CHAPTER IINTRODUCTION

1.1 BackgroundAcidbase homeostasis exerts a major influence on protein function, thereby critically affecting tissue and organ performance. Deviations of systemic acidity in either direction can have adverse consequences and, when severe, can be life-threatening. Yet it is the nature of the condition responsible for severe acidemia or alkalemia that largely determines the patient's status and prognosis. Whereas a blood pH of 7.10 can be of little consequence when caused by a transient or easily reversible condition, such as an isolated seizure, it forecasts an ominous outcome if it is the result of methanol intoxication. Similarly, a blood pH of 7.60 seldom has serious consequences when caused by the anxietyhyperventilation syndrome, but it imparts a major risk to a patient with cardiomyopathy treated with digitalis and diuretics. Consequently, the management of serious acidbase disorders always demands precise diagnosis and treatment of the underlying disease, and in certain circumstances, it requires steps to combat the deviation in systemic acidity itself. In this article, we address general concepts and some specific aspects of the management of life-threatening acidbase disorders.

1.2Purpose of writingUnderstanding more about Management of Life-Threatening Acid Base Balance Disorder

1.3 Problems1.3.1Definition and physiology of Acid Base Balance1.3.2Etiology, pathogenesis, and clinical manifestations of Life-Threatening Acid Base Balance Disorder1.3.3Diagnosis, differential diagnosis, treatment, and prevention of Life-Threatening Acid Base Balance Disorder

1.4Benefits of writing 1.4.1 Provide an understanding of Life-Threatening Acid Base Balance Disorder and management so that the right can be granted 1.4.2 As a source of knowledge for other academics to be the development of subsequent papers

CHAPTER IILITERATURE REVIEW

2.1. DefinitionThe term pH means potentials of Hydrogen. Acidity and alkalinity are expressed on the pH scale, which ranges from 0 (strongly acidic) to 14 (strongly basic, or alkaline). A pH of 7.0, in the middle of this scale, is neutral. Blood is normally slightly basic, alkaline, with a pH range of 7.35 to 7.45. To function properly, the body maintains the pH of blood close to 7.40.An important property of blood is its degree of acidity and alkalinity, and this is referred to as acid-base balance. The acidity or alkalinity of the blood is indicated on the pH scale. The acidity level increases when the level of acidic compounds in the blood rises or when the level of alkaline compounds in the blood falls. Alkalinity levels increases with the reverse process. The level of acidic or alkaline compounds in the body rises through increased intake, production, or decreased elimination and falls through decreased intake, production, or increased elimination.

2.2. Proton concentration and pHMaintaining of stable anion and cation concentrations in blood plasma is denoted as isoionia. Maintaining of constant proton (H+) concentration is isohydria. pH is used for express concentration of the protons:pH = log c(H+)Plasma and extracellular space concentrations of the protons are held in very narrow physiologic range. There is 40 nmol/l of protons in the arterial blood physiologically (note that concentrations of other plasma ions, e.g. [Na+] = 140 mmol/l or [HCO3-] = 25 mmol/l, are three orders of magnitude higher). pH could be easily calculated as follows:pH = -log 40 x 10-9 mol/lpH = 7,4Physiologic range of the pH is 7,36-7,44.Value of pH higher than 7,44 in arteries is denoted as alkalemia, pH lower than 7,36 is acidemia. Extensive deviations of pH value can cause serious consequences. For example change of protein structure (i.e. enzymes), membranes permeability, and electrolyte distribution. Value of pH in arterial blood higher than 7,8, resp. lower than 6,8 are incompatible with life.Values mentioned above apply for arterial blood. Values differ in different body compartments hence there are different H+ concentrations. There is quite variable and lower pH value intracellular, it is about 7,0 ([H+] = 100 nmol/l). Intracellular pH compared to arterial pH gives difference 0,4. This corresponds to fact that there is 2,5 fold difference between intracellular and arterial H+ concentration. This concentration gradient drives the movement of H+ from cells to blood. Therefore it is not surprising that venous pH and pH of interstitial fluid is lower (i.e. more acidic) than arterial pH. Approximate value is 7,35.

2.3. Acids & Bases in the BodyAcid is defined as molecule that can cleave off H+ (Arrhenius) or donor of H+ (Brnsted). Base is au contraire molecule that can cleave off OH- (Arrhenius) or acceptor of H+ (Brnsted). Source of acids in the body is chiefly metabolism, source of bases is predominantly nutrient.Acids and bases undergo either (1) metabolic conversion (e.g. lactate to glucose in gluconeogenesis, lactate to pyruvate and oxidation in cardiomyocytes), or (2) excretion from body. Three types of reactions can be distinguished from point of view of the acid-base balance. (1) proton-productive, (2) proton-consumptive, (3) proton-neutral. Examples follow:1) Proton-productive reactionsa) Anaerobic glycolysis in muscles and erythrocytesGlucose 2 CH3CHOHCOO- + 2 H+b) Ketogenesis production of ketone bodiesFatty acids ketone bodies + n H+c) LipolysisTAG 3 FA + glycerol + 3 H+d) UreagenesisCO2 + 2 NH+4 urea + H2O + 2 H+2) Proton-consumptive reactionsa) Gluconeogenesis2 lactate + 2 H+ Glcb)Neutral and dicarboxylic amino acids oxidation3) Proton-neutral reactionsa) Complete glucose oxidationb) Lipogenesis from glucoseHuman organism (healthy or not) every day produces great quantities of acids source of protons. Organism is acidified by these processes:1) Complete oxidationCarbon skeleton CO2 + H2O HCO3- + H+2) Incomplete oxidationCarbohydrates glucose pyruvate, lactate + H+Triacylglycerol fatty acids, ketone bodies + H+Phospholipids phosphate + H+Proteins amino acids sulphate, urea + H+Acids can be divided into two groups: (1) volatile acids (respiratory acids), (2) non-volatile acids (metabolic acids).The most important volatile acid is carbonic acid (H2CO3). H2CO3 is produced by reaction of carbon dioxide (CO2 is acid-forming oxide) with water. 15 000 20 000 mmol CO2 (therefore same amount of carbonic acid) is produced every day. Respiratory system however very efficiently eliminates it. This justifies the term volatile acid.

Two groups are distinguished among non-volatile acid: (1) organic, and (2) inorganic. 1 mmol/kg of body weight is produced every day. Non-volatile acid could be either (1) metabolised, or (2) excreted (using mainly kidneys).

Organic non-volatile acids are for example: (1) lactic acid, (2) fatty acids, (3) ketone bodies (acetoacetic acid, -hydroxybutyric acid). They are continually produced by metabolism (incomplete oxidation of TAG, carbohydrates, proteins). As organic non-volatile acids are products of metabolism in normal conditions they are oxidized completely to CO2 and H2O. Therefore they have no influence on proton overall balance.Inorganic non-volatile acids are: (1) H2SO4 (sulphuric acid is produced by oxidation of sulfhydryl groups e.g. in amino acids that contain sulphur, i.e. cysteine, methionine), (2) H3PO4 (phosphoric acid is produced by hydrolysis of phosphoproteins, phospholipids, nucleic acids). Inorganic non-volatile acids are predominantly excreted in urine. You should notice now that ATP production is coupled with H+ production. Human body is evolutionary capable to handle acid load.2.4. System responsible for maintenance of the acid-base systemSeveral systems maintain constant pH. The list below is made according to order when they act:1) Chemical buffering systemsBuffers react immediately acute regulation. Capacity of buffers is not indefinite that is why chemical buffers act only in the short-term. Chemical buffering systems deal with pH deviations in common metabolism.2) Respiratory systemRespiration reacts in 1-3 minutes. Respiratory system regulates carbon dioxide. Respiration is able to change pCO2 by its elimination or retention. Respiratory centre is in brainstem.3) KidneysKidneys react in hours-days. Their role in acid-base balance is very complex.

4) LiverLiver is pivotal organ of the energetic metabolism it also have important influence on the acid-base balance. Liver is the most important tissue where ammonium is detoxified in both (1) urea cycle, and (2) glutamine synthesis. Which one of these fates of ammonium is favoured closely depends on status of the acid-base balance:a) NH4+ urea + 2 H+ acidification of the bodyCO2 + 2 NH4+ CO(NH2)2 + 2 H+ + H2OH+ + HCO3- H2O + CO2 (consumption of bicarbonate-)b) NH4+ glutamine synthesis H+ is not produced, glutamine is taken up by the kidneys. In the kidney is H+ excreted as NH4+

5) MyocardiumMyocardium influences acid-base balance through lactate and ketone bodies oxidation.

