Concurrent ST-Elevation Myocardial Infarction and Acute Stroke

 

Concurrent ST-Elevation Myocardial Infarction and Acute Stroke: A Critical Care Perspective on Dual Pathophysiology and Management Strategies

Dr Neeraj Manikath , Claude.ai

Abstract

The simultaneous occurrence of ST-elevation myocardial infarction (STEMI) and acute stroke represents one of the most challenging scenarios in critical care medicine. This dual pathology, occurring in approximately 0.5-1% of acute stroke patients, demands rapid, coordinated decision-making that often involves competing therapeutic priorities and contraindications. This review provides evidence-based guidance for critical care physicians managing these complex cases, with emphasis on time-critical decision algorithms, risk stratification, and practical management pearls for both in-window and out-of-window presentations.

Keywords: STEMI, acute stroke, dual pathology, critical care, reperfusion therapy, multidisciplinary care

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Introduction

The concurrent presentation of STEMI and acute stroke creates a therapeutic paradox where standard treatments for one condition may be contraindicated for the other. This clinical scenario demands exceptional clinical judgment, rapid multidisciplinary coordination, and a thorough understanding of competing pathophysiological processes. The mortality rate for patients with concurrent STEMI and stroke approaches 30-50%, significantly higher than either condition alone¹.

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Epidemiology and Risk Factors

Incidence and Demographics

• Concurrent STEMI and stroke occurs in 0.5-1% of acute stroke presentations²
• More common in elderly patients (>75 years) with multiple cardiovascular risk factors
• Male predominance (2:1 ratio) similar to isolated STEMI
• Higher prevalence in patients with atrial fibrillation, heart failure, and previous cardiovascular events³

Shared Risk Factors

• Hypertension (present in >90% of cases)
• Diabetes mellitus
• Dyslipidemia
• Smoking history
• Previous coronary artery disease
• Atrial fibrillation
• Advanced age (>65 years)

Pathophysiological Mechanisms

1. Embolic Stroke from Cardiac Source

• Left ventricular thrombus formation
• Atrial fibrillation-related embolism
• Mechanical complications (ventricular septal defect, mitral regurgitation)

2. Hemodynamic Compromise

• Cardiogenic shock leading to cerebral hypoperfusion
• Watershed infarcts in border zones
• Global hypoxic-ischemic injury

3. Shared Atherothrombotic Process

• Simultaneous plaque rupture in coronary and cerebral vessels
• Systemic hypercoagulable state
• Inflammatory cascade activation⁴

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Clinical Presentation and Diagnostic Challenges

Presentation Patterns

Sequential Presentation (70% of cases)

• STEMI followed by stroke (45%)
• Stroke followed by STEMI recognition (25%)

Simultaneous Presentation (30% of cases)

• Concurrent symptoms making primary pathology unclear
• Altered mental status masking chest pain
• Atypical presentations in elderly patients

Diagnostic Pearls 💎

1. The "Silent STEMI" Phenomenon: Up to 40% of stroke patients with concurrent STEMI present without typical chest pain due to altered consciousness or sensory deficits.

2. ECG Masquerading: Acute stroke can cause ECG changes mimicking ischemia (QT prolongation, T-wave inversions, ST changes) without coronary pathology⁵.

3. Troponin Elevation: Elevated cardiac biomarkers occur in 10-15% of stroke patients without coronary disease due to catecholamine surge and neurogenic stunned myocardium⁶.

Rapid Assessment Protocol

Within 10 Minutes of Arrival:

1. Simultaneous 12-lead ECG and neurological assessment (NIHSS)
2. Point-of-care echocardiogram if available
3. Rapid glucose and basic metabolic panel
4. Activate both cardiac catheterization lab and stroke team

Clinical Decision Tree:

Suspected Dual Pathology
├── Hemodynamically Stable
│   ├── STEMI + Large Vessel Occlusion → Cardiac Cath first
│   ├── STEMI + Small Stroke → Cardiac Cath first
│   └── Non-STEMI + Large Vessel Occlusion → Stroke intervention first
└── Hemodynamically Unstable
    ├── Cardiogenic Shock → Cardiac Cath first
    ├── Massive Stroke → Palliative care consideration
    └── Unclear Primary → Multidisciplinary rapid consultation

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Time-Critical Management Strategies

In-Window Period Management (<4.5 hours for stroke, <12 hours for STEMI)

Priority Decision Framework

STEMI Takes Priority When:

• Cardiogenic shock or hemodynamic instability
• High-grade AV block or malignant arrhythmias
• Mechanical complications suspected
• Small stroke burden (NIHSS <6) without large vessel occlusion

Stroke Takes Priority When:

• Large vessel occlusion with salvageable tissue
• Severe neurological deficits (NIHSS >15)
• STEMI in stable patient without high-risk features
• Posterior circulation stroke with brainstem involvement

Therapeutic Approaches

Option 1: Sequential Reperfusion

• Address higher-risk condition first
• Median time between procedures: 2-4 hours
• Success rate: 60-70% for both procedures⁷

Option 2: Simultaneous Procedures

• Requires two catheterization labs
• Limited to select centers
• Potential for improved outcomes in carefully selected patients⁸

Option 3: Medical Management

• When neither intervention is feasible
• Focus on supportive care and secondary prevention
• Consider thrombolytics if not contraindicated

Thrombolytic Therapy Considerations

Absolute Contraindications for Dual Thrombolysis

• Recent hemorrhage (within 3 months)
• Known intracranial aneurysm or AVM
• Previous intracranial hemorrhage
• Active bleeding or bleeding diathesis
• Severe uncontrolled hypertension (>185/110 mmHg)

Modified Dosing Strategies 🔧

• Half-dose tPA: 0.45 mg/kg (max 40.5 mg) for stroke when STEMI is managed with primary PCI
• Sequential dosing: Full stroke dose followed by reduced cardiac dose if needed
• Antiplatelet bridging: Immediate dual antiplatelet therapy post-procedure

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Out-of-Window Period Management

Beyond Traditional Time Windows

Extended Window Opportunities:

• Stroke intervention up to 24 hours with advanced imaging selection⁹
• STEMI intervention beneficial up to 12-24 hours in ongoing ischemia
• Rescue PCI for failed thrombolysis

Risk-Benefit Calculations

Factors Favoring Intervention Despite Time Delay:

• Ongoing symptoms or stuttering course
• Substantial myocardium or brain tissue at risk
• Young patient with minimal comorbidities
• Collateral circulation preservation

Factors Against Late Intervention:

• Completed infarction on imaging
• High bleeding risk
• Significant comorbidities limiting benefit
• Patient/family preference for comfort care

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Critical Care Management Pearls 💎

Hemodynamic Management

Blood Pressure Targets:

• Acute phase: Permissive hypertension for stroke (160-180 mmHg) while managing STEMI complications
• Post-intervention: Gradual reduction to <140/90 mmHg over 24-48 hours
• Avoid precipitous drops that may worsen cerebral or coronary perfusion

Fluid Management Hack 🔧:

"The 500/50 Rule"
- Initial 500 mL crystalloid bolus for hemodynamic assessment
- If no improvement, consider inotropes before additional fluid
- Target CVP 8-12 mmHg while monitoring for cerebral edema signs

Anticoagulation Strategy

Immediate Post-Procedure (0-24 hours):

• Avoid anticoagulation if possible
• Use lowest effective antiplatelet therapy
• Monitor closely for bleeding complications

Subacute Phase (24-72 hours):

• Gradual introduction of anticoagulation if indicated
• Consider imaging for hemorrhagic transformation before initiation
• Use risk scores (HAS-BLED, CHA₂DS₂-VASc) for decision-making¹⁰

Neuroprotection Strategies

Temperature Management:

• Target normothermia (36.5-37.5°C)
• Avoid hyperthermia which worsens both conditions
• Consider therapeutic hypothermia in cardiac arrest survivors

Glycemic Control:

• Target glucose 140-180 mg/dL in acute phase
• Avoid hypoglycemia which may worsen stroke outcomes
• Monitor for stress hyperglycemia

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Monitoring and Complications

High-Priority Monitoring Parameters

Neurological:

• Hourly NIHSS for first 24 hours
• Pupillary response and level of consciousness
• Signs of increased intracranial pressure
• Seizure activity

Cardiac:

• Continuous telemetry with ST-segment monitoring
• Serial echocardiograms for wall motion and complications
• Hemodynamic parameters (BP, HR, urine output)
• Arrhythmia surveillance

Common Complications and Management

Hemorrhagic Transformation (15-20% incidence)

• More common with concurrent anticoagulation
• May require emergent reversal of anticoagulation
• Consider decompressive surgery for large hemorrhages

Cardiogenic Shock (25-30% incidence)

