Challenging ABG’s

 

The Acid-Base Puzzle: 5 ICU Scenarios That Need More Than ABG Correction

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath,Claude.ai

Abstract

Background: Complex acid-base disorders in the intensive care unit often present diagnostic and therapeutic challenges that extend beyond simple arterial blood gas interpretation. Traditional approaches focusing solely on pH correction may overlook underlying pathophysiology and lead to suboptimal outcomes.

Objective: To present five challenging ICU scenarios that demonstrate the limitations of conventional acid-base management and highlight advanced diagnostic and therapeutic strategies.

Methods: This review synthesizes current literature and expert consensus on complex acid-base disorders, presenting evidence-based approaches to diagnosis and management through detailed case scenarios.

Results: Five distinct clinical scenarios are presented: (1) D-lactic acidosis in short gut syndrome, (2) Propylene glycol toxicity from continuous sedation, (3) Mixed acid-base disorders in liver failure, (4) Pyroglutamic acidosis from paracetamol therapy, and (5) Hyperchloremic acidosis in fluid resuscitation. Each scenario includes diagnostic pearls, management strategies, and clinical outcomes.

Conclusions: Successful management of complex acid-base disorders requires understanding of underlying pathophysiology, recognition of unmeasured anions, and individualized therapeutic approaches that address root causes rather than merely correcting ABG parameters.

Keywords: Acid-base disorders, intensive care, metabolic acidosis, anion gap, critical care

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Introduction

The interpretation of acid-base disorders in critically ill patients represents one of the most intellectually challenging aspects of intensive care medicine. While arterial blood gas analysis remains the cornerstone of acid-base assessment, the ICU environment presents unique scenarios where traditional approaches fall short. The presence of multiple comorbidities, polypharmacy, and complex pathophysiology creates a perfect storm for unusual acid-base disturbances that can confound even experienced intensivists.

Recent advances in our understanding of strong ion difference theory, unmeasured anions, and complex metabolic pathways have revolutionized the approach to acid-base medicine. However, the gap between theoretical knowledge and clinical application remains significant. This review presents five challenging ICU scenarios that illustrate why successful acid-base management requires more than simple ABG correction and demands a comprehensive understanding of underlying pathophysiology.

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Scenario 1: The Mysterious Metabolic Acidosis - D-Lactic Acidosis in Short Gut Syndrome

Case Presentation

A 45-year-old male with a history of extensive small bowel resection following mesenteric ischemia presents with altered mental status, slurred speech, and ataxia. Initial ABG reveals pH 7.25, PCO₂ 25 mmHg, HCO₃⁻ 12 mEq/L, with an anion gap of 18 mEq/L. Standard lactate level is normal at 1.8 mmol/L.

Clinical Challenge

The patient presents with a classic high anion gap metabolic acidosis, but routine laboratory investigations fail to identify the culprit anion. The neurological symptoms are disproportionate to the degree of acidosis, suggesting a specific toxidrome.

Pathophysiology Deep Dive

D-lactic acidosis represents a unique form of metabolic acidosis caused by bacterial fermentation of unabsorbed carbohydrates in the colon. In patients with short gut syndrome, malabsorbed carbohydrates reach the colon where Lactobacillus species produce D-lactate through fermentation. Unlike L-lactate, D-lactate is poorly metabolized by human lactate dehydrogenase, leading to accumulation and characteristic neurological symptoms.

Key Teaching Point: Standard lactate assays measure only L-lactate, missing the D-isomer entirely.