2.5. Buffering SystemsBuffers are substances capable of releasing and binding H+. Short-term and acute changes in acid-base balance can be balanced by buffers. Each buffer keeps its particular pH. This pH could be calculated by means of the Henderson-Hasselbalch equation:pH = pK + log [conjugated base]/[acid]Henderson-Hasselbalch equation for bicarbonate buffer (HCO3-/CO2):pH = pKH2CO3 + log ([HCO3-] / [H2CO3])pH = pKH2CO3 + log ([HCO3-] / x pCO2) is conversion factor, that is used for calculation of molar concentration (mmol/l) from partial pressure of CO2 (pCO2). = 0,226 for pCO2 in kPA, = 0,03 for pCO2 in mmHg).pH = pK 1 is range where buffers work optimally.In Henderson-Hasselbalch equation above you should notice that for pH that buffers keep depends primarily on ratio of conjugated base and acid (Of course concentration of each component is important but not that much). Therefore it is really important to know the ratio. Ratio of conjugated base and acid could be calculated from relation between pH and pK. For example bicarbonate buffer (pH = 7,4; pK = 6,1):pH = pKH2CO3 + log ([HCO3-] / [H2CO3])7,4 = 6,1 + log ([HCO3-] / [H2CO3])1,3 = log ([HCO3-] / [H2CO3])[HCO3-] / CO2 20 / 1The ratio in bicarbonate buffer is 20:1 (HCO3- : CO2)There are several buffer systems in the body. The most important include: (1) bicarbonate buffer (HCO3-/CO2), (2) hemoglobin buffer (in erythrocytes), (3) phosphate buffer, (4) proteins, and (5) ammonium buffer. Their importance differs as it depends on localization.Main buffer systems according to body compartments.LocalizationBufferCommentary

ISFBicarbonateBuffers metabolic acids

PhosphateLow concentration limited significance

ProteinsLow concentration limited significance

BloodBicarbonateBuffers metabolic acids

HemoglobinBuffers CO2 (carbonic acid production)

Plasma proteinsMinor

PhosphateLow concentration limited significance

ICFProteinsSignificant buffer

PhosphateSignificant buffer

UrinePhosphateResponsible for majority of the titratable urine acidity

AmmoniumSignificant: elimination of ammonium nitrogen and protons; cation

_Following table shows buffering capacity of blood buffers.

2.5.1. Blood Buffers and their buffer capacity

BufferPlasmaErythrocytesTogether

HCO3- / CO235%18%53%

Hb / Hb-H+-35%35%

Plasma proteins7%-7%

Inorganic phosphate1%1%2%

Organic phosphate-3%3%

43%57%100%

Because of fact that all buffer systems are in equilibrium any kind of drift in pH causes response in all buffer systems. Any concentration change of any component of any buffer influences both pH, and all buffer systems.

2.5.2. Bicarbonate buffer (HCO3-/CO2)Bicarbonate buffer is the most important buffer system in blood plasma (generally in the extracellular fluid). This buffer consists of weak acid H2CO3 (pK1 = 6,1) and conjugated base HCO3- (bicarbonate).Bicarbonate concentration is given in mmol/l (average value is 24 mmol/l). Since carbonic acid is very unstable molecule measurement of its concentration is very difficult. H2CO3 is produced from CO2 hence it is possible to express carbonic acid concentration as partial pressure of CO2 (pCO2) because pCO2 is directly proportional to CO2 concentration. pCO2 is easily measured (kPa, mmHg). Average value in arterial blood is 5,3 kPa = 40 mmHg. pCO2 multiplied by gives us molar concentration of dissolved CO2 ( = 0,226 for pCO2 in kPa, = 0,03 if pCO2 for mmHg). Conversion relationship between mmHg and kPa is: 1 Pa = 0,0075 mmHg (i.e. 760 mmHg 100 kPa). In normal plasma pH is HCO3-/CO2 ratio 20 / 1.Henderson-Hasselbalch equation for bicarbonate buffer:pH = pK + log [conjugated base] / [acid]pH = pK + log ([HCO3-] / [H2CO3])pH = 6,1 + log ([HCO3-] / pCO2 x )pH = 6,1 + log (24 / 40 x 0,03)pH = 6,1 + 1,3pH = 7,4HCO3-/CO2 is so called open buffer system. This means body is capable to actively alter both bicarbonate, and carbon dioxide. pCO2 is regulated by respiratory tract (by means of ventilation respiratory rate and depth of breathing). HCO3- levels are altered by the kidneys and the liver. HCO3- could be both synthesized, and eliminated.Now you should recall what is stated above: pH = pK 1 is range where buffers work optimally. This should mean that bicarbonate buffer would work best in range 5,1-7,1, but in pH 7,4 it is very effective because it is open That is: organism is able to actively change both components.We use status of bicarbonate buffer for clinical evaluation of patients acid-base balance. (pH measurement, [HCO3-] a pCO2)

2.5.3. Protein buffersBody proteins (plasma proteins and intracellular) are the most abundant and the most powerful buffer system in whole organism. Some amino acids have acid or basic side chains (His, Lys, Arg, Glu, Asp). Among blood proteins haemoglobin is the most important. It provides 35 % of buffering capacity of blood, remaining proteins provide only 7 %.Role of erythrocytes and haemoglobin in the acid-base balanceIntensive change of blood gases occurs in working tissue. CO2 diffuses to erythrocytes. In the red blood cell CO2 either (1) binds to haemoglobin (and carbaminohemoglobin is formed), or (2) reacts with water. This reaction is catalysed by carbonic anhydrase (CA, carbonate dehydratase):CO2 + H2O H2CO3Produced carbonic acid dissociates:H2CO3 HCO3- + H+More than 70% of produced HCO3- leave erythrocyte using special HCO3-/Cl- antiport. That is bicarbonate is exchanged for Cl-. This process is called Hamburgers effect (chloride shift). In carbonic acid dissociation H+ is produced. Generated protons are buffered by haemoglobin. Deoxygenated haemoglobin is stronger base than oxygenated thus deoxygenated is more capable of taking up protons.In lungs HCO3- is changed to CO2, using enzyme CA. CO2 is exhaled. Reaction HCO3- CO2 + H2O demands H+. Protons for this process are taken from haemoglobin which affinity to H+ has lowered just when it arrived to lungs where is high pO2 and haemoglobin become oxygenated. Reaction catalysed by carboanhydrase has reverse course in lungs in comparison to other tissues:HCO3- + H+ CO2 + H2O

2.5.4. Phosphate bufferPhosphate buffer consists of inorganic and organic bound phosphate (i.e. esters of organic substances, e.g. AMP, ADP, and ATP). Phosphate buffer is important intracellular and urine buffer. In blood it accounts for only 5 % of buffering capacity.2.5.5. Urine buffersThere are two important urine buffers: (1) ammonium buffer (NH3/NH4+) and (2) phosphate buffer. Every day is excreted 30-50 mmol of NH4+. This is important because excretion of NH4+ is significantly regulated when the acid-base balance is disturbed. That is excretion of ammonium could be much decreased or much increased. In acidosis is glutaminase activated in the kidneys. Glutaminase splits glutamine to glutamate and NH3. NH3 is then eliminated to the urine. This process includes also the liver, where less urea and more glutamine is produced in acidosis. Every day is excreted 20 mmol of phosphates (i.e. titratable urine acidity). Physiologic urine pH is 4,4-8,0.

2.6. Role of the respiratory tract in maintaining the acid-base balanceEvery day is exhaled approximately 15-20 moles of CO2 by the respiratory system. CO2 is well soluble in water therefore its concentration in both alveoli and arterial blood is the same (i.e. pCO2 = 5,33 kPa = 40 mmHg). In venous blood is pCO2 6,13 kPa = 46 mmHg.pCO2 depends besides other things on the pulmonary ventilation (= respiratory minute volume). Pulmonary ventilation is defined as respiratory rate (RR) multiplied by tidal volume (VT). For understanding following concept you should recall that pH of buffer depends on ratio of its components (e.g. HCO3- : pCO2) and so when ratio changes, pH changes consequently. You can now easily deduce that:1) increased ventilation leads to drop in pCO2 and that leads to alkalisation (increased pH)2) decreased ventilation leads to accumulation of CO2 increased pCO2 and that leads to acidification (decreased pH)There are many ways for controlling breathing. One of them is chemical control. Chemoreceptors check both pCO2, and pO2. Increased pCO2 activates breathing centre. Sensitivity of chemoreceptors is decreasing when pCO2 is 8 kPa or higher. Only remaining stimulus for breathing centre is decreased pO2.

