What is on the differential diagnosis for Sepsis and Septic Shock?

Key differentials include Hypovolemic shock, Cardiogenic shock, Obstructive shock, Anaphylaxis, Adrenal crisis, Thyroid storm, Drug overdose/withdrawal.

What are the high-yield PANCE pearls for Sepsis and Septic Shock?

Antibiotic delay matters: each hour of delay increases mortality ~7% (Kumar Crit Care Med 2006). Lactate is a marker of tissue hypoperfusion AND adrenergic stress — trend it, but use a serial decrease as a resuscitation target. Balanced crystalloids over 0.9% saline reduce major adverse kidney events (SMART trial). qSOFA is a screening tool, not a diagnostic standard — do not delay treatment in a sick-looking patient who falls short of qSOFA criteria. Source control is sometimes more important than antibiotics: drain pus, remove the line, debride the wound.

Infectious Disease · PANCE / PANRE

Sepsis and Septic Shock

Written & clinically reviewed by Ryan Busch, PA-C · Updated July 2026 · Report an error

Life-threatening organ dysfunction from dysregulated host response to infection; septic shock is sepsis plus pressor-requiring hypotension with lactate >2.

Also known as: sepsis, septic shock, severe sepsis, SIRS, sepsis-3

Overview

Sepsis-3 (2016): life-threatening organ dysfunction caused by a dysregulated host response to infection, operationalized as a SOFA score increase ≥2 attributable to infection. Septic shock: sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥65 mmHg AND serum lactate >2 mmol/L despite adequate volume resuscitation.

Epidemiology

Estimated 1.7 million US adult sepsis cases annually with ~270,000 deaths. Leading cause of hospital mortality and the most expensive condition in US healthcare. Highest incidence in elderly and immunocompromised.

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Risk factors

Extremes of age, immunocompromise (chemotherapy, transplant, HIV, asplenia)
Chronic illness (diabetes, cirrhosis, CKD, COPD, heart failure)
Indwelling devices (central lines, urinary catheters, prosthetic joints)
Recent surgery, trauma, burns
Healthcare exposure (MRSA, VRE, MDR gram-negatives)

Pathophysiology

Pathogen-associated molecular patterns (PAMPs) trigger massive innate immune activation via toll-like receptors, releasing inflammatory cytokines (TNF, IL-1, IL-6). Endothelial dysfunction increases capillary leak; nitric oxide drives vasodilation; coagulation activation produces microthrombi (DIC). Result: distributive shock with maldistributed blood flow, mitochondrial dysfunction, and multi-organ failure. Late phase involves immunoparalysis and secondary infections.

Clinical presentation

Symptoms

Source-specific: cough/dyspnea (pneumonia), dysuria/flank pain (urosepsis), abdominal pain (intra-abdominal), headache/neck stiffness (meningitis), skin erythema (SSTI)
Generalized: fever or hypothermia, chills, malaise, altered mental status
Decreased urine output, lightheadedness, syncope

Signs / physical exam

Tachycardia, tachypnea, hypotension, fever or hypothermia
Altered mentation (often subtle in elderly)
Warm, flushed extremities early (vasodilated 'warm shock'); cool, mottled extremities late
Capillary refill >3 sec, oliguria
Source-specific findings: dullness/crackles, costovertebral angle tenderness, peritoneal signs, indurated cellulitis, purpuric rash

Classic findings

Patient with fever, tachycardia, hypotension, and altered mental status with an identifiable infectious source — qSOFA ≥2 (RR ≥22, altered mentation, SBP ≤100) on the ward warns of high mortality risk.

Differential diagnosis

Hypovolemic shock — GI/hemorrhagic losses, narrow pulse pressure, cool extremities, low CVP; responds rapidly to volume
Cardiogenic shock — MI, severe HF, arrhythmia; elevated JVP, pulmonary edema, low cardiac output despite normal volume
Obstructive shock — Tamponade, tension pneumothorax, massive PE; distended neck veins with hypotension
Anaphylaxis — Acute trigger, urticaria, angioedema, wheezing; epinephrine first-line
Adrenal crisis — Hyponatremia, hyperkalemia, hypoglycemia, refractory hypotension; give hydrocortisone empirically
Thyroid storm — Tachycardia out of proportion, hyperthermia, agitation, AF; TSH/free T4
Drug overdose/withdrawal — Hypotension with specific toxidrome; targeted history and tox screen

Diagnostic workup

Diagnostic criteria

Sepsis = suspected/documented infection + SOFA increase ≥2 from baseline. Septic shock = sepsis + vasopressors needed for MAP ≥65 + lactate >2 mmol/L despite adequate resuscitation. qSOFA (screening): RR ≥22, altered mental status, SBP ≤100 — ≥2 suggests high mortality risk.