Diagnostic Approach

Laboratory Investigations:

• Standard lactate: Normal (measures only L-lactate)
• D-lactate level: Elevated (requires specific assay)
• Urine organic acids: May show increased lactate
• Stool pH: Typically acidic (<5.5)

Clinical Pearls:

1. The "Normal Lactate Paradox": High anion gap acidosis with normal standard lactate should trigger suspicion for D-lactic acidosis in susceptible patients
2. Neurological Red Flags: Ataxia, dysarthria, and altered mental status out of proportion to acidosis severity
3. Dietary History: Recent carbohydrate intake in patients with malabsorption syndromes

Management Strategy

Acute Phase:

1. Discontinue oral intake to halt substrate availability
2. Antibiotic therapy: Vancomycin 125mg PO QID or metronidazole 250mg PO TID
3. Supportive care: Correct dehydration and electrolyte imbalances
4. Avoid routine bicarbonate therapy unless pH <7.15 with hemodynamic compromise

Long-term Management:

• Dietary modification: Restrict simple carbohydrates
• Probiotic therapy: Lactobacillus-free preparations
• Consider thiamine supplementation

Outcome and Teaching Points

With appropriate recognition and management, neurological symptoms typically resolve within 24-48 hours. This case illustrates the importance of considering unmeasured anions in unexplained high anion gap acidosis.

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Scenario 2: The Sedated Patient's Dilemma - Propylene Glycol Toxicity

Case Presentation

A 35-year-old trauma patient on continuous lorazepam and propofol infusions for 72 hours develops progressive metabolic acidosis (pH 7.28, HCO₃⁻ 14 mEq/L, anion gap 16 mEq/L) with acute kidney injury and altered mental status. Lactate is mildly elevated at 3.2 mmol/L, but the clinical picture doesn't fully explain the degree of acidosis.

Clinical Challenge

The patient presents with metabolic acidosis and AKI while receiving standard ICU sedation. The mild lactate elevation doesn't fully account for the anion gap, suggesting an additional unmeasured anion.

Pathophysiology Deep Dive

Propylene glycol, used as a solvent in lorazepam, diazepam, and other medications, can accumulate with continuous high-dose administration. Metabolism occurs via alcohol dehydrogenase and aldehyde dehydrogenase, producing lactate, pyruvate, and other organic acids. Propylene glycol has a molecular weight of 76 Da and can contribute directly to osmolal gap elevation.

Metabolism Pathway: Propylene Glycol → Lactaldehyde → Lactate/Pyruvate → Acidosis

Diagnostic Approach

Laboratory Investigations:

• Osmolal gap calculation: (Measured osmolality - Calculated osmolality)
• Propylene glycol level: Direct measurement (if available)
• Comprehensive metabolic panel: Monitor for AKI progression
• Medication review: Calculate cumulative propylene glycol exposure

Osmolal Gap Formula: Calculated osmolality = 2(Na⁺) + Glucose/18 + BUN/2.8 + Ethanol/4.6

Clinical Pearls:

1. Dose-Duration Relationship: Risk increases with doses >4mg/kg/hr for >48 hours
2. Dual Gap Presentation: Both anion gap and osmolal gap may be elevated
3. Multi-organ Involvement: Combines metabolic acidosis, AKI, and altered mental status

Management Strategy

Immediate Actions:

1. Discontinue propylene glycol-containing medications
2. Switch to alternative sedation: Dexmedetomidine, ketamine, or propofol
3. Enhanced elimination: Consider hemodialysis if severe (propylene glycol >25 mg/dL)
4. Supportive care: Optimize hemodynamics and organ support

Monitoring Parameters:

• Serial osmolal gaps
• Renal function trends
• Neurological status
• Acid-base parameters

Prevention Strategies

ICU Protocols:

• Limit continuous lorazepam to <48 hours when possible
• Calculate daily propylene glycol exposure
• Use alternative sedation in high-risk patients
• Regular monitoring of osmolal gap in long-term sedation

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Scenario 3: The Failing Liver's Cascade - Mixed Acid-Base Disorders in Hepatic Failure

Case Presentation

A 52-year-old female with acute-on-chronic liver failure presents with pH 7.45, PCO₂ 30 mmHg, HCO₃⁻ 20 mEq/L, lactate 4.5 mmol/L, and significant hyperammonemia (ammonia 180 μmol/L). The patient appears alkalemic despite elevated lactate and obvious metabolic derangement.

