Principles of Pathophysiology

Pathophysiology is the study of what happens when compensation fails

The body maintains a stable internal state, called homeostasis, through constant small adjustments known as compensation. Pathophysiology is what you are studying whenever a disease process pushes hard enough that those adjustments are no longer enough.

The cell

The cell is the basic building block of the body. Its membrane is selective, controlling what enters and what leaves. Inside, the nucleus holds the cell's DNA, the endoplasmic reticulum synthesizes proteins, and the mitochondria convert glucose into adenosine triphosphate (ATP). ATP is the cell's fuel; it powers every cellular function, including the sodium-potassium pump that moves ions across the membrane. That ion movement creates the electrical charge that allows muscle, including the heart muscle, to contract. To do all this, a cell has three core requirements: water, glucose and oxygen.

Water must be present in the right amount. Too little and the cell dehydrates and dies; too much and its function is disrupted. Dissolved in the water are the electrolytes, among them potassium, sodium and magnesium, which make the cell's electrical functions possible, from nerve transmission to the depolarization of the heart. Glucose is the raw fuel that is broken down to produce ATP, but most cells cannot take it up on their own: they need insulin to move glucose from the blood into the cell.

Oxygen & metabolism

Cells can produce energy with oxygen or without it, and the difference between the two is enormous. The table below compares the two forms of metabolism.

Table 7.1Oxygen & metabolism

Anaerobic metabolism sets off a downward spiral. The lactic acid it produces causes acidosis, and in an acidotic environment hemoglobin carries less oxygen. Less oxygen means worsening hypoxia, and the spiral continues downward.

Homeostasis & the fight-or-flight response

Homeostasis is regulated by the hypothalamus and the medulla oblongata. When the body is threatened, the sympathetic nervous system produces the fight-or-flight response. The adrenal glands release epinephrine and norepinephrine, which act on beta-2 receptors to dilate the bronchioles and on beta-1 receptors to increase the heart rate and the force of contraction; at the same time the blood vessels constrict, and blood pressure (BP) rises. At rest the parasympathetic nervous system, the feed-or-breed system, dominates instead.

Two situations blunt this response. Beta blockers reduce the effects of epinephrine and norepinephrine, so a patient who takes them may be unable to compensate normally during an emergency. In adrenal insufficiency, as in Addison's disease, the stress hormones the body needs to maintain blood volume and vessel tone are missing, so the normal compensatory response fails; the vessels dilate and the patient goes into shock.

The cardiopulmonary system

The lungs and the heart work as one system, with three jobs: to move oxygen (O2) in, to move carbon dioxide (CO2) out, and to deliver oxygen to the cells. The air we inhale is roughly 79% nitrogen and 21% oxygen; the proportion of oxygen in inhaled air is called the fraction of inspired oxygen, or FiO2. None of this works unless the airway is patent, that is, open and unobstructed.

Lung volumes & respiratory dysfunction

Two measurements describe how much air a patient is moving. Tidal volume is the amount of air moved in one breath, and minute volume is the tidal volume multiplied by the respiratory rate. Not all of each breath reaches the alveoli: about 150 mL of every breath, the dead air space, fills the airway and never takes part in gas exchange. Because minute volume depends on both rate and depth, it can fall in two ways. A heroin overdose (OD) lowers the rate, while an asthma attack lowers the tidal volume; either one reduces the minute volume.

Respiratory dysfunction takes 3 forms:

1. Disruption of respiratory control. Stroke, drugs such as narcotics, brain trauma and spinal cord injury can all impair the control of breathing.
2. Disruption of pressure. A hole in the chest wall or the pleural space lets air or blood accumulate, and the lung collapses.
3. Disruption of lung tissue. Trauma, congestive heart failure (CHF) and sepsis damage the alveoli so that they can no longer exchange gas.

The body has sensors that trigger compensation. Chemoreceptors detect rising CO2 and falling O2 and prompt the brain to increase both the rate and the depth of breathing. Stretch receptors in the blood vessels detect falling pressure and trigger sympathetic activation.

The blood & blood vessels

Two opposing pressures govern the movement of water across the walls of the blood vessels. Plasma oncotic pressure is the pull exerted by large proteins in the plasma, which draws water into the bloodstream. Hydrostatic pressure is the pumping force of the heart, which pushes water out of the vessels. If either pressure is disrupted, the result is edema or dehydration. Liver failure is one example: the failing liver produces too little albumin, oncotic pressure falls, fluid leaks out of the vessels, and the patient develops edema while the blood itself becomes dehydrated. The blood can also fail in its oxygen-carrying role. Anemia, too few red blood cells, reduces the blood's capacity to carry oxygen.