2.7. Role of the kidneys in maintaining the acid-base balanceChemical buffers are capable of stopping increase in acids or bases. Buffers however are not capable of eliminating those acids and bases from body. Respiratory tract can eliminate (or cumulate) volatile carbonic acid by means of eliminating CO2 (or cumulate it). Only the kidneys are able to clean the body from non-volatile (metabolic) acids (i.e. phosphoric acid, sulphuric acid, uric acid, ). Thus preventing acidosis. In addition the kidneys are only organ that is efficiently capable of solving alkalosis (respiratory system btw offers another option, i.e. stop breathing).The kidneys take part in maintaining the acid-base balance by means of:1) Reabsorbing, excreting and producing bicarbonate2) Excreting or producing H+You should notice that loss of bicarbonate is the same as acquire of H+ and production of bicarbonate is the same as loss of H+. It is shown below that these processes are connected (e.g. excretion of H+ in proximal tubule is connected with reabsorption of HCO3- in the same place or excretion of H+ in distal tubule is connected with production of HCO3- in the same place). Next important concept is that higher bicarbonate concentration increases pH, lower bicarbonate concentration decreases pH.In this section are in detail described basic processes as reabsorption of bicarbonate, new bicarbonate production, ammonium ion production, proton excretion in kidneys, bicarbonate secretion.

2.7.1. Bicarbonate reabsorptionBicarbonate reabsorption takes place in proximal tubule cells. In glomerular ultrafiltrate there is filtered bicarbonate. To the lumen of the proximal tubule is transported H+. H+ is transported by Na+/H+ antiport H+ reacts with HCO3- and H2CO3 is thus produced. H2CO3 split up into H2O and CO2. Water and carbon dioxide get through apical membrane of tubular cells. Inside these cells H2CO3 is again produced. H2CO3 dissociates into HCO3- and H+. Now their fates get different: (1) H+ becomes again substrate for Na+/H+ antiport and it is transported again to the lumen of the proximal tubule where it can catch another bicarbonate molecule. (2) Bicarbonate however traverse basolateral membrane into interstitial fluid (and then to the blood of the peritubular capillaries). Bicarbonate gets through basolateral membrane using either Na+/3 HCO3- cotransport, or anion exchanger (Cl-/HCO3- exchange).Together it can be stated: for one secreted H+, one Na+ and one HCO3- are resorbed. Na+ is transported to the blood among other things by active transport i.e. Na+/K+ ATPase.

2.7.2. New bicarbonate production (connected with H+ excretion)New bicarbonate production takes place in intercalated cells type A of distal tubule and collecting duct. These cells absorb CO2 from the blood and inside the cells carbon dioxide reacts with water and carbonic acid is thus produced, catalysed by the enzyme carboanhydrase. Carbonic acid dissociates to H+ and HCO3-. H+ has totally different fate than bicarbonate: (1) H+ is excreted by the H-ATPase to the urine. This process is active, hence it consumes ATP. In order to eliminate as much H+ as possible it is necessary to buffer H+ in the urine. The most important buffers in the urine are ammonium and phosphate buffer. (2) Produced bicarbonate is transported to the blood in peritubular capillaries exchanged for Cl- (Cl-/HCO3- exchanger in basolateral membrane). Aldosterone stimulates H+ secretion (and therefore H+ excretion).

2.7.3. Ammonium ion excretionThis process uses ammonium generated in glutamine metabolism in tubular cells. For every metabolised glutamine two ammonium ions and two bicarbonates are produced. Bicarbonates are transported to the blood, whilst ammonium ions are excreted to the blood.

2.7.4. Proton excretion in the kidneysBoth bicarbonate resorption, and new bicarbonate production (both mentioned above) need transport of H+ (protons) to the tubules (protons are derived from carbonic acid dissociation). Precise mechanism is however quite different. In the cells of the proximal tubule the transport of proton to the lumen is based on its exchange for Na+. On the basolateral membrane act Na+/K+-ATPase and HCO3-/Cl- exchanger.In the intercalated cells type A (in the distal tubule and the collecting duct) the transport of proton to the lumen is based on active transport (H+-ATPase). Aldosterone promotes (1) excretion of H+ and K+ in the distal tubule and the collecting duct and (2) reabsorption of the sodium (and water). The result of both described processes is generation of high concentration gradient for H+, i.e. in the urine there is thousand times higher concentration of protons than in the cells/blood. This thousand fold gradient is however maximal, thus the lowest achievable pH of the urine is 4,4 (40 mol/l H+) compare this value with value of the pH in blood: 7,4 (40 nmol/l H+).

2.7.5. Bicarbonate secretionIn conditions of rising pH (alkalosis) type B of the intercalated cells start to act. They secrete bicarbonate and gain H+. These mechanisms are absolutely inverse than processes described in the type A of the intercalated cells (see above). Even in alkalosis nephrons however excrete less bicarbonate than they retain. We can summarize that extracellular pH is kept by the buffer systems and involved organs. These systems maintain pH value 7,36-7,44. The respiratory system modulates pCO2 and the kidneys modulate concentration of bicarbonate.

2.8. Laboratory assessment of the acid-base balance statusLaboratory assessment of the acid-base balance status consists of: (1) acid-base balance parameters (pH, [HCO3-], pCO2, pO2 a BE) and (2) examination of other substances that can alter acid-base balance. These substances are for example:1) Cations: [Na+], [K+], [Ca2+], [Mg2+]2) Anions: [Cl-], [lactate], albumin3) Metabolites: [urea], [creatinine], [ketone bodies]Acid-base balance status is assessed according to the status of the bicarbonate buffer. It is so called examination of the ABR parameters by Astrup (ASTRUP).This examination is used for assessment of the actual status of the acid-base balance in particular patient. The specimens are measured in analysers and these particular specimens are called Astrup after one of the first acid-base balance theory authors. Some parameters are not measured directly but calculated by software using Henderson-Hasselbalch equation. The specimens are obtained from arterial blood (a. radialis or a. femoralis), sometimes it is necessary to collect capillary blood too. We can analyse only non-clotting blood (for this purpose heparin is added). Arterial blood must not contain air bubbles (because presence of air could alter pO2 (increase), pCO2 (decrease) and pH (increase)) and analysis should take place as soon as possible.Normal arterial Astrup results:Directly measured values:1) pH = 7,36 7,442) pCO2 = 4,8 5,9 kPa (35-45 mmHg), average is 5,3 kPa (40 mmHg)pCO2 < 4,8 kPa is denoted as hypocapniapCO2 > 5,9 kPa is denoted as hypercapnia3) pO2 = 9,9 13,3 kPa (80-100 mmHg)Calculated values:4) [HCO3-] = 22-26 mmol/l5) BE = 0 2,5 mmol/l

2.8.1. BE (base excess)Base excess is defined as number of moles of strong acid that is needed to add to one litre of fully oxygenated blood to achieve pH 7,4 when pCO2 is 5,3 kPa and temperature is 37C. BE is optimal quantity for assessing metabolic component of acid-base balance. Normal values are 0 2,5 mmol/l. Negative value indicates excess of acids (so the value is negative). Excess of acids is metabolic acidosis. Positive value indicates excess of bases (base excess), hence metabolic alkalosis. There is however one very similar quantity base deficit (BD). It indicates deficit of bases in mmol/l.

2.8.2. Ions and pHIon composition of extracellular fluid is closely related to the acid-base parameters. Kalemia is influenced most by acid-base balance disturbances.Acidosis leads to efflux of K+ from the cells. That leads to the hyperkalemia. K+ is lost in the urine. When acidosis is treated quickly alkalization of the body leads to the influx of K+ back to the cells. That leads to hypokalemia. Hypokalemia is mostly dangerous for the heart membrane signal transmission.Alkalosis leads to efflux of H+ from the cells. To maintain electrical charges the same, K+ enter the cells in order to replace H+. Thus alkalosis leads to the hypokalemia. K+ is excreted in the urine instead of H+.

