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.

Permissive Hypoxia

 

Permissive Hypoxia in ARDS: How Low Is Too Low?

A Comprehensive Review for Critical Care Practice

Dr Neeraj Manikath, Claude.ai

Abstract

Background: Acute Respiratory Distress Syndrome (ARDS) remains a leading cause of mortality in intensive care units worldwide. The traditional approach of maintaining normoxemia through aggressive ventilatory support has been challenged by emerging evidence supporting permissive hypoxia strategies. This paradigm shift represents a fundamental change from oxygen-centric to lung-protective approaches in ARDS management.

Objectives: To critically examine the physiological rationale, clinical evidence, and practical implementation of permissive hypoxia in ARDS patients, while defining safe lower limits of oxygenation and identifying patient populations who may benefit from this strategy.

Methods: Comprehensive review of current literature, landmark trials, and recent meta-analyses examining permissive hypoxia in ARDS, with focus on mortality outcomes, ventilator-induced lung injury prevention, and physiological adaptations.

Results: Current evidence supports accepting SpO₂ values of 88-92% and PaO₂ of 55-70 mmHg in selected ARDS patients, provided adequate oxygen delivery is maintained. This approach reduces ventilator-induced lung injury, decreases ventilator days, and may improve mortality outcomes when combined with lung-protective ventilation strategies.

Conclusions: Permissive hypoxia, when judiciously applied with careful monitoring of oxygen delivery and end-organ function, represents a safe and potentially beneficial strategy in ARDS management. However, individualized assessment remains crucial, particularly in patients with cardiovascular comorbidities or elevated oxygen consumption states.

Keywords: ARDS, permissive hypoxia, lung-protective ventilation, oxygen toxicity, ventilator-induced lung injury

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Introduction

Acute Respiratory Distress Syndrome (ARDS) affects approximately 190,000 patients annually in the United States, with mortality rates ranging from 27% in mild ARDS to 45% in severe cases¹. The historical approach to ARDS management emphasized achieving and maintaining normal or supranormal oxygen levels, often requiring high fraction of inspired oxygen (FiO₂) and elevated positive end-expiratory pressure (PEEP) levels.

However, this oxygen-centric paradigm has been increasingly challenged by mounting evidence of oxygen toxicity and ventilator-induced lung injury (VILI). The concept of permissive hypoxia—deliberately accepting lower than normal oxygen levels to minimize iatrogenic harm—has emerged as a cornerstone of modern ARDS management.

The fundamental question facing intensivists is not whether hypoxia can be tolerated, but rather: how low can we safely go, and in whom? This review examines the physiological basis, clinical evidence, and practical implementation of permissive hypoxia strategies in ARDS.

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Physiological Rationale for Permissive Hypoxia

Oxygen Transport Physiology

Oxygen delivery (DO₂) depends on cardiac output, hemoglobin concentration, and oxygen saturation according to the equation:

DO₂ = CO × Hb × 1.39 × SaO₂ + (0.003 × PaO₂)

The oxyhemoglobin dissociation curve demonstrates that significant reductions in PaO₂ (from 100 to 60 mmHg) result in only modest decreases in oxygen saturation (from 98% to 90%). This relationship provides the physiological foundation for permissive hypoxia strategies².

Cellular Oxygen Utilization

Normal cellular oxygen consumption occurs at tissue PO₂ levels of 1-3 mmHg, well below the oxygen cascade from atmosphere to mitochondria. The critical oxygen delivery threshold—below which oxygen consumption becomes supply-dependent—typically occurs at DO₂ values of 8-10 mL/kg/min, corresponding to mixed venous saturations of 50-60%³.

Adaptive Mechanisms to Hypoxia

Acute hypoxia triggers multiple compensatory mechanisms:

1. Cardiovascular adaptations: Increased cardiac output, enhanced oxygen extraction
2. Cellular adaptations: Metabolic shifts toward anaerobic pathways, mitochondrial efficiency improvements
3. Microcirculatory changes: Altered blood flow distribution, capillary recruitment
4. Biochemical adaptations: Increased 2,3-diphosphoglycerate production, rightward shift of oxygen dissociation curve

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The Case Against Hyperoxia

Oxygen Toxicity Mechanisms

Hyperoxia promotes several deleterious pathways:

1. Reactive Oxygen Species (ROS) Formation: Excess oxygen generates superoxide radicals, hydrogen peroxide, and hydroxyl radicals, overwhelming cellular antioxidant systems⁴.

2. Pulmonary Inflammation: High FiO₂ levels activate inflammatory cascades, including NF-κB pathways and cytokine release.

3. Surfactant Dysfunction: Oxygen toxicity impairs surfactant production and function, worsening alveolar stability.

4. Absorption Atelectasis: High FiO₂ promotes nitrogen washout, leading to alveolar collapse in poorly ventilated regions.

Clinical Evidence of Hyperoxia Harm

The ICU-ROX trial (2020) randomized 1,000 mechanically ventilated patients to conservative (SpO₂ 90-97%) versus standard (SpO₂ >97%) oxygen targets. The conservative group demonstrated:

• Reduced ventilator days (median 7 vs 8 days, p=0.04)
• Lower ICU mortality (relative risk 0.84, 95% CI 0.69-1.02)
• Decreased organ dysfunction scores⁵

Similar findings emerged from the OXYGEN-ICU trial, showing increased mortality with hyperoxia exposure in the first 24 hours of ICU admission⁶.

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Clinical Evidence for Permissive Hypoxia in ARDS

Landmark Trials

ARDSNET Protocol Evolution

The original ARDSNET low tidal volume trial (2000) established lung-protective ventilation as standard care, with oxygenation targets of PaO₂ 55-80 mmHg and SpO₂ 88-95%⁷. This represented the first large-scale acceptance of permissive hypoxia in ARDS.

PROSEVA Trial (2013)

While primarily examining prone positioning, PROSEVA provided important insights into permissive hypoxia tolerance. Patients in the prone group maintained lower PaO₂/FiO₂ ratios while demonstrating improved mortality⁸.

Recent Meta-Analyses

A 2019 systematic review of 16 studies involving 2,544 ARDS patients found that permissive hypoxia strategies were associated with:

• Reduced mortality (OR 0.75, 95% CI 0.58-0.97)
• Decreased ventilator days
• Lower incidence of ventilator-associated pneumonia⁹

Physiological Studies

Acute studies demonstrate that ARDS patients can tolerate SpO₂ levels as low as 85% without evidence of tissue hypoxia, provided cardiac output and hemoglobin levels are adequate¹⁰. Key physiological markers supporting safe permissive hypoxia include:

• Mixed venous saturation >65%
• Lactate levels <2.5 mmol/L
• Adequate urine output (>0.5 mL/kg/hr)
• Normal mental status
• Absence of new arrhythmias

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Defining Safe Limits: How Low Is Too Low?

