Wednesday, June 25, 2025

Hyperviscosity Syndrome

Hyperviscosity Syndrome: Rapid Bedside Recognition and Intervention

A Critical Care Review for Postgraduate Medical Education

Dr Neeraj Manikath, Claude.ai

Abstract

Hyperviscosity syndrome (HVS) represents a hematologic emergency requiring immediate recognition and intervention. This comprehensive review addresses the pathophysiology, clinical presentation, diagnostic approaches, and management strategies essential for critical care practitioners. With mortality rates approaching 40% when untreated, early identification and prompt therapeutic plasma exchange can be life-saving. This article provides evidence-based guidance for postgraduate physicians managing this complex condition in the critical care setting.

Keywords: Hyperviscosity syndrome, plasma exchange, multiple myeloma, Waldenström's macroglobulinemia, critical care

Introduction

Hyperviscosity syndrome occurs when blood viscosity increases sufficiently to impair microcirculation, leading to neurological, ophthalmologic, and hemorrhagic complications. First described by Bing and Plum in 1937, HVS remains a diagnostic and therapeutic challenge in modern critical care practice. The syndrome predominantly affects patients with hematologic malignancies, particularly those with elevated serum proteins or cellular components that alter blood rheology.

The critical care physician must maintain high clinical suspicion, as HVS can present with nonspecific symptoms that mimic other neurological emergencies. Early recognition and intervention with therapeutic plasma exchange (TPE) can prevent irreversible complications and reduce mortality from this otherwise fatal condition.

Pathophysiology

Blood viscosity depends on multiple factors: hematocrit, plasma protein concentration, cellular deformability, and flow characteristics. Normal blood viscosity ranges from 1.4-1.8 centipoise (cP) at body temperature. HVS typically manifests when viscosity exceeds 4-5 cP, though symptoms can occur at lower levels in susceptible patients.

Mechanisms of Hyperviscosity

Protein-Related Hyperviscosity:

Monoclonal gammopathies increase plasma viscosity through protein-protein interactions
Immunoglobulin M (IgM) molecules are particularly viscogenic due to their large molecular size (900 kDa)
IgG and IgA can also cause HVS, especially when present in high concentrations or with abnormal polymerization

Cellular Hyperviscosity:

Leukostasis from extreme leukocytosis (typically >100,000/μL)
Increased red cell mass in polycythemia vera
Abnormal cellular rheology in sickle cell disease

The resultant microcirculatory impairment leads to tissue hypoxia, particularly affecting organs with high metabolic demands and terminal circulation patterns, such as the brain, retina, and mucous membranes.

Etiology and Risk Factors

Primary Causes

Hematologic Malignancies (85-90% of cases):

Waldenström's Macroglobulinemia
- Most common cause of protein-related HVS
- IgM levels typically >30 g/L when symptoms develop
- Accounts for 15% of all HVS cases
Multiple Myeloma
- Second most common cause
- Usually associated with IgG or IgA paraproteins
- HVS occurs in 2-6% of myeloma patients
Acute Leukemias
- Primarily acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
- Leukostasis syndrome when blast count >100,000/μL
- Accounts for 10-15% of HVS cases

Secondary Causes

Polycythemia vera (hematocrit >65%)
Essential thrombocythemia (platelet count >1,000,000/μL)
Chronic lymphocytic leukemia with extreme lymphocytosis
Cryoglobulinemia
Systemic lupus erythematosus with hypergammaglobulinemia

Risk Factors for HVS Development

Advanced age (>65 years)
Dehydration
Concurrent infections
Renal insufficiency
Diabetes mellitus
Smoking history

Clinical Presentation

The Classic Triad (Present in 60-70% of cases)

1. Neurological Manifestations

Headache (most common symptom, 84% of cases)
Altered mental status ranging from confusion to coma
Dizziness and vertigo
Seizures (focal or generalized)
Focal neurological deficits mimicking stroke
Ataxia and coordination difficulties

2. Ophthalmologic Changes

Retinal hemorrhages (flame-shaped or dot-blot)
Papilledema
Retinal vein engorgement and tortuosity
Visual field defects
Diplopia
Acute vision loss (medical emergency)

3. Mucosal Bleeding

Epistaxis (nosebleeds)
Gingival bleeding
Gastrointestinal bleeding
Prolonged bleeding from venipuncture sites
Petechiae and ecchymoses

Additional Clinical Features

Cardiovascular:

Congestive heart failure
Hypotension
Arrhythmias

Respiratory:

Dyspnea
Pulmonary edema

Dermatologic:

Livedo reticularis
Digital ischemia
Raynaud's phenomenon

Diagnostic Approach

Laboratory Investigations

Immediate (Stat) Laboratory Studies:

Complete Blood Count with Differential
- Evaluate for leukocytosis, thrombocytosis, or polycythemia
- Look for circulating blasts or abnormal cells
Serum Protein Studies
- Total protein (often >100 g/L in HVS)
- Serum protein electrophoresis (SPEP)
- Immunofixation electrophoresis
- Quantitative immunoglobulins (IgG, IgA, IgM)
Blood Viscosity Measurement
- Serum viscosity >1.8 cP (normal <1.4 cP)
- Whole blood viscosity if available
Peripheral Blood Smear
- Rouleaux formation (pathognomonic finding)
- Blast cells in leukemia
- Abnormal protein precipitates

Pearls for Laboratory Interpretation

🔍 Pearl 1: Rouleaux formation on blood smear is virtually diagnostic of protein-related HVS - red cells stack like coins due to altered surface charge from excess proteins. This finding may be seen alongside other CBC abnormalities.

🔍 Pearl 2: The "reverse albumin-globulin ratio" - when globulin exceeds albumin significantly (>2:1), suspect HVS. Look for total protein >100 g/L as a red flag.

🔍 Pearl 3: Serum monoclonal component concentration >15 g/L warrants hyperviscosity assessment, even in asymptomatic patients.

🔍 Pearl 4: Asymptomatic patients with elevated serum viscosity do not require plasma exchange - treat symptoms, not just numbers.

🔍 Pearl 5: Additional metabolic abnormalities may include hypercalcemia, hypophosphatemia, and hyperkalemia - check comprehensive metabolic panel.

Advanced Diagnostic Studies

Imaging:

Non-contrast head CT to exclude intracranial hemorrhage
MRI brain for subtle ischemic changes
Echocardiography if heart failure suspected

Specialized Tests:

Bone marrow biopsy (when clinically stable)
Flow cytometry for leukemia/lymphoma workup
Cryoglobulin studies if indicated

Management Strategies

Immediate Interventions (First Hour)

1. Airway, Breathing, Circulation Assessment

Secure airway if altered mental status
Supplemental oxygen for respiratory distress
IV access with caution (bleeding risk)

2. Symptom-Directed Supportive Care

Seizure management with benzodiazepines
Blood pressure support if hypotensive
Avoid excessive fluid resuscitation (may worsen viscosity)

3. Emergency Therapeutic Plasma Exchange (TPE)

DO NOT DELAY for definitive diagnosis
Asymptomatic patients with elevated serum viscosity do not require plasma exchange - treat symptomatic patients first
Initiate within 6 hours of recognition when possible
Remove 1-1.5 plasma volumes per session
Replace with normal saline or 5% albumin
Remove approximately 25% of patient's plasma volume per session - done gradually

Therapeutic Plasma Exchange Protocol

Indications for Emergency TPE:

Clinical triad with laboratory support
Serum viscosity >4.0 cP
Neurological symptoms with paraproteinemia
Visual changes with retinal findings

TPE Technical Specifications:

Vascular access: Large-bore central venous catheter
Anticoagulation: Citrate preferred over heparin (bleeding risk)
Replacement fluid: Normal saline or 5% albumin
Volume processed: 1-1.5 total plasma volumes
Frequency: Daily until clinical improvement

Hacks for Optimal TPE Management

🎯 Hack 1: Start TPE before hematology consultation if clinical suspicion is high - time is tissue in HVS. There is no specific diagnostic test - base decision on clinical symptoms and laboratory findings.

🎯 Hack 2: Use the "vision test" - if visual symptoms improve within 4-6 hours post-TPE, you've confirmed the diagnosis and effectiveness.

🎯 Hack 3: Monitor ionized calcium closely during TPE - citrate anticoagulation can cause severe hypocalcemia requiring calcium replacement.

