Abstract
From the perspective of the Stewart approach, it is known that expansion of the sodium chloride ion difference (SCD) induces alkalosis. We investigated the role of SCD expansion by furosemide-induced chloride reduction in pediatric patients with acute respiratory failure. We included patients admitted to our pediatric intensive care unit intubated for acute respiratory failure without underlying diseases, and excluded patients receiving extracorporeal circulation therapy (extracorporeal membrane oxygenation and/or renal replacement therapy). We classified eligible patients into the following two groups: case—those intubated who received furosemide within 24 hours, and control—those intubated who did not receive furosemide within 48 hours. Primary outcomes included SCD, partial pressure of carbon dioxide (PaCO 2 ), and pH results from arterial blood gas samples obtained over 48 hours following intubation. Multiple regression analysis was also performed to evaluate the effects of SCD and PaCO 2 changes on pH. Twenty-six patients were included of which 13 patients were assigned to each of the two groups. A total of 215 gas samples were analyzed. SCD (median [mEq/L] [interquartile range]) 48 hours after intubation significantly increased in the case group compared with the control group (37 [33–38] vs. 31 [30–34]; p = 0.005). Although hypercapnia persisted in the case group, the pH (median [interquartile range]) remained unchanged in both groups (7.454 [7.420–7.467] vs. 7.425 [7.421–7.436]; p = 0.089). SCD and PaCO 2 were independently associated with pH ( p < 0.001 for each regression coefficient). As a result, we provide evidence that SCD expansion with furosemide may be useful in maintaining pH within the normal range in pediatric patients with acute respiratory failure complicated by concurrent metabolic acidosis.
Keywords: acid–base equilibrium, mechanical ventilation, chloride, furosemide
Introduction
Patients with acute respiratory failure complicated by metabolic acidosis often develop severe acidemia. The complications related to severe mixed acidosis (metabolic and respiratory) are life threatening for critically ill patients. 1 As a result, it is important to prevent metabolic acidosis in parallel with ventilatory management of respiratory acidosis. Recently, Zanella et al 2 reported that in a porcine model of respiratory failure, the pH of hypochloremic patients could be controlled despite hypercarbia that developed in the presence of extracorporeal-induced hypochloremia. This treatment represented a novel method for management of acid–base equilibrium by focusing on the relationship between strong ions as described in the Stewart approach. The Stewart approach is a physicochemical approach used in assessing acid–base disorders which has been modified by Figge et al to allow applicability to multiple clinical settings. 3 4 5 6 7 In body fluids, there is an excess of strong cations which Stewart quantified as the strong ion difference (SID). It is known that expansion of SID increases pH and HCO 3 − facilitating movement of systemic acid–base balance toward a metabolic alkalosis. In addition, it was reported that the sodium chloride ion difference (SCD) could be used as a satisfactory SID surrogate. 8
Loop diuretics are commonly used agents in critical care and are known to significantly reduce chloride ion concentration through increased excretion, thus inducing hypochloremia. Therefore, the SCD expansion is possible with the administration of these agents. In this study, we investigated whether SCD expansion through furosemide-induced chloride reduction would induce alkalosis in critically ill pediatric patients with acute respiratory failure through examination of the effects of SCD and partial pressure of carbon dioxide (PaCO 2 ) on arterial pH. Our goal was to confirm or deny the beneficial effect on acid–base status in those patients who received furosemide undergoing mechanical ventilation for acute respiratory failure.
