Cellular Adaptation, Injury, and Fluid & Electrolyte Balance

Cellular Adaptation, Injury, & Death

• This section delves into alterations in cellular and tissue biology, encompassing fluid and electrolyte regulation, action potentials, and acid-base balance. Understanding these concepts is crucial for comprehending how cells respond to various stimuli and maintain homeostasis.

Biological Concepts

• Key concepts to grasp include histones and chromatin. Histones are proteins around which DNA is wound, forming chromatin. Chromatin, the complex of DNA and proteins, is fundamental to DNA packaging and gene regulation within cells. The structure of chromatin influences gene expression.

Mechanisms of Cell Adaptation

• Atrophy: Decrease in cell size. This can occur due to reduced workload, loss of innervation, diminished blood supply, inadequate nutrition, or loss of endocrine stimulation. For example, muscle atrophy occurs in paralyzed limbs.

• Hypertrophy: Increase in cell size. This happens in response to increased demand or hormonal stimulation. It can be physiologic, such as the enlargement of muscles in response to weightlifting, or pathologic, such as cardiac hypertrophy due to hypertension.

• Hyperplasia: Increase in the number of normal cells. This is often a response to increased demand, hormonal stimulation, or chronic injury. Examples include compensatory hyperplasia of the liver after partial resection and hormonal hyperplasia in the endometrium during the menstrual cycle.

• Metaplasia: Replacement of one mature cell type by another. This is usually an adaptive response to chronic irritation or inflammation, allowing for better survival in the altered environment. An example is the replacement of ciliated columnar epithelium in the trachea and bronchi by stratified squamous epithelium in smokers.

• Dysplasia: Alteration in the size, shape, and organization of mature cells; also known as atypical hyperplasia. Dysplasia is not a true adaptive mechanism but rather a precursor to cancer. It is often found in the cervix, respiratory tract, and breast tissue.

Atrophy & Hypertrophy Examples

• Examples of atrophy include the shrinkage of skeletal muscle during prolonged immobilization, while examples of hypertrophy include the enlargement of the heart in response to chronic hypertension.

Pathologic vs. Physiologic Adaptation

• Physiologic Hypertrophy: Uterus during pregnancy (hormonal stimulation and increased demand). This is reversible after pregnancy.

• Pathologic Hypertrophy: Uterine fibroids (abnormal growth due to hormonal imbalances or genetic factors). These are not reversible without intervention.

Left Ventricular Hypertrophy

• Illustrates an example of hypertrophy, specifically in the heart. This condition often arises as a compensatory mechanism in response to increased afterload, such as in hypertension or aortic stenosis.

Cardiac Hypertrophy

• Further emphasizes cardiac hypertrophy, potentially through imaging (CXR). Such imaging can reveal the enlarged heart size and structural changes associated with this condition.

Bronchial Metaplasia

• Normal Ciliated Epithelium: Normal respiratory lining, which includes ciliated cells that help clear mucus and debris from the airways. This lining is essential for respiratory function and protection.

• Metaplasia: Change due to chronic injury or irritation, such as that caused by smoking. In this case, the normal ciliated epithelium is replaced by stratified squamous epithelium, which lacks cilia and the ability to clear mucus, leading to respiratory problems.

• Dysplasia: Result of persistent severe injury or irritation; can progress from metaplasia. Dysplasia involves abnormal changes in cell size, shape, and organization and is considered a precancerous condition.

Cellular Injury

• Normal cells can adapt to stress, undergo reversible injury, or irreversible injury leading to cell death. The outcome depends on the severity and duration of the stress, as well as the cell type and its adaptability.

Common Biochemical Derangements

• Decreased ATP: Leads to cellular swelling, reduced protein synthesis, and impaired membrane transport. Without sufficient ATP, cellular functions are compromised, and the cell's structural integrity is threatened.

• Reactive Oxygen Species (ROS): Destroy cell membranes and structures. These highly reactive molecules cause oxidative damage to lipids, proteins, and DNA, leading to cell injury and death.

• Increased intracellular Calcium (Ca++): Causes intracellular damage via enzyme activation. Excessive calcium influx can activate enzymes such as phospholipases, proteases, endonucleases, and ATPases, leading to cellular damage and apoptosis.

• Membrane Permeability Defects: Result in the release of lysosomal enzymes and cellular digestion. Damage to the cell membrane can cause the leakage of lysosomal enzymes, leading to autodigestion of the cell (autolysis).

Hypoxia

• Obstruction or cessation of blood flow leads to ischemia, causing mitochondrial oxygenation. Ischemia is a critical factor in many types of cell injury, particularly in tissues with high metabolic demands such as the brain and heart.

