10/2020).

Introduction

With the population aging, China's elderly population is expected to exceed 30% of the total population by 2035. The number of surgeries performed on older patients is also expected to increase, in which gastrointestinal cancers are the leading causes of morbidity and mortality in elderly patients. Meanwhile, advanced age is an independent predictor of increased postoperative complications, mortality, and prolonged hospital stay[1].

Perioperative fluid therapy is the cornerstone of critical patient management, while crystals are the fluid solutions of choice used in critically ill patients[2]. Patients undergoing gastrointestinal surgery require a larger volume of fluid which is associated with a reduction in effective circulating blood volume due to rigorous bowel preparation, anesthesia-induced vasodilation, capillary leak generated by surgery-induced inflammation and intraoperative fluid loss, traditionally[3]. However, older individuals have declined organ function reserve and weakened cell metabolic capacity, and they are more susceptible to changes in water and electrolyte fluctuations[4–6], so do the lactate accumulation. Elevated lactate predicts adverse outcomes and is closely related to increased mortality[7]. Therefore, we want to control the lactate levels in elderly patients and thus improve the prognosis.

Currently, the goal-directed fluid therapy (GDFT) has been clinically recognized to be the best approach for fluid management in high-risk surgical patients[8, 9]. However, the optimal strategy of resuscitation crystalloid solution has long been controversial[10]. Normal saline (NS) and LRS are of the most commonly used solutions with different buffers (I.e., chloride vs. lactate) [2]. However, both have their own disadvantages respectively. NS has a high concentration of chloride ion than physiological component, which can cause hyperchloremia during rapid replenishment, aggravating the disorders of electrolyte balance and thus accelerating the disease progression[11]. Although LRS does not have this limitation, it has shown to aggravate the inherent lactic acidosis and increases hepatic metabolism, and aerobic demand[7]. Sodium bicarbonated Ringer’s solution (BRS) is a newly emerging crystalloid solution that has been used recently. Unlike lactate, bicarbonate is metabolized faster, requiring less oxygen demand and extra hepatic, so it could reduce metabolic burden on the liver reserve. Recent studies have shown that BRS has a promising clinical effect in resuscitation of shock and reduction of complications[12–14]. And in our previous study, we found that BRS reduced the incidence and severity of Acute kidney injury (AKI) after classic orthotopic liver transplantation[15].

To date, there is a lack of evidence on comparing internal environment and prognosis of BRS or LRS in elderly patients undergoing major surgery. Therefore, we conducted a randomized controlled trial to compare the effects of BRS with LRS based on goal-directed fluid therapy in elderly patients undergoing gastrointestinal surgery, with the aim of providing clinical reference.

Materials And Methods

Randomization And Blinding

All the included patients were randomly divided in two groups at a 1:1 proportion using computer-generated randomization: BRS group and LRS group. The numbers for allocation were packaged in opaque envelopes, which were opened after the patients enter the operating room by the student who was not participate in the experimental process, and then crystal solution was delivered to the trained anesthesiologist in charge of the patient who was unaware of the experimental content. Data collection and processing were operated by medical research students not participating in the trial. None of the researchers or patients were aware of the treatment assignment until the study and statistical analysis were completed.

Perioperative Management

All included patients were fasted for at least 8 hours prior to surgery with intestinal preparation. Standard monitoring for this procedure included pulse oximetry (SpO₂), electrocardiogram, invasive blood pressure, urine output, and processed electroencephalography (BIS, Aspect Medical Systems, Inc., USA) to monitor and adjust the appropriate depth of anesthesia. In addition, stroke volume variation (SVV) and cardiac index (CI) were continuously monitored by Most Care measurements via arterial catheterization.

For anesthesia induction, etomidate was injected with 0.2-0.3mg/kg, sufentanil with 0.2–0.5µg/kg, and cisatracurium with 0.15-0.3mg/kg, followed by endotracheal intubation and mechanical ventilation. Subsequently, all patients received complete intravenous anesthesia. Propofol was used to maintain BIS at 40–60 combined with remifentanil (2 to 6 ng/ ml) during the whole surgery. Mechanical ventilation parameters are set to maintain the pressure of end-tidal carbon dioxide (P_ETCO₂) near 35 mmHg and SpO₂ at 99–100%. Tidal volume was set at 8–10 ml kg^− 1, and positive end-expiratory pressure of 5–7 cm H₂O was administered as required to keep inspiratory peak below 30 mmHg. Nasopharyngeal temperature is monitored and normal body temperature (core temperature > 36°C) is maintained by forced air heating. During the procedure, arterial blood gas analysis were obtained at least once an hour.