Materials and Methods
This is a retrospective cohort study conducted at the pediatric intensive care unit (PICU) of the National Center for Child Health and Development which is a tertiary children's hospital in Tokyo, Japan. This study was conducted in accordance with the amended Declaration of Helsinki, and was approved by the ethics committee of our institution on January 21, 2020 (No. 2019-105). This article was drafted according to the STrengthening the Reporting of OBservational studies in Epidemiology guidelines. 9
Case Ascertainment and Control Selection
We reviewed electronic medical records of patients admitted to the PICU from January 2015 to December 2019. Inclusion criteria consisted of children younger than 16 years with acute respiratory failure requiring mechanical ventilation for more than 48 hours initiated either 12 hours prior to or following admission to the PICU. The documented severity of preintubation was consistent with the description of “at risk of pediatric acute respiratory distress syndrome (ARDS), and oxygenation by noninvasive mechanical ventilation” as described in consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. 10 Exclusion criteria consisted of patients intubated for nonprimary respiratory disease or associated conditions. This included patients intubated for cardiac or neurological support; elective surgery or procedures; acute or chronic metabolic or renal conditions that affect acid–base balance; patients administered confounding medications such as sodium bicarbonate, acetazolamide, or tolvaptan; and patients receiving extracorporeal circulatory support to include renal replacement therapy and/or extracorporeal membrane oxygenation.
We classified eligible patients into two groups based on whether they received furosemide following endotracheal intubation in the management of acute respiratory failure. The case group included the patients who received furosemide within 24 hours after intubation, and the control group consisted of patients who did not receive furosemide within 48 hours after intubation. The primary goal for patients in the case group was to administer furosemide to remove excess fluid known to be associated with prolonged duration of mechanical ventilation (DMV), PICU length of stay, and mortality. All patients receiving mechanical ventilation were judiciously sedated to preserve spontaneous respiratory effort. Intravenous fluid consisted of Ringer's lactate solution of which the electrolyte contents consisted of sodium 130 mEq/L, potassium 4 mEq/L, calcium 3 mEq/L, chloride 109 mEq/L, and acetate 28 mEq/L for preservation of a maintenance fluid rate (with or without enteral feeding) to achieve a total daily water intake from 70 to 100 mL/kg for the first 48 hours after intubation. The management of mechanical ventilation and fluid or feeding therapy was at the discretion of each bedside PICU physician.
Measurements
We collected patient data consisting of sex, age, Pediatric Index of Mortality 2 (PIM-2), partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FIO2) ratio, oxygenation index (OI), pH, PaCO 2 , peak inspiratory pressure (PIP) at admission, indication for endotracheal intubation, DMV, fluid balance every 24-hour period until 48 hours after intubation, dosage and duration of furosemide, and adverse events. The adverse events recorded consisted of the following: death before hospital discharge, pneumothorax, ventilator-associated pneumonia, difficult extubation (tracheostomy or delayed extubation due to loss of spontaneous respiration), and severe electrolyte abnormalities. The fluid balance for each patient was calculated as a percentage of the cumulative water balance (L) at 24 hours and 48 hours after intubation with respect to the recorded body weight (kg) at PICU admission.
In addition, all measured values of sodium, chloride, pH, and PaCO 2 were collected from arterial blood gas analyses obtained during the 48-hour period following intubation.
We designated time segments as each 8-hour period of time following intubation; the last 8-hour period (40–48 hours after intubation) was designated for the study end point. At the study end point, SCD, sodium, chloride, pH, and PaCO 2 values were compared between the case and control groups. Subsequently, we then examined the effects of SCD and PaCO 2 on pH through multiple regression analysis.
Statistical Analysis
Descriptive statistics were expressed as the median (interquartile range) for continuous data and absolute frequencies, and as percentages for categorical data. Bivariate comparisons between the groups were performed using the Mann–Whitney's U test for continuous data, and the chi-square test complemented by Fisher's exact tests for categorical data. Based on previous work, 11 this study was designed to detect a 3.0 mEq/L between group difference of SCD at the study end point, and seven arterial blood gas samples were required in each group to provide 80% power at a standard deviation of 1.9, and a type I error rate of 0.05. To evaluate the effects of SCD and PaCO 2 on pH, multiple regression analysis was performed using the actual measured values obtained from all arterial blood gas samples until 48 hours after intubation. In this manner, all blood gas samples from the case and control groups were integrated into a single dataset. pH was selected as the objective variable, and, for application in clinical setting, exclusively SCD and PaCO 2 as the explanatory variables. Each variable was assessed for multicollinearity analysis with variance inflation factor (VIF). All analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which utilizes a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient Assignment
Fig. 1 shows the flow diagram associated with patient selection. Twenty-six patients were included in the study and consisted of 13 patients in both the case and control groups. A total of 215 arterial blood gas samples were obtained during the study period and were available for analysis.
