Healing and Recovery

The Acid-base Balance

Normal cell metabolism results in continuous production of carbon dioxide (CO2) and hydrogen ions (H+); both of which tend to reduce pH. This process depends on the maintenance of blood pH within very narrow limits (i.e., the preservation of acid-base balance). Failure to do this, will cripple enzyme mediated reactions in the cell. This can have deleterious effects, including reduced oxygen delivery to tissues, electrolyte disturbances and changes in heart muscle contractility. Survival is rare if blood pH falls below 6.8 and rises above 7.8. The principle buffer system in blood is: the weak acid; carbonic acid (H2CO3), and its conjugate base; bicarbonate (HCO3-). Most of the carbon dioxide produced in the tissues is transported to the lungs as bicarbonate in blood plasma. The lungs ensure removal of carbonic acid (exhalation of CO2) and the kidneys ensure continuous regeneration of bicarbonate.

Normal acid-base homeostasis

Acid-base Disorders

There are many different buffer systems in the body, but the main system for understanding most acid-base disorders is the bicarbonate system present in the extracellular fluid. Acid-base disorders are broadly classified into problems involving metabolic and/or respiratory processes. Metabolic processes primarily direct change in the level of bicarbonate, while respiratory processes primary direct changes in the partial pressure of carbon dioxide (PaCO2). A reduced bicarbonate concentration is a hallmark of metabolic acidosis. An elevated bicarbonate concentration is a feature of metabolic alkalosis. A decreased PaCO2 is a feature of respiratory alkalosis. An elevated PaCO2 is a feature of respiratory acidosis. By examining (1) the pH, (2) the bicarbonate concentration and (3) the PaCO2, it is possible to deduce the nature of the disorder (acid-base disorder) which is present, and the compensatory response.

Four primary acid-base disorders

Calculated Parameters

Laboratories are now (or soon will be) operating in the era of the electronic health record where most health care providers and patients would be offered online platforms where they can question the unexplained variations between analytical procedures. The reference intervals for results obtained by identical analytical procedures must be equivalent, and be within clinically relevant and meaningful limits. In order to enable the optimal use of medical guidelines for disease diagnosis and patient management, the reporting of calculated parameters must be implemented as a vital part of the post-analytical phase. These parameters must be reported by laboratories because they are used by health care providers for important decisions making. Labs have to also implement harmonized reference intervals. Any failure in this process can result in wrong clinical, financial and technical decisions as well as an inability to properly aggregate data from research.

Calculated chemistry parameters

Calculated Osmolality

The measurement of the number of osmoles of solute per kilogram of water is an essential physiologic parameter to understand several medical disorders such as electrolyte disturbances, exogenous intoxication and hydration status. The measurement of serum osmolality is relevant in changes in intracellular and extracellular balance, as a trusted and valuable indicator of solute concentration in the blood. It is useful in cases of dehydration, sodium and potassium disorders, glucose alteration, exogenous poisoning, adrenal insufficiency, neurological injury, physical exercise and others. Most formulas used for the calculation of serum osmolality are based on the levels of sodium, urea, and glucose. Normal values for directly measured serum osmolality are 275 to ≤295 mOsm/kg, while 295 to 300 mOsm/kg is classified as impending dehydration, and >300 mOsm/kg as current dehydration. All values <240 mOsm/kg or >320 mOsm/kg are considered critical values.

A formula used to calculate serum osmolality

The "Anion Gap" (AG)

