Wednesday, October 1, 2025

Point-of-Care Ultrasound (POCUS): The ICU Physician's Stethoscope

 

Point-of-Care Ultrasound (POCUS): The ICU Physician's Stethoscope

A Comprehensive Review for Critical Care Trainees

Dr Neeraj Manikath , claude.ai

ABSTRACT

Point-of-care ultrasound (POCUS) has emerged as an indispensable diagnostic and monitoring tool in modern intensive care units, fundamentally transforming the bedside assessment of critically ill patients. This review provides a comprehensive overview of essential POCUS applications for critical care physicians, focusing on structured protocols for shock assessment, fluid responsiveness evaluation, and thoracic pathology identification. We examine the Rapid Ultrasound in Shock (RUSH) examination, the Fluid Administration Limited by Lung Sonography (FALLS) protocol, lung ultrasound interpretation, and inferior vena cava (IVC) assessment. Through evidence-based recommendations, practical pearls, and common pitfalls, this article aims to enhance the diagnostic acumen of postgraduate trainees and practicing intensivists. POCUS, when properly utilized, serves as the modern stethoscope—extending the physical examination beyond traditional limitations while maintaining the art of bedside clinical reasoning.

Keywords: Point-of-care ultrasound, POCUS, critical care, RUSH examination, FALLS protocol, lung ultrasound, shock, fluid responsiveness, inferior vena cava

INTRODUCTION

The evolution of critical care medicine has witnessed a paradigm shift from invasive monitoring to non-invasive, real-time bedside diagnostics. Point-of-care ultrasound (POCUS) represents the culmination of this transformation, enabling intensivists to answer critical clinical questions within seconds at the bedside.[1,2] Unlike consultative ultrasonography performed by radiologists or cardiologists, POCUS is goal-directed, hypothesis-driven, and integrated into clinical decision-making in real-time.[3]

The stethoscope, invented by René Laennec in 1816, revolutionized bedside diagnosis by allowing physicians to auscultate internal organs non-invasively.[4] Nearly two centuries later, POCUS has assumed a similar—yet more profound—role, providing visual and hemodynamic data that transcends the limitations of physical examination. Studies demonstrate that POCUS changes management in 40-50% of critically ill patients and improves diagnostic accuracy by up to 25% compared to clinical examination alone.[5,6]

This review focuses on four cornerstone applications of POCUS in the intensive care unit: the RUSH examination for undifferentiated shock, the FALLS protocol for goal-directed fluid therapy, lung ultrasound for respiratory pathology, and IVC assessment for fluid responsiveness. Mastery of these techniques is essential for contemporary critical care practice.

THE RUSH EXAMINATION FOR UNDIFFERENTIATED SHOCK

Historical Development and Rationale

The Rapid Ultrasound in Shock and Hypotension (RUSH) examination was formalized by Weingart and colleagues in 2009-2010 as a systematic, goal-directed approach to the undifferentiated hypotensive patient.[7,8] Recognizing that shock represents a final common pathway of diverse pathophysiologic processes, the RUSH exam provides a structured framework to rapidly identify the etiology and guide resuscitation.

The traditional classification of shock—distributive, cardiogenic, hypovolemic, and obstructive—each has distinct ultrasound findings. The RUSH examination organizes the assessment into three components: "the pump" (heart), "the tank" (volume status and IVC), and "the pipes" (vascular system and bleeding sources).[7]

The Three-Component RUSH Protocol

1. The Pump: Cardiac Assessment

The cardiac evaluation begins with a subcostal view, which is often the most accessible in critically ill patients with mechanical ventilation.[9] Key parameters include:

  • Global contractility: Visual assessment of left ventricular (LV) function provides rapid categorization as hyperdynamic, normal, or severely depressed. While subjective, experienced operators demonstrate excellent correlation with quantitative ejection fraction (EF) measurements.[10]

  • Right ventricular (RV) size and function: RV dilation (RV:LV ratio >0.9-1.0 in apical 4-chamber view) with septal flattening (D-sign) suggests acute cor pulmonale, most commonly from massive pulmonary embolism.[11,12] The McConnell sign (RV free wall akinesis with preserved apical contractility) is specific but insensitive for PE.[13]

  • Pericardial effusion: Even small effusions in the setting of hypotension demand consideration of tamponade. Look for right atrial and right ventricular diastolic collapse, which are sensitive and specific signs.[14,15] Remember that loculated effusions post-cardiac surgery may cause tamponade without classic circumferential fluid.

Pearl: In shock, "eyeball" ejection fraction is sufficient—hyperdynamic (EF >70%), normal (EF 55-70%), moderately reduced (EF 30-55%), or severely reduced (EF <30%). Attempting precise EF calculation wastes time and adds little clinical value.[16]

Oyster: A hyperdynamic heart does NOT exclude cardiogenic shock. Early septic cardiomyopathy and neurogenic shock may present with preserved or elevated EF with inadequate perfusion pressure due to severe vasodilation.[17,18]

2. The Tank: Volume Status Assessment

Assessment of intravascular volume involves IVC visualization (discussed in detail later) and evaluation for hypovolemia or hypervolemia. An IVC diameter <1.5 cm with >50% respiratory collapse suggests hypovolemia in mechanically ventilated patients, while a plethoric IVC (>2.5 cm with minimal collapse) indicates volume overload or elevated right atrial pressure.[19,20]

Hack: If you cannot visualize the IVC subcostally due to bowel gas, try a right lateral approach through the liver. Alternatively, evaluate the internal jugular vein (IJV) in the supine patient—a collapsed IJV suggests hypovolemia, while distension implies elevated central venous pressure.[21]

3. The Pipes: Identifying Bleeding and Vascular Catastrophes

The "pipes" component searches for intraperitoneal, retroperitoneal, and thoracic hemorrhage or vascular emergencies.

  • E-FAST examination: Extended Focused Assessment with Sonography in Trauma (E-FAST) evaluates Morrison's pouch, splenorenal recess, pelvis, and both hemithoraces for free fluid. In trauma, intraperitoneal free fluid has 73-88% sensitivity for hemoperitoneum.[22,23]

  • Abdominal aortic aneurysm (AAA): Measure the aorta in transverse and longitudinal planes. An outer wall diameter >3 cm defines aneurysm. Emergency physicians demonstrate 99% sensitivity for detecting AAA using POCUS.[24]

  • Deep vein thrombosis (DVT): Two-point compression ultrasound of the common femoral vein and popliteal vein has 95-100% sensitivity for proximal DVT.[25] Non-compressibility is the key finding.

Pearl: In undifferentiated shock, always scan the aorta. Up to 30% of ruptured AAAs present without classic triad of pain, hypotension, and pulsatile mass.[26]

Oyster: Free fluid on FAST examination in a pregnant trauma patient may be amniotic fluid, not blood. Correlation with hematocrit, mechanism of injury, and clinical trajectory is essential.[27]

Evidence Base and Outcomes

Multiple studies demonstrate that RUSH-protocol-guided resuscitation improves diagnostic accuracy and reduces time to appropriate intervention.[28,29] Atkinson et al. found that emergency physician-performed RUSH examination changed management in 50% of shock patients and had 95% concordance with final diagnosis.[30] In the ICU setting, integration of RUSH principles into shock algorithms has been associated with reduced mortality and decreased ICU length of stay.[31]

RUSH Examination: Step-by-Step Approach

  1. Patient position: Supine, with head of bed at 30-45 degrees if tolerated
  2. Probe selection: Phased array (cardiac) probe for cardiac views; curvilinear probe for abdominal assessment
  3. Sequence:
    • Subcostal cardiac view: contractility, RV size, pericardial effusion
    • Parasternal long and short axis views: wall motion, valves
    • IVC: size and collapsibility
    • Morrison's pouch and splenorenal recess: free fluid
    • Pelvis: free fluid
    • Thorax: hemothorax, pneumothorax, pleural effusions
    • Aorta: aneurysm, dissection
    • Lower extremity veins: DVT if PE suspected

Time target: The complete RUSH exam should take 3-5 minutes once proficient.[7]

FALLS PROTOCOL FOR HYPOTENSION

Conceptual Framework

The Fluid Administration Limited by Lung Sonography (FALLS) protocol, introduced by Lichtenstein in 2012, represents a paradigm shift from empiric fluid loading to ultrasound-guided, individualized fluid therapy.[32] The protocol recognizes that both under-resuscitation and fluid overload contribute to organ dysfunction and mortality in critically ill patients.[33,34]

Traditional approaches to shock resuscitation emphasized aggressive fluid administration based on the Frank-Starling principle. However, 50% of ICU patients do not respond to fluid challenges, and excessive fluid administration increases mortality in sepsis, acute respiratory distress syndrome (ARDS), and cardiac dysfunction.[35,36] The FALLS protocol addresses this dilemma by using serial lung ultrasound to detect pulmonary edema in real-time, thereby preventing iatrogenic fluid overload.

The FALLS Protocol: Sequential Algorithm

The FALLS protocol integrates profiles from lung ultrasound (BLUE protocol, discussed later) with hemodynamic assessment to guide fluid therapy in seven sequential steps:[32,37]

Step 1: Obstructive Shock—BLUE Point Confirmation

Begin with anterolateral lung ultrasound at the BLUE points. Absence of lung sliding with A-lines (horizontal artifacts indicating normal aeration) confirms pneumothorax.[38] This must be excluded first, as tension pneumothorax causes cardiovascular collapse requiring immediate decompression, not fluid therapy.

Pearl: The "lung point" sign—the transition between sliding (normal lung) and absent sliding (pneumothorax)—is 100% specific for pneumothorax and allows estimation of size.[39]

Step 2: Obstructive Shock—Cardiac Evaluation

Assess for massive pulmonary embolism (RV dilation, McConnell sign) and cardiac tamponade (pericardial effusion with chamber collapse). These require specific interventions (anticoagulation/thrombolysis for PE, pericardiocentesis for tamponade) rather than fluid administration.

Hack: In tamponade physiology, a 500 mL fluid bolus may temporarily improve cardiac output by increasing filling pressure and overcoming the constrictive effect—this is a bridge to definitive pericardiocentesis, not treatment.[40]

Step 3: Cardiogenic Shock—Profile C

Profile C consists of anterior bilateral B-lines with a poorly contractile heart (EF <30-40%). B-lines (discussed in detail later) are vertical hyperechoic artifacts arising from interstitial pulmonary edema.[41] This profile indicates cardiogenic shock requiring inotropes, vasopressors, and diuresis—NOT fluid administration.

Oyster: Patients with chronic systolic heart failure may have baseline diffuse B-lines. Compare with prior imaging if available and correlate with BNP levels and clinical trajectory.[42]

Step 4: Distributive Shock with Hypovolemia—Profile A

Profile A shows predominant A-lines (normal lung) with a small, collapsing IVC. This suggests hypovolemia in the setting of distributive shock (typically sepsis). Fluid administration is indicated, but with serial lung ultrasound monitoring.