Fig. 1.
Study flow diagram.
Baseline Patient Characteristics and Findings
Table 1 shows the baseline clinical characteristics and findings for each group. The DMV was the only characteristic significantly different with a longer duration in the case group; otherwise, there were no significant differences between the two groups regarding the other baseline characteristics and findings evaluated. Regarding outcomes, no patients died before discharge from the hospital, and there were no significant adverse events recorded in either group.
Table 1. Baseline patient characteristics and findings.
| Variable | Case group ( n = 13) |
Control group ( n = 13) |
p -Value |
|---|---|---|---|
| Male, n (%) | 5 (38) | 9 (69) | 0.238 |
| Age (mo), median (IQR) | 6 (2–11) | 10 (2–23) | 0.455 |
| Pediatric Index of Mortality 2, median (IQR) | 4.4 (1.1–5.8) | 3.6 (1.0–5.2) | 0.455 |
| PaO 2 /FIO2 ratio, median (IQR) | 168 (135–266) | 184 (127–203) | 0.898 |
| PaO 2 /FIO2 ratio < 200, n (%) | 8 (62) | 9 (69) | 1.000 |
| Oxygenation index, median (IQR) | 6.7 (4.8–9.1) | 5.3 (3.7–10.0) | 0.579 |
| pH, median (IQR) | 7.357 (7.289–7.409) | 7.299 (7.253–7.309) | 0.076 |
| PaCO 2 (mm Hg), median (IQR) | 47 (41–60) | 55 (51–64) | 0.330 |
| Peak inspiratory pressure (cmH 2 O), median (IQR) | 25 (24–26) | 21 (18–24) | 0.058 |
| Indication for endotracheal intubation, n (%) | |||
| Status asthmaticus | 2 (15) | 3 (23) | 0.881 |
| Bacterial or viral pneumonia | 10 (77) | 9 (69) | |
| Bronchitis | 1 (8) | 1 (8) | |
| Duration of mechanical ventilation, median (IQR) | 3 (3–4) | 1 (1–2) | 0.019 |
| Fluid balance (%), median (IQR) | |||
| 24 h after intubation | 2.1 (1.8–6.4) | 3.1 (1.5–5.5) | 0.798 |
| 48 h after intubation | −0.7 (−2.4 to 2.0) | 0.3 (−0.7 to 1.7) | 0.427 |
| Dosage of furosemide | |||
| Maximal dose (mg/kg/d), median (IQR) | 2.0 (2–2) | ||
| Route of administration, n (%) | |||
| Enteral | 4 (30) | ||
| Intermittent intravenous bolus | 1 (8) | ||
| Continuous intravenous infusion | 8 (62) | ||
| Duration of furosemide (d), median (IQR) | 2 (2–3) | ||
| Adverse event, n (%) | |||
| Death before discharge from hospital | 0 | 0 | |
| Pneumothorax | 0 | 0 | |
| Ventilator-associated pneumonia | 0 | 0 | |
| Difficult extubation | 0 | 0 | |
| Tracheostomy | 0 | 0 | |
| Unexpected delayed extubation | 0 | 0 | |
| Severe electrolyte derangement | 0 | 0 | |
Abbreviations: FIO2, fraction of inspired oxygen IQR, interquartile range; PaCO 2 , partial pressure of carbon dioxide; PaO 2 , partial pressure of oxygen.