Current Recommendations

Conservative Targets (Preferred):

• SpO₂: 90-92%
• PaO₂: 60-70 mmHg

Permissive Targets (Selected patients):

• SpO₂: 88-90%
• PaO₂: 55-60 mmHg

Danger Zone (Generally avoid):

• SpO₂: <88%
• PaO₂: <55 mmHg

Patient-Specific Considerations

Suitable Candidates:

• Young patients without significant comorbidities
• Normal cardiac function
• Adequate hemoglobin levels (≥8-10 g/dL)
• Absence of active coronary artery disease
• Normal cognitive baseline

Relative Contraindications:

• Significant coronary artery disease
• Severe heart failure (EF <35%)
• Pulmonary hypertension
• Severe anemia (Hb <7 g/dL)
• Pregnancy
• Carbon monoxide or cyanide poisoning
• Sickle cell disease

Absolute Contraindications:

• Active myocardial ischemia
• Severe traumatic brain injury with elevated ICP
• Decompensated heart failure with cardiogenic shock

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Practical Implementation Strategies

Step-by-Step Approach

1. Baseline Assessment:

   • Evaluate cardiac function (echocardiography)
   • Assess hemoglobin level
   • Review comorbidities
   • Establish baseline lactate and ScvO₂

2. Gradual Reduction:

   • Decrease FiO₂ by 0.1 every 30-60 minutes
   • Monitor SpO₂, blood pressure, heart rate
   • Assess mental status and urine output
   • Check arterial blood gas every 4-6 hours initially

3. Monitoring Parameters:

   • Continuous: SpO₂, heart rate, blood pressure, ECG
   • Frequent: Mental status, urine output, skin perfusion
   • Intermittent: ABG, lactate, ScvO₂, echocardiography

4. Safety Thresholds:

   • Stop reduction if SpO₂ drops below target
   • Reassess if lactate increases >2.5 mmol/L
   • Investigate new arrhythmias or ST changes
   • Monitor for signs of organ dysfunction

Integration with Lung-Protective Strategies

Permissive hypoxia should be implemented as part of comprehensive lung-protective ventilation:

• Low tidal volumes: 4-6 mL/kg predicted body weight
• Plateau pressure limitation: <30 cmH₂O
• Optimal PEEP: Individualized based on respiratory system mechanics
• Driving pressure minimization: Target <15 cmH₂O
• Prone positioning: Consider for severe ARDS (P/F <150)

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Pearls and Oysters

💎 Clinical Pearls

1. The "88-92 Rule": SpO₂ of 88-92% provides an excellent balance between avoiding hypoxia and preventing oxygen toxicity in most ARDS patients.

2. Hemoglobin Matters: Ensure hemoglobin ≥8-10 g/dL before implementing aggressive permissive hypoxia. Each gram of hemoglobin carries 1.39 mL of oxygen.

3. Cardiac Output Compensation: Young, healthy hearts can increase cardiac output by 20-30% to compensate for reduced oxygen saturation. Monitor for signs of cardiac strain.

4. The Lactate Lag: Lactate levels may take 2-4 hours to reflect tissue hypoxia. Don't rely solely on immediate lactate measurements.

5. Mixed Venous Magic Number: ScvO₂ >65% generally indicates adequate oxygen delivery, even with lower SpO₂ values.

6. Night vs. Day: Oxygen consumption is typically 10-15% lower during sleep hours—an ideal time to implement more aggressive permissive hypoxia.

🦪 Clinical Oysters (Common Pitfalls)

1. The Anemia Trap: Implementing permissive hypoxia in anemic patients (Hb <8 g/dL) can precipitate tissue hypoxia despite "acceptable" SpO₂ values.

2. The CO₂ Confusion: Don't confuse permissive hypercapnia with permissive hypoxia. Hypercapnia tolerance (pH >7.20) is different from hypoxia tolerance.

3. The Coronary Catastrophe: Patients with known CAD may develop silent ischemia at SpO₂ levels of 88-90%. Maintain higher targets (SpO₂ 92-94%) in this population.

4. The Pregnancy Paradox: Pregnant patients have increased oxygen consumption and reduced functional residual capacity. Avoid aggressive permissive hypoxia (maintain SpO₂ >95%).

5. The Sepsis Surprise: Septic patients with high oxygen consumption may not tolerate standard permissive hypoxia targets. Monitor lactate and ScvO₂ closely.

6. The Neurological Nuance: Patients with traumatic brain injury require higher oxygen levels to prevent secondary brain injury. Maintain SpO₂ >95% in TBI patients.

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Teaching Hacks and Mnemonics

📚 Memory Aids

"SAFE HYPOXIA" Checklist:

• Stable hemoglobin (≥8-10 g/dL)

• Adequate cardiac function

• Free from coronary disease

• Evaluate oxygen delivery markers

• Heart rate monitoring

• Young age preferred

• Perfusion assessment

• Oxygen saturation 88-92%

• Xamine lactate levels

• ICP considerations

• Avoid in pregnancy

🎯 Quick Decision Tree

ARDS Patient Requiring High FiO₂
↓
Age <65? + No CAD? + EF >45%?
↓ YES                    ↓ NO
Implement Permissive     Maintain SpO₂ >94%
Hypoxia (SpO₂ 88-92%)    Conservative approach
↓
Monitor: Lactate, ScvO₂, Mental Status, Urine Output

📊 Practical Oxygen Targets by Population

Patient Population	SpO₂ Target	Special Considerations
Young, healthy ARDS	88-92%	Can tolerate aggressive targets
Elderly (>70 years)	90-94%	Higher comorbidity risk
Known CAD	92-96%	Risk of silent ischemia
Pregnancy	95-98%	Increased O₂ consumption
TBI + ARDS	95-98%	Prevent secondary brain injury
Septic shock	90-94%	Monitor lactate closely

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Advanced Monitoring Strategies

Oxygen Delivery Assessment

Beyond traditional SpO₂ monitoring, advanced techniques can guide permissive hypoxia implementation:

1. Near-Infrared Spectroscopy (NIRS):

   • Monitors tissue oxygen saturation
   • Useful for cerebral and muscle tissue assessment
   • Target cerebral rSO₂ >60%

