Pathophysiology of Shock

"Shock is the manifestation of the rude unhinging of the machinery of life." - Samuel V. Gross, 1872

1. Definition and Core Concept

• CO = Heart Rate (HR) × Stroke Volume (SV)
• SV is determined by Preload × Contractility / SVR (afterload)
• CaO2 (mL/dL) = (Hb × 1.34 × SaO2) + (PaO2 × 0.003)

2. Cellular and Metabolic Consequences

• Normally: glucose → pyruvate → enters mitochondria → oxidative phosphorylation → ATP (efficient)
• In shock: pyruvate is shunted to anaerobic glycolysis → lactate + only 2 ATP per glucose (vs. 36-38 via aerobic pathway)

3. Phases of Shock

4. The "Vicious Cycle" of Shock

• Cellular hypoxia → metabolic acidosis
• Metabolic acidosis depresses cardiac contractility → further reduced coronary perfusion
• Intracellular fluid loss (cellular swelling) further depletes intravascular volume
• Decreased venous return reduces preload → worsens cardiac output
• Endothelial activation and microcirculatory damage → cellular aggregation → capillary sludging → worsened perfusion

5. Neuroendocrine Response

Afferent Signals

• Baroreceptors in the atria (low-pressure, detect volume), aortic arch and carotid bodies (high-pressure, detect pressure/stretch) - loss of inhibitory input dis-inhibits the ANS, activating sympathetic outflow
• Chemoreceptors in aorta and carotid bodies - detect hypoxia, hypercapnia, and acidemia
• Pain receptors - spinothalamic tracts activate the hypothalamic-pituitary-adrenal (HPA) axis

Efferent Responses

6. Inflammatory and Immune Response

Danger Signals

• Ischemic cells release Damage-Associated Molecular Patterns (DAMPs) - mitochondrial DNA, HMGB1, heparan sulfate, formyl peptides
• Bacterial translocation (especially in septic or prolonged shock) introduces PAMPs (e.g., LPS)
• These activate pattern recognition receptors - Toll-like receptors (TLRs) and RAGE - triggering cellular activation

Inflammatory Mediators Released

SIRS and Immune Paradox

1. SIRS (pro-inflammatory) → CARS (Compensatory Anti-Inflammatory Response Syndrome) → recovery

• Both pro-inflammatory and anti-inflammatory innate immunity genes are upregulated simultaneously
• Adaptive immunity genes are concurrently downregulated
• Some patients exhibit amplified inflammatory responses that are slow to resolve - Miller's Anesthesia 10e, p. 4824-4828

7. Organ-Specific Responses

Brain

• Prime trigger of the neuroendocrine response
• Regional glucose uptake shifts during shock
• Reflexes and cortical electrical activity become depressed with hypotension - reversible with mild hypoperfusion, but permanent with prolonged ischemia

Heart

• Maintained perfusion as long as possible via coronary vasodilation
• Severe acidosis and hypoxia eventually depress myocardial contractility, closing the vicious cycle

Kidney

• Maintains GFR via selective vasoconstriction, shunting blood to medulla and deep cortex
• Prolonged hypotension → renal cell hibernation → tubular epithelial necrosis → acute kidney injury (AKI)
• Adrenal insufficiency occurs in up to 86% of severe hemorrhagic shock patients (observed in an n=59 cohort)

Liver

• Complex microcirculation susceptible to reperfusion injury
• Contributes to the inflammatory response and glucose dysregulation
• Failure of hepatic synthetic function is almost always lethal

Skeletal Muscle

• Metabolically less active; tolerates ischemia better than visceral organs
• Its large mass generates substantial lactic acid and free radicals from ischemic cells
• Sustained ischemia → intracellular Na+ and water accumulation → further depletes vascular volume - Miller's Anesthesia 10e, p. 4822-4856

8. Microcirculatory Failure

• Cellular edema compresses capillaries → no-reflow phenomenon
• Endothelial swelling, cellular aggregation, and microvascular thrombosis reduce effective tissue perfusion
• Leukocyte-endothelial adhesion (mediated by selectins and integrins) promotes capillary plugging and endothelial injury
• Glycocalyx degradation - the endothelial glycocalyx is shed by hypoperfusion, worsening microvascular permeability and contributing to coagulopathy

9. Coagulopathy in Shock

• Tissue hypoperfusion → thrombomodulin-thrombin complex → generation of Activated Protein C (APC) → inactivates Factors Va and VIIIa → impaired fibrin formation
• Endothelial activation and injury supports a DIC-like consumptive picture
• Elevated plasmin relative to thrombin → hyperfibrinolytic state
• Degradation of the endothelial glycocalyx by hypoperfusion further amplifies coagulopathy
• Iatrogenic factors: hypothermia and large-volume crystalloid resuscitation worsen coagulopathy (patients receiving >4L crystalloid pre-hospital are at increased risk regardless of lactate level) - Miller's Anesthesia 10e, p. 4858-4870