Arteries carry blood away from the heart, and that blood is oxygenated, except in the pulmonary artery. Veins carry blood toward the heart, and that blood is deoxygenated, except in the pulmonary vein. The capillaries between them are the site of exchange.

The vessels themselves can fail in several ways. The table below sets out the main problems, their causes and their results.

Table 7.2The blood & blood vessels

Children vasoconstrict powerfully, so a child's blood pressure can remain normal even after massive volume loss. Capillary refill is a better indicator in a child; a refill time of less than 2 seconds is normal.

The heart

Stroke volume is the amount of blood the heart ejects with each beat, about 70 mL. It rises when preload or contractility increases and falls when afterload increases. Cardiac output is the stroke volume multiplied by the heart rate, and it can fall for three reasons: bradycardia, a low stroke volume as in blood loss, or a rate so fast that the ventricles do not have time to fill, which happens above 180 beats per minute (bpm).

A young heart cannot increase its contractility much, so a child compensates mainly by raising the heart rate (HR). Tachycardia in a child is therefore a serious red flag.

The heart can fail mechanically or electrically. Mechanical dysfunction, from trauma, compression of the heart by the pericardium, or a myocardial infarction (MI), can occur even while the electrical system remains intact. Electrical dysfunction takes the form of dysrhythmias, such as ventricular fibrillation (V-fib), bradycardia and tachycardia, and it results from hypoxia, toxins or medications. In infants, bradycardia is often a sign of hypoxia, a ventilation problem, rather than a cardiac problem.

Shock is fundamentally a supply problem, but the cause varies

Shock is defined as inadequate perfusion. The cells do not receive enough oxygen (O2) and nutrients and cannot get rid of their waste, so they shift to anaerobic metabolism, acidosis develops, and cells and then organs die. Whatever its cause, shock is fundamentally a problem of supply. The cause itself varies, however, and the table below sets out the four types of shock by mechanism.

Table 7.3Shock is fundamentally a supply problem, but the cause varies

Shock progresses through stages. In compensated shock the body is still managing: the heart rate and respiratory rate rise, the vessels constrict, the skin becomes pale, cool and diaphoretic, the patient is mildly anxious and capillary refill is delayed, but the blood pressure may still be normal. In decompensated shock compensation has failed: the blood pressure falls and the mental status is altered. If decompensated shock is not reversed, it becomes irreversible shock, and the patient dies. Two exceptions are worth remembering. A patient in cardiogenic shock may not be able to raise the heart rate, and a patient in septic shock may not be able to vasoconstrict, so the usual compensatory signs can be missing.

Fluid balance

About 60% of the body is water, distributed among 3 spaces. Roughly 70% of it is intracellular, inside the cells; 25% is interstitial, between the cells and the vessels; and 5% is intravascular, in the bloodstream. Three mechanisms regulate this balance: the brain and the kidneys, through thirst and urine output; the plasma proteins, through their oncotic pull; and the permeability of the cell and capillary membranes. Dehydration is a loss of fluid, whether from reduced intake, vomiting, diarrhea, rapid breathing, sweating or burns. Edema is a shift of fluid into the interstitial space, as occurs in liver failure, sepsis, high blood pressure (BP) and injury.

Other system dysfunction

The other body systems fail in their own characteristic ways. The brain is protected by the skull, the meninges and the cerebrospinal fluid (CSF), but that protection has a cost: when trauma causes bleeding or swelling inside a closed skull, there is nowhere for the extra volume to go, and intracranial pressure rises. Medical causes of nervous system dysfunction include stroke, meningitis, encephalitis, multiple sclerosis (MS) and hypoglycemia.

The endocrine system fails when a gland produces too much of a hormone, as in Graves' disease, or too little, as in Type 1 diabetes, where the absence of insulin leaves the cells unable to take up glucose and starving. Adrenal insufficiency, with too little cortisol and aldosterone to support the stress response, leads to shock.

Gastrointestinal (GI) bleeding may be chronic or acute; an acute, massive bleed leads to hypovolemic shock. Dark or black stools indicate blood from the upper GI tract. Vomiting and diarrhea, whether viral or bacterial in origin, have dehydration, malnutrition and shock as their complications.

Finally, the immune system can overreact. In hypersensitivity, an exaggerated immune response releases excess histamine. Histamine increases capillary permeability, producing edema and narrowing of the airway, and dilates the blood vessels, so the blood pressure falls. The result is the distributive shock of anaphylaxis.