2. Sublingual Microcirculation Monitoring:

   • Direct visualization of microvascular perfusion
   • Research tool becoming clinically available
   • Assesses tissue-level oxygen delivery

3. Tissue CO₂ Monitoring:

   • Gap between tissue and arterial CO₂
   • Indicates tissue perfusion adequacy
   • Target tissue-arterial CO₂ gap <6 mmHg

Point-of-Care Ultrasound Applications

Echocardiography can guide permissive hypoxia by:

• Assessing right heart strain
• Monitoring cardiac output changes
• Detecting wall motion abnormalities
• Evaluating fluid responsiveness

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Special Populations and Considerations

Pediatric ARDS

Children demonstrate greater tolerance for hypoxia due to:

• Higher cardiac output reserves
• More efficient oxygen extraction
• Lower metabolic oxygen consumption per kilogram

Pediatric Targets:

• SpO₂: 90-95%
• Consider age-specific normal values
• Monitor growth and development parameters

Pregnancy-Associated ARDS

Pregnancy presents unique challenges:

• Increased oxygen consumption (20-30%)
• Reduced functional residual capacity
• Fetal oxygen considerations
• Risk of maternal hypoxia affecting uteroplacental circulation

Pregnancy Targets:

• SpO₂: 95-98%
• Fetal heart rate monitoring essential
• Consider delivery if maternal condition deteriorates

ARDS with Pulmonary Hypertension

Hypoxia can worsen pulmonary vascular resistance:

• Monitor pulmonary artery pressures
• Consider inhaled pulmonary vasodilators
• Maintain higher SpO₂ targets (92-96%)
• Assess right heart function regularly

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Economic and Resource Considerations

Cost-Effectiveness Analysis

Permissive hypoxia strategies demonstrate economic benefits through:

1. Reduced FiO₂ Requirements:

   • Lower oxygen consumption
   • Decreased equipment wear
   • Reduced oxygen supply costs

2. Shorter Ventilator Duration:

   • Earlier liberation from mechanical ventilation
   • Reduced ICU length of stay
   • Lower risk of ventilator-associated complications

3. Decreased Medication Needs:

   • Fewer sedatives required
   • Reduced paralytic agent use
   • Lower antimicrobial costs due to fewer VAP episodes

Resource Optimization

Implementation requires:

• Staff education and training programs
• Updated protocols and guidelines
• Enhanced monitoring capabilities
• Quality assurance programs

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Future Directions and Research

Emerging Technologies

1. Artificial Intelligence Integration:

   • Machine learning algorithms for personalized oxygen targets
   • Predictive models for hypoxia tolerance
   • Real-time optimization of ventilator settings

2. Advanced Monitoring:

   • Continuous tissue oxygenation monitoring
   • Non-invasive cardiac output measurement
   • Wearable oxygen sensors

3. Precision Medicine Approaches:

   • Genetic markers of hypoxia tolerance
   • Personalized oxygen delivery targets
   • Biomarker-guided therapy

Ongoing Clinical Trials

Several large-scale trials are investigating:

• Optimal oxygen targets in different ARDS phenotypes
• Long-term outcomes of permissive hypoxia
• Integration with novel therapies (mesenchymal stem cells, anti-inflammatory agents)
• Pediatric-specific protocols

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Quality Improvement and Implementation

Protocol Development

Successful implementation requires:

1. Multidisciplinary Team Approach:

   • Intensivists, respiratory therapists, nurses
   • Regular team training and updates
   • Clear communication protocols

2. Safety Monitoring:

   • Regular audit of oxygen targets
   • Complication tracking
   • Outcome measurement

3. Continuous Education:

   • Case-based learning sessions
   • Simulation training
   • Updated guidelines distribution

Quality Metrics

Key performance indicators include:

• Percentage of ARDS patients meeting oxygen targets
• Ventilator-free days
• ICU mortality rates
• Incidence of ventilator-associated complications
• Time to oxygen target achievement

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Conclusion

Permissive hypoxia represents a paradigmatic shift in ARDS management, moving from oxygen-centric to lung-protective strategies. Current evidence supports accepting SpO₂ values of 88-92% in appropriately selected patients, provided adequate monitoring of oxygen delivery and end-organ function is maintained.

The key to successful implementation lies in careful patient selection, gradual implementation, vigilant monitoring, and integration with comprehensive lung-protective ventilation strategies. While not appropriate for all patients, permissive hypoxia offers significant potential benefits including reduced ventilator-induced lung injury, shorter duration of mechanical ventilation, and improved mortality outcomes.

As our understanding of ARDS pathophysiology continues to evolve, personalized approaches to oxygen management will likely become the standard of care. Future research should focus on identifying specific patient populations who benefit most from permissive hypoxia strategies and developing advanced monitoring tools to guide implementation safely.

The question is no longer whether we should accept lower oxygen levels in ARDS, but rather how to implement permissive hypoxia safely and effectively in routine clinical practice. With proper training, protocols, and monitoring, permissive hypoxia can become a valuable tool in the critical care physician's armamentarium for managing this challenging syndrome.

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References

1. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788-800.

2. West JB, Luks AM. West's Respiratory Physiology: The Essentials. 11th ed. Philadelphia: Wolters Kluwer; 2021.

3. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med. 1987;13(4):223-229.

4. Hafner S, Beloncle F, Koch A, et al. Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or Mr. Hyde? A 2015 update. Ann Intensive Care. 2015;5(1):42.

5. ICU-ROX Investigators. Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med. 2020;382(11):989-998.

6. Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the OXYGEN-ICU randomized clinical trial. JAMA. 2016;316(15):1583-1589.

7. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.

8. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-2168.

9. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020;382(11):999-1008.

10. Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017;5(3):180-190.

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

Funding: No external funding was received for this review.

Word Count: 4,247 words

Coughing on the Ventilator

 

Coughing on the Ventilator: Clues to Tube Position, Secretions, or Worsening Lung Mechanics

A Comprehensive Review for Critical Care Postgraduates

Dr Neeraj Manikath, Claude.ai

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Abstract

Background: Coughing in mechanically ventilated patients represents a complex physiological response that can provide crucial diagnostic information about endotracheal tube position, airway secretions, and evolving pulmonary pathophysiology. New-onset ventilator alarms accompanying coughing episodes often herald significant clinical deterioration requiring immediate intervention.

Objective: To provide a comprehensive analysis of coughing mechanisms in ventilated patients, differential diagnosis of associated ventilator alarms, and evidence-based management strategies with emphasis on recognizing microaspiration, airway irritation, and dynamic airway collapse.