10. Classification Summary (Hemodynamic Profiles)

Key Summary

Blood Supply of the Heart & Cardiac Causes of Sudden Natural Death (Forensic Notes)

PART I: BLOOD SUPPLY OF THE HEART

Overview

A. Left Coronary Artery (LCA)

1. Left Anterior Descending Artery (LAD)

• Runs in the anterior interventricular groove toward (and sometimes around) the LV apex
• Branches:
  • Septal perforators - supply the anterior 2/3 of the interventricular septum
  • Diagonal branches - supply the anterior LV free wall
• Territory: Anterior wall of LV, anterior interventricular septum, LV apex (usually)
• Forensic importance: "Widow maker" - occlusion causes massive anterior MI

2. Circumflex Artery (Cx)

• Continues laterally in the atrioventricular (AV) groove after its right-angle origin from the left main
• Gives rise to obtuse marginal (OM) branches over the lateral to posterolateral LV free wall
• In left-dominant circulation (10-20% of people): the Cx gives rise to the posterior descending artery (PDA) and supplies the inferior LV
• Territory: Lateral wall and posterolateral LV wall; SA node in ~40% of people

Trifurcation (Ramus Intermedius)

B. Right Coronary Artery (RCA)

• Conus branch - first branch; supplies the right ventricular outflow tract (RVOT); collateral to LAD via Vieussens' ring
• SA node artery - supplies the sinoatrial node in ~60% of people (in the remaining 40%, SA nodal artery comes from the Cx)
• Right ventricular branches - supply the free wall of RV
• Acute marginal (right marginal) branch - large branch along the right heart border
• AV nodal artery - in right-dominant circulation, arises near the crux of the heart; supplies the AV node and bundle of His
• Posterior Descending Artery (PDA) - in right-dominant circulation (~80% of people), arises from the RCA; runs in the inferior interventricular groove and supplies the inferior 1/3 of the interventricular septum and inferior LV wall

C. Coronary Dominance

D. Venous Drainage

E. Nerve Supply

• The heart receives autonomic supply via the cardiac plexus (superficial and deep), formed by sympathetic fibers (from T1-T5 cervicothoracic ganglia) and parasympathetic fibers (vagus nerve, CN X)
• Sympathetic: increases HR, contractility, conduction velocity; dilates coronary arteries
• Parasympathetic: slows HR, reduces conduction; minimal direct effect on ventricular myocardium

PART II: CARDIAC CAUSES OF SUDDEN NATURAL DEATH (FORENSIC PERSPECTIVE)

Definition

Forensic Classification of Cardiac SND

1. Ischemic Heart Disease (IHD) / Coronary Artery Disease - MOST COMMON (65-80%)

• The most common finding at autopsy is severe chronic atherosclerotic disease with fixed critical stenoses (≥75% luminal narrowing) without acute plaque disruption
• SCD can be the first clinical manifestation of IHD - the patient may have had no prior symptoms
• Mechanism: Severe, chronic ischemia creates electrical irritability of the myocardium distant from the conduction system → lethal arrhythmia (ventricular fibrillation or asystole)

• Found in only 10-20% of SCD cases at autopsy
• Coronary angiography (or coronary dissection at autopsy) shows thrombotic occlusion in approximately 50% of cases overall
• 80-90% of SCD victims show no enzymatic or ECG evidence of myocardial necrosis, even when IHD is the cause - this is critical forensically (no classic MI pattern necessary)

• Healed remote MIs are present in ~40% of SCD cases - old infarct scar predisposes to re-entry arrhythmias
• Subendocardial myocyte vacuolization (contraction band necrosis pattern) is a marker of severe chronic ischemia, often found without full infarction

• Cross-section coronary arteries at 3-5 mm intervals throughout their entire length
• Document degree of stenosis, plaque morphology, presence of thrombus, calcification
• Document weight of heart (normal adult ~300-350g), wall thickness (LV >15 mm = hypertrophy)
• Microscopic sections of myocardium essential: necrosis, fibrosis, vacuolization