Labs

Serum lactate (initial and repeat at 2-4 h)
Blood cultures × 2 from separate sites BEFORE antibiotics (do not delay antibiotics if cultures cannot be obtained within 45 min)
CBC, CMP, LFTs, coagulation (PT/PTT/INR), fibrinogen, D-dimer
Urinalysis, urine culture
Source-specific cultures: sputum/respiratory tract, wound, CSF, peritoneal fluid
Procalcitonin and CRP — may help with antibiotic stewardship and de-escalation
ABG/VBG, ScvO2 if central access

Imaging

Chest X-ray (often first), CT chest/abdomen/pelvis if source unclear
Bedside ultrasound (RUSH or FALLS protocol) for shock characterization
Echocardiography to assess cardiac function and volume status

Diagnostic algorithm

flowchart TD
  A[Suspected infection<br/>+ acute organ dysfunction] --> B[Hour-1 Bundle]
  B --> C[Lactate measured]
  B --> D[Blood cultures<br/>before antibiotics]
  B --> E[Broad-spectrum<br/>antibiotics ≤1 h]
  B --> F[30 mL/kg crystalloid<br/>if hypotension or lactate ≥4]
  F --> G{MAP <65 after fluids?}
  G -->|Yes| H[Septic shock — norepinephrine<br/>target MAP ≥65]
  H --> I{Refractory?}
  I -->|Yes| J[Add vasopressin ± hydrocortisone]
  G -->|No| K[Sepsis without shock<br/>continue source control, narrow Abx]

Surviving Sepsis Campaign Hour-1 Bundle and escalation pathway for septic shock.

Treatment

First-line

Hour-1 bundle (Surviving Sepsis Campaign 2021):
1. Measure lactate; remeasure if initial >2
2. Obtain blood cultures before antibiotics
3. Administer broad-spectrum antibiotics within 1 hour (within 3 hours for sepsis without shock if diagnosis uncertain)
4. Begin 30 mL/kg crystalloid IV for hypotension or lactate ≥4 mmol/L (within 3 hours)
5. Vasopressors to maintain MAP ≥65 if hypotensive during/after fluids
Empiric antibiotics — broad-spectrum guided by suspected source:
• Community pneumonia: ceftriaxone + azithromycin or respiratory fluoroquinolone (levofloxacin, moxifloxacin)
• Healthcare-associated pneumonia/VAP: cefepime or piperacillin-tazobactam + vancomycin
• Intra-abdominal: piperacillin-tazobactam or meropenem; add vancomycin if MRSA risk
• Urosepsis: ceftriaxone (community) or piperacillin-tazobactam (catheter/healthcare)
• Skin/soft tissue with concern for MRSA: vancomycin, linezolid, or daptomycin
• Febrile neutropenia: cefepime, meropenem, or piperacillin-tazobactam; add vancomycin if line, hypotension, or MRSA risk
Source control: drain abscess, remove infected line/catheter, debride necrotizing infection — as soon as feasible

Second-line / adjunct

Norepinephrine first-line vasopressor (target MAP ≥65)
Add vasopressin 0.03 U/min (sparing norepinephrine, reduces AF risk) or epinephrine if refractory
Hydrocortisone 200 mg/day if refractory shock despite adequate fluids and vasopressors
Crystalloid preferred over colloid; balanced crystalloid (lactated Ringer's, Plasma-Lyte) over normal saline (SMART trial)
Lung-protective ventilation (TV 6 mL/kg IBW) if ARDS develops
Glycemic control: target 140-180 mg/dL (avoid hypoglycemia)
DVT prophylaxis, stress ulcer prophylaxis

Complications

Multi-organ dysfunction syndrome (MODS): ARDS, AKI, hepatic dysfunction, DIC, encephalopathy
Post-sepsis syndrome: long-term cognitive impairment, ICU-acquired weakness, increased mortality for years
Secondary infections (line sepsis, VAP, C. difficile)
Sepsis-induced cardiomyopathy
Ischemic complications: digital gangrene, bowel ischemia

PANCE pearls

Antibiotic delay matters: each hour of delay increases mortality ~7% (Kumar Crit Care Med 2006).
Lactate is a marker of tissue hypoperfusion AND adrenergic stress — trend it, but use a serial decrease as a resuscitation target.
Balanced crystalloids over 0.9% saline reduce major adverse kidney events (SMART trial).
qSOFA is a screening tool, not a diagnostic standard — do not delay treatment in a sick-looking patient who falls short of qSOFA criteria.
Source control is sometimes more important than antibiotics: drain pus, remove the line, debride the wound.

References

Surviving Sepsis 2021 — Evans et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 (Crit Care Med 2021)
Sepsis-3 — Singer et al., The Third International Consensus Definitions for Sepsis and Septic Shock (JAMA 2016)
SMART Trial — Semler et al., Balanced Crystalloids versus Saline in Critically Ill Adults (NEJM 2018)
VANISH/VASST — Vasopressin trials informing modern shock management

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