Clinical Challenge

The coexistence of metabolic acidosis (elevated lactate) with apparent alkalemia creates a diagnostic puzzle. Understanding the multiple acid-base disturbances in liver failure is crucial for appropriate management.

Pathophysiology Deep Dive

Liver failure creates a complex milieu of acid-base disturbances through multiple mechanisms:

Metabolic Acidosis Components:

• Lactic acidosis from impaired hepatic metabolism
• Ketoacidosis from altered fat metabolism
• Retention of organic acids (bile acids, etc.)

Metabolic Alkalosis Components:

• Hyperammonemia creating intracellular alkalosis
• Volume contraction from diuretics
• Hypokalemia and hypomagnesemia

Respiratory Alkalosis:

• Direct ammonia stimulation of respiratory center
• Hepatopulmonary syndrome with V/Q mismatch

Diagnostic Approach

Stewart Approach Application: Using strong ion difference (SID) and weak acid (Atot) analysis provides better insight than traditional Henderson-Hasselbalch approach.

Laboratory Assessment:

• Strong ions: Na⁺, K⁺, Cl⁻, lactate
• Weak acids: Albumin, phosphate
• Unmeasured anions: Anion gap calculation
• Ammonia level: Direct measurement

Clinical Pearls:

1. The Ammonia Effect: Hyperammonemia can mask metabolic acidosis by creating intracellular alkalosis
2. Albumin Contribution: Hypoalbuminemia reduces weak acid content, contributing to alkalosis
3. Chloride Responsiveness: May help differentiate saline-responsive vs. saline-resistant alkalosis

Management Strategy

Targeted Approach:

1. Address hyperammonemia: Lactulose, rifaximin, L-ornithine L-aspartate
2. Correct electrolyte abnormalities: Particularly K⁺ and Mg²⁺
3. Optimize volume status: Careful fluid management
4. Liver-specific therapies: NAC for acetaminophen toxicity, specific antidotes

Monitoring Strategy:

• Serial ammonia levels
• Electrolyte panels every 6-8 hours
• Neurological assessments
• Consider continuous pH monitoring

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Scenario 4: The Acetaminophen Paradox - Pyroglutamic Acidosis

Case Presentation

A 68-year-old malnourished female on chronic acetaminophen therapy (3g daily for arthritis) presents with high anion gap metabolic acidosis (pH 7.22, anion gap 22 mEq/L) and altered mental status. Acetaminophen level is therapeutic, lactate is normal, and ketones are negative.

Clinical Challenge

The patient presents with unexplained high anion gap acidosis despite therapeutic acetaminophen levels and absence of other obvious causes. The chronicity of acetaminophen use and patient's nutritional status provide important clues.

Pathophysiology Deep Dive

Pyroglutamic acid (5-oxoproline) acidosis results from depletion of glutathione stores, leading to accumulation of pyroglutamic acid. Acetaminophen, even in therapeutic doses, can precipitate this condition in vulnerable patients by depleting glutathione through normal metabolism.

Mechanism:

1. Acetaminophen depletes glutathione stores
2. γ-glutamyl cycle dysfunction occurs
3. Pyroglutamic acid accumulates
4. High anion gap metabolic acidosis develops

Risk Factors:

• Malnutrition
• Chronic acetaminophen use
• Female gender
• Sepsis or critical illness
• Concurrent medications (flucloxacillin, vigabatrin)

Diagnostic Approach

Laboratory Investigations:

• Urine organic acids: Elevated pyroglutamic acid (pathognomonic)
• Plasma amino acids: May show glutathione depletion
• 5-oxoproline level: Direct measurement if available

Clinical Diagnosis: Often requires high index of suspicion based on:

• High anion gap acidosis
• Chronic acetaminophen use
• Malnutrition or critical illness
• Exclusion of other causes

Diagnostic Pearls:

1. The Therapeutic Dose Trap: Occurs with therapeutic, not toxic, acetaminophen levels
2. Gender Predilection: More common in elderly malnourished females
3. Rapid Onset: Can develop within days of starting acetaminophen in susceptible patients