🎯 Hack 4: In resource-limited settings, judicious phlebotomy with concurrent crystalloid/blood product replacement can be a temporizing measure.

🎯 Hack 5: Different apheresis techniques for different causes: Plasmapheresis for elevated immunoglobulins, leukapheresis for leukostasis, plateletpheresis for thrombocytosis, phlebotomy for polycythemia.

Adjunctive Therapies

Immediate (0-24 hours):

Hydration with normal saline (cautiously)
Avoid aspirin and anticoagulants
Platelet transfusion if severe thrombocytopenia with bleeding

Intermediate (24-72 hours):

Chemotherapy for underlying malignancy (after TPE initiation)
Rituximab for Waldenström's macroglobulinemia
Hydroxyurea for leukostasis syndrome

Long-term:

Disease-specific treatment protocols
Maintenance TPE if refractory to chemotherapy

Monitoring and Complications

Key Monitoring Parameters

Clinical Monitoring:

Neurological status (hourly initially)
Visual acuity and fundoscopic exam
Bleeding assessment
Vital signs and urine output

Laboratory Monitoring:

Serum viscosity (pre/post TPE)
Total protein and paraprotein levels
Complete blood count
Electrolytes (especially calcium)
Coagulation studies

Complications of HVS

Untreated HVS:

Cerebral infarction
Retinal detachment and blindness
Congestive heart failure
Gastrointestinal bleeding
Death (mortality 20-40%)

Treatment-Related Complications:

TPE complications (catheter-related, hypocalcemia, allergic reactions)
Tumor lysis syndrome from chemotherapy
Bleeding from anticoagulation

Oysters (Diagnostic Pitfalls)

🦪 Oyster 1: Not all neurological symptoms in hematologic malignancy patients are due to CNS involvement - consider HVS, especially with concurrent visual or bleeding symptoms.

🦪 Oyster 2: Normal hematocrit doesn't exclude HVS - protein-related hyperviscosity can occur with normal cellular elements.

🦪 Oyster 3: Mild symptoms can progress rapidly - a patient with "just a headache" and paraproteinemia may develop coma within hours.

🦪 Oyster 4: TPE can temporarily worsen bleeding by removing clotting factors - balance risk vs. benefit carefully.

🦪 Oyster 5: Don't mistake leukostasis for sepsis - both can present with altered mental status and elevated WBC, but treatments differ dramatically.

Prognosis and Outcomes

Factors Affecting Prognosis

Favorable Prognostic Factors:

Early recognition and treatment
Younger age (<65 years)
Absence of neurological complications at presentation
Underlying disease responsiveness to treatment

Poor Prognostic Factors:

Delayed diagnosis (>24 hours)
Coma at presentation
Concurrent infections
Refractory underlying malignancy

Outcome Data

Recent studies demonstrate significant improvement in HVS outcomes with early TPE:

Mortality reduced from 40% to <10% with prompt intervention
Complete neurological recovery in 85% when treated within 12 hours
Visual recovery in 70% of patients with retinal complications

Future Directions and Research

Emerging Therapies

Novel Approaches:

Selective plasma filtration techniques
Monoclonal antibody therapies targeting specific paraproteins
Advanced cytoreduction strategies for leukostasis

Biomarker Development:

Point-of-care viscosity measurement devices
Rapid paraprotein quantification assays
Predictive models for HVS risk stratification

Areas for Investigation

Optimal TPE protocols for different etiologies
Combination therapies to reduce TPE requirements
Long-term neurological outcomes following HVS

Conclusion

Hyperviscosity syndrome represents a true hematologic emergency requiring immediate recognition and intervention. The critical care physician must maintain high clinical suspicion when encountering the classic triad of neurological symptoms, visual changes, and mucosal bleeding in patients with known or suspected hematologic malignancies. Laboratory clues including elevated serum proteins, rouleaux formation, and increased plasma viscosity support the diagnosis, but treatment should not be delayed pending confirmatory testing.

Therapeutic plasma exchange remains the cornerstone of acute management and should be initiated emergently when clinical suspicion is high. Early intervention with TPE, combined with appropriate supportive care and treatment of the underlying condition, can prevent irreversible complications and significantly improve patient outcomes.

The key to successful HVS management lies in rapid bedside recognition, immediate initiation of TPE, and coordinated multidisciplinary care involving critical care, hematology, and apheresis specialists. With proper recognition and treatment, this previously fatal condition can have excellent outcomes, emphasizing the critical importance of early diagnosis and intervention.

References

Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018;132(13):1379-1385. doi:10.1182/blood-2018-06-846816
Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119(10):2205-2208. doi:10.1182/blood-2011-10-384115
Perez-Rogers A, Estes M. Hyperviscosity Syndrome. StatPearls. 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518963/
Sidiqi MH, Gertz MA. Therapeutic plasma exchange for hyperviscosity syndrome in IgA multiple myeloma. Transfus Apher Sci. 2024;63(4):103916. doi:10.1016/j.transci.2024.103916
Green J, Strahm B, Millward K, et al. The utility of therapeutic plasma exchange in Hyperviscosity syndrome associated with juvenile rheumatoid arthritis: A case report. J Clin Apher. 2021;36(5):736-739. doi:10.1002/jca.21903
Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost. 1999;25(2):199-208. doi:10.1055/s-2007-994920
ACEP Critical Care Medicine Section. Hyperviscosity Syndrome. January 2025. Available from: https://www.acep.org/criticalcare/newsroom/newsroom-articles/january-2025/hyperviscosity-syndrome
Porcu P, Cripe LD, Ng EW, et al. Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management. Leuk Lymphoma. 2000;39(1-2):1-18. doi:10.3109/10428190009053534
Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29(5):467-471. doi:10.1055/s-2003-44555
Schwab PJ, Fahey JL. Treatment of Waldenstrom's macroglobulinemia by plasmapheresis. N Engl J Med. 1960;263:574-579. doi:10.1056/NEJM196009222631202
Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98(5):1614-1615. doi:10.1182/blood.v98.5.1614
Somer T. Hyperviscosity syndrome in plasma cell dyscrasias. Adv Exp Med Biol. 1975;63:89-133. doi:10.1007/978-1-4613-9387-2_8
Adams BD, Baker R, Lopez JA, Spencer S. Myeloproliferative disorders and the hyperviscosity syndrome. Emerg Med Clin North Am. 2009;27(3):459-476. doi:10.1016/j.emc.2009.04.001
Bloch KJ, Maki DG. Hyperviscosity syndromes associated with immunoglobulin abnormalities. Semin Hematol. 1973;10(2):113-124.
Rosenstein ED, Itzkowitz SH, Jacobson IM, et al. Hyperviscosity syndrome in multiple myeloma: clinical correlates and response to plasmapheresis. Am J Med. 1982;73(1):141-145. doi:10.1016/0002-9343(82)90939-3

Tuesday, June 24, 2025

Hemophagocytic Lymphohistiocytosis (HLH) – Early Recognition

Hemophagocytic Lymphohistiocytosis (HLH) – Early Recognition in the ICU: A Critical Review for Postgraduate Physicians

Dr Neeraj Manikath, Claude.ai

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that poses significant diagnostic and therapeutic challenges in the intensive care unit (ICU). This hyperactivation of macrophages and cytotoxic T cells creates a cytokine storm that can rapidly progress to multi-organ failure and death if unrecognized. The clinical presentation frequently mimics sepsis, making early recognition crucial for favorable outcomes. This review provides a comprehensive update on diagnostic approaches, differential diagnosis, and management strategies specifically tailored for critical care physicians managing postgraduate medical education.

Keywords: Hemophagocytic lymphohistiocytosis, HLH, critical care, diagnostic criteria, immunosuppression, ferritin

Introduction

HLH represents one of the most challenging diagnostic entities in critical care medicine, with mortality rates approaching 50-70% in ICU populations despite treatment. The syndrome results from uncontrolled immune activation, leading to excessive cytokine production and macrophage activation. Early recognition and prompt initiation of immunosuppressive therapy are paramount, as delayed treatment significantly worsens outcomes.