• Decreased ATP production, failure of the Na+/K+ pump, increased intracellular Na+ and Ca++, and decreased intracellular K+ result in cell swelling. These ionic imbalances disrupt cellular homeostasis and lead to cellular dysfunction and structural damage.

• Anaerobic glycolysis leads to increased lactate production and decreased pH, contributing to nuclear chromatin clumping. The accumulation of lactic acid results in intracellular acidosis, which can damage cellular structures and impair enzyme function.

Hypoxia (cont.)

• High Altitude: Can cause hypoxia, leading to decreased ATP, anaerobic metabolism, lactic acid production, and metabolic acidosis, as well as increased circulating K+. This is because the reduced oxygen availability at high altitudes leads to decreased oxygen supply to tissues.

• Na+/K+ ATPase Pump Failure: Results in increased intracellular Na+ and Ca++ and decreased K+, causing cell swelling and potential loss of consciousness (LOC), as well as dysrhythmias and cardiac arrest due to hyperkalemia. The failure of this pump disrupts cellular ion balance and membrane potential.

• Capillary-Alveolar Membrane Damage: Increases capillary permeability, leading to interstitial fluid accumulation, pulmonary edema, hypoxemia, and potential dysrhythmias or cardiac arrest. Damage to this membrane impairs gas exchange and fluid balance in the lungs.

Free Radicals (e.g., ROS)

• Atoms with unpaired electrons wreak havoc by forming injurious chemical bonds and initiating chain reactions, destroying cell membranes and structures, leading to apoptosis and necrosis. These unstable molecules cause oxidative damage to cellular components, contributing to aging and various diseases.

• Antioxidants counteract free radicals. These molecules neutralize free radicals, preventing them from causing damage. Examples include vitamins C and E, glutathione, and superoxide dismutase.

• ROS are byproducts of cellular metabolism and exogenous sources. They are produced during mitochondrial respiration and can also come from external sources such as pollution, radiation, and tobacco smoke.

• An overwhelming of antioxidant defenses leads to oxidative stress. This imbalance results in cellular damage and contributes to the pathogenesis of numerous diseases.

ROS & Cell Injury

• ROS result in lipid peroxidation, protein modifications, and DNA damage. These damages compromise cellular function and structural integrity.

• Enzymes like superoxide dismutase (SOD), glutathione peroxidase, and catalase remove free radicals. These enzymes convert free radicals into less harmful substances, protecting cells from oxidative damage.

Ischemia-Reperfusion Injury (IRI)

• Enzyme conversion (xanthine oxidase) with O2 exposure. During ischemia, ATP is broken down into hypoxanthine. Upon reperfusion, xanthine oxidase converts hypoxanthine to xanthine and generates ROS, leading to oxidative stress.

• Increased ATP consumption during ischemia leads to catabolite accumulation, increased ROS with reperfusion, and cell membrane damage, ATP loss, apoptosis, and necrosis. The sudden restoration of blood flow can paradoxically exacerbate tissue damage due to the generation of ROS and inflammatory mediators.

• This leads to oxidative stress, Ca++ overload in mitochondria, inflammation, and neutrophil adhesion to the endothelium, accelerating injury. These processes contribute to further cellular damage and organ dysfunction.

• Complement activation also occurs. The complement system, a part of the immune system, is activated during reperfusion, leading to inflammation and tissue damage.

• Treatment includes antioxidants and anti-inflammatories. These therapies aim to reduce oxidative stress and inflammation, thereby minimizing tissue damage.

Reperfusion Injury

• Illustrates the process where anoxia is followed by reperfusion, leading to the generation of radicals and necrotic cells. This highlights the paradox where restoring blood flow can cause additional harm.

Cellular Injury Mechanisms: Burns

• Major burn injury (>20% TBSA) leads to increased capillary permeability, edema, hypoalbuminemia, and hypovolemia, resulting in tissue ischemia, acidosis, multiple organ failure (MOF/MODS), decreased cardiac output, ROS, and IRI. The severity of these effects depends on the extent and depth of the burn.

• Hypermetabolic response (increased HR, hyperpnea, increased core body temperature [CBT], increased blood glucose [BG], cachexia) occurs until wound closure. This response is characterized by increased energy expenditure and catabolism, which can lead to muscle wasting and malnutrition.

• Severe inflammatory and immunologic response increases capillary permeability and exudation from wounds, leading to immunosuppression and potential wound and systemic sepsis. The impaired immune function increases the risk of infections, which are a major cause of morbidity and mortality in burn patients.