Patients received LRS (H20065323, specification 500 ml; Sichuan Pacific Pharmaceutical, China) in the LRS group and BRS (H20190021, specification 500 ml; Jiangsu Hengrui Pharmaceutical, China) in the BRS group, depending on randomization. Throughout the procedure surgery, patients received 2 ml ideal body weight per hour as baseline rate infusion. The ideal body weight for fluid retention according to Robinson's formula[11]. Male: Ideal weight (kg) = 52 kg + 1.9 kg per 2.5 cm above 150 cm. Female: Ideal weight (kg) = 49 kg + 1.7 kg per 2.5 cm above 150 cm.

In both groups, crystalloid solution (single bolus: 100–200 ml) was administered when SVV > 12% subsequently, but in case hypotension (MAP falling below 65 mmHg within 5 minutes) occurred when SVV < 12%, ephedrine or phenylephrine will be given intermittently, or even noradrenaline will be used continuously. The use of hydroxyethyl starch or gelatins was not allowed.

According to the multimode analgesia protocol, all patients were treated with ultrasound (FUJIFILM Sonosite Inc., USA) guided transversus abdominis plane block (TAPB, 0.375% ropivacaine 20 ml on each side) and flurbiprofen 50mg before surgery, as well as nalbuphine (0.2 mg/kg) was administered at closure. Additional sufentanil was given as needed. Postoperative intravenous analgesia (PCIA) pump was used for all patients, and PCIA regimen was sufentanil 4 µg/kg and flurbiprofen ester 150 mg diluted to 150 ml (background infusion volume 2 ml/h, loading volume 2 ml, extra volume 2 ml, locking time 15 minutes).

All patients were transferred to the post-anesthesia care unit (PACU) after surgery for on-going monitoring, and then postoperative care were extubated according to standardized PACU protocols, and they were finally admitted to the ward after recovering well from anesthesia.

All patients received 1.5 ml·kg^− 1·h^− 1, 5% dextrose-NaCl as postoperative maintenance fluid. If additional volume is required, LRS or NS is given as the doctor prefers. The perioperative patient blood management followed the guidelines of the China, transfusion of whole blood and blood components WS/T 623–2018. Red blood cells were transfused to maintain the hemoglobin ≥ 70 g/L when hemoglobin level dropped below 70 g/L. Albumin was infused when albumin was lower than 30 g/L.

Outcomes And Data Collection

The primary outcome was the lactate level at the end of the surgery. Hyperlactatemia was defined as a measurement of arterial blood lactate levels > 2.0 mmol/L generally.

Secondary outcomes included pH, bicarbonate, BE, hemodynamics (MAP, HR, SVV), plasma biochemistry (Na⁺, K⁺, Mg²⁺, ALB, TBIL, ALT and AST), recovery of gastrointestinal function and postoperative complications within 30 days after surgery.

Sample Size And Statistical Analysis

Sample size was calculated by PASS 11.0 (NCS-PASS 11, USA). Based on preliminary results, the arterial lactic acid level after surgery was 1.84 ± 0.44 mmol/L in the LRS group, and we calculated that a sample of 56 patients (28 patients in each group) would provide 80% power to reduce to 1.50 mmol/L (highest limit of normal status) in the BRS group after randomization with a two-sided α level of 0.05. Considering the 10% drop-out rate, a total of 62 patients (31 in each group) should be enrolled in this study.