2.8.3. Anion Gap (AG)Anion gap is a quantity which is almost equal to the sum of concentrations of unmeasurable anions (albumin plasma proteins, phosphates, sulphates, organic anions). Unmeasurable is not accurate term, more precise is commonly non-measured.AG is calculated as follows:AG = ([Na+] + [K+]) ([Cl-] + [HCO3-])Na+ (140) + K+ (5) = Cl- (105) + HCO3- (25) + AG (15)Normal AG: 14 2 mmol/lAnion gap is used for assessing causes of the metabolic acidosis. One of the causes is the accumulation of the acids. Concentrations of some of them are not commonly measured. When there is accumulation of commonly non-measured acids unexpected rise in difference of measured cations and anions. This increase in difference could be revealed by AG. Therefore when there is increased AG it indicates that commonly non-measured acids accumulated. They become part of AG. Thus greater AG indicates acidosis.Increased AG is caused by:1) Increase in concentration of ions that physiologically make the AG2) Presence of new anionsThis method is unfortunately dependent on accuracy of the measurements. Little mistake in big numbers lead to greater mistake in the result. There are particular situations when we need to measure commonly non-measured acids (anions) concentrations. Then we measure:

1) Lactate in tissue hypoxia2) 3-hydroxybutyrate in diabetic ketoacidosis3) Phosphates and sulphates in renal failure

2.9. Basic disturbances in the acid-base balance and compensationAcidosis is process that leads to the drop in pH value. Alkalosis is au contraire process that leads to the increase in pH value. Acid-base balance parameters are calculated for plasma which pH is alkalic, i.e. pH = 7,4 (H+ concentration is 40 nmol/l). Thus you should notice that even alkalic pH (e.g. 7,2) is acidosis!Respiratory disturbances are indicated by shifts in pCO2 (respiratory disorder hyper- or hypocapnia). Metabolic disturbances are indicated by shifts in BE (or [HCO3-])Four basic acid-base balance disturbances are distinguished:1) Respiratory acidosis (RAC): decreased blood pH; its primary cause is increased pCO22) Respiratory alkalosis (RAL): increased blood pH; its primary cause is decreased pCO23) Metabolic acidosis (MAC): decreased blood pH; its primary cause is decreased BE ([HCO3-])4) Metabolic alkalosis (MAL): increased blood pH; its primary cause is increased BE ([HCO3-])

2.10. Compensation and correction of acid-base disturbancesCompensation is process when organism tries to maintain almost normal pH. Compensation is performed by system that works normally, i.e. the acid-base disturbance is caused by the other system. Compensation thus means metabolic disturbances are compensated by respiratory system and respiratory disturbances are compensated by metabolic components of acid-base balance.Correction is solving the acid-base problem in the spot where it started. I.e. metabolic disturbances are solved by metabolic component of acid-base balance. In the body correction takes place only in metabolic disorders, i.e. metabolic disorder is corrected by another component of the metabolic component of acid-base balance. Doctors however are capable of correction of both respiratory, and metabolic disturbances. Respiratory disturbances can be solved by artificial ventilation, metabolic disturbances by for example dialysis.

2.11. Respiratory acid-base balance disturbanceAll the people (healthy or not) produce every day large quantities of acids. The most important acid is CO2. Carbon dioxide is normally eliminated from the body by the respiratory system. When respiratory system is not capable of normal CO2 elimination (carbon dioxide could be eliminated too much or too few) respiratory acid-base balance disturbances come into existence.Normal pCO2 is 4,8-5,9 kPa (35-45 mmHg). pCO2 lower than 4,8 indicates respiratory alkalosis, pCO2 higher than 5,9 indicates respiratory acidosis. Respiratory disturbances are compensated by the kidneys. The kidneys retain or excrete HCO3- in order to (1) keep ratio HCO3- : pCO2 and (2) draw pH nearer to the normal values. Renal compensation needs hours to days for full development.

2.12. Respiratory acidosis (RAC)Respiratory acidosis emerges when the lungs eliminate too few CO2 (it usually occurs in hypoventilation). Low CO2 elimination leads to increased pCO2 in the blood (hypercapnia). Increased pCO2 causes decreased pH.Causes of RAC are for example:1) Loss of functional lung parenchyma (pneumonia, cystic fibrosis, emphysema)2) Airway obstruction (loss of tonus of tongue muscles)3) Insufficient ventilation (e.g. neuromuscular disorders, CNS disorders, intoxications (opiates), asthmatic paroxysm)4) Thorax movement restriction (e.g. spine deformities)Organism compensates RAC by increased HCO3- concentration in the blood by means of increased resorption and increased production in tubular cells of the kidneys (acidic urine is produced). Thus pH of the blood is drawn nearer to the normal values. Causes of RAC mentioned above can sometimes cause decreased pO2 too. Tissue hypoxia leads to the metabolic acidosis caused by accumulation of lactate, thus it is called lactate acidosis (see below).

2.13. Respiratory alkalosis (RAL)Respiratory alkalosis is caused by hyperventilation. Hyperventilation causes increased elimination of carbon dioxide and that leads to hypocapnia (decreased pCO2). There is one important aspect concerning calcium. One of the important buffers in blood is albumin. You should recall that albumin binds approximately 50 % of plasma calcium. When pH changes, albumin binds or releases H+ and therefore calcemia is changed. This is very important in RAL. In this condition ratio between ionised and bound calcium is changed. In RAL is decreased ionised calcium hence hypocalcemia develops. Hypocalcemia could cause muscle spasms.Causes of RAL are for example:1) Hyperventilation due to psychic reasons (exhalation of the carbon dioxide = exhalation of the emotions) or hyperventilation due to the high altitude (i.e. breathing in lack of oxygen). In both principles pCO2 is lowered and you know that low pCO2 is alkalosis. Interestingly HCO3- is slightly lowered as well. This is because pCO2 is lowered and thus to keep equilibrium part of bicarbonate is converted to CO2. (HCO3- + H+ CO2 + H2O). Ions H+ needed for this reaction are provided from non-bicarbonate buffers.2) CNS trauma3) Salicylates poisoning (Aspirin) fever, etcCompensation is decreased HCO3-. This is provided by larger excretion of HCO3- by the kidneys.

2.14. Metabolic acidosis (MAC)Metabolic acidosis is the most common acid-base balance disorder. It is indicated by decreased pH (increased H+) and negative BE ([HCO3-]). BE is the best marker for assessing metabolic component of the acid-base balance. It can be stated that metabolic acidosis is pH that is too acidic compared with given pCO2 (i.e. metabolic component must be always assessed with knowledge of pCO2 in particular patient).General causes of MAC:1) Accumulation of metabolic acid. Anion of this acid eliminates bicarbonate.2) Loss of bicarbonates (this loss of anion is accompanied by loss of cation, it is not surprising that most abundant cation (Na+) is lost mostly)3) Loss of cations, predominantly Na+. This is compensated by decrease of bicarbonateEvery acid in the body apart from carbonic acid is so called metabolic acid. Metabolic acids are non-volatile, therefore they have to be neutralized and either metabolised, or eliminated by kidneys.Bicarbonate are lost most commonly from the GIT. Duodenal and pancreatic juice have abundant bicarbonates. Normally high concentrations of bicarbonate in these juices neutralize low pH of chyme from stomach. Normally bicarbonates are resorbed in small intestine. There are however some diseases of the GIT (diarrhoea, short intestine syndrome, etc) when bicarbonates are resorbed insufficiently. Bicarbonates can be lost in the kidneys too (renal tubular acidosis, adverse effect of diuretics carbonic anhydrase inhibitors (acetazolamide)). AG calculation is useful in differential diagnosis of MAC. Excessive production of acids leads to high AG. Elevated loss of bicarbonates has normal AG.Now we mention some particular states that lead to MAC:1) Hypoxia lack of oxygen in tissues. This condition makes tissues to process glucose in anaerobic glycolysis. By-product of anaerobic glycolysis is lactate. Thus hypoxia leads to the lactate acidosis. Lactate acidosis is typical companion of RAC, shock or overdose of biguanides (metformin).2) Excessive production of ketone bodies (acetoacetic acid and -hydroxybutyric acid). This condition is caused by situations when glucose cannot be used as source of energy. This leads to excessive use of fatty acids as the main energy source. Thus excessive production of ketone bodies accompanies diabetes mellitus or starving. This condition is called ketoacidosis.3) Alcohol intoxication (e.g. methanol, ethylene glycol). These alcohols are metabolised to strong organic acids (formic acid, oxalic acid). These acids release lots of H+. Oxalates can lead to renal failure. Overdose of salicylates (Aspirin) can cause MAC as well.4) Renal insufficiency leads to condition when normally excreted acids are cumulated (sulphates, phosphates, some other anions). This is called renal acidosis.5) Heavy diarrhoea6) Loss of bicarbonates in the kidneysIn all these conditions at first buffering of excessive H+ takes place (it is carried out by bicarbonate and non-bicarbonate bases). Bicarbonate forms with H+ carbonic acid that forms CO2 and water, carbon dioxide is eliminated by the lungs. Second step is compensation using hyperventilation. You should recall that hyperventilation leads to decreased pCO2 and decreased pCO2 means higher pH. This is often called Kussmaul acidotic breathing (breathing centre is stimulated by high H+ concentration). Third step is correction by kidneys. Correction is launched in case that acidosis despite the compensation is still present. Kidneys perform (1) increased excretion of H+ and (2) new bicarbonate production (intercalated cells type A). This results in acidic urine.