• Treatment includes fluid resuscitation, electrolytes, nutrition, wound management, excision and grafting, scar reduction, comfort measures, infection control/treatment, and thermoregulation. A multidisciplinary approach is essential for optimizing outcomes in burn patients.

• Massive IV fluids may include colloids. Colloids, such as albumin, help maintain oncotic pressure and reduce edema.

Cellular Injury Mechanisms: Burns (cont.)

• Skin loses barrier and vapor functions, and nerve endings are destroyed, impairing dermal elasticity and leading to dry/leathery wounds. The loss of skin integrity compromises the body's ability to regulate temperature and prevent infection.

• Increased capillary permeability in the first 24 hours leads to marked edema, and capillary seal is lost. This results in the leakage of fluid and proteins from the capillaries into the interstitial space, causing swelling.

• Decreased blood volume (BV) results from third spacing, exudation, and evaporation, along with local and systemic inflammatory mediator release, causing widespread cell injury. This hypovolemia can lead to decreased cardiac output and organ dysfunction.

Acute Major Burn: Capillary Leak

• Direct tissue injury and systemic injury response lead to increased capillary permeability, endothelial injury, edema, leukocyte sequestration, tissue ischemia, hypovolemia, hyperviscosity, acidosis, depressed cardiac function, and multiorgan dysfunction. These factors contribute to the complex pathophysiology of burn shock.

Biologic Manifestations of Cell Injury (Cellular Infiltrations)

• Abnormal metabolism, protein mutation, defects in protein folding/transport, or lack of enzymes can lead to fatty liver or accumulation of abnormal proteins. These intracellular accumulations can disrupt cellular function and lead to cell injury.

• Lysosomal storage diseases result in the accumulation of endogenous materials, while ingestion of indigestible materials leads to the accumulation of exogenous materials. These accumulations can impair lysosomal function and cause cellular damage.

Manifestations of Cellular Injury: Clinical

• Fever: Due to endogenous pyrogens and acute inflammatory response. Pyrogens are released by immune cells and act on the hypothalamus to increase body temperature.

• Increased HR: Due to increased metabolism and sympathetic stimulation. This is a compensatory mechanism to maintain cardiac output in the face of tissue hypoxia.

• Increased WBC: Indicates infection or inflammation. White blood cells are recruited to the site of injury to fight infection and remove debris.

• Pain: Due to bradykinins and pressure on nerve endings. Bradykinins are inflammatory mediators that stimulate pain receptors.

• Increased Serum Enzymes: Such as LDH, CK, AST, ALT, ALP, and amylase. These enzymes are released from damaged cells and can indicate tissue injury in specific organs.

• Fatigue/Malaise/Anorexia: Systemic symptoms associated with inflammation and tissue damage. These symptoms are often nonspecific but can indicate underlying cell injury.

Cellular Death: Necrosis

• Sum of cellular changes after local cell death and the process of cellular autodigestion. Necrosis is characterized by uncontrolled cell death and inflammation.

• Widespread cell swelling and rupture of cellular organelles occur, leading to an inflammatory response. The release of intracellular contents triggers an immune response, leading to inflammation.

• Causes include prolonged hypoxia, infection, and cell membrane damage. These factors disrupt cellular homeostasis and lead to irreversible cell damage.

Cellular Death: Apoptosis

• Mainly programmed cellular death (scattered, single cells). Apoptosis is a controlled process that eliminates damaged or unnecessary cells without causing inflammation.

• Enzyme synthesis, protease-induced shrinkage, cell fragmentation, and phagocytosis occur. These steps ensure that the cell is eliminated in an orderly manner.

• Necrosis (Pathologic or Physiologic): Tissue cells swell and lyse, which is slow, messy, and causes inflammation of neighboring cells. This type of cell death is typically associated with injury or infection.

• Apoptosis (Physiologic or Pathologic): Nuclear/cytoplasm shrinkage is quick and clean, with no swelling or inflammation. This process is essential for development, tissue homeostasis, and immune function.

Cellular Death: Necrosis & Apoptosis

• Illustrates the key differences between necrosis and apoptosis at the cellular level, highlighting inflammation in necrosis versus cellular fragmentation and phagocytosis in apoptosis. This helps differentiate the two distinct processes of cell death.

Types of Necrosis

• Coagulation, liquefaction, caseous, and enzymatic fat necrosis

Liquefactive Necrosis

• Hydrolytic enzymes - wet gangrene; brain. This type of necrosis is characterized by the digestion of dead cells, resulting in a liquid mass.