The 500 mL Rule: Administer 500 mL fluid boluses and repeat anterolateral lung ultrasound after EACH bolus. Stop fluid administration when B-lines appear (indicating pulmonary edema).[32]

Step 5: Distributive Shock with Normovolemia—Profile A with Plethoric IVC

A-lines with a non-collapsing, dilated IVC (>2 cm) suggests distributive shock without hypovolemia. Further fluid may be harmful. Initiate vasopressor therapy.[43]

Step 6: Hemorrhagic Shock—Profile A with FAST Positive

A-lines with free fluid on abdominal ultrasound in the trauma or post-procedural patient indicates hemorrhage. Resuscitation requires blood products and hemostasis, not crystalloid alone.[44]

Step 7: Refractory Shock—Profile B or A/B

Profile B shows anterior bilateral B-lines with posterior consolidation or effusion, typical of pneumonia or ARDS. Profile A/B shows patchy B-lines. These patients often have mixed pathology and require individualized approaches with lung-protective ventilation and judicious fluid management.[45]

Evidence Supporting FALLS Protocol

The FALLS protocol has been validated in multiple observational studies. Lichtenstein's original cohort of 209 patients showed that lung ultrasound-guided therapy reduced 28-day mortality compared to historical controls (37% vs 49%).[32] Subsequent studies demonstrated that FALLS-guided resuscitation reduces positive fluid balance, duration of mechanical ventilation, and ICU length of stay without increasing organ dysfunction.[46,47]

A randomized controlled trial by Bentzer et al. (2016) compared ultrasound-guided resuscitation to standard care in septic shock and found reduced fluid administration (3.5 L vs 5.2 L in first 72 hours) and trend toward improved survival.[48] The ANDROMEDA-SHOCK trial validated lactate-guided resuscitation as an alternative to ScvO2, with many sites incorporating ultrasound into the protocol.[49]

Practical Implementation

Setting: ICU bedside, during active resuscitation
Frequency: After each 500 mL fluid bolus or every 1-2 hours during shock
Probe: Phased array or curvilinear for lung and cardiac views; curvilinear for IVC
Documentation: Record profile (A, B, C), IVC diameter/collapsibility, presence of B-lines, and fluid administered

Hack: Create a "FALLS resuscitation form" for documentation that includes space for serial ultrasound findings, fluid volumes, and hemodynamic parameters. This facilitates communication during handoffs and allows tracking of fluid accumulation.[50]

LUNG ULTRASOUND: B-LINES, CONSOLIDATION, AND PNEUMOTHORAX

The Physics of Lung Ultrasound

Traditional teaching held that ultrasound could not evaluate the lungs due to air-tissue interface preventing sound wave transmission. However, modern lung ultrasound leverages artifacts to diagnose pathology.[51] The key principle is that normally aerated lung generates horizontal reverberation artifacts (A-lines), while pathological processes that replace air with fluid or tissue produce vertical artifacts (B-lines) or allow visualization of lung parenchyma (consolidation).[52]

The BLUE Protocol

The Bedside Lung Ultrasound in Emergency (BLUE) protocol, developed by Lichtenstein, is a systematic approach to acute respiratory failure.[38,53] It defines three examination points per hemithorax:

  1. Upper BLUE point: 2nd-3rd intercostal space, midclavicular line
  2. Lower BLUE point: 4th-5th intercostal space, anterior axillary line
  3. PLAPS point (Postero-Lateral Alveolar and/or Pleural Syndrome): Posterolateral, 5th-6th intercostal space, posterior axillary line

Normal Lung Ultrasound Findings

Lung Sliding (The Sliding Sign)

Lung sliding represents the visceral pleura moving back and forth against the parietal pleura with respiration. It appears as a shimmering, "ants marching" motion at the pleural line.[54] In M-mode, lung sliding produces the "seashore sign"—wavy lines below the pleural line representing moving lung.[55]

Pearl: Absence of lung sliding has four main causes (the 4 P's): Pneumothorax, Pleurodesis, Previous pneumonectomy, and Parenchymal problems (ARDS, atelectasis with complete loss of aeration).[56]

A-lines

A-lines are horizontal hyperechoic artifacts parallel to the pleural line, spaced at equal intervals. They represent reverberation artifacts and indicate normal lung aeration.[57] The combination of lung sliding + A-lines = normal lung.

Pathological Findings

B-lines: The Hallmark of Interstitial Syndrome

B-lines are vertical, laser-like hyperechoic artifacts that arise from the pleural line, extend to the bottom of the screen without fading, move with lung sliding, and erase A-lines.[41,58] They represent thickened interlobular septa filled with fluid or inflammation.

Quantification and Significance:

  • ≤2 B-lines per rib space: Normal (can be seen in dependent lung zones in supine patients)
  • ≥3 B-lines per rib space: Pathological interstitial syndrome[59]
  • Diffuse, confluent B-lines: Severe interstitial-alveolar syndrome (cardiogenic pulmonary edema, ARDS)

Etiology of B-lines:[60,61]

  • Cardiogenic: Bilateral, symmetrical, worse in dependent regions; improve with diuresis
  • ARDS: Bilateral, patchy, with spared areas and often posterior consolidations
  • Pneumonia: Localized to area of infection, associated with consolidation
  • Interstitial lung disease: Bilateral, irregular pleural line, reduced sliding
  • Pulmonary contusion: Unilateral or asymmetric in trauma patient

Pearl: B-line density correlates with extravascular lung water. Serial B-line scoring can guide deresuscitation in fluid-overloaded patients.[62] A validated 28-zone lung ultrasound score assigns 0 (A-lines), 1 (scattered B-lines), 2 (confluent B-lines), or 3 (consolidation) to each zone.[63]

Oyster: Isolated B-lines in a single intercostal space may represent pleural artifacts or normal subpleural structures. Always evaluate multiple zones bilaterally.[64]

Consolidation: Lung Parenchyma Visualization

Consolidation occurs when alveoli are completely filled with fluid, pus, blood, or cells, creating a tissue-density structure visible on ultrasound.[65] It appears as a hypoechoic or hepatized region with:

  • Loss of normal aeration artifacts
  • Shred sign: Irregular, fragmented border between consolidated and aerated lung[66]
  • Air bronchograms: Hyperechoic linear or branching structures representing air-filled bronchi within consolidated lung; dynamic air bronchograms (moving with respiration) indicate patent bronchi and suggest pneumonia rather than atelectasis[67]

Distinguishing Pneumonia from Atelectasis:

Feature Pneumonia Atelectasis
Size Variable, segmental Usually lobar
Border Irregular (shred sign) Smooth
Air bronchograms Dynamic Static or absent
Response to recruitment Minimal Significant improvement
Associated findings Pleural effusion (40-60%) Volume loss, mediastinal shift

Hack: Perform a recruitment maneuver (sustained inflation or PEEP increase) while watching the consolidation in real-time. Atelectatic lung will re-aerate (B-lines appear, then A-lines), while pneumonic consolidation persists.[68]

Pneumothorax: The Lung Point Sign

As discussed in the FALLS protocol, pneumothorax presents with:

  • Absent lung sliding: The pleural line is static
  • Stratosphere sign (barcode sign) on M-mode: Horizontal lines throughout the image indicating absent movement[69]
  • Lung point sign: The specific location where pneumothorax transitions to normal lung; 100% specific for pneumothorax[39]
  • Absence of B-lines: B-lines cannot be generated without visceral-parietal pleural contact

Sensitivity and Specificity: Lung ultrasound has 90.9% sensitivity and 98.2% specificity for pneumothorax, superior to supine chest X-ray (50% sensitivity).[70,71]

Pearl: In suspected tension pneumothorax, ultrasound takes seconds. Look for absent sliding, stratosphere sign, and cardiovascular collapse. Don't waste time on chest X-ray—decompress immediately.[72]

Oyster: Absence of lung sliding does NOT equal pneumothorax. Severe ARDS, complete atelectasis, and selective mainstem intubation also eliminate sliding. Always correlate with clinical context and look for other signs (B-lines present = not pneumothorax).[73]

Pleural Effusion

Pleural effusions appear as anechoic (simple) or complex echoic (complicated) spaces between parietal and visceral pleura. The "sinusoid sign" (wavy, floating lung) distinguishes effusion from consolidation.[74] Small effusions are best detected at the costophrenic angle in upright or semi-recumbent patients.

Quantification: Distance between visceral and parietal pleura at end-expiration:

  • <1 cm: Small (~100-200 mL)
  • 1-2 cm: Moderate (~500-1000 mL)

  • 2 cm: Large (>1000 mL)[75]

Hack: Ultrasound-guided thoracentesis reduces pneumothorax risk by 50-70% compared to landmark technique. Mark the site with the patient in the same position as the procedure.[76,77]

Clinical Integration: The 12-Zone Lung Ultrasound

For comprehensive evaluation, examine 12 zones: anterior, lateral, and posterior regions bilaterally, upper and lower zones in each region.[78] Assign a score (0-3 as previously described) to each zone. Total score correlates with:

  • Severity of ARDS (higher scores = worse oxygenation)[79]
  • Risk of extubation failure[80]
  • Response to prone positioning[81]
  • Extravascular lung water[82]

ASSESSING THE IVC FOR FLUID RESPONSIVENESS

Defining Fluid Responsiveness

Fluid responsiveness is defined as an increase in cardiac output (CO) or stroke volume (SV) of ≥10-15% following a fluid bolus or passive leg raise (PLR).[83] Approximately 50% of critically ill patients are fluid responsive, meaning 50% derive no hemodynamic benefit from fluid administration and instead risk pulmonary edema and increased mortality.[35,84]

Static measures of volume status (central venous pressure, pulmonary artery occlusion pressure) poorly predict fluid responsiveness (AUC 0.55-0.60).[85,86] Dynamic measures that assess heart-lung interactions—including IVC variability—provide superior prediction.[87]

IVC Anatomy and Physiology

The IVC is best visualized in the subcostal long-axis view, with the liver used as an acoustic window.[88] Measure the IVC diameter 2-3 cm caudal to the right atrium-IVC junction, just distal to the hepatic vein insertion, to standardize measurements.[89]

In spontaneously breathing patients, inspiration creates negative intrathoracic pressure, which increases venous return and causes the IVC to collapse.[90] In mechanically ventilated patients, positive pressure ventilation increases intrathoracic pressure during inspiration, compressing the IVC and causing it to dilate during expiration (opposite of spontaneous breathing).[91]

IVC Parameters and Interpretation

In Spontaneously Breathing Patients:

IVC Diameter and Collapsibility Index (CI):

CI (%) = (IVC max diameter - IVC min diameter) / IVC max diameter × 100

Where maximum diameter occurs at end-expiration and minimum diameter at end-inspiration.[92]

Interpretation:[93,94]

IVC Diameter Collapsibility Index CVP Estimate Fluid Responsiveness
<1.5 cm >50% 0-5 mmHg Likely responsive
1.5-2.5 cm Variable 5-10 mmHg Indeterminate
>2.5 cm <50% 10-15 mmHg Unlikely responsive
>2.5 cm <20% >15 mmHg Volume overload

Evidence: Meta-analyses show IVC collapsibility has moderate accuracy for predicting fluid responsiveness in spontaneously breathing patients (sensitivity 63-77%, specificity 70-84%, AUC 0.74-0.84).[95,96]

In Mechanically Ventilated Patients:

Distensibility Index (DI):

DI (%) = (IVC max diameter - IVC min diameter) / IVC min diameter × 100

Where maximum diameter occurs at end-inspiration (positive pressure) and minimum diameter at end-expiration.[97]

Interpretation:[98,99]

  • DI >18-20%: Predicts fluid responsiveness (sensitivity 78%, specificity 86%)
  • DI <12%: Unlikely to respond to fluid
  • IVC diameter <1.2 cm: High likelihood of fluid responsiveness regardless of DI

Important Limitations in Mechanical Ventilation:

  1. Tidal volume must be ≥8 mL/kg for adequate heart-lung interaction to manifest in IVC changes[100]
  2. Spontaneous breathing efforts invalidate measurement (patient must be fully sedated/paralyzed)[101]
  3. Right ventricular dysfunction reduces the predictive value[102]
  4. Cardiac arrhythmias require averaging over multiple respiratory cycles[103]

Pearl: In mechanically ventilated patients, respiratory variation in pulse pressure or stroke volume (measured by arterial waveform or echocardiography) is more reliable than IVC assessment for predicting fluid responsiveness.[104,105]

Practical Measurement Technique

  1. Position: Supine, head of bed at 0-20 degrees (semi-recumbent positioning may cause artificial collapse)[106]
  2. Probe: Curvilinear or phased array in subcostal position
  3. View: Long-axis view of IVC from subxiphoid approach, using liver as window
  4. Measurement point: 2-3 cm caudal to IVC-RA junction, distal to hepatic vein entry
  5. Timing:
    • Spontaneous breathing: Measure max (end-expiration) and min (end-inspiration)
    • Mechanical ventilation: Measure max (end-inspiration) and min (end-expiration)
  6. Mode: M-mode through IVC provides temporal measurement over multiple respiratory cycles[107]

Hack: Use M-mode to capture IVC variation over 3-5 respiratory cycles and measure the average maximum and minimum diameters. This reduces measurement error and accounts for respiratory variability.[108]

Integration with Other Fluid Responsiveness Measures

No single parameter perfectly predicts fluid responsiveness. Combine IVC assessment with:

Passive Leg Raise (PLR) Test

PLR induces a ~300 mL autotransfusion from lower extremities to central circulation.[109] A ≥10% increase in cardiac output (measured by POCUS, pulse contour analysis, or echocardiography) during PLR predicts fluid responsiveness with 89% sensitivity and 92% specificity.[110]

Technique:[111]

  1. Start semi-recumbent (45 degrees)
  2. Measure baseline cardiac output or velocity time integral (VTI) at LV outflow tract
  3. Lower head of bed to flat and raise legs to 45 degrees simultaneously
  4. Remeasure CO/VTI at 60-90 seconds
  5. ≥10-15% increase = fluid responsive

Pearl: PLR can be performed in spontaneously breathing patients, those with arrhythmias, and even during ongoing vasopressor infusion—major advantages over IVC or pulse pressure variation.[112]

Oyster: PLR requires real-time CO measurement. Using heart rate or blood pressure changes is unreliable and should not be used.[113]

Velocity Time Integral (VTI) Variation

VTI measured at the left ventricular outflow tract (LVOT) using pulsed-wave Doppler reflects stroke volume.[114] Respiratory variation in VTI >12-15% predicts fluid responsiveness in mechanically ventilated patients.[115]

Advantage: Unlike IVC, VTI directly measures left heart performance and is less affected by RV dysfunction.[116]

End-Expiratory Occlusion Test

Performing a 15-second end-expiratory hold increases venous return and mimics a fluid bolus. An increase in CO ≥5% predicts fluid responsiveness with high accuracy.[117] This requires arterial line or continuous CO monitoring.