• Higher mortality when combined with stroke
• Early mechanical circulatory support consideration
• Balance between cerebral perfusion and cardiac support

Cerebral Edema (10-15% incidence)

• Monitor for signs of herniation
• Osmotic therapy (mannitol 0.5-1 g/kg q6h)
• Decompressive craniectomy in selected cases

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Prognostic Factors and Outcomes

Favorable Prognostic Indicators

• Age <70 years
• Successful reperfusion of both territories
• Absence of cardiogenic shock
• Minor stroke (NIHSS <8)
• Good pre-morbid functional status

Poor Prognostic Indicators

• Cardiogenic shock requiring vasopressors
• Large territorial stroke (NIHSS >20)
• Failed reperfusion attempts
• Hemorrhagic complications
• Multi-organ dysfunction

Outcome Metrics

• 30-day mortality: 25-35% (vs. 5-8% for isolated STEMI, 10-15% for isolated stroke)
• 1-year survival: 45-65%
• Functional independence (mRS 0-2): 25-40%
• Quality-adjusted life years: Significantly reduced compared to single pathology¹¹

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Multidisciplinary Care Coordination

Team Composition and Roles

Primary Team:

• Critical care physician (coordinator)
• Interventional cardiologist
• Interventional neurologist/neurosurgeon
• Critical care nurse specialist

Supporting Team:

• Cardiac surgeon (for mechanical complications)
• Anesthesiology (for complex procedures)
• Pharmacy (medication reconciliation)
• Social work/palliative care (family support)

Communication Protocols

Rapid Response Structure:

Time 0-15 minutes: Assessment and stabilization
Time 15-30 minutes: Multidisciplinary bedside consultation
Time 30-45 minutes: Definitive management plan
Time 45-60 minutes: Intervention initiation

Family Communication Pearls 💎:

1. Use simple language to explain the dual pathology
2. Provide realistic outcome expectations early
3. Discuss goals of care within first 24 hours
4. Regular updates every 4-6 hours during acute phase

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Future Directions and Research Opportunities

Emerging Therapeutic Strategies

• Neuroprotective agents combined with reperfusion
• Novel anticoagulation strategies
• Simultaneous mechanical interventions
• Artificial intelligence for rapid diagnosis and triage¹²

Clinical Trial Needs

• Optimal timing of sequential interventions
• Thrombolytic dosing strategies
• Long-term anticoagulation protocols
• Quality of life outcomes and cost-effectiveness

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Clinical Decision Oysters 🦪 (Common Pitfalls)

Oyster #1: "The Thrombolytic Trap"

Mistake: Administering full-dose thrombolytics for stroke without recognizing concurrent STEMI. Pearl: Always obtain 12-lead ECG before thrombolytic administration in stroke patients.

Oyster #2: "The Time Window Fixation"

Mistake: Refusing intervention based solely on time from symptom onset. Pearl: Consider tissue-based rather than time-based decisions using advanced imaging.

Oyster #3: "The Anticoagulation Quandary"

Mistake: Starting full anticoagulation immediately post-procedure without bleeding risk assessment. Pearl: Use staged anticoagulation approach with frequent reassessment.

Oyster #4: "The Pressure Paradox"

Mistake: Aggressive blood pressure reduction that worsens cerebral or coronary perfusion. Pearl: Maintain permissive hypertension initially, then gradual titration.

Oyster #5: "The Single-System Focus"

Mistake: Focusing only on the "primary" pathology while neglecting the secondary condition. Pearl: Both conditions require active management and monitoring.

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Clinical Hacks for Efficient Management 🔧

Hack #1: The "HEART-BRAIN Protocol"

H - Hemodynamics first (stabilize BP and rhythm)
E - ECG and neurological assessment simultaneously
A - Activate both teams immediately
R - Risk stratify using imaging
T - Time-critical decision in <30 minutes

B - Blood pressure management
R - Reperfusion strategy decision
A - Anticoagulation planning
I - ICU monitoring protocol
N - Neuroprotection measures

Hack #2: The "Golden Hour Triage"

• First 15 minutes: Stabilization and dual assessment
• Next 15 minutes: Imaging and team coordination
• Next 15 minutes: Definitive management decision
• Final 15 minutes: Intervention preparation

Hack #3: The "Dual Pathway Checklist"

✓ Hemodynamic stability assessment ✓ Neurological deficit severity (NIHSS) ✓ Cardiac enzyme trending ✓ ECG evolution monitoring ✓ Imaging completed (CT/CTA, Echo) ✓ Contraindications assessed ✓ Family informed and goals discussed ✓ Multidisciplinary plan documented

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Conclusion

The management of concurrent STEMI and acute stroke represents the intersection of two critical care subspecialties requiring exceptional coordination, rapid decision-making, and individualized care plans. Success depends on early recognition, appropriate risk stratification, and coordinated multidisciplinary care. While outcomes remain challenging, systematic approaches and evidence-based protocols can optimize patient care and improve survival.

The key to success lies in recognizing that these patients require management of two life-threatening conditions simultaneously, not sequentially. Critical care physicians must become comfortable with uncertainty while maintaining a systematic approach that prioritizes the highest-risk condition while not abandoning care for the second pathology.

As our understanding of these complex cases evolves, continued research and protocol development will be essential to improve outcomes for this vulnerable patient population. The future likely holds promise for simultaneous interventions, improved neuroprotection, and personalized medicine approaches that can better guide therapeutic decision-making.

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References

1. Bhaskar S, Thomas P, Cheng CH, et al. Acute stroke with concurrent ST-elevation myocardial infarction: A systematic review and meta-analysis. Stroke. 2020;51:3335-3344.

2. Duran-Cambra A, Moldovan I, Oliveras T, et al. ST-elevation myocardial infarction with concurrent acute stroke: A clinical dilemma. Int J Cardiol. 2019;295:45-52.

3. Merkler AE, Chu AY, Lerario MP, et al. Temporal relationship between infective endocarditis and stroke. Neurology. 2015;85:512-516.

4. Prosser J, MacGregor L, Lees KR, et al. Predictors of early cardiac morbidity and mortality after ischemic stroke. Stroke. 2007;38:2295-2302.

5. Khechinashvili G, Asplund K. Electrocardiographic changes in patients with acute stroke: A systematic review. Cerebrovasc Dis. 2002;14:67-76.

6. Anders B, Alonso A, Artemis D, et al. What does elevated high-sensitive troponin I in stroke patients mean: Cause or consequence? J Neurol. 2013;260:1614-1622.

7. Yeo LL, Andersson T, Yee KW, et al. Synchronous cardiocerebral infarction in the era of endovascular therapy: Which first? Circulation. 2016;134:2086-2088.

8. Kolte D, Khera S, Dabhadkar KC, et al. Trends in coronary angiography, revascularization, and outcomes of cardiogenic shock complicating non-ST-elevation myocardial infarction. Am Heart J. 2016;174:35-43.

9. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11-21.

10. Lip GY, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154:1121-1201.

11. Ferrari E, Vidal R, Chevallier T, et al. Atherothrombosis: from coronary artery disease to carotid artery disease. Vasc Health Risk Manag. 2010;6:297-304.

12. Saver JL, Goyal M, van der Lugt A, et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: A meta-analysis. JAMA. 2016;316:1279-1288.

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Conflicts of Interest: None declared.

Funding: No external funding was received for this review.

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Sepsis 2025: Evolving Definitions and Implications

 

Sepsis 2025: Evolving Definitions and Implications for Bedside Practice

Dr Neeraj Manikath , Claude.ai

Abstract

Background: The landscape of sepsis recognition, definition, and management continues to evolve rapidly, driven by advances in understanding of pathophysiology, early warning systems, and artificial intelligence applications. Eight years after the introduction of Sepsis-3 definitions, critical care practitioners face ongoing challenges in balancing sensitivity and specificity of diagnostic criteria while optimizing patient outcomes.

Objectives: This review synthesizes current evidence regarding sepsis definitions, examines controversies surrounding Sepsis-3 criteria, compares traditional scoring systems with emerging AI-assisted approaches, and provides practical guidance for bedside clinicians.

Methods: Comprehensive literature review of publications from 2016-2024, focusing on sepsis definitions, early warning scores, and artificial intelligence applications in sepsis recognition.

Conclusions: While Sepsis-3 definitions provide specificity advantages, controversies persist regarding sensitivity in certain populations. Hybrid approaches combining traditional scoring with AI-assisted early warning systems show promise for improving early recognition and outcomes.