Coagulative Necrosis

• Protein denaturation (hypoxia) - kidneys, heart, adrenal glands. Coagulative necrosis occurs when proteins are denatured, causing the tissue to become firm and opaque.

Caseous Necrosis

• Combined coagulative and liquefactive (e.g., TB). This type of necrosis is characterized by a cheese-like appearance and is commonly associated with tuberculosis.

Fat Necrosis

• Lipase action - breast, pancreas, abdomen. Fat necrosis occurs when lipases break down triglycerides, releasing fatty acids that combine with calcium to form soaps.

Gangrenous Necrosis

• Hypoxia & bacterial invasion- Dry: coagulative

  • Wet: liquefactive

  • Gas: Clostridium

Gangrenous necrosis is a type of necrosis caused by severe hypoxia and bacterial infection. Dry gangrene involves coagulative necrosis and appears dry and shrunken. Wet gangrene involves liquefactive necrosis and appears moist and swollen. Gas gangrene is caused by Clostridium bacteria, which produce gas and toxins that spread rapidly through the tissues.

Osmotic Equilibrium

• Illustrates how water moves between the intracellular (ICF) and extracellular (ECF) compartments to maintain osmotic equilibrium. This equilibrium is critical for maintaining cell volume and function.

• Normal osmotic equilibrium is disrupted by the addition of solute or free water to the ECF, and equilibrium is re-established through water movement. Osmosis is the driving force behind this water movement.

Plasma & Interstitial Water Movement

• Shows the hydrostatic and oncotic pressures that govern water movement between the plasma and interstitial fluid. These pressures determine the direction and magnitude of fluid movement.

• Net filtration pressure is determined by the balance of these pressures at the arterial and venous ends of capillaries. Understanding this balance is crucial for understanding edema formation.

Water Movement

• Capillary hydrostatic pressure, interstitial osmotic pressure, interstitial hydrostatic pressure, and capillary oncotic pressure influence fluid movement by filtration. These pressures are influenced by factors such as blood pressure, plasma protein concentration, and capillary permeability.

• Intracellular osmotic pressure affects fluid movement by osmosis. This pressure is determined by the concentration of solutes inside the cell.

Edema

• Accumulation of fluid in the interstitial space (Local or systemic).

  • Lymphedema, pitting edema, cerebral edema, pulmonary edema, ascites.

  • Weight gain, swelling, puffiness, impaired wound healing

Edema is the abnormal accumulation of fluid in the interstitial spaces, leading to swelling and discomfort. It can be caused by various factors that disrupt the normal balance of fluid movement between the capillaries and the tissues.

• Mechanisms:

  • Increased capillary hydrostatic pressure (venous obstruction, Na+ & H2O retention).

  • Decreased plasma albumin (liver disease, protein malnutrition).

  • Increased capillary permeability (inflammatory & immune cell injury causes).

  • Lymph obstruction (infection, tumor, surgical removal).

These mechanisms disrupt the balance of hydrostatic and oncotic pressures, leading to fluid accumulation in the interstitial space.

• Treatment: elevation, compression, decreased Na+ intake, diuretics, underlying cause.

Treatment strategies aim to reduce fluid accumulation and address the underlying cause of edema.

Edema (cont.)

• Various causes of edema are outlined, including increased capillary hydrostatic pressure, decreased plasma oncotic pressure due to decreased plasma protein synthesis or increased loss, increased capillary permeability, and lymph obstruction. These causes reflect disruptions in the normal mechanisms of fluid balance.

Na+ Regulation: RAAS

• Renin-Angiotensin-Aldosterone System (RAAS) is activated by decreased renal perfusion, decreased BP, decreased serum Na+, or decreased ECF. This hormonal system plays a key role in regulating blood pressure and fluid balance.

• The kidneys release renin, which converts angiotensinogen (from the liver) to angiotensin I.

• Angiotensin-converting enzyme (ACE) in the lungs converts angiotensin I to angiotensin II.

• Angiotensin II causes vasoconstriction and stimulates the adrenal cortex to release aldosterone, leading to increased sodium and water retention and increased blood pressure.

Natriuretic Peptides

• Natriuretic peptides (ANP, BNP, urodilatin) are released in response to increased total body Na+ and plasma volume. These peptides counteract the effects of the RAAS.

• ANP, BNP release when atrial stretching detected by atrial endocrine cells

• They increase GFR, inhibit the RAAS, and inhibit proximal tubule Na+ reabsorption, leading to increased sodium and water excretion, decreased blood volume, and decreased blood pressure.

