Shock, Sepsis, Inflammation, and Injury

Multisystem Injury Reasoning Map

Shock is best approached as a failure of oxygen delivery, oxygen utilization, or both. Oxygen delivery depends on cardiac output and arterial oxygen content; cardiac output depends on preload, contractility, heart rate, and afterload. Tissue hypoxia forces anaerobic glycolysis, increasing lactate and lowering pH. The compensatory response to most shock states is sympathetic activation: tachycardia, venoconstriction, arteriolar vasoconstriction, RAAS activation, ADH release, and preferential perfusion of brain and heart. Step 1 questions often hide the diagnosis in the hemodynamic profile.

Hypovolemic shock from hemorrhage, vomiting, diarrhea, third spacing, or burns has low preload, low cardiac output, high systemic vascular resistance, cool clammy skin, and narrow pulse pressure. Cardiogenic shock from myocardial infarction, myocarditis, severe arrhythmia, or mechanical valve failure has low cardiac output with elevated filling pressures because blood cannot be pumped forward. Obstructive shock, as in tamponade, tension pneumothorax, or massive pulmonary embolism, also limits forward flow, but the primary problem is impaired filling or outflow rather than intrinsic pump failure.

Distributive shock has pathologic vasodilation or loss of sympathetic tone, so systemic vascular resistance falls. Early septic and anaphylactic shock can have warm skin and bounding pulses because cardiac output may initially rise to compensate for low afterload. Neurogenic shock after high spinal cord injury causes hypotension with relative bradycardia because sympathetic outflow is interrupted and unopposed vagal tone remains. Sepsis is life-threatening organ dysfunction from a dysregulated host response to infection.

On exams, gram-negative lipopolysaccharide activates TLR4, gram-positive lipoteichoic acid and peptidoglycan activate innate receptors, and fungal beta-glucans or viral nucleic acids can do the same through pattern recognition receptors. Tissue macrophages and dendritic cells release TNF-alpha and IL-1, which induce endothelial adhesion molecules, fever, vascular leak, and additional cytokine release.

IL-6 drives hepatic synthesis of acute phase reactants such as CRP, fibrinogen, hepcidin, serum amyloid A, complement proteins, and mannose-binding lectin, while albumin and transferrin fall as negative acute phase reactants. IL-8 recruits neutrophils. Complement fragments C3a and C5a increase inflammation; C5a is a potent neutrophil chemoattractant. Inducible nitric oxide synthase in macrophages and vascular smooth muscle generates nitric oxide, causing low systemic vascular resistance and maldistributed blood flow.

Endothelial injury exposes tissue factor, activates coagulation, suppresses anticoagulant pathways, and impairs fibrinolysis, predisposing to microthrombi and DIC. Microvascular thrombosis plus capillary leak explains renal injury, hepatic dysfunction, altered mental status, ARDS, and lactic acidosis even when total cardiac output is high. Septic shock is not just low blood pressure; it is vasoplegia, endothelial leak, coagulation-inflammation coupling, and impaired cellular oxygen extraction. Fever is a regulated increase in hypothalamic set point.

Exogenous pyrogens stimulate monocytes to release IL-1, TNF-alpha, and IL-6, which increase prostaglandin E2 in the hypothalamus. The patient feels cold and shivers until body temperature reaches the new set point. Antipyretics lower fever by reducing prostaglandin synthesis, which is why sweating occurs as the set point falls. Hyperthermia differs because the set point is normal but heat generation or heat dissipation is abnormal, as in heat stroke, malignant hyperthermia, serotonin syndrome, or anticholinergic toxicity.

Inflammation begins with vascular changes: arteriolar dilation causes redness and heat, and histamine, bradykinin, leukotrienes, PAF, and endothelial contraction increase venular permeability, producing exudate. Neutrophils dominate acute bacterial inflammation during the first 24 to 48 hours, marginate through selectin-mediated rolling, adhere through integrins binding ICAM and VCAM, transmigrate through PECAM-1, and follow chemotactic signals such as C5a, IL-8, LTB4, and bacterial formylated peptides. Opsonins IgG and C3b enhance phagocytosis.

NADPH oxidase generates the respiratory burst, myeloperoxidase converts hydrogen peroxide and chloride into hypochlorous acid, and lysosomal enzymes kill ingested microbes but also injure host tissue. Chronic inflammation is dominated by macrophages, lymphocytes, plasma cells, fibrosis, and angiogenesis. Granulomatous inflammation forms when macrophages activated by Th1-derived interferon-gamma become epithelioid histiocytes and giant cells, as in tuberculosis, fungal infection, sarcoidosis, foreign body reactions, and some vasculitides.

Tissue injury and repair are governed by regenerative capacity and extracellular matrix integrity. Labile cells, such as epidermis, GI mucosa, and marrow, continuously divide. Stable cells, such as hepatocytes and renal tubular cells, can reenter the cell cycle after injury. Permanent cells, such as neurons and cardiac myocytes, heal mainly by scarring. Wound healing starts with hemostasis: vasoconstriction, platelet adhesion, platelet degranulation, fibrin formation, and release of PDGF and TGF-beta.

Neutrophils clean the wound early, but macrophages are the key directors of repair because they remove debris and secrete VEGF, FGF, TGF-beta, and PDGF. Granulation tissue contains new capillaries, proliferating fibroblasts, loose extracellular matrix, and inflammatory cells. Fibroblasts first deposit type III collagen; later remodeling by matrix metalloproteinases and their inhibitors replaces type III with stronger type I collagen and increases cross-linking. Wounds never regain full original tensile strength.

Vitamin C deficiency impairs hydroxylation of proline and lysine, reducing collagen triple helix stability. Copper deficiency impairs lysyl oxidase cross-linking. Zinc deficiency impairs DNA synthesis and epithelialization. Diabetes, ischemia, infection, smoking, malnutrition, glucocorticoids, and foreign bodies delay healing. Primary intention describes clean approximated wounds with minimal granulation tissue and small scars; secondary intention describes large open wounds with more inflammation, granulation tissue, wound contraction by myofibroblasts, and larger scars.

Burns convert local tissue injury into systemic disease. Loss of the epidermal barrier causes fluid loss, evaporative heat loss, and infection risk. Endothelial injury and inflammatory mediators increase capillary permeability, creating edema and third spacing that can produce hypovolemic shock despite total body water excess. Circumferential burns form inelastic eschar that can restrict ventilation or distal blood flow. Inhalation injury causes airway edema, bronchospasm, carbon monoxide toxicity, and cyanide toxicity depending on exposure.

The hypermetabolic phase is catecholamine and cortisol driven, increasing protein catabolism, insulin resistance, and caloric needs. Trauma adds additional patterns: hemorrhage reduces preload; crush injury releases myoglobin that precipitates in renal tubules and generates oxidative injury; long bone fractures can cause fat emboli with respiratory distress, neurologic signs, and petechiae; reperfusion after ischemia generates reactive oxygen species, calcium influx, mitochondrial permeability transition, and neutrophil-mediated injury.

Severe systemic inflammation can culminate in ARDS through diffuse alveolar damage, hyaline membranes, and refractory hypoxemia, or in multiorgan dysfunction through microvascular thrombosis and impaired oxygen use.