2.15. Metabolic alkalosis (MAL)Metabolic alkalosis is characterized by increased pH and risen BE. General causes are:1) Loss of some anions (usually chlorides or proteins). This loss of anions is compensated by replenishing of other anions, predominantly bicarbonates (and increased bicarbonates mean alkalosis)2) Increased cation concentration (most commonly Na+)3) Increased alkali intake (e.g. alkalising medication bicarbonate infusion)Now we mention some particular states that lead to MAL:1) Vomiting loss of HCl (thus loss of H+). So called hypochloremic alkalosis develops (it is caused by diuretics as well (e.g. furosemide causes loss of K+ and Cl-)2) Hypoproteinemia proteins are anions thus decreased protein concentration is compensated by increased bicarbonate concentration (i.e. bicarbonates replenish missing anions). Hypoproteinemia is caused by liver failure, nephrotic syndrome or malnutrition.3) Hyperaldosteronism. High aldosterone causes increased retention of Na+. This increased cation concentration must be accompanied by replenishing of anions because electroneutrality must be maintained (i.e. bicarbonate concentration is increased).4) Iatrogenic bases delivery (e.g. HCO3- infusions)At first buffering takes place. Compensation is second and body uses hypoventilation, thus less CO2 is exhaled and pCO2 rises, that leads to lowering pH. In case that alkalosis is not caused by kidneys, renal correction can take place. It is performed by higher excretion of bicarbonate (intercalated cells type B). One of serious consequences of alkalosis is hypokalemia that can lead to heart rhythm disturbances.

2.16. Mixed disturbances of acid-base balanceMixed disturbances of acid-base balance are quite common. It is defined as either (1) combination of two or more basic disturbances of acid-base balance, or (2) combination of more causes that cause the same acid-base balance disturbance, (3) or both.As an example we can use hypoventilation that leads not only to the respiratory acidosis because less CO2 is exhaled but also to the metabolic acidosis because less O2 is delivered to the tissues.

2.17. Adverse consequences of severe acidemiaThe effects on the cardiovascular system are particularly pernicious and can include decreased cardiac output, decreased arterial blood pressure, decreased hepatic and renal blood flow, and centralization of blood volume. Reentrant arrhythmias and a reduction in the threshold for ventricular fibrillation can occur, while the defibrillation threshold remains unaltered. Acidemia triggers a sympathetic discharge but also progressively attenuates the effects of catecholamines on the heart and the vasculature; thus, at pH values below 7.20, the direct effects of acidemia become dominant.Although metabolic demands may be augmented by the associated sympathetic surge, acidemia decreases the uptake of glucose in the tissues by inducing insulin resistance and inhibits anaerobic glycolysis by depressing 6-phosphofructokinase activity. This effect can have grave consequences during hypoxia, since glycolysis becomes the main source of energy for the organism. The uptake of lactate by the liver is curtailed, and the liver can be converted from the premier consumer of lactate to a net producer. Acidemia causes potassium to leave the cells, resulting in hyperkalemia, an effect that is more prominent in nonorganic acidoses than in organic and respiratory acidoses. Increased net protein breakdown and development of a catabolic state also occur in patients with acidosis. Brain metabolism and the regulation of its volume are impaired by severe acidemia, resulting in progressive obtundation and coma.

2.18. Management of life-threatening acidosis2.18.1. Metabolic acidosisIn the presence of an appropriate ventilatory response, severe metabolic acidemia implies a plasma bicarbonate concentration of 8 mmol per liter or lower. What options are available for replenishing the depleted bicarbonate stores? In certain organic acidoses (e.g., ketoacidosis and lactic acidosis), effective treatment of the underlying disease can foster conversion of the accumulated organic anions to bicarbonate within hours. By contrast, in hyperchloremic acidosis (e.g., that produced by diarrhea), such an endogenous regeneration of bicarbonate cannot occur. Although the kidneys can, of course, contribute to bicarbonate neogenesis in both types of acidoses, several days are required to obtain a meaningful effect. Therefore, even if the cause of the acidosis can be reversed, exogenous alkali is often required for the prompt attenuation of severe acidemia.

2.18.1.1. Alkali therapyThe goal of alkali therapy is to prevent or reverse the detrimental consequences of severe acidemia, especially those affecting the cardiovascular system. In moderating acidemia, the physician buys time, thus allowing general and cause-specific measures as well as endogenous reparatory processes to take effect. Alkali therapy also provides a measure of safety against additional acidifying stresses caused by a further decrease in plasma bicarbonate or an increase in the partial pressure of arterial carbon dioxide.Currently, intravenous sodium bicarbonate is the mainstay of alkali therapy. Other alkalinizing salts, such as sodium lactate, citrate, or acetate, are not reliable substitutes, since their alkalinizing effect depends on oxidation to bicarbonate, a process that can be seriously impaired in several clinical conditions (e.g., liver disease and circulatory failure).How much bicarbonate need be dispensed? Because the administration of sodium bicarbonate entails certain risks, it should be given judiciously in amounts that will return blood pH to a safer level of about 7.20. To accomplish this goal, plasma bicarbonate must be increased to 8 to 10 mmol per liter. There is no simple prescription for reaching this target, since several ongoing, and at times competing, processes can affect the acidbase status (e.g., increased net lactic acid production, vomiting, or renal failure), and the apparent space of distribution of infused bicarbonate is variable. (The apparent space of distribution is calculated by dividing the administered alkali load, in millimoles per kilogram of body weight, by the observed change in the plasma bicarbonate concentration, in millimoles per liter, and multiplying the ratio by 100.) Whereas patients with very low plasma bicarbonate concentrations can have a bicarbonate space of 100 percent of body weight or greater, others with less severe metabolic acidosis have a space closer to 50 percent of body weight, the normal value.Being mindful of overtreatment, we recommend that, as the starting point, bicarbonate space be taken to be 50 percent of body weight. Thus, to raise the plasma bicarbonate concentration from 4 to 8 mmol per liter in a 70-kg patient, one should administer 4 70 0.5, or 140, mmol of sodium bicarbonate. Except in cases of extreme acidemia, sodium bicarbonate should be dispensed as an infusion (over a period of several minutes to a few hours) rather than a bolus. Follow-up monitoring of the patient's acidbase status will determine additional alkali requirements. About 30 minutes must elapse after the infusion of bicarbonate is completed before its clinical effect can be judged.