Water Balance: ADH

• Increased plasma osmolality or decreased plasma volume is detected by brain osmoreceptors, stimulating the hypothalamus to release ADH from the posterior pituitary. ADH, also known as vasopressin, is a hormone that regulates water balance.

• ADH promotes renal water retention, decreasing plasma osmolality and increasing plasma volume. Thirst also increases, leading to increased fluid intake.

Fluid Alterations

• Illustrates isotonic, hypotonic, and hypertonic alterations and their effects on body cells, including neurons and red blood cells. These alterations can have significant effects on cell volume and function.

Action Potential

• Depicts the stages of action potential – resting membrane potential, depolarization (Na+ influx), and repolarization (K+ efflux). The action potential is the fundamental mechanism for nerve and muscle cell communication.

Membrane Excitability

• Shows how alterations in extracellular K+ and Ca++ levels affect membrane excitability. These electrolyte imbalances can alter the threshold for action potential generation.

• Low K+ or high Ca++ decreases excitability (hyperpolarization), while high K+ or low Ca++ increases excitability (depolarization).

ECG Changes with K+ Changes

• ECG changes associated with normokalemia, hypokalemia, and hyperkalemia are outlined.

  • Normal ECG with normokalemia.

  • Hypokalemia: prolonged PR interval, peaked P wave, ST depression, shallow T wave, prominent U wave.

  • Hyperkalemia: decreased R wave amplitude, tall peaked T wave, wide flat P wave, prolonged PR interval, widened QRS, depressed ST segment.

These ECG changes reflect the effects of potassium imbalances on cardiac electrical activity.

Trousseau's Sign

• Description of carpopedal spasm associated with hypocalcemia. This is a clinical sign used to assess for latent tetany in hypocalcemic patients.

Chvostek's Sign

• Method for eliciting Chvostek's sign and the corresponding response. (twitching of the lip at the corner of the mouth to spasm of all facial muscles) This is another clinical sign used to assess for hypocalcemia.

K+ & H+ Relation

• Changes in pH & K+ balance:

  • H+ accumulates in ICF with acidosis.

  • K+ shifts out to maintain cation balance across the membrane.

This reciprocal relationship between potassium and hydrogen ions can have significant clinical implications in acid-base disorders.

Acid-Base Imbalances

• Normal arterial blood pH ranges from 7.35 to 7.45 and is obtained through arterial blood gas (ABG) sampling. Maintaining pH within this range is essential for normal physiological function.

• Acidosis is defined as an increase in H+ concentration, while alkalosis is a decrease in H+ concentration.

Acidosis & Alkalosis

• pH determines acid-base status; PaCO2 represents the respiratory component, and HCO3- represents the metabolic component.

  • Respiratory acidosis: Elevated PaCO2 (ventilatory depression).

  • Respiratory alkalosis: Decreased PaCO2 (alveolar hyperventilation).

  • Metabolic acidosis: Decreased HCO3- (increased acid or decreased base).

  • Metabolic alkalosis: Increased HCO3- (decreased acid or increased base).

Understanding these components is crucial for diagnosing and managing acid-base disorders.

Acid-base Balance

• Illustrates the relationship between pH, carbonic acid, and bicarbonate. These components are central to the buffering system that maintains blood pH.

• Normal blood pH is maintained by respiratory and renal regulation. The lungs regulate CO2 levels, while the kidneys regulate bicarbonate levels.

Acid base Compensation

• Details the parameters including pHa, HCO3-, PaCO2 mmHg, (mmol) WNL, Uncompensated, Compensated, Corrected, Ratio.

Acid base Compensation (cont.)

• A chart illustrating the compensation mechanisms for respiratory and metabolic acidosis and alkalosis, involving renal bicarbonate retention/elimination and respiratory CO2 retention/elimination.

ABG Practice #1

• Case study involving Mr. Smith presenting with disorientation and lethargy.

  • ABGs: pHa 7.32, PaCO2 56 mmHg, HCO3- 30 mEq/L.

  • Requires interpretation of acid-base balance, respiratory/metabolic involvement, and whether it is acute, compensated, or corrected.

ABG Practice #2

• Case study involving Ms. Phelps admitted from PACU with a respiratory rate of 8 bpm and difficulty arousing.

  • ABGs: pHa 7.30, PaCO2 52 mmHg, HCO3- 26 mEq/L.

  • Requires determining acid-base status, respiratory/metabolic components, and whether it is acute, compensated, or corrected.

ABG Practice #3

• Case study involving Mr. L., a 36-year-old man with polydrug overdose admitted to MICU, intubated, and on mechanical ventilation.

  • ABGs in ER: pHa 6.82, PaCO2 16 mmHg, HCO3