Management Strategy

Immediate Management:

1. Discontinue acetaminophen immediately
2. N-acetylcysteine (NAC): 150mg/kg loading dose, then maintenance
3. Supportive care: Correct dehydration and electrolyte abnormalities
4. Nutritional support: Address underlying malnutrition

Monitoring and Follow-up:

• Serial anion gap measurements
• Mental status assessment
• Consider alternative pain management strategies

Recovery Timeline:

• Acidosis typically resolves within 24-48 hours
• Complete recovery expected with appropriate treatment
• Recurrence likely if acetaminophen resumed

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Scenario 5: The Resuscitation Iatrogenesis - Hyperchloremic Acidosis in Fluid Therapy

Case Presentation

A 45-year-old male with septic shock receives 6 liters of normal saline in the first 24 hours. Despite improving hemodynamics, he develops metabolic acidosis with pH 7.32, HCO₃⁻ 18 mEq/L, normal anion gap (12 mEq/L), and hyperchloremia (Cl⁻ 115 mEq/L).

Clinical Challenge

The patient develops metabolic acidosis during resuscitation despite clinical improvement. Understanding the mechanism of normal saline-induced acidosis and its clinical implications is crucial for optimal fluid management.

Pathophysiology Deep Dive

Normal saline-induced hyperchloremic acidosis occurs through dilution of plasma bicarbonate and expansion of extracellular volume. The mechanism involves strong ion difference (SID) theory:

Stewart Physiology:

• Normal saline SID = 0 (154 mEq/L Na⁺ + 154 mEq/L Cl⁻)
• Plasma SID normally ~40 mEq/L
• Infusion of zero-SID solution reduces plasma SID
• Reduced SID → increased [H⁺] → metabolic acidosis

Volume Effects:

• Dilution of existing bicarbonate
• Expansion of chloride space
• Reduced strong ion difference

Diagnostic Approach

Laboratory Patterns:

• Normal anion gap: Chloride replaces unmeasured anions
• Hyperchloremia: Usually >108 mEq/L
• Preserved strong ion gap: Rules out unmeasured anions
• Urinary acidification: Appropriate response to acidosis

Quantitative Assessment: Calculate expected bicarbonate change based on fluid administered:

Formula: ΔCl⁻ × 0.3 = Expected ΔHCO₃⁻ reduction

Clinical Pearls:

1. The 1:1 Rule: For every 1 mEq/L increase in chloride above normal, expect ~0.3 mEq/L decrease in bicarbonate
2. Timing Relationship: Acidosis develops proportionally to volume of normal saline administered
3. Reversibility: Typically resolves with cessation of normal saline and appropriate fluid choice

Management Strategy

Immediate Actions:

1. Switch to balanced crystalloids: Lactated Ringer's, Plasma-Lyte, or Hartmann's solution
2. Assess fluid tolerance: Evaluate for fluid overload
3. Monitor renal function: Ensure adequate chloride elimination
4. Avoid bicarbonate therapy: Unless severe acidosis with hemodynamic compromise

Fluid Selection Guide:

• Balanced crystalloids for maintenance and replacement
• Normal saline only for specific indications (hypochloremic alkalosis, brain injury)
• Albumin solutions for volume expansion in appropriate patients

Prevention Strategies:

• Limit normal saline to <2-3 liters in initial resuscitation
• Use balanced solutions for ongoing maintenance
• Monitor chloride levels in high-volume resuscitation

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Advanced Diagnostic Approaches

The Modern Acid-Base Toolkit

1. Strong Ion Difference (SID) Analysis

• Apparent SID = [Na⁺] + [K⁺] - [Cl⁻] - [Lactate]
• Effective SID = SID - [Unmeasured strong anions]
• Normal range: 38-42 mEq/L