Outcomes of Statistical Analyses
At the designated study end point of 48 hours postintubation, 17 arterial blood gas samples were available for analysis in the case group and 9 samples in the control group. Sodium ion concentration showed no significant difference between the two groups. On the other hand, chloride ion concentration decreased significantly (case: 102 mEq/L [95–103 mEq/L] vs. control: 106 mEq/L [102–108 mEq/L]; p = 0.007) and SCD increased (case: 37 mEq/L [33–38 mEq/L] vs. control: 31 mEq/L [30–34 mEq/L]; p = 0.005). The pH in the case group was maintained a similar level to the control group (case: 7.454 [7.420–7.467] vs. control: 7.425 [7.421–7.436]; p = 0.089) as was the PaCO 2 ( p = 0.066) as seen in Fig. 2 . Table 2 provides an overview of electrolytes, pH, PaCO 2 , and fluid balance trends for each group. Table 3 shows the results of multiple regression analysis of the effect of SCD and PaCO 2 on systemic acid–base balance represented by arterial pH whereby SCD ( p < 0.001) and PaCO 2 ( p < 0.001) were independently associated with pH. The VIF was < 2.0 for each variable which indicated the absence of multicollinearity, and the adjusted R 2 value of 0.82 revealed good correlation with the delivered pH model.
Fig. 2.
Change of electrolytes, pH, and partial pressure of carbon dioxide (PaCO 2 ) every 8 hours after intubation. In all panels, the horizontal axis represents the 48 hours after intubation divided into 8-hour periods with the time of intubation set as 0. White boxes represent the case group and gray boxes represent the control group. The top and bottom of the vertical error bar, the parallel lines within each box, and the top and bottom sides of each box, respectively, represent the maximum, minimum, median, and quartile upper and lower limits for the parameters at each time period. The time period of 40 to 48 hours after intubation was set as the study end point, and between-group comparisons of each parameter during this time period were performed utilizing the Mann–Whitney's U test. For panel A, the upper boxes represent sodium ion, and the lower boxes represent chloride ion concentrations. The chloride ion concentration 40 to 48 hours postintubation shows a significantly lower value ( p = 0.007) in the case group than in the control group. Panel B shows the sodium chloride ion difference (SCD) is significantly lower ( p = 0.005) in case versus control patients. Panels C and D indicate no significant detrimental changes in arterial pH and PaCO 2 associated with reduction in SCD.
Table 2. Summary of serum electrolyte ion concentrations, arterial blood gas, pH, and PaCO 2 trends in each study group .
| Arterial blood gas variables | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0– 8 h | 8–16 h | 16–24 h | 24–32 h | 32–40 h | 40–48 h | |||||||
| Case | Control | Case | Control | Case | Control | Case | Control | Case | Control | Case | Control | |
| ( n = 38) | ( n = 26) | ( n = 24) | ( n = 20) | ( n = 15) | ( n = 16) | ( n = 13) | ( n = 9) | ( n = 18) | ( n = 10) | ( n = 17) | ( n = 9) | |
| Na (mEq/L), median (IQR) | 136 (134–138) | 138 (135–140) | 138 (137–139) | 139 (137–139) | 138 (137–140) | 138 (137–139) | 138 (136–141) | 138 (138–139) | 136 (134–138) | 138 (137–139) | 137 (133–138) | 137 (137–138) |
| Cl (mEq/L), median (IQR) | 106 (103–107) | 106 (103–108) | 107 (105–108) | 106 (104–111) | 106 (104–108) | 104 (103–106) | 104 (100–106) | 103 (102–108) | 100 (98–103) | 104 (102–106) | 102 (95–103) | 106 (102–108) |
| SCD (mEq/L), median (IQR) | 31 (29–33) | 32 (30–34) | 32 (31–32) | 32 (29–33) | 32 (31–34) | 34 (32–34) | 37 (33–38) | 35 (31–35) | 37 (34–38) | 34 (32–35) | 37 (33–38) | 31 (30–34) |
| pH, median (IQR) | 7.365 (7.326–7.409) | 7.300 (7.256–7.358) | 7.350 (7.322–7.439) | 7.329 (7.290–7.369) | 7.403 (7.359–7.421) | 7.407 (7.383–7.421) | 7.413 (7.387–7.435) | 7.421 (7.389–7.434) | 7.441 (7.372–7.457) | 7.438 (7.389–7.451) | 7.454 (7.420–7.467) | 7.425 (7.421–7.436) |
| PaCO 2 (mm Hg), median (IQR) | 47 (41–55) | 51 (43–63) | 48 (43–54) | 53 (43–59) | 45 (43–52) | 46 (43–48) | 48 (46–51) | 45 (41–46) | 46 (42–52) | 44 (39–47) | 45 (41–53) | 40 (39–43) |
Abbreviations: IQR, interquartile range; PaCO 2 , partial pressure of carbon dioxide; SCD, sodium chloride ion difference.