SPSS 25.0 software (SPSS, Inc., Chicago, IL, USA) was used for statistical analysis. Test for normality of continuous data using Shapiro-Wilk tests. Quantitative data were expressed as mean ± standard deviation (SD) or median (quartile distance, IQR) depending on their distribution. Normally distributed data were evaluated by an independent two-sample t-test, while other quantitative data were analyzed by the Mann-Whitney U test. The Pearson χ ² test or Fisher's exact test was used to compare the categorical variables between the two groups. For measures that indicated significant group by time interaction effects, variables were assessed by the repeated measures ANOVA with Bonferroni’s post hoc test correction. For all analyses, p < 0.05 indicates a statistically significant difference. GraphPad Prism 8.0 (GraphPad Software, La Jolla, California, USA) was used to construct the figures.

Results

Baseline Characteristics

A total of 70 patients were initially recruited for the study. Of these patients, 60 completed the study and were included in the statistical analysis finally. Ten patients were ineligible because they did not meet the inclusion criteria or dropped out (Fig. 1). The baseline clinical data of the two groups are summarized in Table 1. There was no significant difference between the two groups in gender, age, BMI, comorbidities, ASA and Charlson index (all p > 0.05). 

Abbreviations: BMI, body mass index. ASA, American Society of Anesthesiologists. 

Intraoperative parameters

As shown in Table 2, the duration of operation, anesthesia, mechanical ventilation and PACU between the two groups were comparable. Likewise, total fluid replacement, urine volume, dosage of propofol and remifentanil, and utilization rate of vasoactive drugs were not different between the two groups(all p>0.05).  

Table 2. Intraoperative parameters.

Note: Values are expressed as mean ± SD, medium (IQR), or number. ϕ Independent t test was used. ¥ Mann–Whitney U test was used. $ Pearson χ ² test was used. # Fisher's exact test was used.

Abbreviations: PACU, post-anesthesia care unit.

Primary Outcomes

There was no statistical difference in lactate level between the two groups before fluid therapy. After infusion, lactate level in the LRS group increased while decreased in the BRS group, and the difference between the two groups was statistically significant at 1 hour after the start of surgery and at the end of operation (p<0.05). Additionally, the incidence of hyperlactacemia occurred in 3.3% (1/30) of the patients in the BRS group versus 40.0% (12/30) of the LRS patients (Table 3, Figure 2).

Table 3. Primary outcomes.

Note: Values are expressed as mean ± SD or number (%). Bonferroni’s post hoc test was performed for each time point.

Abbreviations: T₀, before fluid therapy. T₁, 1 hour after the start of surgery. T₂, end of the surgery.

^# stands for differences between groups, * stands for between-group differences in baseline.

 Secondary outcomes

Other arterial blood gas analysis parameters including pH, bicarbonate and BE concentration had no statistical significance at any time points and were within the normal range, so as the hemodynamics (all p>0.05, Table 4).

Patients had similar plasma biochemical parameters (Na⁺, K⁺, Mg²⁺, ALB, TBIL, ALT and AST) between the two groups before infusion (all p >0.05). Of note, AST and ALT increased in the LRS group over 24 h after fluid resuscitation than before (Table 5).

In terms of postoperative gastrointestinal function recovery, the difference was not significant between the two groups (p>0.05). Four (13.3%) versus ten (33.3%) patients developed major complications in the BRS group and LRS group, respectively (p = 0.127). In the LRS group, 1 patient developed multiple major complications died on the 30th day after surgery, 2 patients with two complications, one with pneumonia and stroke, and the other with anastomotic fistula and peritonitis, while 1 patient with anastomotic fistula and stroke in the BRS group, all recovery after treatment. And the major complications in the BRS group mainly occurred one week after surgery, while in the LRS group may occur within two weeks after surgery (Figure 3). As for minor complications, the incidence of wound bleeding and new impaired liver function in the BRS group was significantly lower than that in the LRS group, and the incidence of paralytic ileus was high in both groups. Moreover, preoperative hemoglobin and albumin showed no difference before inclusion, but intraoperative and postoperative total amount of red blood cells and albumin infusion was statistically lower in BRS group( p<0.05). Length of stay in hospital was 9 days (8-11.25) in the BRS group and 11.5 days (9-15.25) in the LRS group (p = 0.012, Table 6).

Table 4. PH, bicarbonate, BE, MAP, HR, SVV were compared between the two groups at different time points.

Note: Values are expressed as mean ± SD or number (%). Bonferroni’s post hoc test was performed for each time point.