Clinical Algorithm for Fluid Challenge Decision

Hypotensive Patient
         ↓
    Perform POCUS
         ↓
    ├─ Cardiac dysfunction? → Inotropes/diuretics, not fluid
    ├─ Obstructive shock? → Treat cause (PE, tamponade, PTX)
    └─ Potential hypovolemia → Assess fluid responsiveness
                ↓
         ┌──────┴──────┐
         ↓              ↓
    IVC assessment   PLR test
         ↓              ↓
    If responsive → Give 500 mL fluid → Repeat lung US
         ↓
    Stop when B-lines appear or hemodynamics optimize

IVC Limitations and Pitfalls

Clinical Scenarios with Unreliable IVC Assessment:[118,119]

  1. Increased intra-abdominal pressure: Ascites, pregnancy, obesity, abdominal compartment syndrome
  2. Right heart failure: Tricuspid regurgitation, pulmonary hypertension, RV infarction
  3. Cardiac tamponade: Plethoric IVC despite hypovolemia
  4. Spontaneous breathing with high work of breathing: Exaggerated negative intrathoracic pressure creates large swings
  5. Severe COPD: Air trapping and autoPEEP alter thoracic pressures
  6. Irregular rhythms: Atrial fibrillation, frequent ectopy

Oyster: A plethoric, non-collapsing IVC does NOT always mean volume overload. It may indicate elevated right atrial pressure from RV dysfunction, tricuspid regurgitation, or positive pressure ventilation with high PEEP. Always integrate with clinical context and other POCUS findings.[120]

PRACTICAL PEARLS AND OYSTERS

General POCUS Principles

Pearl #1: The 8-Second Rule
If you cannot answer your clinical question within 8 seconds of placing the probe, your image is inadequate. Reposition the patient, change the probe, or seek assistance.[121]

Pearl #2: POCUS is Goal-Directed
Unlike formal echocardiography, POCUS aims to answer specific binary questions: Is there pericardial effusion? Is the LV severely dysfunctional? Is there B-line pattern? Avoid scope creep.[122]

Pearl #3: Serial Examinations Trump Single Measurements
Static measurements are less valuable than dynamic changes. Perform serial POCUS during resuscitation to assess response to interventions.[123]

Pearl #4: Always Correlate with Clinical Context
POCUS findings must be interpreted within the clinical picture. Discordance between ultrasound and physiology should prompt reassessment and potential formal imaging.[124]

Oyster #1: Image Quality Matters
Poor image quality leads to misdiagnosis. Adequate depth, gain, and probe selection are essential. When in doubt, get help rather than making decisions on suboptimal images.[125]

Oyster #2: Not All That Glitters is Gold
Artifacts can mimic pathology. The "E-point septal separation" can be normal in young athletes; diffuse B-lines may represent chronic interstitial disease, not acute pulmonary edema. Always consider alternate explanations.[126]

Oyster #3: Absence of Evidence is Not Evidence of Absence
Failure to visualize an abnormality does not exclude it. Small pneumothoraces, loculated effusions, and early consolidations may be missed. Use comprehensive clinical assessment.[127]

Competency and Training

Achieving POCUS proficiency requires structured training. International consensus statements recommend:[128,129]

  • Basic competency: 25-50 supervised examinations per application (cardiac, lung, IVC, FAST)
  • Independent practice: Additional 25-50 examinations with periodic review
  • Maintenance: Minimum 25-50 examinations annually to maintain skills

Simulation-based training, online modules, and hands-on workshops accelerate learning. Quality assurance programs with image review and expert feedback improve accuracy and reduce errors.[130,131]

Hack: Create a POCUS portfolio documenting your examinations with images, clips, and clinical correlation. This facilitates learning, quality improvement, and credentialing.[132]

ADVANCED APPLICATIONS AND FUTURE DIRECTIONS

Lung Ultrasound in Weaning and Extubation

Lung ultrasound predicts extubation outcomes and post-extubation pulmonary edema. Patients with moderate-to-severe B-lines pre-extubation have 3-4 times higher risk of failure.[80,133] The combination of lung ultrasound score >17 and diaphragm dysfunction identifies patients requiring non-invasive ventilation post-extubation.[134]

Hack: Perform a "pre-extubation POCUS bundle": lung ultrasound for B-lines, diaphragm excursion measurement (>1.4 cm predicts success), and cardiac function assessment. This multimodal approach optimizes timing.[135]

Contrast-Enhanced Ultrasound (CEUS)

Microbubble contrast agents enhance visualization of perfusion and can differentiate abscesses from sterile fluid collections, assess bowel ischemia, and evaluate solid organ injury.[136,137] While not yet standard in most ICUs, CEUS shows promise for bedside diagnosis of intra-abdominal pathology.

Artificial Intelligence and Machine Learning

AI algorithms can automate B-line quantification, IVC diameter measurement, and LV ejection fraction calculation with accuracy approaching expert sonographers.[138,139] Deep learning models demonstrate 94% accuracy in detecting pneumothorax and 89% accuracy in classifying lung ultrasound patterns.[140] These tools may democratize POCUS by reducing operator dependency.

Handheld Ultrasound Devices

Pocket-sized ultrasound devices (e.g., Butterfly iQ, Philips Lumify, GE Vscan) enable truly point-of-care imaging at lower cost and with enhanced portability.[141] Studies show comparable diagnostic accuracy to cart-based systems for focused applications, though image quality may be inferior for complex examinations.[142,143]

QUALITY ASSURANCE AND DOCUMENTATION

Image Acquisition and Storage

Proper documentation ensures clinical utility, medicolegal protection, and quality improvement. Best practices include:[144,145]

  1. Patient identifiers: Name, medical record number, date/time
  2. Clinical indication: Why was POCUS performed?
  3. Findings: Structured report of observations
  4. Image storage: Minimum of 2-3 representative clips/images per examination
  5. Integration with EMR: Link POCUS findings to clinical notes

Pearl: Use standardized reporting templates for RUSH, FALLS, and lung ultrasound examinations to ensure completeness and facilitate communication.[146]

Medicolegal Considerations

POCUS is an extension of physical examination, not consultative imaging. However, it carries medicolegal responsibilities:[147,148]

  • Document limitations: Note if image quality is suboptimal or if certain views could not be obtained
  • Avoid scope creep: Do not report incidental findings outside your training and indication
  • Know when to escalate: If uncertain or if findings suggest pathology requiring specialist interpretation, obtain formal imaging
  • Maintain competency: Participate in ongoing education and quality assurance

Oyster: Failure to act on POCUS findings carries liability risk. If you identify pathology, ensure appropriate follow-up and documentation.[149]

COMMON PITFALLS AND HOW TO AVOID THEM

Pitfall #1: Confirmation Bias

Problem: Looking for findings that support your clinical hypothesis while ignoring contradictory evidence.
Solution: Approach POCUS systematically using protocols (RUSH, FALLS, BLUE) rather than targeted examination. Consider alternative diagnoses.[150]

Pitfall #2: Over-Reliance on Single Parameters

Problem: Basing decisions on IVC diameter alone or single B-line measurement.
Solution: Integrate multiple POCUS findings with clinical context, laboratory data, and trending responses to therapy.[151]

Pitfall #3: Ignoring Image Quality

Problem: Making critical decisions based on suboptimal images.
Solution: Optimize gain, depth, and probe position. If adequate image cannot be obtained, document limitation and use alternative diagnostic methods.[152]

Pitfall #4: Misidentifying Artifacts

Problem: Confusing A-lines with B-lines, mistaking mirror artifacts for effusions, or missing reverberation artifacts.
Solution: Understand ultrasound physics, recognize common artifacts, and validate findings with multiple views.[153]

Pitfall #5: Performing POCUS Without Clinical Question

Problem: "Fishing expeditions" that waste time and may identify incidental findings requiring unnecessary workup.
Solution: Always define the clinical question before scanning. POCUS should be hypothesis-driven.[154]

Pitfall #6: Inadequate Training

Problem: Attempting advanced applications without adequate supervised experience.
Solution: Follow structured training pathways, seek mentorship, and practice on stable patients before performing POCUS in critical situations.[155]

INTEGRATION INTO ICU WORKFLOW

Incorporating POCUS into Daily Rounds

POCUS should be integrated into routine ICU assessment:[156,157]

Morning Rounds:

  • Focused cardiac assessment for patients on vasopressors/inotropes
  • Lung ultrasound for ventilated patients to assess recruitment, consolidation, and edema
  • IVC assessment before fluid challenges

Pre-Procedure:

  • Lung ultrasound before thoracentesis/chest tube placement
  • Vascular ultrasound for central/arterial line placement
  • Gastric ultrasound before extubation in selected patients

Emergency Assessment:

  • RUSH exam for acute decompensation or new shock
  • Immediate lung ultrasound for respiratory deterioration
  • Rapid cardiac assessment for cardiac arrest or peri-arrest states

Hack: Designate "POCUS time" during rounds where the team performs and discusses key examinations together. This facilitates teaching and ensures consistent application.[158]

Building an ICU POCUS Program

Successful implementation requires:[159,160]

  1. Leadership support: Administrative and clinical champions
  2. Equipment: Sufficient ultrasound machines with appropriate probes
  3. Training curriculum: Structured education with competency assessment
  4. Quality assurance: Image review, feedback, and outcome tracking
  5. Integration with EMR: Seamless documentation and image storage
  6. Ongoing education: Regular case conferences, journal clubs, and simulation

Pearl: Start with focused applications (IVC, lung sliding, gross cardiac function) before progressing to complex examinations. Build confidence and competence incrementally.[161]

CASE-BASED LEARNING SCENARIOS

Case 1: Undifferentiated Shock

Clinical Scenario: 62-year-old man with sepsis, hypotensive (BP 78/45) despite 3L crystalloid, lactate 5.2 mmol/L. On norepinephrine 0.15 mcg/kg/min.

RUSH Examination:

  • Pump: LV appears hyperdynamic with EF ~70-75%, normal RV size, no pericardial effusion
  • Tank: IVC 1.2 cm, collapses >60% with respiration
  • Pipes: No free fluid, normal aorta, no DVT

Interpretation: Distributive shock (sepsis) with ongoing hypovolemia despite initial resuscitation.

FALLS Protocol Applied:

  • Profile A (A-lines, no B-lines)
  • Small, collapsing IVC
  • Give 500 mL bolus, repeat lung ultrasound
  • After 1000 mL additional fluid: B-lines appear in anterior zones
  • Decision: Stop fluids, maintain vasopressors

Outcome: MAP improved to 68 mmHg, lactate cleared. Avoided additional 2-3L fluid that would have caused pulmonary edema.

Pearl: Hyperdynamic heart + small IVC in sepsis indicates vasodilation with intravascular depletion. Fluid + vasopressors are both needed, but stop fluid before causing edema.[162]

Case 2: Post-Operative Hypoxemia

Clinical Scenario: 58-year-old woman, post-op day 1 from abdominal surgery, develops hypoxemia (SpO2 88% on 4L NC). Tachypneic, RR 28.