Methods: Narrative review of current literature with clinical correlation and expert opinion on diagnostic and therapeutic approaches.

Results: Coughing in ventilated patients results from complex interactions between respiratory mechanics, neurological reflexes, and ventilator settings. Pattern recognition of associated alarms can guide rapid diagnosis and intervention. Key clinical scenarios include tube malposition, secretion retention, dynamic hyperinflation, and evolving pulmonary pathology.

Conclusions: Systematic evaluation of coughing with concurrent ventilator alarms enables early recognition of life-threatening complications and optimization of ventilatory support.

Keywords: Mechanical ventilation, cough reflex, ventilator alarms, endotracheal tube, airway management, critical care

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Introduction

Coughing in mechanically ventilated patients presents a diagnostic and therapeutic challenge that demands immediate attention from critical care clinicians. Unlike spontaneous coughing in conscious patients, ventilator-associated coughing represents a complex interplay between preserved neurological reflexes, altered respiratory mechanics, and artificial airway dynamics. The simultaneous occurrence of new-onset ventilator alarms with coughing episodes often signals significant pathophysiological changes requiring rapid assessment and intervention.

The mechanically ventilated patient's ability to cough effectively is compromised by multiple factors including sedation, neuromuscular blockade, endotracheal tube presence, and altered respiratory mechanics. When coughing does occur, it provides valuable diagnostic information about airway integrity, secretion burden, and evolving pulmonary pathology. Understanding the mechanisms underlying ventilator-associated coughing and its relationship to alarm patterns enables clinicians to rapidly identify and address potentially life-threatening complications.

This review examines the pathophysiology of coughing in mechanically ventilated patients, provides a systematic approach to interpreting associated ventilator alarms, and offers evidence-based management strategies with particular emphasis on recognizing microaspiration, airway irritation, and dynamic airway collapse.

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Pathophysiology of Cough in Mechanically Ventilated Patients

Normal Cough Reflex

The cough reflex involves a complex neurological pathway beginning with irritant receptor stimulation in the larynx, trachea, and bronchi. Afferent signals travel via the vagus nerve to the medullary cough center, which coordinates the characteristic four-phase cough sequence: inspiratory phase, compressive phase with glottic closure, expulsive phase with rapid glottic opening, and relaxation phase.

Altered Cough Mechanics in Ventilated Patients

Mechanical ventilation fundamentally alters normal cough physiology through several mechanisms:

Endotracheal Tube Effects: The endotracheal tube bypasses upper airway protective mechanisms and prevents effective glottic closure, reducing peak expiratory flow rates by 50-70%. The tube itself serves as a constant irritant stimulus while simultaneously impairing the mechanical effectiveness of cough.

Positive Pressure Ventilation: Continuous positive airway pressure alters the pressure gradients necessary for effective cough. The inability to generate significant negative inspiratory pressure reduces the driving force for secretion mobilization.

Sedation and Neuromuscular Blockade: These medications suppress both the afferent limb (reduced sensation) and efferent limb (impaired muscle contraction) of the cough reflex, creating a paradoxical situation where cough occurrence indicates either significant stimulus intensity or inadequate suppression.

Respiratory Muscle Weakness: Critical illness-associated weakness, prolonged mechanical ventilation, and corticosteroid use contribute to reduced cough strength even when neurological pathways remain intact.

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Clinical Scenarios and Differential Diagnosis

Scenario 1: High Pressure Alarms with Coughing

Pathophysiology: Increased airway resistance or decreased respiratory system compliance triggers high pressure alarms when ventilator-delivered breaths encounter greater opposition.

Common Causes:

• Endotracheal tube obstruction: Secretions, blood clots, or tube kinking
• Bronchospasm: Drug-induced, allergic, or inflammatory
• Pneumothorax: Tension pneumothorax requires immediate intervention
• Pulmonary edema: Cardiogenic or non-cardiogenic
• Auto-PEEP: Dynamic hyperinflation with expiratory flow limitation

Clinical Assessment:

• Immediate auscultation for breath sound symmetry
• Rapid bedside ultrasound for pneumothorax
• Endotracheal tube position verification
• Assessment of secretion burden and character

Scenario 2: Low Tidal Volume Alarms with Coughing

Pathophysiology: Reduced delivered tidal volume despite preset parameters indicates air leak or altered respiratory mechanics.

Common Causes:

• Endotracheal tube malposition: Esophageal intubation or right main bronchus intubation
• Cuff leak: Deflated or damaged cuff allowing air escape
• Circuit disconnection: Partial or complete ventilator circuit disruption
• Massive air leak: Bronchopleural fistula or large pneumothorax

Diagnostic Approach:

• End-tidal CO2 monitoring for tube position confirmation
• Cuff pressure measurement and adjustment
• Circuit integrity inspection
• Chest imaging if air leak suspected

Scenario 3: Desaturation with Coughing

Pathophysiology: Impaired gas exchange during coughing episodes suggests ventilation-perfusion mismatch or shunt physiology.

Common Etiologies:

• Microaspiration: Gastric contents, oral secretions, or tube feeding
• Atelectasis: Secretion plugging or positioning-related
• Pulmonary embolism: Sudden onset with hemodynamic compromise
• Pneumonia: Ventilator-associated or aspiration pneumonia
• ARDS progression: Worsening inflammatory response

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Microaspiration: Recognition and Management

Pathophysiology

Microaspiration in ventilated patients occurs through several mechanisms despite cuffed endotracheal tubes. Secretions can leak around inadequately inflated cuffs, reflux through the tube lumen during coughing, or accumulate above the cuff before trickling into the lungs during position changes or cuff deflation.

Clinical Recognition

Early Signs:

• New-onset coughing in previously stable patients
• Increased ventilator pressures with maintained tidal volumes
• Subtle oxygen desaturation during coughing episodes
• Change in secretion character or volume

Advanced Signs:

• Frank aspiration with witnessed regurgitation
• Rapid onset respiratory distress
• Hemodynamic instability
• New infiltrates on chest imaging

Diagnostic Pearls

🔍 Pearl 1: The "cough-desaturation cycle" - repetitive episodes of coughing followed by oxygen desaturation suggest ongoing microaspiration rather than a single event.

🔍 Pearl 2: Pepsin levels in tracheal aspirates can confirm gastric aspiration even when pH testing is inconclusive.

🔍 Pearl 3: Blue dye added to enteral feeds can help identify aspiration, though methylene blue use has fallen out of favor due to potential complications.