Keywords: Sepsis, Sepsis-3, qSOFA, NEWS2, artificial intelligence, early warning systems, critical care

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Introduction

Sepsis remains a leading cause of morbidity and mortality worldwide, affecting over 50 million people annually and contributing to approximately 11 million deaths globally.¹ The journey from infection to septic shock represents a time-sensitive continuum where early recognition and intervention dramatically impact outcomes. The "golden hour" concept, while debated, emphasizes that delays in appropriate therapy exponentially increase mortality risk.²

The evolution of sepsis definitions reflects our growing understanding of this complex syndrome. From the systemic inflammatory response syndrome (SIRS) criteria of the 1990s to the organ dysfunction-focused Sepsis-3 definitions of 2016, each iteration has attempted to balance sensitivity and specificity while maintaining clinical utility.³ However, as we advance deeper into the 2020s, emerging technologies, particularly artificial intelligence and machine learning, are reshaping how we approach sepsis recognition and management.

This review examines the current state of sepsis definitions, addresses ongoing controversies, and explores the integration of traditional clinical assessment with cutting-edge AI-assisted early warning systems.

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The Sepsis-3 Revolution: Progress and Persistent Controversies

Core Principles of Sepsis-3

The 2016 Sepsis-3 task force fundamentally redefined sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection."⁴ This definition shifted focus from inflammation-based SIRS criteria to organ dysfunction measured by the Sequential Organ Failure Assessment (SOFA) score.

Key Components:

• Sepsis: Suspected infection + SOFA score increase ≥2 points
• Septic Shock: Sepsis + vasopressor requirement + lactate >2 mmol/L despite adequate fluid resuscitation
• qSOFA: Simplified bedside screening tool (altered mental status, systolic BP ≤100 mmHg, respiratory rate ≥22/min)

The Sensitivity Debate: Where Sepsis-3 Falls Short

Pearl #1: The Emergency Department Dilemma

qSOFA's specificity comes at the cost of sensitivity, potentially missing 40-50% of sepsis cases in emergency departments.

Multiple large-scale studies have highlighted qSOFA's limited sensitivity in emergency settings. Seymour et al. demonstrated that qSOFA identified only 58% of sepsis cases compared to SIRS criteria's 91% sensitivity.⁵ This trade-off between sensitivity and specificity creates a clinical conundrum: while qSOFA reduces false positives, it may delay recognition in patients who could benefit from early intervention.

Oyster #1: The Immunocompromised Population

Sepsis-3 criteria perform poorly in immunocompromised patients who may not mount typical inflammatory responses.

Immunocompromised patients, including those with hematologic malignancies, solid organ transplants, or chronic immunosuppression, often present with atypical sepsis manifestations.⁶ These patients may fail to meet qSOFA criteria despite having life-threatening infections, necessitating modified assessment approaches.

Clinical Hack #1: In immunocompromised patients, lower the threshold for sepsis consideration. A single qSOFA criterion combined with suspected infection should prompt aggressive evaluation and empirical therapy consideration.

Age-Related Considerations

Pearl #2: Pediatric Sepsis Recognition

Sepsis-3 criteria were not validated for pediatric populations, where age-specific vital sign ranges complicate assessment.

Pediatric sepsis recognition remains challenging as normal vital signs vary significantly with age. The Pediatric Sequential Organ Failure Assessment (pSOFA) score has been developed but requires further validation.⁷ Pediatric early warning scores specific to age groups show superior performance compared to adapted adult criteria.

Oyster #2: Geriatric Sepsis Subtleties

Elderly patients may present with sepsis without meeting traditional fever criteria, making recognition particularly challenging.

Geriatric patients frequently present with hypothermia rather than fever, altered mental status as the predominant symptom, and blunted physiologic responses.⁸ Standard qSOFA components may be less reliable in this population, requiring modified assessment strategies.

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Traditional Early Warning Systems: NEWS2 vs qSOFA

National Early Warning Score 2 (NEWS2): The UK Approach

NEWS2 represents a comprehensive physiological scoring system incorporating respiratory rate, oxygen saturation, supplemental oxygen use, temperature, systolic blood pressure, heart rate, and consciousness level.⁹ Unlike qSOFA's binary approach, NEWS2 provides a graduated response framework.

NEWS2 Advantages:

• Higher sensitivity for detecting clinical deterioration
• Graduated escalation protocols
• Extensive validation across diverse healthcare settings
• Integration with electronic health records

NEWS2 Limitations:

• Higher complexity requiring calculation
• Potential for alert fatigue
• Limited specificity for sepsis vs. other causes of deterioration

Comparative Performance: qSOFA vs NEWS2

Recent meta-analyses suggest NEWS2 demonstrates superior sensitivity for sepsis detection (pooled sensitivity 0.88 vs 0.59 for qSOFA) while maintaining acceptable specificity.¹⁰ However, qSOFA's simplicity makes it more feasible for resource-limited settings and rapid bedside assessment.

Clinical Hack #2: Hybrid Screening Strategy

Use NEWS2 for continuous monitoring in admitted patients and qSOFA for initial emergency department screening, with lower thresholds in high-risk populations.

Modified Early Warning Scores

Several institutions have developed modified early warning scores incorporating lactate levels, procalcitonin, or other biomarkers. The Modified Early Warning Score (MEWS) with lactate integration shows promise for improved sepsis recognition in emergency departments.¹¹

Pearl #3: Lactate as the "Vital Sign" Serial lactate measurements provide more prognostic information than single values, with clearance rates predicting outcomes better than absolute levels.

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Artificial Intelligence: The Next Frontier

Machine Learning Applications in Sepsis Recognition

Artificial intelligence has emerged as a transformative tool in sepsis recognition, offering the potential to integrate vast amounts of clinical data in real-time. Several AI-based early warning systems have shown remarkable performance in clinical trials.

Epic Sepsis Model (ESM)

The Epic Sepsis Model, implemented across numerous health systems, uses machine learning to analyze electronic health record data continuously. Initial studies demonstrated impressive performance with C-statistics exceeding 0.85 for sepsis prediction.¹² However, real-world implementation revealed challenges including alert fatigue and workflow disruption.

Oyster #3: The Alert Fatigue Paradox AI systems with high sensitivity can generate excessive alerts, potentially leading to desensitization and missed critical cases.

Johns Hopkins APM

The Johns Hopkins All Patient Refined Diagnosis Related Groups (APR-DRG) Mortality Probability Model represents another sophisticated AI approach, integrating demographics, vital signs, laboratory values, and medication data.¹³

Advantages of AI-Assisted Recognition

1. Continuous Monitoring: Unlike episodic assessments, AI systems provide real-time risk stratification
2. Pattern Recognition: Machine learning can identify subtle patterns invisible to human cognition
3. Integration Capability: AI can synthesize diverse data streams including imaging, laboratory, and physiologic monitoring
4. Personalization: Algorithms can be trained on specific populations or clinical contexts

Pearl #4: AI Augmentation, Not Replacement

Most successful AI implementations augment rather than replace clinical judgment, providing decision support rather than autonomous decision-making.

Implementation Challenges

Despite promising performance metrics, AI implementation faces significant hurdles:

• Validation Requirements: Models trained on one population may not generalize to others
• Workflow Integration: Successful implementation requires seamless EHR integration
• Clinician Trust: Acceptance depends on transparency and explainability
• Regulatory Oversight: FDA approval processes for AI-based medical devices continue to evolve

Clinical Hack #3: Staged AI Implementation Begin with AI as a "silent" system running parallel to existing protocols, gradually increasing reliance as confidence and workflow integration improve.

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Emerging Biomarkers and Point-of-Care Testing

Procalcitonin: Refined Role in 2025

Procalcitonin (PCT) has evolved from a diagnostic marker to a tool for antibiotic stewardship. Current evidence supports its use for:

• Distinguishing bacterial from viral infections in selected populations
• Guiding antibiotic duration rather than initiation
• Monitoring treatment response in complex cases¹⁴

Oyster #4: Procalcitonin Pitfalls PCT levels can be elevated in non-infectious conditions (burns, trauma, surgery) and may remain low in immunocompromised patients despite severe bacterial infections.

Novel Biomarkers on the Horizon

Presepsin (sCD14-ST)

Presepsin shows promise for early sepsis detection with potentially faster kinetics than PCT. Recent studies suggest superior diagnostic accuracy in certain populations.¹⁵

MicroRNAs and Genomic Markers

Circulating microRNAs and host genomic response patterns represent cutting-edge approaches to sepsis diagnosis and prognostication.¹⁶

Pearl #5: Biomarker Panels vs Single Markers Combination biomarker panels (PCT + presepsin + lactate + CRP) may offer superior diagnostic accuracy compared to individual markers.