Abbreviations: T₀, before fluid therapy. T₁, 1 hour after the start of surgery. T₂, end of the surgery. 

^# stands for differences between groups, * stands for between-group differences in baseline.

Table 5. Electrolytes levels and plasma biochemical parameters were compared between the two groups at different time points.

Note: Values are expressed as mean ± SD or number (%). Bonferroni’s post hoc test was performed for each time point.

Abbreviations: T₀, before fluid therapy.T₃, one day after surgery. T₄, one week after surgery. ALB, albumin. TBIL, total bilirubin. ALT, alanine transaminase. AST, aspartate aminotransferase.

^# stands for difference between groups, * stands for between-group differences in baseline.

Table 6. Postoperative recovery profile.

Note: Values are expressed as median (IQR) or number (%). ¥ Mann–Whitney U test was used. $ Pearson χ ² test was used. # Fisher's exact test was used.

Abbreviations: POD, postoperative delirium. PONV, postoperative nausea and vomiting. RBC, red blood cells. FFP, fresh frozen plasma. ALB, albumin.

Discussion

The main findings of this study were that sodium bicarbonated Ringer's solution reduced the lactate levels, the incidence of hyperlactacidemia, the risk of wound bleeding and impaired liver function, red blood cells and albumin infusion, and hospital stay in elderly patients undergoing gastrointestinal surgery, compared to sodium lactated Ringer’s solution.

Lactate, as a precursor of bicarbonate, 70% is metabolized through the liver in about 60 minutes and 25-30% through kidney[16]. Though Zitek et al[17] have illustrated that the administration of 30 ml/kg lactated Ringer’s solution does not increase serum lactate in healthy individuals, our results showed that arterial blood lactate levels in LRS group increased gradually while decreased in BRS group during fluid therapy in elderly patients. It indicates that high plasma volume LRS administration over a short period of time is likely to promote lactate accumulation in elderly patients during surgery because it is over the liver functional reserve[18, 19]. While BRS with bicarbonate as buffer system does not increase exogenous lactate, it does not mainly dependent on liver metabolism. In addition, we found no significant differences in pH, bicarbonate and BE concentration between the two groups. Which is contrary to Ma J’s finding that BRS group had significantly higher pH level than LRS group in patients with shock[20]. The reasons may be that the bicarbonate is directly dissociate from sodium bicarbonate and can be rapidly excreted through respiration without accumulation over time, especially in the intervention to control P_ETCO₂ at a low level. 

In fact, there are no new clinically relevant indicators in internal environment for elderly patients, and previous studies take the base excess(BE) 24 h after inclusion[21] or blood gas(lactate concentration, serum electrolytes, and pH from blood gas)[22] as the primary outcomes. BE is generally used as an indirect estimate of tissue acidosis and a surrogate marker for elevated lactate elevation in patients with tissue perfusion injury such as sepsis[23]. However, based on goal-directed fluid therapy in combination with vasoactive drugs for hemodynamics management in our study, the results show less probability of tissue hypoperfusion. Meanwhile, hyperlactatemia may occur with or without concurrent metabolic acidosis because when hyperlactatemia occurs without worsening tissue perfusion, the buffering mechanisms may compensate[24]. Additionally, both lactate and BE were suitable predictors of prognosis in critical patients and there is currently no clear evidence that BE predicts better than lactate[25]. Therefore, the significance of BE in the diagnosis for exogenous lactate infusion is limited and we finally took the lactate level as the primary outcome.