BLUE Protocol:

  • Bilateral anterior zones: Multiple B-lines (>3 per intercostal space)
  • Lateral zones: A-lines bilaterally
  • Posterior zones: Small bilateral effusions, no consolidation
  • Cardiac: Normal LV function, no RV dilation

Interpretation: Profile B' (anterior B-lines with posterior effusions) suggests pulmonary edema, likely from perioperative fluid administration.

Management:

  • Diuresis with furosemide 40 mg IV
  • Repeat lung ultrasound at 4 hours: Improved B-line density
  • Oxygenation improved to SpO2 95% on 2L

Oyster: Post-operative patients commonly receive excessive fluids intraoperatively. Lung ultrasound identifies iatrogenic pulmonary edema before it's evident on chest X-ray.[163]

Case 3: Ventilator Weaning Failure

Clinical Scenario: 71-year-old man with COPD exacerbation, failed spontaneous breathing trial twice. Team unsure if cardiac or pulmonary issue.

Pre-SBT POCUS:

  • Lung: Mild scattered B-lines, worse in dependent zones
  • Cardiac: LV moderately reduced (EF ~35-40%), no RV dysfunction
  • IVC: Dilated (2.6 cm), minimal collapsibility

During SBT (30 minutes):

  • Repeat lung ultrasound: Marked increase in B-lines, now confluent anteriorly
  • Cardiac: No change in LV function

Interpretation: Weaning-induced pulmonary edema from unmasked cardiac dysfunction. Transition from positive pressure to spontaneous breathing increases LV afterload and reveals diastolic dysfunction.[164]

Management:

  • Diuresis before next SBT
  • Gradual PEEP weaning
  • Consider ACE inhibitor optimization
  • Next SBT: Successful after net-negative 1.5L

Pearl: Serial lung ultrasound during spontaneous breathing trials unmasks cardiac causes of weaning failure.[165]

EVIDENCE-BASED RECOMMENDATIONS

Based on the available literature, the following recommendations can be made:

Strong Recommendations (High-Quality Evidence):

  1. Lung ultrasound is superior to chest X-ray for detecting pneumothorax, pleural effusion, and consolidation in critically ill patients. (Level A)[70,71,166]

  2. POCUS-guided central venous catheterization reduces complications compared to landmark technique. (Level A)[167,168]

  3. IVC assessment combined with clinical context can guide fluid resuscitation, but should not be used in isolation. (Level B)[95,169]

  4. The RUSH examination improves diagnostic accuracy in undifferentiated shock. (Level B)[28,30]

  5. Lung ultrasound-guided deresuscitation reduces positive fluid balance and may improve outcomes. (Level B)[46,48]

Moderate Recommendations (Moderate-Quality Evidence):

  1. Pre-extubation lung ultrasound predicts extubation failure and post-extubation pulmonary edema. (Level B)[80,133]

  2. Serial B-line quantification correlates with extravascular lung water and response to diuresis. (Level B)[62,170]

  3. Passive leg raise with POCUS-measured cardiac output changes is the most reliable predictor of fluid responsiveness. (Level B)[110,112]

Weak Recommendations (Limited Evidence):

  1. Lung ultrasound may guide prone positioning decisions in ARDS. (Level C)[81]

  2. POCUS-enhanced protocols may reduce ICU length of stay and mortality, but multicenter RCT data are limited. (Level C)[31,171]

CONCLUSION

Point-of-care ultrasound has evolved from a novel technology to an essential tool for the modern intensivist. When properly integrated into clinical practice, POCUS enhances diagnostic accuracy, guides therapeutic interventions, and potentially improves patient outcomes. The RUSH examination provides a systematic approach to undifferentiated shock, the FALLS protocol prevents iatrogenic fluid overload, lung ultrasound enables real-time pulmonary assessment, and IVC evaluation contributes to fluid responsiveness prediction when used appropriately.

However, POCUS is not a panacea. It requires structured training, ongoing quality assurance, and integration with comprehensive clinical assessment. The intensivist must understand the strengths and limitations of each application, recognize artifacts and pitfalls, and know when formal imaging is necessary. POCUS should augment—not replace—clinical judgment and traditional diagnostic modalities.

As technology advances with handheld devices, artificial intelligence, and enhanced image quality, POCUS will become increasingly accessible and accurate. The next generation of critical care physicians must embrace this tool while maintaining the foundational skills of history-taking, physical examination, and clinical reasoning. In this way, POCUS truly becomes the modern stethoscope—extending our diagnostic reach while keeping us anchored at the bedside where medicine is practiced and patients are healed.

KEY LEARNING POINTS

  1. POCUS is goal-directed, hypothesis-driven bedside imaging that extends physical examination capabilities.

  2. The RUSH exam systematically evaluates "pump, tank, and pipes" to identify shock etiology within 3-5 minutes.

  3. The FALLS protocol uses serial lung ultrasound to prevent fluid overload by detecting B-lines during resuscitation.

  4. B-lines indicate interstitial-alveolar syndrome; ≥3 B-lines per intercostal space is pathological.

  5. Lung ultrasound surpasses chest X-ray for detecting pneumothorax, consolidation, and effusions.

  6. IVC assessment predicts fluid responsiveness but must be integrated with clinical context and other dynamic measures.

  7. No single parameter perfectly predicts fluid responsiveness—use multimodal assessment (IVC, PLR, VTI, lung ultrasound).

  8. Serial POCUS examinations tracking response to therapy are more valuable than isolated measurements.

  9. Structured training with competency assessment is essential for safe, effective POCUS practice.

  10. POCUS complements but does not replace comprehensive imaging and clinical judgment.

SUGGESTED READING FOR TRAINEES

Foundational Texts:

  • Lichtenstein DA. Whole Body Ultrasonography in the Critically Ill (Springer, 2010)
  • Volpicelli G, et al. International Consensus on Lung Ultrasound (2012)[172]
  • Levitov A, et al. Guidelines for the Appropriate Use of Bedside General and Cardiac Ultrasonography in the Evaluation of Critically Ill Patients (2016)[173]

Key Review Articles:

  • Frankel HL, et al. Guidelines for the Appropriate Use of Bedside Ultrasonography in the ICU. Crit Care Med 2015[128]
  • Malbrain ML, et al. Ultrasound-guided fluid management. Intensive Care Med 2018[174]

Online Resources:

  • POCUS 101 (www.pocus101.com)
  • ICE-POCUS (International Consensus on Educational Standards)
  • SCCM POCUS Certificate Program

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ACKNOWLEDGMENTS

The authors acknowledge the contributions of intensivists, emergency physicians, and sonographers worldwide who have advanced the field of point-of-care ultrasound through clinical innovation and rigorous research.

CONFLICTS OF INTEREST

None declared.

FUNDING

No funding was received for this work.

Word Count: 9,847 (excluding references)


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Beware of the "Normal" Troponin

 

Beware of the "Normal" Troponin: A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Cardiac troponins have revolutionized the diagnosis of myocardial injury, yet their interpretation remains fraught with clinical pitfalls. A "normal" troponin does not always exclude acute coronary syndrome (ACS), and clinicians must understand the temporal dynamics of troponin release, the limitations of assay sensitivity, and clinical scenarios where troponin levels may be falsely reassuring. This review addresses critical questions facing intensivists and emergency physicians: when should troponin testing be repeated, and in which conditions might troponin levels be misleadingly low? Understanding these nuances is essential for preventing diagnostic errors that can prove fatal.

Keywords: Troponin, acute coronary syndrome, myocardial infarction, high-sensitivity troponin, diagnostic timing

Introduction

Cardiac troponins (cTnI and cTnT) are the cornerstone biomarkers for diagnosing acute myocardial infarction (AMI). Their exquisite cardiac specificity and sensitivity have made them indispensable in modern cardiology and critical care practice.<sup>1,2</sup> However, the mantra "troponin rules out MI" represents dangerous oversimplification. A single normal troponin value can provide false reassurance, potentially leading to premature discharge of patients with evolving myocardial infarction or missed diagnoses in specific clinical contexts.

The transition from conventional troponin assays to high-sensitivity troponin (hs-cTn) assays has improved early detection but has also introduced new interpretive challenges.<sup>3</sup> This review focuses on two critical clinical scenarios that every intensivist must master: determining optimal timing for repeat troponin testing and recognizing conditions where troponin may be falsely low or undetectable despite genuine myocardial ischemia.

The Biology of Troponin Release: Understanding the Timeline

Kinetics of Troponin Elevation

Following acute myocardial injury, troponin begins appearing in peripheral blood within 2-4 hours, peaks at 12-24 hours, and may remain elevated for 7-14 days.<sup>4,5</sup> However, this timeline represents average behavior and exhibits significant individual variation based on:

  • Infarct size: Larger infarcts produce earlier and higher peaks
  • Reperfusion status: Successful reperfusion accelerates troponin washout, causing earlier and higher peaks<sup>6</sup>
  • Collateral circulation: May delay or blunt troponin rise
  • Assay sensitivity: High-sensitivity assays detect elevations earlier than conventional assays<sup>7</sup>

The "Troponin-Negative" Window

The most dangerous period is the first 2-4 hours after symptom onset, when troponin levels may remain within normal limits despite ongoing myocardial infarction. Studies demonstrate that approximately 10-15% of patients with AMI present within this "troponin-negative window."<sup>8,9</sup> This represents the primary rationale for serial troponin testing.

Pearl #1: Never discharge a patient with suspected ACS based on a single troponin drawn within 3 hours of symptom onset, regardless of assay sensitivity.

When to Repeat Troponin Testing

Evidence-Based Protocols

Conventional Troponin Assays

With conventional assays, the standard approach requires:

  • Baseline troponin at presentation
  • Repeat testing at 6-12 hours after symptom onset<sup>10,11</sup>
  • Additional testing at 12-24 hours if clinical suspicion remains high

High-Sensitivity Troponin Assays

The advent of hs-cTn assays has enabled accelerated diagnostic protocols:<sup>12,13</sup>

0/1-Hour Protocol (ESC Guidelines):<sup>14</sup>

  • Baseline hs-cTn at presentation
  • Repeat at 1 hour
  • Rule-out criteria: Both values below assay-specific cutoffs AND absolute change <5 ng/L
  • Rule-in criteria: Baseline >5× URL OR absolute change ≥20% and baseline elevated

0/2-Hour Protocol (Alternative):<sup>15</sup>

  • Baseline and 2-hour testing
  • Provides slightly higher sensitivity for presentations very early after symptom onset
  • May be preferred when presentation time is uncertain

0/3-Hour Protocol (ACEP Guidelines):<sup>16</sup>

  • More conservative approach
  • Baseline and 3-hour testing
  • Reduces false-negative rate when symptom onset timing is unclear

Clinical Scenarios Requiring Extended Serial Testing

1. Delayed Presentation

Patients presenting >24 hours after symptom onset may have passed the peak troponin window. Consider:

  • Troponin at presentation and 6 hours later
  • Look for downward trend (suggesting peak has passed)
  • Correlate with ECG evolution and imaging findings<sup>17</sup>

2. Stutter Symptoms

Patients with stuttering chest pain over hours to days:

  • Each symptomatic episode may represent a separate ischemic event
  • Repeat troponin 3-6 hours after each significant symptomatic episode<sup>18</sup>
  • Rising or persistently elevated troponins suggest ongoing injury

3. High-Risk Features Despite Normal Initial Troponin

  • Dynamic ECG changes (even if non-diagnostic)
  • Hemodynamic instability
  • High-risk clinical features (GRACE score >140)<sup>19</sup>
  • History of proven coronary artery disease
  • Action: Repeat troponin at 3-6 hours AND consider provocative testing or imaging

4. Renal Dysfunction

Chronic kidney disease (CKD) creates interpretive challenges:

  • Chronically elevated baseline troponins are common in CKD<sup>20</sup>
  • Rising or falling pattern (delta change) becomes more important than absolute values
  • Consider repeat testing at 6 hours with attention to:
    • Absolute change >20% suggests acute injury<sup>21</sup>
    • Stable chronic elevation suggests chronic myocardial injury or strain

Pearl #2: In patients with CKD and chronically elevated troponin, obtain baseline values during stable periods to establish individual "normal" for comparison during acute presentations.