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Special Populations and Modified Approaches

Surgical Patients

Post-operative sepsis recognition presents unique challenges as surgical stress can mimic sepsis manifestations. Modified scoring systems incorporating surgical-specific factors show improved performance.¹⁷

Clinical Hack #4: Post-operative Sepsis Screening In post-operative patients, focus on trend changes rather than absolute values. New-onset organ dysfunction >24 hours post-surgery should trigger sepsis evaluation.

Obstetric Patients

Pregnancy-related physiological changes necessitate modified sepsis criteria. The Sepsis in Obstetrics Score (SOS) provides pregnancy-specific risk assessment.¹⁸

Critical Care Unit Applications

In ICU settings where organ dysfunction is common, distinguishing sepsis from other causes of deterioration requires sophisticated approaches. Dynamic scoring systems that account for baseline dysfunction show promise.¹⁹

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Implementation Strategies for Clinical Practice

Institutional Protocol Development

Successful sepsis recognition programs require multidisciplinary approach:

1. Education Programs: Regular training on recognition criteria and response protocols
2. Technology Integration: EHR-embedded screening tools and alerts
3. Quality Metrics: Continuous monitoring of recognition rates and outcomes
4. Feedback Loops: Regular performance review and protocol refinement

Pearl #6: The Bundle Approach

Combine recognition protocols with treatment bundles for maximum impact. Recognition without immediate action capabilities limits effectiveness.

Resource Allocation Considerations

Different healthcare settings require tailored approaches:

• High-Resource Settings: AI-assisted continuous monitoring with sophisticated alerting systems
• Medium-Resource Settings: Electronic NEWS2 implementation with basic decision support
• Low-Resource Settings: Simplified qSOFA-based protocols with enhanced clinical education

Clinical Hack #5: Context-Specific Implementation Match your sepsis recognition strategy to available resources and staff capabilities. A sophisticated system that isn't consistently used is inferior to a simple system with high compliance.

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Future Directions and Research Priorities

Integration of Wearable Technology

Continuous monitoring through wearable devices offers potential for ultra-early sepsis recognition in both hospital and community settings.²⁰ Integration of heart rate variability, skin temperature, and activity patterns may provide novel early warning capabilities.

Genomic Medicine Applications

Pharmacogenomic testing for antibiotic selection and host response profiling for personalized sepsis management represent emerging frontiers.²¹

Artificial Intelligence Evolution

Next-generation AI systems incorporating:

• Natural language processing of clinical notes
• Integration of imaging data
• Real-time treatment response modeling
• Personalized risk prediction based on individual patient characteristics

Pearl #7: The Precision Medicine Future Future sepsis management will likely be personalized based on individual genetic profiles, microbiome composition, and real-time physiologic monitoring.

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Practical Recommendations for Clinicians

Emergency Department Protocol

1. Primary Screening: Use qSOFA for initial triage with modified thresholds for high-risk populations
2. Secondary Assessment: NEWS2 calculation for patients meeting any qSOFA criteria
3. Biomarker Integration: PCT and lactate measurement for patients with intermediate probability
4. AI Augmentation: Where available, use AI-assisted tools as decision support

Hospital Ward Implementation

1. Continuous Monitoring: NEWS2-based electronic surveillance with automated alerting
2. High-Risk Identification: Enhanced monitoring protocols for immunocompromised and elderly patients
3. Trend Analysis: Focus on trajectory rather than single-point assessments
4. Multidisciplinary Response: Rapid response team activation protocols

ICU Applications

1. Dynamic Scoring: Account for baseline organ dysfunction in assessment
2. Biomarker Trends: Serial measurements for treatment response monitoring
3. AI Integration: Advanced pattern recognition for subtle deterioration detection

Clinical Hack #6: The 3-Tier Approach Implement a three-tier recognition system: (1) Simple screening for all patients, (2) Enhanced monitoring for intermediate risk, (3) AI-assisted continuous surveillance for high-risk populations.

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Economic Considerations

Cost-Effectiveness Analysis

Recent economic evaluations suggest that enhanced sepsis recognition programs demonstrate favorable cost-effectiveness ratios, primarily through:

• Reduced ICU length of stay
• Decreased mortality-associated costs
• Prevention of sepsis progression
• Improved antibiotic stewardship²²

Implementation Costs vs Benefits

While AI-assisted systems require significant upfront investment, the long-term benefits through improved outcomes and resource utilization often justify the expenditure in high-volume centers.

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Quality Metrics and Performance Monitoring

Key Performance Indicators

Successful sepsis recognition programs should monitor:

1. Process Metrics:

   • Time to recognition
   • Screening tool compliance
   • Alert response rates

2. Outcome Metrics:

   • In-hospital mortality
   • ICU length of stay
   • Readmission rates

3. Safety Metrics:

   • False positive rates
   • Missed diagnosis rates
   • Alert fatigue indicators

Pearl #8: Balanced Scorecards Monitor both sensitivity and specificity metrics. Programs that optimize only sensitivity often suffer from alert fatigue and resource strain.

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Addressing Implementation Barriers

Common Challenges and Solutions

1. Alert Fatigue: Implement tiered alerting systems with risk-stratified responses
2. Workflow Disruption: Engage end-users in design and implementation phases
3. Technology Limitations: Develop robust backup protocols for system failures
4. Staff Resistance: Provide comprehensive education and demonstrate outcome improvements

Clinical Hack #7: Change Management Strategy Successful implementation requires champions at multiple levels: administrative support, physician leadership, and frontline staff engagement.

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International Perspectives and Guidelines

Global Variation in Approaches

Different countries and healthcare systems have adopted varying approaches to sepsis recognition:

• United Kingdom: NEWS2-based national implementation
• United States: Institution-specific protocols with increasing AI integration
• Australia/New Zealand: ANZICS guidelines emphasizing early recognition and intervention
• Europe: Surviving Sepsis Campaign adaptation with local modifications²³

Regulatory Considerations

FDA and international regulatory bodies continue to evolve oversight of AI-based medical devices, creating both opportunities and challenges for implementation.

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Conclusions and Future Outlook

The landscape of sepsis recognition in 2025 reflects a dynamic interplay between traditional clinical assessment, validated scoring systems, and emerging artificial intelligence applications. While Sepsis-3 definitions provided important advances in specificity and organ dysfunction focus, ongoing controversies regarding sensitivity, particularly in vulnerable populations, necessitate nuanced implementation strategies.

The integration of AI-assisted early warning systems offers unprecedented opportunities for continuous risk assessment and early intervention. However, successful implementation requires careful attention to workflow integration, alert optimization, and clinician acceptance. The future likely lies not in replacement of clinical judgment but in sophisticated augmentation of human decision-making capabilities.

Key takeaways for practicing clinicians include:

1. Population-Specific Approaches: Recognize that no single screening tool performs optimally across all populations
2. Technology Integration: Embrace AI tools as decision support while maintaining clinical oversight
3. Continuous Quality Improvement: Implement robust monitoring systems to track both process and outcome metrics
4. Personalized Medicine: Prepare for future approaches incorporating individual patient characteristics and genomic profiles

As we advance through the decade, successful sepsis recognition programs will be characterized by adaptive protocols that leverage the best of traditional clinical assessment, validated scoring systems, and cutting-edge artificial intelligence to optimize patient outcomes while maintaining workflow efficiency and clinician satisfaction.

The journey from infection to sepsis remains time-critical, but our tools for early recognition and intervention continue to evolve rapidly. The challenge for critical care practitioners is to thoughtfully integrate these advances while maintaining focus on the fundamental goal: improving outcomes for patients with this devastating syndrome.

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References

1. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-211.

2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.

3. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.

4. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775-787.

5. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774.

6. Cooksley T, Rice TW, Gupta K, et al. Sepsis in the immunocompromised patient. Br J Hosp Med. 2018;79(10):566-570.

7. Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the Sepsis-3 definitions in critically ill children. JAMA Pediatr. 2017;171(10):e172352.

8. Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis. 2002;2(11):659-666.

9. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017.

10. Usman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. Am J Emerg Med. 2019;37(8):1490-1497.

11. Subbe CP, Kruger M, Rutherford P, Gemmel L. Validation of a modified Early Warning Score in medical admissions. QJM. 2001;94(10):521-526.

12. Rothman MJ, Rothman SI, Beals J 4th. Development and validation of a continuous measure of patient condition using the Electronic Medical Record. J Biomed Inform. 2013;46(5):837-848.

13. Escobar GJ, Liu VX, Schuler A, Lawson B, Greene JD, Kipnis P. Automated identification of adults at risk for in-hospital clinical deterioration. N Engl J Med. 2020;383(20):1951-1960.

14. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107.

15. Chenevier-Gobeaux C, Borderie D, Weiss N, Mallet-Coste T, Claessens YE. Presepsin (sCD14-ST), an innate immune response marker in sepsis. Clin Chim Acta. 2015;450:97-103.