Furthermore, it is known that elderly patients  have a high risk of postoperative complications, and lactate is associated with increased rates of  liver and renal dysfunction, length of hospital stay and 90-day mortality[26]. The normal range of lactate concentrations in adults is 0.5 to 1.5 mmol/L and less than 2 mmol/L is generally accepted as normal in critical illness[27]. Therefore, hyperlactatemia has clinical significance which was defined as a measurement of arterial blood lactate levels > 2.0 mmol/L. We found that the major complication rate was 33.3% in the LRS group, which is similar to a previous study included 507 patients undergoing major gastrointestinal surgery with a complication rate of 33.5%[28]. However, the incidence of major complications in the BRS group was lower at 13.3%, though there was no statistical difference between the two groups. We also found an improvement in the minor complications in the BRS group like reducing the incidence of wound bleeding and impaired liver function. It indicates that BRS can alleviate liver function metabolic burden and inhibit the aggravation of coagulation dysfunction to a certain extent during fluid therapy[29]. Study by Su et al. showed that LRS can cause granulocyte respiration bursts, aggravate systemic inflammations and then increase the capillary permeability and aggravate the tissue edema[30]. While human coagulation function is closely associated with tissue edema and liver metabolism[31]. This also explains the increased intraoperative and postoperative blood transfusion and albumin infusion in LRS group due to liver function injury and poor coagulation function. An observational study involving 874 patients undergoing major abdominal surgery showed that older patients were at increased risk of minor complications while major complication rates were similar to the younger patients[32]. Therefore, the reduction of minor complications rate by BRS infusion is meaningful for the prognosis of elderly patients with gastrointestinal surgery.

Considering various factors can affect arterial blood gas indexes and prognosis, we improved the experimental design. First, we have implemented adequate multimodal analgesia. As a new technique emerging in recent years, transversus abdominis plane block (TAPB) has been widely used for its superior pain and rare complications including reducing the hypotension caused by spinal anesthesia[33]. Theoretically, it is extremely beneficial to the elderly with fragile heart and brain functions[34]. And Mao et al found that low dose of nalbuphine combined with flurbiprofen is superior for elderly patients undergoing elective open gastrointestinal surgery with TAPB in terms of the efficient postoperative analgesia and decreased severity of postoperative nausea and vomiting[35]. Second, numerous complications were associated with intraoperative hypothermia, including decreased drug metabolism, coagulation impairment, and shivering[36]. Forced air prewarming was used to prevent hypothermia before anesthesia induction, and temperature changes were monitored and treated immediately after induction. Third, we used GDFT for fluid resuscitation and maintenance, as opposed to traditional weight calculation formulas or restrictive normovolemic resuscitation. Existing studies have shown that GDFT appears to be the overall best approach in fluid therapy, and available evidence supports GDFT can help reduce postoperative complications[37] and contribute to postoperative bowel function recovery particularly in patients undergoing gastrointestinal surgery[38].

However, there are some limitations in our study. Firstly, we only recruited elderly patients who underwent open gastrointestinal surgery, and whether the current findings could be generalized to other patients should be explored. Secondly, the arterial blood gas analysis data should have been collected up to postoperative 24 h, considering the accuracy of the results, re-injury of the artery, infection and other factors, we did not have a re-puncture test. Thus, there are still doubts about metabolism after the infusion. Finally, it is a single center study, though the sample size was adequate for the primary outcome, further multi-center, large-sample randomized trials will be better to detect variations in adverse outcomes (i.e., complications, mortality).   

In conclusion, we observed that compared to sodium lactated Ringer's solution, sodium bicarbonated Ringer's solution reduced the lactate levels, as well as exhibited better clinical improvement such as reducing the risk of wound bleeding and impaired liver function, reducing the amount of red blood cells and albumin infusion, and decreasing the length of hospital stay in elderly patients undergoing gastrointestinal surgery. Hence, BRS was to be considered as the better choice of fluid for elderly patients. 

Abbreviations

Declarations

Ethics approval and consent to participate

Ethical approval was provided by the Ethical Committee of The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (PJ2020-15-21). All patients provided informed consent and all procedures were conducted according to the Declaration of Helsinki.

Consent for publication 

Not applicable. 

Availability of data and materials

The datasets of the current study are available from the corresponding author upon reasonable request.

Competing interests 

The authors declare that they have no competing interests. 

Funding

This study is supported by the China primary health care foundation (YLGX-WS-2020001 to LC).

Authors’ contributions

Study design: JL, YG, LC. Ethics approval and registration: JL, LC. Patient recruitment: JL, YG, ZH, HW. Data collection: JL, YG, ZH, HZ, HW. Data analysis: JL, HW, LC. Drafting: JL, MN, LC. JL and YG contributed equally to this work and share first authorship. Final approval of the manuscript: all authors.

Acknowledgements 

Not applicable.

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