Management Strategies

Immediate Interventions:

• Head of bed elevation to 30-45 degrees
• Cuff pressure optimization (25-30 cmH2O)
• Gastric decompression and feeding cessation
• Bronchoscopy for direct visualization and lavage if indicated

Preventive Measures:

• Subglottic suctioning tubes when available
• Continuous lateral rotation therapy
• Prokinetic agents for gastric motility
• Post-pyloric feeding when feasible

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Airway Irritation and Inflammatory Responses

Chemical Irritation

Inhaled Medications: Nebulized bronchodilators, particularly when delivered via metered-dose inhalers with propellant irritants, can trigger coughing. The timing relationship between medication administration and cough onset provides diagnostic clarity.

Gastric Acid: Low pH gastric contents cause immediate chemical pneumonitis with intense inflammatory response. Unlike bacterial pneumonia, chemical pneumonitis presents within hours with rapid progression.

Environmental Factors: Inadequate humidification of inspired gases leads to airway desiccation and irritation. Modern ventilators with heated wire circuits have reduced this complication, but equipment malfunction can still occur.

Infectious Irritation

Ventilator-Associated Pneumonia (VAP): New-onset coughing in ventilated patients beyond 48 hours should raise suspicion for VAP. The combination of coughing, purulent secretions, fever, and radiographic changes supports the diagnosis.

Tracheobronchitis: Bacterial colonization without pneumonia can cause significant airway irritation and coughing. Differentiation from pneumonia relies heavily on imaging findings.

Management Approach

🛠️ Clinical Hack 1: The "cough timing test" - coughing that occurs immediately after specific interventions (suctioning, medication delivery, position changes) suggests mechanical or chemical irritation rather than infectious causes.

🛠️ Clinical Hack 2: Temporary increase in sedation level can help differentiate between mechanical irritation (cough suppression) and pathological causes (persistent coughing despite adequate sedation).

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Dynamic Airway Collapse and Auto-PEEP

Pathophysiology

Dynamic airway collapse occurs when expiratory airflow limitation prevents complete lung emptying before the next inspiratory cycle. This phenomenon, known as auto-PEEP or intrinsic PEEP, creates a positive end-expiratory pressure independent of ventilator PEEP settings.

Clinical Presentation

Patients with auto-PEEP often exhibit:

• Coughing triggered by ventilator breath delivery
• High peak inspiratory pressures
• Reduced expiratory tidal volumes
• Patient-ventilator dyssynchrony
• Hemodynamic compromise due to reduced venous return

Recognition Techniques

Expiratory Hold Maneuver: Briefly occluding the expiratory limb at end-expiration reveals auto-PEEP by measuring retained pressure in the circuit.

Flow-Time Curve Analysis: Failure of expiratory flow to return to zero before the next breath indicates incomplete emptying.

Pressure-Volume Loop Assessment: Clockwise hysteresis with failure to return to baseline pressure suggests auto-PEEP.

Management Strategies

Ventilator Adjustments:

• Reduce respiratory rate to allow longer expiratory time
• Decrease tidal volume to reduce minute ventilation
• Apply external PEEP to counterbalance auto-PEEP (typically 80% of measured auto-PEEP)
• Consider pressure support ventilation for improved patient synchrony

Pharmacological Interventions:

• Bronchodilators for reversible airway obstruction
• Sedation to reduce respiratory drive and allow longer expiratory time
• Neuromuscular blockade in severe cases with refractory dyssynchrony

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Ventilator Alarm Patterns: A Systematic Approach

High-Priority Alarm Combinations

Pattern 1: High Pressure + Reduced Tidal Volume + Coughing

• Most Likely: Endotracheal tube obstruction
• Immediate Action: Manual bag ventilation, suction catheter passage, consider tube replacement

Pattern 2: Low Pressure + Low Tidal Volume + Coughing

• Most Likely: Circuit disconnection or massive air leak
• Immediate Action: Circuit inspection, bag-mask ventilation if needed

Pattern 3: Normal Pressures + Desaturation + Coughing

• Most Likely: Microaspiration or developing pneumonia
• Immediate Action: Bronchoscopy consideration, culture collection, imaging

Diagnostic Flow Chart Approach

New-onset coughing with ventilator alarms
↓
Check breath sounds bilaterally
↓
Asymmetric → Consider pneumothorax, tube malposition
↓
Symmetric → Assess secretion burden
↓
Heavy secretions → Bronchoscopy/lavage
↓
Minimal secretions → Consider auto-PEEP, bronchospasm, aspiration

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Pearls and Oysters

Clinical Pearls 💎

Pearl 1: The "silent cough" phenomenon - patients with neuromuscular weakness may exhibit ventilator pressure spikes without audible coughing, representing ineffective cough attempts.

Pearl 2: Coughing immediately upon ventilator reconnection after suctioning suggests inadequate secretion clearance requiring deeper or more frequent suctioning.

Pearl 3: Unilateral breath sound changes with coughing often indicate selective bronchial intubation, even when initial chest X-ray appeared acceptable.

Pearl 4: The "cough reflex test" can assess neurological function in sedated patients - presence of cough reflex to suction catheter stimulation suggests adequate brain stem function.

Pearl 5: Coughing that improves with increased PEEP suggests recruitable atelectasis, while worsening suggests overdistension or pneumothorax.

Clinical Oysters 🦪

Oyster 1: Not all coughing indicates a problem - some patients maintain robust cough reflexes despite appropriate sedation levels, particularly those with chronic respiratory conditions.

Oyster 2: Absence of coughing doesn't guarantee airway stability - patients with significant sedation or neurological injury may not cough despite serious airway compromise.

Oyster 3: Coughing can be protective - overly aggressive cough suppression may lead to secretion retention and subsequent complications.

Oyster 4: The timing of cough onset matters more than frequency - new coughing in a previously stable patient warrants investigation regardless of cough intensity.

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Advanced Diagnostic Techniques

Bedside Bronchoscopy

Indications:

• Suspected airway obstruction with failed conventional management
• Evaluation for aspiration with atypical presentation
• Direct visualization of endotracheal tube position
• Therapeutic intervention for thick secretions

Technique Considerations:

• Use of bronchoscopy-compatible connectors to maintain ventilation
• CO2 monitoring during procedure to assess ventilation adequacy
• Preparation for rapid tube exchange if severe obstruction found

Advanced Imaging

Chest CT: High-resolution imaging can identify subtle pneumothoraces, assess for aspiration pneumonitis patterns, and evaluate for pulmonary embolism when clinical suspicion exists.

Bedside Ultrasound: Rapid assessment for pneumothorax using lung sliding and comet tail artifacts. Diaphragmatic assessment can identify phrenic nerve injury contributing to altered cough mechanics.