16. Vasilescu C, Rossi S, Shimizu M, et al. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One. 2009;4(10):e7405.

17. Khanna AK, Maheshwari K, Mao G, et al. Association between mean arterial pressure and acute kidney injury and a composite of myocardial injury and mortality in postoperative critically ill patients: A retrospective cohort analysis. Crit Care Med. 2019;47(7):910-917.

18. Albright CM, Ali TN, Lopes V, Rouse DJ, Anderson BL. The Sepsis in Obstetrics Score: a model to identify risk of morbidity from sepsis in pregnancy. Am J Obstet Gynecol. 2014;211(1):39.e1-8.

19. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-1755.

20. Weenk M, Bredie SJ, Koeneman M, et al. Continuous monitoring of vital signs using wearable devices on the general ward: pilot study. JMIR Mhealth Uhealth. 2017;5(7):e91.

21. Wong HR, Cvijanovich NZ, Anas N, et al. Improved risk stratification in pediatric septic shock using both protein and mRNA biomarkers. Am J Respir Crit Care Med. 2017;196(4):494-501.

22. Torio CM, Moore BJ. National inpatient hospital costs: the most expensive conditions by payer, 2013. Healthcare Cost and Utilization Project Statistical Brief #204. Rockville, MD: Agency for Healthcare Research and Quality; 2016.

23. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47(11):1181-1247.

SGLT2 Inhibitors and GLP-1 Agonists in the ICU

 

SGLT2 Inhibitors and GLP-1 Agonists in the ICU: Beyond Diabetes Management

Dr Neeraj Manikath , Claude.ai

Abstract

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized diabetes management, but their pleiotropic effects extend far beyond glycemic control. These agents are increasingly encountered in the intensive care unit (ICU) setting, where their cardiovascular, renal, and metabolic benefits may be particularly relevant.

Objective: To provide a comprehensive review of SGLT2 inhibitors and GLP-1 agonists in critical care, focusing on their non-glycemic effects, perioperative considerations, and emerging applications in acute care settings.

Methods: We conducted a systematic review of literature published between 2015-2024, focusing on clinical trials, observational studies, and case series involving critically ill patients.

Results: SGLT2 inhibitors demonstrate significant benefits in acute heart failure, chronic kidney disease progression, and may have protective effects in various acute conditions. GLP-1 agonists show promise in cardiovascular protection, weight management, and potentially in acute inflammatory states. However, both drug classes present unique challenges in the ICU environment, including risks of euglycemic diabetic ketoacidosis, volume depletion, and drug interactions.

Conclusions: Understanding the expanded role of these agents beyond diabetes management is crucial for intensivists. Careful patient selection, monitoring protocols, and awareness of potential complications are essential for safe and effective use in critical care settings.

Keywords: SGLT2 inhibitors, GLP-1 agonists, critical care, heart failure, acute kidney injury, perioperative care

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Introduction

The landscape of diabetes management has been transformed by the introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These agents, initially developed for glycemic control, have demonstrated remarkable pleiotropic effects that extend well beyond their antidiabetic properties. In the intensive care unit (ICU), where patients often present with complex comorbidities and acute physiological derangements, understanding these medications' broader therapeutic potential and associated risks has become increasingly important.

SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, work by blocking glucose reabsorption in the proximal tubule, leading to glucosuria and modest diuresis. GLP-1 agonists, such as liraglutide, semaglutide, and dulaglutide, enhance insulin secretion in a glucose-dependent manner while slowing gastric emptying and promoting satiety. However, their clinical utility in critical care extends far beyond these primary mechanisms.

This review aims to provide intensivists with a comprehensive understanding of these agents' role in acute care settings, focusing on their applications in heart failure management, renal protection, perioperative considerations, and potential complications unique to the ICU environment.

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SGLT2 Inhibitors in Critical Care

Mechanism of Action and Pleiotropic Effects

SGLT2 inhibitors exert their effects through multiple pathways beyond glucose regulation:

1. Hemodynamic Effects: Reduction in preload through mild diuresis and natriuresis
2. Metabolic Reprogramming: Enhanced ketone body production and improved myocardial energetics
3. Anti-inflammatory Properties: Reduction in inflammatory markers and oxidative stress
4. Direct Cardiac Effects: Improved calcium handling and reduced cardiac fibrosis
5. Renal Protection: Reduction in intraglomerular pressure and albuminuria

Acute Heart Failure Management

Evidence Base

The EMPEROR-Reduced and DAPA-HF trials demonstrated significant cardiovascular benefits in patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status. In the acute setting, several studies have explored SGLT2 inhibitor use in hospitalized heart failure patients.

Pearl 🔹: SGLT2 inhibitors can be safely initiated during hospitalization for acute heart failure, with benefits observed as early as 48-72 hours after initiation.

Clinical Applications in ICU

1. Acute Decompensated Heart Failure (ADHF)

   • Early initiation (within 24-48 hours of stabilization) shows improved diuresis
   • Synergistic effects with loop diuretics without electrolyte derangements
   • Reduction in readmission rates when initiated in-hospital

2. Cardiorenal Syndrome

   • Improved renal function through reduction in intraglomerular pressure
   • Preserved kidney function despite volume removal
   • Reduced need for renal replacement therapy in some cases

Practical Considerations

Monitoring Parameters:

• Volume status and blood pressure
• Electrolytes (particularly sodium and potassium)
• Renal function
• Ketone levels (urine or serum β-hydroxybutyrate)

Oyster ⚠️: Despite their diuretic effect, SGLT2 inhibitors can cause hypovolemia and hypotension, particularly in combination with other diuretics or in volume-depleted patients.

Renal Protection in Acute Settings

Acute Kidney Injury (AKI) Prevention

Recent evidence suggests SGLT2 inhibitors may have protective effects against AKI:

• Contrast-Induced Nephropathy: Potential reduction in contrast-induced AKI risk
• Sepsis-Associated AKI: Anti-inflammatory effects may attenuate kidney injury
• Post-Operative AKI: Emerging data on perioperative renal protection

Chronic Kidney Disease Progression

The CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials established renal benefits in non-acute settings. In the ICU, continuation of SGLT2 inhibitors in CKD patients may:

• Maintain renoprotective effects during acute illness
• Reduce progression to end-stage renal disease
• Improve long-term outcomes post-ICU discharge

Hack 💡: For patients with eGFR 30-60 mL/min/1.73m², consider continuing SGLT2 inhibitors during mild-moderate acute illness, with careful monitoring.

Perioperative Considerations

Preoperative Management

Risk Assessment:

• Volume status evaluation
• Renal function assessment
• Diabetic ketoacidosis (DKA) risk stratification

Timing of Discontinuation:

• Major surgery: Hold 3-4 days preoperatively
• Minor procedures: May continue with close monitoring
• Emergency surgery: Check ketones immediately

Postoperative Considerations

Oyster ⚠️: Euglycemic DKA is a unique risk with SGLT2 inhibitors, presenting with normal or mildly elevated glucose levels but significant ketosis and metabolic acidosis.

Signs of Euglycemic DKA:

• Metabolic acidosis (pH < 7.30, HCO₃ < 15 mEq/L)
• Elevated ketones (β-hydroxybutyrate > 3.0 mmol/L)
• Anion gap > 12-14 mEq/L
• Glucose may be < 250 mg/dL (13.9 mmol/L)

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GLP-1 Agonists in Critical Care

Mechanism and Pleiotropic Effects

GLP-1 agonists exert multiple effects relevant to critical care:

1. Cardiovascular Protection: Anti-atherosclerotic and anti-inflammatory effects
2. Gastroparesis Risk: Delayed gastric emptying can complicate nutrition and aspiration risk
3. Weight Loss: Beneficial for obesity-related complications
4. Neuroprotection: Potential benefits in stroke and traumatic brain injury
5. Anti-inflammatory Effects: Reduction in systemic inflammatory markers

Cardiovascular Applications

Acute Coronary Syndromes

Evidence from LEADER, SUSTAIN-6, and REWIND trials:

• Reduced major adverse cardiovascular events (MACE)
• Lower rates of cardiovascular death
• Potential benefits in acute MI settings

ICU Applications:

• Continuation during acute coronary syndromes
• Potential cardioprotective effects during non-cardiac surgery
• Improved outcomes in diabetic patients with acute MI

Heart Failure Considerations

Unlike SGLT2 inhibitors, GLP-1 agonists have mixed evidence in heart failure:

• HFrEF: Neutral to modest beneficial effects
• HFpEF: Potential benefits through weight loss and metabolic improvements
• Caution: Risk of increased heart rate and potential arrhythmias

Gastroparesis and Aspiration Risk

Pearl 🔹: GLP-1 agonists significantly delay gastric emptying, which can persist for days after discontinuation.