Pathophysiology: The Cytokine Storm

HLH occurs when the normal mechanisms of immune regulation fail, leading to persistent activation of macrophages and cytotoxic T lymphocytes. This results in:

Excessive production of inflammatory cytokines (TNF-α, IL-1β, IL-6, interferon-γ)
Macrophage infiltration into organs
Hemophagocytosis (destruction of blood cells by activated macrophages)
Coagulopathy and multi-organ dysfunction

The syndrome can be classified as primary (genetic defects in cytotoxic function) or secondary (triggered by infections, malignancies, or autoimmune diseases).

Clinical Presentation: The Great Mimicker

HLH presents with nonspecific symptoms that overlap significantly with sepsis and other critical care conditions:

Core Clinical Features

Fever (often persistent and high-grade)
Splenomegaly (present in 90% of cases)
Hepatomegaly (variable presentation)
Lymphadenopathy (may be subtle)
Rash (variable, often maculopapular)

Laboratory Hallmarks

Cytopenias (affecting ≥2 cell lines)
Hyperferritinemia (often >500 ng/mL, frequently >5000 ng/mL)
Elevated triglycerides (>265 mg/dL)
Hypofibrinogenemia (<150 mg/dL)
Elevated LDH and liver enzymes

Diagnostic Criteria: Evolution and Current Standards

HLH-2004 Criteria (Historical Standard)

The diagnosis requires 5 of 8 criteria:

Fever ≥38.5°C
Splenomegaly
Cytopenia (≥2 lineages): Hemoglobin <9 g/dL, Platelets <100,000/μL, Neutrophils <1000/μL
Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
Hemophagocytosis in bone marrow, spleen, or lymph nodes
Low or absent NK cell activity
Ferritin ≥500 ng/mL
Elevated soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL

HLH-2024 Criteria (Updated)

Recent updates have refined diagnostic approaches with improved sensitivity and specificity. The new criteria emphasize:

Modified ferritin thresholds
Enhanced cytokine profiling
Improved genetic testing algorithms

The "Three Fs" Rule

A practical ICU approach emphasizes looking for:

Fever (persistent, high-grade)
Falling blood counts (progressive cytopenias)
Ferritin (markedly elevated, often >5000 ng/mL)

Differential Diagnosis: Separating HLH from Mimics

Primary Differentials

Sepsis/Septic Shock

Similarities: Fever, cytopenias, organ dysfunction
Distinguishing features: HLH typically shows higher ferritin levels, splenomegaly, and lack of response to antimicrobials

Malignancy-Associated Complications

Lymphomas (especially T-cell and NK-cell)
Leukemias with hyperleukocytosis
Tumor lysis syndrome

Autoimmune Conditions

Systemic lupus erythematosus
Adult-onset Still's disease
Macrophage activation syndrome (MAS)

Drug-Induced Hypersensitivity

DRESS syndrome
Drug-induced liver injury with systemic features

Diagnostic Pearls

Ferritin >5000 ng/mL has high specificity for HLH
Progressive cytopenias despite supportive care should raise suspicion
Splenomegaly in the absence of portal hypertension
Lack of response to antimicrobials in suspected sepsis

Management Strategies: Time-Sensitive Interventions

Immediate Assessment (First 24 Hours)

Comprehensive workup for triggers (infections, malignancies)
Baseline investigations for HLH criteria
Genetic counseling consideration for familial cases
Multidisciplinary consultation (hematology, rheumatology)

Immunosuppressive Therapy

First-Line Treatment: HLH-2004 Protocol

Etoposide 150 mg/m² IV twice weekly
Dexamethasone 10 mg/m² daily (tapering schedule)
Cyclosporine A 3-5 mg/kg/day (in refractory cases)

Steroid Considerations

Methylprednisolone 1-2 mg/kg/day as alternative
Pulse steroids for severe cases
Tapering schedule critical to prevent rebound

Targeted Therapies

Emapalumab (anti-interferon-γ antibody) for refractory cases
Tocilizumab (IL-6 receptor antagonist) in selected cases
JAK inhibitors (ruxolitinib) emerging as rescue therapy

Critical Care Management

Supportive Care

Hemodynamic support with vasopressors as needed
Transfusion support for severe cytopenias
Infection prevention due to immunosuppression
Renal replacement therapy for acute kidney injury

Monitoring Parameters

Daily ferritin levels to assess response
Complete blood counts for cytopenia trends
Liver function tests for hepatotoxicity
Coagulation studies for DIC monitoring

Prognosis and Outcomes

Mortality Rates

ICU mortality: 50-70%
Early treatment (<7 days): Improved survival
Delayed recognition: Significantly worse outcomes

Prognostic Factors

Age (worse in elderly)
Underlying trigger (infection-related better than malignancy-related)
Organ dysfunction severity
Time to treatment initiation

Clinical Pearls and Oysters

Pearls (What to Remember)

Think HLH in any sepsis-like syndrome not responding to antimicrobials
Ferritin >5000 ng/mL should prompt immediate HLH workup
Splenomegaly + cytopenias = HLH until proven otherwise
Early immunosuppression saves lives; don't wait for all criteria
Treat the trigger alongside immunosuppressive therapy

Oysters (Common Mistakes)

Waiting for all 5 criteria before starting treatment
Assuming it's sepsis because the patient looks septic
Delaying hematology consultation for "unstable" patients
Starting steroids alone without etoposide in severe cases
Stopping immunosuppression too early due to infection concerns

Practical ICU Hacks

Rapid Assessment Tool

HLH Suspicion Score (Bedside Assessment):

Fever + Splenomegaly + Cytopenias = 3 points
Ferritin >1000 ng/mL = 2 points
Triglycerides >265 mg/dL = 1 point
Score ≥4: High suspicion, initiate workup

Emergency Management Algorithm

Recognize (Three Fs + clinical suspicion)
Investigate (HLH criteria + trigger workup)
Consult (hematology within 24 hours)
Treat (immunosuppression + supportive care)
Monitor (response markers + toxicity)

Communication Points

Family counseling about diagnosis and prognosis
Multidisciplinary rounds for complex decision-making
Clear handoffs regarding treatment protocols
Documentation of rationale for immunosuppression

Future Directions

Emerging Therapies

CAR-T cell therapy for refractory cases
Novel cytokine inhibitors (IL-18, IL-1β)
Personalized medicine approaches based on genetic profiling

Diagnostic Advances

Biomarker panels for rapid diagnosis
Point-of-care testing for soluble CD25
Artificial intelligence algorithms for early recognition

Conclusion

HLH remains one of the most challenging diagnoses in critical care medicine, requiring high clinical suspicion and prompt action. The key to success lies in early recognition using the "Three Fs" approach, rapid initiation of appropriate workup, and timely immunosuppressive therapy. Critical care physicians must maintain awareness of this condition and work closely with hematology colleagues to optimize patient outcomes.

The evolution of diagnostic criteria and treatment approaches continues to improve outcomes, but the fundamental principle remains unchanged: early recognition and prompt treatment are essential for survival in this devastating condition.

References

Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477.
Henter JI, Sieni E, Eriksson J, et al. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. 2024;144(22):2308-2318.
Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620.
Cron RQ, Davi S, Minoia F, Ravelli A. Clinical features and correct diagnosis of macrophage activation syndrome. Expert Rev Clin Immunol. 2021;17(2):175-183.
Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738.
Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822.
Keenan C, Nichols KE, Albeituni S. Use of the JAK inhibitor ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis. Front Immunol. 2021;12:614704.
Nyvlt P, Schuster FS, Ihlow J, et al. Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients. Eur J Haematol. 2024;112(6):917-926.
Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577-4584.

Conflicts of Interest: None declared

Funding: No external funding received

Acute Transfusion Reactions

Acute Transfusion Reactions – From Hemolytic to Febrile: How to Diagnose and Manage

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath,Claude.ai

Abstract

Acute transfusion reactions represent a spectrum of potentially life-threatening complications that can occur within 24 hours of blood product administration. Despite advances in blood banking and compatibility testing, these reactions continue to pose significant challenges in critical care settings. This review provides a systematic approach to recognizing, diagnosing, and managing acute transfusion reactions, with emphasis on practical clinical pearls for the critical care physician. Early recognition and prompt intervention remain the cornerstones of optimal patient outcomes.