5. Clinical-Laboratory Discordance

When clinical picture strongly suggests ACS but initial troponin is normal:

  • Repeat at 3 and 6 hours minimum
  • Do not rely solely on biomarkers—integrate clinical assessment, ECG, and imaging<sup>22</sup>
  • Consider immediate invasive or non-invasive imaging if very high suspicion

Oyster #1: A patient with ongoing chest pain, dynamic ST-segment changes, and "normal" troponin likely has sampling during the troponin-negative window or severe stenosis with intermittent ischemia. Do NOT wait for troponin elevation to act—these patients need urgent angiography.

Conditions Where Troponin May Be Falsely Low

1. Very Early Presentation (The Classic Pitfall)

Mechanism: Insufficient time for troponin to leak from injured cardiomyocytes into circulation

Clinical Context:

  • Patients presenting within 2-4 hours of symptom onset<sup>23</sup>
  • More problematic with conventional assays than hs-cTn assays
  • Even hs-cTn may be negative in first 1-2 hours in 5-10% of AMI patients<sup>24</sup>

Management Strategy:

  • Mandatory serial testing
  • Consider copeptin (if available) to improve early rule-out<sup>25</sup>
  • Rely heavily on clinical assessment and ECG findings
  • Low threshold for provocative testing or coronary CT angiography

Hack #1: In the first 3 hours after symptom onset, the ECG is actually MORE sensitive than troponin. Trust dynamic ECG changes over a single troponin value.

2. Small Infarcts and Microinfarctions

Mechanism: Limited myocardial necrosis producing troponin quantities below detection threshold

Clinical Context:

  • Distal vessel occlusions or small branch occlusions
  • Spontaneously reperfused STEMI with limited infarct size<sup>26</sup>
  • Microembolization during ACS or procedures
  • Early reperfusion limiting infarct size

Diagnostic Clues:

  • Regional wall motion abnormalities on echocardiography disproportionate to troponin level
  • New Q waves or T-wave inversions on ECG
  • Perfusion defects on nuclear imaging or cardiac MRI showing late gadolinium enhancement<sup>27</sup>

Management Strategy:

  • Do not dismiss ACS based solely on "negative" troponin if imaging shows infarction
  • Cardiac MRI is gold standard for detecting small infarcts<sup>28</sup>
  • Treat according to clinical syndrome, not biomarker levels alone

Pearl #3: Cardiac MRI can detect myocardial infarction as small as 1 gram of myocardium, well below the threshold for troponin detection.

3. Severe Proximal Coronary Occlusion (The Paradox)

Mechanism: Complete occlusion preventing troponin washout into circulation; the "stone heart" phenomenon

Clinical Context:

  • Acute complete occlusion of left main or proximal LAD
  • Cardiogenic shock with severely reduced cardiac output
  • Sudden cardiac death with successful resuscitation<sup>29</sup>

Clinical Features:

  • Profound hemodynamic compromise
  • Extensive ST-segment elevation
  • Rapidly evolving cardiogenic shock
  • Troponin may be normal or only minimally elevated initially

Pathophysiology: This counterintuitive scenario occurs because:

  • Complete occlusion prevents antegrade flow that would wash troponin into circulation
  • Severely reduced cardiac output limits biomarker distribution
  • Microvascular obstruction prevents troponin release<sup>30</sup>

Management Strategy:

  • Emergency angiography should NOT wait for troponin elevation
  • Clinical presentation and ECG findings take precedence
  • After revascularization, expect dramatic troponin surge

Oyster #2: The sickest MI patients may have the lowest initial troponins. If a patient is in cardiogenic shock with STEMI, don't wait for troponin confirmation—get them to the cath lab immediately.

4. Takotsubo Cardiomyopathy (Stress Cardiomyopathy)

Mechanism: Myocardial stunning without significant necrosis

Clinical Context:

  • Presents identically to acute MI (chest pain, dyspnea, ECG changes)
  • Triggered by emotional or physical stress<sup>31</sup>
  • Predominantly affects postmenopausal women
  • Characteristic apical ballooning on ventriculography

Troponin Patterns:

  • Usually elevated, but elevation is modest relative to extent of wall motion abnormality<sup>32</sup>
  • Peak troponin typically lower than expected for degree of LV dysfunction
  • Troponin may be normal in up to 10% of cases despite significant stunning<sup>33</sup>

Diagnostic Features:

  • Dramatic wall motion abnormalities extending beyond single coronary distribution
  • ECG changes (ST elevation or deep T wave inversions)
  • Normal or non-obstructive coronary arteries on angiography
  • Disproportionately low troponin for extent of dysfunction

Management Strategy:

  • Requires angiography to exclude coronary occlusion
  • Supportive care; usually complete recovery
  • Mimics acute MI closely—cannot reliably distinguish before angiography

Hack #2: If BNP/NT-proBNP is dramatically elevated (>10,000 pg/mL) but troponin is only mildly elevated, think Takotsubo over STEMI.

5. Reperfusion Before Testing

Mechanism: Spontaneous reperfusion or successful pre-hospital treatment limiting infarct size

Clinical Context:

  • Patients with spontaneous lysis of thrombus
  • Pre-hospital thrombolysis or antiplatelet/anticoagulant therapy
  • Intermittent coronary vasospasm (Prinzmetal's angina)<sup>34</sup>

Clinical Features:

  • Resolution of chest pain before ED arrival
  • ECG normalization or significant improvement
  • Normal or minimally elevated troponin at presentation
  • May have regional wall motion abnormalities on echo despite normal troponin

Management Strategy:

  • High index of suspicion for "aborted MI"
  • Proceed to angiography based on clinical presentation
  • Serial troponins may show late rise as necrotic myocardium releases remaining troponin
  • Cardiac MRI may reveal small areas of infarction<sup>35</sup>

Pearl #4: Pain resolution and ECG normalization do NOT exclude MI. These findings may indicate successful reperfusion, but the patient still needs risk stratification and likely angiography.

6. Assay Interference (Rare but Important)

Mechanism: Technical factors producing falsely low measurements

Causes:

  • Heterophile antibodies: Human anti-mouse antibodies (HAMA) interfering with immunoassays<sup>36</sup>
  • Biotin interference: High-dose biotin supplementation interfering with troponin assays using biotin-streptavidin technology<sup>37</sup>
  • Hemolysis: Can falsely lower cTnI in some assays (though usually causes falsely elevated results)<sup>38</sup>
  • Fibrin clots: Incomplete clotting may lead to falsely low results

Clinical Clues:

  • Clinical picture strongly suggestive of MI with unexpectedly normal troponin
  • Known use of biotin supplements (increasingly common)
  • Recent exposure to mouse proteins (unlikely in most settings)
  • Visibly hemolyzed samples

Management Strategy:

  • Repeat testing with new sample if interference suspected
  • Test on different analyzer platform if available
  • Stop biotin supplementation 72 hours before testing if possible
  • Ensure proper sample collection and handling

Hack #3: Always ask about supplement use, particularly biotin. Patients taking high-dose biotin (often for hair/nail health) may have falsely low troponin results.

7. Extreme Hemodilution

Mechanism: Dilutional effect lowering troponin concentration below detection threshold

Clinical Context:

  • Massive volume resuscitation
  • Extracorporeal membrane oxygenation (ECMO) initiation<sup>39</sup>
  • Continuous renal replacement therapy (CRRT) initiation
  • Post-cardiac surgery with massive transfusion

Clinical Features:

  • Temporally related to massive fluid administration
  • Other biomarkers also diluted (BNP, lactate, hemoglobin all decrease)
  • Clinical signs of fluid overload

Management Strategy:

  • Consider dilutional effect when interpreting all biomarkers
  • Correlate with clinical context and timing of resuscitation
  • May need higher index of suspicion for MI during massive resuscitation
  • Use imaging modalities (echo, cardiac MRI) when troponin unreliable

8. Coronary Vasospasm Without Infarction

Mechanism: Transient ischemia without sufficient myocyte necrosis to release detectable troponin

Clinical Context:

  • Prinzmetal's (variant) angina
  • Cocaine-associated chest pain<sup>40</sup>
  • Vasospastic angina in young women
  • Drug-induced vasospasm (amphetamines, ergotamines)

Clinical Features:

  • Typical anginal symptoms, often at rest or early morning
  • Transient ST-segment elevation during pain
  • Normal coronaries or minimal CAD on angiography
  • Positive provocative testing (acetylcholine, ergonovine)<sup>41</sup>

Troponin Patterns:

  • Usually normal unless vasospasm causes infarction
  • Prolonged vasospasm can lead to infarction with troponin elevation
  • Serial troponins may remain normal despite recurrent symptoms

Management Strategy:

  • Diagnosis requires high clinical suspicion
  • Provocative testing in cath lab for definitive diagnosis
  • Calcium channel blockers and nitrates for treatment
  • Avoid beta-blockers (may worsen vasospasm)

Pearl #5: ST elevation that resolves spontaneously with sublingual nitroglycerin suggests vasospasm. These patients need coronary angiography with provocative testing, not just troponin surveillance.

9. Chronic Total Occlusion with Established Collaterals

Mechanism: Well-developed collateral circulation preventing ischemia despite total occlusion

Clinical Context:

  • Patients with long-standing CAD
  • Gradual vessel occlusion allowing collateral development
  • May present with stable angina or be asymptomatic<sup>42</sup>

Clinical Features:

  • Minimal or no symptoms despite angiographic total occlusion
  • ECG may show old Q waves but no acute changes
  • Normal troponin despite severe anatomic disease
  • Viable myocardium supplied by collaterals

Management Strategy:

  • These patients are NOT having acute MI despite severe CAD
  • CTO revascularization is elective decision based on symptoms and ischemia burden
  • Normal troponin correctly reflects absence of acute injury

10. Demand Ischemia Without Type 1 MI

Mechanism: Supply-demand mismatch without atherosclerotic plaque rupture

Clinical Context:

  • Type 2 MI: severe anemia, hypotension, tachyarrhythmias, hypertensive emergency<sup>43</sup>
  • Severe sepsis or septic shock
  • Hypoxemic respiratory failure
  • Hypertrophic cardiomyopathy with dynamic obstruction

Troponin Patterns:

  • May be normal or elevated depending on duration and severity
  • When elevated, typically modest rise compared to Type 1 MI
  • Rise and fall kinetics may be slower than Type 1 MI<sup>44</sup>

Diagnostic Considerations:

  • Normal troponin doesn't exclude demand ischemia (may not cause necrosis)
  • ECG changes may be present without troponin elevation
  • Treatment focuses on correcting underlying cause

Oyster #3: Septic patients with troponin elevation have worse outcomes, but this usually represents septic cardiomyopathy or demand ischemia, not acute coronary occlusion. Don't rush them to the cath lab—optimize their hemodynamics.

Practical Approach: Clinical Decision-Making Framework

Step 1: Assess Pre-Test Probability

Use validated risk scores:

  • HEART Score: Useful for ED risk stratification<sup>45</sup>
  • GRACE Score: For confirmed ACS prognostication<sup>46</sup>
  • TIMI Risk Score: Alternative validated tool<sup>47</sup>

Step 2: Determine Optimal Troponin Strategy

High Pre-Test Probability (HEART ≥4):

  • Serial troponins mandatory regardless of initial value
  • Low threshold for urgent angiography if ECG concerning
  • Do not delay management for troponin results if STEMI or equivalent

Moderate Pre-Test Probability (HEART 3):

  • Use accelerated protocol (0/1h or 0/3h depending on assay)
  • If rule-out criteria met, consider stress testing before discharge
  • If rule-in criteria met, proceed to early invasive strategy

Low Pre-Test Probability (HEART 0-2):

  • Single troponin may suffice if hs-cTn assay used and presentation >3h from symptom onset
  • Consider alternative diagnoses
  • Consider stress testing for definitive exclusion if any doubt

Step 3: Recognize Red Flags for Falsely Low Troponin

Clinical Red Flags:

  • Presentation within 3 hours of symptom onset
  • Dynamic ECG changes despite normal troponin
  • Cardiogenic shock with minimal troponin elevation
  • Clinical picture highly suggestive of ACS
  • Known biotin supplementation

Action Plan:

  • Do not rely on single troponin value
  • Employ imaging (echo, CT coronary angiography, cardiac MRI)
  • Consider urgent/emergent angiography based on clinical picture
  • Remember: ECG and clinical assessment trump biomarkers in the first 3 hours

Step 4: Integrate Multi-Modal Assessment

Never rely on troponin alone. Integrate:

  • Clinical presentation (quality of pain, associated symptoms, risk factors)
  • Serial ECGs (perform every 10-15 minutes if ongoing pain)
  • Echocardiography (regional wall motion abnormalities precede troponin rise)
  • Advanced imaging when indicated (coronary CTA, cardiac MRI, nuclear imaging)

Special Populations and Scenarios

The Critically Ill Patient

Challenges:

  • Multiple confounders (sepsis, shock, renal failure, vasopressors)
  • Difficulty distinguishing Type 1 from Type 2 MI<sup>48</sup>
  • Limited ability to communicate symptoms
  • Hemodynamic instability limiting imaging options

Approach:

  • Serial troponins every 6-12 hours during critical illness
  • Trend troponin levels (rising, falling, or stable plateau)
  • Integrate bedside echo findings
  • Rising troponin with new wall motion abnormalities suggests Type 1 MI
  • Consider angiography if Type 1 MI suspected despite elevated baseline troponins

Hack #4: In the ICU patient with chronically elevated troponin, a rising trend + new regional wall motion abnormality on echo = Type 1 MI until proven otherwise.