2. Hypertensive Heart Disease

• Increased cardiac mass is an independent risk factor for SCD
• In some young individuals and athletes, hypertensive LV hypertrophy or unexplained increased cardiac mass may be the only pathologic finding at autopsy
• Mechanism: Hypertrophied myocardium is prone to ischemia (increased O2 demand, reduced subendocardial perfusion reserve) and fibrosis → arrhythmic substrate
• In high-resource countries where IHD prevalence is declining, SCD increasingly occurs in hearts that are hypertrophic and fibrotic from hypertension, obesity, or cocaine use - Robbins & Kumar, p. 1511

3. Cardiomyopathies

• A leading cause of SCD in young people and athletes (aged <35 years)
• Autosomal dominant mutations in sarcomeric proteins (most commonly beta-myosin heavy chain, myosin-binding protein C)
• Pathology: Asymmetric septal hypertrophy, myocyte disarray, interstitial fibrosis
• Mechanism: Outflow tract obstruction, diastolic dysfunction, and arrhythmic substrate from disarray and fibrosis
• Forensic finding: Disproportionate septal hypertrophy (septal:free wall ratio >1.3), disorganized myofiber arrangement on microscopy

• Dilated, poorly contracting ventricles; causes include viral myocarditis, idiopathic, alcohol, genetic
• SCD via ventricular arrhythmias from stretched, fibrotic myocardium

• Fibro-fatty replacement of the RV myocardium
• Classic cause of SCD in young athletes, especially during exercise
• Forensic finding: RV dilation with fatty infiltration, thinned RV wall - requires histological confirmation

4. Channelopathies (Structurally Normal Hearts)

5. Myocarditis

• Inflammatory infiltrate of the myocardium, most commonly viral (Coxsackievirus B, adenovirus, SARS-CoV-2, etc.)
• Can cause fatal arrhythmias even before clinical diagnosis
• Forensic significance: Myocarditis can occur in young, apparently healthy individuals
• Autopsy finding: Edematous, flabby heart; microscopy shows lymphocytic infiltrate with myocyte necrosis (Dallas criteria)
• Sarcoid myocarditis is a less common but important cause of SCD via VF

6. Valvular Heart Disease

• Aortic stenosis: Critical AS (valve area <1 cm²) can cause SCD via decreased cardiac output or arrhythmia, particularly on exertion
• Mitral valve prolapse (MVP): Most cases are benign; however, myxomatous MVP with thickened, redundant leaflets and papillary muscle fibrosis can cause SCD, particularly in young women
• Infective endocarditis: Vegetations can embolize to coronary arteries or cause sudden valvular destruction

7. Congenital Coronary Artery Anomalies

• Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA): causes myocardial ischemia from birth
• Anomalous origin from wrong sinus: especially the left coronary from the right sinus (with an interarterial course between the aorta and pulmonary trunk) - may be compressed during exercise → SCD in young athletes
• These anomalies occur in 1-2% of the population; some are only discovered at autopsy
• Forensic approach: Careful examination of coronary ostia and their relationship to the aortic valve is mandatory at every cardiac autopsy

8. Aortic Dissection / Rupture

• Type A dissection can extend to the coronary ostia → acute MI and tamponade → SCD
• Marfan syndrome and bicuspid aortic valve are predisposing conditions
• Forensic finding: Hemopericardium (cardiac tamponade), intimal tear in ascending aorta

9. Cardiac Tamponade

• Sudden accumulation of blood in pericardial sac (200-300 mL can be fatal)
• Causes: Aortic dissection, ventricular rupture post-MI, trauma (forensic must exclude), tumor
• Forensic note: Must distinguish natural (hemopericardium from MI rupture, dissection) vs. traumatic tamponade

Forensic Autopsy Protocol for Cardiac SND

1. Gross examination: Heart weight, ventricular wall thickness (LV, RV, septum), chamber size, epicardial fat, valves, chordae tendineae
2. Coronary arteries: Serial cross-sections at 3-5 mm intervals; document stenosis %, thrombus, dissection, calcification
3. Myocardium: Slice in short-axis planes (bread-loaf technique); document infarct age (acute, healing, healed), fibrosis, hypertrophy
4. Histology (mandatory): Sections from LV, RV, septum, SA node, AV node; stain with H&E, Masson's trichrome (fibrosis), Congo red (amyloid) as needed
5. Toxicology: Cocaine, amphetamines, and other cardiotoxic substances must be excluded
6. Molecular autopsy: Genetic panel (KCNQ1, KCNH2, SCN5A, RYR2, MYBPC3, MYH7, etc.) in structurally normal hearts, especially in the young

Summary Table: Cardiac Causes of Sudden Natural Death

BLOOD SUPPLY OF THE HEART - Revision Notes

Coronary Arteries - Origin

• Both arise from aortic sinuses of Valsalva, just above the aortic valve
• Fill predominantly during diastole (when myocardial wall tension is lowest)