Note: n = the number of arterial blood gas samples for each study group at each designated 8-h interval.
Table 3. Multiple regression analysis to evaluate the effect of SCD and PaCO 2 on systemic acid–base balance (arterial pH) .
| Variables | VIF | Estimated partial regression coefficients | 95% confidence interval | p -Value | |
|---|---|---|---|---|---|
| Lower limit | Upper limit | ||||
| SCD (mEq/L) | 1.05 | 8.408 × 10 −3 | 7.144 × 10 −3 | 9.671 × 10 −3 | < 0.001 |
| PaCO 2 (mm Hg) | 1.05 | −7.540 × 10 −3 | −8.021 × 10 −3 | −7.057 × 10 −3 | < 0.001 |
| Delivered pH equation Adjusted R2 | |||||
| pH = 7.469 + (8.408 × 10 −3 × SCD) − (7.540 × 10 −3 × PaCO 2 ) 0.82 | |||||
Abbreviations: PaCO 2 , partial pressure of carbon dioxide; SCD, sodium chloride ion difference; VIF, variance inflation factor.
Discussion
In the present study, after administration of furosemide, the chloride ion concentration decreased, and the sodium concentration was maintained within the normal range resulting in SCD expansion. Multiple regression analysis of the effect of SCD and PaCO 2 on pH revealed no multicollinearity between SCD and PaCO 2 , and the fit of model derived using these two explanatory variables was good (adjusted R 2 = 0.82). These results provide proof of concept that alkalosis induced by expansion of SCD with furosemide may counteract metabolic acidosis through maintenance of arterial pH despite hypercapnia commonly seen despite lung protective strategies utilized during the ventilatory management of patients with acute respiratory failure of patients to include those of the pediatric age group as noted in this study.
Permissive hypercapnia is a recommended ventilator management strategy utilized during acute respiratory failure which is performed through low tidal volume (6–8 mL/kg) and low peak and plateau pressures (≤ 28–30 mm Hg) ventilation resulting in “permissive hypercapnia” to avoid volutrauma and barotrauma, respectively. This strategy is commonly utilized to avoid the risk and management of the presence of ARDS. 12 13 Paradoxically, the accumulation of carbon dioxide plays an auxiliary beneficial role in cardiac function by increasing coronary artery blood flow and reducing afterload of the heart. 14 15 In addition, recent studies suggest that hypercapnia may also have an immunomodulatory role through suppression of apoptosis, oxidative stress, and inflammation in alveolar epithelial cells. 15 16 17 It has also been shown to improve neurological outcome in patients resuscitated from cardiac arrest by increasing cerebral perfusion. 18 19 20 Unfortunately, critically ill patients commonly demonstrate a mixed acidosis which may be aggravated by the use of permissive hypercapnia. Severe acidemia inhibits myocardial contraction, 21 increases pulmonary vascular resistance, 22 and transiently stimulates sympathetic nerves to increase heart rate sometimes resulting in serious arrhythmias. 23 24 Therefore, it is important to control metabolic acidosis in patients with acute respiratory failure requiring mechanical ventilation and the use of lung protective strategies such as permissive hypercapnia.