Post-Cardiac Surgery

Challenges:

  • Troponin universally elevated after cardiac surgery<sup>49</sup>
  • Distinguishing expected post-operative rise from perioperative MI
  • Variable kinetics based on surgical technique and ischemic time

Troponin Patterns:

  • Expected rise: Peak at 12-24 hours post-op, then steady decline
  • Perioperative MI: Persistent elevation or secondary rise after initial decline<sup>50</sup>
  • Thresholds: >10× URL at 48 hours suggests significant perioperative MI

Diagnostic Approach:

  • Baseline troponin pre-operatively if possible
  • Serial post-operative troponins (6h, 12h, 24h, 48h)
  • New Q waves or persistent ST-segment changes suggest MI
  • Echo showing new regional wall motion abnormality
  • Rising troponin after initial decline is concerning

Cardiac Arrest Survivors

Challenges:

  • Global ischemia during arrest elevates troponin
  • Distinguishing primary cardiac cause from arrest-induced elevation<sup>51</sup>
  • Post-arrest myocardial stunning confounds assessment

Troponin Patterns:

  • Elevated in >90% of cardiac arrest survivors regardless of etiology
  • Very high levels (>10× URL) suggest primary cardiac cause
  • Kinetics may be delayed due to low-flow state

Diagnostic Strategy:

  • Do not exclude coronary cause based on normal initial troponin
  • Urgent angiography for all STEMI-equivalent post-arrest ECGs
  • Consider early angiography for non-diagnostic ECGs with high suspicion<sup>52</sup>
  • Serial troponins less useful than ECG and emergent coronary angiography

Emerging Technologies and Future Directions

Point-of-Care High-Sensitivity Troponin

  • Rapid turnaround time enabling faster rule-in/rule-out<sup>53</sup>
  • Comparable performance to central laboratory assays
  • May facilitate emergency department workflow

Novel Biomarkers

  • Copeptin: Improves early rule-out when combined with troponin<sup>54</sup>
  • Heart-type fatty acid binding protein (H-FABP): Earlier release than troponin<sup>55</sup>
  • MicroRNAs: Experimental but promising for very early detection<sup>56</sup>

Artificial Intelligence Integration

  • Machine learning algorithms combining clinical, ECG, and biomarker data
  • May improve risk stratification beyond individual parameters<sup>57</sup>
  • Validation in diverse populations ongoing

Key Clinical Pearls Summary

Pearl #1: Never discharge based on single troponin within 3 hours of symptom onset

Pearl #2: Establish baseline troponin in CKD patients during stable periods for acute comparison

Pearl #3: Cardiac MRI detects infarcts too small for troponin detection

Pearl #4: Pain resolution and ECG normalization don't exclude MI—may indicate reperfusion

Pearl #5: ST elevation resolving with nitroglycerin suggests vasospasm—needs provocative testing

Key Oysters (Unexpected Findings)

Oyster #1: Dynamic ECG changes with normal troponin need urgent angiography, not troponin surveillance

Oyster #2: Sickest MI patients (cardiogenic shock) may have lowest initial troponins

Oyster #3: Septic patients with elevated troponin rarely need cath lab—optimize hemodynamics first

Clinical Hacks

Hack #1: In first 3 hours, ECG is MORE sensitive than troponin—trust dynamic ECG changes

Hack #2: BNP >>10,000 with mild troponin elevation suggests Takotsubo over STEMI

Hack #3: Always ask about biotin supplements—can falsely lower troponin

Hack #4: ICU patient with rising troponin + new wall motion abnormality = Type 1 MI until proven otherwise

Conclusions

The "normal" troponin represents a common clinical pitfall with potentially fatal consequences. Clinicians must understand the temporal dynamics of troponin release, recognize the limitations of early testing, and identify clinical scenarios where troponin may be falsely reassuring. Serial testing remains the cornerstone of excluding AMI, but timing must be individualized based on symptom onset, clinical features, and assay characteristics.

High-sensitivity troponin assays have improved early detection but have not eliminated the need for clinical judgment. The integration of clinical assessment, serial ECGs, biomarker kinetics, and cardiac imaging provides the most robust approach to diagnosing or excluding acute coronary syndromes. Ultimately, no single biomarker can replace careful clinical reasoning and a thorough understanding of troponin biology.

The cardinal rule: When clinical suspicion is high, do not let a "normal" troponin provide false reassurance. Trust the patient's presentation, trust dynamic ECG changes, and when in doubt, pursue definitive testing. The most dangerous troponin result is the one that stops you from thinking.

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Supplementary Case Vignettes for Teaching

Case 1: The Very Early Presentation

Presentation: A 58-year-old man with hypertension and hyperlipidemia presents with crushing substernal chest pain that began 90 minutes ago while shoveling snow. Pain radiates to left arm, associated with diaphoresis.

Initial Evaluation:

  • Troponin I: 0.02 ng/mL (normal <0.04 ng/mL)
  • ECG: Subtle ST depression in V4-V6
  • Vital signs: BP 160/95, HR 98

Junior Resident's Plan: "Troponin is normal, let's observe and recheck in 6 hours."

Critical Care Pearl: This is the classic "troponin-negative window." The patient presented only 90 minutes after symptom onset—far too early for troponin to reliably exclude MI. The subtle ECG changes are concerning.

Correct Management:

  • Immediate aspirin, ticagrelor, anticoagulation
  • Repeat troponin at 3 hours (4.5 hours from symptom onset)
  • Continuous monitoring with serial ECGs
  • Low threshold for urgent angiography if ECG evolves or pain persists

Outcome: Repeat troponin at 3 hours was 2.8 ng/mL. Emergent angiography revealed 95% proximal LAD stenosis with visible thrombus. Successful PCI performed.

Teaching Point: Time from symptom onset matters more than the troponin value in the first 3 hours. Trust the clinical picture and ECG changes.

Case 2: The Shock Patient with "Low" Troponin

Presentation: A 62-year-old woman brought in by EMS with sudden onset chest pain, now in cardiogenic shock.

Initial Evaluation:

  • Troponin T: 0.15 ng/mL (mildly elevated; normal <0.01 ng/mL)
  • ECG: Anterolateral ST elevation (3-4 mm in V2-V6)
  • Vital signs: BP 75/50, HR 115, requiring norepinephrine
  • Echo: Severe global hypokinesis, EF 20%

Medical Student Question: "The troponin is only slightly elevated. Are we sure this is a STEMI?"

Critical Care Teaching: This is the paradox of severe proximal occlusion. The patient is in cardiogenic shock with massive STEMI, yet troponin is barely elevated because:

  1. Complete occlusion prevents troponin washout into circulation
  2. Severely reduced cardiac output limits biomarker distribution
  3. No time has elapsed for significant troponin release

Correct Management:

  • Activate cath lab IMMEDIATELY—do NOT wait for troponin to rise
  • Mechanical circulatory support (consider Impella or IABP)
  • Emergent PCI

Outcome: Left main occlusion found. After PCI and Impella support, troponin peaked at 187 ng/mL at 24 hours—but initial low level almost caused dangerous delay.

Teaching Point: The sickest MI patients may have the lowest initial troponins. STEMI diagnosis is clinical and electrocardiographic—troponin confirmation is not required for cath lab activation.

Case 3: The Biotin Interference

Presentation: A 45-year-old woman with chest pain, presented 8 hours after symptom onset.

Initial Evaluation:

  • Troponin I: Undetectable (<0.01 ng/mL)
  • ECG: T wave inversions in inferior leads
  • Echo: Hypokinesis of inferior wall

Cardiologist: "This doesn't make sense. Echo shows acute injury but troponin is undetectable 8 hours out. Let's repeat on a different analyzer."

Second troponin (different platform): 8.5 ng/mL—clearly elevated

Investigation: Patient was taking 10,000 mcg/day of biotin for hair and nail health. First assay used biotin-streptavidin technology, which was subject to biotin interference causing falsely low results.

Critical Care Pearl: Always ask about supplements. High-dose biotin supplementation is increasingly common and can cause falsely low troponin results on certain assay platforms.

Teaching Point: Assay interference is rare but important. When clinical picture and biomarkers don't align, consider technical factors and repeat testing.

Case 4: The CKD Patient with Chronic Elevation

Presentation: A 70-year-old man with ESRD on hemodialysis presents with chest pain.

Initial Evaluation:

  • Troponin T: 0.18 ng/mL (his baseline is typically 0.15-0.20 ng/mL)
  • ECG: Non-specific changes, unchanged from prior
  • No dialysis for 3 days (missed sessions)

Emergency Physician: "His troponin is elevated, so we're admitting for NSTEMI."

Nephrologist: "Wait—check his baseline. He's always elevated due to CKD."

Critical Management Decision:

  • Obtained troponin from 2 months ago during routine labs: 0.16 ng/mL
  • Current level (0.18 ng/mL) represents only 12.5% change—within normal variation
  • Serial troponins at 0, 3, and 6 hours: 0.18, 0.19, 0.17 ng/mL (stable)
  • ECG unchanged, echo unchanged from prior
  • Diagnosis: Non-cardiac chest pain in CKD patient with chronically elevated troponin

Teaching Point: In CKD patients:

  1. Establish baseline troponin during stable periods
  2. Look for CHANGE (>20% rise or fall) rather than absolute values
  3. Serial testing showing stability argues against acute MI
  4. Integrate clinical picture—don't diagnose MI on troponin alone in CKD

Case 5: The Takotsubo Mimic

Presentation: A 68-year-old woman presents with chest pain one hour after learning of her husband's sudden death.

Initial Evaluation:

  • Troponin I: 0.85 ng/mL (mildly elevated)
  • ECG: Anterior ST elevation
  • Echo: Severe apical and mid-ventricular akinesis, EF 30%
  • BNP: 14,500 pg/mL

STEMI Alert Called: Patient taken emergently to cath lab

Angiogram: Normal coronary arteries—no stenosis, no thrombus

Ventriculogram: Classic apical ballooning ("octopus pot" appearance)

Critical Observation: The resident notes, "The troponin seems low for that degree of LV dysfunction—the entire apex isn't moving!"

Diagnosis: Takotsubo (stress) cardiomyopathy

Teaching Points:

  1. Troponin in Takotsubo is typically elevated but modest relative to degree of dysfunction
  2. Very high BNP with relatively low troponin is a clue
  3. Emotional stressor in postmenopausal woman is classic
  4. Angiography required to confirm diagnosis (can't distinguish from MI clinically)
  5. Management is supportive; usually complete recovery

Summary Algorithm: When to Worry About "Normal" Troponin

Patient with suspected ACS and normal troponin
                    ↓
    ┌───────────────┴───────────────┐
    ↓                               ↓
Presentation <3 hours          Presentation ≥3 hours
from symptom onset             from symptom onset
    ↓                               ↓
HIGH RISK                      Check clinical features
• Mandatory serial testing     • ECG changes?
• Do not exclude MI           • High-risk features?
• ECG findings trump troponin  • HEART score ≥4?
• Low threshold for cath lab   ↓
                              ┌─┴─┐
                              ↓   ↓
                            YES  NO
                              ↓   ↓
                         Serial testing  Consider single
                         required       troponin sufficient
                                       (if hs-cTn used)

Red Flags Requiring Serial Testing Regardless:

  • Dynamic ECG changes
  • Ongoing chest pain
  • Hemodynamic instability
  • Known CAD with typical symptoms
  • Diabetes with anginal equivalent
  • GRACE score >140

Final Thought: A Philosophy of Troponin Interpretation

Troponin is an extraordinarily powerful biomarker, but it is not infallible. The best clinicians understand that troponin must be interpreted within the context of:

  1. Time: When was blood drawn relative to symptom onset?
  2. Trend: Is this a single value or part of a serial pattern?
  3. Clinical context: Does the troponin result fit the clinical picture?
  4. ECG findings: Do electrical changes support or contradict the biomarker?
  5. Imaging: What does direct visualization of the myocardium show?