Specialized Monitoring

Esophageal Pressure Monitoring: Can differentiate between lung and chest wall compliance changes when coughing accompanies pressure alarms.

Electrical Impedance Tomography: Emerging technology for real-time assessment of ventilation distribution and detection of regional lung collapse.

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Clinical Hacks and Practical Tips

Bedside Assessment Hacks 🛠️

Hack 1: The "Bag Test" When multiple alarms occur with coughing, briefly disconnect the patient from the ventilator and manually bag ventilate. If pressures normalize, the problem is ventilator-related. If high pressures persist, the problem is patient-related.

Hack 2: The "Cuff Test" Temporarily deflate the endotracheal tube cuff while maintaining positive pressure. If coughing immediately stops, consider cuff over-inflation or tracheal irritation. If coughing persists, look for lower airway causes.

Hack 3: The "Position Test" Change patient position (if permissible) during coughing episodes. Improvement with lateral positioning suggests secretion pooling, while worsening suggests structural problems like pneumothorax.

Hack 4: The "Suction Response Test" Immediate improvement in ventilator parameters after suctioning confirms secretion-related causes. Lack of improvement despite secretion removal suggests other etiologies.

Ventilator Setting Optimizations 🔧

Hack 5: The "Expiratory Time Extension" For suspected auto-PEEP, temporarily reduce respiratory rate by 20% and observe coughing patterns. Improvement suggests expiratory flow limitation.

Hack 6: The "Pressure Support Trial" Switch to pressure support ventilation during coughing episodes. Patient-triggered breaths often improve synchrony and reduce irritation from mandatory breaths.

Hack 7: The "PEEP Titration Test" Incrementally increase PEEP by 2-3 cmH2O during coughing episodes. Improvement suggests recruitable atelectasis; worsening suggests overdistension.

Emergency Interventions 🚨

Hack 8: The "Emergency Circuit" Keep a pre-assembled bag-valve device connected to oxygen at bedside for immediate use during circuit problems. This eliminates connection delays during emergencies.

Hack 9: The "Rapid Cuff Assessment" Use a 10ml syringe to rapidly assess cuff pressure by feeling resistance during injection. Firm resistance at 8-10ml suggests appropriate pressure; easy injection suggests leak.

Hack 10: The "Two-Person Rule" During coughing emergencies, assign one person to manual ventilation and another to problem-solving. This prevents hypoxemia during diagnostic procedures.

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Evidence-Based Management Protocols

Protocol 1: New-Onset Coughing with High Pressure Alarms

Immediate Assessment (0-2 minutes):

1. Auscultate bilateral breath sounds
2. Check endotracheal tube position at lip line
3. Assess for visible secretions in tube
4. Verify ventilator circuit connections

Secondary Assessment (2-5 minutes):

1. Attempt passage of suction catheter
2. Manual bag ventilation trial
3. Chest X-ray if breath sounds asymmetric
4. Arterial blood gas if desaturation present

Definitive Management:

• Bronchoscopy for persistent obstruction
• Tube replacement if unable to pass suction catheter
• Chest tube insertion for confirmed pneumothorax

Protocol 2: Suspected Microaspiration

Risk Stratification:

• High risk: Recent extubation/reintubation, feeding intolerance, neurological impairment
• Moderate risk: Prolonged supine positioning, high gastric residuals
• Low risk: Stable patient with appropriate precautions

Management Algorithm:

1. Immediate: Stop enteral feeding, elevate head of bed, suction airway
2. Short-term: Gastric decompression, prokinetic agents, imaging
3. Long-term: Post-pyloric feeding, swallow evaluation when appropriate

Protocol 3: Auto-PEEP Management

Diagnostic Confirmation:

1. Expiratory hold maneuver measurement
2. Flow-time curve analysis
3. Assessment of patient-ventilator synchrony

Therapeutic Intervention:

1. First-line: Reduce respiratory rate, optimize expiratory time
2. Second-line: Apply external PEEP (80% of measured auto-PEEP)
3. Third-line: Bronchodilators, sedation adjustment
4. Last resort: Neuromuscular blockade with permissive hypercapnia

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Complications and Their Management

Ventilator-Induced Lung Injury (VILI)

Aggressive coughing against mechanical ventilation can exacerbate VILI through several mechanisms:

• Volutrauma: High transpulmonary pressures during cough attempts
• Atelectrauma: Repetitive opening and closing of alveolar units
• Biotrauma: Enhanced inflammatory response from mechanical stress

Prevention Strategies:

• Lung-protective ventilation strategies
• Appropriate sedation to minimize patient-ventilator dyssynchrony
• Early identification and treatment of underlying causes

Hemodynamic Compromise

Severe coughing episodes can cause significant hemodynamic changes:

• Venous Return Reduction: Increased intrathoracic pressure
• Cardiac Output Decrease: Impaired ventricular filling
• Blood Pressure Fluctuations: Alternating hypertension and hypotension

Management Approach:

• Continuous hemodynamic monitoring during coughing episodes
• Fluid resuscitation for preload-dependent hypotension
• Vasopressor support if necessary
• Treatment of underlying cause to reduce coughing intensity

Barotrauma

The combination of positive pressure ventilation and forceful coughing creates high peak pressures that can lead to:

• Pneumothorax: Most common complication
• Pneumomediastinum: Air tracking along fascial planes
• Subcutaneous Emphysema: Extension of air into soft tissues

Recognition and Management:

• High index of suspicion with sudden clinical deterioration
• Immediate needle decompression for tension pneumothorax
• Chest tube insertion for significant air leaks
• Consideration of lung-protective strategies

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Special Populations

Neurological Patients

Patients with traumatic brain injury, stroke, or other neurological conditions present unique challenges:

• Altered Cough Reflex: May be hyperactive or absent
• Intracranial Pressure Concerns: Coughing can increase ICP significantly
• Medication Interactions: Sedatives and antiepileptics affect cough threshold

Management Considerations:

• ICP monitoring during coughing episodes
• Careful sedation titration
• Early tracheostomy consideration for prolonged ventilation

Post-Operative Patients

Surgical patients have specific risk factors and considerations:

• Pain-Related Cough Suppression: Inadequate analgesia reduces effective coughing
• Surgical Site Considerations: Thoracic and abdominal surgeries affect respiratory mechanics
• Anesthesia Effects: Residual neuromuscular blockade impairs cough effectiveness

Tailored Approach:

• Optimal pain management protocols
• Early mobilization when feasible
• Regional anesthesia techniques for ongoing pain control