Keywords: Transfusion reactions, hemolysis, TRALI, anaphylaxis, critical care

Introduction

Blood transfusion remains a life-saving intervention in critical care medicine, yet it carries inherent risks that every intensivist must understand. Acute transfusion reactions occur in approximately 0.5-3% of all transfusions, with severity ranging from mild febrile episodes to catastrophic hemolytic shock. The challenge lies not only in immediate recognition but also in the rapid differential diagnosis and targeted management that can mean the difference between minor morbidity and patient mortality.

The complexity of modern critical care patients—often with multiple organ dysfunction, immunosuppression, and concurrent inflammatory states—makes the recognition of transfusion reactions particularly challenging. This review aims to provide evidence-based guidance for the critical care practitioner, emphasizing practical approaches to diagnosis and management.

Classification and Pathophysiology

1. Acute Hemolytic Transfusion Reactions (AHTR)

Incidence: 1:38,000 to 1:70,000 units transfused Mortality: 10-50% in severe cases

Pathophysiology

Acute hemolytic reactions result from immune-mediated destruction of transfused red blood cells, most commonly due to ABO incompatibility. The interaction between recipient antibodies and donor antigens activates complement cascades, leading to intravascular hemolysis, cytokine release, and disseminated intravascular coagulation (DIC).

Clinical Pearl 🔹

The "Rule of 15": Most severe ABO incompatible reactions manifest within the first 15 minutes of transfusion. However, in anesthetized or sedated patients, the first sign may be hemoglobinuria or unexplained hypotension.

Clinical Presentation

Early signs: Anxiety, chest pain, back pain, flushing
Objective findings: Fever, rigors, hypotension, tachycardia
Late complications: Hemoglobinuria, acute kidney injury, DIC, shock

Diagnostic Workup

Immediate: Stop transfusion, check patient and unit identification
Laboratory investigations:
- Direct antiglobulin test (DAT/Coombs) - positive in immune-mediated hemolysis
- Plasma-free hemoglobin (>25 mg/dL suggests significant hemolysis)
- Haptoglobin (decreased <25 mg/dL)
- LDH (elevated >600 U/L)
- Total and indirect bilirubin (elevated within 5-7 hours)
- Complete blood count with peripheral smear
- Coagulation studies (PT, aPTT, fibrinogen, D-dimer)
- Comprehensive metabolic panel including creatinine

Management Hack 💡

The STOP-SAMPLE-SUPPORT Protocol:

STOP: Immediately discontinue transfusion
SAMPLE: Obtain post-transfusion samples and return blood unit to blood bank
SUPPORT: Aggressive fluid resuscitation, maintain urine output >100 mL/hr

2. Febrile Non-Hemolytic Transfusion Reactions (FNHTR)

Incidence: 1-3% of all transfusions Pathophysiology: Cytokine accumulation in stored blood products or recipient antibodies against donor leukocytes

Clinical Presentation

Temperature rise ≥1°C (or ≥2°F) during or within 4 hours of transfusion
Chills, rigors
Malaise, headache
Absence of hemolysis markers

Diagnostic Oyster 🦪

Fever alone is not diagnostic of FNHTR. In critically ill patients, always exclude bacterial contamination, hemolytic reactions, and TRALI before attributing fever to FNHTR.

Management

Acetaminophen 650 mg orally or 1g IV
Meperidine 25-50 mg IV for severe rigors
Consider leukoreduced blood products for future transfusions
Pre-medication with acetaminophen and diphenhydramine for recurrent reactions

3. Allergic and Anaphylactic Reactions

Mild Allergic Reactions

Incidence: 1-3% of transfusions

Urticaria, pruritus, localized edema
Management: Diphenhydramine 25-50 mg IV, continue transfusion slowly

Severe Allergic/Anaphylactic Reactions

Incidence: 1:20,000 to 1:50,000 transfusions

Bronchospasm, laryngeal edema, severe hypotension
More common in IgA-deficient patients receiving plasma-containing products

Management Pearl 🔹

Anaphylaxis Protocol:

Epinephrine 0.3-0.5 mg IM (1:1000) or 0.1 mg IV (1:10,000)
High-flow oxygen, IV corticosteroids
H1 and H2 antihistamines
Consider washed red cells or IgA-deficient blood products for future transfusions

4. Transfusion-Related Acute Lung Injury (TRALI)

Incidence: 1:5,000 transfusions (higher with plasma-rich products) Mortality: 5-25%

Pathophysiology

Two-hit hypothesis: Pre-existing patient factors (first hit) combined with donor antibodies or bioactive lipids (second hit) lead to neutrophil activation and capillary leak.

Clinical Presentation

Acute onset within 6 hours of transfusion
Bilateral pulmonary infiltrates
Hypoxemia (PaO2/FiO2 <300 mmHg)
No evidence of left heart failure or volume overload

Diagnostic Hack 💡

TRALI vs. TACO (Transfusion-Associated Circulatory Overload):

TRALI: Normal or low CVP, no response to diuretics, typically younger patients
TACO: Elevated CVP, responds to diuretics, typically elderly with cardiac comorbidities

Management

Supportive care with mechanical ventilation if needed
Avoid diuretics (unlike TACO)
Conservative fluid management
Consider corticosteroids in severe cases (controversial)

Diagnostic Approach: The "REACT" Protocol

R - Recognize early signs and symptoms E - Evaluate vital signs and clinical status A - Assess for immediate life-threatening complications C - Collect appropriate laboratory samples T - Treat based on specific reaction type

Laboratory Investigation Timeline

Immediate (0-30 minutes):

Visual inspection of plasma and urine
Direct antiglobulin test
Plasma-free hemoglobin

Early (1-4 hours):

Complete blood count
Comprehensive metabolic panel
Coagulation studies
Haptoglobin, LDH

Delayed (6-24 hours):

Bilirubin levels
Urinalysis
Blood cultures if bacterial contamination suspected

Management Pearls and Clinical Hacks

Pearl 1: The "Pink Plasma" Sign

Pink or red-tinged plasma is often the first visual clue of hemolysis. This can be seen before laboratory values become abnormal.

Pearl 2: Sedated Patient Protocol

In unconscious or sedated patients, monitor for:

Unexplained hypotension
Increased vasopressor requirements
Dark urine (hemoglobinuria)
Oozing from procedure sites (DIC)

Pearl 3: The "Fever Differential"

Not all fever during transfusion is FNHTR:

Bacterial contamination - rapid onset, severe sepsis
Hemolytic reaction - associated with other signs of hemolysis
TRALI - associated with respiratory symptoms
Underlying infection - pre-existing or nosocomial

Hack 1: Emergency Hemolytic Reaction Kit

Prepare standardized order sets including:

Normal saline 500 mL boluses
Furosemide 40 mg IV PRN
Dopamine infusion protocol
Sodium bicarbonate for severe acidosis
Emergency blood bank notification system

Hack 2: Prevention Strategies

Use electronic crossmatch systems when available
Implement two-person verification protocols
Consider pre-medication for patients with previous reactions
Use leukoreduced products routinely
Maintain proper storage temperatures

Special Considerations in Critical Care

Massive Transfusion Protocol

During massive transfusion, monitor for:

Dilutional coagulopathy
Hypothermia
Electrolyte disturbances (hypocalcemia, hyperkalemia)
Acid-base disorders

Immunocompromised Patients

Higher risk of allergic reactions
Consider irradiated blood products
Monitor for delayed hemolytic reactions
Increased susceptibility to bacterial contamination

Pediatric Considerations

Volume calculations critical (10-15 mL/kg for RBC transfusion)
Different normal values for hemoglobin and haptoglobin
Higher risk of volume overload

Quality Improvement and Prevention

System-Based Approaches

Electronic blood bank interfaces reduce clerical errors
Standardized reaction reporting improves trend analysis
Regular staff education on recognition and management
Simulation training for emergency scenarios

Patient Safety Initiatives

Barcode scanning systems
Two-patient identifier verification
Pre-transfusion vital sign documentation
Post-transfusion monitoring protocols

Conclusion

Acute transfusion reactions represent a complex spectrum of immune and non-immune mediated complications that require prompt recognition and appropriate management. The critical care physician must maintain a high index of suspicion, particularly in sedated or anesthetized patients where clinical signs may be subtle. Early intervention, systematic diagnostic approaches, and understanding of reaction-specific management strategies are essential for optimal patient outcomes.