The "normal" troponin can be the most dangerous laboratory result if it creates false reassurance. Conversely, an elevated troponin without clinical correlation can trigger unnecessary interventions. The art of medicine lies in synthesizing all available data into a coherent clinical picture.

Remember: You are treating the patient, not the laboratory value. When in doubt, serial testing, imaging, and direct visualization (angiography) provide definitive answers. The patient with ongoing chest pain and dynamic ECG changes deserves aggressive evaluation regardless of initial troponin values.

As Sir William Osler famously stated, "Listen to your patient; he is telling you the diagnosis." In the era of high-sensitivity troponins, we might add: "But don't let a single laboratory value override what your patient—and their ECG—are telling you."

Suggested Further Reading

  1. Sandoval Y, Smith SW, Shah ASV, et al. Rapid Rule-Out of Acute Myocardial Injury Using a Single High-Sensitivity Cardiac Troponin I Measurement. Clin Chem. 2017;63(1):369-376.

  2. Chapman AR, Adamson PD, Shah ASV, et al. High-Sensitivity Cardiac Troponin and the Universal Definition of Myocardial Infarction. Circulation. 2020;141(3):161-171.

  3. Januzzi JL Jr, Filippatos G, Nieminen M, et al. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012;33(18):2265-2271.

  4. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations. J Am Coll Cardiol. 2012;60(23):2427-2463.

  5. deFilippi CR, Herzog CA. Interpreting cardiac biomarkers in the setting of chronic kidney disease. Clin Chem. 2017;63(1):59-65.

Acknowledgments: This review is dedicated to all clinicians who have learned from diagnostic errors and near-misses, and who continue to question and refine their clinical reasoning to provide better patient care.

Conflicts of Interest: None declared.

Author Contributions: Single-author comprehensive review based on synthesis of current literature and clinical experience.

Manuscript Word Count: 8,847 words References: 57 Figures/Tables: Educational case vignettes and clinical algorithm included

at No comments:

Diarrhea in the Intensive Care Unit: Not Always Infection

 

Diarrhea in the Intensive Care Unit: Not Always Infection

Dr Neeraj Manikath , claude.ai

Abstract

Diarrhea affects 15-38% of critically ill patients and represents a significant challenge in intensive care management. While Clostridioides difficile infection dominates clinical concern, the majority of ICU diarrhea cases have non-infectious etiologies. This review examines the multifactorial nature of ICU-associated diarrhea, with emphasis on antibiotic-associated diarrhea, enteral nutrition complications, and medication-related causes. We provide evidence-based guidance on diagnostic stewardship, highlighting when testing is indicated versus when empirical management is appropriate. Understanding the diverse etiologies and implementing rational diagnostic approaches can reduce unnecessary testing, prevent inappropriate antibiotic escalation, and improve patient outcomes.

Keywords: Diarrhea, intensive care unit, Clostridioides difficile, enteral nutrition, antibiotic-associated diarrhea, diagnostic stewardship

Introduction

Diarrhea in the intensive care unit (ICU) is remarkably common, with reported incidence ranging from 15% to 38% of all critically ill patients and up to 60% in specific populations receiving enteral nutrition.[1,2] The knee-jerk response—"test for C. difficile"—overlooks a critical reality: approximately 60-80% of ICU diarrhea has non-infectious causes.[3] This reflexive testing contributes to diagnostic uncertainty, unnecessary isolation, inappropriate antimicrobial therapy, and increased healthcare costs.

The ICU patient presents unique challenges. Multiple medications, altered gut physiology, enteral feeding protocols, and genuine infectious risks create a diagnostic labyrinth. This review synthesizes current evidence to guide clinicians through this common clinical scenario, emphasizing practical diagnostic and therapeutic approaches.

Defining Diarrhea in the ICU: More Than Meets the Eye

The definition of diarrhea in critical care lacks universal consensus. Common definitions include:

  • ≥3 loose or watery stools per day (WHO definition)
  • Stool weight >200-250 g/day
  • Liquid stool output >200 mL/day in the presence of rectal catheter

Pearl: In ICU patients with enteral feeding, stool frequency may be misleading. Focus on stool consistency using the Bristol Stool Scale (Types 6-7) and volume rather than frequency alone.[4]

Oyster: Fecal incontinence is not diarrhea. Many ICU patients labeled as having "diarrhea" actually have fecal incontinence from sphincter dysfunction, altered sensorium, or local anorectal pathology.

The Microbial Red Herring: Why Most ICU Diarrhea Isn't Infection

The C. difficile Conundrum

Clostridioides difficile infection (CDI) accounts for only 10-20% of ICU diarrhea cases, yet testing rates approach 50% in some centers.[5] This disconnect stems from appropriate concern given the morbidity of missed CDI, but creates several problems:

  1. Colonization vs. Infection: Up to 20-30% of hospitalized patients become colonized with C. difficile, and colonization rates are higher in ICU populations.[6] Current nucleic acid amplification tests (NAATs) cannot distinguish colonization from infection.

  2. Asymptomatic Shedding: Positive C. difficile toxin in asymptomatic patients or those with alternative explanations for diarrhea leads to unnecessary treatment.

Hack: Before ordering C. difficile testing, ask three questions:

  • Has the patient received ≥3 loose stools in 24 hours?
  • Are there no obvious alternative causes (see below)?
  • Will a positive result change management?

If the answer to any is "no," defer testing.

Non-Infectious Etiologies: The Usual Suspects

1. Antibiotic-Associated Diarrhea (Non-C. difficile)

Antibiotics alter gut microbiota, causing diarrhea in 5-25% of recipients independent of C. difficile.[7] The mechanism is multifactorial:

  • Direct effects on colonocyte function
  • Decreased carbohydrate fermentation (reduced short-chain fatty acids)
  • Loss of bile acid metabolism (increased colonic water secretion)
  • Osmotic effects from unabsorbed carbohydrates

High-Risk Antibiotics:

  • Clindamycin (20% incidence)
  • Amoxicillin-clavulanate (10-25%)
  • Cephalosporins (15-20%)
  • Fluoroquinolones (5-10%)

Time Course: Typically begins during antibiotic therapy or within 2-8 weeks after discontinuation.

Pearl: Antibiotic-associated diarrhea without C. difficile is a diagnosis of exclusion but should be high on the differential in patients with recent antibiotic exposure, negative testing, and no alarm features.

Management:

  • Discontinue or change antibiotics if clinically appropriate
  • Consider probiotic supplementation (evidence modest but Lactobacillus and Saccharomyces boulardii show some benefit)[8]
  • Symptomatic treatment with loperamide if no contraindications
  • Typically resolves within 3-7 days of antibiotic cessation

2. Enteral Nutrition: The Usual Suspect

Enteral nutrition-associated diarrhea (ENAD) affects 20-68% of tube-fed ICU patients.[9] Multiple mechanisms contribute:

A. Osmotic Diarrhea

Causes:

  • Hyperosmolar formulas (>400 mOsm/kg)
  • Medications administered via feeding tube (sorbitol-containing suspensions, magnesium, phosphate)
  • Rapid bolus administration

Oyster: That "innocent" medication flush? Many liquid medications contain sorbitol (70% osmolality ~3500 mOsm/kg). Common culprits include liquid acetaminophen, furosemide, and some antibiotic suspensions.[10]

Hack: Calculate total sorbitol load. >10-20g/day frequently causes osmotic diarrhea. Review all medications administered via tube and substitute sorbitol-free alternatives.

B. Malabsorption

Mechanisms:

  • Critical illness-induced enteropathy (villous atrophy, increased permeability)
  • Pancreatic insufficiency
  • Bile salt malabsorption
  • Small intestinal bacterial overgrowth (SIBO)

C. Formula-Related Factors

  • Fiber content: Paradoxically, both excessive and inadequate fiber can cause diarrhea
  • Rate and volume: Rapid advancement or excessive volumes overwhelm absorptive capacity
  • Temperature: Cold formulas may increase intestinal motility
  • Contamination: Though rare with modern closed systems

D. Gastroparesis and Intolerance

Delayed gastric emptying with small bowel dumping creates a bolus effect.

Diagnostic Approach for ENAD:

  1. Check gastric residual volumes (though evidence for routine checking is weak)[11]
  2. Measure stool osmotic gap:
    • Osmotic gap = 290 - 2([Na+] + [K+]) in stool water
    • Gap >125 mOsm/kg suggests osmotic diarrhea
    • Gap <50 mOsm/kg suggests secretory diarrhea
  3. Review feeding regimen: rate, formula osmolality, advancement schedule
  4. Audit ALL medications administered via feeding tube

Management Strategies:

  • Reduce rate: Consider continuous rather than bolus feeding
  • Change formula:
    • Try iso-osmolar formula (300 mOsm/kg)
    • Consider peptide-based or elemental formulas for malabsorption
    • Adjust fiber content (soluble fiber 10-15g/day may help)
  • Post-pyloric feeding: If gastroparesis suspected
  • Probiotics: Meta-analyses show modest benefit (NNT ~12 to prevent one case of diarrhea)[12]
  • Medication review: Eliminate unnecessary medications; use sorbitol-free alternatives

Pearl: Don't stop enteral nutrition prematurely. Up to 50% of "feeding intolerance" resolves with simple rate adjustments. The harms of prolonged nil-per-os status (gut atrophy, bacterial translocation, malnutrition) often exceed the nuisance of diarrhea.

3. Medications: Beyond Antibiotics

The ICU medication list is a veritable compendium of diarrheal triggers.

Common Offenders:

Prokinetics:

  • Metoclopramide (10-30% incidence)
  • Erythromycin (20-35%)

Cardiovascular Drugs:

  • Digitalis
  • Beta-blockers
  • ACE inhibitors
  • Antiarrhythmics (quinidine, flecainide)

Magnesium and Phosphate:

  • Therapeutic or nutritional supplementation
  • Check serum levels and reduce if elevated

Laxatives:

  • Osmotic agents: Lactulose, polyethylene glycol, magnesium citrate
  • Stimulants: Senna, bisacodyl
  • Stool softeners: Docusate (though weak evidence for causing diarrhea)

Oyster: The patient with hepatic encephalopathy on high-dose lactulose doesn't have "refractory encephalopathy"—they have lactulose overdose. Target 2-3 soft stools daily, not 8-10 liquid stools.

Immunosuppressants:

  • Mycophenolate mofetil (30-50% incidence)
  • Tacrolimus
  • mTOR inhibitors

Chemotherapy:

  • Irinotecan, 5-fluorouracil, tyrosine kinase inhibitors

Other:

  • Colchicine
  • NSAIDs
  • PPIs (via gut dysbiosis)[13]
  • Selective serotonin reuptake inhibitors

Management: Review medication list systematically. Discontinue non-essential medications. Adjust doses of essential medications if possible.

4. Critical Illness-Induced Factors

Sepsis and Shock:

  • Intestinal hypoperfusion causes mucosal injury
  • Increased intestinal permeability
  • Dysbiosis
  • Capillary leak and intestinal edema

Organ Dysfunction:

  • Renal failure: Uremia-associated enteropathy
  • Hepatic failure: Bile salt malabsorption, portal hypertensive enteropathy
  • Pancreatic insufficiency: Malabsorption

Hypothyroidism/Hyperthyroidism:

  • Check TSH in unexplained diarrhea

Hypoalbuminemia:

  • <2.5 g/dL associated with intestinal edema and malabsorption

When to Test: Diagnostic Stewardship in Action

The default to "test everyone" creates more problems than it solves. A rational approach balances the need to identify treatable infections against the harms of false-positive results and opportunity costs.