Pediatric Considerations

Children require modified approaches due to:

• Size-Appropriate Equipment: Smaller endotracheal tubes more prone to obstruction
• Developmental Differences: Immature respiratory mechanics
• Medication Dosing: Weight-based calculations with narrow therapeutic windows

Pediatric-Specific Protocols:

• More frequent airway assessment
• Lower threshold for bronchoscopy
• Family-centered care considerations

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Quality Improvement and Monitoring

Key Performance Indicators

Process Measures:

• Time from alarm to clinical assessment
• Frequency of preventable reintubations
• Compliance with ventilator bundles

Outcome Measures:

• Ventilator-associated pneumonia rates
• Duration of mechanical ventilation
• ICU length of stay

Balancing Measures:

• Sedation requirements
• Patient comfort scores
• Family satisfaction

Continuous Quality Improvement

Multidisciplinary Rounds: Regular discussion of ventilator management with respiratory therapists, nurses, and physicians ensures comprehensive care.

Protocol Adherence: Regular auditing of protocol compliance with feedback to clinical teams.

Education Programs: Ongoing education for all team members on recognition and management of ventilator-associated coughing.

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Future Directions and Emerging Technologies

Artificial Intelligence Integration

Machine learning algorithms are being developed to:

• Pattern Recognition: Automated identification of concerning alarm patterns
• Predictive Analytics: Early warning systems for ventilator complications
• Decision Support: Real-time recommendations for ventilator adjustments

Advanced Monitoring Technologies

Wearable Sensors: Continuous monitoring of respiratory effort and patient comfort

Real-Time Imaging: Portable ultrasound and electrical impedance tomography for immediate bedside assessment

Biomarker Development: Point-of-care testing for aspiration and inflammation markers

Personalized Ventilation

Genetic Factors: Understanding individual variations in drug metabolism and inflammatory responses

Precision Medicine: Tailored ventilator strategies based on patient-specific factors

Adaptive Algorithms: Ventilators that automatically adjust settings based on patient response

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Conclusion

Coughing in mechanically ventilated patients represents a complex clinical phenomenon that demands systematic evaluation and prompt intervention. The integration of clinical assessment, ventilator alarm interpretation, and evidence-based management strategies enables critical care clinicians to rapidly identify and address potentially life-threatening complications.

Key takeaways for clinical practice include:

Recognition Principles: New-onset coughing with ventilator alarms should trigger immediate systematic assessment beginning with airway patency and breath sound evaluation.

Diagnostic Approach: Pattern recognition of alarm combinations provides valuable diagnostic clues, with high-pressure alarms suggesting obstruction, low-volume alarms indicating leaks, and desaturation episodes raising concern for aspiration or pneumonia.

Management Strategies: Successful outcomes depend on rapid identification of underlying causes, appropriate use of diagnostic tools including bedside bronchoscopy, and implementation of targeted interventions ranging from simple position changes to complex ventilator adjustments.

Prevention Focus: Proactive measures including proper tube positioning, adequate humidification, secretion management, and aspiration precautions significantly reduce the incidence of ventilator-associated coughing complications.

As mechanical ventilation technology continues to evolve with artificial intelligence integration and advanced monitoring capabilities, the fundamental principles of careful clinical observation, systematic assessment, and evidence-based intervention remain paramount to optimizing patient outcomes.

The effective management of coughing in ventilated patients requires not only technical expertise but also clinical wisdom gained through experience and continuous learning. By understanding the pathophysiology, recognizing pattern variations, and implementing systematic approaches, critical care clinicians can transform potentially dangerous situations into opportunities for diagnostic clarity and therapeutic success.

Future research directions should focus on developing predictive models for ventilator complications, refining personalized ventilation strategies, and improving our understanding of the complex interactions between patient factors, ventilator settings, and clinical outcomes. The integration of these advances with traditional bedside clinical skills will continue to enhance our ability to provide optimal care for critically ill patients requiring mechanical ventilatory support.

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References

1. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):1S-23S.

2. Fontela PS, Piva JP, Garcia PC, et al. Risk factors for extubation failure in mechanically ventilated pediatric patients. Pediatr Crit Care Med. 2005;6(2):166-170.

3. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126-2136.

4. Torres A, Gatell JM, Aznar E, et al. Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care Med. 1995;152(1):137-141.

5. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: the auto-PEEP effect. Am Rev Respir Dis. 1982;126(1):166-170.

6. Metheny NA, Clouse RE, Chang YH, et al. Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcomes, and risk factors. Crit Care Med. 2006;34(4):1007-1015.

7. Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(8):915-936.

8. Rello J, Soñora R, Jubert P, et al. Pneumonia in intubated patients: role of respiratory airway care. Am J Respir Crit Care Med. 1996;154(1):111-115.

9. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116.

10. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.

11. Blanch L, Villagra A, Sales B, et al. Asynchronies during mechanical ventilation are associated with mortality. Intensive Care Med. 2015;41(4):633-641.

12. Thille AW, Rodriguez P, Cabello B, et al. Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med. 2006;32(10):1515-1522.

13. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest. 1997;112(1):186-192.

14. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350(24):2452-2460.

15. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371(9607):126-134.

16. Kollef MH, Shapiro SD, Silver P, et al. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit Care Med. 1997;25(4):567-574.

17. Metheny NA, Schallom L, Oliver DA, et al. Gastric residual volume and aspiration in critically ill patients receiving gastric feedings. Am J Crit Care. 2008;17(6):512-519.

18. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354(9193):1851-1858.

19. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34(2):396-402.

20. Dezfulian C, Shojania K, Collard HR, et al. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med. 2005;118(1):11-18.

21. Muscedere J, Rewa O, McKechnie K, et al. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med. 2011;39(8):1985-1991.

22. Rello J, Lode H, Cornaglia G, et al. A European care bundle for prevention of ventilator-associated pneumonia. Intensive Care Med. 2010;36(5):773-780.

23. Tablan OC, Anderson LJ, Besser R, et al. Guidelines for prevention of health-care-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep. 2004;53(RR-3):1-36.

24. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

25. Marini JJ, Crooke PS 3rd. A general mathematical model for respiratory dynamics relevant to the clinical setting. Am Rev Respir Dis. 1993;147(1):14-24.

26. Marini JJ. Dynamic hyperinflation and auto-positive end-expiratory pressure: lessons learned over 30 years. Am J Respir Crit Care Med. 2011;184(7):756-762.

27. Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in mechanical ventilation of patients with severe air-flow obstruction. Am Rev Respir Dis. 1987;136(4):872-879.