Left Coronary Artery (LCA)

LAD (Left Anterior Descending)

• Runs in anterior interventricular groove
• Branches: Septal perforators (anterior 2/3 septum) + Diagonal branches (anterior LV wall)
• Territory: Anterior LV, anterior septum, apex
• "Widow maker" - occlusion = massive anterior MI

Circumflex (Cx)

• Runs in AV groove laterally
• Gives Obtuse Marginal (OM) branches to lateral/posterolateral LV
• In left-dominant (10-20%): gives rise to PDA
• Supplies SA node in ~40% of people

Ramus Intermedius

• Present in ~30%; trifurcation of left main → supplies lateral LV

Right Coronary Artery (RCA)

Coronary Dominance

Dominant artery = supplies both PDA and AV nodal artery

Venous Drainage

• Coronary sinus → drains ~75% venous blood → empties into RA

Arterial Supply - Regional Summary

CARDIAC CAUSES OF SUDDEN NATURAL DEATH - Forensic Notes

Definition

• Death from natural cardiac cause within 1 hour of symptom onset (or within 24 hours of last being seen alive/well)
• Cardiac causes = 70-80% of all sudden natural deaths
• Mechanism is almost always a lethal arrhythmia (VF, VT, asystole) - the structural lesion is the cause, arrhythmia is the mechanism

1. Ischemic Heart Disease (CAD) - MOST COMMON (65-80%)

Key Forensic Points:

• Most common finding = severe fixed atherosclerotic stenosis WITHOUT acute plaque rupture
• Acute plaque disruption/thrombosis found in only 10-20% of cases
• Coronary thrombosis found in ~50% on angiography/autopsy
• 80-90% show NO enzymatic or ECG evidence of myocardial necrosis - no MI pattern needed for diagnosis
• ~40% have healed remote MI (old infarct scar = re-entry arrhythmia substrate)
• Subendocardial myocyte vacuolization = chronic ischemia marker

Autopsy:

• Serial cross-sections of coronaries at 3-5 mm intervals (entire length)
• Document: % stenosis, thrombus, plaque calcification, acute vs chronic changes
• Heart weight, LV wall thickness (>15 mm = hypertrophy)

2. Hypertensive Heart Disease

• Increased cardiac mass = independent risk factor for SCD
• In some young individuals/athletes, LVH may be the only pathologic finding at autopsy
• Mechanism: ↑ O2 demand + reduced subendocardial perfusion + fibrosis → arrhythmic substrate
• Increasingly seen as IHD prevalence declines (obesity, cocaine, hypertension)

3. Cardiomyopathies

• HCM: Septal:free wall ratio >1.3:1; autosomal dominant sarcomeric mutations
• ARVC: Particularly in young athletes; standard gross examination may miss - histology mandatory

4. Channelopathies - "Structurally Normal Heart" SCD

Forensic challenge: Heart is grossly and histologically normal - cause of death = "SADS" (Sudden Arrhythmic Death Syndrome) without molecular autopsy Molecular autopsy (genetic panel) is mandatory in young SCD with no structural findings

5. Myocarditis

• Most commonly viral (Coxsackievirus B, adenovirus, SARS-CoV-2)
• Can be first presentation in apparently healthy young individuals
• Sarcoidosis - granulomatous myocarditis is an important cause of SCD in young/middle-aged
• Autopsy: Flabby, edematous heart; microscopy = lymphocytic infiltrate + myocyte necrosis (Dallas criteria)

6. Valvular Causes

7. Congenital Coronary Anomalies

• Anomalous LCA from right sinus (interarterial course) = compression between aorta and PA during exercise → SCD in young athletes
• ALCAPA (Anomalous LCA from pulmonary artery) = ischemia from birth
• Occur in 1-2% of population; discovered at autopsy
• Coronary ostia examination is mandatory at every cardiac autopsy

8. Other Important Causes

Forensic Autopsy Protocol for Cardiac SND

Age-Based Pattern Recognition (Exam Tip)

One-Liner Key Facts

• Mechanism of death in cardiac SND = always ventricular fibrillation/asystole
• Most common cause overall = CAD/atherosclerosis
• Most common cause in young athletes = HCM
• Structurally normal heart SCD = channelopathy (LQTS, Brugada, CPVT) → needs molecular autopsy
• SCD can be the first manifestation of IHD in up to 25% of cases
• No MI at autopsy ≠ no ischemic cause - 80-90% of SCD from IHD show no MI
• Old infarct scar found in ~40% of SCD cases
• Coronary thrombus found in only ~50% of fatal CAD cases