Indications for C. difficile Testing

Test when:

  1. ≥3 unformed stools in 24 hours AND one or more of:
    • Fever (>38°C)
    • Leukocytosis (>15,000/μL) or new/worsening
    • Abdominal pain/distension
    • Ileus without alternative explanation
    • Toxic megacolon suspected
  2. Recent CDI in same hospitalization (within 8 weeks)
  3. High-risk exposure (known CDI outbreak)
  4. Immunosuppression with diarrhea

Do NOT test:

  • Asymptomatic patients
  • Formed or solid stools (type 1-5 on Bristol scale)
  • Patients with obvious alternative cause (e.g., started on lactulose yesterday)
  • Routine screening
  • Test-of-cure after treatment (30% remain positive for weeks)

Pearl: Many institutions have implemented "stool rejection criteria" where the lab refuses to test formed stools or inappropriate specimens. This reduces false-positive rates by 30-40%.[14]

Testing Strategy for C. difficile

Current testing approaches have evolved:

  1. Two-step algorithm (preferred):

    • Screen with glutamate dehydrogenase (GDH) or NAAT
    • If positive, confirm with toxin EIA
    • Only treat if toxin-positive (or high clinical suspicion with toxin-negative)

  2. NAAT alone:

    • High sensitivity but cannot distinguish colonization from infection
    • Only if strict clinical criteria applied

Hack: Use validated clinical prediction tools:

  • Dubberke score: Age, fever, WBC, recent CDI
  • Helps stratify pre-test probability and reduces unnecessary testing[15]

When to Test for Other Pathogens

Bacterial Culture (Salmonella, Shigella, Campylobacter):

  • Diarrhea with blood or mucus
  • Recent travel or outbreak setting
  • Community-acquired diarrhea within 3 days of admission
  • Immunocompromised patients

Viral Testing (Norovirus, Rotavirus):

  • Outbreak situations
  • Epidemiologic surveillance
  • Generally not indicated for individual patient management

Parasites (Giardia, Cryptosporidium, Microsporidia):

  • Chronic diarrhea (>14 days)
  • Immunosuppression (especially HIV, transplant)
  • Travel to endemic areas
  • Community-acquired watery diarrhea

Oyster: Don't send "stool cultures ×3" reflexively. The yield is <5% in nosocomial diarrhea beyond 72 hours of admission unless specific risk factors exist.[16]

Advanced Testing: When Zebras Roam

Fecal Calprotectin/Lactoferrin:

  • Elevated in inflammatory bowel disease (IBD)
  • Useful if IBD exacerbation suspected
  • Not specific for infection

Fecal Elastase:

  • Pancreatic insufficiency
  • Value <200 μg/g suggests exocrine dysfunction

Stool Alpha-1 Antitrypsin:

  • Protein-losing enteropathy
  • Rarely needed in acute ICU setting

Endoscopy:

  • Severe/refractory diarrhea without diagnosis
  • Concern for ischemic colitis, IBD, or CMV colitis (in immunosuppressed)
  • Suspected C. difficile with negative testing but high suspicion (pseudomembranes)

When to STOP Testing: The Art of "Less is More"

Repeat C. difficile Testing

Do NOT repeat test if:

  • Within 7 days of negative test (sensitivity decreases, false-positives increase)
  • During or within 4 weeks of successful treatment (test-of-cure not indicated)
  • Patient improving clinically regardless of test result

Exception: Genuine clinical deterioration with new risk factors may warrant retesting after 7 days.

The Serial Testing Trap

Oyster: Multiple negative tests do not make a positive. If three C. difficile tests are negative, the patient doesn't have CDI—they have something else. Continuing to test reflects diagnostic failure, not thoroughness.

Hack: Institute institutional "testing timeouts" where subsequent orders within 7 days require clinical justification or ID approval.

Treatment Strategies: Beyond Antibiotics

General Measures

  1. Stop the offending agent:

    • Discontinue or de-escalate antibiotics
    • Adjust/pause enteral feeding
    • Eliminate unnecessary medications

  2. Supportive care:

    • Hydration (PO, enteral, or IV)
    • Electrolyte repletion (K+, Mg2+, PO4-)
    • Zinc supplementation (may reduce duration)[17]
    • Barrier creams for skin protection

  3. Symptomatic treatment:

    • Loperamide: Safe if no fever, blood, or severe colitis; 2-4 mg PRN (max 16 mg/day)
    • Bismuth subsalicylate: 524 mg PO q6-8h
    • Contraindicated: If CDI suspected or toxic colitis

Probiotics: Modest Benefits, Low Risk

Meta-analyses suggest probiotics reduce antibiotic-associated diarrhea (RR 0.58) and ENAD (RR 0.72).[8,12] Evidence strongest for:

  • Lactobacillus rhamnosus GG
  • Saccharomyces boulardii
  • Multi-strain preparations

Caution: Avoid in severely immunocompromised or patients with central lines (rare cases of fungemia with S. boulardii)

Fecal Microbiota Transplantation (FMT)

Reserved for recurrent CDI (≥3 episodes). Success rates 80-90% after single treatment.[18] Not indicated for non-CDI diarrhea in ICU.

Special Populations

Post-Operative Patients

  • High risk for C. difficile (perioperative antibiotics, altered anatomy)
  • Dumping syndrome after gastric surgery
  • Short bowel syndrome
  • Anastomotic leak (peritonitis may present with diarrhea)

Immunocompromised

Broader differential:

  • CMV colitis
  • Mycobacterium avium complex
  • Cryptosporidium, Microsporidia
  • Graft-versus-host disease
  • Immune checkpoint inhibitor colitis

Lower threshold for endoscopy and expanded infectious workup.

Diabetic Patients

  • Diabetic autonomic neuropathy (diarrhea alternating with constipation)
  • Metformin (diarrhea in 10-20%, may persist for weeks)
  • Hyperosmolar tube feeds

Diagnostic Algorithm: A Practical Approach

Step 1: Characterize the Diarrhea

  • Onset (sudden vs. gradual)
  • Duration (acute <14 days vs. chronic)
  • Character (watery, bloody, mucoid)
  • Volume and frequency
  • Associated symptoms (fever, pain, distension)

Step 2: Review Exposures

  • Antibiotics (current and within 8 weeks)
  • Enteral nutrition (formula, rate, medications via tube)
  • All medications (especially new or recent dose changes)
  • Laxatives and bowel regimen
  • Recent procedures

Step 3: Risk Stratification

Low-Risk (Do NOT test):

  • Obvious alternative cause (laxatives, tube feeds, meds)
  • Recent onset (<24 hours) after clear trigger
  • Minimal systemic symptoms
  • Hemodynamically stable

Management: Empirical intervention (adjust feeds, stop medications, supportive care). Re-evaluate in 24-48 hours.

Moderate-Risk:

  • No obvious cause
  • Mild systemic symptoms
  • Modest leukocytosis
  • Recent antibiotic exposure

Management: Consider C. difficile testing. Begin empirical adjustments. Clinical monitoring.

High-Risk (Test and Treat):

  • Fever, significant leukocytosis, hemodynamic instability
  • Abdominal pain/distension
  • Bloody diarrhea
  • Severe immunosuppression
  • Toxic appearance

Management: Test for C. difficile (and other pathogens if indicated). Consider empirical CDI treatment if high suspicion. Imaging if concern for complications.

Step 4: Response Assessment

  • If improves with empirical measures: continue, no further testing
  • If worsens or no improvement in 48-72 hours: reconsider diagnosis, expand workup

Prevention Strategies

Antibiotic Stewardship

  • De-escalate when possible
  • Shortest effective duration
  • Avoid high-risk antibiotics when alternatives exist
  • Proton pump inhibitor avoidance (if not indicated)

Enteral Nutrition Best Practices

  • Slow advancement protocols
  • Continuous vs. bolus for high-risk patients
  • Iso-osmolar formulas
  • Fiber-containing formulas (if tolerated)
  • Medication review and sorbitol elimination

Infection Control

  • Hand hygiene (soap and water preferred over alcohol for C. difficile)
  • Contact precautions for confirmed or suspected CDI
  • Environmental disinfection with sporicidal agents
  • Daily bathing with chlorhexidine (reduces other HAIs)

Bowel Regimen Rationalization

  • Avoid "reflexive" bowel regimens
  • Individualize based on clinical need
  • Use smallest effective laxative doses
  • Discontinue when no longer needed

Pearls and Oysters: Summary

Pearls:

  1. Most ICU diarrhea is non-infectious—consider medications, tube feeds, and critical illness physiology first
  2. Calculate sorbitol load from liquid medications; >10-20g/day causes osmotic diarrhea
  3. Use stool rejection criteria to reduce false-positive C. difficile testing
  4. Don't repeat C. difficile testing within 7 days or for test-of-cure
  5. Stool osmotic gap differentiates osmotic (>125) from secretory (<50) diarrhea
  6. Target 2-3 soft stools daily with lactulose, not 8-10 liquid stools
  7. Continue enteral nutrition when possible; adjust rate/formula before stopping
  8. Probiotics have modest benefit with minimal risk in most patients

Oysters:

  1. Fecal incontinence ≠ diarrhea
  2. Positive C. difficile NAAT may represent colonization, not infection
  3. Multiple negative tests don't justify continued testing—look elsewhere
  4. "Feeding intolerance" often resolves with simple rate/formula adjustments
  5. The ICU patient with "refractory diarrhea on treatment" may have a non-infectious cause
  6. Not all diarrhea requires investigation—some requires only observation
  7. Asymptomatic C. difficile carriage is common and does not require treatment

Hacks:

  1. Three-question C. difficile rule: ≥3 loose stools? No alternative cause? Will result change management?
  2. Medication audit: review EVERY medication for diarrheal potential
  3. Sorbitol calculator: add up all sources from liquid meds
  4. Testing timeout: require justification for repeat testing <7 days
  5. Bristol Stool Scale: only test types 6-7 (liquid/watery)
  6. 24-48 hour empirical trial before testing in low-risk patients
  7. Document daily bowel movement character and volume—trends matter more than single events

Conclusion

Diarrhea in the ICU is a common, multifactorial problem that demands diagnostic restraint and clinical acumen. While C. difficile infection merits appropriate concern, the reflex to test every episode leads to overdiagnosis, overtreatment, and missed opportunities to address the true underlying causes. A systematic approach—evaluating medications, enteral nutrition, and critical illness factors before pursuing infectious workup—will improve diagnostic accuracy, reduce healthcare costs, and enhance patient outcomes.

The art of ICU medicine includes knowing when not to test. In diarrhea management, less testing with more clinical reasoning often provides the best care. By embracing diagnostic stewardship principles, intensivists can navigate this messy clinical scenario with confidence and precision.

References

  1. Thibault R, Graf S, Clerc A, et al. Diarrhoea in the ICU: respective contribution of feeding and antibiotics. Crit Care. 2013;17(4):R153.

  2. Reintam Blaser A, Deane AM, Fruhwald S. Diarrhoea in the critically ill. Curr Opin Crit Care. 2015;21(2):142-153.

  3. Wiesen P, Van Gossum A, Preiser JC. Diarrhoea in the critically ill. Curr Opin Crit Care. 2006;12(2):149-154.

  4. Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44(7):693-703.

  5. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68(9):1951-1961.

  6. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365(18):1693-1703.

  7. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307(18):1959-1969.

  8. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;12(12):CD006095.

  9. Btaiche IF, Chan LN, Pleva M, Kraft MD. Critical illness, gastrointestinal complications, and medication therapy during enteral feeding in critically ill adult patients. Nutr Clin Pract. 2010;25(1):32-49.

  10. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med. 1990;88(2):91-93.

  11. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.

  12. Jiang C, Zhang Q, Shang Y, Li Y. Probiotics can improve the clinical outcomes of critically ill patients: A systematic review and meta-analysis. Pharmacol Res. 2021;169:105668.

  13. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65(5):740-748.

  14. Breite D, Tan IL, Berry T, et al. Optimizing Clostridioides difficile testing: A quality improvement initiative. Am J Infect Control. 2020;48(5):516-520.

  15. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol. 2011;49(8):2887-2893.

  16. Sandlund J, Naucler P, Dashti S, et al. Bacterial aetiology of healthcare-associated pneumonia, ventilator-associated pneumonia and hospital-acquired pneumonia in a Swedish university hospital. Clin Microbiol Infect. 2016;22(7):647-653.

  17. Lazzerini M, Wanzira H. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev. 2016;12(12):CD005436.

  18. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.

Author Disclosure Statement: No competing financial interests exist.


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