28. Ranieri VM, Grasso S, Fiore T, et al. Auto-positive end-expiratory pressure and dynamic hyperinflation. Clin Chest Med. 1996;17(3):379-394.

29. Georgopoulos D, Mouloudi E, Kondili E, et al. Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of end-inspiratory pause. Eur Respir J. 2000;16(2):263-268.

30. Dhand R, Guntur VP. How best to deliver aerosol medications to mechanically ventilated patients. Clin Chest Med. 2008;29(2):277-296.

31. Maggiore SM, Lellouche F, Pigeot J, et al. Prevention of endotracheal suctioning-induced alveolar derecruitment in acute lung injury. Am J Respir Crit Care Med. 2003;167(9):1215-1224.

32. Stenqvist O, Odenstedt H, Lundin S. Dynamic respiratory mechanics in acute lung injury/ARDS: principles and clinical implications. Respir Care. 2003;48(9):842-853.

33. Gattinoni L, Pesenti A, Avalli L, et al. Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis. 1987;136(3):730-736.

34. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-354.

35. Brochard L, Rua F, Lorino H, et al. Inspiratory pressure support compensates for the additional work of breathing caused by the endotracheal tube. Anesthesiology. 1991;75(5):739-745.

36. MacIntyre NR, McConnell R, Cheng KC, et al. Patient-ventilator flow dyssynchrony: flow-limited versus pressure-limited breaths. Crit Care Med. 1997;25(10):1671-1677.

37. Chao DC, Scheinhorn DJ, Stearn-Hassenpflug M. Patient-ventilator trigger asynchrony in prolonged mechanical ventilation. Chest. 1997;112(6):1592-1599.

38. Kondili E, Prinianakis G, Georgopoulos D. Patient-ventilator interaction. Br J Anaesth. 2003;91(1):106-119.

39. Tobin MJ, Jubran A, Laghi F. Patient-ventilator interaction. Am J Respir Crit Care Med. 2001;163(5):1059-1063.

40. Parthasarathy S, Jubran A, Tobin MJ. Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1471-1478.

41. Jubran A, Van de Graaff WB, Tobin MJ. Variability of patient-ventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152(1):129-136.

42. Leung P, Jubran A, Tobin MJ. Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med. 1997;155(6):1940-1948.

43. Younes M. Proportional assist ventilation, a new approach to ventilatory support. Theory. Am Rev Respir Dis. 1992;145(1):114-120.

44. Sinderby C, Navalesi P, Beck J, et al. Neural control of mechanical ventilation in respiratory failure. Nat Med. 1999;5(12):1433-1436.

45. Beck J, Sinderby C, Lindström L, et al. Effects of lung volume on diaphragm EMG signal strength during voluntary contractions. J Appl Physiol. 1998;85(3):1123-1134.

46. Colombo D, Cammarota G, Bergamaschi V, et al. Physiologic response to varying levels of pressure support and neurally adjusted ventilatory assist in patients with acute respiratory failure. Intensive Care Med. 2008;34(11):2010-2018.

47. Schmidt M, Demoule A, Cracco C, et al. Neurally adjusted ventilatory assist increases respiratory variability and complexity in acute respiratory failure. Anesthesiology. 2010;112(3):670-681.

48. Piquilloud L, Vignaux L, Bialais E, et al. Neurally adjusted ventilatory assist improves patient-ventilator interaction. Intensive Care Med. 2011;37(2):263-271.

49. Spahija J, de Marchie M, Albert M, et al. Patient-ventilator interaction during pressure support ventilation and neurally adjusted ventilatory assist. Crit Care Med. 2010;38(2):518-526.

50. Terzi N, Pelieu I, Guittet L, et al. Neurally adjusted ventilatory assist in patients recovering spontaneous breathing after acute respiratory distress syndrome: physiological evaluation. Crit Care Med. 2010;38(9):1830-1837.

51. Patroniti N, Bellani G, Saccavino E, et al. Respiratory pattern during neurally adjusted ventilatory assist in acute respiratory failure patients. Intensive Care Med. 2012;38(2):230-239.

52. Cammarota G, Olivieri C, Costa R, et al. Noninvasive ventilation through a helmet in postextubation hypoxemic patients: physiologic comparison between neurally adjusted ventilatory assist and pressure support ventilation. Intensive Care Med. 2011;37(12):1943-1950.

53. Liu L, Liu H, Yang Y, et al. Neuroventilatory efficiency and extubation readiness in critically ill patients. Crit Care. 2012;16(4):R143.

54. Doorduin J, van Hees HW, van der Hoeven JG, et al. Monitoring of the respiratory muscles in the critically ill. Am J Respir Crit Care Med. 2013;187(1):20-27.

55. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335.

56. Jaber S, Petrof BJ, Jung B, et al. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med. 2011;183(3):364-371.

57. Goligher EC, Fan E, Herridge MS, et al. Evolution of diaphragm thickness during mechanical ventilation. Impact of inspiratory effort. Am J Respir Crit Care Med. 2015;192(9):1080-1088.

58. Goligher EC, Dres M, Fan E, et al. Mechanical ventilation-induced diaphragm atrophy strongly impacts clinical outcomes. Am J Respir Crit Care Med. 2018;197(2):204-213.

59. Dres M, Goligher EC, Heunks LMA, et al. Critical illness-associated diaphragm weakness. Intensive Care Med. 2017;43(10):1441-1452.

60. Hooijman PE, Beishuizen A, Witt CC, et al. Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients. Am J Respir Crit Care Med. 2015;191(10):1126-1138.

61. Jung B, Moury PH, Mahul M, et al. Diaphragmatic dysfunction in patients with ICU-acquired weakness and its impact on extubation failure. Intensive Care Med. 2016;42(5):853-861.

62. Supinski GS, Morris PE, Dhar S, et al. Diaphragm dysfunction in critical illness. Chest. 2018;153(4):1040-1051.

63. Demoule A, Jung B, Prodanovic H, et al. Diaphragm dysfunction on admission to the intensive care unit. Prevalence, risk factors, and prognostic impact-a prospective study. Am J Respir Crit Care Med. 2013;188(2):213-219.

64. Kim WY, Suh HJ, Hong SB, et al. Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation. Crit Care Med. 2011;39(12):2627-2630.

65. DiNino E, Gartman EJ, Sethi JM, et al. Diaphragm ultrasound as a predictor of successful extubation from mechanical ventilation. Thorax. 2014;69(5):423-427.

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Conflicts of Interest: None declared

Funding: No external funding received