2. Anion Gap Subtypes

• Albumin-corrected AG: AG + 2.5 × (4.0 - [Albumin])
• Strong ion gap: AG - [Lactate] - [Ketones]
• Delta-delta ratio: Δ(AG)/Δ(HCO₃⁻)

3. Osmolal Gap Assessment

• Calculated osmolality = 2[Na⁺] + [Glucose]/18 + [BUN]/2.8
• Osmolal gap = Measured - Calculated osmolality
• Normal: <10 mOsm/kg H₂O

Clinical Decision-Making Framework

Step 1: Primary Disorder Identification

• pH analysis for primary disturbance
• Compensation assessment
• Mixed disorder evaluation

Step 2: Anion Gap Analysis

• Calculate corrected anion gap
• Identify unmeasured anions
• Assess strong ion gap

Step 3: Clinical Context Integration

• Patient history and medications
• Physical examination findings
• Ancillary laboratory tests

Step 4: Therapeutic Approach

• Address underlying cause
• Supportive measures
• Monitoring strategy

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Clinical Pearls and Oysters

Diagnostic Pearls

Pearl 1: The "Normal" Lactate Trap Normal L-lactate doesn't exclude lactic acidosis - consider D-lactate in patients with short gut syndrome or bacterial overgrowth.

Pearl 2: The Medication Detective Always calculate cumulative drug exposure for medications containing propylene glycol, especially in patients on continuous infusions.

Pearl 3: The Osmolal Gap Window An osmolal gap >25 mOsm/kg in the setting of metabolic acidosis suggests toxic alcohol or propylene glycol ingestion.

Pearl 4: The Albumin Adjustment Always correct the anion gap for hypoalbuminemia - each 1 g/dL decrease in albumin reduces the anion gap by ~2.5 mEq/L.

Pearl 5: The Stewart Advantage Use strong ion difference analysis when traditional approaches fail to explain acid-base disturbances, especially in complex ICU patients.

Diagnostic Oysters (Potential Pitfalls)

Oyster 1: The Bicarbonate Reflex Reflexive bicarbonate administration for acidosis can worsen intracellular acidosis and delay diagnosis of underlying disorders.

Oyster 2: The Single ABG Fallacy A single ABG provides only a snapshot - serial measurements are essential for understanding acid-base trends in critically ill patients.

Oyster 3: The Compensation Confusion Over-reliance on predicted compensation can miss mixed disorders - always consider clinical context and additional laboratory data.

Oyster 4: The Normal Saline Assumption Assuming normal saline is "physiologic" ignores its potential to cause hyperchloremic acidosis, especially in large volumes.

Oyster 5: The Lactate Tunnel Vision Focusing solely on lactate clearance can miss other important unmeasured anions contributing to persistent acidosis.

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Practical Management Hacks

ICU Bedside Calculations

Quick Anion Gap Correction: For every 1 g/dL ↓ in albumin, add 2.5 to the anion gap

Osmolal Gap Estimation: If unable to measure osmolality, suspect toxic ingestion when:

• High anion gap acidosis + altered mental status + normal lactate

Fluid Choice Decision Tree:

• Hyperchloremic acidosis → Switch to balanced crystalloids
• Hyponatremia → Consider normal saline
• Hypochloremic alkalosis → Normal saline indicated

Monitoring Strategies

High-Risk Patient Identification:

• Continuous sedation >48 hours → Monitor osmolal gap
• Chronic acetaminophen + malnutrition → Consider pyroglutamic acidosis
• Short gut syndrome + acidosis → Check D-lactate

Laboratory Ordering Hacks:

• Order D-lactate when standard lactate normal but high AG acidosis present
• Calculate osmolal gap routinely in unexplained altered mental status
• Check medication list for propylene glycol content in acidotic patients

Therapeutic Shortcuts

NAC Dosing for Pyroglutamic Acidosis: Use standard acetaminophen poisoning protocol even with therapeutic levels

Antibiotic Selection for D-lactic Acidosis: Oral vancomycin or metronidazole - avoid IV antibiotics that don't reach colonic lumen

Hemodialysis Indications: Consider for propylene glycol levels >25 mg/dL or osmolal gap >50 mOsm/kg

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Future Directions and Emerging Concepts

Point-of-Care Diagnostics

The development of rapid, bedside testing for unmeasured anions represents a significant advancement in critical care. Emerging technologies include:

Handheld Spectrometry: Portable devices capable of measuring D-lactate, propylene glycol, and other metabolites within minutes of sample collection.