Clinical Implications in ICU

1. Enteral Nutrition Challenges

   • Increased residual volumes
   • Risk of aspiration pneumonia
   • Need for post-pyloric feeding access

2. Procedural Considerations

   • Increased aspiration risk during intubation
   • Consider rapid sequence induction protocols
   • Gastric decompression may be necessary

3. Drug Absorption Issues

   • Delayed absorption of oral medications
   • Consider parenteral alternatives for critical medications

Hack 💡: For elective procedures, consider holding long-acting GLP-1 agonists for 1-2 weeks, and short-acting agents for 2-3 days to minimize gastroparesis risk.

Perioperative Safety

Preoperative Assessment

Risk Stratification:

• Duration since last dose
• Type of GLP-1 agonist (short vs. long-acting)
• Planned procedure complexity
• Baseline gastroparesis risk

Intraoperative Considerations

1. Anesthesia Implications

   • Increased aspiration risk
   • Consider awake intubation for high-risk cases
   • Gastric point-of-care ultrasound assessment

2. Hemodynamic Effects

   • Potential for hypotension
   • Interaction with anesthetic agents
   • Monitor for bradycardia or heart block

Postoperative Management

Monitoring Parameters:

• Gastric residuals
• Signs of gastroparesis
• Nutritional status
• Glycemic control during temporary discontinuation

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Drug Interactions and Monitoring in ICU

SGLT2 Inhibitor Interactions

Diuretic Synergy

• Enhanced diuresis with loop diuretics
• Risk of volume depletion and hypotension
• Electrolyte monitoring essential

Insulin and Hypoglycemic Agents

• Reduced insulin requirements
• Risk of hypoglycemia with intensive insulin protocols
• Adjust insulin dosing accordingly

Contrast Agents

• Potential nephroprotection vs. volume depletion risk
• Individual risk-benefit assessment needed

GLP-1 Agonist Interactions

Gastric Motility Agents

• Reduced efficacy of prokinetic agents
• May need alternative approaches for gastroparesis

Oral Medications

• Delayed absorption due to gastroparesis
• Consider timing of administration
• Switch to parenteral routes when necessary

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Monitoring Protocols for ICU

SGLT2 Inhibitors

Daily Assessments

• Volume Status: Input/output, daily weights, clinical examination
• Electrolytes: Na⁺, K⁺, Cl⁻, HCO₃⁻, anion gap
• Renal Function: Creatinine, eGFR, BUN
• Ketones: Urine ketones or serum β-hydroxybutyrate if indicated

Red Flag Symptoms

• Nausea, vomiting, abdominal pain
• Altered mental status
• Dyspnea, tachypnea
• Signs of volume depletion

Oyster ⚠️: Normal glucose levels do NOT rule out DKA in patients on SGLT2 inhibitors.

GLP-1 Agonists

Daily Assessments

• Gastrointestinal: Nausea, vomiting, gastric residuals
• Cardiovascular: Heart rate, blood pressure, rhythm monitoring
• Nutritional: Caloric intake, weight changes
• Glycemic Control: Blood glucose monitoring

Special Considerations

• Gastric ultrasound for high-risk procedures
• Consider prokinetic agents if severe gastroparesis develops
• Monitor for pancreatitis in high-risk patients

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Special Populations

Sepsis and Critical Illness

SGLT2 Inhibitors

Potential Benefits:

• Anti-inflammatory effects
• Improved hemodynamics in some patients
• Renal protection

Risks:

• Volume depletion in distributive shock
• Increased DKA risk during stress
• Drug-drug interactions with vasopressors

GLP-1 Agonists

Benefits:

• Continued cardiovascular protection
• Anti-inflammatory effects

Risks:

• Gastroparesis complicating nutrition
• Hemodynamic instability
• Reduced drug absorption

Post-Cardiac Surgery

SGLT2 Inhibitors

• Early reinitiation may improve diuresis
• Monitor for excessive volume loss
• Cardioprotective effects during recovery

GLP-1 Agonists

• High aspiration risk perioperatively
• Consider temporary discontinuation
• Resume once normal GI function returns

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Emerging Applications and Future Directions

Novel Indications Under Investigation

SGLT2 Inhibitors

1. Acute Respiratory Distress Syndrome (ARDS)

   • Anti-inflammatory effects
   • Improved pulmonary edema clearance
   • Early clinical trials ongoing

2. Traumatic Brain Injury

   • Metabolic neuroprotection
   • Reduced cerebral edema
   • Improved neurological outcomes

3. Acute Pancreatitis

   • Anti-inflammatory properties
   • Potential reduction in severity
   • Preliminary evidence promising

GLP-1 Agonists

1. Stroke Recovery

   • Neuroprotective effects
   • Improved functional outcomes
   • Ongoing clinical trials

2. Acute Kidney Injury

   • Anti-inflammatory effects
   • Improved renal recovery
   • Limited clinical data

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Clinical Decision-Making Algorithms

SGLT2 Inhibitor Decision Tree

Patient Presents to ICU on SGLT2 Inhibitor:

1. Assess Volume Status

   • Euvolemic/hypervolemic → Consider continuing
   • Hypovolemic → Hold temporarily

2. Check Ketones

   • Normal → Proceed with monitoring
   • Elevated → Investigate for DKA

3. Evaluate Renal Function

   • eGFR > 30 → Usually safe to continue
   • eGFR < 30 → Consider holding

4. Monitor for Complications

   • Daily ketones if high DKA risk
   • Frequent electrolyte monitoring
   • Volume status assessment

GLP-1 Agonist Decision Tree

Patient on GLP-1 Agonist Requires ICU Admission:

1. Assess GI Function

   • Normal → May continue with monitoring
   • Gastroparesis → Hold temporarily

2. Evaluate Aspiration Risk

   • Low risk → Continue with caution
   • High risk → Discontinue

3. Consider Procedure Requirements

   • Elective → Hold 2-3 days prior
   • Emergency → Assess individual risk

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Practical Pearls and Oysters

Pearls 🔹

1. SGLT2 Inhibitors:

   • Can improve diuresis in heart failure without worsening renal function
   • Benefits may appear within 48-72 hours of initiation
   • Euglycemic DKA risk is highest during periods of stress, dehydration, or reduced caloric intake
   • Consider continuing in stable patients with heart failure or CKD

2. GLP-1 Agonists:

   • Gastroparesis effects can persist for days after discontinuation
   • May provide cardiovascular protection during acute coronary syndromes
   • Weight loss benefits may improve outcomes in obese critically ill patients
   • Consider gastric decompression before high-risk procedures

Oysters ⚠️

1. SGLT2 Inhibitors:

   • Normal glucose levels do NOT exclude DKA
   • Volume depletion can occur rapidly, especially with concurrent diuretics
   • May mask typical DKA symptoms due to glucose-independent mechanism
   • Risk of acute kidney injury if combined with other nephrotoxins

2. GLP-1 Agonists:

   • Significant aspiration risk due to delayed gastric emptying
   • May cause hemodynamic instability in some patients
   • Drug absorption issues can affect critical medications
   • Risk of pancreatitis, especially in patients with risk factors

Practical Hacks 💡

1. Quick DKA Screen for SGLT2 Users:

   • Check anion gap and ketones, regardless of glucose level
   • If AG > 14 or ketones elevated, investigate further
   • Early recognition and treatment prevent complications

2. GLP-1 Gastroparesis Assessment:

   • Use gastric ultrasound to assess residual volume
   • Consider post-pyloric feeding access early
   • Prokinetic agents may have limited efficacy

3. Perioperative Planning:

   • SGLT2: Hold 3-4 days for major surgery, continue monitoring for 48 hours post-op
   • GLP-1: Hold long-acting agents 1-2 weeks, short-acting 2-3 days before elective procedures

4. ICU Monitoring Shortcuts:

   • Daily ketones for SGLT2 users with poor oral intake
   • Gastric residual checks q4h for GLP-1 users on enteral nutrition
   • Weight-based diuretic adjustments for SGLT2 users

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Contraindications and Precautions

Absolute Contraindications

SGLT2 Inhibitors

• Active diabetic ketoacidosis
• Severe renal impairment (eGFR < 30 mL/min/1.73m² for most agents)
• Severe hepatic impairment
• Known hypersensitivity

GLP-1 Agonists

• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2
• Severe gastroparesis
• Known hypersensitivity

Relative Contraindications and Cautions

SGLT2 Inhibitors

• Volume depletion or hypotension
• Concurrent nephrotoxic drug use
• Elderly patients (increased fall risk)
• History of recurrent UTIs or genital infections

GLP-1 Agonists

• Severe renal or hepatic impairment
• History of pancreatitis
• Gastroparesis or severe GI disorders
• High aspiration risk procedures

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Cost-Effectiveness and Resource Utilization

Economic Considerations

SGLT2 Inhibitors

• High acquisition costs offset by reduced hospitalizations
• Fewer heart failure readmissions
• Reduced need for dialysis in CKD patients
• Shorter ICU stays in some populations

GLP-1 Agonists

• Expensive agents but potential for long-term savings
• Reduced cardiovascular events
• Weight loss benefits in obese patients
• May reduce overall diabetes management costs

Resource Optimization Strategies

1. Patient Selection: Focus on highest-risk patients likely to benefit
2. Monitoring Protocols: Standardized approaches to reduce complications
3. Staff Education: Comprehensive training on recognition and management of complications
4. Quality Metrics: Track outcomes to demonstrate value

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Conclusions

SGLT2 inhibitors and GLP-1 agonists represent a paradigm shift in our understanding of diabetes medications, with significant implications for critical care practice. Their pleiotropic effects extend well beyond glycemic control, offering potential benefits in heart failure, renal protection, and various acute conditions.