2.18.1.2. Risk of sodium bicarbonate therapyThe administration of sizable amounts of sodium bicarbonate is associated with certain risks. Infusion of the usual undiluted 1N preparation (containing 1000 mmol of sodium bicarbonate per liter) can give rise to hypernatremia and hyperosmolality. This complication can be avoided by adding two 50-ml ampules of sodium bicarbonate (each containing 50 mmol of sodium bicarbonate) to 1 liter of 0.25 N sodium chloride or three ampules to 1 liter of 5 percent dextrose in water, thereby rendering these solutions nearly isotonic. Alkali therapy can lead to extracellular-fluid volume overload, especially in patients with congestive heart failure or renal failure. Administration of loop diuretics may prevent or treat this complication. If adequate diuresis cannot be established, hemofiltration or dialysis may be required. Overshoot alkalosis, in which an abrupt and poorly tolerated transition from severe acidemia to alkalemia develops, can result from overly aggressive alkali loading (especially when compounded by endogenous regeneration of bicarbonate from accumulated organic anions) and persistent hyperventilation. Alkali stimulates 6-phosphofructokinase activity and organic acid production, effects that must be considered in the management of lactic acidosis and ketoacidosis. Such effects are usually viewed as nonsalutary, since they limit the alkalinizing action of bicarbonate. However, alkali-induced stimulation of 6-phosphofructokinase activity may allow the partial regeneration of depleted ATP stores in vital organs (e.g., in cases of tissue hypoperfusion and hypoxemia), thereby fostering survival.Buffering of protons by bicarbonate releases carbon dioxide (HCO3- + H+ H2CO3 H2O + CO2) and can raise the prevailing partial pressure of carbon dioxide in body fluids. This effect can be consequential in patients with limited ventilatory reserve, those in advanced circulatory failure, or those undergoing cardiopulmonary resuscitation. Under these circumstances, paradoxical worsening of intracellular (and even extracellular) acidosis can occur if the fractional increase in partial pressure of carbon dioxide exceeds the fractional increase in the bicarbonate concentration. This counterproductive effect may be evident only in mixed venous blood, which better reflects the acidbase status of the tissues.

2.18.1.3. Alternative alkalinizing agentsConcern about the carbon dioxideproducing effect of bicarbonate led to the development of Carbicarb, which consists of equimolar concentrations of sodium bicarbonate and sodium carbonate. Because carbonate is a stronger base, it is used in preference to bicarbonate for buffering hydrogen ions, generating bicarbonate rather than carbon dioxide in the process (CO3 2- + H+ HCO3-). In addition, the carbonate ion can react with carbonic acid, thereby consuming carbon dioxide (CO3 2- + H2CO3 2HCO3-). Thus, Carbicarb limits but does not eliminate the generation of carbon dioxide. In experimental lactic acidosis, Carbicarb increased blood and intracellular pH with little or no rise in the arterial or venous partial pressure of carbon dioxide. However, the risks of hypervolemia and hypertonicity are similar with the two alkalinizing agents, and neither agent prevented the progressive reduction in myocardial-cell pH in animals with ventricular fibrillation. Clinical experience with Carbicarb is limited, and this product is not yet commercially available for clinical use.Another carbon dioxideconsuming alkalinizing agent is THAM, a commercially available solution of 0.3 N tromethamine. This sodium-free solution buffers both metabolic acids (THAM + H+ THAM+) and respiratory acids (THAM + H2CO3 THAM+ + HCO3-). Like Carbicarb, THAM limits carbon dioxide generation and increases both extracellular and intracellular pH. Nevertheless, THAM has not been documented to be clinically more efficacious than bicarbonate. In fact, serious side effects, including hyperkalemia, hypoglycemia, ventilatory depression, local injury in cases of extravasation, and hepatic necrosis in neonates, markedly limit its usefulness.

2.18.1.4. Specific disordersLactic AcidosisConventionally, two broad types of lactic acidosis are recognized: type A, in which there is evidence of impaired tissue oxygenation, and type B, in which no such evidence is apparent. However, inadequate tissue oxygenation may at times defy clinical detection, and tissue hypoxia can be a part of the pathogenesis of certain conditions that cause type B lactic acidosis. Thus, the distinction between the two types is occasionally blurred. Most cases of lactic acidosis are caused by tissue hypoxia arising from circulatory failure. Both overproduction and underuse of lactic acid contribute to its accumulation. In turn, the resultant acidemia, when severe, compounds the hemodynamic disarray and further suppresses lactate consumption by the liver and the kidneys, thereby establishing an ominous vicious circle. Experimental data have implicated the lactate ion itself, in addition to the acidemia associated with lactic acid, as a contributor to circulatory malfunction. Therapy should focus primarily on securing adequate tissue oxygenation and on identifying and treating the underlying cause. Improvement of tissue oxygenation may require a number of measures, including maintenance of a high inspired oxygen fraction, ventilator support, repletion of the volume of extracellular fluid, afterload-reducing agents, and inotropic compounds such as dopamine and dobutamine. Drugs causing vasoconstriction (such as norepinephrine) should be avoided, since they can worsen tissue hypoxia.Cause-specific measures should be instituted promptly, including antibiotics for sepsis; operative intervention for trauma or tissue ischemia; dialytic removal of certain toxins, such as methanol and ethylene glycol; discontinuation of metformin and nitroprusside; administration of insulin in patients with diabetes mellitus; glucose infusion in those with alcoholism and certain forms of congenital lactic acidosis; correction of thiamine deficiency in cases of ethanol intoxication, short-bowel syndrome, fulminant beriberi, and pyruvate dehydrogenase deficiency; a low-carbohydrate diet and antibiotics in cases of d-lactic acidosis (for example, with short-bowel syndrome); and treatment of an underlying cancer or pheochromocytoma.In the presence of severe metabolic acidemia, these measures should be supplemented by the cautious administration of sodium bicarbonate, initially at a dose of no more than 1 to 2 mmol per kilogram of body weight, given as an infusion rather than as a bolus. Infusion of additional sodium bicarbonate should be guided by careful monitoring of the patient's acidbase status. Amelioration of extreme acidemia with alkali should be regarded as a temporizing measure adjunctive to cause-specific measures. Particular restraint should be exercised in using alkali during cardiopulmonary resuscitation; the markedly reduced pulmonary blood flow can lead to retention of some of the carbon dioxide generated in the process of buffering, potentially exacerbating the prevailing acidosis.There is considerable excitement about the therapeutic potential of dichloroacetate in lactic acidosis. This investigational agent stimulates pyruvate kinase, thereby accelerating the oxidation of pyruvate to acetylcoenzyme A. Although the effects of dichloroacetate in experimental lactic acidosis were impressive, and the initial clinical observations were promising, a controlled clinical study failed to demonstrate a substantial advantage of dichloroacetate over conventional management of lactic acidosis.The prognosis of patients with lactic acidosis remains ominous, because the underlying disease frequently cannot be managed effectively. Its development should therefore be prevented by maintaining adequate fluid balance, optimizing cardiorespiratory function, managing infection, and being cautious when prescribing drugs that promote lactic acidosis. Particular attention should be paid to patients at special risk for lactic acidosis, such as those with diabetes mellitus or advanced cardiac, respiratory, renal, or hepatic disease.

Diabetic KetoacidosisInsulin administration is the cornerstone of the treatment of diabetic ketoacidosis. Water, sodium, and potassium deficits should also be replaced. Alkali should not be administered routinely, since the metabolism of the retained ketoacid anions in response to insulin therapy results in swift regeneration of bicarbonate with partial or complete resolution of the acidemia. Indeed, the administration of alkali may even delay recovery by augmenting hepatic ketogenesis. Nonetheless, small amounts of bicarbonate may benefit patients with marked acidemia (blood pH, 80 mm Hg).Chronic hypercapnia results from many conditions, including chronic obstructive or restrictive pulmonary diseases, upper-airway obstruction, central nervous system depression, neuromuscular impairment, and abnormal chest-wall mechanics. Respiratory decompensation in patients with these conditions, commonly resulting from infection, use of narcotics, or uncontrolled oxygen therapy, superimposes an acute element of carbon dioxide retention and acidemia on the chronic base-line disorder. Progressive narcosis and coma, known as hypercapnic encephalopathy, can ensue. Management of respiratory decompensation depends on the cause, severity, and rate of progression of carbon dioxide retention. Vigorous treatment of pulmonary infections, bronchodilator therapy, and removal of secretions can offer considerable benefit. Naloxone will reverse the suppressive effect of narcotic agents on ventilation. Avoidance of tranquilizers and sedatives, gradual reduction of supplemental oxygen (aiming at a partial pressure of arterial oxygen of about 60 mm Hg), and treatment of a superimposed element of metabolic alkalosis will optimize the ventilatory drive.Whereas an aggressive approach that favors the early use of ventilator assistance is most appropriate for patients with acute respiratory acidosis, a more conservative approach is advisable in those with chronic diseases that limit pulmonary reserve, because of the great difficulty often encountered in weaning such patients from ventilators. However, if the patient is obtunded or unable to cough, and if hypercapnia and acidemia are worsening, mechanical ventilation should be instituted. Minute ventilation should be raised so that the partial pressure of arterial carbon dioxide gradually returns to near its long-term base line and excretion of excess bicarbonate by the kidneys is accomplished (assuming that chloride is provided). By contrast, overly rapid reduction in the partial pressure of arterial carbon dioxide risks the development of posthypercapnic alkalosis, with potentially serious consequences. Should posthypercapnic alkalosis develop, it can be ameliorated by providing chloride, usually as the potassium salt, and administering the bicarbonate-wasting diuretic acetazolamide at doses of 250 to 375 mg once or twice daily. Noninvasive mechanical ventilation with a nasal or facial mask is being used with increasing frequency to avert the possible complications of endotracheal intubation.