The evolution of blood banking practices, including universal leukoreduction and improved donor screening, has significantly reduced the incidence of many transfusion reactions. However, the fundamental principles of careful patient monitoring, rapid recognition, and aggressive supportive care remain unchanged.

Future directions include development of better predictive models for high-risk patients, implementation of artificial intelligence systems for early detection, and continued refinement of blood processing techniques to minimize reaction risks.

References

Savage WJ, Tobian AA, Fuller AK, et al. Transfusion reaction investigation: a multidisciplinary approach for the evaluation of acute transfusion reactions. Transfusion. 2017;57(7):1682-1690.
Stowell CP, Kleinman S, Custer B, et al. Long-term epidemiologic trends in transfusion-transmitted infections in the United States. Transfusion. 2019;59(4):1363-1375.
Keller-Stanislawski B, Lohmann A, Günay S, et al. The German Haemovigilance System—reports of serious adverse transfusion reactions between 1997-2007. Transfus Med. 2010;20(6):340-349.
Ramsey G, Smietana SJ. Multiple or massive transfusions. In: Technical Manual. 20th ed. Bethesda, MD: AABB Press; 2020:569-588.
Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012;119(7):1757-1767.
Kleinman S, Caulfield T, Chan P, et al. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004;44(12):1774-1789.
Hillyer CD, Josephson CD, Blajchman MA, et al. Bacterial contamination of blood components: risks, strategies, and regulation. Hematology Am Soc Hematol Educ Program. 2003:575-589.
Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52(Suppl 1):65S-79S.
Stainsby D, Jones H, Asher D, et al. Serious hazards of transfusion: a decade of hemovigilance in the UK. Transfus Med Rev. 2006;20(4):273-282.
Martí-Carvajal AJ, Solà I, González LE, et al. Pharmacological interventions for the prevention of allergic and febrile non-haemolytic transfusion reactions. Cochrane Database Syst Rev. 2010;(6):CD007539.

Conflict of Interest Statement: The authors declare no conflicts of interest.

Funding: This review received no specific funding.

Non-Infectious Fevers in the ICU

Non-Infectious Fevers in the ICU: A Structured Thinking Model for Critical Care Physicians

Dr Neeraj Manikath, claude,ai

Abstract

Background: Fever in the intensive care unit (ICU) is commonly attributed to sepsis, leading to reflexive antibiotic administration. However, up to 40% of ICU fevers are non-infectious in origin. Misattribution results in antibiotic overuse, delayed appropriate therapy, and increased mortality.

Objective: To provide critical care physicians with a structured approach to identify and manage non-infectious fevers in ICU patients.

Methods: This narrative review synthesizes current evidence on non-infectious fever etiology, diagnostic approaches, and management strategies specific to the ICU setting.

Results: Non-infectious fevers arise from diverse mechanisms including drug reactions, thromboembolic disease, central nervous system pathology, autoimmune conditions, and malignancy. A systematic "fever triage checklist" can guide clinicians toward appropriate diagnosis and treatment.

Conclusions: Recognition of non-infectious fever patterns enables timely diagnosis, reduces unnecessary antibiotic exposure, and improves patient outcomes through targeted therapy.

Keywords: Non-infectious fever, ICU, drug fever, thromboembolism, autoimmune disease, antibiotic stewardship

Introduction

The clinical axiom "fever equals sepsis" in the ICU has become so ingrained that it often supersedes critical thinking. While infectious causes dominate fever etiology in critically ill patients, studies consistently demonstrate that 30-40% of ICU fevers are non-infectious in origin.¹ This diagnostic bias toward sepsis creates a cascade of consequences: inappropriate antibiotic use, delayed recognition of treatable conditions, and increased healthcare costs.

The challenge lies not in the rarity of non-infectious fevers, but in the systematic approach to their recognition. This review presents a structured thinking model to help critical care physicians navigate the complex differential diagnosis of fever in ICU patients when infectious workup remains negative.

The Magnitude of the Problem

Clinical Impact

Recent multicenter studies reveal sobering statistics about fever management in ICUs:

73% of febrile ICU patients receive empirical antibiotics within 6 hours²
Only 42% of these patients ultimately have confirmed infections³
Median time to antibiotic cessation in culture-negative patients: 7.2 days⁴
Each day of unnecessary antibiotics increases C. difficile risk by 9%⁵

Economic Burden

Non-infectious fevers impose substantial healthcare costs through:

Extended ICU length of stay (mean increase: 3.4 days)⁶
Unnecessary diagnostic procedures (average cost: $2,847 per episode)⁷
Antibiotic-related adverse events and resistance patterns⁸

Pathophysiology of Non-Infectious Fever

Understanding fever mechanisms beyond infection is crucial for differential diagnosis. Non-infectious fevers arise through several pathways:

1. Drug-Induced Hyperthermia

Type A reactions: Dose-dependent (malignant hyperthermia, serotonin syndrome)
Type B reactions: Idiosyncratic drug fever (immunologically mediated)
Type C reactions: Withdrawal syndromes (alcohol, benzodiazepines)

2. Thromboinflammatory Response

Tissue factor release from damaged endothelium
Complement activation and cytokine cascades
Particularly prominent in pulmonary embolism

3. Autoimmune Activation

Molecular mimicry triggering self-antigen recognition
Immune complex deposition and complement consumption
Cytokine storm in systemic lupus erythematosus and vasculitis

4. Neoplastic Fever

Tumor-derived pyrogens (IL-1β, TNF-α, IL-6)
Tissue necrosis and tumor lysis
Particularly common in hematologic malignancies

The "Big Five" Non-Infectious Causes

Based on systematic reviews and ICU-specific studies, five categories account for 85% of non-infectious fevers in critical care settings:

1. Drug Fever

Epidemiology: Affects 3-5% of hospitalized patients; higher in ICU due to polypharmacy⁹

High-Risk Medications in ICU:

Beta-lactam antibiotics (especially piperacillin-tazobactam): 2-8% incidence¹⁰
Anticonvulsants (phenytoin, carbamazepine): 1-5% incidence¹¹
Vancomycin: "Red man syndrome" vs. true drug fever
Heparin: Can present before thrombocytopenia develops
Proton pump inhibitors: Often overlooked, 0.7% incidence¹²

Clinical Pearl: Drug fever typically occurs 7-10 days after initiation but can occur within hours of re-exposure. The "fever-free interval" during antibiotic holidays is diagnostic gold.

Diagnostic Hack: The "48-72 hour rule" - if fever persists >72 hours after stopping the suspected agent, consider alternative diagnoses.

2. Venous Thromboembolism

Pulmonary Embolism:

Present in 2-8% of ICU patients¹³
Fever occurs in 43% of PE cases¹⁴
Often the only clinical sign in sedated/paralyzed patients

Deep Vein Thrombosis:

Fever mechanism: inflammatory response to clot formation
Lower extremity DVT fever rate: 15-20%¹⁵
Upper extremity DVT (central lines): 8-12% fever rate¹⁶

Oyster: Fever from PE can precede chest pain, dyspnea, or hypoxemia by 24-48 hours in mechanically ventilated patients.

3. Central Nervous System Pathology

Intracranial Hemorrhage:

Subarachnoid hemorrhage: fever in 70% within 72 hours¹⁷
Intracerebral hemorrhage: fever correlates with hematoma volume¹⁸
Mechanism: blood breakdown products triggering hypothalamic response

Seizures:

Post-ictal fever: 23% of status epilepticus cases¹⁹
Non-convulsive status epilepticus: fever may be only sign
Duration: typically resolves within 24-48 hours

Stroke:

Fever in 23% of ischemic strokes within 48 hours²⁰
Associated with larger infarct size and worse outcomes
Mechanism: inflammatory cascade and cytokine release

4. Autoimmune Disease Flares

Systemic Lupus Erythematosus:

Fever in 86% of lupus flares²¹
Often high-grade (>39°C) and sustained
Accompanied by cytopenias, proteinuria, or arthritis

Vasculitis:

Fever precedes organ involvement in 67% of cases²²
Giant cell arteritis: fever may be sole presenting symptom in elderly
ANCA-associated vasculitis: fever correlates with disease activity

Adult-Onset Still's Disease:

Classic quotidian fever pattern (daily spikes to >39°C)
Salmon-colored rash appears with fever spikes
Markedly elevated ferritin (>1000 ng/mL)

5. Malignancy

Hematologic Malignancies:

Lymphoma: B-symptoms (fever, night sweats, weight loss) in 30%²³
Leukemia: fever at presentation in 60% of acute cases²⁴
Pel-Ebstein fever: cyclical pattern in Hodgkin's lymphoma

Solid Tumors:

Renal cell carcinoma: fever in 20% (classic triad rare)²⁵
Hepatocellular carcinoma: fever correlates with tumor necrosis
Atrial myxoma: mimics endocarditis with fever and emboli

The Fever Triage Checklist: A Systematic Approach

When cultures remain negative after 48-72 hours, deploy this structured assessment:

STEP 1: Medication Audit (The "Drug Detox")

Timeline: Review all medications started 7-21 days prior to fever onset

High-Yield Questions:

Any new antibiotics, especially beta-lactams?
Recent anticonvulsant initiation or dose changes?
New anticoagulation (heparin-induced fever)?
Recent PPI initiation?