Electronic Nose Technology: Breath analysis systems that can detect volatile metabolites associated with specific acid-base disorders.

Continuous Monitoring Systems: Implantable or wearable devices that provide real-time acid-base monitoring in high-risk patients.

Artificial Intelligence Applications

Machine learning algorithms are being developed to:

• Predict acid-base complications based on medication profiles
• Identify subtle patterns in laboratory data that suggest specific disorders
• Optimize fluid selection based on patient characteristics and clinical status

Precision Medicine Approaches

Genetic testing for enzyme polymorphisms affecting drug metabolism may help identify patients at increased risk for:

• Propylene glycol toxicity
• Pyroglutamic acidosis
• Abnormal lactate metabolism

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Conclusions

The management of complex acid-base disorders in the ICU requires a sophisticated understanding that extends far beyond simple ABG interpretation. The five scenarios presented illustrate several key principles:

1. Unmeasured anions play a crucial role in many ICU acid-base disorders and require specific diagnostic approaches and treatments.

2. Medication-related acidosis is increasingly common in the ICU setting, requiring vigilance in drug dosing and selection.

3. Mixed acid-base disorders are the rule rather than the exception in critically ill patients, necessitating systematic approaches to diagnosis.

4. Iatrogenic acidosis from fluid resuscitation can be prevented through appropriate crystalloid selection.

5. Therapeutic success depends on addressing underlying pathophysiology rather than merely correcting ABG parameters.

The integration of advanced diagnostic techniques, including strong ion difference analysis and targeted testing for specific metabolites, represents the future of acid-base medicine in the ICU. As our understanding of complex acid-base physiology continues to evolve, the ability to provide precision-based therapy for these challenging disorders will undoubtedly improve patient outcomes.

Successful management of complex acid-base disorders requires a combination of theoretical knowledge, clinical experience, and systematic diagnostic approaches. By understanding the limitations of traditional ABG interpretation and embracing advanced diagnostic techniques, clinicians can provide more effective care for critically ill patients with complex acid-base disturbances.

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References

1. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162-174.

2. Gunnerson KJ, Saul M, He S, Kellum JA. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit Care. 2006;10(1):R22.

3. Uribarri J, Oh MS, Carroll HJ. D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore). 1998;77(2):73-82.

4. Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines. Chest. 2005;128(3):1674-1681.

5. Duffull SB, Begg EJ, Robinson BA, Deely JM, Chin PK. Pyroglutamic acidosis: an adverse drug reaction. Expert Opin Drug Saf. 2012;11(5):815-825.

6. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. JAMA. 2012;307(15):1593-1601.

7. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983;61(12):1444-1461.

8. Kellum JA, Elbers PW. Stewart's Textbook of Acid-Base. 2nd ed. Amsterdam: AcidBase.org; 2009.

9. Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014;371(15):1434-1445.

10. Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371(19):1821-1831.

11. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3(1):208-225.

12. Gabow PA, Kaehny WD, Fennessey PV, Goodman SI, Gross PA, Schrier RW. Diagnostic importance of an increased serum anion gap. N Engl J Med. 1980;303(15):854-858.

13. Moviat M, Pickkers P, van der Voort PH, van der Hoeven JG. Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients. Crit Care. 2006;10(1):R14.

14. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-1572.

15. Guidet B, Soni N, Della Rocca G, et al. A balanced view of balanced solutions. Crit Care. 2010;14(5):325.

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Funding: This work received no specific funding.

Conflicts of Interest: The authors declare no conflicts of interest.