SCD expansion may induce a physiological reservoir of PaCO 2 ; however, it may be beneficial in the management of mixed acidosis in patients with acute respiratory failure aggravated by the use of lung protective strategies through furosemide administration leading to a reduction in chloride ion without the risk of concurrent lowering of the pH through the elevation of the PaCO 2 as seen in this study. In an attempt to manage metabolic acidosis, Cove and Kellum 25 used the concept of SCD expansion based on the Stewart approach to explain how sodium bicarbonate may improve acidosis. However, sodium bicarbonate has several adverse effects including hypernatremia and increased local intracellular acidosis. 26 27 In contrast, loop diuretics are drugs that inhibit the action of the Na–K–2Cl cotransporter present on luminal membranes in the nephron and maintain high urine osmolality, thereby reducing free water reabsorption and increasing diuresis. 28 The current study further revealed that furosemide (a loop diuretic) induced a higher degree of chloride ion reduction in contrast to sodium ion reduction resulting in an increase in SCD. This finding is supported by Zazzeron et al 11 who suggested that loop diuretics promote the excretion of urinary ions through an acute “switching off” of ion exchange at Henle's loop and diminished chloride ion reabsorption due to secondarily increased activation of aldosterone. Additionally, we hypothesize that the urinary sodium concentrations reaching the collecting duct are elevated at which point sodium is preferentially reabsorbed through epithelial sodium channels thereby leading to selective chloride excretion in the urine. In compensation, urinary excretion of the weak acid NH 4 + is increased to maintain electrical neutrality in the urine. 29 However, serum chloride is not reabsorbed (in comparison with sodium) leading to SCD expansion, and subsequent transition of the pH toward an alkaline state.
There are several major limitations of this study. First, we examined a limited number of patients in a small retrospective observational study conducted at a single institution. However, we offer unique findings based on arterial blood gas samples ( n = 26) obtained at the study end point, exceeding the sample size estimated ( n = 7) to detect significant between-group difference of SCD at the designated study end point. As a result, it was considered that adequate samples were collected to support the findings of this study. Second, to reduce errors due to complexity, we did not evaluate potential confounding variables such as lactate, albumin, phosphate, other nonvolatile acids, concurrent acute and/or chronic organ dysfunction as seen with metabolic and renal diseases all of which are factors other than SCD that could affect arterial pH. Third, the case group demonstrated an increase in DMV. However, this may be explained by an increase in severity of illness based on elevated PIM-2, lower PaO 2 /FIO2 ratio, higher OI, higher PIP, and a greater incidence of primary respiratory failure due to infectious causes in the case group. Furthermore, it is possible that this finding was also due to the severity of bronchial asthma and the specific causative microorganisms of pneumonia leading to respiratory failure. Fourth, the expansion of SCD in the case group may be a compensatory change of respiratory acidosis due to relatively high PaCO 2 rather than the effect of furosemide. However, patients were allowed spontaneous respiratory effort through nonuse of neuromuscular-blocking agents allowing patients to self-adjust their PaCO 2 as seen in the case group who demonstrated a median PaCO 2 of 47. Therefore, it was considered that the alkalosis associated with expansion of SCD in the case group took place following administration of furosemide and was not associated with a rapid compensatory changes as seen in patients with greater degrees of hypercarbia who receive furosemide. Finally, there is insufficient long-term assessment of adverse events associated with hypochloremia, alkalosis, and loop diuretics. A prospective multicenter, interventional study is necessary to more fully evaluate the effectiveness and safety of furosemide administration to facilitate chloride reduction in an effort to maintain acid–base balance through expansion of SCD in patients at risk of mixed acidosis due to acute respiratory failure requiring mechanical ventilation.
Conclusion
SCD expansion with furosemide may counteract metabolic acidosis through maintenance of arterial pH within the normal range despite hypercapnia in critically ill patients with acute respiratory failure requiring mechanical ventilation.
Acknowledgments
We thank the medical editor from the Division of Education for Clinical Research, National Center for Child Health and Development for editing this article.
Conflict of Interest None declared.
Authors' Contribution
• H.N.: Conceptualized, collected data, drafted the initial manuscript, and approved the final manuscript as submitted.
• N.T.: Conceptualized, reviewed, revised the manuscript, and approved the final manuscript as submitted.
• T.O.: Collected data, reviewed, revised the manuscript, and approved the final manuscript as submitted.
• Y.T.: Collected data, reviewed, revised the manuscript, and approved the final manuscript as submitted.
• I.O.: Reviewed, revised the manuscript, and approved the final manuscript as submitted.
• N.N.: Reviewed, revised the manuscript, and approved the final manuscript as submitted.
• S.N.: Reviewed, revised the manuscript, and approved the final manuscript as submitted.
• All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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