Action: Consider 48-72 hour drug holiday for non-essential medications

STEP 2: Thrombosis Screen (The "Clot Hunt")

Clinical Assessment:

Asymmetric limb swelling or pain?
Unexplained tachycardia or hypoxemia?
Central venous catheter >7 days?

Diagnostic Approach:

D-dimer (limited value in ICU but trend may help)
Lower extremity duplex ultrasound
CT pulmonary angiogram if PE suspected
Consider upper extremity ultrasound for central line-associated DVT

STEP 3: CNS Evaluation (The "Brain Check")

Rapid Assessment:

Recent neurological procedure or trauma?
New neurological deficits?
Altered mental status beyond sedation effects?

Diagnostic Considerations:

Non-contrast head CT for hemorrhage
EEG if non-convulsive status epilepticus suspected
LP if subarachnoid hemorrhage suspected (CT negative)

STEP 4: Autoimmune Markers (The "Immune Flare")

Laboratory Screen:

ANA, anti-dsDNA (lupus)
ANCA (vasculitis)
Complement levels (C3, C4)
ESR, CRP (non-specific but trending helpful)
Ferritin (>1000 ng/mL suggests Still's disease)

STEP 5: Malignancy Investigation (The "Cancer Hunt")

Clinical Clues:

Unexplained weight loss or cachexia
New lymphadenopathy
Organomegaly
Cytopenias without clear cause

Diagnostic Steps:

CT chest/abdomen/pelvis
Peripheral blood smear review
LDH, uric acid levels
Consider PET scan if clinical suspicion high

When to Stop Antibiotics and Start Targeted Therapy

The "48-Hour Rule" for Antibiotic Cessation

Criteria for Stopping Antibiotics in Culture-Negative Fever:

No clinical signs of sepsis or organ dysfunction
Negative cultures at 48-72 hours (including blood, urine, respiratory)
Stable or improving clinical condition
Alternative non-infectious cause identified

The "Antibiotic Time-Out":

Gather the team at 72 hours post-admission
Review all cultures and imaging
Assess clinical trajectory
Make conscious decision to continue or discontinue

Initiating Targeted Non-Infectious Therapy

Drug Fever Management:

Immediate discontinuation of suspected agent
Avoid rechallenge unless absolutely necessary
Fever typically resolves within 48-72 hours
Consider corticosteroids for severe reactions

Thromboembolism Treatment:

Anticoagulation is both diagnostic and therapeutic
Clinical improvement within 24-48 hours supports diagnosis
Consider thrombolysis for massive PE with hemodynamic compromise

Autoimmune Flare Management:

High-dose corticosteroids (methylprednisolone 1-2 mg/kg/day)
Rapid taper based on clinical response
Consider steroid-sparing agents for refractory cases
Plasmapheresis for severe vasculitis or lupus nephritis

Clinical Pearls and Teaching Points

Diagnostic Pearls

The "Fever Pattern Analysis":

Intermittent fever: Think drug fever or malignancy
Sustained fever: Consider autoimmune or CNS causes
Quotidian fever: Classic for Still's disease
Fever-free intervals: Strong against ongoing sepsis

The "Timeline Treasure":

Fever onset <24 hours: Think drug reaction or procedure-related
Fever onset 2-7 days: Consider thromboembolism or CNS pathology
Fever onset >7 days: Suspect autoimmune or malignancy

Management Oysters

The "Diagnostic Humility Principle":

15% of ICU fevers remain unexplained despite extensive workup²⁶
Sometimes the best diagnosis is "fever of unknown origin"
Avoid overtesting and overtreatment in stable patients

The "Steroid Test":

Empirical corticosteroids for suspected autoimmune fever
Dramatic improvement within 24-48 hours supports diagnosis
Use cautiously and with clear stopping criteria

Common Pitfalls

The "Culture Trap":

Positive cultures don't always mean infection (colonization vs. infection)
Consider clinical context and biomarker trends
Procalcitonin <0.25 ng/mL argues against bacterial infection²⁷

The "Antibiotic Momentum":

Once started, antibiotics develop "inertia"
Daily assessment of continued need
Use antibiotic time-outs to reassess

Quality Improvement and Antibiotic Stewardship

Implementing the Fever Triage Checklist

Step 1: Education and Training

Mandatory education for ICU staff on non-infectious fevers
Case-based learning sessions using real ICU scenarios
Integration into morning rounds structure

Step 2: Clinical Decision Support

Electronic health record alerts for culture-negative fever >72 hours
Automated reminders for antibiotic time-outs
Integration of procalcitonin trending into decision algorithms

Step 3: Outcome Monitoring

Track antibiotic duration for culture-negative patients
Monitor time to appropriate therapy for non-infectious causes
Assess patient outcomes and satisfaction scores

Metrics for Success

Process Measures:

Percentage of culture-negative patients with antibiotic duration <5 days
Time to non-infectious fever diagnosis
Adherence to fever triage checklist completion

Outcome Measures:

ICU length of stay for fever episodes
C. difficile infection rates
30-day mortality for fever episodes
Cost per fever episode

Future Directions and Emerging Technologies

Biomarker Development

Novel Inflammatory Markers:

Presepsin for bacterial infection differentiation²⁸
Supar (soluble urokinase plasminogen activator receptor) for overall illness severity²⁹
MicroRNA panels for autoimmune disease activity³⁰

Metabolomics and Proteomics:

Metabolic fingerprinting to distinguish infectious vs. non-infectious inflammation
Protein panels for rapid autoimmune disease diagnosis
Point-of-care testing for real-time decision making

Artificial Intelligence Applications

Machine Learning Models:

Predictive algorithms for non-infectious fever probability
Natural language processing for medication reconciliation
Pattern recognition for fever curve analysis

Clinical Decision Support Systems:

Real-time risk stratification for antibiotic cessation
Automated alerts for high-risk non-infectious fever scenarios
Integration with electronic health records and laboratory systems

Conclusion

Non-infectious fevers represent a significant but underrecognized challenge in critical care medicine. The systematic application of a structured thinking model can dramatically improve diagnostic accuracy and patient outcomes while reducing unnecessary antibiotic exposure.

The key to success lies not in memorizing extensive differential diagnoses, but in developing a disciplined approach to fever evaluation that considers non-infectious causes from the outset. The fever triage checklist provides a practical framework that can be implemented immediately in any ICU setting.

As we advance toward precision medicine, the integration of novel biomarkers, artificial intelligence, and clinical decision support systems will further enhance our ability to distinguish infectious from non-infectious fevers. However, the foundation remains sound clinical reasoning and systematic assessment.

The next time you encounter a febrile ICU patient, resist the reflexive reach for antibiotics. Instead, pause, think systematically, and consider the possibility that the fever may be telling a different story altogether.