It is routine practice to measure only four charged particles, i.e., sodium, potassium, chloride and bicarbonate ions. When the number of cations (Na+ and K+) are added, one will always find that they outnumber the anions (Cl- and HCO3-). The calculated difference is what is foreshadowed by the term "Anion Gap" (AG) and reflects the unmeasured anions. Since there are more unmeasured anions (albumin, phosphate, and lactate) than unmeasured cations (calcium, magnesium, and potassium), the value of the AG is usually positive. Metabolic acidosis is the most common cause of raised anion gap. The reliability of the AG has been questioned due to its underestimation in patients with hypoalbuminemia, which is a frequent occurrence in critically ill patients. Correction of the AG for serum albumin improves the accuracy of this parameter. As a whole, an extreme elevation in the AG requires the presence of renal failure, hemoconcentration, and increases in serum phosphorus and albumin concentrations. Metabolic acidosis may be associated to elevated tissue acids (mainly lactate and/or unmeasured anions), hyperchloremia, or a combination of both. The Cl-Na ratio and albumin are usually low in the presence of tissue acids, and hence could be used as alternatives (i.e., to the AG) in identifying raised tissue acids. It is hypothesized that metabolic acidosis associated with a rise in tissue acids, is accompanied by a decrease in plasma chloride (Cl) relative to sodium (Na). Therefore, a Cl-Na ratio <0.75 is a good predictor of increased tissue acids, whereas a high ratio (>0.79) excludes the presence of raised tissue acids. In conclusion, a Cl-Na ratio >0.79 has an acidifying effect on plasma, while a Cl-Na ratio <0.75 has an alkalinizing effect.

Decreased or Negative AG

Calculation of the AG remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxication. A low serum AG is relatively uncommon occurrence, most frequently the result of laboratory error or severe hypoalbuminemia. Hypoalbuminemia decreases the AG by 2.3 – 2.5 mEq/L for every g/dL where albumin is below 4 g/dL (40 g/L). To appreciate this fact, the correction factor was set to 2.5. Besides hypoalbuminemia, polyclonal gammopathy and monoclonal gammopathy with excessive accumulation of cationic IgG are the most common clinical disorders associated with a low serum AG. Once laboratory error and hypoalbuminemia have been excluded, a search for accumulation of IgG should be initiated. In patients with disturbed mentation, or unexplained clinical findings, the possibility of lithium ingestion, bromide, or iodide intoxication should be considered (i.e., thiazide diuretics, renal insufficiency, congestive heart failure and volume depletion). The antimicrobial polymyxin B, which is used for treatment of serious gram-negative infections, possesses polycationic properties. Polymyxin B has been reported to produce a low or even negative serum AG.

Determinants of the Serum Anion Gap

Immunoglobulin classes (isotypes)

Immunoglobulins (Ig), are glycoprotein molecules that make up an important part of the immune system. They are produced by B-lymphocytes. Immunoglobulins identify and destroy foreign substances, e.g., bacteria, protozoan parasites and viruses. Immunoglobulins are classified into five categories: IgA (15%), IgD (0.2%), IgE (0.004%), IgG (75%) and IgM (10 – 12%). IgA, IgG and IgM are found in significant amounts in the human body. IgA is present on mucus membranes and provides protection on those surfaces which present gateways for microbes. IgG enhances phagocytosis in macrophages (specialized eater cells) and neutrophils (another type of white blood cell); neutralizes toxins; inactivates viruses and kills bacteria. The Fc portion of IgG can bind to natural killer cells to set in motion a process called antibody-dependent cell-mediated cytotoxicity, which can kill or limit the effects of invading microbes. IgM is the first line of defense (i.e., the first immunoglobulin made during a typical immunological response). IgM agglutinates invading material, compelling the individual pieces to stick together for easier clearing from the body. IgM also promotes lysis and phagocytosis of micro-organisms. The C-region of IgG and IgM activates the complement system.

Innate Immunity (The Complement System)

The complement system is an integral part of the innate immune response and acts as a bridge between innate and acquired immunity. The complement consists of a series of proteins that are mostly (although not exclusively) synthesized in the liver, and exist in the plasma and on cell surfaces as inactive precursors (zymogens). The Complement mediates responses to inflammatory triggers through a coordinated sequential enzyme cascade leading to clearance of foreign cells through pathogen recognition, opsonization and lysis. Complement also possesses anti-inflammatory functions: it binds to immune complexes and apoptotic cells, and assists in their removal from the circulation and damaged tissues. The complement proteins are activated by, and work with IgG and IgM antibodies. Many complement proteins exist as precursor-forms which are activated at the site of inflammation. The complement system is more complex than many enzymatic cascades. It requires the formation and activation of sequential non-covalently associated protein fragments. These in turn become convertases and cleave components for the next enzymatic complex in the cascade. The rapid dissociation of these complexes (loss of enzymatic activity) forms an integral part of the elegant regulation of complement activity.