Permissive HypercapniaIt has long been standard practice to prescribe tidal volumes two to three times normal (i.e., 10 to 15 ml per kilogram) when instituting mechanical ventilation for patients with acute respiratory distress syndrome, severe airway obstruction, or other types of respiratory failure. This approach is being challenged by data indicating that alveolar overdistention can cause tissue injury, culminating in increased microvascular permeability and lung rupture. Although the evidence is incomplete, there is a growing tendency to prescribe tidal volumes of 5 to 7 ml per kilogram (or less) to achieve a plateau airway pressure no higher than 35 cm of water. Because an increase in the partial pressure of arterial carbon dioxide might ensue, the strategy is referred to as permissive hypercapnia or controlled hypoventilation. The severity of carbon dioxide retention varies widely in different reports, but the partial pressure of arterial carbon dioxide rarely exceeds 80 mm Hg.Uncontrolled clinical trials and a preliminary report of a randomized study suggest that permissive hypercapnia results in lower morbidity and mortality than conventional mechanical ventilation. However, the available results remain inconclusive. The increased respiratory drive associated with permissive hypercapnia causes extreme discomfort, making sedation necessary. Because the patients commonly require neuromuscular blockade as well, accidental disconnection from the ventilator can cause sudden death. Furthermore, after the neuromuscular-blocking agent is discontinued, there may be weakness or paralysis for several days or weeks. There are several contraindications to the use of permissive hypercapnia, including cerebrovascular disease, brain edema, increased intracranial pressure, and convulsions; depressed cardiac function and arrhythmias; and severe pulmonary hypertension. It is important to note that most of these entities can develop as adverse effects of permissive hypercapnia itself, especially when hypercapnia is associated with substantial acidemia. In fact, some experimental evidence indicates that correction of acidemia attenuates the adverse hemodynamic effects of permissive hypercapnia. It appears prudent, although still controversial, to keep the blood pH at approximately 7.30 by administering intravenous alkali when controlled hypoventilation is prescribed.

Alkali TherapyThe presence of an element of metabolic acidosis is the primary indication for alkali therapy in patients with respiratory acidosis. However, this practice entails some risks, including pH-mediated depression of ventilation, enhanced carbon dioxide production from bicarbonate decomposition, and volume expansion. Yet alkali therapy may have a special role in patients who have acidemia and severe bronchospasm from any cause by restoring the responsiveness of the bronchial musculature to beta-adrenergic agonists, as well as in patients treated with controlled hypoventilation. The use of THAM has been suggested in patients with chronic hypercapnia, because of its theoretical potential to decrease the partial pressure of arterial carbon dioxide. However, this expectation has not been borne out. The resultant decrease in alveolar ventilation worsens hypoxemia and offsets the disposal of carbonic acid that is due to the buffering effect of THAM.

2.18.3. Mixed acidosisCoexistent respiratory acidosis and metabolic acidosis can be observed in several clinical conditions, including cardiorespiratory arrest, chronic obstructive pulmonary disease complicated by circulatory failure or sepsis, severe pulmonary edema, combined respiratory and renal failure, diarrhea or renal tubular acidosis complicated by hypokalemic paresis of the respiratory muscles, and poisoning with various toxic agents and drugs. The additive effects on blood acidity of primary hypercapnia, on the one hand, and the bicarbonate deficit, on the other, can produce profound acidemia requiring prompt therapy. Whenever possible, treatment must be targeted at both components of the mixed acidosis.

2.19. Adverse consequences of severe alkalemiaSevere alkalemia (blood pH greater than 7.60) can compromise cerebral and myocardial perfusion by causing arteriolar constriction, an effect that is more pronounced in respiratory than in metabolic alkalosis.Neurologic abnormalities may ensue, including headache, tetany, seizures, lethargy, delirium, and stupor. The associated reduction in the plasma concentration of ionized calcium probably contributes to these manifestations. Although it exerts a moderate positive inotropic effect on the isolated heart, alkalemia reduces the anginal threshold and predisposes the patient to refractory supraventricular and ventricular arrhythmias. This arrhythmogenic action is more pronounced in patients with underlying heart disease. Alkalemia depresses respiration, causing hypercapnia and hypoxemia. Such effects are of little consequence in patients with adequate ventilatory reserve, but they can be consequential in patients with compromised ventilation. Even mild alkalemia can frustrate efforts to wean patients from mechanical ventilation.Hypokalemia is an almost constant feature of alkalemic disorders, but it is more prominent in those of metabolic origin. Translocation of potassium into cells and renal and extrarenal losses contribute in varying degrees to its generation. In turn, hypokalemia can have several adverse effects, including neuromuscular weakness; sensitization to digitalis-induced arrhythmias; polyuria; and increased ammonia production, which can heighten the risk of hepatic encephalopathy. Alkalemia stimulates anaerobic glycolysis and increases the production of lactic acid and ketoacids. Along with the alkalemic titration of plasma proteins and the hyperproteinemia accompanying chloride-responsive metabolic alkalosis, this effect contributes to the characteristic moderate elevation in the plasma anion gap. Although acute alkalemia can reduce the release of oxygen to the tissues by tightening the binding of oxygen to hemoglobin, chronic alkalemia negates this effect by increasing the concentration of 2,3-diphosphoglyceric acid in red cells.