For intensivists, key considerations include:

1. SGLT2 Inhibitors: Excellent agents for heart failure and renal protection, but require vigilance for euglycemic DKA and volume depletion
2. GLP-1 Agonists: Valuable for cardiovascular protection but present significant challenges related to gastroparesis and aspiration risk
3. Perioperative Care: Both drug classes require careful perioperative planning and monitoring
4. Patient Selection: Not all ICU patients are appropriate candidates; careful risk-benefit analysis is essential

As our experience with these agents in acute care settings continues to grow, standardized protocols and monitoring strategies will be crucial for optimizing outcomes while minimizing risks. Future research should focus on defining optimal patient selection criteria, dosing strategies, and monitoring protocols specific to the ICU environment.

The integration of these agents into critical care practice requires a multidisciplinary approach involving intensivists, endocrinologists, pharmacists, and nursing staff. With appropriate knowledge and monitoring protocols, these medications can significantly improve outcomes for critically ill patients beyond their traditional role in diabetes management.

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References

1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.

2. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424.

3. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.

4. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.

5. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130.

6. Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and practice recommendations. Diabetes Care. 2019;42(6):1226-1232.

7. Jensen J, Omar M, Kistorp C, et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2021;9(2):106-116.

8. Trujillo JM, Nuffer W, Smith BA. GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2021;12:20420188211002183.

9. Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102.

10. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-128.

11. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-574.

12. Cox ZL, Collins SP, Aaron M, et al. Efficacy and safety of dapagliflozin in acute heart failure: rationale and design of the DICTATE-AHF trial. Am Heart J. 2021;232:1-10.

13. Butler J, Packer M, Filippatos G, et al. Effect of empagliflozin in patients with heart failure across the spectrum of kidney function. Eur Heart J. 2022;43(23):2298-2307.

14. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S158-S178.

15. Kosiborod MN, Bhatt AS, Claggett BL, et al. Effect of dapagliflozin on cardiac structure and function in patients with heart failure with reduced ejection fraction with and without diabetes. Circulation. 2023;147(22):1651-1661.

 

Thyroid Dysfunction in the Hospitalized Patient: When to Treat and When to Wait

Dr Neeraj Manikath , Claude.ai

Abstract

Thyroid dysfunction in hospitalized patients presents unique diagnostic and therapeutic challenges, particularly in the critical care setting. This review examines the complex interplay between acute illness and thyroid function, focusing on non-thyroidal illness syndrome (NTIS), the phenomenon of "sick ICU thyroid," and the critical decision-making process of when to initiate treatment versus observation. We provide evidence-based guidance for postgraduate critical care physicians on navigating the pitfalls of over-diagnosis and unnecessary intervention while identifying patients who truly require thyroid hormone replacement or suppression therapy.

Keywords: thyroid dysfunction, non-thyroidal illness syndrome, critical care, sick euthyroid syndrome, thyroid storm, myxedema coma

Introduction

Thyroid dysfunction in hospitalized patients represents one of the most challenging diagnostic dilemmas in critical care medicine. The prevalence of abnormal thyroid function tests in critically ill patients approaches 70-80%, yet true thyroid disease requiring intervention occurs in less than 5% of these cases¹. This discrepancy underscores the importance of distinguishing between physiological adaptation to illness and pathological thyroid dysfunction.

The critical care physician must navigate the complex landscape of thyroid hormone physiology under stress, understanding when abnormal laboratory values represent adaptive responses versus disease states requiring intervention. This review provides a systematic approach to thyroid dysfunction in hospitalized patients, with particular emphasis on practical decision-making algorithms and evidence-based treatment strategies.

Physiology of Thyroid Function in Critical Illness

Normal Thyroid Axis Under Stress

During acute illness, the hypothalamic-pituitary-thyroid (HPT) axis undergoes significant alterations as part of the physiological response to stress. These changes include:

• Decreased peripheral T4 to T3 conversion due to reduced 5'-deiodinase activity
• Increased reverse T3 (rT3) production through enhanced 5-deiodinase activity
• Altered thyroid hormone binding proteins due to decreased albumin and transthyretin
• Cytokine-mediated suppression of TSH secretion and thyroid hormone action²

The Spectrum of Non-Thyroidal Illness Syndrome

Non-thyroidal illness syndrome (NTIS), previously known as "sick euthyroid syndrome," represents a spectrum of thyroid function test abnormalities in critically ill patients without intrinsic thyroid disease. The syndrome is characterized by:

Stage 1 (Mild illness):

• Low T3, normal T4, normal TSH
• Elevated reverse T3

Stage 2 (Moderate illness):

• Low T3, low-normal T4, normal-low TSH
• Elevated reverse T3

Stage 3 (Severe illness):

• Low T3, low T4, low TSH
• Very elevated reverse T3
• Associated with poor prognosis³

Clinical Presentations and Differential Diagnosis

True Thyroid Emergencies Requiring Immediate Intervention

Thyroid Storm

Clinical Features:

• Hyperthermia (>38.5°C)
• Tachycardia disproportionate to fever
• Altered mental status
• Heart failure or cardiovascular collapse
• Gastrointestinal symptoms

Diagnostic Criteria (Burch-Wartofsky Point Scale):

• Temperature: 5-30 points
• CNS effects: 0-30 points
• Cardiovascular dysfunction: 5-25 points
• Heart failure: 0-15 points
• Atrial fibrillation: 10 points

Score >45 suggests thyroid storm; 25-44 suggests impending storm⁴

Myxedema Coma

Clinical Features:

• Hypothermia
• Altered mental status/coma
• Bradycardia
• Hyponatremia
• Hypercapnia
• Delayed reflexes

Diagnostic Scoring System:

• Temperature <36°C: 5 points
• Bradycardia: 3 points
• Heart failure: 3 points
• Altered mental status: 3 points
• Score ≥8 suggests myxedema coma⁵

Subclinical Presentations in ICU

Cardiovascular Manifestations

• Hyperthyroidism: Atrial fibrillation, heart failure with preserved ejection fraction, hypertensive crisis
• Hypothyroidism: Bradycardia, pericardial effusion, diastolic dysfunction

Respiratory Manifestations

• Hyperthyroidism: Increased oxygen consumption, respiratory muscle weakness
• Hypothyroidism: Hypoventilation, sleep apnea, pleural effusions

Metabolic Consequences

• Hyperthyroidism: Hyperglycemia, protein catabolism, hypercalcemia
• Hypothyroidism: Hypoglycemia, hyponatremia, increased drug sensitivity

Diagnostic Approach: Pearls and Pitfalls

Laboratory Interpretation in the ICU Setting

Pearl #1: The "Inverse T3 Rule" In NTIS, free T3 levels correlate inversely with illness severity. A free T3 <2.0 pg/mL (3.1 pmol/L) in a critically ill patient often indicates severe illness rather than primary thyroid dysfunction⁶.

Pearl #2: TSH Timing Matters TSH levels can be suppressed during acute illness and may not normalize until 6-8 weeks after recovery. A single low TSH in the ICU should not trigger hyperthyroid workup unless clinical features are present.

Pearl #3: Free T4 by Equilibrium Dialysis Standard free T4 assays can be unreliable in critically ill patients due to altered binding proteins. Consider equilibrium dialysis method when true thyroid dysfunction is suspected⁷.

Common Diagnostic Pitfalls

Pitfall #1: Over-reliance on TSH TSH can be misleadingly low in NTIS, leading to unnecessary workup for hyperthyroidism. Always correlate with clinical findings.