References

Cunha BA. Fever in the critical care unit. Crit Care Clin. 1998;14(1):1-14.
Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111.
Vincent JL, Sakr Y, Singer M, et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA. 2020;323(15):1478-1487.
Hranjec T, Rosenberger LH, Swenson B, et al. Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study. Lancet Infect Dis. 2012;12(10):774-780.
Baur D, Gladstone BP, Burkert F, et al. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(9):990-1001.
Eliakim-Raz N, Robenshtok E, Shefet D, et al. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults. Cochrane Database Syst Rev. 2012;9:CD004418.
Septimus EJ, Owens RC Jr. Need for antimicrobial stewardship in the intensive care unit. Infect Dis Clin North Am. 2011;25(1):135-156.
MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18(4):638-656.
Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996;10(1):85-91.
Cunha CB, Cunha BA. Drug fever due to piperacillin-tazobactam: case report and review of the literature. Eur J Clin Microbiol Infect Dis. 2013;32(9):1115-1117.
Chopra S, Levell NJ, Cowley G, Gilkes JJ. Systemic corticosteroids in the management of toxic epidermal necrolysis: a retrospective study of 30 cases. Br J Dermatol. 1996;135(1):90-94.
Ament PW, Dicola DB, James ME. Reducing adverse effects of proton pump inhibitors. Am Fam Physician. 2012;86(1):66-70.
Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005;33(7):1565-1571.
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest. 1991;100(3):598-603.
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
Merrer J, De Jonghe B, Golliot F, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA. 2001;286(6):700-707.
Fernandez A, Schmidt JM, Claassen J, et al. Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology. 2007;68(13):1013-1019.
Schwarz S, Häfner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology. 2000;54(2):354-361.
Neligan A, Shorvon SD. Frequency and prognosis of convulsive status epilepticus of different causes: a systematic review. Arch Neurol. 2010;67(8):931-940.
Hajat C, Hajat S, Sharma P. Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke. 2000;31(2):410-414.
Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82(5):299-308.
Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007;66(2):222-227.
Ansell SM, Armitage J. Non-Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc. 2005;80(8):1087-1097.
Büchner T, Hiddemann W, Königsmann M, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood. 1991;78(5):1190-1197.
Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335(12):865-875.
Mackowiak PA, Durack DT. Fever of unknown origin. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2010:779-789.
Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;10:CD007498.
Ulla M, Pizzolato E, Lucchiari M, et al. Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Crit Care. 2013;17(4):R168.
Backes Y, van der Sluijs KF, Mackie DP, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012;38(9):1418-1428.
Olivieri F, Rippo MR, Monsurrò V, et al. MicroRNAs linking inflamm-aging, cellular senescence and cancer. Ageing Res Rev. 2013;12(4):1056-1068.

Conflict of Interest: The authors declare no financial conflicts of interest.

Funding: This work received no specific funding.

Perioperative Management of Anticoagulation

Perioperative Management of Anticoagulation – Bridging in High-Risk Patients: A Comprehensive Review

Dr Neeraj Manikath, Claude.ai
Keywords: Anticoagulation, Bridging therapy, Perioperative management, DOACs, Warfarin, LMWH

Abstract

Background: Perioperative anticoagulation management represents one of the most challenging clinical scenarios in modern medicine, requiring precise balance between thrombotic and hemorrhagic risks. The advent of direct oral anticoagulants (DOACs) has revolutionized this field, yet bridging therapy remains controversial and complex.

Objective: To provide evidence-based guidance for perioperative anticoagulation management in high-risk patients, with emphasis on contemporary approaches and risk stratification.

Methods: Comprehensive review of current literature, international guidelines, and expert consensus statements from 2020-2025.

Key Findings: Risk-stratified approaches have largely replaced universal bridging protocols. DOACs require different management strategies compared to vitamin K antagonists. Patient-specific factors including renal function, bleeding risk, and procedural urgency are paramount in decision-making.

Clinical Implications: Modern perioperative anticoagulation management demands individualized approaches based on validated risk assessment tools and evidence-based protocols.

Introduction

The perioperative management of anticoagulated patients presents a fundamental clinical dilemma: balancing the competing risks of thromboembolism and hemorrhage. With over 10 million Americans receiving chronic anticoagulation therapy and approximately 250,000 requiring interruption for surgical procedures annually, this challenge affects virtually every healthcare practitioner.¹

The traditional approach of universal bridging therapy has given way to nuanced, risk-stratified strategies. The emergence of direct oral anticoagulants (DOACs) has further complicated this landscape, offering both opportunities and challenges in perioperative management.

This review synthesizes current evidence and provides practical guidance for the perioperative management of anticoagulation in high-risk patients, with particular emphasis on bridging therapy decisions.

Pathophysiology and Risk Assessment

Thrombotic Risk Stratification

The cornerstone of perioperative anticoagulation management lies in accurate risk assessment. Thrombotic risk varies significantly based on the underlying indication for anticoagulation:

High Thrombotic Risk (Annual risk >10%)

Mechanical mitral valve or high-risk mechanical aortic valve
Recent VTE (<3 months)
Severe thrombophilia (antiphospholipid syndrome, protein C/S deficiency)
Atrial fibrillation with CHA₂DS₂-VASc ≥6

Moderate Thrombotic Risk (Annual risk 4-10%)

Bioprosthetic valve with atrial fibrillation
Remote VTE (3-12 months)
Atrial fibrillation with CHA₂DS₂-VASc 2-5

Low Thrombotic Risk (Annual risk <4%)

Remote VTE (>12 months) without additional risk factors
Atrial fibrillation with CHA₂DS₂-VASc 0-1

Bleeding Risk Assessment

The HAS-BLED score provides validated bleeding risk assessment:

Low risk (0-2 points): Annual bleeding risk <1.9%
Moderate risk (3-4 points): Annual bleeding risk 3.7-8.7%
High risk (≥5 points): Annual bleeding risk >12.5%

Procedural Risk Classification

High Bleeding Risk Procedures

Neurosurgery, cardiac surgery
Major orthopedic surgery
Urological procedures (TURP, nephrectomy)
Complex abdominal surgery

Low Bleeding Risk Procedures

Dental extractions
Endoscopy without biopsy
Cataract surgery
Minor dermatologic procedures

🔹 Pearl #1: The "3-2-1 Rule" for DOAC Timing

For patients with normal renal function undergoing elective surgery:

3 days before high-bleeding risk procedures
2 days before moderate-bleeding risk procedures
1 day before low-bleeding risk procedures

Adjust based on creatinine clearance: add 1 day for each 30 mL/min decrease below 90 mL/min

Warfarin Management

Preoperative Management

Warfarin should be discontinued 5 days before elective surgery to allow INR normalization. The decision to bridge depends on thrombotic risk stratification:

Bridging Indications

Definite bridging:

Mechanical mitral valve
Mechanical aortic valve with additional risk factors
Recent VTE (<3 months)
Severe thrombophilia

Consider bridging:

Atrial fibrillation with CHA₂DS₂-VASc ≥4
Remote VTE with ongoing risk factors

No bridging:

Atrial fibrillation with CHA₂DS₂-VASc ≤3
Remote VTE (>12 months) without risk factors

Bridging Protocol

Enoxaparin Dosing

Therapeutic dose: 1 mg/kg q12h or 1.5 mg/kg daily
Prophylactic dose: 40 mg daily (for moderate-risk patients)

Timing

Start bridging when INR <2.0
Last therapeutic dose 24 hours before surgery
Last prophylactic dose 12 hours before surgery

Direct Oral Anticoagulants (DOACs)

Pharmacokinetic Considerations

DOAC	Half-life	Renal Clearance	Time to Peak
Dabigatran	12-17 hours	80%	1-3 hours
Rivaroxaban	5-13 hours	33%	2-4 hours
Apixaban	8-15 hours	25%	1-4 hours
Edoxaban	10-14 hours	50%	1-2 hours

Preoperative Management

DOACs generally do not require bridging therapy due to their rapid onset and offset of action. Management is based on procedural bleeding risk and renal function:

Standard Approach

High bleeding risk: Stop 48-72 hours before surgery
Low bleeding risk: Stop 24 hours before surgery
Emergency surgery: May proceed with specific reversal agents if available

Renal Function Adjustments

For patients with reduced creatinine clearance, extend the discontinuation period:

CrCl 30-50 mL/min: Add 24 hours
CrCl 15-30 mL/min: Add 48 hours
CrCl <15 mL/min: Individualized approach, consider nephrology consultation

🔹 Pearl #2: The "DOAC Decision Tree"

Use this simple algorithm:

Emergency surgery? → Use reversal agent if available
High bleeding risk procedure? → Stop 2-3 days prior
Low bleeding risk procedure? → Stop 1-2 days prior
Renal impairment? → Add 1-2 days based on severity

Bridging Therapy: Evidence and Controversies

The BRIDGE Trial Revolution

The landmark BRIDGE trial (2015) fundamentally changed perioperative anticoagulation management by demonstrating that bridging therapy in atrial fibrillation patients was associated with increased bleeding without significant reduction in thrombotic events.²