2.20. Management of life-threatening alkalosis2.20.1. Metabolic alkalosisIn the presence of an appropriate ventilatory response, severe alkalemia of metabolic origin requires that the plasma bicarbonate concentration exceed 45 mmol per liter. Just as in severe metabolic acidemia, the immediate goal of therapy is moderation but not full correction of the alkalemia. Reducing plasma bicarbonate to less than 40 mmol per liter is an appropriate short-term goal, since the corresponding pH is on the order of 7.55 or lower. Most severe metabolic alkalosis is of the chloride-responsive form, the most common causes being loss of gastric acid and the administration of loop or thiazide diuretics. The characteristic hypochloremic hyperbicarbonatemia results from the loss of hydrochloric acid in gastric secretions or from urinary excretion of excess ammonium chloride caused by these chloruretic diuretics.Substantial contraction of the volume of extracellular fluid as a result of diuretic-induced losses of sodium chloride can further amplify the resulting hyperbicarbonatemia by limiting the space of distribution of bicarbonate. Such a contraction alkalosis is particularly likely in patients with massive edema treated with combination regimens of diuretics (such as furosemide and metolazone). Maintenance of chloride-responsive metabolic alkalosis is then effected by heightened renal bicarbonate reabsorption, frequently coupled with a reduced glomerular filtration rate, changes that are mediated by chloride depletion itself, contraction of extracellular-fluid volume, and the associated potassium deficit.If the processes that generate metabolic alkalosis are still ongoing, every effort should be made to moderate or stop them, even if only temporarily. Vomiting should be countered with antiemetics. If continuation of gastric drainage is required, the loss of gastric acid can be reduced by administering H2-receptor blockers or inhibitors of the gastric H+/K+ATPase. Notably, these treatments substitute loss of sodium chloride for loss of hydrochloric acid. Decreasing the dose of loop and thiazide diuretics can be coupled with the addition of potassium-sparing diuretics (spironolactone, amiloride, or triamterene), drugs that decrease distal acidification and curtail potassium excretion.Prompt attention should be given to additional factors that might compound the alkalosis. Administration of bicarbonate or its precursors, such as lactate, citrate, and acetate (the latter being a common ingredient of parenteral-nutrition solutions), should be discontinued. At times, absorbable alkali is not a complicating factor but the very cause of the metabolic alkalosis, as in patients ingesting inordinate amounts of calcium carbonate or large quantities of absorbable alkali and milk; severe metabolic alkalosis coupled with variable degrees of hypercalcemia and renal impairment can occur. Coadministration of cation-exchange resins with aluminum hydroxide in effect renders the nonabsorbable alkali absorbable. If drugs with mineralocorticoid activity, such as fludrocortisone and various glucocorticoid compounds, are being administered, their indication and dose should be reassessed.Having addressed the factors that cause or aggravate the alkalosis, the clinician must then focus on ameliorating the existing hyperbicarbonatemia. Patients with volume depletion require provision of both sodium chloride and potassium chloride. Repair of the prevailing sodium, potassium, and chloride deficits and of the often-present functional azotemia will promote bicarbonaturia heralded by alkalinization of the urine. Administration of acetazolamide (250 to 375 mg once or twice daily) fosters bicarbonaturia but requires consideration of the associated kaliuresis and phosphaturia.If the pace of correction of the alkalemia must be accelerated, alkali stores can be titrated by infusing hydrochloric acid. Hydrochloric acid administered intravenously as a 0.1 to 0.2 N solution (that is, one containing 100 to 200 mmol of hydrogen per liter) is safe and effective for the management of severe metabolic alkalosis. The acid can be infused as such or can be added to amino acid and dextrose solutions containing electrolytes and vitamins without causing adverse chemical reactions. Because of its sclerosing properties, hydrochloric acid must be administered through a central venous line at an infusion rate of no more than 0.2 mmol per kilogram of body weight per hour. However, it can also be administered through a peripheral vein if it is added to an amino acid solution and mixed with a fat emulsion.Calculation of the amount of hydrochloric acid solution to be infused is based on a bicarbonate space of 50 percent of body weight.15 Thus, to reduce plasma bicarbonate from 50 to 40 mmol per liter in a 70-kg patient, the estimated amount of hydrochloric acid required is 10 70 0.5, or 350 mmol. Precursors of hydrochloric acid, such as ammonium chloride (20 g per liter, with 374 mmol of hydrogen per liter) and arginine monohydrochloride (100 g per liter, with 475 mmol of hydrogen per liter), can substitute for hydrochloric acid, but they entail substantial risks and are used less commonly. Both of these preparations are hyperosmotic solutions; to avoid local tissue injury, they must be infused through a central catheter. In addition, ammonium chloride can raise serum ammonia concentrations in patients with liver failure, and arginine monohydrochloride can induce serious hyperkalemia in patients with renal failure, especially when there is coexisting liver disease.Treatment of severe chloride-responsive metabolic alkalosis is considerably more challenging in patients with cardiac or renal dysfunction. Expansion of the extracellular-fluid volume may either accompany alkalemia or develop as a result of treatment. Potassium chloride can induce hyperkalemia in patients with renal failure. In certain cases, downgrading the diuretic regimen, adding acetazolamide, and cautiously administering sodium chloride and potassium chloride may suffice. In many other cases, however, cardiac and renal failure pose such limitations that the physician must resort to more aggressive measures. Infusion of hydrochloric acid can be efficacious, but the associated fluid load is often problematic. Under these circumstances, use of an extracorporeal device is advisable. Hemodialysis and ultrafiltration can rapidly correct severe alkalemia and volume overload, especially if the bicarbonate concentration of the standard dialysate is reduced. In patients with unstable hemodynamics, the same goals can be achieved by continuous arteriovenous or venovenous hemofiltration with sodium chloride as the replacement solution.Life-threatening alkalemia is a very rare occurrence in chloride-resistant metabolic alkalosis. Disorders of mineralocorticoid excess, severe potassium depletion, and Bartter's or Gitelman's syndrome are the causes of this form of alkalosis. Aggressive potassium repletion will correct or ameliorate chloride-resistant alkalosis, but the thrust of the therapy should be directed at reversing the underlying disorder, if possible. When the cause of the mineralocorticoid excess cannot be reversed, potassium-sparing diuretics coupled with moderate restriction of sodium chloride can provide symptomatic relief. Identifying laxative abuse as the culprit may prevent recurrence of the problem. Potassium-sparing diuretics, nonsteroidal antiinflammatory drugs, or angiotensin-convertingenzyme inhibitors can ameliorate Bartter's or Gitelman's syndrome.

2.20.2. Respiratory alkalosisRespiratory alkalosis is the most frequently encountered acidbase disorder, since it occurs in normal pregnancy and with high-altitude residence. The pathologic causes of respiratory alkalosis include various hypoxemic conditions, pulmonary disorders, central nervous system diseases, salicylate intoxication, hepatic failure, sepsis, and the anxietyhyperventilation syndrome. Respiratory alkalosis is particularly prevalent among the critically ill; in these patients, its presence is a bad prognostic sign, because mortality increases in direct proportion to the severity of the hypocapnia.Hypocapnia elicits a secondary change in plasma bicarbonate that, as in hypercapnia, has two components. A moderate acute decrease in plasma bicarbonate originates from tissue buffering. A larger decrease accompanies chronic hypocapnia as a result of down-regulation of renal acidification and requires two to three days to reach completion. Because blood pH does not exceed 7.55 in most cases of respiratory alkalosis, severe manifestations of alkalemia are usually absent. Marked alkalemia can be observed, however, in certain circumstances, such as with inappropriately set ventilators, some psychiatric conditions, and lesions of the central nervous system. Obviously, clinical manifestations of severe alkalemia are more likely to occur in the acute, rather than the chronic, phase of respiratory alkalosis.Management of respiratory alkalosis must be directed toward correcting the underlying cause, whenever possible. Because most cases of respiratory alkalosis, especially chronic cases, pose little risk to health and produce few or no symptoms, measures to treat the deranged acidbase composition are not required. The anxietyhyperventilation syndrome is an exception. An active therapeutic approach that provides reassurance, sedation, and ultimately psychotherapy is most helpful in these cases. Rebreathing into a paper bag or any other closed system provides prompt, but unfortunately short-lived, symptomatic relief. If hypocapnia-induced alkalemia is severe and persistent, sedation may be required.

2.20.3. Pseudorespiratory alkalosisArterial hypocapnia does not necessarily imply respiratory alkalosis or the secondary response to metabolic acidosis but can be observed in an idiotypic form of respiratory acidosis. This entity, which we have termed pseudorespiratory alkalosis, occurs in patients with profound depression of cardiac function and pulmonary perfusion but with relative preservation of alveolar ventilation, including patients undergoing cardiopulmonary resuscitation. The severely reduced pulmonary blood flow limits the carbon dioxide delivered to the lungs for excretion, thereby increasing the mixed venous partial pressure of carbon dioxide. By contrast, the increased ventilation:perfusion ratio causes the removal of a larger-than-normal amount of carbon dioxide per unit of blood traversing the pulmonary circulation, thereby creating arterial eucapnia or frank hypocapnia. Nonetheless, the absolute excretion of carbon dioxide is decreased and the carbon dioxide balance of the body is positive the hallmark of respiratory acidosis. Such patients may have severe venous acidemia (often due to mixed respiratory and metabolic acidosis) accompanied by an arterial pH that ranges from the mildly acidic to the frankly alkaline. Furthermore, the extreme oxygen deprivation prevailing in the tissues may be completely disguised by the reasonably preserved values of arterial oxygen. To rule out pseudorespiratory alkalosis in a patient with circulatory failure, blood gas monitoring must include sampling of mixed (or central) venous blood. The management of pseudorespiratory alkalosis must be directed toward optimizing systemic hemodynamics.

2.20.4. Mixed alkalosisExtreme alkalemia can occur in patients with metabolic and respiratory alkalosis, even in the presence of only moderate changes in plasma bicarbonate and the partial pressure of arterial carbon dioxide. This disorder can occur in various settings, including among patients with primary hypocapnia associated with chronic liver disease, in whom metabolic alkalosis develops because of vomiting, nasogastric drainage, diuretics, profound hypokalemia, or alkali administration, especially in the context of renal insufficiency. Mixed alkalosis is also observed in patients with end-stage renal disease in whom primary hypocapnia develops; the inappropriately high plasma bicarbonate level reflects the absence of the renal response to the prevailing hypocapnia and the dialysis-induced alkali load. Patients undergoing peritoneal dialysis are more vulnerable than those undergoing hemodialysis, because peritoneal dialysis maintains plasma bicarbonate at a higher level (25 to 26 mmol per liter, as compared with a value of 20 to 21 mmol per liter before hemodialysis). Reducing the base concentration of the dialysate or switching the patient from peritoneal dialysis to hemodialysis will ameliorate the situation.

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