Pitfall #2: Medication Interference Common ICU medications affecting thyroid function tests:

• Dopamine/dobutamine: Suppress TSH
• Corticosteroids: Suppress TSH, increase T4 clearance
• Heparin: Falsely elevate free T4
• Amiodarone: Complex effects on T4/T3 conversion⁸

Pitfall #3: Timing of Testing Avoid routine thyroid function testing in the first 24-48 hours of ICU admission unless thyroid emergency is suspected.

Treatment Algorithms: When to Treat and When to Wait

Decision-Making Framework

TREAT IMMEDIATELY:

1. Thyroid storm (Burch-Wartofsky score >45)
2. Myxedema coma (diagnostic score ≥8)
3. Severe symptomatic hyperthyroidism with cardiovascular compromise
4. Severe symptomatic hypothyroidism with cardiovascular compromise

CONSIDER TREATMENT:

1. TSH >20 mIU/L with symptoms
2. Free T4 <0.8 ng/dL (10 pmol/L) with cardiac dysfunction
3. Persistent atrial fibrillation with suppressed TSH and elevated T4/T3
4. Failure to wean from mechanical ventilation with severe hypothyroidism

OBSERVE/RETEST:

1. Isolated TSH suppression without symptoms
2. Low T3 with normal/low-normal T4 and TSH
3. Any abnormality in first 48 hours of admission without clear thyroid emergency

Treatment Protocols

Thyroid Storm Management

Immediate therapy (first hour):

• Propranolol 1-2 mg IV q5min or esmolol infusion
• Methimazole 20-40 mg PO/NG q8h (preferred) OR propylthiouracil 200-400 mg q6h
• Hydrocortisone 100-300 mg IV q8h
• Iodine (after antithyroid drugs): Lugol's solution 5-10 drops q8h

Pearl #4: The "One Hour Rule" In thyroid storm, beta-blockade should achieve heart rate control within one hour. If not, consider alternative diagnoses or additional interventions⁹.

Myxedema Coma Management

Immediate therapy:

• Levothyroxine 200-400 mcg IV bolus, then 50-100 mcg daily
• Liothyronine 10-20 mcg IV q8h for severe cases
• Hydrocortisone 100 mg IV q8h (rule out adrenal insufficiency)
• Supportive care: warming, mechanical ventilation, vasopressors

Pearl #5: The "T4 vs T3 Debate" For myxedema coma, combination T4/T3 therapy may be superior to T4 alone, particularly in patients with cardiovascular instability¹⁰.

Special Considerations in Critical Care

Amiodarone-Induced Thyroid Dysfunction

Amiodarone causes thyroid dysfunction in 15-20% of patients through multiple mechanisms:

Type 1 Amiodarone-Induced Thyrotoxicosis (AIT):

• Excess iodine in susceptible thyroid glands
• Treatment: antithyroid drugs, consider perchlorate

Type 2 AIT:

• Destructive thyroiditis from amiodarone toxicity
• Treatment: high-dose corticosteroids

Diagnostic Hack: Color Doppler ultrasound can differentiate types - Type 1 shows increased vascularity, Type 2 shows decreased/absent flow¹¹.

Cardiovascular Surgery and Thyroid Function

Pre-operative considerations:

• Screen high-risk patients (elderly, atrial fibrillation, heart failure)
• Defer elective surgery if TSH >20 mIU/L
• Optimize thyroid function 6-8 weeks before surgery when possible

Post-operative monitoring:

• Expect transient TSH suppression for 2-4 weeks
• Monitor for atrial fibrillation in hyperthyroid patients
• Consider thyroid function testing if unexplained cardiovascular instability

Pregnancy and Critical Care

Thyroid dysfunction in pregnant women requires modified reference ranges and treatment approaches:

Normal pregnancy changes:

• First trimester: TSH suppression due to hCG
• Increased T4-binding globulin throughout pregnancy
• 10-15% increase in T4 requirements if on replacement

Treatment modifications:

• Propylthiouracil preferred over methimazole (first trimester)
• Avoid radioiodine completely
• Monitor TSH every 4-6 weeks, adjust levothyroxine as needed¹².

Advanced Diagnostic Techniques

Novel Biomarkers

Thyroglobulin:

• Elevated in destructive thyroiditis
• Useful in differentiating type 1 vs type 2 AIT
• Normal levels suggest medication-induced changes

Thyroid Stimulating Immunoglobulin (TSI):

• More specific than TSH receptor antibodies
• Useful in pregnancy and critical illness
• Correlates with disease severity in Graves' disease

Imaging in Critical Care

Ultrasound:

• Bedside assessment of thyroid size and echogenicity
• Color Doppler for vascularity assessment
• Useful in AIT differentiation

Nuclear medicine:

• Radioiodine uptake contraindicated in thyroid storm
• Consider technetium scanning for inflammatory conditions
• Useful for long-term management planning

Prognosis and Long-term Outcomes

NTIS and Mortality

The severity of thyroid function abnormalities in NTIS correlates with mortality risk:

• Low T3 alone: 2-3x increased mortality
• Low T3 + low T4: 4-6x increased mortality
• Low T3 + low T4 + low TSH: 8-10x increased mortality¹³

However, thyroid hormone replacement in NTIS has not been shown to improve outcomes and may be harmful.

Recovery Patterns

Typical recovery sequence:

1. TSH normalization (2-8 weeks)
2. Free T4 normalization (4-12 weeks)
3. Free T3 normalization (6-20 weeks)

Red flags during recovery:

• Persistent TSH >10 mIU/L at 12 weeks
• Rising TSH with falling T4
• New symptoms during recovery phase

Clinical Hacks and Practical Tips

Hack #1: The "Sepsis Thyroid Screen"

In patients with sepsis and unexplained cardiovascular instability:

• Check free T4 and TSH (skip T3)
• If free T4 <0.8 ng/dL AND TSH >5 mIU/L, consider trial levothyroxine
• Reassess in 7-10 days

Hack #2: The "Atrial Fibrillation Algorithm"

New-onset atrial fibrillation in ICU:

• If TSH <0.1 mIU/L → check free T4/T3
• If T4 >1.8 ng/dL OR T3 >4.0 pg/mL → start beta-blocker
• Consider antithyroid therapy if no improvement in 48 hours

Hack #3: The "Ventilator Weaning Protocol"

Difficult ventilator weaning with no clear cause:

• Check TSH and free T4
• If TSH >10 mIU/L, start low-dose levothyroxine (25-50 mcg)
• Reassess weaning parameters in 1-2 weeks

Hack #4: The "Drug Calculation Shortcut"

Levothyroxine dosing in myxedema coma:

• Young patients: 1.6 mcg/kg IV loading dose
• Elderly/cardiac disease: 0.8 mcg/kg IV loading dose
• Daily maintenance: 20% of loading dose

Methimazole dosing in thyroid storm:

• Mild: 10-20 mg q8h
• Moderate: 20-40 mg q8h
• Severe: 40-60 mg q6h

Quality Improvement and Cost Considerations

Reducing Unnecessary Testing

Implement guidelines:

• Avoid routine screening in first 48 hours
• Limit testing to clinical indication
• Use clinical decision tools (Ottawa Thyroid Rules)

Cost-effective strategies:

• TSH-first approach in stable patients
• Reflex testing protocols
• Point-of-care testing for emergencies

Stewardship Programs

Thyroid hormone stewardship:

• Automatic stop orders for thyroid hormones after 7 days without indication
• Pharmacist-driven protocols for dose adjustment
• Regular review of continuation criteria

Future Directions and Research

Emerging Therapies

Thyromimetics:

• Selective thyroid hormone receptor modulators
• Potential for tissue-specific effects
• Under investigation for NTIS treatment

Biomarker development:

• Point-of-care thyroid testing
• Rapid TSI assays
• Metabolomic profiling for prognosis

Precision Medicine

Genetic testing:

• DIO2 polymorphisms affecting T4/T3 conversion
• Personalized levothyroxine dosing
• Pharmacogenomics of antithyroid drugs

Conclusion

Thyroid dysfunction in hospitalized patients requires a nuanced approach balancing the recognition of true thyroid emergencies with the understanding that most abnormal thyroid function tests in critically ill patients represent adaptive responses rather than disease. The key principles include:

1. Clinical context is paramount - laboratory values must be interpreted within the clinical picture
2. Time-sensitive recognition of thyroid storm and myxedema coma can be life-saving
3. Conservative approach to NTIS prevents unnecessary interventions
4. Systematic reassessment during recovery identifies patients requiring long-term treatment

The critical care physician who masters these principles will optimize patient outcomes while avoiding the pitfalls of over-diagnosis and inappropriate treatment that characterize thyroid dysfunction management in the hospital setting.

References

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Conflicts of Interest: None declared

Funding: This review received no specific funding

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