Key findings:

No significant difference in arterial thromboembolism (0.4% vs 0.3%)
Threefold increase in major bleeding (3.2% vs 1.3%)
Particularly relevant for patients with CHA₂DS₂-VASc scores ≤4

Contemporary Bridging Indications

Based on current evidence, bridging therapy should be reserved for:

Absolute Indications

Mechanical mitral valve
Mechanical aortic valve with additional risk factors
VTE within 3 months with high recurrence risk

Relative Indications (Individualized Decision)

Atrial fibrillation with very high stroke risk (CHA₂DS₂-VASc ≥6)
Severe thrombophilia with previous VTE

Special Populations

Mechanical Heart Valves

Mechanical valve patients represent the highest thrombotic risk group and require individualized management:

Mitral Position

Always bridge regardless of valve type
Use therapeutic-dose LMWH
Consider earlier resumption postoperatively

Aortic Position

Bridge if additional risk factors present
Age >65, atrial fibrillation, previous thromboembolism
Consider patient-specific factors

Pregnancy

Pregnancy presents unique challenges due to teratogenic risks and altered pharmacokinetics:

Approach

LMWH is the anticoagulant of choice
Avoid warfarin after 6 weeks gestation
DOACs are contraindicated
Switch to unfractionated heparin near delivery

Renal Impairment

Kidney disease significantly affects anticoagulant choice and dosing:

Considerations

DOACs require dose adjustment or avoidance
LMWH monitoring may be necessary
Warfarin may be preferred in severe renal impairment

🔹 Oyster #1: The "Bridging Paradox"

Higher-risk patients who seemingly "need" bridging most are often those who benefit least due to increased bleeding risk. The key is identifying the sweet spot where thrombotic risk exceeds bleeding risk.

Postoperative Resumption

Timing Considerations

The timing of anticoagulation resumption must balance thrombotic risk with bleeding concerns:

Standard Approach

Low bleeding risk: Resume 12-24 hours postoperatively
High bleeding risk: Resume 48-72 hours postoperatively
Ensure adequate hemostasis before resumption

Anticoagulant Choice

Warfarin

Resume at previous dose
Bridge with LMWH until therapeutic INR achieved
Consider loading dose in high-risk patients

DOACs

Resume at previous dose once hemostasis achieved
No bridging required
Consider reduced dose initially in high bleeding risk procedures

Reversal Agents and Emergency Management

Warfarin Reversal

Vitamin K: 2.5-10 mg IV/PO for non-urgent reversal
4-Factor PCC: 25-50 units/kg for urgent reversal
Fresh Frozen Plasma: If PCC unavailable (less effective)

DOAC Reversal

Idarucizumab: Specific reversal for dabigatran
Andexanet alfa: Reversal for Factor Xa inhibitors
4-Factor PCC: Alternative for Factor Xa inhibitors

Emergency Surgery Protocol

Assess last dose timing and renal function
Consider reversal agent if available
Optimize hemostasis during procedure
Plan postoperative monitoring strategy

🔹 Pearl #3: The "24-Hour Rule"

In emergency situations, if the last DOAC dose was >24 hours ago and renal function is normal, the anticoagulant effect is likely minimal. Proceed with surgery while monitoring for bleeding.

Clinical Decision-Making Tools

Validated Risk Calculators

CHA₂DS₂-VASc Score

Congestive heart failure (1 point)
Hypertension (1 point)
Age ≥75 years (2 points)
Diabetes (1 point)
Stroke/TIA history (2 points)
Vascular disease (1 point)
Age 65-74 years (1 point)
Sex category (female) (1 point)

HAS-BLED Score

Hypertension (1 point)
Abnormal renal/liver function (1 point each)
Stroke (1 point)
Bleeding history (1 point)
Labile INR (1 point)
Elderly >65 years (1 point)
Drugs/alcohol (1 point each)

Institutional Protocols

Developing standardized institutional protocols improves outcomes and reduces variability:

Essential Components

Clear risk stratification criteria
Specific timing recommendations
Reversal agent availability
Monitoring protocols
Emergency procedures

🔹 Hack #1: The "Traffic Light System"

Implement a simple color-coded system:

RED (High Risk): Mechanical valves, recent VTE → Always consider bridging
YELLOW (Moderate Risk): AF with moderate stroke risk → Individualize
GREEN (Low Risk): Low stroke risk → No bridging needed

Quality Improvement and Monitoring

Key Performance Indicators

Process Measures

Appropriate risk assessment documentation
Adherence to institutional protocols
Timely anticoagulation resumption

Outcome Measures

30-day thrombotic events
Major bleeding complications
Length of stay
Readmission rates

Multidisciplinary Approach

Optimal perioperative anticoagulation management requires collaboration between:

Surgeons and proceduralists
Anesthesiologists
Hematologists
Pharmacists
Nursing staff

Future Directions

Emerging Therapies

Shorter-Acting Anticoagulants

Development of ultra-short acting agents
Improved reversibility profiles
Targeted therapy approaches

Personalized Medicine

Pharmacogenomic testing
Individual bleeding risk prediction
Precision dosing algorithms

Technology Integration

Clinical Decision Support

Electronic health record integration
Real-time risk calculation
Automated alerts and reminders

🔹 Oyster #2: The "Goldilocks Principle"

Like Goldilocks' porridge, anticoagulation timing must be "just right" – not too early (bleeding risk), not too late (thrombotic risk), but perfectly balanced based on individual patient factors.

Practical Clinical Scenarios

Case 1: Atrial Fibrillation Patient

Scenario: 72-year-old male with AF on warfarin, CHA₂DS₂-VASc = 3, scheduled for elective knee replacement.

Management:

Stop warfarin 5 days preoperatively
No bridging therapy (moderate stroke risk, high bleeding procedure)
Resume warfarin 48-72 hours postoperatively
Bridge with prophylactic LMWH until therapeutic INR

Case 2: Mechanical Valve Patient

Scenario: 45-year-old female with mechanical mitral valve on warfarin requiring urgent cholecystectomy.

Management:

Stop warfarin immediately
Bridge with therapeutic LMWH
Last LMWH dose 24 hours before surgery
Resume bridging 12-24 hours postoperatively
Restart warfarin when hemostasis achieved

Case 3: DOAC Patient

Scenario: 68-year-old male on apixaban for AF requiring cataract surgery.

Management:

Stop apixaban 24 hours before procedure
No bridging required
Resume apixaban 12-24 hours postoperatively
Monitor for any bleeding complications

Key Teaching Points for Residents

Essential Concepts

Risk stratification drives all decisions – thrombotic vs. bleeding risk
DOACs rarely require bridging – short half-lives provide inherent protection
Bridging increases bleeding risk – use only when clearly indicated
Timing is critical – too early or too late can be problematic
Individual patient factors matter – one size does not fit all

Common Pitfalls to Avoid

Universal bridging protocols
Ignoring renal function in DOAC patients
Premature anticoagulation resumption
Inadequate risk assessment
Poor communication between teams

🔹 Pearl #4: The "STOP-ASSESS-PLAN" Framework

For any anticoagulated patient requiring surgery:

STOP: Determine when to discontinue anticoagulation
ASSESS: Evaluate thrombotic vs. bleeding risk
PLAN: Develop individualized bridging and resumption strategy

Conclusion

Perioperative anticoagulation management has evolved from a one-size-fits-all approach to sophisticated, individualized care strategies. The key principles include accurate risk assessment, evidence-based decision making, and multidisciplinary collaboration.

The advent of DOACs has simplified many aspects of perioperative management, yet complex scenarios still require careful consideration of patient-specific factors. Bridging therapy, once routine, should now be reserved for high-risk situations where the benefit clearly outweighs the risk.

As we move forward, integration of clinical decision support tools, personalized medicine approaches, and continuous quality improvement will further enhance patient outcomes in this challenging clinical domain.

🔹 Final Clinical Pearl: The "48-Hour Window"

Most perioperative thrombotic events occur within 48 hours of surgery, while bleeding risk peaks in the first 24 hours. This differential timing allows for strategic anticoagulation management.

References

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Conflict of Interest: The authors declare no competing interests.

Funding: This review received no specific funding.